@article {pmid41510728,
year = {2026},
author = {González-Jiménez, KA and Herrera-Mayorga, EV and Paredes Sánchez, FA and Niño-García, N and Torres-Castillo, JA and Martínez-Padrón, HY and Sánchez-Sánchez, M},
title = {New Drug Therapies Against Targeting Neurodegenerative Diseases: A Comprehensive Review.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249397580251117044621},
pmid = {41510728},
issn = {1875-6166},
abstract = {Neurodegenerative diseases encompass well-characterized behavioral, cognitive, and movement disorders that affect older people, impacting all facets of daily life. In Alzheimer's disease, specific antibodies targeting the β-amyloid protein (aducanumab, lecanemab, and others) are gaining special interest due to the approval of the first particular drugs against this disease. In Parkinson's disease, most drugs were approved several decades ago; however, new Phase II clinical trials point to monoclonal antibodies as a promising approach, and the report of alkaloids also suggests various therapeutic targets against this disease. Pick's disease has a low prevalence; currently, no drugs are approved by government agencies. However, thanks to molecular tools, it has been possible to elucidate therapeutic targets implicated in the appearance of the disease. α-synuclein is the main therapeutic target in Lewy body disease; most of the reported molecules are in clinical Phases I and II. Additionally, drug repositioning may emerge as a viable option in the search for effective treatments against this disease. In amyotrophic lateral sclerosis, the appearance of newly approved drugs such as tofersen and edaravone, and some others in clinical Phase II (bosutinib), opens a new era in the understanding and treatment of this condition. Altered emotions and progressive damage in some brain regions characterize schizophrenia and vascular dementia. Combinations of tricyclic drugs are a trend that aims to increase the cognitive performance of patients with schizophrenia. In vascular dementia, numerous in vivo trials with molecules of different natures (flavonoids and lactones) have yielded positive results, delaying the progression of the disease. This review examines recent reports on molecules evaluated in vivo and in vitro models of the primary neurodegenerative diseases.},
}

@article {pmid41510718,
year = {2026},
author = {Prabakaran, A and Sivaperuman, A and Natarajan, R and Nagarajan, NC and Solomon, VR},
title = {Innovative Approaches to Alzheimer's Treatment: Utilizing Tacrine Hybrids to Inhibit Amyloid Beta Aggregation as a Strategic Focus.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575422492251116190843},
pmid = {41510718},
issn = {1875-5607},
abstract = {Alzheimer's disease (AD) is a complex and progressive brain disorder marked by memory loss, cognitive decline, and behavioral changes. One of its defining features is the build-up of amyloid plaques, clumps of β-amyloid (Aβ) peptides, in the brain, along with the formation of neurofibrillary tangles. These Aβ peptides are generated when the amyloid precursor protein (APP) is cleaved by enzymes, with β-secretase (BACE1) playing a key role in the first step of this process. Because BACE1 starts the cascade that leads to harmful Aβ build-up, it has become an important target in the search for effective Alzheimer's treatments. As Aβ accumulates in neurons, it disrupts communication between brain cells and triggers oxidative stress, which worsens damage and accelerates disease progression. This is often exacerbated by imbalances in metal ions, such as copper and iron. While tacrine, an early acetylcholinesterase inhibitor, has shown benefits in managing AD symptoms, its limitations have led researchers to explore improved versions. One promising direction is the development of tacrine-based hybrid molecules. By combining tacrine with other chemical groups that have anti-β-amyloid (Aβ) effects, antioxidant properties, and metal-chelating properties, scientists aim to create compounds that target multiple aspects of the disease simultaneously. This review examines the emerging potential of tacrine hybrids, particularly their capacity to inhibit BACE1 and prevent Aβ aggregation, providing new hope for more effective and disease-modifying therapies for Alzheimer's disease.},
}

@article {pmid41510716,
year = {2026},
author = {Bano, A and Khan, AA and Kushwaha, SP and -, A and Zaidi, SMH and Misbahul Hasan, S and Fatima, A},
title = {Indole Scaffolds in Neurological Therapeutics: Synthesis, Structure-Activity Relationships and Drug-Receptor Interactions.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575415521251021091530},
pmid = {41510716},
issn = {1875-5607},
abstract = {INTRODUCTION: Indole is a privileged heterocyclic scaffold that plays a crucial role in medicinal chemistry due to its strong ability to bind to various biological receptors and interact with diverse molecular targets. Indole exhibits both biological and chemical significance. Its structural versatility allows for precise chemical modifications, making it an essential framework in drug discovery. This review discusses the structure-activity relationships, synthesis, and interactions of indole derivatives, particularly in relation to targets within the central nervous system.

METHODS: A detailed literature survey was conducted using databases such as Google Scholar, Elsevier, PubMed, ACS, PubChem, ScienceDirect, and RSC to understand the structural modifications of indole derivatives and their therapeutic potential. Both research and review articles related to indole- based compounds were thoroughly studied to prepare this review article.

RESULTS: There are over 40 FDA-approved drugs containing an indole nucleus used to treat various diseases, underscoring its potential in neurotherapeutics. This review highlights innovative synthetic strategies, including green chemistry approaches, that improve the drug-likeness and bioavailability of indole derivatives. Indole continues to be an indispensable scaffold in the development of novel therapeutics aimed at addressing the growing burden of neurological disorders.

DISCUSSION: This review aims to provide a comprehensive analysis of the therapeutic potential of indole-based compounds for the treatment of neurological disorders. However, challenges like blood-brain barrier permeability and long-term safety must be addressed for clinical success. Nonetheless, this review will help in designing and developing newer indole-based molecules in the discovery of neurological drug development.

CONCLUSION: Due to its broad spectrum of biological activities and favorable pharmacokinetic properties, indole is an impressive scaffold for the treatment of various neurological disorders. Indole demonstrates remarkable therapeutic potential against a range of central nervous system-related conditions, including Alzheimer's disease, epilepsy, migraine, stroke, Parkinson's disease, prion disease, amyotrophic lateral sclerosis, and Huntington's disease.},
}

@article {pmid41510671,
year = {2026},
author = {Liao, D and Zhang, M and Yang, Q and Li, T and Cao, Z and Liu, D and Zhang, Z and Li, X and Tian, Z and Li, X and Luo, P},
title = {Targeting CXCL8 in post-traumatic stress disorder and Alzheimer's disease: insights from cross-disorder molecular analysis.},
journal = {Annals of medicine},
volume = {58},
number = {1},
pages = {2610559},
doi = {10.1080/07853890.2025.2610559},
pmid = {41510671},
issn = {1365-2060},
mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics/immunology ; *Stress Disorders, Post-Traumatic/drug therapy/genetics/immunology ; *Interleukin-8/genetics/metabolism/antagonists & inhibitors/immunology ; Computational Biology ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use ; Drug Repositioning ; },
abstract = {BACKGROUND: Emerging clinical evidence indicates that post-traumatic stress disorder (PTSD) may accelerate Alzheimer's disease progression, yet the molecular mechanisms linking these disorders remain poorly understood.

METHODS: We conducted an integrative bioinformatics analysis combining blood cell profiles from PTSD and Alzheimer's disease cohorts to identify shared pathogenic pathways and therapeutic targets. Computational drug repositioning and experimental validation were used to pinpoint effective treatments.

RESULTS: Our analysis revealed convergent dysregulation in neuroimmune and metabolic pathways, including compensatory upregulation of terpenoid biosynthesis and impaired JAK-STAT neuroprotective signaling. Cross-disorder network analysis identified CXCL8 as a central hub gene, prioritized through network pharmacology and machine learning. Mechanistic studies demonstrated that CXCL8 is dually regulated by stress-responsive transcriptional activators and neurodegeneration-associated microRNAs, positioning it as a key mediator of peripheral-central immune crosstalk. Immunoassays further linked CXCL8 to T cell recruitment (γδ T, CD8[+] T), suggesting its role in sustaining neuroinflammation common to both diseases. Among potential therapeutics, nonsteroidal anti-inflammatory drugs emerged as modulators of CXCL8-driven pathology, with ibuprofen significantly suppressing neurodegeneration-associated CXCL8 overexpression.

CONCLUSIONS: Our findings highlight CXCL8-mediated neuroimmune dysregulation as a critical link between PTSD and Alzheimer's disease, supporting targeted anti-inflammatory strategies to mitigate stress-related dementia risk. This study advances a precision medicine framework for neurodegenerative comorbidities by integrating cross-disease molecular signatures.},
}

Humans
*Alzheimer Disease/drug therapy/genetics/immunology
*Stress Disorders, Post-Traumatic/drug therapy/genetics/immunology
*Interleukin-8/genetics/metabolism/antagonists & inhibitors/immunology
Computational Biology
Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use
Drug Repositioning

@article {pmid41510572,
year = {2026},
author = {Tang, C and Han, K and Wen, X and Zhang, J and Sun, W and Yue, X and Shi, L and Liu, Z and Zhao, J and Yan, C and Liu, M and Yao, Z and Kong, Z and Liu, Y and Fu, Z and Zhao, X and Yang, Z and Han, M and Chen, C and Xing, Z and Zhou, X and Yang, F and Zhang, Y and Jiang, X},
title = {Synthetic Disaggregators Enhance Central-Peripheral Amyloid-β Clearance in Alzheimer's Disease.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e20002},
doi = {10.1002/adma.202520002},
pmid = {41510572},
issn = {1521-4095},
support = {2024YFA0918400//National Key Research and Development Program of China/ ; 82350125//National Natural Science Foundation of China/ ; 82425056//National Natural Science Foundation of China/ ; 82173763//National Natural Science Foundation of China/ ; 82303810//National Natural Science Foundation of China/ ; ZR2022ZD18//Fundamental Research Funds of Shandong Province/ ; ZR2023QH224//Natural Science Foundation of Shandong Province/ ; 2022M721967//China Postdoctoral Science Foundation/ ; 2024T170524//China Postdoctoral Science Foundation/ ; SYS202202//Shandong Provincial Laboratory Project/ ; NO.tsqnz20221165//Taishan Scholar Foundation of Shandong Province/ ; 2025CXPT177//Key R&D Program of Shandong Province/ ; 2025CXPT177//Key R&D Program of Shandong Province/ ; },
abstract = {Pathogenic amyloid-β (Aβ) accumulation defines Alzheimer's disease (AD), directly inflicting neuronal damage and driving chronic neuroinflammation. While both central microglia and peripheral macrophages are critical for Aβ clearance, their functional impairment in AD inexorably leads to escalating Aβ burden and disease progression. We here report an in situ engineered synthetic Aβ disaggregator (SAD) delivered to macrophages via neuroprotective DHA-based lipid nanoparticles (DLNPs). This platform transcends current therapeutic limitations by not only potently dismantling neurotoxic Aβ aggregates but also by fundamentally reprogramming peripheral macrophages to enhance Aβ clearance. Specifically, our results demonstrate that DLNPs effectively reprogram peripheral macrophages to produce and secrete cerebral-penetrating SAD both in vitro and in vivo. The SAD can promote cerebral Aβ disaggregation, thereby inhibiting neuroinflammatory pathology progression. Moreover, the DLNPs efficiently reprogram the peripheral macrophages to enhance phagocytosis, further facilitating drainage of Aβ and reducing cerebral Aβ accumulation in mouse models. Collectively, these findings uncover a dual-action mechanism of SAD through the synergistic interplay of direct Aβ disaggregation and enhanced macrophage-mediated clearance. In sum, our findings establish that the central-peripheral targeting therapeutic strategy significantly reversed AD pathology, highlighting the therapeutic potential of mRNA-based in situ fusion protein in AD treatment.},
}

@article {pmid41510365,
year = {2026},
author = {Wang, Y and Alexander, GC and Mehta, HB},
title = {Treatment of type 2 diabetes among medicare beneficiaries with and without alzheimer's disease: A retrospective cohort study.},
journal = {Journal of diabetes and metabolic disorders},
volume = {25},
number = {1},
pages = {25},
pmid = {41510365},
issn = {2251-6581},
abstract = {PURPOSE: While Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) commonly co-occur in older adults, little is known regarding whether and how the treatment of T2DM varies by AD status. This study aimed to compare and contrast T2DM treatment among individuals with and without AD.

METHODS: We conducted a retrospective cohort study using 20% Medicare Fee-for-Service claims data from 2016 to 2020. The primary outcome was initiation of any antidiabetic medication within one year of T2DM diagnosis, and we also examined initiation patterns across specific drug classes. We used multivariable logistic regression to estimate adjusted odds ratios for the association between AD and treatment initiation.

RESULTS: Among 388,359 beneficiaries newly diagnosed with T2DM, 9,584 had AD. Within one year, overall treatment initiation was lower for individuals with AD compared to those without. At initiation, individuals with AD were more likely to receive insulin and less likely to receive metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists. In adjusted models, AD was associated with lower odds of antidiabetic treatment initiation, and among those initiating treatment, lower odds of initiating newer agents such as GLP-1 receptor agonists and SGLT2 inhibitors.

CONCLUSION: Beneficiaries with AD were less likely to initiate antidiabetic therapy, particularly newer agents. Future work could explore the basis for these differences.},
}

@article {pmid41510304,
year = {2025},
author = {Wang, Y and Zhou, M and Tang, Z and Xiong, C and Asken, B and Yang, B and Su, J and Zhou, X and Song, Q},
title = {CauReL: Dynamic Counterfactual Learning for Precision Drug Repurposing in Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8206648/v1},
pmid = {41510304},
issn = {2693-5015},
abstract = {Alzheimer's disease has few effective therapies, and decades of amyloid- and tau-focused trials have delivered only modest benefit with substantial toxicity. Drug repurposing using real-world data offers a faster and lower-risk route to new treatments, yet current approaches typically average effects across populations, model disease onset and progression separately, and provide little insight into which patients are most likely to benefit. We present CauReL, a dynamic counterfactual representation learning framework that enables transparent, patient specific estimation of treatment effects from large-scale electronic health records for precision drug repurposing in AD. CauReL first learns balanced latent representations of treated and untreated patients using Integral Probability Metric regularization, then jointly predicts two clinically linked outcomes, incident AD and time from mild cognitive impairment (MCI) to AD, to generate paired counterfactual outcomes for every individual. A counterfactual explanation module quantifies how clinical features shape benefit at the patient level, and uplift trees transform complex heterogeneity into simple, rule-based subgroups suitable for trial enrichment and clinical decision support.Using independent cohorts from OneFlorida + and All of Us, we screened outpatient prescriptions with at least 20 percent exposure among 28,605 individuals with mild cognitive impairment, of whom 4,990 progressed to Alzheimer's disease. CauReL substantially improved covariate balance and distributional overlap across drug cohorts and achieved strong predictive accuracy for both incidence (AUC greater than 0.90) and progression timing (C index 0.81 to 0.84; Spearman 0.80 to 0.86). Twenty drugs showed consistent protective associations, with four emerging as highly reproducible across both networks, the metabolic agents liraglutide and empagliflozin and the neuroactive agents entacapone and amantadine. These drugs were associated with meaningful absolute risk reductions and clinically significant delays in progression from mild cognitive impairment to Alzheimer's disease. Metabolic drugs produced the strongest benefits in individuals with diabetes, obesity, or cardiovascular disease, whereas neuroactive drugs provided broadly consistent protection across most subgroups.CauReL is available as an open source Python package with a companion web server for direct application to new cohorts or disease settings (https://caurel.site/). This work delivers a scalable and interpretable framework for prioritizing repurposable drugs and designing targeted clinical trials for the patients most likely to benefit.},
}

@article {pmid41510240,
year = {2025},
author = {Iadecola, C and Ahn, SJ and Anfray, A and Losson, Y and Qian, L and Yoval-Sánchez, B and Wang, G and Zhou, P and Galkin, A and Park, L and Khatib, ME and Vinogradov, S and Anrather, J},
title = {Microvascular dysfunction and aberrant network activity drive reduced brain oxygenation in a mouse tauopathy model.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8205391/v1},
pmid = {41510240},
issn = {2693-5015},
abstract = {Tauopathies such as Alzheimer's disease and frontotemporal dementia are leading causes of cognitive impairment, characterized by accumulation of hyperphosphorylated tau, a microtubule-associated protein, in brain. In addition to driving neural network hyperactivity and neuronal damage, tau disrupts neurovascular function, which may further contribute to disease pathogenesis. Using a mouse tauopathy model, we demonstrate that tau causes a profound breakdown of the normally well-coordinated segmental vasodilation induced by neural activity, resulting in dampened and delayed blood-flow increases, heterogeneous capillary perfusion, and frequent capillary stalling. These neurovascular alterations arise in the context of pronounced network hyperactivity and hypersynchrony, which combined with impaired neurovascular coupling, lead to reduced oxygen availability, episodic hypoxia, and disturbed metabolic homeostasis. Collectively, these findings identify reduced brain oxygenation driven by an imbalance between neuronal hyperactivity and diminished oxygen delivery as a previously-unappreciated early pathogenic consequence of tau accumulation and bolster the rationale for therapies to restore cerebral oxygenation.},
}

@article {pmid41510223,
year = {2025},
author = {Jiang, L and Tucker, A and Sepehri, C and Patel, D and Wang, Q and Yuan, S and Sherman, E and Chen, Y and Beh, J and Downey, A and Goldberg, D and Gniadzik, W and Ma, X},
title = {Inhibition of N6-Methyladenosine Accumulation by Targeting METTL3 Mitigates Tau Pathology and Cognitive Decline in Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8379573/v1},
pmid = {41510223},
issn = {2693-5015},
abstract = {Dysregulation of N6-methyladenosine (m6A) modification of RNA has emerged as a novel feature of Alzheimer's disease (AD). Here, we investigate the relationship between m6A modification and AD pathology, and the therapeutic potential of modulating excessive m6A via its "writer" methyltransferase METTL3 in a humanized P301S tau transgenic mouse model of AD (PS19). We observed significantly elevated m6A levels in human post-mortem AD frontal cortex tissue compared to healthy controls, which positively correlated with hyperphosphorylated tau and amyloid-β (Aβ) deposition. These effects were recapitulated in the PS19 tau mice model of AD. Importantly, treatment of PS19 mice with the METTL3 inhibitor STM2457 reduced excessive m6A, alleviated tau pathology, and attenuated neurodegeneration. Behavioral assessments further demonstrated that STM2457-treated PS19 mice exhibited significantly improved learning and memory relative to untreated PS19 mice. Our results identify m6A as a critical contributor to AD pathogenesis and demonstrate that pharmacological inhibition of METTL3 represents a promising therapeutic strategy to improve cognition in AD.},
}

@article {pmid41509946,
year = {2025},
author = {Shen, Z and Zhou, X and He, L and Wu, M and Zhou, C},
title = {Natural progression of meningeal lymphatic dysfunction in APP/PS1 mice creates a critical window for Alzheimer's disease intervention.},
journal = {Turkish journal of medical sciences},
volume = {55},
number = {6},
pages = {1576-1583},
pmid = {41509946},
issn = {1303-6165},
mesh = {Animals ; *Alzheimer Disease/physiopathology/pathology ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Disease Progression ; Amyloid beta-Protein Precursor/genetics ; *Lymphatic Vessels/physiopathology/pathology ; *Meninges/physiopathology/pathology ; Amyloid beta-Peptides/metabolism ; Presenilin-1/genetics ; Male ; },
abstract = {BACKGROUND/AIM: Meningeal lymphatic vessels (mLVs) facilitate the clearance of toxic metabolites like amyloid-beta (Aβ) from the central nervous system. Dysfunction in MLVs is implicated in Alzheimer's disease (AD). However, current knowledge relies on exogenous intervention models that fail to capture spontaneous mLV decline during AD progression. In this study, we investigated the age-dependent correlation between mLV/deep cervical lymph node (dCLN) dysfunction and Aβ pathology in APP/PS1 mice under noninterventional conditions.

MATERIALS AND METHODS: APP/PS1 and wild-type (WT) mice at 3, 6, and 9 months of age were evaluated. Cognitive function was tested using the Morris water maze. mLV/dCLN drainage was assessed by intracisternal Texas Red dextran 3 injection. Lymphatic structure/function and Aβ pathology were analyzed via immunohistochemistry, immunofluorescence, and tracer penetration.

RESULTS: APP/PS1 mice developed significant cognitive deficits at 6 and 9 months. Aβ plaques emerged at 6 months and progressed by 9 months in APP/PS1 mice, but were absent in controls. At 6 months, APP/PS1 mice had reduced tracer drainage in mLVs/dCLNs, decreased LYVE-1 expression, and impaired tracer penetration in the hippocampus/cortex compared to WT mice.

CONCLUSION: Lymphatic functional decline starts at 6-months old, providing a critical timeframe for early AD intervention. Our findings underscore the value of the APP/PS1 model for studying lymphatic clearance mechanisms in AD.},
}

Animals
*Alzheimer Disease/physiopathology/pathology
Mice
Mice, Transgenic
Disease Models, Animal
Disease Progression
Amyloid beta-Protein Precursor/genetics
*Lymphatic Vessels/physiopathology/pathology
*Meninges/physiopathology/pathology
Amyloid beta-Peptides/metabolism
Presenilin-1/genetics
Male

@article {pmid41509712,
year = {2026},
author = {Sanchez-Migallon, P and Flores-Cuadrado, A and Villanueva-Anguita, P and Rabano, A and Vaamonde, J and Saiz-Sanchez, D and Mohedano-Moriano, A and Astillero-Lopez, V and Soriano-Herrador, C and Martinez-Marcos, A and Ubeda-Banon, I},
title = {Huntingtin in the amygdaloid basolateral complex is correlated with Vonsattel staging in Huntington's disease.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcaf502},
pmid = {41509712},
issn = {2632-1297},
abstract = {Huntington's disease has traditionally been considered a motor disorder, but it is currently classified as a multisystem neurodegenerative disease that involves brain regions, such as the amygdala, and causes depression. The aim of the present study was to analyse the distribution of huntingtin in the human amygdaloid basolateral complex, considering its nuclei, sex, triplet repeats and Vonsattel score, as well as to characterize the cellular relationships between huntingtin and associated copathologies. The present study included 23 human brain samples from patients (males and females) with and without Huntington's disease, Parkinson's disease and Alzheimer's disease. An unbiased stereology approach was used to quantify huntingtin deposits. Multiple immunofluorescence experiments were conducted to analyse the relationship between huntingtin and glial populations. Immunohistochemistry against pathological markers of other neurodegenerative diseases was also carried out. Quantification data did not reveal differences among different nuclei (basomedial, basolateral or lateral) in the basolateral complex or according to sex. Huntingtin deposits did not correlate with cytosine-adenine-guanine (CAG) repeats. However, these deposits were positively correlated with pathological Vonsattel grades. Additional aggregates of other pathological proteinopathies were also observed. This correlation between the human basolateral amygdaloid complex and the Vonsattel stage provides a new perspective for neuropathological diagnosis and helps in understanding nonmotor symptoms such as depression.},
}

@article {pmid41509525,
year = {2025},
author = {Denne, E and Channell, MM and White, N and Fidler, D and Baumer, N and Wu, J and Tapia, IE and Froehlich, T and Hartley, S and Esbensen, AJ},
title = {A Review of Clinical Trials in Down Syndrome.},
journal = {International review of research in developmental disabilities},
volume = {69},
number = {},
pages = {1-49},
pmid = {41509525},
issn = {2211-6095},
abstract = {Down syndrome (DS) is a prevalent neurogenetic condition that impacts thousands of individuals, their families, and their communities each year. Due to the relatively high prevalence of DS and co-occurring conditions associated with this diagnosis, it is increasingly becoming the focus of clinical trials. In an effort to review the scope of interventions for this population across time, we reviewed ClinicalTrials.gov for clinical trials being conducted in DS. The goal was to evaluate the targets of clinical trials with individuals with DS, describe changes with the onset of the INCLUDE project, and identify gaps in clinical trial targets with individuals with DS. Across 138 clinical trials related to DS registered on ClinicalTrials.gov, the following target condition emerged (with some trials targeting more than one condition): motor functioning (n = 46), cognition (n = 24), Alzheimer's disease (n = 17), sleep (n = 12), adaptive daily living skills (n = 11), leukemia (n = 10), communication (n = 7), prenatal (n = 4), dental (n = 3), Attention Deficit Hyperactivity Disorder (n = 3), and other (n = 13; any category with <3 registered trials). Collectively, across these conditions, the number and variety in clinical trials in DS have increased substantially post-INCLUDE. Implications and future directions across each area of research are discussed.},
}

@article {pmid41509440,
year = {2025},
author = {Tisdale, RK and Sun, Y and Miller, SR and Lee, SM and Park, S and Shin, J and Allocca, G and Palop, JJ and Kilduff, TS},
title = {Sleep-Wake Transitions Are Impaired in the App [NL-G-F] Mouse Model of Early Onset Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.29.696818},
pmid = {41509440},
issn = {2692-8205},
abstract = {Poor sleep quality and reduced sleep duration are associated with Alzheimer's disease (AD)-related β-amyloid (Aβ) pathologies. We conducted two studies of sleep/wake, activity and body temperature in App [NL-G-F] mice, a strain that exhibits three mutations in the human App gene associated with elevated risk for early onset AD. First, App [NL-G-F] mice were compared to wildtype (WT) littermates at 14-18 and 18-22 months of age and, at both ages, were found to exhibit partial insomnia with more Wake and less NREM and REM sleep than WT littermates. This long wake/short sleep phenotype was evident during the dark phase at 14-18 months but occurred in both the light and dark phases at 18-22 months. App [NL-G-F] mice had fewer short (<60 sec) and more long (>260 sec) Wake bouts and were hyperactive at 18-22 months, which undoubtedly contributed to the increased Wake/reduced sleep. Despite this partial insomnia phenotype, App [NL-G-F] mice were no sleepier than WT mice and the sleep homeostat was functional in both strains. In the second study, sex differences in these parameters were assessed at 18-24 months. Partial insomnia was evident in both sexes of App [NL-G-F] mice but was clearly stronger in females. Wake and REM sleep bout durations were longer in both sexes of App [NL-G-F] mice than in WT littermates. EEG spectral power during NREM sleep was reduced in female App [NL-G-F] mice between 4.88-10.50 Hz compared to WT mice whereas, during REM sleep, both male and female App [NL-G-F] mice exhibited reduced spectral power in the theta range. These results suggest that Aβ deposition may impair state transition mechanism(s) in App [NL-G-F] mice and demonstrate that, as in human AD patients, female App [NL-G-F] mice exhibit a stronger insomniac-like phenotype, thus supporting the use of this strain as a model to investigate interventions that mitigate AD burden during early disease stages.},
}

@article {pmid41509380,
year = {2025},
author = {Saha, D and Xun, S and Luo, J and Zheng, W},
title = {Residue-Specific Modulation of Aggregation-Associated Interactions by Spermine in Tau, α-Synuclein, and Aβ40.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.23.696224},
pmid = {41509380},
issn = {2692-8205},
abstract = {Preventing neurodegenerative diseases associated with intrinsically disordered proteins (IDPs) remains a major challenge due to the lack of a detailed, sequence-level picture of disease-relevant structures formation and the influence of cellular factors that modulate these transitions. Here, we probe spermine (Spm), a +4 charged polyamine abundant in cells, to determine how it reshapes the conformational ensembles and fibril-associated contact propensities of three disease-linked IDPs: the K18 domain of Tau, α-synuclein (αS) and amyloid-β40 (Aβ40). Using long all-atom molecular dynamics simulations across a range of Spm concentrations, we quantify residue-level changes in intra-chain contacts relative to native contacts observed in fibrils, and corroborate computational predictions with ThT fluorescence assays for Tau constructs. Spm acts in a sequence-and region-specific manner, not simply through overall net charge. In K18, Spm binds near the fourth microtubule binding repeat, disrupting intra-chain contacts associated with Alzheimer's fibril structures and thereby inhibiting aggregation. In αS, Spm binds mainly to acidic residues in the C-terminal half of the sequence and redistributes intramolecular contacts in a way that increases contact propensity in the central aggregation-prone region and therefore aggregation, in line with previous studies showing Spm-enhanced αS aggregation. For Aβ40, Spm neutralizes acidic residues near positions 22-24 and shifts the balance of intra-chain interactions toward its aggregation-prone core, resulting in a net promotion of fibril-like conformations. These divergent effects show that net charge alone cannot predict polyamine influence on IDPs. Instead, residue-specific binding hotspots and local reweighting of aggregation-linked contacts determine whether Spm promotes or suppresses fibril-like conformations. This combined simulation-experimental framework provides a mechanistic basis for how small molecules reprogram IDP conformational ensembles and suggests principles for designing ligands that exploit similar residue-level modulation.},
}

@article {pmid41509366,
year = {2025},
author = {Malone, TJ and Cekada, K and Tyan, J and Chen, L and Wang, G and Gu, Y},
title = {Aberrant medial entorhinal cortex dynamics link tau pathology to spatial memory impairment.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.30.696887},
pmid = {41509366},
issn = {2692-8205},
abstract = {Early Alzheimer's disease (AD) manifests spatial memory impairment and tau accumulation in the entorhinal cortex (EC). However, how EC neural activity contributes to memory deficits in tauopathy remains unclear. Here, we combined in vivo two-photon calcium imaging with virtual reality to examine medial EC (MEC) activity in PS19 tauopathy mice during 10 days of spatial learning. PS19 males exhibited pronounced learning deficits and their MEC neurons showed impaired speed modulation, unstable spatial encoding, and weakened representations in cue-poor relative to cue-rich regions, suggesting disrupted path integration. These deficits were most prominent in pyramidal cells, which accumulated higher levels of phosphorylated tau than stellate cells, particularly in males. Notably, MEC activity robustly predicted learning performance, especially via non-grid and pyramidal cells, and distinguished PS19 from wild-type mice. Together, these findings identify MEC dysfunction as a key neural correlate of spatial memory decline in AD-related tauopathy, with potential diagnostic and therapeutic implications.},
}

@article {pmid41509358,
year = {2026},
author = {Jati, S and Kal, S and Munoz-Mayorga, D and Tang, K and Sahoo, D and Chen, X and Mahata, SK},
title = {Catestatin ameliorates tauopathy and amyloidogenesis via adrenergic inhibition.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.04.697519},
pmid = {41509358},
issn = {2692-8205},
abstract = {Neurodegenerative disorders like Alzheimer's disease (AD), Corticobasal Degeneration (CBD), and Progressive Supranuclear Palsy (PSP) are characterized by Tau aggregation, synaptic dysfunction, neuroinflammation, and progressive cognitive decline. Although metabolic dysregulation and neuropeptide imbalance have been linked to these disorders, the functional consequences of such imbalance and its potential for therapeutic reversal remain poorly understood. Our previous work identified chromogranin A (CgA), which encodes a pro-hormone for several metabolic peptides, as a key regulator of Tau pathology. Here, we investigate Catestatin (CST), a CgA-derived peptide that is a potent inhibitor of catecholamine release and has been shown to increase insulin sensitivity and lower peripheral blood pressure. We report significant reductions in CST levels in the hippocampus and cortex of AD brains, as well as in the frontal cortex of CBD and the basal ganglia of PSP. Supplementing CST in cortical neuronal cultures and organotypic slice cultures (OTSC) decreased Tau phosphorylation and aggregation. In vivo , CST administration in PS19 Tauopathy mice reduced pathological Tau species, attenuated gliosis, and improved cognitive function. CST treatment also lowered amyloid plaque burden and neuroinflammation in 5xFAD mice. Mechanistically, CST decreased epinephrine (EPI) levels in both PS19 and 5xFAD mice and suppressed downstream protein kinase A (PKA) hyperactivation in PS19 and OTSC. These findings reveal a previously unrecognized neuropeptidergic mechanism linking CST deficiency to elevated adrenergic receptor (ADR)-EPI-PKA stress signaling and Tauopathy-driven neurodegeneration, suggesting CST replacement as a promising therapeutic approach.},
}

@article {pmid41509352,
year = {2025},
author = {Cockell, S and Harris, SM and Morgan, RK and Patti, GJ and Ware, EB and Bakulski, KM},
title = {Identification of chemicals targeting dementia genes and pathways in the Comparative Toxicogenomics Database.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.19.695572},
pmid = {41509352},
issn = {2692-8205},
abstract = {INTRODUCTION: Dementia is a public health challenge and exposures likely contribute to risk, though many have not been evaluated. We screened chemicals for enrichment with dementia genes and related pathways.

METHODS: We obtained gene lists from the Comparative Toxicogenomics Database for 1,008 chemicals and nine dementia-related pathways (e.g., Alzheimer's disease, tauopathies). We tested pairwise chemical-dementia gene enrichment using Fisher's exact tests and proportional reporting ratios (PRR), accounting for multiple comparisons with false discovery rate (FDR<1×10 [-] [6]).

RESULTS: Of the chemicals tested, 742 (73.6%) were enriched for at least one dementia pathway and 15 with all nine pathways, including benzo(a)pyrene, ethanol, paraquat, and particulate matter. We observed 295 chemicals enriched for Alzheimer's disease, including sodium arsenite (PRR = 57.9) and 305 enriched for tauopathies, including bisphenol A (PRR=37.7).

DISCUSSION: We identified chemicals enriched for dementia pathways, suggesting broad classes of chemicals contribute to dementia.},
}

@article {pmid41509294,
year = {2025},
author = {Khandelwal, P and Duong, MT and Levorse, LM and Trotman, W and Bahena, A and Lim, SA and Denning, AE and Chung, E and Olm, CA and Radhakrishnan, H and Ittyerah, R and Prabhakaran, K and Mizsei, G and Schuck, T and Emrani, S and Vizcarra, JA and Robinson, J and Ohm, DT and Phillips, JS and Cohen, J and Wisse, LEM and Detre, JA and Nasrallah, IM and Brown, CA and Das, SR and Lee, EB and Tisdall, MD and Irwin, DJ and McMillan, CT and Wolk, DA and Yushkevich, PA},
title = {Postmortem brain MRI reveals differential associations of subcortical and limbic volumes with cortical thinning and neuropathology patterns.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.30.697140},
pmid = {41509294},
issn = {2692-8205},
abstract = {INTRODUCTION: The impact of different neuropathologies on deep brain structures remains to be understood. Here, we distinguish subcortical and limbic volumetry in neurodegenerative diseases involving p-tau, α-synuclein and TDP-43.

METHODS: We acquired neuropathological measures and brain segmentations from postmortem analysis of 132 donors with Alzheimer's disease (AD; n=60), Lewy body disease (LBD; n=26), Frontotemporal Lobar Degeneration with TDP-43 (FTLD-TDP; n=21) and FTLD-Tau (n=25).

RESULTS: In FTLD-TDP and FTLD-Tau, thalamus and striatum volumes were lower than in AD or LBD. While AD had diffuse cortico-subcortical and cortico-limbic morphometric associations, LBD had more limited parieto-occipital cortico-limbic associations. FTLD-TDP had cortico-subcortical associations while FTLD-Tau had cortico-limbic associations. In AD and FTLD-Tau, hippocampal volumes correlated with p-tau burden, neuron loss and gliosis. In LBD, thalamic α-synuclein severity was associated with subcortical and limbic volumes. In FTLD-TDP, TDP-43 load had no such significant associations.

DISCUSSION: Postmortem neuroimaging reveals unique structure-structure and structure-pathology relationships across regions and diseases.

HIGHLIGHTS: ● FTLD-Tau and FTLD-TDP show lower thalamic and striatal volumes than AD or LBD groups.● Subcortical and limbic volume loss significantly correlates with global brain shrinkage in AD.● LBD exhibits less postmortem subcortical and limbic atrophy compared to other groups. Parieto-occipital atrophy corresponds to limbic but not subcortical volume loss in LBD.● FTLD-Tau has cortico-limbic morphometric associations while FTLD-TDP has cortico-subcortical associations.● In AD and FTLD-Tau, hippocampal volume correlates with p-tau load, neuronal loss and gliosis semiquantitative measures.● In LBD, thalamic α-synuclein burden is associated with subcortical and limbic volumes.● In FTLD-TDP, TDP-43 pathology burden shows no significant volume associations.},
}

@article {pmid41509288,
year = {2025},
author = {Evitts, K and Turschak, E and Williams, CA and Kinoshita, C and Rosner, A and Battista, W and Hui, K and Beck, I and Reid, A and Zheng, Y and Young, JE},
title = {Evaluating Microglial Contributions to the Neurovascular Unit in Health and Neurodegeneration Using Human In Vitro Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.19.695574},
pmid = {41509288},
issn = {2692-8205},
abstract = {BACKGROUND: Microglia are emerging as critical regulators of neurovascular function in health and Alzheimer's disease (AD), yet their interactions with the human neurovascular unit (NVU), particularly brain endothelial cells, remain incompletely understood. Current in vitro NVU platforms typically exclude microglia and lack perfusable vascular networks with physiologically relevant architecture. Here, we established complementary two-dimensional (2D) and three-dimensional (3D) NVU models to investigate microglia-endothelial and microglia-neurovascular interactions.

METHODS: Human induced pluripotent stem cell derived-neurons (iNs), astrocytes (iAs), and microglia-like cells (iMGLs) were incorporated into a soft-lithography based engineered microvessel system to establish a multicellular neuroimmune-vascular model. To specifically evaluate iMGL-endothelial cell (EC) interactions, iMGL were co-cultured with primary human brain microvascular endothelial cells (HBMECs) and junctional protein localization was evaluated using immunofluorescence. The barrier integrity of engineered microvessels containing iMGL was evaluated using dextran permeability. Our 2D and 3D systems were stimulated with tumor necrosis factor-α (TNFα) to evaluate whether iMGL would promote or attenuate EC inflammation and barrier breakdown.

RESULTS: Incorporation of iNs, iAs, and iMGLs into a perfusable vascular model enabled a more complete representation of NVU cellular diversity and promoted neuronal health. In monolayer co-culture with iMGL, HBMECs enhanced the junctional localization of tight and adherens junction proteins through both contact-dependent and paracrine mechanisms. Following an inflammatory challenge, iMGLs reduced endothelial inflammatory activation, suggesting a protective role in response to AD-relevant inflammatory conditions. Finally, when embedded in 3D collagen matrices surrounding perfusable endothelialized lumen networks, iMGLs reduced dextran permeability and preserved endothelial barrier integrity following TNFα challenge.

CONCLUSIONS: Together, these findings establish a 3D perfusable neuroimmune-vascular model that enables the dissection of microglial contributions to neurovascular function in health and disease.},
}

@article {pmid41509283,
year = {2026},
author = {Xu, H and Lotfy, P and Englert, B and Oberhauser, J and Byer, LIJ and Wihlman, J and Colangelo, K and Okar, SV and Thommana, A and Puttonen, H and Mäyränpää, MI and Tuimala, J and Pedrosa, R and Kumar, D and Haberberger, JF and Atkins, ME and Alimukhamedov, S and Pragana, A and Benson, J and Gabrielle, ME and Dong, A and Laforet, VD and Lin, PB and Keene, CD and Latimer, CS and Prater, KE and Holtzman, DM and Isakova, A and Wyss-Coray, T and Schafer, DP and Reich, DS and Lehtimäki, T and Karhunen, PJ and Kok, EH and Jansson, D and Yang, AC and Myllykangas, L and Ordovas-Montanes, J and Lehtinen, MK},
title = {Multi-modal choroid plexus pathology in aging and Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.30.697051},
pmid = {41509283},
issn = {2692-8205},
abstract = {Brain barriers, cerebrospinal fluid (CSF) dynamics, and peripheral factors are implicated as significant contributors to Alzheimer's disease (AD). The choroid plexus (ChP) is a blood-brain interface that produces CSF and forms the blood-CSF barrier. However, how ChP pathology develops across the lifespan and contributes to AD has not been systematically characterized. Here, we report a multi-modal ChP atlas integrating single-nucleus transcriptomics from 49 individuals, AI-assisted quantitative histopathology across >500 postmortem samples age 16 to 105, spatial transcriptomics, and functional studies in 5xFAD mice. We identify fibrosis, calcification, and macrophage abnormalities as hallmarks of ChP aging, with AD pathology conferring additional effects, including expansion of a pro-inflammatory fibroblast-macrophage signaling niche. In 5xFAD mice, macrophage dysfunction is associated with impaired epithelial barrier maintenance and repair. Together, these data provide a foundational resource for understanding ChP dysfunction in aging and AD and propose the macrophage-fibroblast-epithelial barrier axis as a driver of ChP pathology.},
}

@article {pmid41509252,
year = {2026},
author = {Jesudason, CD and Rangel-Barajas, C and Beach, CJ and Beck, DE and Caballero-Floran, IH and Clayton, WB and Da Silva, L and David, JC and Doolen, S and Faulkner, AN and Hamdani, AK and Huhe, H and Huynh, K and Imhoff, RD and Javens-Wolfe, J and Mason, ER and Moussaif, M and Singhal, K and Soni, DM and van Buuren-Milne, M and Williams, SP and Angus, SP and Chu, S and Dage, JL and Hipskind, PA and Johnson, TS and Kaddurah-Daouk, R and Lamb, BT and Meikle, PJ and Mesecar, AD and Palkowitz, AD and Quinney, SK and Sukoff Rizzo, SJ and Oblak, AL and Richardson, TI},
title = {Optimization and Characterization of SHIP1 Ligands for Cellular Target Engagement and Activity in Alzheimer's Disease Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.31.697127},
pmid = {41509252},
issn = {2692-8205},
abstract = {Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1), encoded by the gene INPP5D, is a lipid phosphatase that negatively regulates immune receptor signaling in hematopoietic cells and microglia. Here, we describe a pyridyl-pyrazole-piperidine scaffold and the lead compound 3-((2-chlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine (32), which demonstrates SHIP1 target engagement, brain exposure, and evidence of a central pharmacodynamic response in vivo . Structure-activity relationship studies, guided by biochemical and cellular assays using multiple human and murine protein constructs and cells, identified SHIP1-active ligands. A thermal shift assay using full-length SHIP1 was used to assess compounds for cellular target engagement, while studies in IL-4 conditioned THP-1 cells was used to demonstrate changes in downstream AKT signaling. Targeted lipidomics revealed changes in the overall phosphoinositide pool consistent with SHIP1 target engagement and reduction of phospho-AKT levels. In a protein-lipid overlay assay, compound 32 induced changes in the relative association of SHIP1 with multiple phosphatidylinositols on a membrane surface. In high-content cellular imaging assays, compound 32 enhanced the uptake of myelin/membrane debris and fibrillar amyloid by primary murine microglia, phenocopying a genetic model with reduced SHIP1 expression. Finally, oral administration of compound 32 resulted in brain exposure sufficient to alter gene expression and reduce IL-1β levels as pharmacodynamic markers of microglial activation and neuroinflammation in an amyloidosis mouse model of Alzheimer's disease. Collectively, these results define a scaffold with SHIP1 target engagement, CNS exposure, and in vivo activity, providing a foundation for the optimization of brain-penetrant SHIP1 ligands suitable for further mechanistic studies and therapeutic development for the treatment of Alzheimer's disease.},
}

@article {pmid41509243,
year = {2025},
author = {Noterman-Soulinthavong, MF and Sancho, M and Huerta de la Cruz, S and Yarboro, M and Mandala, M and Koide, M and Beaufort, N and Todorov-Völgyi, K and Moreland, E and Hill-Eubanks, D and Dichgans, M and Nelson, MT},
title = {Endothelial Arf6 sustains capillary electrical signaling and cerebral blood flow through PIP 2 regeneration and activation of Kir2.1 channels.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.23.696233},
pmid = {41509243},
issn = {2692-8205},
abstract = {UNLABELLED: Brain capillaries sense neural activity and direct blood flow to active regions-a process termed neurovascular coupling that underlies activity-dependent increases in local perfusion (functional hyperemia). A key contributor to functional hyperemic responses is the capillary endothelial cell (cEC) inward rectifier K [+] (Kir2.1) channel, which is activated by neuronal activity-derived extracellular K [+] and initiates vasodilatory electrical signals that propagate through the vascular network. Kir2.1 channel function requires continual production of its lipid cofactor, phosphatidylinositol-4,5-bisphosphate (PIP 2), and is compromised in mouse models of cerebral small vessel (cSVD). Although decreased PIP 2 availability is a common feature of cSVD, mechanisms underlying PIP 2 synthesis remain poorly understood. We hypothesized that Arf6, a small GTPase expressed in cECs that stimulates PIP 2 production, is critical for this process. Using patch-clamp electrophysiology, we demonstrate that inhibiting Arf6 activity progressively decreased cEC Kir2.1 channel activity. This deficit corresponded to loss of capillary-to-arteriole electrical signaling in isolated vessels and diminished functional hyperemia in vivo . Exogenously provided PIP 2 restored Kir2.1 currents and functional hyperemia after Arf6 inhibition or genetic knockdown. Collectively, our data indicate that cEC Arf6 sustains Kir2.1 activity by maintaining PIP 2 levels and demonstrate that diminished PIP 2 synthesis is sufficient to impair functional hyperemia. Furthermore, we identify Arf6 as a mechanistic link between PIP 2 production and endothelial electrical signaling, highlighting Arf6 as a potential therapeutic target for restoring functional hyperemia.

SIGNIFICANCE STATEMENT: Active brain regions send electrical signals through capillaries to dilate upstream arterioles and increase blood flow. The resulting activity-dependent increase in local blood flow (functional hyperemia) is mediated through inward-rectifier potassium (Kir2.1) channels. These channels- and hence functional hyperemia-require continuous regeneration of the lipid cofactor PIP 2 (phosphatidylinositol-4,5-bisphosphate). If PIP 2 is deficient, electrical signaling fails-a defect characteristic of models of cerebral small vessel disease and Alzheimer's disease. We identify the small GTPase Arf6 as a key to maintaining PIP 2 and thus preserving capillary Kir2.1 activity and functional hyperemia. Our findings reveal an important pathway for PIP 2 homeostasis and position Arf6 as a cornerstone upholding functional hyperemic responses, highlighting Arf6 as a target for restoring cerebral blood flow in disease.},
}

@article {pmid41509242,
year = {2025},
author = {Kumari, R and Bowen, C and Srivastava, U and Brandelli, AD and Kumar, P and Kour, D and Malepati, S and Jang, WE and Bromwich, M and Zeng, H and Sing, A and Sloan, SA and Wulff, H and Rangaraju, S},
title = {Kv1.3 inhibition alleviates neuropathology via neuroinflammatory and resilience pathways in a mouse model of Aβ pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.25.696456},
pmid = {41509242},
issn = {2692-8205},
abstract = {Inhibition of voltage-gated potassium channel Kv1.3 is a therapeutic strategy to curb microglia-mediated neuroinflammation in neurodegeneration, although the cellular and signaling mechanisms of disease-modification by Kv1.3 blockers are unclear. In this study, we delineate protective mechanisms of Kv1.3 blockade in a mouse model of Alzheimer's disease (AD) pathology using comprehensive transcriptomics and proteomics profiling of brain, corresponding with neuropathological effects of two translationally relevant Kv1.3 blockers, namely small molecule PAP-1 and peptide ShK-223. Following 3 months of treatment, both molecules reduced Ab plaque burden. Single nuclear RNA seq (snRNA seq) of brain nuclei showed that PAP-1 disproportionately impacted oligodendrocytes and microglia and increased crosstalk between neurons and astrocytes with endothelial cells. In contrast, ShK-223 had pronounced effects on glutamatergic neurons and astrocytes. Both blockers increased expression of myelination genes in oligodendrocytes and synaptic genes in neurons. Neuroprotective effects of PAP-1 were further confirmed by bulk brain transcriptomics and proteomics whereby PAP-1 increased levels of synaptic, cognitive resilience and mitochondrial proteins, while decreasing glial and immune pathways including STAT1/3 phosphorylation. Using proximity labeling and co-immunoprecipitation, we found that Kv1.3 interacts with STAT1/3 in microglia. Using microglial cell lines and primary microglia, we discovered a preferential functional coupling between Kv1.3 and type 2 but not type 1 IFN signaling. Brain-level disease modification by Kv1.3 blockade was reflected in the cerebrospinal fluid (CSF) via reduced levels of neurofilament-light (NEFL) and resilience protein RPH3A, both of which are increased in human AD CSF. Together, this study demonstrates functional links between Kv1.3 channels and type 2 IFN signaling and reveals distinct cellular effects of Kv1.3 blockers in AD pathology that correspond with reduced neuropathology and neuroinflammation, augmentation of resilience and neuro-vascular pathways, along with biomarkers of therapeutic effect.},
}

@article {pmid41509234,
year = {2025},
author = {Fan, F and Joshi, P and Liu, X and Kotturu, SK and Abiola, M and Liu, Q and Lou, X},
title = {NAD+ hydrolase Sarm1 is a key driver of synapse degeneration and memory loss in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.21.695860},
pmid = {41509234},
issn = {2692-8205},
abstract = {UNLABELLED: Synapse degeneration is a hallmark of neurodegenerative diseases [1-3] , including Parkinson's and Alzheimer's disease (AD). Synapse loss has been known for decades as the strongest correlate with cognition and disease progression in AD patients [4-8] , but the molecular mechanisms that drive synapse degeneration remain elusive. Here, we identify Sarm1, a new class of NAD+ hydrolase required for Wallerian degeneration of periphery nerves after injuries [9-12] , as the key mediator of synaptic degeneration in AD brains. Sarm1 knockout largely reversed synapse loss, amyloid-β (Aβ) burden, and cognitive decline in 5XFAD mice. We found that Sarm1 is enriched in synaptic terminals and becomes activated in synaptic dystrophies adjacent to Aβ plaques, leading to synapse degeneration and subsequent neuroinflammation. Sarm1 deletion in the AD mice prevented synaptic dystrophies and rescued short-term and long-term synaptic plasticity. Further, Sarm1 deletion protected synapses from C1q tagging and phagocytosis, and C1q-MERTK signaling in complement cascades [7,13-15] was significantly reduced. The reduced synapse degeneration, in turn, broke the feed-forward loop of "glia activation-neuroinflammation-Aβ deposition". These data suggest that Sarm1 plays a key role in driving synapse degeneration in AD before C1q-tagging and phagocytic clearance, and targeting Sarm1 may offer a novel intervention to attenuate synapse degeneration and memory loss in AD.

HIGHLIGHT: Sarm1 is enriched at presynaptic dystrophies and correlated with Aβ.Genetic deletion of Sarm1 prevents synapse degeneration in AD.Sarm1 depletion is sufficient to reverse synaptic dysfunction and memory loss.Sarm1 depletion reduces Aβ burden and neuroinflammationC1q--MERTK axis acts downstream of synaptic Sarm1 activation.},
}

@article {pmid41509121,
year = {2025},
author = {Akbarizadeh-Mashkani, MH and Afshinmajd, S and Iranzadeh, S and Roghani, M},
title = {Involvement of synaptophysin and microtubule-associated protein 2 in the neuroprotective effect of berberine in an amyloid β-induced rat model of Alzheimer's disease.},
journal = {Avicenna journal of phytomedicine},
volume = {15},
number = {6},
pages = {1741-1754},
pmid = {41509121},
issn = {2228-7930},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a major public health concern. Berberine has shown promise in animal models by improving memory retention through multiple mechanisms. This study aimed to evaluate berberine therapeutic potential in ameliorating cognitive deficits in a rat AD model induced by intrahippocampal amyloid β1-42.

MATERIALS AND METHODS: The AD model was induced through bilateral injection of amyloid β1-42 into the CA1 region of the hippocampus. Berberine was administered orally, starting one hour post-surgery for one week. Rats were divided into sham, amyloid β, amyloid β + berberine 10 mg/kg, and amyloid β + berberine 50 mg/kg groups. The assessments encompassed cognitive testing and analysis of hippocampal markers, including oxidative stress, inflammation, apoptosis, and synaptic plasticity. Additionally, we evaluated acetylcholinesterase (AChE) activity and quantified neuronal loss in the hippocampal CA1 region.

RESULTS: Berberine improved the cognitive performance of amyloid-microinjected rats in the Y-maze, novel object recognition, and passive avoidance tests in a dose-dependent manner. Berberine attenuated hippocampal levels of malondialdehyde (MDA), nitrite, and tumor necrosis factor α (TNFα). Furthermore, berberine improved the activity of superoxide dismutase (SOD) and reduced caspase-3 and AChE activity. Berberine also enhanced synaptophysin and microtubule-associated protein 2 (MAP2) levels and inhibited neuronal loss in the CA1 region.

CONCLUSION: Berberine demonstrated protective effects against amyloid β-induced cognitive deficits in a rat AD model, and these effects were associated with reduced oxidative and nitrosative stress, inflammation, apoptosis, and AChE activity, alongside enhanced synaptic protection.},
}

@article {pmid41508961,
year = {2026},
author = {Arish, M and Hashemzehi, Z and Baghaei, V and Maleki, A and Salari, AM and Rasouli, S and Dakkali, MS},
title = {MicroRNA Signatures in Alzheimer's Disease and Normal-Tension Glaucoma: A Comparative Expression Analysis of miR-128 and miR-455-3p.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050425207251129073017},
pmid = {41508961},
issn = {1875-5828},
abstract = {INTRODUCTION: The relationship between Alzheimer's disease (AD) and normal-tension glaucoma (NTG) is an emerging area of interest owing to shared neurodegenerative features. Nevertheless, few studies have ascertained circulating microRNAs (miR) across both conditions. This study aimed to compare the expression of miR-128 and miR-455-3p in patients with NTG and AD and in controls, and to explore their potential as circulating biomarker candidates.

MATERIALS AND METHODS: In this cross-sectional study, serum miRNAs were extracted using a column- based kit and quantified by SYBR Green qRT-PCR (normalized to U6). Each reaction was run in triplicate. Data were analyzed via ANCOVA adjusted for age and sex, followed by Bonferroni post-hoc tests.

RESULTS: Both miR-128 and miR-455-3p were significantly upregulated in the AD and NTG groups compared with controls (p < 0.001 for both). Adjusted mean expression for miR-128 was approximately 2.1 in AD, 2.6 in NTG, and 0.3 in controls, while the corresponding miR-455-3p values were 2.9, 3.1, and 0.8, respectively. Post-hoc comparisons confirmed higher expression in both disease groups compared with controls, but not between AD and NTG. Power analysis revealed >0.99 power for group comparisons with controls, consistent with robust group-level differences.

DISCUSSION: miR-128 and miR-455-3p are implicated in neuronal stress responses, mitochondrial regulation, and amyloid-beta processing. Their parallel upregulation in AD and NTG suggests overlapping molecular signatures and may reflect systemic responses to neurodegenerative stress. These findings are also consistent with growing evidence that the eye and brain share vulnerability to similar cellular processes in neurodegeneration.

CONCLUSION: Elevated serum miR-128 and miR-455-3p in both AD and NTG indicate overlapping expression profiles across conditions. These miRNAs may serve as promising circulating biomarker candidates and support the concept of a molecular interplay between ocular and cerebral pathologies. However, their diagnostic and mechanistic potential warrants validation in largescale, longitudinal studies.},
}

@article {pmid41508864,
year = {2026},
author = {Francesconi, V and Carbone, A and La Spada, G and Odino, D and Canale, C and Relini, A and Pricl, S and Catto, M and Tonelli, M},
title = {Assessing the Multitarget Therapeutic Potential of Novel 9-Aminoacridine Derivatives for Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00839},
pmid = {41508864},
issn = {1948-7193},
abstract = {The escalating number of Alzheimer's disease (AD) cases and the limitations of current therapies pose a significant threat to human health, necessitating the discovery of novel drugs with innovative modes of action. To address this challenge, we pursued multitarget ligand strategy with the expectation of improved disease management. Continuing our efforts to discover new multitarget agents for AD, we decorated the planar 6-Cl-2-OCH3-9-aminoacridine core with basic heterocyclic or benzyl side chains as polar and hydrophobic structural features, respectively. All the compounds inhibited acetylcholinesterase, and in several cases also inhibited butyrylcholinesterase, with potencies comparable to or exceeding those of reference drugs. Exploring activity against MAO isoforms, heterocyclic derivatives 2, 5, 6, 9, 11, and 12 proved to be selective MAO-A inhibitors, while the 3,4-dichlorobenzyl derivative 20 provided balanced inhibition of both MAO-A and MAO-B enzymes. Favorable predicted blood-brain barrier permeability and low toxicity toward SH-SY5Y neuronal cells were also observed. Intriguingly, compounds 4, 12 and 20 altered the aggregation morphology of the neurotoxic Aβ42 peptide, revealing distinct inhibition profiles likely reflecting the different nature of the side chain. Based on these findings, the planar 6-Cl-2-OCH3-9-aminoacridine ring emerges as a valuable scaffold for future development of multitargeted anti-AD agents.},
}

@article {pmid41508691,
year = {2026},
author = {Mangaonkar, AA and Bolton, KL and Patnaik, MM},
title = {Clonal Hematopoiesis of Indeterminate Potential and Clonal Cytopenias of Undetermined Significance: 2026 Update on Clinical Associations and Management Recommendations.},
journal = {American journal of hematology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ajh.70205},
pmid = {41508691},
issn = {1096-8652},
support = {CSDG-23-1020347-01-IBCD//American Cancer Society/ ; },
abstract = {CONDITION OVERVIEW: Clonal hematopoiesis (CH) refers to the presence of somatic variants in hematopoietic stem and progenitor cells (HSPC) that result in expansion over time.

DIAGNOSIS: CH of indeterminate potential (CHIP) is operationally defined as pathogenic variants in oncogenic driver genes occurring in HSPCs at variant allele frequencies ≥ 2%.

CLINICAL ASSOCIATIONS: CH is associated with increased risk for progressive cytopenias (also called clonal cytopenia of undetermined significance), hematological (predominantly myeloid but also lymphoid) neoplasms, cytosis (including monocytosis), and nonhematological conditions such as atherosclerotic cardiovascular and cerebrovascular disease. CH is linked to numerous other diseases including venous thromboembolism, type 2 diabetes mellitus, chronic obstructive pulmonary disease, osteoporosis, and gout, with a potential protective impact in Alzheimer's disease (AD).

MANAGEMENT RECOMMENDATIONS: CH detection is becoming increasingly common due to the ubiquitous use of somatic and germline sequencing in clinical practice, particularly, in oncology. The clinical implications of CH are most relevant in therapy-related myeloid neoplasms (t-MN), with antecedent CH clones in genes such as TP53, PPM1D, and/or CHEK2 having a clear selection advantage. Furthermore, genetic predisposition to CH has provided some clarity on the origin and evolution of CH. We are currently defining the role for CH assessment in individuals with persistent (≥ 4 months) unexplained cytopenias, in patients with malignancies prior to adjuvant cytotoxic chemotherapy and/or radiation or radionuclide therapy, screening prior to autologous hematopoietic stem cell transplantation or chimeric antigen receptor T cell (CAR-T) therapy, and to work-up potentially germline mosaic variants.},
}

@article {pmid41508538,
year = {2026},
author = {Cheong, CY and Yap, P and Ng, TP and Tan, BY and Malhotra, C},
title = {Psychometric Validation of the Bedford Alzheimer Nursing-Severity Scale in Community-Dwelling Persons With Severe Dementia.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {1},
pages = {e70187},
doi = {10.1002/gps.70187},
pmid = {41508538},
issn = {1099-1166},
support = {HSRGEoL16Dec002//Ministry of Health -Singapore/ ; },
mesh = {Humans ; Male ; Female ; Aged, 80 and over ; Psychometrics ; Aged ; *Severity of Illness Index ; *Dementia/diagnosis/psychology ; Prospective Studies ; Reproducibility of Results ; Independent Living ; Longitudinal Studies ; Factor Analysis, Statistical ; Psychiatric Status Rating Scales ; },
abstract = {OBJECTIVES: Measuring disease severity in persons with severe dementia is essential for clinical care and research. Most instruments encounter issues, for example floor effects in characterising persons with severe dementia. We aimed to evaluate the psychometric properties of the Bedford Alzheimer Nursing-Severity Scale (BANS) and its short version, BANS-6, in community-dwelling persons with severe dementia.

METHODS: We used baseline data from a multi-centre prospective longitudinal study. 215 caregivers of community-dwelling persons with severe dementia (≥ FAST stage 6c) were recruited (mean age 83.6 ± 8.2). We evaluated BANS' construct validity with exploratory factor analysis, correlation with other established measures, and predictive validity.

RESULTS: Factor analysis revealed a two-factor solution (variance 58.35%) with item-2 (sleep-wake cycle) not loading onto any factor. Dropping item-2 (BANS-6) revealed a single-factor solution (variance 49.26%) and Cronbach's α improved from 0.701 to 0.782. FAST did not correlate with the Cohen-Mansfield Agitation Inventory and Quality of Life in Late-Stage Dementia Scale, but both BANS and BANS-6 did. For predictive validity, after adjusting for age, sex and comorbidities, BANS-6 remained significantly associated with key clinical complications of severe dementia: pneumonia (β = 2.09, 95% CI = 0.13-4.05), fever episodes (β = 1.24, 95% CI = 0.10-2.40) and oral antibiotic use (β = 1.33, 95%CI = 0.11-2.55), tube feeding (β = 4.42, 95% CI = 2.62-6.22), pressure sores (β = 2.51, 95% CI = 0.85-4.18), eating problems (β = 3.27, 95%CI = 2.20-4.34), and malnutrition (β = 1.63, 95% CI = 0.24-3.02) in the last 4 months. BANS was not significantly associated with pneumonia, oral antibiotics, and pressure sores, and FAST was not significantly associated with any outcome.

CONCLUSIONS: BANS and its short version, BANS-6, are valid, reliable, and clinically relevant tools for assessing dementia severity in community-dwelling persons with severe dementia, warranting further exploration in diverse population settings. The findings suggest that BANS-6 has better psychometrics and clinical utility than BANS.},
}

Humans
Male
Female
Aged, 80 and over
Psychometrics
Aged
*Severity of Illness Index
*Dementia/diagnosis/psychology
Prospective Studies
Reproducibility of Results
Independent Living
Longitudinal Studies
Factor Analysis, Statistical
Psychiatric Status Rating Scales

@article {pmid41508516,
year = {2026},
author = {Zhang, P and Long, J and Zeng, Z and Yan, X and Yang, Y and Fu, R and Lin, Y and Gong, D and Zeng, C and Yu, P},
title = {Identification, antioxidant and acetylcholinesterase inhibitory activities of soluble and insoluble-bioactive components from Cinnamomum camphora seed kernel residue.},
journal = {Food research international (Ottawa, Ont.)},
volume = {225},
number = {},
pages = {118116},
doi = {10.1016/j.foodres.2025.118116},
pmid = {41508516},
issn = {1873-7145},
mesh = {*Cholinesterase Inhibitors/pharmacology/analysis/chemistry/isolation & purification ; *Antioxidants/pharmacology/analysis/chemistry/isolation & purification ; *Seeds/chemistry ; *Cinnamomum camphora/chemistry ; *Plant Extracts/chemistry/pharmacology ; Phenols/analysis ; Acetylcholinesterase/metabolism ; Phytochemicals/analysis ; Alkaloids/analysis ; Solubility ; },
abstract = {Cinnamomum camphora seed kernel (CCSK) is a rich source of phytochemicals (e.g., phenolic compounds and alkaloids), but has not been comprehensively explored yet. In this study, both the SBC and IBC were prepared for the first time from the solid fraction obtained during the aqueous extraction of CCSK oil, and their composition, antioxidant activity, and acetylcholinesterase (AChE) inhibitory capacity were investigated. The SBC was extracted directly by 80 % ethanol aqueous solution; the IBC extraction conditions were optimized to yield the following parameters: cellulase to acidic protease ratio of 2:1 (w/w), extraction temperature of 60 °C, enzyme dosage of 940 U/g, extraction time of 4 h, liquid-to-solid ratio of 43 mL/g, and pH value of 5.0. Under the optimized conditions, the TPC and lindoldhamine yield in the IBC were determined to be 142.39 ± 5.30 mg GAE/10 g dw and 240.78 ± 1.91 mg/10 g dw, respectively. A total of 21 phenolic compounds and 16 alkaloids were identified in the SBC, while 14 phenolic compounds and 14 alkaloids were identified in the IBC by HPLC-ESI-QTOF-MS[2]. Furthermore, the IBC exhibited significantly stronger antioxidant activities and AChE inhibitory capacity than SBC, attributing to its higher lindoldhamine content. These findings highlight the considerable potential of SBC and IBC for application in antioxidant formulations and the prevention of Alzheimer's disease.},
}

*Cholinesterase Inhibitors/pharmacology/analysis/chemistry/isolation & purification
*Antioxidants/pharmacology/analysis/chemistry/isolation & purification
*Seeds/chemistry
*Cinnamomum camphora/chemistry
*Plant Extracts/chemistry/pharmacology
Phenols/analysis
Acetylcholinesterase/metabolism
Phytochemicals/analysis
Alkaloids/analysis
Solubility

@article {pmid41508235,
year = {2025},
author = {Bai, JM and Li, T and Shi, YJ and Zhang, YX and Shen, YF and Shan, SY and Yang, JX and Xu, ZL and Xiao, HH},
title = {[Shenzao Jiannao Oral Liquid suppresses NF-κB signaling pathway to alleviate neuroinflammation in Alzheimer's disease].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {19},
pages = {5434-5443},
doi = {10.19540/j.cnki.cjcmm.20250709.401},
pmid = {41508235},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/immunology/metabolism ; *NF-kappa B/genetics/metabolism/immunology ; *Drugs, Chinese Herbal/administration & dosage ; *Signal Transduction/drug effects ; Mice ; Male ; Disease Models, Animal ; Administration, Oral ; Humans ; Network Pharmacology ; *Neuroinflammatory Diseases/drug therapy ; },
abstract = {This study aims to use network pharmacology methods and animal experiments to decipher the mechanism by which Shenzao Jiannao Oral Liquid treats Alzheimer's disease(AD). Firstly, a mouse model of AD was established with APP/PS1 mice. Mice were assigned into 6 groups(n=10): blank, model, positive drug(donepezil hydrochloride, 0.65 mg·kg~(-1)), and low-, medium-, and high-dose(0.3, 1.5, and 7.5 g·kg~(-1), respectively) Shenzao Jiannao Oral Liquid, and administrated with corresponding agents by gavage for 28 days. Morris water maze and Y maze were used to evaluate the effects of Shenzao Jiannao Oral Liquid on the learning and memory abilities of mice. Hematoxylin-eosin and Nissl staining methods were used to detect pathological damage in mouse brain tissue. Secondly, network pharmacology methods were used to construct a "Shenzao Jiannao Oral Liquid active ingredient-AD-target" network by searching databases such as TCMSP, BATMAN, UniProt, OMIM, and GeneCards. STRING was used for Gene Ontology(GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis. Lastly, the immunofluorescence method and Western blot were employed to determine the expression of tumor necrosis factor(TNF)-α, interleukin(IL)-1β, synaptophysin(SYN), postsynaptic density protein 95(PSD95), and nuclear factor kappaB(NF-κB) signaling pathway proteins. The results showed that compared with the model group, the high-dose Shenzao Jiannao Oral Liquid group showed significantly shortened escape latency and swimming distance, significantly increased platform crossings, neat arrangement of neurons in the hippocampus, increased Nissl bodies, and restored cell morphology. The network pharmacology methods screened out 129 active ingredients of Shenzao Jiannao Oral Liquid, which shared 70 common targets with AD. The KEGG enrichment results suggested that Shenzao Jiannao Oral Liquid ameliorated AD by regulating the dopaminergic synaptic transmission, TNF signaling pathway, and NF-κB signaling pathway. Furthermore, Shenzao Jiannao Oral Liquid groups showed significantly down-regulated expression levels of TNF-α, IL-1β, and NF-κB signaling pathway proteins and up-regulated expression levels of SYN and PSD95. The results verify that Shenzao Jiannao Oral Liquid can alleviate the cognitive impairment and pathological changes in the brain tissue of AD mice by inhibiting the activation of the NF-κB signaling pathway, reducing inflammation, and enhancing synaptic plasticity.},
}

Animals
*Alzheimer Disease/drug therapy/genetics/immunology/metabolism
*NF-kappa B/genetics/metabolism/immunology
*Drugs, Chinese Herbal/administration & dosage
*Signal Transduction/drug effects
Mice
Male
Disease Models, Animal
Administration, Oral
Humans
Network Pharmacology
*Neuroinflammatory Diseases/drug therapy

@article {pmid41508224,
year = {2025},
author = {Ma, YJ and Deng, SX and Liao, ZH and Gao, MH and Ding, HX and Xu, ZQ and Lu, YT and Yang, C and Wang, Q},
title = {[Treatment of Alzheimer's disease from gut-brain interactions based on theory of "spleen deficiency leading to obstruction of nine orifices"].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {19},
pages = {5330-5339},
doi = {10.19540/j.cnki.cjcmm.20250618.501},
pmid = {41508224},
issn = {1001-5302},
mesh = {*Alzheimer Disease/drug therapy/physiopathology/metabolism ; Humans ; *Brain/physiopathology/drug effects/metabolism ; *Spleen/physiopathology/drug effects ; Animals ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use ; Gastrointestinal Microbiome ; },
abstract = {Alzheimer's disease(AD) is the most common form of dementia. The decline in sensory function is associated with pathological damage in specific brain regions during the early stages of AD. Such decline often precedes cognitive impairment, worsens as the pathology progresses, and constitutes a high-risk factor for the onset of AD. According to traditional Chinese medicine(TCM), all orifices are connected to the brain, and the brain governs all orifices. The mind originates from and depends on both the brain and orifices, with their physiological and pathological states being closely interconnected. In AD, dysfunction of the sensory orifices is closely linked to the later-stage manifestations of impaired mental clarity and consciousness. The theory that "spleen deficiency leading to obstruction of nine orifices" emphasizes that insufficiency of the spleen and stomach is the root cause of orifice dysfunction. Both internal and external pathogenic factors in AD can damage the spleen and stomach, leading to the abnormal movement of turbid substances generated by these organs, which may transform into turbid toxins. This, in turn, gradually impairs the orifices, brain, and mind, thereby exacerbating the progression of AD. The digestive, absorptive, and transport functions of the spleen and stomach are similar to those of the gut microbiota. Spleen deficiency is a core pathological factor in diseases associated with gut microbiota dysbiosis. Such dysbiosis can lead to dysfunction in the neural, metabolic, and immune pathways involved in gut-brain interactions, constituting the biological basis for the TCM concept that "spleen deficiency leading to obstruction of nine orifices". Under the guidance of this theory, employing spleen-strengthening and cognition-enhancing drugs alongside aromatic orifice-opening drugs to support spleen function, and using ingredients that promote dampness elimination, lubrication, and blood stasis resolution to dispel pathogenic factors from the orifices, can help restore the structural balance of the gut microbiota, regulate related metabolic and immune dysfunctions, and ultimately delay the progression of AD. This article explores the etiology, pathogenesis, and therapeutic strategies of AD based on the theory of "spleen deficiency leading to obstruction of nine orifices", and interprets its biological significance from the perspective of gut-brain interactions, aiming to provide new insights for the prevention and treatment of AD.},
}

*Alzheimer Disease/drug therapy/physiopathology/metabolism
Humans
*Brain/physiopathology/drug effects/metabolism
*Spleen/physiopathology/drug effects
Animals
Medicine, Chinese Traditional
Drugs, Chinese Herbal/therapeutic use
Gastrointestinal Microbiome

@article {pmid41508200,
year = {2025},
author = {Zhang, YX and Wang, J and Chen, QQ and Zhang, JL and Wang, Q and Long, YL and Zhou, SJ and Gong, ZP and Zheng, L and Huang, Y and Li, YT},
title = {[Study on quality markers of Pleione yunnanensis for "same treatment for different diseases" in liver inflammation and Alzheimer's disease based on UHPLC fingerprint and network pharmacology].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {20},
pages = {5684-5696},
doi = {10.19540/j.cnki.cjcmm.20250710.202},
pmid = {41508200},
issn = {1001-5302},
mesh = {Network Pharmacology ; *Drugs, Chinese Herbal/chemistry/therapeutic use ; *Alzheimer Disease/drug therapy/genetics/metabolism ; Chromatography, High Pressure Liquid/methods ; Humans ; Molecular Docking Simulation ; Biomarkers/analysis ; Quality Control ; },
abstract = {This study aims to screen quality markers(Q-markers) of Pleione yunnanensis for the treatment of liver inflammation and Alzheimer's disease(AD) based on the concept of "same treatment for different diseases" using ultra-high-performance liquid chromatography(UHPLC) fingerprinting combined with network pharmacology and molecular docking, and to perform quantitative analysis of the identified Q-markers. The UHPLC fingerprints of 15 batches of P. yunnanensis were established and subjected to similarity evaluation, cluster analysis(CA), principal component analysis(PCA), and orthogonal partial least squares discriminant analysis(OPLS-DA) to identify characteristic components responsible for quality variations. Network pharmacology and molecular docking were employed to explore the potential active components, related targets, and signaling pathways underlying the "same treatment for different diseases" mechanism for liver inflammation and AD. Based on the criteria of effectiveness, specificity, and measurability, Q-markers of P. yunnanensis were identified and quantified. Ten common peaks were identified in the UHPLC fingerprints of 15 batches, with eight components identified. Similarity scores ranged from 0.774 to 0.987. Chemical pattern recognition analysis identified that shancigusin H, militarine, and gymnoside Ⅴ were the major characteristic components contributing to quality differences among batches. RESULTS:: of network pharmacology and molecular docking revealed that dactylorhin A and militarine were the key active components exerting anti-inflammatory and neuroprotective effects. These components acted on 13 core targets, including SRC, CASP3, and CTNNB1, and regulated signaling pathways such as the PI3K-Akt signaling pathway and arachidonic acid metabolism. Based on the effectiveness, specificity, and measurability of Q-marker, dactylorhin A and militarine were selected as the Q-markers of P. yunnanensis. Quantitative analysis demonstrated that the content of dactylorhin A ranged from 0.527% to 2.21%, and militarine ranged from 0.731% to 2.58% across the 15 batches. The UHPLC fingerprint method and Q-marker-based quantification approach are robust and reliable, providing experimental evidence for quality control and standardization of P. yunnanensis.},
}

Network Pharmacology
*Drugs, Chinese Herbal/chemistry/therapeutic use
*Alzheimer Disease/drug therapy/genetics/metabolism
Chromatography, High Pressure Liquid/methods
Humans
Molecular Docking Simulation
Biomarkers/analysis
Quality Control

@article {pmid41508178,
year = {2025},
author = {Hou, WX and Liu, YX and Miao, JR and Zhu, ZK and Yin, Y and Liu, JL and Zhao, DY},
title = {[Mechanism of Liuwei Dihuang Pills in enhancing GPNMB expression to regulate FcγRⅡB/c-Src pathway for prevention and treatment of Alzheimer's disease].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {21},
pages = {6062-6071},
doi = {10.19540/j.cnki.cjcmm.20250805.401},
pmid = {41508178},
issn = {1001-5302},
mesh = {Animals ; *Drugs, Chinese Herbal/administration & dosage ; *Alzheimer Disease/drug therapy/genetics/metabolism/prevention & control ; Male ; Mice ; *Membrane Glycoproteins/genetics/metabolism ; Humans ; Signal Transduction/drug effects ; *src-Family Kinases/metabolism/genetics ; Hippocampus/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Memory/drug effects ; Eye Proteins ; },
abstract = {This study investigated the effect of Liuwei Dihuang Pills on the Fcγ receptor Ⅱ-b(FcγRⅡB)/c-Src tyrosine kinase(c-Src) pathway in senescence-accelerated mouse prone 8(SAMP8) by regulating the expression of the glycoprotein non-metastatic melanoma protein B(GPNMB) and explored the mechanism of the kidney-tonifying and essence-strengthening therapy in the treatment of Alzheimer's disease.(1) For the effects of Liuwei Dihuang Pills on the learning and memory ability, hippocampal β-amyloid protein(Aβ), GPNMB, and autophagy function in SAMP8 mice, eight seven-month-old male senescence-accelerated mouse resistant 1(SAMR1) mice were used as a control group, and 16 male SAMP8 mice of the same age were randomly divided into a model group and a Liuwei Dihuang Pills group. The Liuwei Dihuang Pills group was given 2.36 g·kg~(-1) concentrated Liuwei Dihuang Pills solution by gavage, while the control group and the model group were given the same volume of normal saline twice a day for four consecutive weeks. The learning and memory ability of mice in each group was detected by the Morris water maze experiment; the expression level of Aβ in the hippocampus of mice were detected by enzyme-linked immunosorbent assay(ELISA) and immunohistochemistry; the expression of GPNMB in the hippocampus of mice was detected by immunofluorescence and Western blot; the expression level of ubiquitin-binding protein p62 and microtubule-associated protein light chain 3(LC3) Ⅱ/LC3Ⅰ in the hippocampus of mice was measured by Western blot.(2) For the regulatory effect of GPNMB on the FcγRⅡB/c-Src pathway, eight seven-month-old male SAMR1 mice were used as a control group, and 24 male SAMP8 mice of the same age were randomly divided into a model group, an LV-Vector group, and an LV-GPNMB~(OE) group. The bilateral hippocampus of the LV-Vector group and LV-GPNMB~(OE) group was injected with LV-Vector and LV-GPNMB~(OE) of 2 μL/each side, respectively. Western blot was used to detect the expression level of p62, LC3Ⅱ/LC3Ⅰ, FcγRⅡB, Src homology 2 protein tyrosine phosphatase 1(SHP-1), and c-Src proteins in the hippocampus of mice.(3) For the effect of Liuwei Dihuang Pills in regulating the FcγRⅡB/c-Src pathway by increasing the GPNMB expression, 32 seven-month-old male SAMP8 mice were randomly divided into a model group, a Liuwei Dihuang Pills group, a Liuwei Dihuang Pills + LV-NC group, and a Liuwei Dihuang Pills + LV-shGPNMB group. The bilateral hippocampus of the Liuwei Dihuang Pills + LV-NC group and Liuwei Dihuang Pills + LV-shGPNMB group was injected with LV-NC and LV-shGPNMB, respectively, before the drug treatment. Western blot was used to detect the expression level of p62, LC3Ⅱ/LC3Ⅰ, FcγRⅡB, SHP-1, and c-Src proteins in the hippocampus of mice. The results showed that(1) compared with those of the control group, the escape latency of the model group was significantly increased, and the time spent in the target quadrant and the effective area was significantly decreased. The expression level of Aβ, GPNMB, and p62 in the hippocampus was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. Compared with those of the model group, the escape latency of the Liuwei Dihuang Pills group was significantly shortened, and the time spent in the target quadrant and the effective area was significantly increased. The level of Aβ was significantly decreased, and the expression level of GPNMB was significantly increased. The expression level of p62 was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased.(2) Compared with those of the control group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src proteins in the hippocampus of the model group was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. Compared with those of the model group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the LV-GPNMB~(OE) group was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased.(3) Compared with those of the model group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the Liuwei Dihuang Pills group was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased. Compared with those of the Liuwei Dihuang Pills group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the Liuwei Dihuang Pills + LV-shGPNMB group was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. These results indicate that Liuwei Dihuang Pills can inhibit the FcγRⅡB/c-Src pathway by up-regulating the GPNMB expression, thereby increasing autophagy levels, enhancing neuroprotective ability, and alleviating Alzheimer's disease.},
}

Animals
*Drugs, Chinese Herbal/administration & dosage
*Alzheimer Disease/drug therapy/genetics/metabolism/prevention & control
Male
Mice
*Membrane Glycoproteins/genetics/metabolism
Humans
Signal Transduction/drug effects
*src-Family Kinases/metabolism/genetics
Hippocampus/drug effects/metabolism
Amyloid beta-Peptides/metabolism
Memory/drug effects
Eye Proteins

@article {pmid41508141,
year = {2026},
author = {Bacci, JR and Karagianni, S and Alexopoulou, ZS and Moukaled, S and Tato-Fernández, C and Arunachalam, P and Aslanyan, A and Aye, S and Rocha, ASL and Crugel, M and Fawad, A and Sogorb-Esteve, A and Schöll, M and König, A and Paterson, RW},
title = {Clinical translation of fluid, imaging, and digital biomarkers for Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01921-5},
pmid = {41508141},
issn = {1758-9193},
support = {Wallenberg Centre for Molecular and Translational Medicine; KAW2014.0363 and KAW2023.0371//Knut and Alice Wallenberg Foundation/ ; 2017-02869, 2021-02678, 2021-06545 and 2023-06188//Swedish Research Council/ ; 101132933 (AD-RIDDLE) and 101112145 (PROMINENT)//European Union's Horizon Europe research and innovation program/ ; R01 AG081394-01//National Institute of Health/ ; RS-2023-00263612//National Research Foundation of Korea/ ; ALFGBG-813971 and ALFGBG-965326//ALF-agreement/ ; FO2021-0311 and FO2024-0372//Swedish Brain Foundation/ ; AF-1011738//Swedish Alzheimer Foundation/ ; PTC-22-982162//Alzheimer's Association Part the Cloud award/ ; },
}

@article {pmid41508098,
year = {2026},
author = {Yang, D and Wang, S and Lu, Y and Zhu, J and Chen, J and Zhang, B and Cai, H and Teng, B and Wei, R and Cen, Z and Luo, W},
title = {Interpretable machine-learning prediction of PSEN1 missense variant pathogenicity based on multi-omics enrichment in six core Alzheimer's disease genes.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01950-0},
pmid = {41508098},
issn = {1758-9193},
support = {No. 82302081//the National Natural Science Foundation of China/ ; No. LQ24H090003//the Zhejiang Provincial Natural Science Foundation of China/ ; No. 2024C03100//the Science and Technology Program of Zhejiang Province/ ; },
abstract = {BACKGROUND AND OBJECTIVE: The clinical interpretation of Alzheimer's disease (AD) is frequently complicated by the prevalence of missense variants designated as being of uncertain significance within associated genes. Conventional computational prediction tools often overlook disease-specific pathophysiological contexts and lack pertinence and interpretability. Therefore, the present study aimed to develop a novel, interpretable framework for predicting the pathogenicity of AD missense variants by integrating transcriptomic and proteomic data enrichment patterns with machine learning methods.

METHODS: A cross-sectional variant-level analysis was performed using publicly available databases. Missense variants in APOE, APP, PSEN1, PSEN2, SORL1, and TREM2 reported in AD patients were retrieved from Alzforum and compared with missense variants from individuals without neurological diseases, as cataloged in the gnomAD v2.1.1 non-neuro subset. Variants were annotated with tissue-specific expression, secondary structure, relative solvent accessibility, and other functional features using tools like AlphaFold. Enrichment of specific features was assessed with Fisher's exact tests with Bonferroni correction for multiple comparisons. Given that PSEN1 showed the strongest enrichment signals, six machine-learning algorithms were trained on PSEN1 variants to distinguish AD-associated variants from gnomAD variants, using a 10 × 5 nested cross-validation scheme. External validation was conducted using PSEN1 missense variants from ClinVar annotated as pathogenic/likely pathogenic or benign/likely benign. Model performance was compared with SIFT and PolyPhen-2, and interpretability was evaluated by feature ablation and SHapley Additive exPlanations analyses.

RESULTS: AD-associated variants exhibited statistically significant enrichment within some transcriptomic or proteomic features, with PSEN1 contributing significantly to the enrichment observed across these features. Random forest and gradient boosting models achieved high performance in the internal training dataset and maintained high recall in the external validation dataset, outperforming SIFT and approaching the performance of PolyPhen-2. Relative solvent accessibility was the most discriminative individual feature, while regional and topological features provided complementary discriminative power.

CONCLUSIONS: This integrative, multi-omics framework links disease-specific enrichment patterns with interpretable gene-level machine learning for AD missense variants. The results highlight the importance of expression level, structural context, etc. for PSEN1 variant pathogenicity and may help prioritize variants for functional studies. Further validation in additional genes and independent cohorts is warranted prior to any clinical application.},
}

@article {pmid41508094,
year = {2026},
author = {Anderson, ED and Cronkite, CA and Baldwin, PR and Abella, CP and Duman, JG and Simmonds, AN and Waxham, MN and Tolias, KF and Ludtke, SJ},
title = {Primary cortical neurons precipitate and extrude large mitochondria-associated calcium-phosphate sheets with a bone-precursor-like ultrastructure.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-025-01272-0},
pmid = {41508094},
issn = {1756-6606},
support = {F31NS132517/NS/NINDS NIH HHS/United States ; R01NS101686/NS/NINDS NIH HHS/United States ; NS062829/NS/NINDS NIH HHS/United States ; R35GM151999/GM/NIGMS NIH HHS/United States ; 2021FIB-41//Arnold and Mabel Beckman Foundation/ ; },
abstract = {Calcium-phosphate (CaP) is a ubiquitous inorganic compound that plays an important structural role in healthy bone and teeth formation, but its pathologic buildup can occur in dyshomeostatic calcium disorders like Alzheimer's disease and Leigh syndrome. The nexus of pathologic extracellular CaP in the nervous system is not well understood, but prior evidence suggests mitochondria could be a source. We have observed mitochondria-sized sheet-like CaP aggregates within functional wild type cortical neuron cultures at 1 and 20 days in vitro. Neurons were extracted from embryonic day 18 (E18) rat embryos following standard protocols to study neuronal structure and function. We have used a combination of cryo-ET, cryo-CLEM, and LDSAED to demonstrate that these aggregates are octacalcium phosphate-like, are associated with mitochondria, and that at least a portion are extruded via migrasomes. Visually similar aggregates were previously observed in Huntington's disease model neurons, but in that study they were not observed in WT controls. These findings show that this CaP aggregation process occurs routinely in WT neurons and may reveal an important link for how mitochondria may participate in calcification, highlighting them as potential therapeutic targets in neurological disorders characterized by pathological calcification, such as Alzheimer's disease.},
}

@article {pmid41508060,
year = {2025},
author = {Sun, CX and Han, XY and Xiao, YT and Liu, YX and Ye, TY},
title = {[Research progress on prevention and treatment of Alzheimer's disease with Danggui Shaoyao San].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {22},
pages = {6215-6226},
doi = {10.19540/j.cnki.cjcmm.20250626.601},
pmid = {41508060},
issn = {1001-5302},
mesh = {*Alzheimer Disease/drug therapy/prevention & control/metabolism ; *Drugs, Chinese Herbal/therapeutic use/administration & dosage ; Humans ; Animals ; },
abstract = {Alzheimer's disease is a neurodegenerative disorder associated with aging. In traditional Chinese medicine(TCM), it is classified as a syndrome of root deficiency and branch excess. Danggui Shaoyao San, a classic formula traditionally used to treat gynecological disorders, has the effects of promoting blood circulation, removing blood stasis, opening orifices, awakening the mind, strengthening the spleen, resolving phlegm, and tonifying Qi to nourish the spirit. Modern clinical studies have found that Danggui Shaoyao San can slow the progression of Alzheimer's disease and has great potential for clinical application. Recent studies indicate that Danggui Shaoyao San treats Alzheimer's disease through multi-target and multi-level mechanisms. These include clearing amyloid β(Aβ) plaques and abnormally phosphorylated tau protein, maintaining brain-gut homeostasis, reducing oxidative stress, and regulating autophagy. Its key components, paeoniflorin and ferulic acid, have also been reported to exert antioxidant, anti-inflammatory, and anti-apoptotic effects, eliminate pathological products, and regulate the cholinergic system in the brain. This paper traces the classic formula of Danggui Shaoyao San, conducts a theoretical integration of ancient and modern medical systems, and systematically summarizes and analyzes the research related to the treatment of Alzheimer's disease using Danggui Shaoyao San and its key components. It aims to provide a valuable reference for further research and modern application of Danggui Shaoyao San in the treatment of Alzheimer's disease.},
}

*Alzheimer Disease/drug therapy/prevention & control/metabolism
*Drugs, Chinese Herbal/therapeutic use/administration & dosage
Humans
Animals

@article {pmid41508058,
year = {2026},
author = {Yao, M and Sun, N and Linville, R and Wei, Z and Kakazu, A and Ouyang, Y and Li, R and Du, L and Wang, H and Zhou, Y and Jiang, Y and Zhang, Z and Li, A and Garcia, FJ and Lu, H and Xu, J and Kellis, M and Heiman, M and Duan, W},
title = {Neurovascular and metabolic dysfunction with cell type-specific transcriptomic changes in presymptomatic 5XFAD mice.},
journal = {Fluids and barriers of the CNS},
volume = {23},
number = {1},
pages = {3},
pmid = {41508058},
issn = {2045-8118},
support = {F32NS128067/NS/NINDS NIH HHS/United States ; R01NS129032/NS/NINDS NIH HHS/United States ; R01NS124084/NS/NINDS NIH HHS/United States ; R01AG071515/AG/NIA NIH HHS/United States ; R01AG080104/AG/NIA NIH HHS/United States ; R01AG081932/AG/NIA NIH HHS/United States ; R01AG081932/AG/NIA NIH HHS/United States ; P41EB031771/NH/NIH HHS/United States ; U01DA053631/DA/NIDA NIH HHS/United States ; U01DA053631/DA/NIDA NIH HHS/United States ; },
}

@article {pmid41508043,
year = {2026},
author = {Kimura, T and Masuda-Suzukake, M and Hashimoto, M and Sekiyama, K and Kametani, F and Tomita, T and Aoyagi, H and Hisanaga, SI and Hasegawa, M},
title = {Repetitive mild traumatic brain injury with the closed-head impact model of engineered rotational acceleration (CHIMERA) promotes tau pathology in tau transgenic mice and its propagation in brains injected with tau fibrils.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {13},
pmid = {41508043},
issn = {2051-5960},
support = {JP17pc0101006//Japan Agency for Medical Research and Development/ ; JP17pc0101006//Japan Agency for Medical Research and Development/ ; JP17pc0101006//Japan Agency for Medical Research and Development/ ; JP17pc0101006//Japan Agency for Medical Research and Development/ ; JP17pc0101006//Japan Agency for Medical Research and Development/ ; JP17pc0101006//Japan Agency for Medical Research and Development/ ; },
mesh = {Animals ; *tau Proteins/metabolism/administration & dosage/genetics ; Mice, Transgenic ; *Brain Concussion/pathology/metabolism ; Disease Models, Animal ; Mice ; *Brain/pathology/metabolism ; *Tauopathies/pathology/metabolism ; Acceleration ; Mice, Inbred C57BL ; Phosphorylation ; Male ; Chronic Traumatic Encephalopathy/pathology ; Humans ; },
abstract = {Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease characterized by the presence of abnormally phosphorylated tau aggregates. Tau is a microtubule-associated protein expressed mainly in axons of neurons with a role in the regulation of microtubule dynamics and axonal transport. It is totally unknown when and how tau is abnormally hyperphosphorylated in CTE brains. Unlike other tauopathies such as Alzheimer's disease, in which diseases start several decades before clinical symptoms and the time point of onset is not clear, in the case of CTE it is evident when and what impacts are given to cause the diseases. Repetitive mild traumatic brain injury (rmTBI) is a known causative factor for CTE, particularly in athletes engaged in contact sports, individuals involved in traffic accidents, and military personnel exposed to blast injuries. We hypothesized rmTBI to be a useful experimental paradigm for investigating the initial processes of tau hyperphosphorylation in CTE. Among the various experimental models for TBI reported to date, we focus on the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA), because it appears to replicate human TBI more faithfully than other models particularly regarding on the impact mechanism and pathology. After verifying that CHIMERA rmTBI induced brain injuries analogous to human CTE, we investigated tau pathology in wild-type (WT) and P301S human tau transgenic (Tg) mice subjected to CHIMERA rmTBI. While no hyperphosphorylated tau signal was observed in any region of the WT mouse brain, an increased number of AT8-positive cells were detected in the motor and sensory cortices of P301S Tg mouse brains, accompanied by dendritic abnormalities, after rmTBI. Further, we found that CHIMERA rmTBI enhanced the spreading of tau pathology in brains of WT mice when tau fibrils were inoculated. These results suggest a possibility that rmTBI constitutes a risk factor stimulating the progression and propagation of tau pathology, rather than causing the initial events, if tau aggregates are present in the brain and that CHIMERA rmTBI may serve as a valuable experimental model for investigating its molecular mechanisms.},
}

Animals
*tau Proteins/metabolism/administration & dosage/genetics
Mice, Transgenic
*Brain Concussion/pathology/metabolism
Disease Models, Animal
Mice
*Brain/pathology/metabolism
*Tauopathies/pathology/metabolism
Acceleration
Mice, Inbred C57BL
Phosphorylation
Male
Chronic Traumatic Encephalopathy/pathology
Humans

@article {pmid41507977,
year = {2026},
author = {Altahona-Medina, MA and Fernandez-Alvarez, M and Lopez-Vilaret, KM and Rugg, MD and Cantero, JL and Atienza, M},
title = {When Alzheimer's pathology meets cardiometabolic risk: intrinsic subcortical-cortical connectivity signatures of retroactive interference in aging.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01956-2},
pmid = {41507977},
issn = {1758-9193},
support = {PID2023-149270OB-I00//Spanish Ministry of Science and Innovation and State Research Agency/ ; PID2023-151095NB-I00//Spanish Ministry of Science and Innovation and State Research Agency/ ; NED21PI02C//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; AARG-NTF-22-924702/ALZ/Alzheimer's Association/United States ; },
}

@article {pmid41507627,
year = {2026},
author = {Ghaiad, HR and El-Shiekh, RA and Atwa, AM and Mustafa, AM and Elgindy, AM and Alkabbani, MA and Elkady, WA and Ibrahim, KM},
title = {From nutrition to therapeutics: the diverse inflammopharmacological and biomedical roles of astaxanthin.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41507627},
issn = {1568-5608},
abstract = {Astaxanthin, a xanthophyll carotenoid derived primarily from Hematococcus lacustris, has been proposed as a potent bioactive compound demonstrating wide therapeutic applicability. In addition to its distinct molecular structure, astaxanthin has exceptional antioxidant property, surpassing that of other carotenoids and conventional antioxidants, while also exerting robust anti-inflammatory effects. The present review focuses on the current evidence of the complex multifaceted therapeutic actions of astaxanthin, including cardiovascular protection, neuroprotection, hepatoprotection, renal support, dermatological health, immune modulation, and emerging roles in metabolic disorders, reproductive health, and cancer prevention. Mechanistic insights highlight its potential to control key molecular mechanisms, including the NF-κB, Nrf2, MAPK, and TGF-β/Smad pathways, alongside the enhancement of endogenous antioxidant defenses. Preclinical and clinical findings have demonstrated benefits in conditions such as atherosclerosis, myocardial ischemia, nonalcoholic fatty liver disease, hypertension, Alzheimer's disease, Parkinson's disease, and inflammatory skin diseases. By integrating evidence drawn from molecular, experimental, and clinical studies, this review underscores astaxanthin's potential as a complementary therapeutic agent and functional nutraceutical. The breadth of its bioactivity positions astaxanthin as a promising natural compound for targeted disease prevention and health promotion.},
}

@article {pmid41507323,
year = {2026},
author = {Doulatpour, N and Rahnamaye Aliabad, HA and Sabbaghzadeh, R and Azadparvar, M},
title = {Optoelectronic properties of piperidine under hydrostatic pressure, temperature, and the companion inhibition activity by DFT and molecular docking approaches.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-34873-9},
pmid = {41507323},
issn = {2045-2322},
abstract = {The optoelectronic and biophysical properties of Piperidine with a monoclinic crystal structure are investigated under hydrostatic pressure and temperature. The full potential-linearized augmented plane wave method and the molecular docking approach are used. The exchange-correlation potentials are calculated by the Perdew-Burke-Ernzerhof generalized gradient approximation as implemented in the WIEN2k package. The results indicate that Piperidine exhibits an indirect band gap of 4.55 eV at zero pressure, confirming its insulating nature. Upon increasing the pressure to 2.76 GPa, the band gap increases to 4.85 eV. At zero pressure, the static dielectric constants in the x, y and z directions are 2.27, 2.21, and 2.30, respectively. In the ultraviolet spectral range, the main peaks of the dielectric function demonstrate a blue shift (a shift to higher energies) under pressure. Optical spectra show dielectric behavior in the ultraviolet region and metallic behavior in the extreme ultraviolet region. The maximum value of the absorption coefficient is observed in the extreme ultraviolet region. Furthermore, increasing pressure causes a sharp decrease in the ultraviolet and visible regions, accompanied by a blue shift in the absorption threshold. The obtained absorption coefficient values for Piperidine are in good agreement with experimental results. The electron energy loss spectrum indicates that the plasmon frequency increases with pressure, suggesting the potential for high-performance optoelectronic devices. Furthermore, temperature variations did not significantly affect the optical properties of the Piperidine compound. Molecular docking studies reveal that Piperidine exhibits inhibitory effects on the Beta-secretase enzyme and cannabinoid receptor in Alzheimer's disease. The negative formation energy shows that the structure of the Piperidine compound is thermodynamically stable and will maintain its structural integrity during experimental syntheses. This stability makes it a promising candidate for pharmaceutical and industrial applications.},
}

@article {pmid41507317,
year = {2026},
author = {Lu, Y and Yu, H and Li, T and Meng, Y and Lu, J and Li, P},
title = {A lightweight CVTC model for accurate Alzheimer's MRI analysis and lesion annotation.},
journal = {NPJ digital medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41746-025-02212-x},
pmid = {41507317},
issn = {2398-6352},
support = {T2541012//National Natural Science Foundation of China/ ; No.242300420242//Natural Science Foundation of Henan Province/ ; No.242102310103//Key Science and Technology Research Project of Henan Province/ ; },
abstract = {In clinical practice, MRI images are widely used to diagnose neurodegenerative diseases like Alzheimer's disease (AD). However, complex MRI patterns often mimic normal aging, relying on subjective experience and risking misdiagnosis. This paper proposes the Cross Vision Transformer with Coordinate (CVTC) to assess AD severity and accurately annotate suspicious lesions, reducing clinicians' burden and improving reliability. CVTC integrates scale-adaptive embedding, dynamic position bias, and long-short attention mechanisms to enhance capture of local and global MRI features. For annotation, the Coordinate and Feature Map Guided Mechanism (CAGM) leverages pixel coordinates and feature maps to compute an importance threshold, generating lesion overlay maps for precise localization. A user-friendly UI is developed to enable intuitive exploration and validation in clinical settings. CVTC demonstrates robust performance across datasets: 98.80% accuracy on ADNI (AD/MCI/CN), 98.51% on AD subtypes (EMCI/LMCI/SMC/CN); cross-dataset validation on tumor and multiple sclerosis MRIs confirms CAGM's annotation accuracy; NACC (96.30%), OASIS-1 (98.16%), and pseudo-RGB datasets (92.96%) highlight superior generalization. Ablation and cross-validation affirm robustness. With a 21.850MB lightweight design, CVTC offers an efficient, accurate tool for diverse clinical applications.},
}

@article {pmid41507267,
year = {2026},
author = {Abhyankar, SD and Luo, Q and Hartman, GD and Mahajan, N and Corson, TW and Oblak, AL and Lamb, BT and Bhatwadekar, AD},
title = {High-fat Western diet induces retinal and metabolic alterations in APOE3 and APOE4 knock-in mice.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-34776-9},
pmid = {41507267},
issn = {2045-2322},
support = {R01EY027779-S1/EY/NEI NIH HHS/United States ; R01EY027779-S1/EY/NEI NIH HHS/United States ; R01EY027779-S1/EY/NEI NIH HHS/United States ; R01EY027779-S1/EY/NEI NIH HHS/United States ; R01EY027779-S1/EY/NEI NIH HHS/United States ; R01EY027779-S1/EY/NEI NIH HHS/United States ; Unrestricted Grant//Research to Prevent Blindness/ ; Unrestricted Grant//Research to Prevent Blindness/ ; Unrestricted Grant//Research to Prevent Blindness/ ; Unrestricted Grant//Research to Prevent Blindness/ ; Unrestricted Grant//Research to Prevent Blindness/ ; T32DK064466/DK/NIDDK NIH HHS/United States ; },
abstract = {The APOE genotype influences metabolic and neurodegenerative outcomes, with APOE4 carriers at higher risk for Alzheimer's disease (AD) and metabolic dysfunction. This study examines how long-term dietary interventions affect systemic metabolism, retinal structure/ function in APOE3-knock-in (KI, neutral for AD) and APOE4-KI mice. Humanized APOE3 and APOE4-KI mice received either a control diet (CD) or a Western diet (WD) for 2, 6, or 12 months. Body weight, glucose metabolism, lipid profiles, retinal structure, function, vasculature, visual performance, and inflammatory markers were analyzed. WD induced early glucose intolerance in APOE4 mice (2 months); APOE3 mice showed impairment only after prolonged exposure (6-12 months). Notably, WD-fed APOE3 mice exhibited more pronounced hyperlipidemia than APOE4 mice. APOE4 CD mice displayed early retinal thinning (6 months), while APOE4 WD mice initially exhibited retinal swelling, followed by degeneration (12 months). WD exacerbated retinal vascular dysfunction in APOE4 mice, with increased tortuosity and reduced vascular area. Elevated Il1b expression in WD-fed APOE4 mice confirmed inflammation-associated retinal dysfunction. APOE4 mice showed heightened dietary vulnerability, with WD worsening metabolic, retinal, and vascular impairments. While CD showed better glucose tolerance, it did not prevent retinal dysfunction. These findings underscore the need for genotype-specific dietary strategies to mitigate APOE4-associated risks.},
}

@article {pmid41507065,
year = {2026},
author = {De Rui, M and Salerno Trapella, G and Ceolin, C and Ceccato, F and Antonelli, G and Ravelli, A and Andreuzza, R and Conti, E and Sarlo, M and Coin, A and Zanforlini, BM and Bertocco, A and Curreri, C and Tizianel, I and Mapelli, D and Sergi, G and Devita, M},
title = {Effect of cognitive training on cortisol levels in patients with neurocognitive disorders.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbaf243},
pmid = {41507065},
issn = {1758-5368},
abstract = {OBJECTIVES: Elevated cortisol levels are linked to a greater risk and faster progression of neurocognitive disorders (NCDs). While interventions such as exercise and mindfulness have shown benefits in reducing cortisol, the impact of cognitive training (CT) on cortisol regulation remains unexplored. This study investigated whether CT affects cortisol levels and secretion patterns in individuals with minor or major NCD and compared its effects with those of pharmacological treatment.

METHODS: Sixty-two older adults with NCD and 43 healthy controls were recruited from the University Hospital of Padua in Italy. Among patients with NCD, 34 underwent CT (CT-NCD group), and 28 received pharmacological treatment (PH-NCD group). Salivary cortisol was measured at six points during the day, at baseline, and at 3 months (T1) and 6 months (T2) post-intervention.

RESULTS: Compared with pharmacological treatment (PH), CT showed a larger percentage decrease of daily cortisol exposure (AUC) from baseline; however, the between-group difference did not remain statistically significant after covariate adjustment, and the only robust time-point effect was in the afternoon (F(1,47)=5.13; p = 0.028). Morning values decreased within groups, but between-group differences in the CAR were not significant; at bedtime, CT showed only a trend towards lower cortisol than PH (p = 0.071). Median morning values changed from 7.75 to 6.20 in CT and from 5.80 to 5.15 in PH.

DISCUSSION: CT may help lower cortisol levels and enhance cognitive function in NCD patients, suggesting its potential as a nonpharmacological tool to modulate hypothalamic-pituitary-adrenal axis activity. Larger randomized studies are needed to confirm and extend these findings.},
}

@article {pmid41506881,
year = {2026},
author = {Cao, H and Yao, N and Liu, B and Dong, X and Cong, S},
title = {[Research advances on the triad of glucose metabolism, neuroinflammation and oxidative stress in driving Alzheimer's disease].},
journal = {Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology},
volume = {42},
number = {1},
pages = {77-83},
pmid = {41506881},
issn = {1007-8738},
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Oxidative Stress ; *Glucose/metabolism ; Animals ; *Inflammation/metabolism ; *Neuroinflammatory Diseases/metabolism ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; tau Proteins/metabolism ; Signal Transduction ; },
abstract = {Research on the pathomechanism of Alzheimer's disease (AD) has long focused on β-amyloid (Aβ) deposition and Tau protein hyperphosphorylation. However, recent metabolomics studies have revealed that brain energy metabolism disorders occur in the early stages of AD. This paper systematically integrates the latest evidence and proposes the "metabolism-inflammation-oxidative stress triangle" hypothesis to elucidate the pivotal role of glucose metabolism network dysregulation in AD pathology. The results demonstrate that AD patients exhibit abnormal activity of key glycolysis enzymes, impaired insulin signaling pathways and mitochondrial oxidative phosphorylation dysfunction. These metabolic disturbances form a bidirectional positive feedback loop with neuroinflammation and oxidative stress through mechanisms including the metabolic reprogramming of microglial cells, the release of damage-associated molecular patterns (DAMPs), and activation of nuclear factor κB/mitogen-activated protein kinase (NF-κB/MAPK) pathway. This interplay drives Aβ and Tau deposition, as well as the oxidative stress, creating a vicious cycle of Aβ deposition and Tau phosphorylation. This paper reveals the central role of brain metabolic disorders as an early driver of AD, and emphasizes the therapeutic potential of multi-target strategies targeting key interaction nodes within the metabolism-inflammation-oxidative stress, which provides a novel theoretical framework for early AD intervention.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Oxidative Stress
*Glucose/metabolism
Animals
*Inflammation/metabolism
*Neuroinflammatory Diseases/metabolism
Amyloid beta-Peptides/metabolism
Brain/metabolism
tau Proteins/metabolism
Signal Transduction

@article {pmid41506734,
year = {2026},
author = {, and , },
title = {[Guidelines for the management of chronic insomnia comorbid with common neuropsychiatric disorders in adults (2025 edition)].},
journal = {Zhonghua nei ke za zhi},
volume = {65},
number = {1},
pages = {18-44},
doi = {10.3760/cma.j.cn112138-20250911-00539},
pmid = {41506734},
issn = {0578-1426},
support = {2021YFC2501400//National Key Research and Development Program of China/ ; },
mesh = {Humans ; *Sleep Initiation and Maintenance Disorders/therapy/epidemiology/complications ; *Mental Disorders/therapy/complications/epidemiology ; Comorbidity ; Adult ; Parkinson Disease ; },
abstract = {Chronic insomnia frequently co-occurs with common neuropsychiatric disorders, including migraine, stroke, Alzheimer's disease, Parkinson's disease, epilepsy, generalized anxiety disorder, depressive disorder, body distress disorder, post-traumatic stress disorder, and disorders due to use of alcohol. The prevalence of these neuropsychiatric disorders is hiher among patients with chronic insomnia than in the general population, and the conditions mutually exacerbate each other. Comorbidities not only exacerbate the severity and increases the relapse risk of each condition but also lead to a poorer prognosis, more severe impairment of social functioning, a higher all-cause mortality risk, and greater treatment challenges. Therefore, the Sleep Disorders Group, Chinese Society of Neurology and Sleep Medicine Group,China Neurologist Association have convened experts in relevant fields, based on current medical evidence, to establish guideline for the management of Chinese adults with chronic insomnia comorbid with the aforementioned 10 categories of common neuropsychiatric disorders. The aim is to standardize clinical practice and improve treatment effectiveness and cure rates.},
}

Humans
*Sleep Initiation and Maintenance Disorders/therapy/epidemiology/complications
*Mental Disorders/therapy/complications/epidemiology
Comorbidity
Adult
Parkinson Disease

@article {pmid41506720,
year = {2026},
author = {Nolan, T},
title = {Liraglutide for Alzheimer's disease . . . and other research.},
journal = {BMJ (Clinical research ed.)},
volume = {392},
number = {},
pages = {r2633},
doi = {10.1136/bmj.r2633},
pmid = {41506720},
issn = {1756-1833},
}

@article {pmid41506537,
year = {2026},
author = {Liang, YZ and Jiang, MZ and Xu, XT and Zhu, T and Guo, H and Ding, L and Zhong, H and Bao, J and Qin, LQ and Li, YH},
title = {Ameliorating effect and mechanism of p-coumaric acid liposome on cognitive dysfunction and mitochondrial damage under intermittent hypoxia.},
journal = {Life sciences},
volume = {387},
number = {},
pages = {124197},
doi = {10.1016/j.lfs.2026.124197},
pmid = {41506537},
issn = {1879-0631},
abstract = {AIMS: Alzheimer's disease (AD) has become a global public health problem. Mitochondrial dysfunction contributes to AD pathogenesis, and adequate oxygen supply is essential to maintain mitochondrial homeostasis. P-coumaric Acid (CA) is a polyphenol with anti-hypoxia and anti-AD properties. In this study, CA was formulated into a biomimetic liposome (CA-Lip) to enhance its therapeutic efficacy, and the underlying mechanisms were studied.

MATERIALS AND METHODS: APP/PS1 mice were divided into four groups: AD group, hypoxia treatment group (AD-HY group), hypoxia + CA treatment group (CA group), hypoxia + CA-Lip treatment group (CA-Lip group). Age-matched wild-type littermates were used as controls. Mice in the hypoxia treatment groups were exposed to a hypoxia chamber for 6 h daily for 8 weeks. Cognitive performance and mitochondrial function were subsequently evaluated to determine the ameliorating effects and mechanisms of CA-Lip.

RESULTS: Cognitive impairment and mitochondrial dysfunction were more pronounced in the AD-HY group than in the AD group. CA-Lip produced greater neuroprotective effects than CA. Mechanistic analyses showed that CA-Lip reduced amyloid-β (Aβ) accumulation, enhanced mitochondrial biogenesis (upregulation of PGC-1α expression), maintained mitochondrial dynamics (upregulation of MFN2 expression, and downregulation of DRP1 expression), inhibited excessive mitophagy (downregulation of PINK1 and Parkin expression), enhanced cell autophagy (upregulation of ATG7 and LC3B expression and downregulation of mTOR and P62 expression), and reduced neuronal apoptosis.

CONCLUSIONS: CA-Lip effectively ameliorates hypoxic cognitive impairment by reducing Aβ generation and improving mitochondrial function.},
}

@article {pmid41506481,
year = {2026},
author = {Chen, J and Wang, B and Chen, Z and Ding, F and Wang, J and Ding, C and Cao, X},
title = {Exogenous Aβ1-42 Monomers Rescue Memory Deficits in Presenilin-1 and Presenilin-2 Conditional Double Knockout Mice.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111715},
doi = {10.1016/j.brainresbull.2026.111715},
pmid = {41506481},
issn = {1873-2747},
abstract = {Emerging evidence challenges the direct causal relationship between amyloid-β (Aβ) deposition and cognitive decline in Alzheimer's disease (AD), as exemplified in presenilin-1 and presenilin-2 conditional double knockout (cDKO) mice which exhibit no amyloid plaques and reduced soluble Aβ1-42 monomers, but paradoxically display AD-like memory deficits. In this study, we hypothesize that reduced soluble Aβ1-42 monomers critically underlie memory dysfunction in cDKO mice. Combining behavioral assessments and in vivo multichannel electrophysiology, we show that cDKO mice exhibit impaired spatial and episodic memory, accompanied by reduced theta oscillation power and theta-gamma phase-amplitude coupling in the dorsal hippocampal CA1. Remarkably, exogenous supplementation of physiological level Aβ1-42 monomers rescued memory deficits and restored neural oscillatory dynamics, while co-administration of the α7-nicotinic acetylcholine receptors (α7-nAChRs) antagonist methyllycaconitine blocked these rescuing effects. Our findings reveal that soluble Aβ1-42 monomers help to sustain hippocampal memory through α7-nAChRs-dependent pathways, thereby contributing toa revised perspective on the roles of Aβ1-42 monomers in cognition and suggesting potential avenues for Aβ-targeted AD treatments.},
}

@article {pmid41506439,
year = {2026},
author = {Zhang, SZ and Ma, Y and Ding, Y and Yin, YQ and Wang, BW and Hu, G and Zhou, JW},
title = {Astrocytic TPK1 mitigates amyloid pathology via TFEB-mediated endocytosis.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115640},
doi = {10.1016/j.expneurol.2026.115640},
pmid = {41506439},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles, and progressive neurodegeneration. Deregulation of glial cell activity plays an important role in the amyloid pathology. However, it is still unclear how changes in astrocytes contribute to Aβ deposition and clearance in AD. Here, we showed that deficiency of astrocytic thiamine pyrophosphokinase 1 (Tpk1), exacerbated Aβ burden leading to exacerbated spatial memory deficits in a mouse model of AD. While selective overexpression of Tpk1 in astrocytes ameliorated cognitive decline and significantly reduced hippocampal and cortical Aβ plaque burden. Enhanced Tpk1 expression augmented astrocyte endocytic capacity. Mechanistically, Tpk1-promoted endocytic activity depended on the activation of transcription factor EB (TFEB)-mediated pathways. Collectively, our findings demonstrate that astrocytic TPK1 mitigates cognitive impairment in 5xFAD mice by upregulating TFEB expression, thereby enhancing astrocyte-mediated engulfment and degradation of neurotoxic aggregates, including Aβ. This study suggests that astrocytic TPK1/TFEB pathway is a promising target for developing disease-modifying AD therapies.},
}

@article {pmid41506265,
year = {2026},
author = {Hamagami, N and Kapadia, D and Barclay, KM and Huang, Y and Abduljawad, N and Cheng, Z and McLaughlin, L and Singhania, D and Ding, X and Yang, J and Sun, Z and Karra, V and Du, S and Bayguinov, P and Yu, G and Li, YE and Gabel, HW and Li, Q},
title = {State-specific enhancer landscapes govern microglial plasticity.},
journal = {Immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.immuni.2025.11.023},
pmid = {41506265},
issn = {1097-4180},
abstract = {Single-cell transcriptomic studies have identified distinct microglial subpopulations with shared and divergent gene signatures across development, aging, and disease. Whether these microglial subsets represent ontogenically separate lineages of cells or are manifestations of plastic changes in microglial states downstream of some converging signals is unknown. Furthermore, despite the well-established role of enhancer landscapes underlying the identity of microglia, the extent to which histone modifications and DNA methylation regulate microglial state switches at enhancers has not been defined. Here, using genetic fate mapping, we demonstrated the common embryonic origin of proliferative-region-associated microglia enriched in developing white matter and tracked their dynamic transitions into disease-associated microglia and white matter-associated microglia in disease and aging contexts, respectively. This study links spatiotemporally discrete microglial states through their transcriptomic and epigenomic plasticity, while revealing state-specific enhancer histone modifications and transcription regulators that govern state transitions in health and disease.},
}

@article {pmid41506061,
year = {2025},
author = {Iizuka, T and Umeda-Kameyama, Y and Fukasawa, M and Akishita, M and Kameyama, M},
title = {Smiling difficulties in Alzheimer's disease linked to reduced nucleus accumbens and pallidum brain volume: Deep learning insights.},
journal = {Artificial intelligence in medicine},
volume = {173},
number = {},
pages = {103347},
doi = {10.1016/j.artmed.2025.103347},
pmid = {41506061},
issn = {1873-2860},
abstract = {Patients tend to lose the ability to smile during the course of dementia. However, such impairments have rarely been reported, likely due to challenges in quantifying facial expressions. However, feature extraction is now automated due to recent developments in deep learning, which is a machine learning method used in artificial intelligence (AI). We used the output of image-classification AI to quantify smiles in participants with Alzheimer's disease (AD) and with normal cognition (NC). We found that the ability to form a smile upon request is impaired in patients with AD and that it is associated with reduced volumes of the nucleus accumbens and pallidum. Furthermore, smiling faces were classified with higher accuracy than neutral faces in discriminating between AD and NC. A score from neutral face showed significant correlation with cognitive function. These findings generate hypotheses regarding the neural mechanisms underlying impaired facial expressions in dementia.},
}

@article {pmid41506004,
year = {2025},
author = {Sala-Vila, A and Tintle, NL and Westra, J and Harris, WS},
title = {Blood omega-3 is inversely related to risk of early-onset dementia.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {57},
number = {},
pages = {106559},
doi = {10.1016/j.clnu.2025.106559},
pmid = {41506004},
issn = {1532-1983},
abstract = {BACKGROUND & AIMS: Early-onset dementia (EOD, defined as diagnosis < age 65) imposes a high socio-economic burden. It is less prevalent and less investigated than late-onset dementia (LOD). Observational data indicate that many EOD cases are associated with potentially modifiable risk factors, yet the relationship between diet and EOD has been under-explored. Omega-3 fatty acids are promising dietary factors for dementia prevention; however, existing research has primarily focused on cohorts aged >65. We examined the associations between omega-3 blood levels (which objectively reflect dietary intake) and incident EOD by leveraging data from the UK Biobank cohort.

METHODS: We included participants aged 40-64, free of dementia at baseline and for whom plasma omega-3 levels and relevant covariates were available. We modeled the relationships between the three omega-3 exposures (total omega-3, DHA, and non-DHA omega-3) and incident EOD with quintiles (Q) and continuous linear relationships. We constructed Cox proportional hazards adjusting for sex, age at baseline and APOE-ε4 allele load, besides other lifestyle variables reported to relate to incident EOD. We also assessed the interaction between each exposure of interest and APOE-ε4 allele load.

RESULTS: The study included 217,122 participants. During the mean follow-up of 8.3 years, 325 incident EOD cases were ascertained. Compared to participants at Q1 of total omega-3, those at Q4 and Q5 showed a statistically significantly lower risk of EOD (Q4, hazard ratio [95 % confidence interval] = 0.62 [0.43, 0.89]; Q5, 0.60 [0.42, 0.86]). A statistically significant inverse association was also observed for total omega-3 as a continuous variable. Compared to participants at Q1 of DHA, those at Q5 of non-DHA showed a significant lower risk of EOD. A statistically significant lower risk was observed in Q3, Q4 and Q5 of non-DHA omega-3. Finally, we observed no evidence of interaction omega-3 × APOE-ε4 allele load.

CONCLUSIONS: This study expands the evidence of a beneficial association of omega-3 and LOD to EOD as well. These findings suggest that an increased intake of omega-3 fatty acids earlier in life may slow the development of EOD. Additional research is needed to confirm our findings, particularly in more diverse populations.},
}

@article {pmid41505703,
year = {2025},
author = {Pike, JR and Lu, Y and Walker, KA and Sullivan, KJ and Griswold, ME and Thyagarajan, B and Mielke, MM and Lutsey, PL and Hughes, TM and Knopman, DS and Sharrett, AR and Mosley, TH and Gottesman, RF and Jack, CR and Coresh, J and Palta, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106603},
doi = {10.1002/alz70856_106603},
pmid = {41505703},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Female ; Male ; Aged ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; Magnetic Resonance Imaging ; Middle Aged ; *Alzheimer Disease/blood/pathology ; Neurofilament Proteins/blood ; Aged, 80 and over ; Glial Fibrillary Acidic Protein/blood ; *Brain/pathology/diagnostic imaging ; Longitudinal Studies ; Cognitive Dysfunction/blood ; },
abstract = {BACKGROUND: Plasma biomarkers show promise as a noninvasive method for measuring Alzheimer's disease pathology and neurodegeneration throughout the lifecourse. However, the relationship between longitudinal changes in these biomarkers and late-life brain morphology in community-dwelling populations requires further investigation.

METHOD: Between 2011 and 2013, 1,977 participants from the Atherosclerosis Risk in Communities Study received an adjudicated cognitive diagnosis and underwent 3 Tesla magnetic resonance imaging scans. Whole-brain cortical thickness was quantified by Freesurfer. Stored plasma samples collected in midlife (1993-95, mean age 59.0 years) and late-life (2011-13, mean age 76.8 years) from a subsample of 1,515 participants were assayed in 2022 using Quanterix SiMoA. The assay quantified amyloid-β (Aβ)42/40, phosphorylated tau at threonine 181 (p-Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Linear regression models estimated the association of plasma biomarkers from midlife, late-life, and the change from midlife to late-life with cortical thickness in late-life. Interactions and effect modification by age were examined in exploratory analyses.

RESULT: The sample (Table 1) included 920 (60.7%) women, 387 (25.5%) Black participants, 513 (33.9%) participants with mild cognitive impairment, and 85 (5.6%) participants with dementia. The average age in late-life was 76.8 (5.3 SD) years and the average cortical thickness was 2.27 (0.11 SD) millimeters. Cortical thickness was lower in individuals with adjudicated mild cognitive impairment or dementia compared to individuals without cognitive impairment (2.25 mm versus 2.29 mm, p <0.0001). In models adjusted for demographics, lifestyle factors, cardiovascular factors, and the presence of APOE ε4 alleles, higher midlife measures of p-Tau181 and increases from midlife to late-life in NfL and GFAP were associated with lower cortical thickness in late-life (Table 2). Concurrent measures of plasma biomarkers in late-life were associated with lower cortical thickness (Table 2) and exhibited a stronger association among participants ≥75 years compared to <75 years (Table 3).

CONCLUSION: Plasma biomarkers of Alzheimer's disease pathology and neurodegeneration obtained in midlife and late-life were associated with late-life differences in cortical thickness. Additional longitudinal research is needed to determine whether plasma biomarkers predict cortical thinning over time and may serve as an early indicator of accelerated brain atrophy.},
}

Humans
*Biomarkers/blood
Female
Male
Aged
tau Proteins/blood
Amyloid beta-Peptides/blood
Magnetic Resonance Imaging
Middle Aged
*Alzheimer Disease/blood/pathology
Neurofilament Proteins/blood
Aged, 80 and over
Glial Fibrillary Acidic Protein/blood
*Brain/pathology/diagnostic imaging
Longitudinal Studies
Cognitive Dysfunction/blood

@article {pmid41505679,
year = {2025},
author = {Arnold, D and Machado, LS and Rahmouni, N and Therriault, J and Servaes, S and Stevenson, J and Macedo, AC and Schumacher-Schuh, AF and Mattjie, C and Lussier, FZ and Chamoun, M and Bezgin, G and Benedet, AL and Pascoal, TA and Barros, RC and Bastiani, M and Rosa-Neto, P and Zimmer, ER and Borelli, WV and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105937},
doi = {10.1002/alz70856_105937},
pmid = {41505679},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging/cerebrospinal fluid ; Female ; Male ; *Biomarkers/cerebrospinal fluid ; *tau Proteins/cerebrospinal fluid ; Aged ; *Machine Learning ; Positron-Emission Tomography ; *Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Prediction of Alzheimer's disease (AD) biomarkers can improve public health strategies, especially if achieved with easily collectable data in a single consultation. Machine learning (ML) offers versatile tools for clinical and research applications. This study investigated a ML model's ability to predict amyloid and tau positivity using easily obtainable features.

METHOD: Individuals with amyloid and tau status were selected from ADNI, TRIAD, and PPMI datasets (Model Building) and from the NACC dataset (Validation). Shared clinical features included age, sex, education, clinical diagnosis, MoCA scores, and BMI. Amyloid positivity was defined by amyloid-PET (PIB-PET, FBB-PET, or AZD4694-PET) or CSF AB42, and tau positivity by Tau-PET (MK6240-PET, AV1451-PET) or CSF p-tau181. For NACC, positivity derived from fields AMYLPET and TAUPETAD. Data processing is summarized in Figure 1.

RESULT: The Model Building sample included 1593 individuals (mean MoCA 25.3 ± 4.3). The Validation cohort included 861 individuals (mean MoCA 22.2 ± 2.8). The model achieved high performance for predicting amyloid and tau positivity, with mean AUCs of 0.89 and 0.83 for Model Building and Validation, respectively (Figure 2a, 2b). In Validation, high sensitivity (0.93) came at the expense of specificity (0.65), while Model Building showed balanced sensitivity and specificity (0.81 and 0.83). Higher age, lower MoCA, cognitive impairment, female sex, and lower BMI increased the probability of positivity (Figure 2c, 2d). Cognitive impairment was the most impactful feature in both Model Building and Validation datasets, followed by MoCA and age (Figure 2e, 2f).

CONCLUSION: Predicting AD biomarkers using ML and readily collectable features is feasible and accurate. The model's high sensitivity indicates a potential research utility in clinical trials for population screening to minimize false negatives. Future efforts should enhance generalizability, explore additional features, and prioritize real-world validation.},
}

Humans
*Alzheimer Disease/diagnosis/diagnostic imaging/cerebrospinal fluid
Female
Male
*Biomarkers/cerebrospinal fluid
*tau Proteins/cerebrospinal fluid
Aged
*Machine Learning
Positron-Emission Tomography
*Amyloid beta-Peptides/cerebrospinal fluid/metabolism
Middle Aged
Aged, 80 and over

@article {pmid41505674,
year = {2025},
author = {Gillespie, NA and Neale, MC and Castro-de-Araujo, LFS and Barlow, J and Rissman, RA and Vo, TT and Bell, TR and Reynolds, CA and Franz, CE and Kremen, WS and Panizzon, MS and Elman, JA and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105865},
doi = {10.1002/alz70856_105865},
pmid = {41505674},
issn = {1552-5279},
mesh = {Humans ; Male ; *Biomarkers/blood ; Middle Aged ; Aged ; *tau Proteins/blood ; *Alzheimer Disease/blood/genetics/diagnosis ; },
abstract = {BACKGROUND: Plasma phosphorylated tau at threonine 231 (pTau231) is a promising Alzheimer's disease biomarker, especially for preclinical stages, though early measurements often fall below detection limits. Assay detection limits create left-censored data that can bias biomarker heritability estimates and associations with other variables. Standard approaches such as treating values as continuous, setting censored values to zero, or coding them as missing can bias results. We developed a model to estimate heritability that integrates censored and uncensored observations, providing a framework for analyzing left-censored biomarker data.

METHOD: We analyzed plasma pTau231 data from Quanterix Simoa assays of 1,071 male twins aged 60-73 years within the Vietnam Era Twin Study of Aging. Our Integrated Censored and Uncensored (ICU) model treats observations below the limit of detection (LOD=0.621 pg/mL) as ordinal data and above-limit values as continuous measures before decomposing variance into additive genetic effects, shared environmental factors common to twins, and unique environmental influences specific to each twin.

RESULT: Using our ICU model adjusted for site and storage time covariates, we found that plasma pTau231 was moderately heritable, with additive genetic influences explaining 38% of the variance (95% CI: 0.26-0.48), while unique environmental influences explained the remaining 62%. Different approaches to handling censored data produced varying results, with some methods suggesting no genetic influence. Simulation studies will demonstrate conditions where the ICU maintains reliable performance while other approaches may produce biased estimates.

CONCLUSION: Our ICU modeling strategy offers a theoretically grounded approach for estimating heritability from left-censored biomarker data without requiring arbitrary decisions about censored values. These findings have implications for genetic association studies and other biomarker analyses - appropriate handling of censored values is crucial since different approaches can substantially alter estimates of genetic influence, potentially leading to spurious or missed genetic associations. The moderate heritability of plasma pTau231 supports its potential as an AD biomarker while suggesting substantial environmental influence on individual differences. Reference 1. Snieder, H., Boomsma, D.I., Van Doornen, L.J., Neale, M.C. (1999) Bivariate genetic analysis of fasting insulin and glucose levels. Genet Epidemiol. 16:426-446.},
}

Humans
Male
*Biomarkers/blood
Middle Aged
Aged
*tau Proteins/blood
*Alzheimer Disease/blood/genetics/diagnosis

@article {pmid41505669,
year = {2025},
author = {Nafash, MN and Svirsky, SE and Zeng, X and Chen, Y and Gogola, A and Kofler, JK and Tudorascu, DL and Shaaban, CE and Lingler, JH and Pascoal, TA and Klunk, WE and Villemagne, VL and Berman, SB and Sweet, R and Ikonomovic, MD and Snitz, BE and Kamboh, MI and Cohen, AD and Lopez, OL and Okonkwo, DO and Puccio, AM and Karikari, TK},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106909},
doi = {10.1002/alz70856_106909},
pmid = {41505669},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood/cerebrospinal fluid ; *tau Proteins/blood/cerebrospinal fluid ; Male ; Female ; *Alzheimer Disease/blood/diagnosis/cerebrospinal fluid ; *Brain Injuries, Traumatic/blood/cerebrospinal fluid ; Reproducibility of Results ; Aged ; Middle Aged ; Cohort Studies ; },
abstract = {BACKGROUND: BD-tau has emerged as a promising biomarker in predicting Alzheimer's disease-specific neurodegeneration. However, to our knowledge, there is only one commercially available but not fully validated assay, the BD-tau Advantage Plus kit (BD-tau Adv Plus) from Quanterix, for measuring BD-tau in plasma. This study aims to validate BD-tau Adv Plus, both analytically and clinically, to evaluate its reliability as a blood-based BD-tau assay for clinical research.

METHOD: Using the Quanterix® Simoa HD-X analyzer, we evaluated the following analytical metrics: selectivity, recovery, dilution linearity, sample stability, and LLOQ. We also compared BD-tau levels in plasma versus serum using blood collected from participants (n = 48) enrolled in the Pittsburgh Alzheimer's Disease Research Center (Pitt-ADRC) to determine the matrix effect. Finally, we used a Pittsburgh traumatic brain injury (TBI) cohort with plasma (n = 64) and CSF (n = 20) samples to evaluate its clinical performance in TBI settings.

RESULT: Repeated measurements of 3 plasma samples across 18 analytical runs indicated average intra-plate and inter-plate CVs at 8.00% and 4.34%, respectively. An average drift of 11.1% (decrease) was observed from the start to the end of a full plate run. Robust linearity was observed between 4 to 16-fold dilutions. Spiked recovery experiments showed high recoveries when spiked at 140 pg/ml (89.3%) and 75 pg/ml (88.5%) but low when spiked at 9 pg/ml (27.8%). Sample stability tests showed a slight increasing trend with increasing freeze/thaw cycles. BD-tau Adv Plus showed strong selectivity towards BD-tau against peripheral-tau (PNS-tau), with drastically lower signals in samples spiked with PNS-tau compared to BD-tau. Strong positive correlations were observed between plasma and serum in the Pitt-ADRC cohort (r = 0.8392; p <0.0001), as well as between plasma and CSF (n =  20 pairs, r=0.6150, p = 0.0039) in the TBI cohort. Lastly, BD-tau effectively distinguished severe-acute TBI, chronic-mixed TBI, and control groups. In severe TBI patients, significant correlations were observed between BD-tau and classical AD/TBI biomarkers such as, p-tau217 (plasma: r=0.5761, p = 0.0005; CSF: r=0.9667, p = 0.0002 in CSF), NfL (plasma: r=0.8910, p = 0.0001), and GFAP (plasma: r=0.5424, p = 0.0011).

CONCLUSION: The BD-tau Advantage PLUS kit produced robust BD-tau readings that were proven reliable in detecting TBI and distinguishing injury severity.},
}

Humans
*Biomarkers/blood/cerebrospinal fluid
*tau Proteins/blood/cerebrospinal fluid
Male
Female
*Alzheimer Disease/blood/diagnosis/cerebrospinal fluid
*Brain Injuries, Traumatic/blood/cerebrospinal fluid
Reproducibility of Results
Aged
Middle Aged
Cohort Studies

@article {pmid41505658,
year = {2025},
author = {Xiong, C and Luo, J and Wolk, DA and Shaw, LM and Roberson, ED and Bateman, RJ and Morris, JC and Schindler, SE},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106922},
doi = {10.1002/alz70856_106922},
pmid = {41505658},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; *Amyloid beta-Peptides/blood ; Female ; *Alzheimer Disease/blood/genetics ; Aged ; Cross-Sectional Studies ; Black or African American ; White People ; *Peptide Fragments/blood ; Aged, 80 and over ; Middle Aged ; Cohort Studies ; White ; },
abstract = {BACKGROUND: Whereas longitudinal data are needed to pinpoint the exact age when individuals become positive for biomarkers of Alzheimer disease (AD), cross-sectional data can be used to examine the typical age of biomarker positivity across groups. Using cross-sectional data, we estimated the age when groups of self-identified Black and White individuals reached a threshold for plasma Aβ42/40 positivity.

METHODS: We assembled plasma samples and data from a large cohort of 324 Black or African American and 1,547 White individuals from three AD Research Centers (Washington University, University of Pennsylvania, and University of Alabama at Birmingham). Plasma Aβ42/40 was measured with C2N Diagnostics mass spectrometry-based assays. Locally estimated scatterplot smoothing (LOESS) was used to estimate the mean levels of plasma Aβ42/40 as a nonparametric function of age. Statistical calibration was then used to estimate the age when plasma Aβ42/40 reached the threshold for positivity (0.100). Analyses were performed with and without matching the Black and White groups by major AD covariates, and also in groups with and without comorbidities.

RESULTS: Unmatched analyses revealed an estimated age at plasma Aβ42/40 positivity of 69.6 years for the group of White participants and 86.9 years for the group of Black participants. Black participants (n = 317) were then matched 1:2 with White participants (n = 634) by age, sex, APOE ε4 carrier status, global Clinical Dementia Rating (CDR) (CDR=0, 0.5, >=1), and years of education (>12 years vs. <=12 years). The matched analyses estimated an age at plasma Aβ42/40 positivity of 68.4 years for the group of White participants and 86.9 years for the group of Black participants. Interestingly, participants with hypertension, stroke, or diabetes had a later age at plasma Aβ42/40 positivity.

CONCLUSIONS: The typical age at plasma Ab42/40 positivity may depend on racialized group and also medical comorbidities. These results are consistent with recent reports that groups of Black individuals have a lower incidence of AD biomarker positivity compared to groups of White individuals. These findings may aid design and analyses of future clinical trials of AD.},
}

Humans
*Biomarkers/blood
Male
*Amyloid beta-Peptides/blood
Female
*Alzheimer Disease/blood/genetics
Aged
Cross-Sectional Studies
Black or African American
White People
*Peptide Fragments/blood
Aged, 80 and over
Middle Aged
Cohort Studies
White

@article {pmid41505651,
year = {2025},
author = {Almanza, DLV and Trevisiol, A and Koletar, MM and Hill, M and McLaurin, J and Stefanovic, B and Stanisz, G},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106905},
doi = {10.1002/alz70856_106905},
pmid = {41505651},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/diagnostic imaging/complications/pathology/physiopathology ; Magnetic Resonance Imaging ; *Hippocampus/diagnostic imaging/blood supply/physiopathology ; Biomarkers ; Rats ; *Obesity ; Disease Models, Animal ; Male ; Rats, Inbred F344 ; Rats, Transgenic ; },
abstract = {BACKGROUND: Interaction of Alzheimer's Disease (AD) pathology and vascular comorbidities is difficult to study in humans due to slow course of AD and high prevalence of patients with mixed pathologies. Vascular comorbidities (e.g., with obesity) are highly prevalent and increase the risk of developing dementia. There is thus a pressing need to examine experimental AD models incorporating obesity and to establish sensitive and translational imaging assays therein.

METHOD: TgF344-AD (TgAD) rats and their non-transgenic (nTg) littermates were given three months ad lib access to high carbohydrate high fat (HCHF) food items, so as to imitate the highly palatable foods consumed in the obesogenic population, before MR imaging them at 12 months of age (established AD). Pseudo continuous arterial spin labeling (pCASL) MRI was utilized to establish an assay of hippocampal neurovascular compromise and its sensitivity to AD and its interaction with obesity.

RESULT: In CHOW-fed cohorts, hippocampal functional hyperemia (CBF change and volume of activation) in response to electrical stimulation of the forepaw was attenuated in TgAD rats (CBF change: 7 ± 14 ml/100g/min and volume of activation: 0.03 ± 0.08) relative to nTg rats (CBF change: 49 ± 21 ml/100g/min, p = 0.029 and volume of activation: 0.34 ± 0.14, p <0.001). In contrast, the functional hyperemia was enhanced with HCHF diet in TgAD rats (CBF change: 60 ± 26 ml/100g/min, p <0.001 and volume of activation: 0.25 ± 0.15, p <0.001).

CONCLUSION: The observed rescue of functional hyperemia with HCHF in established AD, but not in normal aging, is speculated to result from metabolically dysregulated AD brain profiting from calorie-dense food consumption. This work demonstrates a non-invasive neuroimaging assay to assess hippocampal neurovascular function in AD and its vascular comorbidities, offering high translational potential. This assay affords ease of delivering somatosensory stimuli and limited effect of aging and neurodegeneration on somatosensation, making somatosensory protocol a particularly easy one to deploy in patients.},
}

Animals
*Alzheimer Disease/diagnostic imaging/complications/pathology/physiopathology
Magnetic Resonance Imaging
*Hippocampus/diagnostic imaging/blood supply/physiopathology
Biomarkers
Rats
*Obesity
Disease Models, Animal
Male
Rats, Inbred F344
Rats, Transgenic

@article {pmid41505649,
year = {2025},
author = {Dang, C and Kang, MJ and Eratne, D and Velakoulis, D},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106010},
doi = {10.1002/alz70856_106010},
pmid = {41505649},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Biomarkers/blood ; *Glial Fibrillary Acidic Protein/blood ; *tau Proteins/blood ; Aged ; *Neurofilament Proteins/blood ; *Alzheimer Disease/blood ; *Stress, Psychological/blood ; Middle Aged ; Depression/blood ; *Psychological Distress ; },
abstract = {BACKGROUND: Symptoms of depression, anxiety and stress have been associated with biomarkers of Alzheimer's disease and neurodegeneration, as well as increased risk of poor mental health and dementia. Understanding how these relationships vary across clinical groups may provide insight into modifiable risk factors and potential intervention strategies for neurodegenerative disease.

METHOD: Participants were from the MiND Study (N = 98; control=62, ND=18, PPD=18). Multiple regression analyses examined relationships between psychological distress (DASS-21 total score) and blood-based biomarkers (neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and p-tau217)), with diagnostic group as a moderator. Covariates included age, sex, and weight.

RESULT: Psychological distress levels significantly differed across all diagnostic groups (all p <.013), with the highest levels in PPD and the lowest in controls. When also controlling for psychological distress, NfL was significantly higher for ND compared to control (p = .005) and PPD (p <.001) but did not differ between control and PPD (p = .161). GFAP levels were not significantly different between groups (all p >.300). p-tau217 was higher for ND compared to controls (p = .012) but not PPD (p = .078). No difference was observed between controls and PPD (p = .701). Psychological distress was associated with higher NfL for controls (b=.006, p = .009) but not for ND (p = .320) or PPD (p = .626), indicating a moderating effect of diagnostic group (p = .012). Psychological distress was significantly associated with higher GFAP for controls (b=.005, p = .027) and PPD (b=.004, p = .016), but not for ND (p = .032). The interaction was non-significant. Psychological distress did not predict p-tau217 for any diagnostic group.

CONCLUSION: Psychological distress being associated with higher NfL and GFAP for controls suggests that distress may have harmful effects on brain health even in the absence of neurodegenerative or psychiatric conditions, highlighting the importance of mental health as a modifiable risk factor for future neurodegeneration. The observed association between psychological distress and GFAP for PPD is consistent with prior research, which links chronic stress and psychiatric conditions to increased neuroinflammation. In contrast, the lack of an association between psychological distress and p-tau217 reinforces its role as an Alzheimer's Disease-specific biomarker, independent of psychological distress. Longitudinal research is needed to determine whether distress-related neurobiological changes contribute to future neurodegeneration.},
}

Humans
Male
Female
*Biomarkers/blood
*Glial Fibrillary Acidic Protein/blood
*tau Proteins/blood
Aged
*Neurofilament Proteins/blood
*Alzheimer Disease/blood
*Stress, Psychological/blood
Middle Aged
Depression/blood
*Psychological Distress

@article {pmid41505616,
year = {2025},
author = {Estragués-Gázquez, I and Contador, J and Martinez, LD and Fernández-Lebrero, A and Iaccarino, G and Garcia-Escobar, G and Manero-Borràs, RM and Navalpotro-Gómez, I and Grau-Rivera, O and Ortiz-Romero, P and Diego-Osaba, M and Blasco-Forniés, H and Jiménez-Moyano, E and Torres-Torronteras, J and Sánchez, JJH and Padrós, A and Villoslada, P and Del Campo, M and Puig-Pijoan, A and Suarez-Calvet, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106918},
doi = {10.1002/alz70856_106918},
pmid = {41505616},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Female ; *Alzheimer Disease/blood/diagnosis ; Male ; Aged ; Prospective Studies ; *tau Proteins/blood ; Middle Aged ; Spain ; Aged, 80 and over ; },
abstract = {BACKGROUND: Blood-based biomarkers (BBMs) offer a cost-effective, non-invasive approach for detecting Alzheimer's disease (AD) pathology, but their impact on improving diagnostic certainty and patient management remains unclear. The PLASMAR study is a prospective, single-center, blinded, randomized controlled trial assessing the effect of early versus delayed BBM adoption on clinical practice in a public hospital memory clinic. This abstract presents an interim analysis on changes in patient management.

METHOD: From February to October 2024, 224 patients with cognitive or behavioral complaints (GDS 2-4) referred to the memory clinic at Hospital del Mar (Barcelona, Spain) were prospectively enrolled. Eligibility criteria are detailed in Table 1. At baseline, blood samples were collected for BBMs, and neurologists assessed diagnostic confidence based on routine clinical evaluation without BBM results. Participants were randomized to the Early (BBM results disclosed at 3 months) or Late (disclosed at 9 months) arms. Patient management changes were compared between arms. Plasma p-tau217 levels, classified by validated cutoffs, stratified patients into low, intermediate, or high risk for AD pathology.

RESULT: Of 224 enrolled patients, 27 were lost to follow-up, leaving 197 participants (mean age 71.6 ± 8.9 years; 56.9% female). There were no demographic differences between study arms. Initial diagnoses included SCD (44.7%), MCI (31.4%), or dementia (21.3%), with AD suspected in 30%. By December 2024, 114 patients (87 Early, 27 Late) had BBM results disclosed. AD risk was classified as low (52.4%), intermediate (17.5%), or high (30%). At 3-months follow-up, Early-arm patients had higher discharge rates and initiated AchEIs sooner (p <0.01), while Late-arm patients more frequently received longitudinal cognitive monitoring (p <0.01). Among SCD patients, Early-arm participants had higher discharge rates and underwent more lumbar punctures for CSF biomarkers according to their AD pathology risk (p <0.05), while Late-arm patients were more likely to undergo cognitive monitoring (p <0.001). Among MCI patients, Early-arm participants had higher discharge rates (p <0.01). Similar trends were observed in the low-risk AD group (p <0.05).

CONCLUSION: This interim analysis demonstrates that early disclosure of BBM results influences patient management and accelerates the initiation of specific AD treatments, also reducing the need for follow-up of cognitive assessments.},
}

Humans
*Biomarkers/blood
Female
*Alzheimer Disease/blood/diagnosis
Male
Aged
Prospective Studies
*tau Proteins/blood
Middle Aged
Spain
Aged, 80 and over

@article {pmid41505615,
year = {2025},
author = {Kerchove, AVD and Mlinarič, T and Verovnik, B and Barinaga, ZI and Hulle, MV},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105377},
doi = {10.1002/alz70856_105377},
pmid = {41505615},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis/physiopathology ; *Electroencephalography/methods ; *Frontotemporal Dementia/diagnosis/physiopathology ; *Biomarkers ; Machine Learning ; Male ; Female ; Aged ; *Brain/physiopathology ; Diagnosis, Differential ; Middle Aged ; },
abstract = {BACKGROUND: Frontotemporal dementia (FTD) is frequently misdiagnosed as Alzheimer's disease (AD) due to their overlapping symptoms, leading to a decreased quality of life and misallocation of resources. Research indicates that neuroimaging techniques outperform cognitive tests in differentiating between these conditions, with electroencephalography (EEG) offering a cost-effective, accessible, and faster alternative. Moreover, resting-state EEG is less taxing on patients, which is particularly important for those with cognitive impairments. While EEG-based classification between AD and healthy controls (HC), as well as FTD and HC, has shown promising results, accurately distinguishing AD from FTD remains challenging. Functional connectivity (FC) graphs are key features used to construct machine learning (ML) models for this problem. However, most of the research using ML with FC features has been conducted using flat Euclidean metrics, even though some connectivity graphs naturally reside on non-Euclidean manifolds. Riemannian geometry provides a more suitable framework for analysing and classifying complex data structures, like some FC graphs, enhancing ML performance.

METHOD: We propose a classification strategy using Riemannian geometry and resting-state EEG to differentiate between AD, FTD, and HC (Figure 1). This method utilizes stacked generalization to combine predictions obtained by a set of Riemannian geometry classifiers each trained on one of various FC features across different frequency bands (delta, theta, alpha, beta, gamma). A logistic regression meta-classifier combined with sequential feature selection is used to reach a decision based on the predictions per FC feature.

RESULT: Our proposed model was evaluated on an openly available dataset (doi:10.18112/openneuro.ds004504.v1.0.7) with 36 AD, 23 FTD, and 29 HC age-matched subjects. Leave-one-subject-out cross validation yielded the following classification performances for 3 binary classification problems while accounting for class imbalance: AD/FTD: 74%, AD/HC: 85%, FTD/HC: 74%.

CONCLUSION: By using smaller, efficient models that account for data geometry and a meta-classifier, our proposed method reaches good performance while allowing for enhancement through alternative feature selection and hyperparameter optimization. Additionally, our method identifies the most informative FC graphs for classification, which are valuable for model interpretation and can provide specific distinctive neural signals that can be used in future research to develop diagnostic tools.},
}

Humans
*Alzheimer Disease/diagnosis/physiopathology
*Electroencephalography/methods
*Frontotemporal Dementia/diagnosis/physiopathology
*Biomarkers
Machine Learning
Male
Female
Aged
*Brain/physiopathology
Diagnosis, Differential
Middle Aged

@article {pmid41505606,
year = {2025},
author = {Leo, H and Gills, JL and Bubu, OM and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106888},
doi = {10.1002/alz70856_106888},
pmid = {41505606},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Aged ; Male ; Female ; Cross-Sectional Studies ; *Amyloid beta-Peptides/blood ; *Alzheimer Disease/blood/diagnosis ; *tau Proteins/blood ; Proteomics ; Cohort Studies ; },
abstract = {BACKGROUND: Plasma biomarkers like Aβ42/Aβ40, p-tau isoforms, and NfL are crucial for assessing Alzheimer's disease (AD) pathology. Advanced platforms such as SomaScan 11k, Olink 5k, and ALAMAR (NULISA-based) enable precise protein measurement. We examined associations between Alamar's NULISA proteins related to AD (ATN & I) with SomaScan and Olink proteins and conducted pathway enrichment analysis to identify proteomic profiles linked to AD biomarkers.

METHOD: This cross-sectional study used plasma samples from 116 ARIC cohort participants (age 74.3 ± 4.7 years, 88.8% cognitively normal). ATN & I biomarkers included: A (Aβ proteinopathy) - Aβ-42, Aβ-40, and Aβ-42/40; T (phosphorylated and secreted AD tau) - p-tau217, p-tau181, p-tau231 and their ratios with Aβ-42; N (neuropil injury) - NfL and Total Tau; and I (inflammation) - GFAP. Biomarkers were quantified using the ALAMAR NULISA platform and compared to SomaScan 11k and Olink 5k data. Cross-platform correlations and pathway enrichment analyses (KEGG library) were conducted. Bonferroni correction adjusted for multiple comparisons, and analyses were adjusted for age, sex, APOE ε4 status, and glomerular filtration rate.

RESULT: There were 3,418 proteins (92 with unique IDs) across SomaScan, Olink, and NULISA platforms. Aβ42 had the most intersecting proteins (268), NEFL had 146, and GFAP had 57. Between Alamar and Olink, Aβ40 had 456 significantly correlated proteins, NEFL had 379, and Aβ42 had 359 after Bonferroni adjustment (p < .00001). Between Alamar and SomaScan, Aβ40 had 408 and Aβ42 had 351 significantly correlated proteins (p < .00001). In Olink pathway enrichment, Aβ42/40 had the most correlated pathways, while in SomaScan, Ptau231 had the most. Common pathways included cytokine-cytokine interaction, insulin signaling, MAPK signaling, cell adhesion, and endocytosis.

CONCLUSION: Our analysis identified shared proteomic profiles associated with AD biomarkers across multiple proteomic platforms. The Alamar ATN & I plasma biomarkers demonstrated moderate to strong correlations with Olink 5k and Soma 11k proteins subserving muscular integrity, inflammation, kidney function, cell membrane integrity, fatty acid degradation. Cytokine-cytokines and axonal pathways were among the highest correlated pathways among the ATN & I biomarkers across Olink and Soma platforms. Future investigations should examine tissue specific pathways in older individuals across the AD continuum.},
}

Humans
*Biomarkers/blood
Aged
Male
Female
Cross-Sectional Studies
*Amyloid beta-Peptides/blood
*Alzheimer Disease/blood/diagnosis
*tau Proteins/blood
Proteomics
Cohort Studies

@article {pmid41505596,
year = {2025},
author = {Izydorczak, AM and Farinas, MF and Zeng, X and Sehrawat, A and Klunk, WE and Pascoal, TA and Cohen, AD and Villemagne, VL and Tudorascu, DL and Shaaban, CE and Lingler, JH and Snitz, BE and Abrahamson, EE and Berman, SB and Kofler, JK and Ikonomovic, MD and Kamboh, MI and Lopez, OL and Karikari, TK},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106861},
doi = {10.1002/alz70856_106861},
pmid = {41505596},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/blood/genetics ; Male ; Female ; Presenilin-1/genetics ; Aged ; Mutation/genetics ; Middle Aged ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; Aged, 80 and over ; Cohort Studies ; },
abstract = {BACKGROUND: A major pathological hallmark of Alzheimer's disease (AD) is plaque deposition of amyloid-β (Aβ) peptide which is cleaved from a larger Aβ precursor protein (APP). One of the most common causes of autosomal dominant AD (ADAD) are mutations in the PSEN1 gene, encoding a component of γ-secretase, which alter APP processing and increase the production and aggregation potential of Aβ. However, the impact of PSEN1 mutations on blood biomarker levels of neurodegeneration-related proteins is largely unexplored.

METHOD: We applied a novel Nucleic Acid Linked Immuno-Sandwich Assay (NULISA), the NULISAseq CNS Disease Panel, to quantify 127 key neurodegenerative proteins in plasma samples from a cohort consisting of ADAD cases with PSEN1 mutations (n = 6), neuropathologically diagnosed sporadic AD (sAD; n = 8), and cognitively unimpaired controls (n = 7). Normalized protein quantification (NPQ) was used as a proxy for protein levels. Statistical comparisons were performed using the Kriskal-Wallis and Wilcoxon rank-sum tests. Spearman correlation was employed to evaluate the association between NULISA and Single Molecule Array (SIMOA)-based measurements.

RESULT: The NULISA had high detectability (95.5% ± 13.6%) and reproducibility (median intra-plate coefficient of variation [CV]=6.3%). NULISA and SIMOA correlated robustly for p-tau181, p-tau217, GFAP, NfL, and Aβ42 (Spearman coefficients ρ range 0.721 to 0.947), but less so for Aβ40 (ρ=0.302). Total-tau (MAPT), p-tau181, p-tau217, and p-tau231 were among the proteins most significantly different across the sample groups (p values range 0.001 to 0.003), followed by NfL, NfH, CCL2, GFAP, and PDGFRB (p values range 0.005 to 0.046). Several targets, including NfH (p = 0.001), CCL11 (p = 0.013), CHIT1 (p = 0.021), PDGFRB (p = 0.029), PTN (p = 0.029), and CNTN2 (p = 0.043), showed statistically significant differences between ADAD and sAD.

CONCLUSION: Proteomic profiling of key neurodegenerative proteins in plasma revealed significant differences among the sample groups and include identified targets that can distinguish ADAD from sAD. Further validation with larger cohorts is needed to confirm these findings.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/blood/genetics
Male
Female
Presenilin-1/genetics
Aged
Mutation/genetics
Middle Aged
tau Proteins/blood
Amyloid beta-Peptides/blood
Aged, 80 and over
Cohort Studies

@article {pmid41505595,
year = {2025},
author = {McLachlan, M and Bettcher, B and McVea, AK and Zammit, MD and LeMerise, L and Rouanet, JP and Price, JC and Tudorascu, DL and Laymon, CM and Keator, DB and Lao, PJ and Brickman, A and Fryer, TD and Hartley, SL and Ances, B and Rosas, HD and Johnson, SC and Betthauser, TJ and Stone, CK and Zaman, S and Handen, BL and Head, E and Mapstone, M and Christian, BT},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106826},
doi = {10.1002/alz70856_106826},
pmid = {41505595},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Middle Aged ; *Down Syndrome/diagnostic imaging/metabolism/pathology ; tau Proteins/metabolism ; Aniline Compounds ; *Alzheimer Disease/diagnostic imaging ; *Neurofibrillary Tangles/pathology/metabolism ; Carbolines ; Adult ; *Brain/diagnostic imaging/metabolism/pathology ; Aged ; Longitudinal Studies ; Ethylene Glycols ; Disease Progression ; },
abstract = {BACKGROUND: Previous work in the Down syndrome (DS) population has revealed early and accelerated accumulation of Alzheimer's disease (AD) pathology when compared with neurotypical adults. Temporal models of [[11]C]PiB PET beta-amyloid (Aβ) trajectories aligned with the progression of [[18]F]flortaucipir neurofibrillary tau (NFT) burden through Braak-associated regions (Zammit 2023). These analyses were extended to a larger DS cohort that includes individuals who underwent Aβ imaging with [[18]F]florbetapir. This work investigated the temporal relationship between regional NFT burden and a standardized model of Aβ onset in the DS population.

METHOD: 282 participants with DS underwent longitudinal NFT and Aβ PET imaging (Table 1). PiB and florbetapir scans underwent Centiloid (CL) processing using a previously calibrated pipeline. Flortaucipir scans were realigned, summed 80-100 min, and warped into standard space. SUVR was calculated (inferior cerebellar grey reference) for Braak-associated NFT regions (described in Figure 1). Using the sampled iterative local approximation (SILA) method, the average rate of change was discretely sampled across the CL range, yielding a generalized model for amyloid progression. The estimated time-to-Aβ onset (or Aβ chronicity) was calculated for each participant by aligning their trajectories to the model. Flortaucipir SUVR and % Change were binned within discrete Aβ chronicity stages and fit to a linear mixed effects model for each region, using: SUVR or % Change ∼ Age+Sex+Scanner+APOE4+Chronicity Stage+Cognitive Status+(1|Participant) The model was used to estimate the influence of biological parameters and the relative time of significant NFT onset.

RESULT: Across all NFT regions, participants with dementia had the highest flortaucipir SUVR and latest chronicity, followed by MCI (Figure 1). SUVR was significantly increased by the 0-5 years chronicity window in NFT I and II, while NFT III-VI were not significantly increased until 5-10 years (Figure 2). % Change was significantly increased in the 0-5 years chronicity window for NFT I and in the >10 years window for NFT III-VI. Scanner, cognitive status, and age effects were significant in each region.

CONCLUSION: This work supports previous findings that NFT regions I-II demonstrate earlier increases to flortaucipir SUVR than other NFT regions when using a standardized temporal model for Aβ onset.},
}

Humans
Female
Male
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
Biomarkers/metabolism
Middle Aged
*Down Syndrome/diagnostic imaging/metabolism/pathology
tau Proteins/metabolism
Aniline Compounds
*Alzheimer Disease/diagnostic imaging
*Neurofibrillary Tangles/pathology/metabolism
Carbolines
Adult
*Brain/diagnostic imaging/metabolism/pathology
Aged
Longitudinal Studies
Ethylene Glycols
Disease Progression

@article {pmid41505532,
year = {2026},
author = {Piller, C},
title = {Fake data from trial sites ruin studies, drug firms say.},
journal = {Science (New York, N.Y.)},
volume = {391},
number = {6781},
pages = {112-114},
doi = {10.1126/science.aef2599},
pmid = {41505532},
issn = {1095-9203},
mesh = {*Drug Industry/ethics ; Humans ; *Alzheimer Disease/drug therapy ; *Clinical Trials as Topic ; United States ; *Drug Development ; Antibodies, Monoclonal, Humanized ; },
abstract = {Alzheimer's drug developer accuses companies it hired of providing "medically impossible" results.},
}

*Drug Industry/ethics
Humans
*Alzheimer Disease/drug therapy
*Clinical Trials as Topic
United States
*Drug Development
Antibodies, Monoclonal, Humanized

@article {pmid41505526,
year = {2025},
author = {Rentoumi, V and Vassiliou, E and Demiraj, A and Papageorgiou, M and Sali, D and Tsolaki, M and Papatriantafyllou, JD and Paliouras, G},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104966},
doi = {10.1002/alz70856_104966},
pmid = {41505526},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers ; *Cognitive Dysfunction/diagnosis/classification ; *Alzheimer Disease/diagnosis/classification ; Female ; Male ; Aged ; Machine Learning ; Depression/diagnosis ; Aged, 80 and over ; },
abstract = {BACKGROUND: Advances in automated language and speech analysis using machine learning have validated digital biomarkers for non-invasive detection of subtle cognitive changes. While distinguishing Alzheimer's Disease (AD) from Normal Controls (NC) is straightforward, classifying Mild Cognitive Impairment (MCI) remains challenging, due to its potential progression to AD or its association with other factors such as affective disorders, requiring detailed expert evaluation. Expanding upon prior research, this study assesses LANGaware's biomarker capabilities on recent data for (a) binary classification of AD versus NC, (b) multi-class classification into AD, NC, and MCI, and (c) binary classification of Depression (D) versus NC.

METHOD: Diagnoses have been collected for the above cases, provided by medical experts following standardized protocols. Participants were engaged in simple elicitation tasks, such as describing a picture or narrating an event. Digital biomarkers that reflect linguistic, speech, and acoustic features were extracted from recorded audio and corresponding transcripts. These biomarkers were then used as input for classification tasks, employing a tailored neural network and an XGBoost model to perform binary and multi-class (three-class) classifications. The methodology was designed to be easily adaptable to multiple languages.

RESULT: For cognitive classification, 15827 elicitation tasks (5173 AD, 7660 MCI, 2994 NC) from English- and Greek-speaking participants were analyzed using nested cross-validation. The binary classifier (AD vs. Healthy) achieved an average F1-macro score of 89.01%, while the three-class one (AD vs. MCI vs. NC) attained a score of 73.0%. For depression classification, 4421 elicitation tasks (1481 D, 2940 NC) from English-speaking participants were evaluated, achieving an average F1-macro score of 70.38%.

CONCLUSION: The results obtained confirm the strong discriminative capability of the proposed biomarkers for the early detection of cognitive decline. The findings support the applicability of automated assessment, facilitating early diagnosis and timely intervention. Additionally, the depression classification experiment further complements the cognitive analysis, given the established link between depression and MCI. This study is crucial for ensuring the quality and reliability of the LANGaware product as it is increasingly adopted by diagnostic centers and hospitals. We express our gratitude to all organizations that contributed valuable data to this work.},
}

Humans
*Biomarkers
*Cognitive Dysfunction/diagnosis/classification
*Alzheimer Disease/diagnosis/classification
Female
Male
Aged
Machine Learning
Depression/diagnosis
Aged, 80 and over

@article {pmid41505514,
year = {2025},
author = {Honhar, P and Fu, JF and Lois, C and Garimella, A and Johnson, KA and Price, JC},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105725},
doi = {10.1002/alz70856_105725},
pmid = {41505514},
issn = {1552-5279},
mesh = {Humans ; Female ; *Positron-Emission Tomography/methods ; Male ; Middle Aged ; *Biomarkers/metabolism ; Radiopharmaceuticals ; Aged ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; *Brain/diagnostic imaging/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; },
abstract = {BACKGROUND: Honhar et al. (PMCID:10993874) reported a method for bias and noise correction in standardized-uptake value ratios (SUVR, simplified outcome), relative to distribution volume ratios (DVR, quantitative gold-standard), without the need for dynamic data outside SUVR time-window. The method performed well for rapidly-reversible radiotracers, [[18]F]FE-PE2I and [[11]C]LSN3172176 (i.e., radiotracers kinetics described by 1-tissue compartment or simplified reference tissue models). Herein, we tested this method on human [[18]F]MK-6240 PET data.

METHODS: Dynamic [[18]F]MK-6240 PET data (0-120 min) in 22 human participants (age: 61±18 y, 8 females, 16 cognitively unimpaired controls [HC], 5 mild cognitive impairment [MCI], 1 Alzheimer's disease [AD]) were reanalyzed. Metabolite-corrected arterial input functions were used to compute regional 2-tissue compartment model DVR values (reference: eroded cerebellar gray matter). Regional SUVR (80-100 min and 90-110 min) values were corrected as: SUVRC =SUVR / [1-βref/k2 ,ref+βtar SUVR/(R1 k2 ,ref)], where SUVRC: corrected SUVR, k2 ,ref: population-based rate constant for efflux of the radiotracer from reference region, [βref, βtar]: clearance rates of the radiotracer from the reference and target tissues during SUVR time-window, R1=0.75 (population-averaged value for ratio of target:reference radiotracer delivery rate). The primary outcome measures were the percent bias (%bias) in SUVR (and SUVRc) relative to DVR, and the standard deviation of %bias.

RESULTS: Across subjects and selected regions of interest (ROIs, Tables 1-3), the mean %bias was 0.9% for SUVR 80-100 min and 1.2% for SUVR 90-110 min. The variability in %bias was 13.1% for SUVR 80-100 min and 11.9% for SUVR 90-110 min. The mean %bias in SUVRc across subjects and ROIs was comparable for SUVRc 80-100 min (-1.3%) and SUVRc 90-110 min (-0.1%), with similar variability (∼11%) for SUVRc 80-100 min and SUVRc 90-110 min. Regional measures for (averaged across subjects) are listed in Tables 1-2. Similar performance metrics were observed for a subcohort analysis of 5 high-binding individuals with highest average regional DVR values (1 AD,3 MCI,1 HC).

CONCLUSIONS: [[18]F]MK-6240 SUVR in this cohort was already minimally biased; SUVRc did not significantly decrease the variability in SUVR bias. This SUVR correction method might not be beneficial for radiotracers that deviate considerably from its assumption of 1-tissue compartment model kinetics.},
}

Humans
Female
*Positron-Emission Tomography/methods
Male
Middle Aged
*Biomarkers/metabolism
Radiopharmaceuticals
Aged
*Cognitive Dysfunction/diagnostic imaging/metabolism
*Brain/diagnostic imaging/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism

@article {pmid41505498,
year = {2025},
author = {Gutstein, D and Mather, MA and Gill, NP and Barbieri, E and Sridhar, J and Lapins, A and Weintraub, S and Vassar, RJ and Geula, C and Mesulam, M and Gefen, T and Parrish, T},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106210},
doi = {10.1002/alz70856_106210},
pmid = {41505498},
issn = {1552-5279},
mesh = {Humans ; Female ; Positron-Emission Tomography ; Male ; Aged, 80 and over ; Biomarkers/metabolism ; *Memory, Episodic ; *Brain/diagnostic imaging/metabolism ; Neuropsychological Tests ; Longitudinal Studies ; Alzheimer Disease/diagnostic imaging ; Aged ; },
abstract = {BACKGROUND: SuperAgers (SAs) are individuals aged 80+ with episodic memory performance comparable to those 20-30 years younger. Preliminary examination of longitudinal neuropsychological performance suggests that, whereas many SAs maintain exceptional memory performance over time, some show gradual memory decline. Mechanisms of maintenance vs decline in SAs are not yet known but may include accumulation of the hallmark amyloid and tau pathologies of Alzheimer's disease. The current study investigated the association between PET amyloid burden in the brain and longitudinal episodic memory performance in SAs.

METHOD: A total of 14 SAs enrolled in the Northwestern University SuperAging Program received a baseline PET amyloid scan (Mage = 84.88; 36% female). Individual memory trajectories were estimated from serial scores on the Rey Auditory Verbal Learning Test (RAVLT) delayed recall measure. The weighted mean for standardized uptake value ratio (SUVR), a quantitative measure of PET amyloid burden, was derived using the Susan Landau method and the FreeSurfer toolkit (v. 7); SUVR for all but one participant fell below the binary threshold for positivity. Linear mixed effects models accounting for PET tracer, sex, and age assessed the relationship between baseline SUVR and longitudinal memory performance.

RESULT: Higher baseline SUVR was associated with a more negative longitudinal RAVLT slope (p < 0.05). However, this relationship was likely driven by the single participant with an elevated measure of PET amyloid burden (SUVR = 1.72), who also demonstrated a sharply negative slope of change in RAVLT score. When only individuals with SUVR below the positivity threshold were included, the relationship between baseline SUVR and slope of change in RAVLT over time was no longer statistically significant.

CONCLUSION: Among SAs with SUVR measures of PET amyloid burden below the positivity threshold, variance in SUVR did not predict trajectory of change in memory performance over time. While accumulation of amyloid burden above known thresholds for PET positivity may increase risk for memory decline in SAs, this relationship was not apparent at lower levels of PET amyloid burden. Future study will investigate other in-vivo markers of neurodegeneration to explore putative neuropathologic substrates of memory preservation vs decline in this unique population.},
}

Humans
Female
Positron-Emission Tomography
Male
Aged, 80 and over
Biomarkers/metabolism
*Memory, Episodic
*Brain/diagnostic imaging/metabolism
Neuropsychological Tests
Longitudinal Studies
Alzheimer Disease/diagnostic imaging
Aged

@article {pmid41505496,
year = {2025},
author = {Groot, C and Coomans, EM and Rowe, CC and Dore, V and Feizpour, A and van de Giessen, E and van der Flier, WM and Pijnenburg, YAL and Visser, PJ and den Braber, A and Pontecorvo, MJ and Burnham, SC and Kennedy, IA and Lu, M and Jagust, WJ and Baker, SL and Harrison, TM and Gispert, JD and Shekari, M and Minguillón, C and Smith, R and Mattsson-Carlgren, N and Palmqvist, S and Strandberg, O and Stomrud, E and Brickman, A and Luchsinger, JA and Manly, JJ and Lao, PJ and Kreisl, WC and Malpetti, M and O'Brien, JT and Rowe, JB and Jäger, E and Bischof, GN and Drzezga, A and Xie, F and Mao, X and Guan, Y and Garibotto, V and Frisoni, GB and Peretti, DE and Schöll, M and Skoog, I and Kern, S and Sperling, RA and Johnson, KA and Risacher, S and Saykin, AJ and Carrillo, MC and Dickerson, B and Apostolova, LG and Rabinovici, GD and Barthel, H and Rullmann, M and Messerschmidt, K and Vandenberghe, R and Laere, KV and Spruyt, L and Petersen, R and Jack, CR and Franzmeier, N and Brendel, M and Gnörich, J and Benzinger, T and Lagarde, J and Sarazin, M and Bottlaender, M and Villeneuve, S and Poirier, J and Seo, SW and Gu, Y and Kim, JP and Mormino, B and Young, CB and Vossler, H and Rosa-Neto, P and Therriault, J and Rahmouni, N and Coath, W and Cash, DM and Schott, JM and Hanseeuw, BJ and Salman, Y and Malotaux, V and Jansen, WJ and Joie, R and Rosen, HJ and Johnson, SC and Christian, BT and Betthauser, TJ and Landau, SM and O'Bryant, SE and Hansson, O and Ossenkoppele, R and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105387},
doi = {10.1002/alz70856_105387},
pmid = {41505496},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *tau Proteins/metabolism/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; Aged ; *Alzheimer Disease/diagnostic imaging/genetics/metabolism ; Positron-Emission Tomography ; Educational Status ; Cohort Studies ; *Cognitive Dysfunction/diagnostic imaging/genetics ; Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Aged, 80 and over ; Sex Factors ; Middle Aged ; Apolipoprotein E4/genetics ; },
abstract = {BACKGROUND: Sex, education and race/ethnicity are all associated with risk of Alzheimer's disease dementia. Here, we assess the effects of self-reported sex, educational attainment and race/ethnicity on amyloid-positivity, and tau-PET-positivity in 12,048 (7,394 cognitively unimpaired [CU], 2,177 MCI, and 2,477 dementia) individuals from 42 cohorts worldwide.

METHOD: Logistic generalized estimating equations were used to estimate frequency of amyloid-positivity (using cohort-specific thresholds for amyloid-PET [84%] or CSF) and tau-PET-positivity (cohort-specific thresholds of 2SD above mean temporal uptake in amyloid-negative controls). We assessed: i) sex and APOEε4 (N = 10,098) associations, to complement earlier findings of a higher frequency of tau-positivity in females, ii) effects of lower/higher education (N = 10,970; cohort-specific median-split), and iii) effects of race/ethnicity (non-Hispanic White [hereafter: White], N = 4880; Asian, N = 116; Black or African-American [hereafter: Black], N = 353; Hispanic, N = 356, only from Northern-American cohorts). Outcomes were frequency of amyloid-positivity in CU individuals only, and tau-PET-positivity in both amyloid-positive (AB+) CU and cognitively impaired (CI, i.e. MCI and dementia) individuals. Interaction effects on the relationship between age and amyloid/tau-positivity were assessed and only retained in the models when significant.

RESULT: Female sex was associated with an APOEε4-independent increased frequency of amyloid-positivity (β=0.51[0.22], p = 0.02) in CU and increase of tau-positivity in both AB+CU (β=0.27[0.08]) and AB+CI (β=0.37[0.08], both p <0.01). Remarkably, tau-positivity frequencies of female APOEε4 non-carriers were equivalent to male APOEε4 carriers in AB+CI (Figure 1). No significant sex*APOE interactions were observed. In CU, higher education was associated with lower amyloid-positivity frequency (β=-0.12[0.05], p = 0.02). In contrast, among AB+CU, there was an age*education interaction effect that indicated more pronounced age effects on tau-positivity in individuals with higher education (age*education:βinteraction=0.03[0.01], p <0.01). There were no education effects in AB+CI (Figure 2). In CU, an age*race/ethnicity interaction effect was observed across all non-White groups compared to White (Hispanic:βinteraction=-0.05[0.01], p <0.01; Black:-0.04[0.01], p <0.01; Asian:-0.02[0.01], p = 0.04). This suggests that the impact of age on amyloid-positivity was less pronounced in non-White groups. Furthermore, in AB+CI, Hispanic ethnicity was related to higher tau-positivity frequency than White (β=0.51[0.22], p = 0.02; Figure 3).

CONCLUSION: In this multi-center initiative comprised of clinical and community-based cohorts, we observed that self-reported sex, educational attainment and race/ethnicity were related to positivity-frequencies of Alzheimer's disease pathology.},
}

Humans
Female
Male
*tau Proteins/metabolism/cerebrospinal fluid
*Biomarkers/cerebrospinal fluid
Aged
*Alzheimer Disease/diagnostic imaging/genetics/metabolism
Positron-Emission Tomography
Educational Status
Cohort Studies
*Cognitive Dysfunction/diagnostic imaging/genetics
Amyloid beta-Peptides/cerebrospinal fluid/metabolism
Aged, 80 and over
Sex Factors
Middle Aged
Apolipoprotein E4/genetics

@article {pmid41505453,
year = {2025},
author = {Salajkova, Z},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106395},
doi = {10.1002/alz70856_106395},
pmid = {41505453},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging ; *Biomarkers ; Male ; Case-Control Studies ; Female ; *Retina/diagnostic imaging ; Aged ; Machine Learning ; Aged, 80 and over ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, with current diagnostic methods being limited by invasiveness and accessibility constraints. Retinal imaging has emerged as a promising non-invasive approach for detecting AD-related biomarkers, given the retina's embryonic and pathological similarities to the brain. This study explores reflectance spectral imaging of the retina as a novel biosensor for early AD detection.

METHOD: A custom-built multispectral imaging module, compatible with commercial fundus cameras, was developed to capture retinal reflectance images in blue (<520 nm), green (520-580 nm), and red (>600 nm) spectral regions. A case-control study included participants diagnosed with AD and age-matched healthy subjects. Spectral intensity ratios were extracted from the images and analyzed using machine learning models, particularly XGBoost, to classify AD and healthy subjects. SHapley Additive exPlanations (SHAP) analysis was applied to determine the most predictive spectral features.

RESULT: Significant differences in spectral intensity ratios between AD and healthy subjects were observed (p < 0.001). The XGBoost model incorporating spectral intensity ratios achieved high classification performance, with an accuracy of 82%, sensitivity of 87%, and an area under the ROC curve (AUC) of 0.89. SHAP analysis identified the blue spectral intensity as the most relevant predictor, suggesting its potential role in detecting AD-related retinal alterations.

CONCLUSION: Retinal spectral imaging offers a non-invasive, accessible, and cost-effective method for early AD screening. The integration of this approach with existing ophthalmic equipment presents a viable strategy for large-scale population screening and monitoring of disease progression. Further longitudinal studies are warranted to validate the predictive value of retinal biomarkers in preclinical AD stages.},
}

Humans
*Alzheimer Disease/diagnosis/diagnostic imaging
*Biomarkers
Male
Case-Control Studies
Female
*Retina/diagnostic imaging
Aged
Machine Learning
Aged, 80 and over

@article {pmid41505448,
year = {2025},
author = {Steward, A and Dewenter, A and Roemer-Cassiano, S and Biel, D and Zhu, Z and Frontzkowski, L and Hirsch, F and Klonowksi, M and Gnörich, J and Dehsarvi, A and Brendel, M and Franzmeier, N},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105476},
doi = {10.1002/alz70856_105476},
pmid = {41505448},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/cerebrospinal fluid/metabolism/blood ; *Alzheimer Disease/genetics/diagnostic imaging/cerebrospinal fluid/metabolism ; Biomarkers/cerebrospinal fluid/blood ; Female ; Male ; *Apolipoprotein E4/genetics ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Aged ; Positron-Emission Tomography ; Aged, 80 and over ; Cross-Sectional Studies ; Alleles ; Brain/diagnostic imaging/metabolism ; },
abstract = {BACKGROUND: Understanding factors influencing Alzheimer's disease (AD) progression is crucial for optimising treatment timing and targets. A major genetic risk factor, the Apolipoprotein E ε4 allele (ApoE4), is associated with earlier tau pathology accumulation and spread at lower amyloid-beta (Aβ) levels (Steward, JAMA Neurol, 2023). However, the mechanisms underlying this association remain unclear (Figure 1A). Therefore, we assessed how ApoE4 accelerates Aβ-related tau aggregation. Specifically, we investigated whether ApoE4 promotes Aβ-driven secretion of phospho tau (p-tau) or ptau dependent tau aggregation, and determined whether ApoE4 promotes tau pathology in an allele dose-dependent manner.

METHOD: We analysed data from APOE-genotyped AD-spectrum participants in the ADNI (n = 201) and A4 cohorts (n = 200), integrating cross-sectional fluid biomarker measures (plasma ptau217, CSF ptau181) and longitudinal Flortaucipir tau-PET and Florbetaben/Florbetapir amyloid-PET. Using linear regression, we assessed whether the interaction between amyloid-PET and ApoE4 allele dosage influences plasma ptau217, and replicated this analysis with CSF ptau181 in an ADNI subset (n = 115). Secondly, to investigate whether ApoE4 enhances tau fibrilisation and spread, we calculated annual tau-PET SUVR accumulation rates across a connectivity-based tau spreading stages, using our prior methodology (e.g. Franzmeier, Sci Adv, 2020). Linear regressions tested the interaction between ptau217 (or CSF ptau181) and ApoE4 allele count on connectivity-mediated tau-PET accumulation in four connectivity stages that capture progressive tau spread.

RESULT: ApoE4 allele dosage did not moderate the relationship between amyloid-PET and plasma ptau217 in either sample (Figure 1B, ADNI: β=0.13, p = 0.32; A4: β=-0.20, p = 0.17) nor between amyloid-PET and CSF ptau181 in ADNI subsample (Figure 1B, b=-.16, p = 0.42). However, a significant ApoE4 allele dose effect was observed in moderating the relationship between plasma ptau217 and tau-PET accumulation across connectivity stages independent of amyloid burden (Figure 1C, ADNI: Q1-4 mean β=0.44, Q1-4 p <0.001; A4: Q1-4 mean β = 0.56, Q1,2,4 p <0.001, Q3 p <0.05), with the strongest effect in individuals carrying two ApoE4 alleles.

CONCLUSION: ApoE4 exerts an allele dose-dependent effect on ptau induced tau aggregation, driving accelerated tau spreading at lower Aβ levels. This suggests that attenuating soluble ptau increases in ApoE4 carriers may mitigate downstream tau fibrilisation and delay dementia onset, highlighting the potential of personalised therapeutic approaches.},
}

Humans
*tau Proteins/cerebrospinal fluid/metabolism/blood
*Alzheimer Disease/genetics/diagnostic imaging/cerebrospinal fluid/metabolism
Biomarkers/cerebrospinal fluid/blood
Female
Male
*Apolipoprotein E4/genetics
Amyloid beta-Peptides/metabolism/cerebrospinal fluid
Aged
Positron-Emission Tomography
Aged, 80 and over
Cross-Sectional Studies
Alleles
Brain/diagnostic imaging/metabolism

@article {pmid41505400,
year = {2025},
author = {Galvis-Garrido, ND and Barbosa-Carvajal, JPP and Lozano-Trujillo, LA and Salomón-Cruz, ID and Kosik, KS and Aguirre-Acevedo, DC and Niño, DFA and Area-Gomez, E and Gomez, GPC},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105806},
doi = {10.1002/alz70856_105806},
pmid = {41505400},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/genetics/blood/diagnosis ; Male ; Female ; Apolipoproteins E/genetics ; Middle Aged ; Aged ; Presenilin-1/genetics ; Cohort Studies ; Adult ; *Lipids/blood ; tau Proteins/blood ; Bayes Theorem ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifactorial condition influenced by modifiable and non-modifiable risk factors. It affects approximately 50 million people globally, a number that is expected to triple by 2050 due to aging populations. Identifying early biological changes associated with AD is essential to designing primary interventions. In this context, fluid biomarkers hold significant potential, as they can offer insights into the disease's earliest stages. This study proposes serum lipid signatures as biomarkers for AD risk in preclinical stages.

METHOD: The study included a cohort of 320 participants clinically and genetically characterized. Genetic profiling included APOE isoforms and the PSEN1-E280A variant, which is pathogenic for early-onset familial AD. To classify population subgroups, a Latent Profile Analysis (LPA) model was applied using the "mclust" package in RStudio. This approach used Bayesian statistical models and multiple variables to create distinct profiles based on lipidomic data obtained via high-resolution mass spectrometry (HR-Mass Spect), remaining blind to clinical information. Additionally, 192 samples were analyzed for protein biomarkers NFL, GFAP, pTau 231, and pTau 217 using the SIMOA ultrasensitivity technology.

RESULT: The analysis identified five distinct lipid profiles. Of these, two profiles were associated with an increased genetic risk of AD, while one profile suggested protective effects. Similar results were observed in the analysis performed exclusively on children in an age and sex-dependent mode. On the other hand, protein biomarkers were unable to distinguish genetically at-risk individuals under the age of 20. Furthermore, the lipid analysis provided valuable insights into lipid classes that may be linked to both aging and neurodegenerative processes, further supporting their utility as early biomarkers.

CONCLUSION: These findings underscore the potential of lipidome as a powerful tool for early detection of AD risk, offering significant advantages over traditional protein biomarkers. Lipid profiles were able to discriminate between genetic risk groups decades before protein biomarkers showed similar sensitivity, highlighting their value in preclinical identification. Additionally, the study suggests that specific lipid pathways may serve as enzymatic targets for designing primary prevention strategies, offering new avenues for intervention in populations at risk for Alzheimer's disease.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/genetics/blood/diagnosis
Male
Female
Apolipoproteins E/genetics
Middle Aged
Aged
Presenilin-1/genetics
Cohort Studies
Adult
*Lipids/blood
tau Proteins/blood
Bayes Theorem

@article {pmid41505399,
year = {2025},
author = {Otsuka, F and Rodriguez, RD and Liu, C and Grinberg, LT and Otaduy, MCG},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106173},
doi = {10.1002/alz70856_106173},
pmid = {41505399},
issn = {1552-5279},
mesh = {Humans ; Magnetic Resonance Imaging ; *Alzheimer Disease/pathology/diagnostic imaging ; Male ; *Biomarkers ; Female ; Aged ; *Locus Coeruleus/pathology/diagnostic imaging ; Disease Progression ; Aged, 80 and over ; },
abstract = {BACKGROUND: The magnetic susceptibility of Locus Coeruleus was evaluated against Braak staging in order to establish possible MRI biomarkers related to magnetic proeprties of LC during AD progression.

METHOD: 12 postmortem subjects were recruited. MRI as performed with a 7T scanner. Magnetic susceptibility (QSM), diamagnetic (DCS) and paramagnetic (PCS) components maps were calculated using the DECOMPOSE algorithm, with phase pre-processing steps using the STISuite toolbox. The LC was manually segmented from the 1st echo magnitude images (Figure 1A) and mean values of each map was calculated on the entire segmented ROI. Alzheimer's pathological staging was performed according to Braak stage for AD pathology. To assess correlation between Braak staging and QSM, PCS and DCS the Kendall's tau test was used. Statistical significance was considered when p <0.05.

RESULT: The lack of contrast on all images (Figure 1B) suggests that magnetic susceptibility effects are not the main factors for the LC contrast in MRI. However, the evaluation of these maps indicated that QSM continuously increases over Braak staging (Figure 2). This increase was found to be due to a decrease of DCS, rather than increase of PCS, which suggests that demyelination is the main contributing factor on the observed changes, rather than iron overload. The inclusion of more subjects is necessary to improve the statistical power of this study. The inclusion of other modalities, such as diffusion tensor imaging from MRI, spectroscopic measurements for metal concentration (mass spectrometry and electron paramagnetic resonance), and histopathological analysis for protein/metal burden may help better understand these alterations in LC over pathology progression.

CONCLUSION: Our preliminary results suggest that LC undergoes magnetic changes mostly related to diamagnetic sources, potentially demyelination processes. No evidence of paramagnetic-related effects were observed, indicating that iron overload effects are not sufficient to observe any changes. The inclusion of additional modalities may help improve these findings.},
}

Humans
Magnetic Resonance Imaging
*Alzheimer Disease/pathology/diagnostic imaging
Male
*Biomarkers
Female
Aged
*Locus Coeruleus/pathology/diagnostic imaging
Disease Progression
Aged, 80 and over

@article {pmid41505392,
year = {2025},
author = {Brum, WS and Therriault, J and Macedo, AC and Trudel, L and Bittemcourt, F and Nakouzi, M and Pola, I and Wong, M and Kac, PR and Real, APB and Witherow, C and Karikari, TK and Moscoso, A and Schöll, M and Benedet, AL and Pascoal, TA and Ashton, NJ and Zimmer, ER and Zetterberg, H and Blennow, K and Rosa-Neto, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106492},
doi = {10.1002/alz70856_106492},
pmid = {41505392},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood/cerebrospinal fluid ; *Alzheimer Disease/blood/cerebrospinal fluid/diagnosis ; *tau Proteins/blood/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Cognitive Dysfunction/blood ; Phosphorylation ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) plasma biomarkers have transformed the field due to their scalability and minimal invasiveness, especially when evidence of AD biomarker abnormality is required for novel anti-amyloid immunotherapies. Among plasma biomarker candidates, phosphorylated tau (p-tau) variants show most promise for clinical application. While establishing cutoffs is crucial for implementation, understanding continuous-level changes is critical for accurate interpretation in research and clinical settings. Given the variety of p-tau biomarkers and emerging assays, robust estimates of continuous-level plasma p-tau changes across the clinical spectrum of AD are needed.

METHOD: We screened databases for studies (01-Jul-1984 to 09-Dec-2024) reporting plasma p-tau concentrations alongside Aβ-PET, CSF biomarkers, or neuropathology. Plasma p-tau fold-changes across the AD clinical spectrum were assessed in two analyses: i) from CU Aβ- to CU Aβ+, MCI Aβ+, and Aβ+ dementia and (ii) CI Aβ-positive vs. CI Aβ-negative. Random-effects models using the ratio of means method estimated fold-change effect sizes. This PRISMA-compliant study was pre-registered (PROSPERO-ID: CRD42023422143).

RESULT: Of 2112 titles screened, 71 studies were included in this preliminary analysis. Plasma p-tau217 showed a stepwise increase across the AD clinical spectrum, increasing 2.17-fold (95%CI 1.98-2.37) in CU Aβ-positive (n = 1451), 3.16-fold (95%CI 2.84-3.52) in MCI Aβ-positive (n = 1185), and 4.95-fold (95%CI 4.18-5.87) in Aβ-positive dementia (n = 925) compared with CU Aβ-negative (n = 3973) (Figure 1). When comparing Aβ-positive CI vs. Aβ-negative CI individuals, p-tau217 increased nearly twice as much (3.58-fold, 95%CI 3.25-3.93; n = 5995) compared to p-tau181 (1.71-fold, 95%CI 1.61-1.82; n = 8342) and p-tau231 (1.71-fold, 95%CI 1.53-1.90; n = 1019) (Figure 2), and similar to p-tau217/np-tau217 (%p-tau217: 3.59-fold, 95%CI 2.74-4.71; n = 1019). Effect size summaries for each p-tau variant across analyses are shown in Figure 3. Sensitivity analyses preserving only the median-performing assay in head-to-head studies led to similar results.

CONCLUSION: P -tau217 is the plasma biomarker with the largest dynamic range across the entire clinical AD spectrum, with its large AD-related effect sizes in symptomatic patients making it a robust candidate for clinical implementation. Results do not demonstrate any consistent superiority of %p-tau217 over p-tau217, but few studies used the ratio. Data extraction is ongoing until March/2025. A paired diagnostic accuracy meta-analysis was also submitted.},
}

Humans
*Biomarkers/blood/cerebrospinal fluid
*Alzheimer Disease/blood/cerebrospinal fluid/diagnosis
*tau Proteins/blood/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid/blood
Cognitive Dysfunction/blood
Phosphorylation

@article {pmid41505339,
year = {2026},
author = {Kobylinski, M and Krupa, N and Tam, H and Nguyen, L and Jahansooz, JR and Herndon, K and Pacpaco, K and Matsunaga, M and Kim, ST and Zhi, Q and Sonson, M and Siriwardhana, C and Carrazana, E and Liow, K},
title = {Utilizing ZIP code-based choropleth maps as a visual tool to analyze Native Hawaiian and Pacific Islander (NHPI) recruitment patterns in Alzheimer's disease clinical trials in Hawai'i: A retrospective study.},
journal = {Science progress},
volume = {109},
number = {1},
pages = {368504251411203},
doi = {10.1177/00368504251411203},
pmid = {41505339},
issn = {2047-7163},
mesh = {Humans ; *Alzheimer Disease/therapy ; Hawaii ; Retrospective Studies ; *Native Hawaiian or Pacific Islander/statistics & numerical data ; *Patient Selection ; Female ; Male ; Aged ; *Clinical Trials as Topic ; Aged, 80 and over ; },
abstract = {ObjectiveQuantify recruitment of Native Hawaiian and Pacific Islander (NHPI) participants from 22 Alzheimer's disease (AD) clinical trials over 5 years and utilize choropleth maps as a visual tool to identify where in the Hawaiian community recruited participants are located in order to better inform future recruitment efforts and improve equity and population diversity for future AD clinical trials.MethodsA retrospective chart review was conducted at a dual-site origin clinical trial center in Hawai'i. Inclusion criteria were a diagnosis of mild cognitive impairment and participation in one or more AD clinical trials conducted between 2020 and 2024. Demographic information of clinical trial participants was collected via chart review and included self-identified race/ethnicity, age, residence, and number of clinical trials the patient has participated in. Clinical trial participants were categorized by ZIP codes established by the US Census Bureau. Differences across race/ethnicity groups were assessed using either Pearson's Chi-squared test or Fisher's exact test.ResultsA total of 244 patients participated across the state of Hawai'i in 22 AD clinical trials between 2020 and 2024. Of this total, 169 (69%) patients provided their race/ethnicity, and 75 (31%) did not provide their race/ethnicity. White patients had the highest percentage of participation (44%), followed by Asian patients (34%) and NHPI patients (15%). The population distribution visualized in this study's choropleth maps suggests that NHPI were under-recruited from the west side of O'ahu.ConclusionsOur retrospective study applied choropleth maps to visualize the recruitment data and patterns of AD clinical trials. By utilizing choropleth maps to analyze recruitment areas, the NHPI community and other underrepresented populations may benefit from targeted, culturally informed recruitment strategies.},
}

Humans
*Alzheimer Disease/therapy
Hawaii
Retrospective Studies
*Native Hawaiian or Pacific Islander/statistics & numerical data
*Patient Selection
Female
Male
Aged
*Clinical Trials as Topic
Aged, 80 and over

@article {pmid41505330,
year = {2025},
author = {Javid, S and Zhu, AH and Somu, S and Low, K and Narula, S and Villalon-Reina, JE and Gleave, EJ and Thomopoulos, SI and Thompson, PM and Jahanshad, N and Nir, TM},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105352},
doi = {10.1002/alz70856_105352},
pmid = {41505330},
issn = {1552-5279},
mesh = {Humans ; Male ; Biomarkers ; Female ; Aged ; *Alzheimer Disease/diagnostic imaging/pathology ; Middle Aged ; Amyloid beta-Peptides/metabolism ; Hippocampus/pathology/diagnostic imaging ; Positron-Emission Tomography ; Aged, 80 and over ; Diffusion Magnetic Resonance Imaging ; Magnetic Resonance Imaging ; *Brain/pathology/diagnostic imaging ; Cognitive Dysfunction/diagnostic imaging ; Disease Progression ; Gray Matter/pathology/diagnostic imaging ; Cross-Sectional Studies ; },
abstract = {BACKGROUND: Diffusion MRI (dMRI) is sensitive to microstructural brain abnormalities, which may precede standard MRI macrostructural changes in the progression of Alzheimer's disease (AD) and related dementias. dMRI may allow for earlier amyloid beta (Aβ) detection and intervention before significant cognitive decline and help differentiate between Aβ+ and Aβ- dementias. Event-based modeling (EBM) is a probabilistic data-driven method applicable to cross-sectional data that can order multimodal biomarkers as they become abnormal in the course of disease progression. We used EBM to examine whether changes in cortical microstructure precede T1-weighted (T1w) cortical thickness (CTh) and hippocampal volume changes with respect to Aβ status.

METHOD: T1w, dMRI, and Aβ-PET data were analyzed for 1,033 participants from ADNI3, HABS-HD, OASIS3, and PREVENT-AD (age range: 46-92; Figure 1A). DTI and two more advanced models were fitted to the dMRI data, yielding 10 diffusion metrics extracted from the cortical gray matter (Figure 1B). CTh and hippocampal volumes were also extracted. All MRI measures were harmonized for cross-scanner differences using ComBat. First, we identified whether full cortex dMRI measures, total CTh, hippocampal volume, and MMSE differed between Aβ- and Aβ+ individuals. Measures that differed significantly were then ordered based on the Aβ- to Aβ+ continuum using EBM. To validate the resulting order, we tested for associations between EBM-derived subject-wise Aβ stage estimates and 1) clinical diagnosis and 2) Aβ positivity within the dementia group indicative of AD.

RESULT: All biomarkers differed significantly between Aβ+ and Aβ- participants and were sequenced with EBM (Figure 2A). Full cortex changes in all dMRI measures preceded hippocampal volume, MMSE, and total CTh. Subject-level Aβ stage estimates showed significant differences between all diagnostic groups (Figure 3A). In regional analyses, 73 biomarkers were associated with Aβ status (Figure 1B). Regional EBM revealed earliest abnormalities in pericalcarine CTh and temporal dMRI measures (Figure 2C). Subject-level stages showed significant differences between diagnostic groups (Figure 3B), and between Aβ- and Aβ+ dementia participants (Figure 3C).

CONCLUSION: Aβ-related abnormalities in dMRI cortical microstructure may precede abnormalities in traditional biomarkers of brain atrophy in AD. Future work will determine if EBM-derived Aβ stage estimates may also help to differentiate AD from other dementia subtypes.},
}

Humans
Male
Biomarkers
Female
Aged
*Alzheimer Disease/diagnostic imaging/pathology
Middle Aged
Amyloid beta-Peptides/metabolism
Hippocampus/pathology/diagnostic imaging
Positron-Emission Tomography
Aged, 80 and over
Diffusion Magnetic Resonance Imaging
Magnetic Resonance Imaging
*Brain/pathology/diagnostic imaging
Cognitive Dysfunction/diagnostic imaging
Disease Progression
Gray Matter/pathology/diagnostic imaging
Cross-Sectional Studies

@article {pmid41505312,
year = {2026},
author = {Sahuquillo, R and Navarro, B and Fernández-Aguilar, L and Ros, L and Sebastiá, EM and Párraga-Martínez, I and Rojas-Bartolome, L and Feria-Vilar, I and Latorre, JM},
title = {Mood induction in older adults in Alzheimer's disease: Emotional reactivity using film clips.},
journal = {Emotion (Washington, D.C.)},
volume = {},
number = {},
pages = {},
doi = {10.1037/emo0001640},
pmid = {41505312},
issn = {1931-1516},
support = {//European Union; European Regional Development Fund/ ; //Regional Government of Castilla-La Mancha; Agencia de Investigación e Innovación de Castilla-La Mancha/ ; },
abstract = {The study of emotions is complex due to the diverse methodologies used. One effective mood induction procedure is the use of film clips. Early Alzheimer's disease (AD) involves behavioral and emotional changes affecting mood and relationships, yet little research explores emotional experiences in its early stages. This study examined emotional reactivity in older adults with AD using film clips to elicit pleasant and unpleasant affective states, based on dimensional and discrete emotion models. The data were collected between 2022 and 2024. The sample included older adults with mild AD (n = 42) and healthy older adults (n = 56). We assessed valence, arousal, and discrete emotions (amusement, tenderness, anger, fear, sadness, disgust) in response to five emotional targets, an AD-related clip, and two neutral stimuli for baseline and recovery. The AD group found the amusement clip less pleasant than the healthy controls group. Arousal was similar across groups. Emotional reactivity was generally attenuated in the AD group, with the presence of mixed emotions and difficulties in emotional recovery, showing higher levels of sadness and disgust. In the AD-related clip, the AD group also experienced less sadness and tenderness than the healthy controls. Our findings suggest early deterioration in emotional processing. The sample was ethnically homogeneous, consisting entirely of Spanish-origin participants; future studies should thus include more diverse populations. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid41505268,
year = {2025},
author = {Lu, Y and Xing, Y and Tang, Y},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105318},
doi = {10.1002/alz70856_105318},
pmid = {41505268},
issn = {1552-5279},
mesh = {Humans ; Male ; *Alzheimer Disease/therapy/diagnostic imaging/physiopathology ; Female ; Magnetic Resonance Imaging ; Aged ; *Transcranial Direct Current Stimulation/methods ; Biomarkers/cerebrospinal fluid ; *Brain/diagnostic imaging/physiopathology ; Middle Aged ; *Glymphatic System/diagnostic imaging ; },
abstract = {BACKGROUND: Gamma transcranial alternating current stimulation (tACS) has shown promise in enhancing cognitive function in patients with Alzheimer's disease (AD). However, the impact of gamma tACS on regional glymphatic flow remain unclear.

METHOD: A total of 46 patients with mild AD were randomly assigned in a 1:1 ratio to receive either 30 one-hour sessions of 40Hz (gamma) tACS or sham stimulation over 15 consecutive days (Clinical Trial: NCT03920826). Global blood oxygen level-dependent (BOLD) signals and cerebrospinal fluid (CSF) inflow coupling were measured using resting-state functional MRI to evaluate glymphatic flow, which was acquired at baseline and right after the intervention, along with cognitive assessments.

RESULTS: Compared to baseline, patients in the tACS group exhibited increased BOLD-CSF coupling in the left frontal lobe, left posterior lobe, right posterior lobe, and bilateral rostral hippocampus at the end of the intervention. Additionally, changes in regional glymphatic flow in the right temporal lobe, right parietal lobe, and bilateral rostral hippocampus showed a positive correlation with changes in cognitive assessments.

CONCLUSION: The findings demonstrated the beneficial effects of gamma tACS on regional brain glymphatic flow, which might represent a potential therapeutic mechanism of tACS.},
}

Humans
Male
*Alzheimer Disease/therapy/diagnostic imaging/physiopathology
Female
Magnetic Resonance Imaging
Aged
*Transcranial Direct Current Stimulation/methods
Biomarkers/cerebrospinal fluid
*Brain/diagnostic imaging/physiopathology
Middle Aged
*Glymphatic System/diagnostic imaging

@article {pmid41505261,
year = {2025},
author = {Zhou, L and Wang, XH and Butler, TA and Chiang, G and de Leon, MJ and Li, Y},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105139},
doi = {10.1002/alz70856_105139},
pmid = {41505261},
issn = {1552-5279},
mesh = {Humans ; Male ; Aged ; Female ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging ; *Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging ; Biomarkers/cerebrospinal fluid ; Positron-Emission Tomography ; *Choroid Plexus/diagnostic imaging/blood supply ; Magnetic Resonance Imaging ; Middle Aged ; Aged, 80 and over ; *Lateral Ventricles/diagnostic imaging/metabolism ; *Cerebrospinal Fluid/metabolism ; tau Proteins/cerebrospinal fluid ; },
abstract = {BACKGROUND: Cerebrospinal fluid (CSF) turnover plays a vital role in maintaining brain homeostasis and clearing neurotoxic substances, such as amyloid-beta and tau proteins, which is implicated in Alzheimer's disease (AD) and mild cognitive impairment (MCI). The choroid plexus (CP), responsible for CSF production, has been hypothesized to influence CSF turnover via its blood flow and volume. However, the relative contributions of CP blood flow and volume to lateral ventricle CSF turnover, particularly in the context of aging and neurodegeneration, remain poorly understood.

METHOD: We analyzed data from 40 subjects (age 69.92±8.56 years, 13 males), including 13 diagnosed with MCI/AD and 27 cognitively normal controls (CN), using multimodal imaging to measure lateral ventricle CSF turnover rate (vCSF)measured from dynamic 18F-MK6240 PET and CP blood flow estimated using arterial spin labeling (ASL) magnetic resonance (MR). CP volume was assessed using MR T1w and T2FLAIR. See Figure 1. Multivariable linear regression models were employed to evaluate the associations of CSF turnover with diagnosis group, CP blood flow, CP volume, and age, adjusting for sex and intracranial volume (ICV). Additional analyses examined the relationships between these variables and age controlling for sex and diagnosis.

RESULT: Lateral ventricle CSF turnover rate vCSF was significantly associated with diagnostic group (MCI/AD: t=-4.27, p <0.001) and CP blood flow (t=2.11, p <0.05), but not CP volume (t=0.79, p = 0.43), see Figure 2. Both CSF turnover rate (t=-1.93, p <0.05) and CP blood flow (t=-2.72, p <0.05) were negatively associated with age. In contrast, CP volume exhibited a positive association with age (t=2.71, p <0.05). See Figure 3. These findings indicate that CP blood flow, rather than its volume, is a critical driver of CSF turnover in the lateral ventricle, particularly in the context of aging and neurodegeneration.

CONCLUSION: Our results suggest that reduced CP blood flow, rather than structural changes in CP volume, underlies the decline in CSF turnover observed in aging and neurodegenerative conditions such as MCI/AD. These findings highlight the importance of maintaining CP vascular function for preserving CSF turnover and brain health in aging populations. Future studies should validate these findings in larger cohorts and explore causal links between CP perfusion, CSF turnover, and amyloid/tau accumulation.},
}

Humans
Male
Aged
Female
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging
*Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging
Biomarkers/cerebrospinal fluid
Positron-Emission Tomography
*Choroid Plexus/diagnostic imaging/blood supply
Magnetic Resonance Imaging
Middle Aged
Aged, 80 and over
*Lateral Ventricles/diagnostic imaging/metabolism
*Cerebrospinal Fluid/metabolism
tau Proteins/cerebrospinal fluid

@article {pmid41505234,
year = {2026},
author = {Cody, KA and Sokołowski, A and Johns, E and Guerra, LM and Winer, JR and Young, CB and Younes, K and Dumitrescu, L and Archer, DB and Durant, A and Sathe, A and Koran, MEI and Mez, J and Saykin, AJ and Toga, A and Cuccaro, M and Tosun, D and Insel, PS and Johnson, SC and Harrison, TM and Hohman, TJ and Mormino, EC},
title = {Characterizing amyloid and tau positron emission tomography-based stages across the clinical continuum.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71017},
doi = {10.1002/alz.71017},
pmid = {41505234},
issn = {1552-5279},
support = {U24AG074855//Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC)/ ; U01AG068057//Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC)/ ; R01AG059716//Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC)/ ; U24AG021886//National Centralized Repository (NCRAD)/ ; U24AG072122//National Alzheimer's Coordinating Center/ ; U24AG041689//Genetics of Alzheimer's Disease Data Storage Site (NIAGADS)/ ; U01 AG024904/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; AG067418//U24/ ; AG072980//U24/ ; AG069453//U24/ ; P30 AG019610/AG/NIA NIH HHS/United States ; P30 AG013846/AG/NIA NIH HHS/United States ; P30 AG062428/AG/NIA NIH HHS/United States ; P20AG068053//Cleveland ADRC/ ; P50 AG008702/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30AG066511//Emory University/ ; R01 AG19771//Indiana University/ ; P30 AG10133//Indiana University/ ; P30 AG072976/AG/NIA NIH HHS/United States ; R01 AG061788/AG/NIA NIH HHS/United States ; R01 AG053993/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; //Indiana University Department of Radiology and Imaging Sciences/ ; P30 AG066507/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; R01 AG054110/AG/NIA NIH HHS/United States ; R01 AG053509/AG/NIA NIH HHS/United States ; 30AG066512-01S2//New York University/ ; R01AG056031//New York University/ ; R01AG056531//New York University/ ; P30 AG013854/AG/NIA NIH HHS/United States ; R01 AG045571/AG/NIA NIH HHS/United States ; R56 AG045571/AG/NIA NIH HHS/United States ; R01 AG067781/AG/NIA NIH HHS/United States ; U19 AG073153/AG/NIA NIH HHS/United States ; R01 DC008552/DC/NIDCD NIH HHS/United States ; R01 AG077444/AG/NIA NIH HHS/United States ; R01 NS075075/NS/NINDS NIH HHS/United States ; R01 AG056258/AG/NIA NIH HHS/United States ; P30 AG008017/AG/NIA NIH HHS/United States ; R56 AG074321/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; P30AG066515//Rush University/ ; P50 AG047366/AG/NIA NIH HHS/United States ; //University of Alabama, Birmingham/ ; P30 AG10129//P20; University of California/ ; P30 AG072972/AG/NIA NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; P30AG062429//P20; University of California/ ; P30 AG062422/AG/NIA NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; P30 AG028283-15S1//University of California, San Francisco/ ; P30AG053760//University of California, San Francisco/ ; P30AG072931//University of California, San Francisco/ ; U19 NS120384/NS/NINDS NIH HHS/United States ; R01 AG068338/AG/NIA NIH HHS/United States ; S10OD026738-01//University of Michigan Site PI Henry Paulson/ ; AG058724//University of Michigan Site PI Henry Paulson/ ; R35 AG072262/AG/NIA NIH HHS/United States ; W81XWH2110743//University of Michigan Site PI Henry Paulson/ ; R01 AG073235/AG/NIA NIH HHS/United States ; 1I01RX001534//University of Michigan Site PI Henry Paulson/ ; IRX001381//University of Michigan Site PI Henry Paulson/ ; P20 AG068077/AG/NIA NIH HHS/United States ; 2019NF4100087335//University of Pennsylvania/ ; R01 AG055005/AG/NIA NIH HHS/United States ; P50 AG005133/AG/NIA NIH HHS/United States ; P50 AG005142/AG/NIA NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; P50 AG033514/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30AG072947//Vanderbilt University/ ; P01 AG03991//Washington University, St. Louis/ ; AG026276//Washington University, St. Louis/ ; P20 MH071616//Washington University, St. Louis/ ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 NS098577/NS/NINDS NIH HHS/United States ; R01 AG021910/AG/NIA NIH HHS/United States ; R01 AG043434/AG/NIA NIH HHS/United States ; R01 EB009352/EB/NIBIB NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; U24 RR021382/RR/NCRR NIH HHS/United States ; AG047270//Washington University, St. Louis/ ; R01AG052560//Washington University, St. Louis/ ; R01AG062276//Washington University, St. Louis/ ; P30AG066506-03//Washington University, St. Louis/ ; P50 AG047266/AG/NIA NIH HHS/United States ; R01 AG021155/AG/NIA NIH HHS/United States ; //Webb Family Foundation/ ; AACSF-24-1307411/ALZ/Alzheimer's Association/United States ; K99 AG071837/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Positron-Emission Tomography ; Aged ; *tau Proteins/metabolism ; Male ; Female ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; Cohort Studies ; Aged, 80 and over ; *Amyloid/metabolism ; Middle Aged ; *Amyloid beta-Peptides/metabolism ; *Brain/diagnostic imaging/metabolism ; Severity of Illness Index ; },
abstract = {INTRODUCTION: We standardized positron emission tomography (PET) data across multiple cohorts and tracers to characterize the frequency of amyloid and tau PET severity along the clinical continuum.

METHODS: Clinical stage was defined using cohort-specific criteria and included cognitively unimpaired (CU), mild cognitive impairment (MCI), and dementia. Amyloid severity was staged using Centiloids (CL). Tau severity was staged using a hierarchical Braak-based schema. The cumulative probabilities of PET-based stages were estimated using ordinal logistic regressions.

RESULTS: Among 10,396 individuals (mean [standard deviation] age: 71.9 [7.1] years), amyloid levels ≥ 25 CL increased with age among CU and MCI, while amyloid levels ≥ 100 CL were most common in dementia. In 3295 with tau PET, tau severity increased with amyloid and clinical stage and showed complex associations with age. Within each clinical stage, the full spectrum of amyloid and tau PET severity was observed.

DISCUSSION: PET-based staging revealed heterogeneous amyloid and tau burden along the clinical continuum.

HIGHLIGHTS: PET-based staging is feasible across multiple cohorts and PET tracers. There is heterogeneity in amyloid and tau severity across the clinical spectrum. The frequency of amyloid and tau PET severity increased with clinical severity. The likelihood of tau PET severity differed by age, amyloid, and clinical severity.},
}

Humans
*Positron-Emission Tomography
Aged
*tau Proteins/metabolism
Male
Female
*Cognitive Dysfunction/diagnostic imaging/metabolism
Cohort Studies
Aged, 80 and over
*Amyloid/metabolism
Middle Aged
*Amyloid beta-Peptides/metabolism
*Brain/diagnostic imaging/metabolism
Severity of Illness Index

@article {pmid41505233,
year = {2026},
author = {Schultz, SA and Rao, Y and Liu, L and Ostaszewski, B and Anderson, AK and Yau, WW and Shirzadi, Z and Gordon, BA and Hassenstab, J and Morris, JC and Perrin, RJ and Allegri, RF and Barthélemy, NR and Fox, N and Day, GS and Jucker, M and Levey, AI and Levin, J and Mori, H and Salloway, S and Schofield, P and McDade, E and Sperling, RA and Bateman, RJ and Selkoe, DJ and Chhatwal, JP and , },
title = {Plasma levels of an N-terminal tau fragment predict Alzheimer's and neurodegenerative disease biomarkers in autosomal dominant Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71049},
doi = {10.1002/alz.71049},
pmid = {41505233},
issn = {1552-5279},
support = {U19AG032438//The Dominantly Inherited Alzheimer Network/ ; SG-20-690363-DIAN//National Institute on Aging (NIA), the Alzheimer's Association/ ; JP23dk0207066//Japan Agency for Medical Research and Development/ ; JP22dk0207049//Japan Agency for Medical Research and Development/ ; HI21C0066//Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; R01AG071865/AG/NIA NIH HHS/United States ; //Davis APP program/ ; //Instituto de Salud Carlos III/ ; //Korea Dementia Research Center/ ; //Korea Health Industry Development Institute/ ; //Raul Carrea Institute for Neurological Research/ ; SG-20-690363-DIAN/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/blood/genetics/diagnosis ; Biomarkers/blood ; Male ; Female ; Cross-Sectional Studies ; Middle Aged ; Longitudinal Studies ; *Peptide Fragments/blood ; Aged ; *Neurodegenerative Diseases/blood ; },
abstract = {INTRODUCTION: Tau species lacking truncation of the N-terminal region, including plasma N-terminal tau fragment 1 (NT1), have been previously associated with cognitive decline, neurodegeneration, and tau pathology in late-onset sporadic Alzheimer's disease (AD).

METHODS: Here, we examined cross-sectional and longitudinal plasma NT1 as a possible predictor of cognitive, clinical, and core AD biomarker trajectories in autosomal dominant AD (ADAD).

RESULTS: NT1 levels in ADAD mutation carriers (MC; n = 132) increased across the disease continuum, compared to non-carriers (NC; n = 75), becoming elevated about a decade prior to estimated symptom onset. Cross-sectional and longitudinal NT1 levels in MC were associated with clinical, cognitive, and biomarker changes. NT1 increases continued in symptomatic phases of disease, a distinct trajectory from that seen with CSF p-tau217 and other phospho-tau species.

DISCUSSION: Together, our results suggest that plasma NT1-alone or combined with other tau measures-may be useful in studying AD-related clinical, cognitive, and biomarker outcomes.

HIGHLIGHTS: Leveraging a deeply phenotyped cohort of individuals carrying a pathogenic variant for autosomal dominant Alzheimer's disease (ADAD) and their non-carrier family members, our results suggest that plasma N-terminal tau fragment 1 (NT1) levels mirrored changes in clinical, cognitive, and neurodegenerative measures in ADAD, particularly in late asymptomatic and early symptomatic phases of disease. NT1 levels correlated with cerebrospinal fluid (CSF) measures of tau pathology but less so with CSF or imaging measures of β-amyloid pathology. Together with previous supportive findings in preclinical and symptomatic sporadic AD, these results suggest that plasma NT1-alone or combined with other tau measures-may be useful in studying AD-related tau pathology and neurodegeneration across a wide spectrum of disease.},
}

Humans
*tau Proteins/blood
*Alzheimer Disease/blood/genetics/diagnosis
Biomarkers/blood
Male
Female
Cross-Sectional Studies
Middle Aged
Longitudinal Studies
*Peptide Fragments/blood
Aged
*Neurodegenerative Diseases/blood

@article {pmid41505232,
year = {2025},
author = {Kim, HK and Lee, JH and Chun, JH and Park, M and Kim, YJ and West, T and Kirmess, KM and Verghese, PB and Connell, D and Braunstein, JB and Ryu, YH and Lyoo, CH and Cho, H},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106209},
doi = {10.1002/alz70856_106209},
pmid = {41505232},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/blood ; *Biomarkers/blood ; Male ; Female ; Positron-Emission Tomography ; Aged ; *Cognitive Dysfunction/diagnostic imaging/blood ; Aniline Compounds ; Middle Aged ; Neuropsychological Tests ; Stilbenes ; Aged, 80 and over ; Brain/diagnostic imaging/metabolism ; Amyloid beta-Peptides ; Carbolines ; },
abstract = {BACKGROUND: This study aimed to assess the differential predictive performance of plasma p-tau217 for early and advanced stages of amyloid and tau pathology in cognitively unimpaired (CU) and cognitively impaired (CI) individuals, evaluating its stage-specific utility across cognitive states.

METHODS: A total of 237 participants underwent [18]F-florbetaben (FBB) and [18]F-flortaucipir (FTP) PET imaging, as well as plasma biomarker assessments, including p-tau217, %p-tau217, and APS2. Participants were categorized as CU or CI based on neuropsychological evaluations. Amyloid pathology stages were defined as FBB G+ (early amyloid pathology) and FBB Str+ (advanced amyloid pathology), while tau pathology stages were classified as FTP MTL+ (early tau pathology) and FTP NEO+ (advanced tau pathology). The predictive performance of p-tau217 for each stage was assessed using ROC analysis.

RESULTS: In the CU group, plasma biomarkers demonstrated excellent predictive performance for both early (FBB G+) and advanced (FBB Str+) stages of amyloid pathology, with AUC values exceeding 0.9. Specifically, for FBB G+, p-tau217 achieved an AUC of 0.954, while for FBB Str+, it reached 0.968. Regarding tau pathology, p-tau217 showed high accuracy for both FTP MTL+ (AUC = 0.944) and FTP NEO+ (AUC = 0.975) in the CU group. In the CI group, while the predictive performance for early amyloid pathology (FBB G+) remained strong (AUC = 0.961), it declined for advanced amyloid pathology (FBB Str+, AUC = 0.775). For tau pathology, p-tau217 performed better for FTP NEO+ (AUC = 0.915) compared to FTP MTL+ (AUC = 0.842). Notably, comparative analysis revealed that p-tau217 reflected amyloid pathology significantly better in the CU group compared to the CI group, particularly for FBB Str+ (p < 0.001). Conversely, in the CI group, p-tau217 showed a stronger association with advanced tau pathology (FTP NEO+) compared to early tau pathology (FTP MTL+, p =  0.028).

CONCLUSION: This differential performance suggests that p-tau217 more accurately reflects amyloid burden in CU individuals, while being more indicative of advanced tau pathology in CI individuals. These results highlight the stage- and cognitive status-dependent utility of plasma p-tau217 as a biomarker in Alzheimer's disease pathology.},
}

Humans
*tau Proteins/blood
*Biomarkers/blood
Male
Female
Positron-Emission Tomography
Aged
*Cognitive Dysfunction/diagnostic imaging/blood
Aniline Compounds
Middle Aged
Neuropsychological Tests
Stilbenes
Aged, 80 and over
Brain/diagnostic imaging/metabolism
Amyloid beta-Peptides
Carbolines

@article {pmid41505229,
year = {2026},
author = {Do, AN and Song, S and Ali, M and Timsina, J and Wang, L and Western, D and Liu, M and Sanford, J and Rosende-Roca, M and Boada, M and Puerta, R and Wilson, EN and Ruiz, A and Pastor, P and , and Wyss-Coray, T and Cruchaga, C and Sung, YJ},
title = {CSF proteomic profiling with amyloid and tau pathology identifies distinctive sex-specific alteration of multiple proteins involved in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71063},
doi = {10.1002/alz.71063},
pmid = {41505229},
issn = {1552-5279},
support = {R01AG074007/NH/NIH HHS/United States ; R01AG044546/NH/NIH HHS/United States ; P01AG003991/NH/NIH HHS/United States ; RF1AG053303/NH/NIH HHS/United States ; RF1AG058501/NH/NIH HHS/United States ; U01AG058922/NH/NIH HHS/United States ; //Chan Zuckerberg Initiative/ ; //Michael J. Fox Foundation/ ; ZEN-22-848604//Alzheimer's Association Zenith Fellows Award/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/pathology/genetics ; Female ; Male ; *Amyloid beta-Peptides/cerebrospinal fluid ; *tau Proteins/cerebrospinal fluid ; Proteomics ; Aged ; Sex Factors ; Biomarkers/cerebrospinal fluid ; *Peptide Fragments/cerebrospinal fluid ; *Sex Characteristics ; },
abstract = {INTRODUCTION: In Alzheimer's disease (AD), females have higher prevalence and faster progression, but sex-specific molecular findings in AD are limited.

METHODS: We comprehensively examined 6162 proteins in cerebrospinal fluid (CSF) from 2496 participants to identify sex-specific proteomic alteration by CSF amyloid beta (Aβ)42 and phosphorylated tau (p-tau) levels.

RESULTS: We identified and replicated 68 male-specific and 116 female-specific proteins associated with Aβ42 and/or p-tau levels. Apolipoprotein E ε4 carrier status modified sex-specific alterations of multiple proteins including S100A9 and NEFL for Aβ42 and MAPK9 and MAPKAPK2 for p-tau. Male-specific proteins, enriched in microglia, were involved in activating innate immune response. The male network exhibited direct connections among 30 proteins and highlighted MAPKAPK2 as a hub. Female-specific proteins, enriched in endothelial cells, were involved in regulating protein metabolic process. The female network exhibited direct connections among 43 proteins and highlighted CSNK2A2 and PRKCA as hubs.

DISCUSSION: Our findings provide insights into mechanistic understanding of sex differences in AD risk.

HIGHLIGHTS: Our proteomic study of 6162 proteins (targeted by 7006 aptamers) in cerebrospinal fluid (CSF) from 2496 participants identified and replicated 68 male-specific and 116 female-specific proteins associated with cerebrospinal fluid amyloid beta 42 and/or phosphorylated tau levels. Male-specific proteins, enriched in microglia, were involved in activation of innate immune response. The male network highlighted MAPKAPK2 involved in chronic neuronal neuroinflammation as a hub. Female-specific proteins, enriched in endothelial cells, were involved in regulation of protein metabolic process and response to external stimuli. The female network highlighted PRKCA regulating synaptic plasticity and CSNK2A2 protein involved in neuroplasticity as hubs.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/pathology/genetics
Female
Male
*Amyloid beta-Peptides/cerebrospinal fluid
*tau Proteins/cerebrospinal fluid
Proteomics
Aged
Sex Factors
Biomarkers/cerebrospinal fluid
*Peptide Fragments/cerebrospinal fluid
*Sex Characteristics

@article {pmid41505228,
year = {2026},
author = {Head, E and Cohen, A and Fortea, J and McGlinchey, E},
title = {Novel insights into Alzheimer's disease through the study of individuals with Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71074},
doi = {10.1002/alz.71074},
pmid = {41505228},
issn = {1552-5279},
support = {U19AG068054//NIH/NIA/ ; U19AG068054//NIH/NIA/ ; P30AG066519//NIH/NIA/ ; RF1AG079519//NIH/NIA/ ; U19AG068054//NIH/NIA/ ; P30AG066519//NIH/NIA/ ; RF1AG079519//NIH/NIA/ ; R01AG056850//NIH/NIA/ ; R21AG056974//NIH/NIA/ ; R01AG061566//NIH/NIA/ ; 1R01AG081394//NIH/NIA/ ; R61AG066543//NIH/NIA/ ; //Fondo de Investigaciones Sanitario/ ; INT21/00073//Carlos III Health Institute/ ; PI20/01473//Carlos III Health Institute/ ; PI23/01786//Carlos III Health Institute/ ; //Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Program 1/ ; //Fondo Europeo de Desarrollo Regional/ ; SLT006/17/00119//Department de Salut de la Generalitat de Catalunya/ ; //Fundación/ ; IIBSP-DOW-2020-151//Tatiana Pérez de Guzmán el Bueno/ ; H2020-SC1-BHC-2018-2020//Horizon 2020-Research and Innovation Framework Programme/ ; HPE-ADRD 24HPE1284307//Alzheimer Association/ ; },
}

@article {pmid41505225,
year = {2025},
author = {Ramirez-Galvan, FA and Jimenez-Galaviz, DA and Padilla-Mendoza, JR and Jijon-Lorenzo, R and Silva-Lucero, MD and Cardenas-Aguayo, MD},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105315},
doi = {10.1002/alz70856_105315},
pmid = {41505225},
issn = {1552-5279},
mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy/blood/complications ; Biomarkers/blood ; Male ; *Cognitive Dysfunction/blood/metabolism ; Female ; Autophagy/drug effects ; Aged ; Metformin/pharmacology ; Glycated Hemoglobin/metabolism ; Middle Aged ; Hypoglycemic Agents/pharmacology ; },
abstract = {BACKGROUND: Type 2 Diabetes (T2D) is highly prevalent in Latin America, particularly in Mexico, with 15.6% of the population affected (ENSANUT 2020, Montoya 2023). T2D increases the risk of complications: hypertension and dementia. Mild Cognitive Impairment (MCI) precedes Alzheimer's dementia, the most common type. Metformin, the primary treatment for T2D, enhances autophagy, a cellular process for recycling primary components. Autophagy impairment is linked to dementia (Nixon 2024). This study utilizes human olfactory neuroepithelial precursor cells (hONE-NPCs) as a model for neurodegeneration. Olfactory dysfunction is an early indicator of dementia, suggesting that alterations in hONE-NPCs may reflect early stages of the disease.

METHOD: This study included four groups: healthy controls, individuals with cognitive impairment, those with T2D, and with T2D and cognitive impairment (T2D-MCI). hONE NPCs were isolated from each participant and characterized using Western Blotting and immunocytofluorescence. Blood samples were collected for HbA1c and protein samples for autophagy markers. Participants underwent a MoCA Test by a certified applicator (MXRAMFR710802563-01), a medical interview to assess metformin treatment history, and an olfactory test. hONE-NPCs were treated with or without metformin for 24 hours. Protein samples were collected for Western Blotting analysis in three groups in vitro: Diabetes+MCI+Metformin, Diabetes-MCI-Metformin, and Control+Metformin.

RESULT: Culture cells hONE-NPCs from Diabetes+MCI and Pre-Diabetic+MCI from patients that had been treated with metformin and their cells were treated with metformin show an impairment in the autophagy flux since p62 was elevated and LC3-II was downregulated. Conversely, culture cells from control individuals who had never been treated with metformin responded to metformin in vitro treatment with an increase in autophagy flux, showing p62 reduction and an increase in LC3-II.

CONCLUSION: Our results suggest a preconditioning effect of hONE-NPCs from patients receiving metformin treatment on their response to this drug in vitro. Cells from patients who were prescribed metformin show an impairment in the autophagy flux; however, culture hONE.NPCs cells from control individuals who had never been treated with metformin responded to metformin in vitro treatment with an increase in autophagy flux. This finding may have clinical implications in the long-term effects of metformin treatment in peripheral cells as a systemic effect.},
}

Humans
*Diabetes Mellitus, Type 2/drug therapy/blood/complications
Biomarkers/blood
Male
*Cognitive Dysfunction/blood/metabolism
Female
Autophagy/drug effects
Aged
Metformin/pharmacology
Glycated Hemoglobin/metabolism
Middle Aged
Hypoglycemic Agents/pharmacology

@article {pmid41505204,
year = {2026},
author = {Chen, CD and Aguero, C and Melloni, A and Healy, BC and Thibault, EG and Fu, JF and Farrell, ME and Schultz, S and Yang, HS and Bellier, JP and Chhatwal, J and Webb, PK and Arnold, S and Penney, D and Davis, R and Rentz, D and Gomez-Isla, T and Sperling, RA and Johnson, KA and Price, JC},
title = {Identifying early changes in imaging, plasma, and digital cognitive biomarkers that correspond to Alzheimer's disease pathology in the presence of autopsy-confirmed co-pathologies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71092},
doi = {10.1002/alz.71092},
pmid = {41505204},
issn = {1552-5279},
support = {T32AG066592/GF/NIH HHS/United States ; K99AG081457/GF/NIH HHS/United States ; R00AG081457/GF/NIH HHS/United States ; K01AG083062/GF/NIH HHS/United States ; K01AG084816/GF/NIH HHS/United States ; R01AG080667/GF/NIH HHS/United States ; 5U2CAG060426-04S1/GF/NIH HHS/United States ; 5U2CAG057441-03S1/GF/NIH HHS/United States ; P30AG062421-06/GF/NIH HHS/United States ; P01AG036694/GF/NIH HHS/United States ; P30AG062421/GF/NIH HHS/United States ; P50AG005134/GF/NIH HHS/United States ; K24AG035007/GF/NIH HHS/United States ; FA9550-23-1-0399//Air Force Research Laboratory/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/blood/diagnosis ; Positron-Emission Tomography ; Male ; *Biomarkers/blood ; Female ; tau Proteins/blood ; Amyloid beta-Peptides/metabolism ; Autopsy ; Aged ; *Cognitive Dysfunction/pathology/diagnostic imaging ; *Brain/pathology/diagnostic imaging ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) biomarkers are assessed on their ability to detect AD pathophysiology in vivo, with confirmation of AD neuropathology only at autopsy.

METHODS: Positron emission tomography (PET), plasma, and cognitive AD biomarkers were compared to AD neuropathology in Harvard Aging Brain Study participants (10 cognitively unimpaired; 6 mild cognitive impairment). Different PET methods were evaluated, for example, standardized uptake volume ratio (SUVR), distribution volume ratio (DVR), spatial extent (EXT), and partial-volume correction (PVC).

RESULTS: Amyloid beta (Aβ)-PET ([11]C-Pittsburgh compound B [PiB]), tau-PET ([18]F-flortaucipir [FTP]), and plasma tau phosphorylated at threonine 217 (p-tau217) correlate with Aβ plaques (A-score), Braak tau neurofibrillary tangle (NFT) stage (B-score), and neuritic plaques (C-score), whereas plasma glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and cognitive measures did not; although digital Clock Drawing Test (dCDT) latency features did, in an exploratory comparison. Correlations were stronger for Aβ-PET DVR and Aβ-PET EXT (than SUVR with/without PVC) and tau-PET SUVR (composite reference and PVC).

DISCUSSION: These findings support the innovative use of imaging, plasma, and digital cognitive tools for detecting AD pathophysiology in a largely cognitively unimpaired population.

HIGHLIGHTS: Amyloid beta-positron emission tomography (Aβ-PET), tau-PET imaging, and plasma tau phosphorylated at threonine 217 (p-tau217) correlate with ABC scores Correlations were larger for Aβ-PET distribution volume ratio (DVR) and tau-PET standardized uptake volume ratio (SUVR; composite reference, partial volume correction [PVC]) Digital Clock Drawing Test latency features correlate with A- and Cscores Standard cognitive measures mostly did not correlate with ABC scores Plasma glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) biomarkers did not correlate with ABC scores.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/blood/diagnosis
Positron-Emission Tomography
Male
*Biomarkers/blood
Female
tau Proteins/blood
Amyloid beta-Peptides/metabolism
Autopsy
Aged
*Cognitive Dysfunction/pathology/diagnostic imaging
*Brain/pathology/diagnostic imaging
Aged, 80 and over

@article {pmid41505203,
year = {2026},
author = {Lyketsos, CG and Peters, ME},
title = {Neuropsychiatric symptoms in Alzheimer's disease: Past, present, and future.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71077},
doi = {10.1002/alz.71077},
pmid = {41505203},
issn = {1552-5279},
support = {P30AG066507//Johns Hopkins Alzheimer's Disease Research Center/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology/complications ; *Cognitive Dysfunction/psychology ; Disease Progression ; *Depression/etiology ; },
abstract = {Noncognitive neuropsychiatric symptoms (NPS; e.g., depression, agitation) are nearly universal throughout the course of Alzheimer's disease (AD), cause significant adverse impact to patients and caregivers, and are associated with more rapid progression to severe dementia. Although the importance and presence of NPS was recognized by Dr. Alois Alzheimer himself, it was a series of research roundtables in the 2010s that propelled the understanding and treatment of NPS in AD forward. The mild behavioral impairment (MBI) construct was developed as a complementary behavioral analogue to mild cognitive impairment, solidifying the importance of NPS prior to dementia onset. Neurobiological underpinnings of NPS are being studied and the NPS treatment pipeline includes novel therapeutics, repurposing of existing pharmaceuticals, and non-pharmacologic interventions. The Alzheimer's Disease Research Centers and The National Alzheimer's Coordinating Center, being recognized in this special issue, have played a pivotal role in the recognition and study of NPS in AD. HIGHLIGHTS: Noncognitive neuropsychiatric symptoms (NPS) are nearly universal throughout the course of Alzheimer's disease (AD), cause significant adverse impact to patients and caregivers, and are associated with more rapid progression to severe dementia. A series of research roundtables in the last decade and a half have propelled the understanding and treatment of NPS in AD forward. The mild behavioral impairment (MBI) construct was developed as a complementary behavioral analogue to mild cognitive impairment, solidifying the importance of NPS prior to dementia onset. Neurobiological underpinnings of NPS are being studied and the treatment pipeline includes novel therapeutics, repurposing of pharmaceuticals, and non-pharmacologic interventions. The Alzheimer's Disease Research Centers and The National Alzheimer's Coordinating Center have played a pivotal role in the recognition and study of NPS in AD.},
}

Humans
*Alzheimer Disease/psychology/complications
*Cognitive Dysfunction/psychology
Disease Progression
*Depression/etiology

@article {pmid41505172,
year = {2025},
author = {Mohs, R and Beauregard, DW and Levey, AI and Johnson, ECB and Nicodemus-Johnson, J and Wolz, R and Dwyer, J},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105032},
doi = {10.1002/alz70856_105032},
pmid = {41505172},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/blood/diagnosis ; *Biomarkers/blood ; Aged ; *Cognitive Dysfunction/diagnostic imaging/blood ; Positron-Emission Tomography ; Amyloid beta-Peptides/blood/metabolism ; tau Proteins/blood ; Aged, 80 and over ; Proteomics ; Brain/diagnostic imaging/metabolism ; Middle Aged ; },
abstract = {BACKGROUND: Screening for clinical trials identifies persons with clinical symptoms of Mild Cognitive Impairment (MCI) or Alzheimer's disease (AD) but no amyloid on PET. We compared blood biomarkers and proteomics in these screen failures with cognitively normal, amyloid PET negative persons and with amyloid PET positive MCI or mild AD patients.

METHOD: We analyzed data from 296 persons with clinical symptoms of MCI or mild AD from the Bio-Hermes study who were amyloid PET negative (MCI + AD AB-); we compared them with 313 Bio-Hermes participants who were cognitively normal and amyloid PET negative (CN AB-) and with 258 amyloid PET positive persons with clinical MCI or mild AD (MCI + AD AB+). Measures included regional amyloid PET, plasma A-beta40 and 42, total tau, p-tau 181, p-tau 217, NfL, GFAP, a panel of 69 cytokines (Fireplex) and 7596 proteins from the Somalogic panel.

RESULT: Relative to the CN AB- group, the MCI + AD AB- group were older, more cognitvely and functionally impaired, had slightly less education and were more likely to be non-white; the groups did not differ in gender or APOE4 rates. The groups did not differ on amyloid SUVR, p-tau 217, t-tau or GFAP. NfL was higher in MCI + AD AB- persons compared with CN AB- persons (Table 1 and 2). After using a False Discovery Rate adjustment there were no Somalogic proteins significantly different in MCI + AD AB- participants vs CN AB- participants. Several proteins were different in amyloid PET positive persons compared with amyloid PET negative parsons (Figure 1).

CONCLUSION: NfL data indicate very significant neurodegeneration in symptomatic but amyloid PET negative clinical trial screen failures. Biomarkers reflecting amyloid and tau were not different and the proteomics profile did not find specific abnormalities in amyloid negative, symptomatic persons.},
}

Humans
Male
Female
*Alzheimer Disease/diagnostic imaging/blood/diagnosis
*Biomarkers/blood
Aged
*Cognitive Dysfunction/diagnostic imaging/blood
Positron-Emission Tomography
Amyloid beta-Peptides/blood/metabolism
tau Proteins/blood
Aged, 80 and over
Proteomics
Brain/diagnostic imaging/metabolism
Middle Aged

@article {pmid41505171,
year = {2025},
author = {Coughlan, GT and Klinger, HM and Seto, M and Birkenbihl, C and Li, A and Farrell, ME and Thibault, EG and Properzi, MJ and Schultz, AP and Townsend, DL and Langford, O and Chhatwal, JP and Yang, HS and Raman, R and Donohue, MC and Johnson, KA and Sperling, RA and Buckley, RF},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106874},
doi = {10.1002/alz70856_106874},
pmid = {41505171},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/blood/metabolism ; Male ; Female ; *Biomarkers/blood ; Aged ; Positron-Emission Tomography ; *Amyloid beta-Peptides/blood/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Longitudinal Studies ; *Brain/metabolism/diagnostic imaging ; Middle Aged ; Peptide Fragments/blood ; Aged, 80 and over ; Phosphorylation ; },
abstract = {BACKGROUND: The pathophysiological cascade of Alzheimer's Disease(AD) is characterized by amyloid-β(Aβ) related secretion of soluble phosphorylated tau (p-tau), followed by aggregation of tau tangles and subsequent cognitive decline. Previous literature suggests that tau proliferation is more aggressive at younger ages, but the extent to which this is true and can be detected by plasma markers remains unclear. We examined whether age interacts with plasma p-tau217 and p-tau217/Aβ42 and to predict rates of regional tau-PET accumulation in baseline clinical normal adults.

METHOD: Participants were 578 clinically normal individuals (mean age 72.2; 295 APOEε4-carriers [56%]; mean years of education 16.3) with baseline plasma p-tau217 and longitudinal tau-PET from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study as well as the Alzheimer's Disease Neuroimaging Initiative. Medial temporal lobe (amygdala, parahippocampal gyrus, entorhinal cortex) and neocortical (inferior parietal, fusiform, inferior temporal) tau composites were chosen as longitudinal tau-PET outcomes. The average tau-PET follow-up time was 3.5 years (SD=1.6 years, range=1.3-7.1 years). Random-effects regression estimated the interaction between baseline age and baseline p-tau217 longitudinal tau composites, adjusting for sex and years of education (including participant-specific intercepts and slopes).

RESULT: In A4/LEARN, age moderated the association between plasma p-tau217 and neocortical tau accumulation (β=-0.06, =-0.09 - -0.04, p <0.001; Figure 1A), such that the effects of elevated p-tau217 on tau were stronger at younger ages. Similarly in ADNI, age moderated the association between p-tau217/Aβ42 and neocortical tau accumulation (β=-0.12, =-0.18 - -0.06, p <0.001;Figure 1B, such that the effects of elevated p-tau217/Aβ42 on tau accumulation were stronger at younger ages. The raw tau trajectories for one neocortical region as a function of age and p-tau217 is illustrated in Figure 1C. In Post-hoc analysis covarying APOEε4 status, the interactive effects of age and p-tau217 remained significant.

CONCLUSION: There is evidence for more aggressive tau-related processes in younger individuals. These findings highlight the critical need for early identification and enrollment in AD clinical trials, potentially using plasma biomarkers in primary care and secondary care.},
}

Humans
*tau Proteins/blood/metabolism
Male
Female
*Biomarkers/blood
Aged
Positron-Emission Tomography
*Amyloid beta-Peptides/blood/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Longitudinal Studies
*Brain/metabolism/diagnostic imaging
Middle Aged
Peptide Fragments/blood
Aged, 80 and over
Phosphorylation

@article {pmid41505107,
year = {2025},
author = {Lee, YR and Zeng, X and Gu, JM and Farinas, MF and Kofler, JK and Tudorascu, DL and Shaaban, CE and Lingler, JH and Pascoal, TA and Klunk, WE and Villemagne, VL and Berman, SB and Sweet, R and Snitz, BE and Ikonomovic, MD and Kamboh, MI and Lopez, OL and Cohen, AD and Karikari, TK},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106865},
doi = {10.1002/alz70856_106865},
pmid = {41505107},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/blood/diagnosis ; Male ; Female ; Aged ; Amyloid beta-Peptides/blood ; *Dried Blood Spot Testing/methods ; tau Proteins/blood ; Aged, 80 and over ; },
abstract = {BACKGROUND: Efforts to diagnose Alzheimer's disease (AD) through blood tests have identified many promising biomarkers. However, traditional plasma collection via venipuncture requires a medical professional and cold-chain transport, making it unsuitable for remote or home-based testing. Dried plasma spots (DPS) allow self-sampling and easier storage/transport but only collect a small amount of plasma. The Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA) is an innovative platform that quantifies biomarkers from small plasma. This study compares DPS and traditional plasma using NULISA to evaluate DPS's potential for AD biomarkers.

METHOD: Venous blood from 85 paricipants at the University of Pittsburgh Alzheimer's Disease Research Center, Connectomics in Brain Aging (CoBrA), and INflammation ROles in Aging and Alzheimer's disease Study (INROAADS). DPS samples were created by applying blood to Telimmune Duo Plasma Prep Cards. Traditional plasma samples were collected through centrifugation. Alamar sample diluent was used to extract proteins from DPS. NULISAseq CNS Panel was performed on an Argo HT following the manufacturer's instructions. The reproducibility of assays was evaluated using a Sample Control run in triplicate across runs. Spearman correlation assessed the concordance between DPS and traditional plasma samples.

RESULT: The NULISAseq CNS panel quantified 127 targets with high reproducibility, showing median intra- and inter-plate coefficients of variation <10%. In DPS samples, 104 targets (82%) were detected above the limit of detection (LOD) in >50% of samples, compared to 123 (97%) in plasma. Median sample detectability was 82.7% for DPS and 96.1% for plasma. Among the classical AD biomarkers, NFL, GFAP, MAPT, p-tau181, p-tau217, and p-tau231 showed high detectability (71% to 99%), while Aβ38, Aβ40, and Aβ42 had low detectability (29% to 35%). A moderate correlation was observed between DPS and plasma samples for these biomarkers, with correlation coefficients ranging from 0.197 to 0.616. Across the whole panel, the median correlation coefficient was 0.369, with NEFH (0.831), CHIT1 (0.829), and IL5 (0.783) showing the highest correlation.

CONCLUSION: Our results support the potential of DPS for remote and home-based testing, enabled by technologies like NULISA that quantify biomarkers from low plasma volumes. Further optimization of DPS methods is needed to improve concordance with classical plasma samples.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/blood/diagnosis
Male
Female
Aged
Amyloid beta-Peptides/blood
*Dried Blood Spot Testing/methods
tau Proteins/blood
Aged, 80 and over

@article {pmid41505106,
year = {2026},
author = {Huang, AY and Cheng, Y and Ku, J and Zhao, B and Park, J and Kim, D and Choi, J and Lee, EA},
title = {Accurate detection of somatic single-nucleotide variants from bulk RNA-seq data using RNA-MosaicHunter.},
journal = {Nucleic acids research},
volume = {54},
number = {1},
pages = {},
doi = {10.1093/nar/gkaf1450},
pmid = {41505106},
issn = {1362-4962},
support = {DP2AG072437/NH/NIH HHS/United States ; R01AG070921/NH/NIH HHS/United States ; R56AG079857/NH/NIH HHS/United States ; R01AG088082/NH/NIH HHS/United States ; R01AG070921/NH/NIH HHS/United States ; },
mesh = {Humans ; *Polymorphism, Single Nucleotide ; *Software ; *RNA-Seq/methods ; Alzheimer Disease/genetics ; *Computational Biology/methods ; *Sequence Analysis, RNA/methods ; Mutation ; },
abstract = {Somatic variants are increasingly recognized as contributors to diverse non-cancer, developmental, and aging-related disorders. However, most tools for detecting somatic single-nucleotide variants (sSNVs) were designed for DNA sequencing and primarily tailored to cancer datasets, leaving a critical gap in harnessing the rich potential of RNA-seq for sSNV identification, particularly in non-cancer tissues with low mutation rates. Here, we introduce RNA-MosaicHunter, a novel bioinformatic tool for accurate sSNV detection from bulk RNA-seq. In two benchmarking datasets, it demonstrated high precision (94.7% in TCGA and 99.3% in a cell-line mixture) with sensitivities of 53.4% and 38.9%, respectively, in the default mode that maximizes precision. We then applied RNA-MosaicHunter to profile 827 RNA-seq samples in three tissue types from the Genotype Tissue Expression project (GTEx), where it outperformed previous methods in capturing mutational characteristics associated with normal aging. We further utilized RNA-MosaicHunter to analyze RNA-seq data from 382 Alzheimer's disease (AD) brain samples and 480 age-matched controls and revealed a significantly higher burden of sSNVs in AD cerebral cortex, suggesting the potential contribution of sSNVs to AD pathogenesis. RNA-MosaicHunter enables accurate profiling and characterization of sSNVs from RNA-seq data, advancing the understanding of the role of somatic variants across diverse tissues and diseases.},
}

Humans
*Polymorphism, Single Nucleotide
*Software
*RNA-Seq/methods
Alzheimer Disease/genetics
*Computational Biology/methods
*Sequence Analysis, RNA/methods
Mutation

@article {pmid41505031,
year = {2025},
author = {Lin, M and Maiti, P and Zhang, J and Blazhenets, G and Rocha, S and Shankar, R and Amuiri, A and Hammers, DB and Eloyan, A and Kirby, K and Koeppe, RA and Carrillo, MC and Dickerson, BC and Apostolova, LG and Rabinovici, GD and Joie, R and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105737},
doi = {10.1002/alz70856_105737},
pmid = {41505031},
issn = {1552-5279},
mesh = {Humans ; Positron-Emission Tomography ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology/classification ; *tau Proteins/metabolism ; Biomarkers/metabolism ; Middle Aged ; Aged ; Longitudinal Studies ; *Brain/diagnostic imaging/metabolism/pathology ; Disease Progression ; Cross-Sectional Studies ; Carbolines ; },
abstract = {BACKGROUND: The clinical heterogeneity of Early-Onset Alzheimer's Disease (EOAD) is a key factor behind delayed diagnosis within this young(<65yo) group. However, most research has focused on late-onset amnestic participants and largely underutilized tau-PET, despite its ability to link neuropathology with clinical outcomes. We aimed to characterize tau-based subtypes through a robust data-driven approach in the Longitudinal Early-onset Alzheimer's Disease Study.

METHOD: Baseline [18F]Flortaucipir-PET scans from 365 amyloid-PET-positive participants with sporadic EOAD were quantified in 10 regions: left and right medial temporal, lateral temporal, occipital, parietal, and frontal. Tau-PET values were z-scored against 85 amyloid-PET-negative cognitively normal age-matched controls and fitted into Subtype and Stage Inference (SuStaIn), an unsupervised clustering algorithm that simultaneously models subtypes and progression from cross-sectional data.

RESULT: Three tau-PET-based subtypes were identified (Figure 1): Subtype1 (n = 144, 39.5%) had a typical bilateral temporoparietal pattern, while Subtype2 (n = 111, 30.4%) showed predominant left temporal binding, and Subtype3 (n = 104, 28.5%) showed early occipital tau. Subtypes show no significant demographic differences (Figure 2a) but were associated with clinical presentations. Subtype1 was enriched in amnestic participants, while Subtype2 accounted for 61% participants with primary progressive aphasia, and Subtype3 included 79% participants with posterior cortical atrophy (Figure 2b). At baseline, higher SuStaIn stages were associated with higher CDR-SB (Figure 2c). All subtypes showed longitudinal increase in CDR-SB, but clinical decline was faster in Subtype1 (Figure 2d). When follow-up Flortaucipir-PET scans were fitted to SuStaIn trained on baseline data, 85.6% participants were clustered within the same subtype as their baseline scans; SustaIn stage increased by 0.56/year on average with no difference across subtypes (Figure 3a-b). Modeling voxelwise tau-PET over time revealed striking differences (Figure 3c), as each subtype showed significant accumulation in regions that were relatively spared at baseline: tau-PET increase predominated in the occipital lobe for Subtype1, in bilateral frontal and right temporal areas for Subtype2, and bilateral frontotemporal lobes for Subtype3.

CONCLUSION: SuStaIn was able to identify robust tau-PET-based subtypes that were associated, but not redundant with known clinical phenotypes in AD. Subtypes exhibited differences in prospective clinical decline and patterns of tau-PET changes, highlighting their potential to refine prognosis and improve progression monitoring in clinical practice and trials.},
}

Humans
Positron-Emission Tomography
Male
Female
*Alzheimer Disease/diagnostic imaging/metabolism/pathology/classification
*tau Proteins/metabolism
Biomarkers/metabolism
Middle Aged
Aged
Longitudinal Studies
*Brain/diagnostic imaging/metabolism/pathology
Disease Progression
Cross-Sectional Studies
Carbolines

@article {pmid41505027,
year = {2025},
author = {Kinton, S and Dujardin, S and Levit, M and Pao, PC and Sardi, P and Zhang, B and Dodge, J and Krishnan, R and Rizzo, M and Teunissen, CE and Zetterberg, H and Blennow, K and Kollmorgen, G and Ramia, N and Fernandes, SBG and Krüger, R and Borejko, O and Aarsland, D and Hu, M and Klockgether, T and Brockmann, K and Gasser, T and Jessen, F and Spottke, A and van der Flier, WM and Lemstra, AW and Tijms, BM and Frisoni, GB and Hort, J and Nedelska, Z and Chevalier, C and Visser, PJ and Vos, SJB},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106780},
doi = {10.1002/alz70856_106780},
pmid = {41505027},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid ; *tau Proteins/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid ; Female ; Male ; Aged ; Cross-Sectional Studies ; Proteomics ; Middle Aged ; Peptide Fragments/cerebrospinal fluid ; },
abstract = {BACKGROUND: Aggregation of amyloid beta (Aβ) and tau proteins is a hallmark of Alzheimer's disease (AD) and tauopathies. In AD, extracellular deposition of Aβ peptide precedes tau aggregation and the onset of neuroinflammatory processes. Both neuroinflammation and tau deposition are associated with synaptic loss, neurodegeneration, and cognitive decline. However, the precise sequence of events from amyloid deposition to tau aggregation, neuroinflammation, and neurodegeneration remains unclear. A cross-sectional analysis of tau and other proteins in the cerebrospinal fluid (CSF) of AD patients can provide insight into the inflammatory and degenerative processes. Tau levels may be used as a proxy for disease progression, and we hypothesize that the expression of neuroinflammatory markers will be modulated in response to increasing tau aggregation.

METHOD: To investigate this, we collaborated with the EPND-biomarker consortium to analyze over 150 human CSF samples from AD and control patients. We measured levels of Aβ1-40, Aβ1-42, pTau181, and total tau, and conducted proteomic profiling using the O-link and SomaScan platforms. Next, AD patients were stratified into Aβ+Tau+ and Aβ+Tau- groups to identify biomarkers associated with Aβ and/or tau aggregation.

RESULT: As expected, inflammation markers were elevated in AD CSF samples compared to controls. Interestingly, we observed distinct correlations between these markers and amyloid versus tau pathology biomarkers. Approximately 10% of the measured CSF proteins (∼250 proteins) showed significant differences (p < 0.05) between AD and control samples. CSF samples with elevated tau levels exhibited altered levels of proteins involved in the complement cascade, cytokine-cytokine receptor interactions, cell adhesion, and vesicular transport.

CONCLUSION: Increased inflammation markers were observed in AD. Proteins linked to innate immune response and synaptic loss were significantly altered in relation to tau aggregation. These findings are crucial for guiding therapeutic strategies for neurodegenerative diseases and assessing their efficacy.},
}

Humans
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid
*tau Proteins/cerebrospinal fluid
*Amyloid beta-Peptides/cerebrospinal fluid
Female
Male
Aged
Cross-Sectional Studies
Proteomics
Middle Aged
Peptide Fragments/cerebrospinal fluid

@article {pmid41505017,
year = {2026},
author = {Araki, K and Yamauchi, K and Ito, S and Koike, M and Hioki, H},
title = {The difference in immunohistochemical reactivity of monoclonal antibodies against amino-terminal residues of amyloid-β peptide.},
journal = {Anatomical science international},
volume = {},
number = {},
pages = {},
pmid = {41505017},
issn = {1447-073X},
support = {JP23K06310//Japan Society for the Promotion of Science/ ; JP22K20692//Japan Society for the Promotion of Science/ ; JP20K07743//Japan Society for the Promotion of Science/ ; JP21H02592//Japan Society for the Promotion of Science/ ; JP21dm0207112//Japan Agency for Medical Research and Development/ ; JPMJMS2024//Japan Science and Technology Agency/ ; },
abstract = {Immunohistochemistry for amyloid-β peptide is a valuable method for Alzheimer's disease research. Despite a wide variety of available antibodies against the peptides, the difference of immunohistochemical reactivity is not fully described among them. Immunohistochemical reactivity of amyloid-β antibodies is critical for accurate and reliable evaluation of amyloid-β burden in patients as well as models of Alzheimer's disease. Here, we examined immunohistochemical reactivity of two mouse and one rabbit monoclonal antibodies against the N-terminal region of amyloid-β peptides using two Alzheimer's disease mouse models, App[NL-F] and App[NL-G-F]. 6E10, 82E1 and D54D2 Aβ antibodies were used. We found significant differences in the immunohistochemical reactivity in both App[NL-F] and App[NL-G-F] models. While 6E10 immunoreactivity was mainly localized to amyloid-β plaques, D54D2 and 82E1 antibodies stained much more broadly beyond plaques. Interestingly, the latter two antibodies showed blurred filamentous immunoreactivity beyond plaque cores. Double immunostaining using a tyramide signal amplification method, Fluorochromized Tyramide-Glucose Oxidase, suggested that the differential immunohistochemical outcomes were only partially attributable to their sensitivity. Moreover, heat induced epitope retrieval did not affect the differential immunohistochemical outcomes. Our analysis indicates that outcomes of amyloid-β immunohistochemistry are highly contingent on the antibody used in the study.},
}

@article {pmid41505001,
year = {2026},
author = {Wang, Y and Zhang, G and Wang, L and Cheng, Z and Zhao, Z},
title = {Pristimerin Alleviates Nanoparticulate Titanium Dioxide-Triggered Neurodegeneration in Hippocampal and Cortex by Downregulation of Inflammation and Oxidative Damage.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {41505001},
issn = {1559-0720},
support = {2022J01785//Fujian Province Scientific Foundation/ ; 2021QH1124//Startup Fund for Scientific Research, and Fujian Medical University/ ; },
abstract = {The utilization and toxicity of titanium have become global concerns, primarily owing to the increasing prevalence of titanium dioxide nanoparticles (TNPs) in the environment. The toxicity of TNPs is pivotal in the pathophysiology of neurodegenerative diseases, which are characterized by the formation of neuritic plaques and neurofibrillary tangle associated with Alzheimer's disease (AD). This study assessed behavioral changes in mice triggered by TNPs, focusing on β-amyloid aggregation, DNA damage, inflammation, oxidative stress (OS), and histopathological abnormalities. In addition, the neuroprotective efficacy of pristimerin (PST) against TNP-induced neurotoxicity was evaluated. Mice were orally administered TNPs (5 mg/kg body weight) and treated with PST (12 mg/kg body weight) for 65 days. Spatial working memory was assessed using object recognition, Morris water maze, T-, and Y-maze evaluations. TNPs markedly increased β-amyloid accumulation, altered cytokine levels, heightened DNA damage, decreased antioxidant enzymatic activity, and elevated OS while impairing cognitive memory capacity in the murine brain cortex (CTX) and hippocampus (HPC). In conclusion, TNPs may exhibit significant neurotoxicity following exposure, and PST may serve as a potential protective mechanism against neuronal degeneration.},
}

@article {pmid41504939,
year = {2026},
author = {Evola, V and Parmar, MS},
title = {Targeting neuroinflammation in neurodegenerative disorders: the emerging potential of semaglutide.},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
volume = {75},
number = {1},
pages = {13},
pmid = {41504939},
issn = {1420-908X},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/immunology ; *Glucagon-Like Peptides/therapeutic use/pharmacology ; Animals ; *Neuroprotective Agents/therapeutic use ; *Neuroinflammatory Diseases/drug therapy ; *Anti-Inflammatory Agents/therapeutic use ; Glucagon-Like Peptide-1 Receptor Agonists ; Glucagon-Like Peptide 1 ; },
abstract = {BACKGROUND: Chronic neuroinflammation is increasingly recognized not as a secondary effect but as a primary driver of neurodegenerative disease progression. In conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD), and Lewy body dementia (LBD), dysregulated glial activity, marked by sustained microglial and astrocytic activation, initiates a cascade of cytokine release, oxidative stress, and impaired neuronal support. This review synthesizes recent advances in understanding these shared inflammatory processes, emphasizing how glia-centric pathology shapes disease-specific trajectories and therapeutic responses.

FINDINGS: Within this framework, we evaluate the therapeutic potential of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) with emerging neuroprotective properties. Preclinical studies suggest that semaglutide can suppress pro-inflammatory signaling, mitigate oxidative injury, and enhance key anti-inflammatory and neuroprotective pathways that restore trophic support and cellular resilience. We also examine real-world evidence and emerging human clinical trial data, which recently demonstrated that semaglutide rapidly modulates AD pathology by significantly reducing cerebrospinal fluid (CSF) levels of p-tau, t-tau, and neurogranin, and promoting a less inflammatory CD8[+]T-cell signature. In addition to reduction in neuroinflammation marker, YKL-40. While subsequent large-scale Phase 3 trials in early AD did not meet primary cognitive endpoints (CDR-SB) despite favorable biomarker modulation.

CONCLUSION: Positioning semaglutide as a therapeutic option targeting neuroinflammation-mediated neuropathology, this review underscores its potential for repurposing as a disease-modifying therapy across diverse neurodegenerative disorders and highlights the urgent need for targeted trials in MS, ALS, FTD, HD, and LBD-conditions that remain without effective immunomodulatory treatments despite clear inflammatory origins. However, while direct CSF measurements confirm limited but measurable BBB penetration, the clinical translation of its effects remains a key challenge.},
}

Humans
*Neurodegenerative Diseases/drug therapy/immunology
*Glucagon-Like Peptides/therapeutic use/pharmacology
Animals
*Neuroprotective Agents/therapeutic use
*Neuroinflammatory Diseases/drug therapy
*Anti-Inflammatory Agents/therapeutic use
Glucagon-Like Peptide-1 Receptor Agonists
Glucagon-Like Peptide 1

@article {pmid41504851,
year = {2025},
author = {Yang, D and Jiang, X and Niu, Y and Qu, Z and Kim, W and Thomas, C and Jiang, W and Tan, J and Xuan, F},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106773},
doi = {10.1002/alz70856_106773},
pmid = {41504851},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/diagnosis/blood ; tau Proteins/blood ; Immunoassay/methods ; Reproducibility of Results ; Amyloid beta-Peptides ; Neurofilament Proteins/blood ; Glial Fibrillary Acidic Protein/blood ; },
abstract = {BACKGROUND: Neurodegenerative diseases such as Alzheimer's disease (AD) require highly sensitive and specific diagnostic tools for early detection and monitoring. Immunoassay-based detection of disease-associated biomarkers in biofluids shows promise but faces challenges in sensitivity, reproducibility, and scalability. Our study presents a semi-automated immunoassay workflow powered by SPEAR (Successive Proximity Extension Amplification Reaction) technology to enhance detection capabilities and enable high-throughput biomarker analysis. Robustness was demonstrated through consistent results across different qPCR instruments, highlighting the method's adaptability in diverse laboratory settings.

METHOD: The core SPEAR technology employs a 2-factor authentication mechanism to minimize background from non-specific interactions and uses a homogeneous, wash-free workflow with a real-time PCR readout. This design facilitates straightforward integration into automation systems without requiring proprietary equipment. The majority of the workflow was automated on a Formulatrix F.A.S.T™ liquid handler using only 1 µL of diluted sample and paired with multiple qPCR instruments to demonstrate cross-platform consistency. Clinical plasma samples were tested for key AD biomarkers, including phosphorylated tau (p-Tau 217, p-Tau 231), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP).

RESULT: The SPEAR-based semi-automated workflow enables high-precision quantification of low-abundance biomarkers in single-digit femtomolar (fM) range. Intra- and inter-assay coefficients of variation (CV) were below 10%, and sample readings were consistent across different qPCR platforms, confirming the assay's robustness and scalability.

CONCLUSION: This SPEAR-powered semi-automated immunoassay workflow advances biomarker quantification for neurodegenerative disease diagnostics by improving sensitivity, reducing operator variability, and supporting high-throughput processing. Its cross-platform consistency underscores the assay's versatility in diverse laboratory environments. The platform's ability to detect low-abundance biomarkers from minimal sample volumes positions it as a valuable tool for both clinical and research applications.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/diagnosis/blood
tau Proteins/blood
Immunoassay/methods
Reproducibility of Results
Amyloid beta-Peptides
Neurofilament Proteins/blood
Glial Fibrillary Acidic Protein/blood