@article {pmid41469705,
year = {2025},
author = {Li, T and Zhang, J and Song, H and Zhang, R and Fan, F and Huang, Z and Zeng, ML and Peng, BW and Zhang, J},
title = {Border-associated macrophages: an emerging perspective from physiological basis and multi-disease roles to the mechanism of vascular cognitive impairment and dementia.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {302},
pmid = {41469705},
issn = {1742-2094},
support = {82501747//the Natural Science Foundation of China/ ; 82571371//the Natural Science Foundation of China/ ; 2025AFC006//the Natural Science Foundation of Hubei Province/ ; PTXM2025032//Medical Sci-Tech Innovation Platform of Zhongnan Hospital, Wuhan University/ ; ZY2023Z018//Key projects of Traditional Chinese Medicine Scientific research in 2023-2024 by Hubei Provincial Administration of Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Cognitive Dysfunction/pathology/immunology/metabolism ; *Dementia, Vascular/pathology/immunology/metabolism/physiopathology ; Animals ; *Macrophages/pathology/metabolism/immunology ; *Brain/pathology/immunology/metabolism ; },
abstract = {Brain border-associated macrophages (BAMs) are resident immune cells at the border of the central nervous system (CNS), and their physiological functions and roles in neurological diseases have been widely reported. However, the specific mechanisms by which BAMs contribute to vascular cognitive impairment and dementia (VCID) remain unclear. This article systematically reviews the subsets, origin and differentiation, molecular markers of BAMs, and their research progress in various brain diseases such as hypertension, Alzheimer's disease (AD), and stroke. On this basis, this article deeply analyzes the potential hypotheses of BAMs' involvement in the pathogenesis of VCID, including their regulation of neurovascular unit (NVU) homeostasis, their core role in neuroimmune inflammation, their impact on the lipid metabolism pathways in the CNS, and their involvement in the pathogenesis of vascular risk factor-related cognitive impairment (VRFCI). The mechanistic hypotheses proposed in this article aim to provide new perspectives for understanding the pathophysiology of VCID and may open up new directions for the development of early intervention and targeted treatment strategies.},
}

Humans
*Cognitive Dysfunction/pathology/immunology/metabolism
*Dementia, Vascular/pathology/immunology/metabolism/physiopathology
Animals
*Macrophages/pathology/metabolism/immunology
*Brain/pathology/immunology/metabolism

@article {pmid41468784,
year = {2025},
author = {Palanivel, V and Salkar, A and Shenoy, A and Eva, TA and Perera, R and Chitranshi, N and Gupta, V and You, Y and Mirzaei, M and Graham, SL and Gupta, V and Basavarajappa, D},
title = {Neuropeptide Y at the crossroads of neurodegeneration: Mechanistic insights and emerging therapeutic strategies.},
journal = {Neuropeptides},
volume = {115},
number = {},
pages = {102583},
doi = {10.1016/j.npep.2025.102583},
pmid = {41468784},
issn = {1532-2785},
abstract = {Neuropeptide Y (NPY), a widely distributed and highly conserved neuropeptide, plays a central role in the regulation of diverse physiological processes, including stress responses, energy homeostasis, vascular tone, and immune modulation, via activation of its receptor subtypes. Beyond its physiological roles, the dysregulation of NPY expression has been documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Machado-Joseph disease, and retinal disorders such as diabetic retinopathy and glaucoma. These alterations in NPY levels and receptor activity highlight its potential not only as a biomarker for disease progression but also as a promising therapeutic target. Previous evidence revealed that NPY exerts neuroprotection by alleviating excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation while concurrently facilitating neurogenesis, synaptic plasticity, and cellular resilience. NPY activates receptor-mediated intracellular signaling cascades like PI3K/Akt, MAPK/ERK, and p38K, that control cellular survival, proteostasis, and inflammation and thereby influence disease trajectories. Understanding NPY operation with these mechanisms can unveil new avenues for targeted therapy. Current insights into the complex roles of NPY in neurodegeneration are discussed in this review, and their implications in diagnostic and treatment strategies are addressed.},
}

@article {pmid41467972,
year = {2025},
author = {Chang, ST and Wu, HY and Chiu, YL and Chuang, YF},
title = {Anti-herpetic treatment reduces dementia risk: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409323},
doi = {10.1177/13872877251409323},
pmid = {41467972},
issn = {1875-8908},
abstract = {BackgroundHuman herpesvirus (HHV) infections, particularly for herpes simplex virus (HSV) and varicella-zoster virus (VZV), may increase dementia risk, yet the protective effects of anti-herpetic medications remained unclear.ObjectiveThis systematic review and meta-analysis of observational studies aimed to examine the association between anti-herpetic medications and dementia, focusing on HSV or VZV-related infections.MethodsThis study followed PRISMA guidelines (CRD42022368318). Cohort or nested case-control studies published from databases' inception to December 2024 were systematically searched in PubMed, MEDLINE, Embase, Cochrane Library, PsycINFO, and Web of Science. Eligible studies evaluated anti-herpetic medications (e.g., acyclovir, famciclovir, ganciclovir, valacyclovir, valganciclovir) and dementia risk in non-demented adults aged ≥50. Pooled adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) were analyzed using random-effects models. Subgroup and meta-regression analyses were performed to explore potential sources of heterogeneity and effect modifiers.ResultsFourteen cohort studies involving more than 10 million older adults were included. To demonstrate the effects of anti-herpetic medications in various clinical scenarios, the meta-analysis compared: diagnosed and treated versus diagnosed but untreated (aHR=0.77, 95% CI: 0.67-0.89); treated versus untreated regardless of diagnosis (aHR=0.90, 95% CI: 0.87-0.94); and diagnosed and treated versus neither diagnosed nor treated (aHR=0.87, 95% CI: 0.78-0.97). Subgroup analysis and meta-regression identified infection severity as a significant modifier (p < 0.0001), explaining 89.01% of heterogeneity.ConclusionsThis systematic review and meta-analysis reveals notable protective effect of anti-herpetic medication usage on dementia, and the effect is especially pronounced in patients with severe alpha herpesvirus infections.},
}

@article {pmid41467438,
year = {2025},
author = {Zhao, J and Wang, J and Guo, X},
title = {Organoids: Key advances, optimization, and technological iterations in their application to neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00924},
pmid = {41467438},
issn = {1673-5374},
abstract = {Organoid technology, as an innovative approach, has shown great potential in disease modeling, target screening, and the development of treatment strategies. However, traditional organoids still have three major limitations in research: the absence of specific cell types, the lack of blood-brain barrier structure, and insufficient reproducibility of experimental results. In recent years, researchers have gradually overcome these limitations by introducing innovative techniques such as advanced culture methods, microfluidic systems, bioprinting, organoid transplantation, and assembloid construction. This progress has facilitated the widespread application of organoids in the study of neurodegenerative diseases. This paper aims to systematically review the technological innovations of organoids in the study of neurodegenerative diseases. By summarizing classical organoid construction strategies and their limitations, it emphasizes the value of organoids in comprehensive applications within neurodegenerative disease research. In this review, we focus on five specific neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Research in these diseases demonstrates that organoids improve experimental accessibility and reduce development cycles in disease modeling, target discovery, and therapeutic strategy formation. Using customized equipment and gene editing techniques, these organoids can be tailored to specific needs, providing pathophysiologically relevant disease models and enhancing our understanding of neurodegenerative diseases. Although organoid technology has demonstrated significant advantages in disease research, its potential for treating neurodegenerative diseases has not yet been fully explored, which may become an important direction for future research.},
}

@article {pmid41467376,
year = {2025},
author = {Alexandrova, EG and Abakumova, TR and Ziganshina, LE},
title = {Use of nootropics in Alzheimer's disease: An analysis of regulatory positions and drug policies in the countries of the Commonwealth of Independent States.},
journal = {The International journal of risk & safety in medicine},
volume = {},
number = {},
pages = {9246479251410817},
doi = {10.1177/09246479251410817},
pmid = {41467376},
issn = {1878-6847},
abstract = {ObjectiveTo analyse regulatory positions and drug policies of the Commonwealth of Independent States (CIS), compared to those of the EU, UK, USA i of the nootropics, used in Russia for Alzheimer's disease.MethodsWe searched E-library to reveal the list of nootropics used and studied in Russia for Alzheimer's disease. We assessed official pharmaceutical registries of nine countries for registration status of identified nootropics, 7 National Essential Medicines Lists (EML), and four clinical practice guidelines (CPG) on Alzheimer's disease. We compared the results of Russia with other countries regulatory and policy positions.ResultsE-Library searches identified 11 nootropicspiracetam, citicoline, idebenone, vinpocetine, choline alfoscerate, Cerebrolysin®, Kortexin®, ethylmethylhydroxypyridine succinate, glycine, nicergoline, nimodipine. Eight nootropic have registration for use in all CIS countries (excluding idebenone, nimodipine), four (piracetam, nimodipine, nicergoline, idebenone) - in UK, nimodipine - in the USA, and idebenone - in EU. National EMLs included: nine nootropics (Russia), 8 - Belarus and Kazakhstan, 4 - Uzbekistan, 2 - Armenia. The studied nootropic agents are not included on the WHO Model EML and on the National EML of the Kyrgyz Republic. They are not listed in the CPG for Treatment of dementia and Alzheimer's disease in the USA, the EU, and the UK. Russian CPGs for Alzheimer's disease recommend Cerebrolysin® and choline alfoscerate.ConclusionsThe studied nootropics are registered for use and listed on National EMLs of Russia, Armenia, Belarus, Kazakhstan, Uzbekistan. None is included on the WHO Model EML and the National EML of Kyrgyzstan, Only CPG of the RF recommend using two nootropics as adjuvant therapy of Alzheimer's disease, Cerebrolysin® and choline alfoscerate. CPG of the European Union, the United Kingdom, and the USA do not mention nootropics as potential treatment options for Alzheimer's disease.},
}

@article {pmid41466363,
year = {2026},
author = {de Magalhães, CG and Moldakozhayev, A and Lopez, MV and Bowman, GL and Chhatwal, JP and Kellis, M and Mohs, R and Nisenbaum, L and Quiroz, YT and Raju, RM and Sperling, RA and Moqri, M and Gladyshev, VN},
title = {The Right Person, the Right Treatment, at the Right Time in Alzheimer's Disease: Insights From the 2025 Brain Aging Symposium.},
journal = {Aging cell},
volume = {25},
number = {1},
pages = {e70351},
doi = {10.1111/acel.70351},
pmid = {41466363},
issn = {1474-9726},
mesh = {Humans ; *Alzheimer Disease/therapy/pathology/metabolism ; *Brain/pathology/metabolism ; *Aging/pathology ; Biomarkers/metabolism ; },
abstract = {On October 22nd, 2025, Brain Aging Symposium took place at Harvard Medical School bringing together leading researchers from academia and partner organizations to discuss recent advances in measuring and monitoring human brain aging trajectories, with a particular focus on Alzheimer's disease (AD). A central theme emerged: achieving "the right treatment for the right person and the right time" through precision medicine approaches. Key advances included the unprecedented validation of plasma-based biomarkers, particularly brain-derived p-Tau217 that can identify seeding AD pathology with remarkable specificity, making large-scale screening newly feasible. Integrating multi-level "omic" modalities, spanning genetic information, molecular biomarkers of nutrition, lipid and protein signatures, neuroimaging measures, cognitive assessments, and lifestyle factors, enhances disease risk modeling and trajectory prediction beyond the capacity of any single marker. Early findings highlight critical roles for nutritional and lipid metabolism, and myelin integrity in brain aging, with cell and sex-specific vulnerabilities identified in response to nutrition, social isolation, and metabolic stress. Computational approaches that combine single-cell genomics, epigenomics, and artificial intelligence have been shown to accelerate causal discovery and therapeutic development. However, significant challenges remain: current biomarkers explain only half the variance in cognitive decline, racial and ethnic differences in biomarker levels lack mechanistic understanding, and scalable tools for comprehensive brain aging assessment are needed. The symposium underscored that preventing AD will require intervening during the preclinical asymptomatic phase. These multimodal screening platforms, coupled with mechanistically driven therapeutics, reduction in modifiable risk factors, including nutrition, vascular health, and social determinants of health, could profoundly impact the field.},
}

Humans
*Alzheimer Disease/therapy/pathology/metabolism
*Brain/pathology/metabolism
*Aging/pathology
Biomarkers/metabolism

@article {pmid41465832,
year = {2025},
author = {Pilśniak, J and Węgrzynek-Gallina, J and Bednarczyk, B and Buczek, A and Pilśniak, A and Chmiela, T and Jarosińska, A and Siuda, J and Holecki, M},
title = {The Role of Glucagon-like Peptide-1 Receptor Agonists in Alzheimer's and Parkinson's Disease: A Literature Review of Clinical Trials.},
journal = {Life (Basel, Switzerland)},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/life15121893},
pmid = {41465832},
issn = {2075-1729},
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes and obesity due to their metabolic effects. Emerging evidence suggests they may also have neuroprotective effects, indicating their potential as disease-modifying therapies in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Preclinical studies in animal models have demonstrated that GLP-1RAs can reduce neuroinflammation, oxidative stress, neuronal apoptosis, and pathological protein aggregation, while enhancing glucose metabolism and mitochondrial function. This narrative review analyzed results from human clinical trials evaluating GLP-1RAs in AD and PD, based on a search of four databases (Web of Science, Medline, Embase, and Clinical Trials). The analysis included eleven studies. In AD, clinical trials suggest that GLP-1RAs such as liraglutide and semaglutide may enhance brain glucose metabolism, facilitate glucose transport across the blood-brain barrier, and benefit neuronal networks. However, most studies did not demonstrate improvements in cognitive functions or radiological markers. Short-term clinical trials of GLP-1RAs, including exenatide and lixisenatide, demonstrated promising effects on motor and selected non-motor symptoms in patients with PD, but their disease-modifying effects remain unproven. GLP-1RAs showed a favorable safety profile. Despite promising findings, small study populations, heterogeneous protocols, and short observation periods limit definitive conclusions. Further larger, long-term studies are needed, particularly to clarify the risk-benefit balance, weight control, and long-term outcomes.},
}

@article {pmid41465466,
year = {2025},
author = {Xu, C and Owen, JE and Gislason, T and Benediktsdottir, B and Ye, J and Robinson, SR},
title = {Limited Microvascular Remodelling Occurs in the Aged Human Hippocampus in Obstructive Sleep Apnoea.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
doi = {10.3390/ijms262412040},
pmid = {41465466},
issn = {1422-0067},
support = {Not applicable//RMIT University/ ; },
mesh = {Humans ; *Sleep Apnea, Obstructive/pathology/physiopathology/therapy ; Male ; Middle Aged ; Female ; Aged ; *Hippocampus/blood supply/pathology ; *Microvessels/pathology/physiopathology ; Adult ; *Aging/pathology ; *Vascular Remodeling ; Continuous Positive Airway Pressure ; },
abstract = {In mice, intermittent hypoxia is associated with an increase in microvessels in the hippocampus, whereas in humans with obstructive sleep apnoea (OSA), microvessels are lost from the heart and retina. The present study investigated microvascular changes in the hippocampus of patients with OSA, and whether patient age or use of continuous positive airway pressure (CPAP) influence microvascularisation. Using autopsy samples from 31 people with confirmed OSA, microvessels were immunolabelled and quantitatively analysed. Compared to the Low OSA group, the High OSA group had larger mean microvessel diameters in the fimbria and CA4, and greater mean microvessel length in the fimbria, which are indicative of microvascular remodelling. An absence of angiogenesis was indicated by similar mean vessel counts in both OSA severity groups. Increased age was associated with microvascular remodelling in the fimbria only. Treatment with CPAP was not associated with changed patterns of microvascularisation. We conclude that: (i) no evidence was found for angiogenesis in the human hippocampus in OSA or ageing; (ii) increased OSA severity is associated with microvascular remodelling in the fimbria and CA4; (iii) microvascular remodelling does not appear to be influenced by CPAP use; (iv) limited adaptability of the microvasculature may underpin the vulnerability of the hippocampus to hypoxic injury, particularly in severe OSA.},
}

Humans
*Sleep Apnea, Obstructive/pathology/physiopathology/therapy
Male
Middle Aged
Female
Aged
*Hippocampus/blood supply/pathology
*Microvessels/pathology/physiopathology
Adult
*Aging/pathology
*Vascular Remodeling
Continuous Positive Airway Pressure

@article {pmid41465142,
year = {2025},
author = {Machowska, M and Leszek, J and Mikołajczyk-Tarnawa, A and Głowacka, K and Trypka, E and Rąpała, M and Piechota, J and Wiela-Hojeńska, A},
title = {The Diagnostic Reliability of BIN1 and TOMM40 Genotyping in Assessing Dementia Risk.},
journal = {Genes},
volume = {16},
number = {12},
pages = {},
doi = {10.3390/genes16121469},
pmid = {41465142},
issn = {2073-4425},
support = {RPDS.01.02.01-02-0002/20//Regional Operational Programme of the Lower Silesian Voivodeship 2014-2020, co-financed by the European Union, European Regional Development Fund/ ; },
mesh = {Humans ; *Mitochondrial Precursor Protein Import Complex Proteins/genetics ; Male ; Female ; Aged ; *Cognitive Dysfunction/genetics/diagnosis ; *Tumor Suppressor Proteins/genetics ; Polymorphism, Single Nucleotide ; *Adaptor Proteins, Signal Transducing/genetics ; *Alzheimer Disease/genetics/diagnosis ; *Nuclear Proteins/genetics ; Genotype ; *Dementia/genetics/diagnosis ; *Membrane Transport Proteins/genetics ; Genetic Predisposition to Disease ; Case-Control Studies ; Aged, 80 and over ; Middle Aged ; },
abstract = {OBJECTIVES: Alzheimer's disease (AD) and other dementias represent a growing public health concern, highlighting the need for reliable biomarkers for early diagnosis and treatment monitoring. This study evaluated the potential utility of BIN1 and TOMM40 genotyping in diagnosing mild cognitive impairment (MCI) and early-stage dementia.

METHODS: The BIN1 rs744373 and TOMM40 rs2075650 polymorphisms were genotyped in a cohort of 105 individuals diagnosed with MCI or dementia and in 164 cognitively healthy controls. Genotype distributions were compared between the groups, and the potential role of these variants in diagnostic assessment was explored.

RESULTS: A significantly higher frequency of the TOMM40 rs2075650 GG genotype was observed in patients with AD compared with cognitively healthy controls. In contrast, no statistically significant differences in genotype distribution were found among individuals with mild MCI, vascular dementia, or mixed dementia. Furthermore, the distribution of BIN1 rs744373 alleles did not differ significantly across the analyzed groups.

CONCLUSIONS: Data on the effects of BIN1 rs744373 and TOMM40 rs2075650 polymorphisms in MCI and dementia remain limited and inconsistent. In our study, significant differences were observed only for the TOMM40 rs2075650 GG genotype and G allele, which were more frequent in Alzheimer's disease patients than in controls. No significant associations were found for MCI, vascular dementia, or mixed dementia, nor for the BIN1 rs744373 polymorphism. These results suggest that TOMM40 rs2075650 genotyping may serve as an additional marker for assessing AD risk.},
}

Humans
*Mitochondrial Precursor Protein Import Complex Proteins/genetics
Male
Female
Aged
*Cognitive Dysfunction/genetics/diagnosis
*Tumor Suppressor Proteins/genetics
Polymorphism, Single Nucleotide
*Adaptor Proteins, Signal Transducing/genetics
*Alzheimer Disease/genetics/diagnosis
*Nuclear Proteins/genetics
Genotype
*Dementia/genetics/diagnosis
*Membrane Transport Proteins/genetics
Genetic Predisposition to Disease
Case-Control Studies
Aged, 80 and over
Middle Aged

@article {pmid41463129,
year = {2025},
author = {Eroglu, B and Velez, D and Jones, K and Deak, F and Eroglu, A},
title = {Amelioration of Alzheimer's Disease Pathology in Zebrafish by Photobiomodulation.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13123121},
pmid = {41463129},
issn = {2227-9059},
abstract = {Background/Objectives: The zebrafish is a widely used research model due to its characteristics, such as being transparent during development, sharing 70% of its genes with humans, and having conserved features of vertebrate aging, including deterioration of mitochondrial and cognitive functions. While affecting approximately 15% of the world population, neurodegenerative diseases, such as Alzheimer's disease (AD), are currently incurable, requiring testing of alternative treatment strategies. Hence, this study was conducted to test the hypothesis that an optimized photobiomodulation (PBM) therapy improves AD pathology through its multifaceted beneficial effects, including enhancing mitochondrial function and reducing oxidative stress and neuroinflammation. Methods: A pharmacological zebrafish model of AD was developed by adding small amounts (100 nM) of okadaic acid (OKA) directly to fish tanks for nine days. Next, some of OKA-treated and control zebrafish were subjected to an optimized near-infrared PBM therapy while others remain untreated. Results: When examined after OKA treatment, zebrafish brains displayed histological hallmarks of AD including, neurofibrillary tangles, vacuoles, and neuroinflammation. Behavioral tests using a T-maze revealed that OKA-treated zebrafish spent significantly less time in the reward arm than untreated controls (15.2% vs. 50%). In contrast, a sequential PBM therapy significantly reduced formation of neurofibrillary tangles, vacuoles, neuroinflammation, and improved mitochondrial biogenesis in brains of OKA-treated zebrafish while also improving their cognitive function as evidenced by being able to recall the reward arm and spending more time there similar to controls (55 and 57%, respectively). Conclusions: These findings suggest that (1) a fast, cost-effective zebrafish AD model can be developed using OKA treatment and (2) PBM therapy holds promise to ameliorate AD pathology.},
}

@article {pmid41463053,
year = {2025},
author = {N F Guimarães, G and Dos Santos Cardoso, F and Gamboa, L and W Barrett, D and Gonzalez-Lima, F},
title = {Abdominal Photobiomodulation and the Gut-Brain Axis: A Systematic Review of Mechanistic and Translational Evidence.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13123042},
pmid = {41463053},
issn = {2227-9059},
abstract = {Background/Objectives: Bidirectional communication between the gut and brain is central to neurological and psychiatric health, and abdominal photobiomodulation (PBM) has emerged as a promising non-invasive way to modulate this axis by targeting intestinal mitochondria, epithelial integrity, and the microbiota. We systematically reviewed preclinical and clinical evidence on abdominal PBM, alone or in combined protocols, reporting microbiome, metabolic, or neurobehavioral outcomes. Methods: Following PRISMA 2020 recommendations, we searched MEDLINE, Scopus, Web of Science, and ScienceDirect through May 2025 for animal and human studies applying PBM to the abdomen and reporting gut-related, metabolic, or brain-related outcomes. Results: Nine studies met the eligibility criteria (five human, four animal). Human trials, mainly in Parkinson's and Alzheimer's disease, used 630-904 nm light and reported gains in mobility, balance, cognition, and olfaction; one trial also showed microbiota modulation with a decreased Firmicutes:Bacteroidetes ratio. Animal models revealed cognitive improvement, reduced neuroinflammation, dopaminergic neuroprotection, and microbial rebalancing. Mechanistic findings converged on enhanced mitochondrial bioenergetics, redox and anti-inflammatory signaling, vagal activation, and short-chain fatty acid-mediated effects. Conclusions: Current evidence, though limited by small samples, heterogeneous dosimetry, combined treatment sites, and few sham-controlled human trials, suggests that abdominal PBM can influence the gut-brain axis through converging mitochondrial, immune, and microbial mechanisms. Adequately powered randomized trials with standardized dosimetry, validated mechanistic biomarkers, and integrative multi-omics analyses are needed to clarify causal pathways and optimize translational applications.},
}

@article {pmid41462869,
year = {2025},
author = {Sarbu, M and Ica, R and Biricioiu, MR and Dehelean, L and Zamfir, AD},
title = {Glycosphingolipids in Dementia: Insights from Mass Spectrometry and Systems Biology Approaches.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13122854},
pmid = {41462869},
issn = {2227-9059},
support = {PN-IV-P2-2.1-TE-2023-0175//UEFISCDI/ ; UAV-IRG-1-2025-8//Aurel Vlaicu University of Arad, Romania/ ; },
abstract = {This narrative literature review synthesizes recent evidence on glycosphingolipid (GSL) dysregulation in dementia, emphasizing discoveries enabled by mass spectrometry (MS) and systems biology. Focusing on the research published within the last decade, we selected studies that are relevant to GSL alterations in dementia and notable for their methodological advances. The findings were conceptually integrated to emphasize key molecular, analytical, and systems-level aspects across the major dementia types. The results from MS-based glycolipidomics in Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, Parkinson's disease dementia, and Huntington's disease consistently indicate altered GSL metabolism and shared molecular vulnerabilities in neuronal lipid regulation. At the same time, distinct GSL signatures differentiate individual dementias, reflecting the disease-specific mechanisms of neurodegeneration. The literature also reveals that recent advances in high-resolution MS and integrative analytical workflows have shifted GSL research from descriptive to mechanistic, facilitating the detailed mapping of species linked to neuroinflammation, protein aggregation, and synaptic dysfunction. Systems-level analyses combining MS data with other omics approaches increasingly depict GSLs as active regulators of neuronal function rather than inert membrane components. At the same time, emerging trends position GSLs as promising early biomarkers and potential therapeutic targets, while the growing use of artificial intelligence in MS data analysis is accelerating the detection of their subtle patterns, improving cross-disease comparisons. Together, these results reinforce the major role of MS-based platforms in discovering dementia-associated GSLs, identifying therapeutic targets, and influencing future strategies for diagnosis and treatment.},
}

@article {pmid41462867,
year = {2025},
author = {Fonseca, N and Nunes, M and Silva, PMA and Bousbaa, H and Ricardo, S},
title = {Galanthamine Fails to Reverse P-gp-Mediated Paclitaxel Resistance in Ovarian Cancer Cell Lines.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13122852},
pmid = {41462867},
issn = {2227-9059},
abstract = {Background: Ovarian cancer has the poorest prognosis of all gynecological malignancies, largely due to its chemoresistance, which poses significant treatment challenges. In this context, drug repurposing emerges as an innovative strategy that employs non-cancer treatments to interact with various signaling pathways, enhancing chemotherapy efficacy while minimizing toxicity. This study investigated the cytotoxic effects of galanthamine, currently used as an Alzheimer's disease, as a potential treatment for high-grade serous carcinoma, both individually and in combination with paclitaxel. Methods: The Presto Blue assay, viability marker assessments, immunocytochemical analysis of apoptosis, and a cumulative assay were employed to evaluate the functionality of P-glycoprotein. Results: The results indicated that galanthamine did not demonstrate cytotoxic or synergistic effects in either high-grade serous carcinoma cell line tested, suggesting that it is not a viable strategy for overcoming paclitaxel resistance in this context. The immunocytochemistry analysis indicated that galanthamine does not affect the expression of proteins related to cell viability and proliferation and is not associated with chemoresistance. Additionally, functional assays showed that galanthamine treatment did not affect its drug efflux function at the cellular level. Conclusions: Overall, the results indicate that galanthamine is unsuitable for reversing paclitaxel resistance despite some literature suggesting its potential interaction with P-glycoprotein.},
}

@article {pmid41461739,
year = {2025},
author = {Palachai, N and Buranrat, B and Pariwatthanakun, C and Noisa, P and Mairuae, N},
title = {Neuroprotective effects of Cratoxylum formosum (L.) leaf extract on β-amyloid-induced injury in human neuroblastoma SH-SY5Y cells.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {44730},
pmid = {41461739},
issn = {2045-2322},
support = {//the Faculty of Medicine, Mahasarakham University/ ; //Thai Traditional Medical Knowledge Fund/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/toxicity ; *Plant Extracts/pharmacology/chemistry ; *Plant Leaves/chemistry ; *Neuroprotective Agents/pharmacology/chemistry ; Cell Line, Tumor ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Cell Survival/drug effects ; *Neuroblastoma/metabolism/pathology/drug therapy ; Cyclic AMP Response Element-Binding Protein/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; *Peptide Fragments/toxicity ; Caspase 3/metabolism ; Apoptosis/drug effects ; Phosphorylation/drug effects ; },
abstract = {In Alzheimer's disease (AD), Amyloid beta peptide (Aβ), the primary constituent of senile plaques, has been documented as triggering oxidative stress and leading to the death of neuronal cells. Therefore, this research aims to investigate how the Cratoxylum formosum (L.) leaf extract mitigates oxidative stress and cellular damage induced by Aβ in SH-SY5Y cells. The SH-SY5Y cells were treated with Cratoxylum formosum (L.) extract both with and without Aβ25-35. Neuroprotection was evaluated through viability and lactate dehydrogenase (LDH) assays, accompanied by an analysis of various mechanisms including caspase-3/7 activity, levels of reactive oxygen species (ROS), phosphorylation of protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (ERK1/2), and cAMP-responsive element binding protein (CREB), expression of B-cell lymphoma 2 (Bcl-2) proteins, as well as catalase (CAT) and superoxide dismutase (SOD) activities. Results indicated an escalation in oxidative stress in cells exposed to Aβ, evidenced by increased ROS levels. Aβ further exacerbated caspase-3/7 activity, LDH release, and a decline in cell viability. Conversely, treatment with Cratoxylum formosum (L.) extract exhibited a concentration-dependent reduction in Aβ-induced neurotoxicity, manifesting in enhanced cell survival, reduced LDH release and ROS production, and suppression of caspase-3/7 activity. Moreover, it led to increased phosphorylation of Akt, ERK1/2, CREB, upregulated expression of Bcl-2 proteins, and enhanced activity of SOD and CAT. High-performance liquid chromatography (HPLC) analysis identified chlorogenic acid, 1,5-dicaffeoylquinic acid, and ferulic acid as the major phenolic constituents of Cratoxylum formosum (L.) extract. These results imply that the extract may provide protective effects against Aβ-induced neurotoxicity, although further studies are required to clarify its role in AD.},
}

Humans
*Amyloid beta-Peptides/toxicity
*Plant Extracts/pharmacology/chemistry
*Plant Leaves/chemistry
*Neuroprotective Agents/pharmacology/chemistry
Cell Line, Tumor
Oxidative Stress/drug effects
Reactive Oxygen Species/metabolism
Cell Survival/drug effects
*Neuroblastoma/metabolism/pathology/drug therapy
Cyclic AMP Response Element-Binding Protein/metabolism
Proto-Oncogene Proteins c-akt/metabolism
*Peptide Fragments/toxicity
Caspase 3/metabolism
Apoptosis/drug effects
Phosphorylation/drug effects

@article {pmid41461684,
year = {2025},
author = {Saremi, M and Safari, S and Alikhani, MY and Komaki, A and Siadat, SD and Asghari, B},
title = {Evidence for neuroprotection by Bacillus coagulans ATCC 7050 via synaptic plasticity and oxidative balance in Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {44690},
pmid = {41461684},
issn = {2045-2322},
support = {Grant Number: 140303292888//Vice Chancellor for Research and Technology, Hamadan University of Medical Sciences/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Oxidative Stress/drug effects ; Male ; *Neuronal Plasticity/drug effects ; Rats ; Rats, Wistar ; *Bacillus coagulans/physiology ; Disease Models, Animal ; Hippocampus/metabolism ; Amyloid beta-Peptides ; *Probiotics/pharmacology/administration & dosage ; Long-Term Potentiation ; *Neuroprotection ; Superoxide Dismutase/metabolism ; Memory, Short-Term ; Glutathione Peroxidase/metabolism ; Malondialdehyde/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic impairment, and oxidative stress. Probiotics with antioxidant and anti-inflammatory properties have been proposed as potential adjunctive strategies. This study examined whether oral administration of Bacillus coagulans ATCC 7050 could attenuate hippocampal oxidative stress, modulate synaptic plasticity, and influence spatial working memory in an Aβ1-42-induced rat model of AD. Adult male Wistar rats were assigned to Sham, AD, BC (probiotic only), and AD + BC groups. Working memory was assessed by Y-maze, synaptic function by perforant path-dentate gyrus long-term potentiation (LTP) recordings, and oxidative status by hippocampal malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) assays. AD rats exhibited reduced alternation percentage, impaired LTP (fEPSP slope and PS amplitude), elevated MDA, and decreased SOD and GPx activities versus Sham. B. coagulans treatment improved alternation percentage without affecting total entries, preserved PS amplitude from 30 min post-HFS, reduced MDA, and restored SOD activity, with partial GPx recovery. fEPSP slope remained reduced. These findings suggest B. coagulans ATCC 7050 mitigates oxidative stress, preserves neuronal excitability, and improves working memory in an Aβ-based AD model, supporting further investigation of its potential as a safe adjunct in early-stage disease.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology
*Oxidative Stress/drug effects
Male
*Neuronal Plasticity/drug effects
Rats
Rats, Wistar
*Bacillus coagulans/physiology
Disease Models, Animal
Hippocampus/metabolism
Amyloid beta-Peptides
*Probiotics/pharmacology/administration & dosage
Long-Term Potentiation
*Neuroprotection
Superoxide Dismutase/metabolism
Memory, Short-Term
Glutathione Peroxidase/metabolism
Malondialdehyde/metabolism

@article {pmid41461311,
year = {2025},
author = {Li, R and Wu, X and Yao, J and Chen, J and Shui, X and Zheng, X and Tian, W and Wang, L and Zhou, Y and Zhang, T and Chen, D and Liu, Y and Lee, TH},
title = {Selective degradation of DAPK1 via a novel hydrophobic tagging attenuates tau pathology in Alzheimer's disease.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2025.12.037},
pmid = {41461311},
issn = {2090-1224},
abstract = {INTRODUCTION: The upregulation of death-associated protein kinase 1 (DAPK1) is involved in tau hyperphosphorylation, neuronal apoptosis and cognitive dysfunction, which are key pathological features of Alzheimer's disease (AD). This result suggests that DAPK1 is novel therapeutic target for AD.

OBJECTIVES: This study aimed to evaluate the efficacy and mechanism of action of CJ1, a novel hydrophobic tagging (HyT)-based degrader, in targeting DAPK1 and alleviating in AD.

METHODS: A library of HyT-based bifunctional molecules was synthesized and systematically screened for their ability to degrade DAPK1 in vitro. CJ1 emerged as the most potent candidate degrader of DAPK1, and its capacity to induce DAPK1 degradation via the proteasome system was further evaluated. Its effects on tau phosphorylation and neuronal viability were evaluated in multiple cellular models. The in vivo efficacy of systemic CJ1 administration was assessed in two tau-related pathology (tauopathy) mouse models, AAV-hTau-P301L and hTau transgenic mice. Behavioral, biochemical, and histological analyses were performed to evaluate cognitive function, tau pathology, neuroinflammation, neurodegeneration, and safety.

RESULTS: CJ1 selectively promoted the posttranslational degradation of DAPK1 by the proteasome system without affecting DAPK1 mRNA expression. In vitro studies demonstrated that CJ1 significantly reduced tau phosphorylation at multiple AD-related sites. In vivo, CJ1 effectively penetrated the BBB, decreased the levels of both the soluble and insoluble forms of hyperphosphorylated tau, and suppressed the formation of neurofibrillary tangles. Additionally, CJ1 treatment restored synaptic and dendritic structures, enhanced spatial learning and memory, attenuated neuroinflammatory responses, preserved neuronal populations, and produced no evidence of systemic toxicity.

CONCLUSION: CJ1 functions as a potent and selective degrader of DAPK1, exerting neuroprotective effects by reducing tau hyperphosphorylation and preserving neuronal structural integrity. These findings support DAPK1 as a promising therapeutic target and suggest that further preclinical studies are warranted to evaluate CJ1 as a potential treatment for tauopathies associated with AD.},
}

@article {pmid41460672,
year = {2025},
author = {Sun, L and Wei, G and Ji, F and Ding, Y and Fan, J and Xu, Y and He, C and Zhou, Y and Liu, Z and Sun, Z and Zhou, D},
title = {Proteome-wide association study identifies novel Alzheimer's disease-associated proteins.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409352},
doi = {10.1177/13872877251409352},
pmid = {41460672},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disease with limited prevention and treatment options.ObjectiveWe aimed to identify proteins with genetically regulated plasma levels associated with AD and its related phenotypes.MethodsWe conducted a proteome-wide association study (PWAS) using Olink-based plasma proteomes (N = 45,540) from the UK Biobank Pharma Proteomics Project (UKB-PPP) and a large-scale genome-wide association study for AD (N case = 85,934, N control = 401,577). To validate and expand these findings, we conducted longitudinal analyses of AD and mild cognitive disorder (MCD) over a 13.7-year follow-up, along with genetic-based PWAS analyses and cross-sectional studies on hippocampal volume. Protein-protein interaction networks were constructed to explore mechanistic association.ResultsWe identified 30 AD-associated plasma proteins by PWAS, including 17 previously reported and 13 novel candidates (including FES, LRP11, and HDGF). Longitudinal cohort studies supported the role of PILRB and FES in AD and/or MCD. Additionally, the genetically determined higher levels of LRP11 were found to be associated with an increased hippocampal volume, including its subdivisions, along with a reduced risk of AD. In contrast, higher plasma levels of HDGF were linked to a decreased hippocampal volume, accompanied by an increased risk of AD. Protein-protein interaction analysis linked PILRA, PILRB, FES, and LRP11 to several pathological proteins associated with AD, including BIN1, ABCA7, and SORL1.ConclusionsThis study identified 13 novel candidates, with potential roles in hippocampal volume and AD risk, providing insights into disease mechanisms.},
}

@article {pmid41460605,
year = {2025},
author = {Fassbender, RV and Kehm, C and Otta, AL and Fink, GR and Onur, OA},
title = {Repetitive transcranial magnetic stimulation enhances alpha power in Alzheimer's disease patients.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251406972},
doi = {10.1177/13872877251406972},
pmid = {41460605},
issn = {1875-8908},
abstract = {BackgroundWith Alzheimer's disease (AD) presenting an ongoing challenge, innovative treatment methods are essential. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising noninvasive intervention, particularly targeting alpha band oscillations associated with AD-related cognitive decline.ObjectiveThis study aimed to investigate the effects of low-intensity rTMS over posterior cortical areas on alpha band oscillations and memory performance in AD patients compared to age-matched healthy controls.MethodsIn a single-blinded, sham-controlled rTMS-EEG study, we examined 14 amyloid-positive AD patients and 14 age-matched healthy controls. Continuous EEG was recorded at rest (eyes closed) before, during, and after stimulation. During stimulation, participants completed an episodic memory task.ResultsWe were able to demonstrate that during rTMS alpha power increased compared to sham, with a notable 25% increase observed in AD patients. However, comparison of memory performance under the sham and stimulation conditions revealed no significant stimulation effect.ConclusionsThese findings support and extend current knowledge of noninvasive brain stimulation mechanisms. Our results suggest that alpha frequency-tuned rTMS over posterior cortical areas can modulate pathological brain activity in AD patients even at low intensities. Given the limited sample size and moderate effect sizes, results should be interpreted with caution. Nevertheless, our results warrant further studies with long-term EEG-rTMS protocols to evaluate the potential therapeutic benefit.},
}

@article {pmid41460506,
year = {2025},
author = {Bernard, PJ and Więckowska, A and Grosjean, S and Godyń, J and Sałat, K and Detka, J and Palacz, N and Tyrybon, W and Jończyk, J and Szałaj, N and Zaręba, P and Martin, H and Maj, M and Jozwiak, K and Marco-Contelles, J and Ismaili, L},
title = {First Sustainable One-Pot Tandem Hantzsch Multicomponent Reaction/Click Reaction Approach for Novel Multitarget-Directed Ligands in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00806},
pmid = {41460506},
issn = {1948-7193},
abstract = {This study explores novel multitarget-directed ligands (MTDLs) showing anticholinesterase, antioxidant, neuroprotective, and calcium channel inhibitory activities, as promising compounds for Alzheimer's disease (AD) treatment. The rational design combined dihydropyridines (DHPs), known for calcium channel blocking and neuroprotective properties, with tacrine, a cholinesterase inhibitor. The key innovation of this work lies in the one-pot tandem Hantzsch multicomponent/click reaction used to synthesize new 18 DHPs IIIa-r. This sustainable and original approach aligns with green chemistry principles by reducing waste, energy consumption, and derivatives formation. Notably, DHP IIIj and IIIk demonstrated a multitarget profile and effectively reversed scopolamine-induced amnesia in a mouse model, showcasing its antiamnesic properties. These results suggested that DHP IIIj and IIIk hold promise as innovative therapeutic candidates for AD, validating the potential of MTDL strategy and highlighting the one-pot tandem synthesis as a significant advancement in medicinal chemistry.},
}

@article {pmid41460033,
year = {2026},
author = {Hu, XH and Jin, Q and Xie, JL and Wu, CL and Pan, JP},
title = {Docosahexaenoic acid modulates microglial autophagy via miR-589-5p/toll-like receptor 4 axis in Alzheimer's disease.},
journal = {Neuroreport},
volume = {37},
number = {2},
pages = {77-85},
doi = {10.1097/WNR.0000000000002236},
pmid = {41460033},
issn = {1473-558X},
mesh = {*Alzheimer Disease/metabolism ; *Autophagy/drug effects ; *MicroRNAs/metabolism ; *Docosahexaenoic Acids/pharmacology ; *Toll-Like Receptor 4/metabolism/drug effects ; Humans ; *Microglia/drug effects/metabolism ; Animals ; Male ; Mice ; Female ; Aged ; Amyloid beta-Peptides ; Cell Line ; },
abstract = {OBJECTIVE: To investigate the neuroprotective mechanism by which docosahexaenoic acid (DHA) promotes microglial autophagy via the miR-589-5p/toll-like receptor 4 (TLR4) axis in Alzheimer's disease.

METHODS: In vitro, BV2 microglial cells were treated with Aβ25-35 to establish an Alzheimer's disease model and subjected to DHA treatment with or without miR-589-5p inhibition and TLR4 overexpression. Cytotoxic effects were assessed by methylthiazolyldiphenyl-tetrazolium bromide assays. Autophagy markers (LC3-II/I ratio, Beclin1, and p62) were evaluated by Western blot and immunofluorescence. The miR-589-5p/TLR4 interaction was assessed using dual luciferase assays. For clinical validation, peripheral blood samples from healthy controls, patients with mild Alzheimer's disease, and patients with severe Alzheimer's disease (n = 30 each) were analyzed for miR-589-5p and TLR4 mRNA expression via quantitative reverse transcription PCR (qRT-PCR).

RESULTS: In cellular assays, DHA significantly enhanced autophagy by increasing the LC3-II/I ratio and Beclin1 expression while decreasing p62 levels (P < 0.05). Mechanistic validation showed that miR-589-5p inhibition abolished DHA's autophagy-promoting effects, while TLR4 overexpression reversed these benefits. Conversely, miR-589-5p mimic treatment rescued autophagy even under TLR4 overexpression conditions. Dual-luciferase assays confirmed that miR-589-5p directly targets TLR4. Clinically, qRT-PCR analysis revealed that miR-589-5p expression was downregulated and TLR4 expression was upregulated in Alzheimer's disease patients compared to healthy controls, and these alterations were correlated with disease severity (P < 0.05).

CONCLUSION: DHA enhances microglial autophagy via a novel miR-589-5p/TLR4 regulatory axis, a potential Alzheimer's disease therapy and biomarker for Alzheimer's disease progression.},
}

*Alzheimer Disease/metabolism
*Autophagy/drug effects
*MicroRNAs/metabolism
*Docosahexaenoic Acids/pharmacology
*Toll-Like Receptor 4/metabolism/drug effects
Humans
*Microglia/drug effects/metabolism
Animals
Male
Mice
Female
Aged
Amyloid beta-Peptides
Cell Line

@article {pmid41460031,
year = {2026},
author = {Fu, C and Kan, Y and Guo, K and Jiang, L and Zhang, Y and Dong, H and Xie, J},
title = {Tenuigenin ameliorates Alzheimer's disease by targeting MAP2K1: integrated evidence from network pharmacology and experimental validation.},
journal = {Neuroreport},
volume = {37},
number = {2},
pages = {53-66},
doi = {10.1097/WNR.0000000000002239},
pmid = {41460031},
issn = {1473-558X},
support = {gzwkj2025-129//Science and Technology Fund Project of the Guizhou Provincial Health Commission/ ; gzwkj2025-130//Science and Technology Fund Project of the Guizhou Provincial Health Commission/ ; 20222121020675//Project of the Heilongjiang Provincial Health and Family Planning Commission/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Network Pharmacology/methods ; *Neuroprotective Agents/pharmacology ; *Drugs, Chinese Herbal/pharmacology ; Molecular Docking Simulation ; Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; },
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder primarily characterized by progressive cognitive impairment and synaptic dysfunction. Despite substantial research efforts, effective therapeutic options remain limited. Tenuigenin (TEN), a principal bioactive constituent isolated from the traditional Chinese medicinal herb Polygala tenuifolia, has demonstrated promising neuroprotective effects.

METHODS: This study adopted a comprehensive multitiered approach, combining network pharmacology, machine learning, molecular modeling, and in-vitro experiments, to elucidate the therapeutic targets and mechanisms of TEN in AD. Computational analyses identified mitogen-activated protein kinase kinase 1 (MAP2K1) as a critical target, mediating the effects of TEN. Gene set enrichment analysis indicated that TEN could activate the 26S proteasome pathway, promoting the degradation of neurotoxic proteins, such as amyloid-β (Aβ), thereby reducing their pathological accumulation.

RESULTS: Immune infiltration analysis further revealed that TEN could modulate the distribution of activated natural killer cells and M0 macrophages, playing a role in restoring immune balance in the AD microenvironment. Molecular docking and dynamics simulations demonstrated strong binding affinity and structural compatibility between TEN and MAP2K1. Experimental validation using Aβ-treated SH-SY5Y cells indicated that TEN significantly enhanced cell viability and suppressed MAP2K1 protein expression.

CONCLUSION: In conclusion, this study provided the first integrated evidence that TEN exerts neuroprotective effects in AD by targeting MAP2K1. These findings highlight the multitarget, multipathway therapeutic potential of TEN and support its development as a natural agent for AD prevention and treatment.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
Network Pharmacology/methods
*Neuroprotective Agents/pharmacology
*Drugs, Chinese Herbal/pharmacology
Molecular Docking Simulation
Amyloid beta-Peptides/metabolism
Cell Line, Tumor

@article {pmid41458258,
year = {2026},
author = {Jing, C and Li, J and Yu, D and Chao, M and Yan, H and Ge, K and Ma, G and Wang, J and Gao, F and Zhang, G},
title = {Heterotrimetallic Au@Cu2Se nanozymes target inflamed neurons via suppression of oxidative stress and apoptosis to alleviate Alzheimer's disease.},
journal = {Materials today. Bio},
volume = {36},
number = {},
pages = {102646},
pmid = {41458258},
issn = {2590-0064},
abstract = {Neuronal dysfunction mediated by oxidative stress and amyloid-β (Aβ) deposition is widely recognized as a core mechanism in the pathogenesis of Alzheimer's disease (AD). Aβ oligomers specifically interact with key mitochondrial proteins-such as alcohol dehydrogenase, cyclophilin D, and ATP synthase-markedly increasing reactive oxygen species (ROS) production, which leads to mitochondrial membrane potential collapse and disruption of energy metabolism. Although cuprous selenide and gold nanospheres can mimic the catalytic activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD), effectively scavenge excess ROS, restore mitochondrial membrane potential, and promote ATP synthesis through synergistic action, their therapeutic potential is limited by poor targeting specificity in vivo. Moreover, while antioxidant nanoagents show promise in mitigating oxidative stress, their non-specific distribution often necessitates high doses, raising potential off-target toxicity concerns and reducing treatment efficacy. Therefore, developing a delivery system that combines multifunctional neuroprotection with precise targeting to diseased microenvironments remains an urgent need. To address this, we functionalized the surface of Au@Cs nanoparticles with hyaluronic acid (HA) to construct a CD44-targeted Au@Cs-HA-PEG nanosystem. By taking advantage of the high expression of CD44 in microglia and astrocytes under inflammatory conditions, the precise targeting of inflammatory regions in the brains of AD model mice was promoted. In vitro experiments demonstrated that Au@Cs-HA-PEG effectively reduced ROS levels in HT22 cells, reversed mitochondrial membrane potential attenuation, and restored neuronal function. In vivo results showed that these nanoparticles achieved rapid brain enrichment, significantly reduced Aβ plaque deposition and neuroinflammation, and markedly improved learning, memory, and cognitive abilities in AD mice. In conclusion, this study confirms that the Au@Cs-HA-PEG nanosystem ameliorates cognitive dysfunction in AD mice by regulating ROS homeostasis, offering a novel strategy and experimental foundation for targeted therapy of Alzheimer's disease.},
}

@article {pmid41457950,
year = {2025},
author = {Algeciras-Schimnich, A and Theobald, JP and Figdore, DJ and Ashrafzadeh Kian, S and Bornhorst, JA},
title = {False positive plasma p-tau217 results associated with heterophilic antibody interference: A potential clinical pitfall.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71045},
pmid = {41457950},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/blood/immunology ; *Alzheimer Disease/blood/diagnosis ; *Antibodies, Heterophile/blood ; False Positive Reactions ; Amyloid beta-Peptides/blood ; Biomarkers/blood ; Immunoassay ; Phosphorylation ; Female ; Male ; Aged ; Peptide Fragments ; },
abstract = {INTRODUCTION: Plasma phosphorylated tau at threonine 217 (p-tau217) has emerged as one of the most promising blood-based biomarkers for Alzheimer's disease (AD). While rare, heterophilic antibodies (HAb) are a persistent potential confounding factor in immunoassays.

METHODS: Potential HAb interference in the Lumipulse G pTau217 assay in samples exhibiting concentrations > 10 pg/mL were investigated. Samples were subjected to HAb blocking reagent (HBT), and in some cases, polyethylene glycol (PEG) precipitation and serial dilutions.

RESULTS: In 14 of the 15 suspected HAb cases, HBT treatment greatly reduced measured p-tau217 concentrations. and in one of three specimens selected for further investigation, reduced Aβ42 concentrations PEG precipitation in the three selected samples also reduced p-tau217 concentrations, while serial dilution yielded mixed effects. Control specimens were unaffected by sample treatment or dilutions.

DISCUSSION: HAb may result in falsely elevated p-tau217 and p-tau217/Aβ42 ratio. HAb interference should be considered in cases of unusually high p-tau217 concentrations prior to clinical interpretation.

HIGHLIGHTS: Potential heterophile antibody (HAb) interference in the Lumipulse p-tau217 immunoassay was investigated. Investigation was performed using HAb blocking reagent, and in some cases also using PEG precipitation . Patients with p-tau217 concentrations > 10 pg/mL exhibited positive HAb interference in 14 of 15 cases. HAb interference can lead to falsely positive p-tau217/Aβ42 ratios.},
}

Humans
*tau Proteins/blood/immunology
*Alzheimer Disease/blood/diagnosis
*Antibodies, Heterophile/blood
False Positive Reactions
Amyloid beta-Peptides/blood
Biomarkers/blood
Immunoassay
Phosphorylation
Female
Male
Aged
Peptide Fragments

@article {pmid41457949,
year = {2025},
author = {Chen, Q and Wen, Q and Zhong, T and Liu, J and Gao, H},
title = {Deep cervical lymphaticovenous anastomosis for Alzheimer's disease: A narrative review.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71038},
pmid = {41457949},
issn = {1552-5279},
support = {No.B2025292//Medical Scientific Research Foundation of Guangdong Province/ ; GMUCR2025-02028//Plan on enhancing scientific research in GMU，Guangdong, China/ ; },
mesh = {Humans ; *Alzheimer Disease/surgery ; *Lymphatic Vessels/surgery ; *Anastomosis, Surgical/methods ; *Glymphatic System/surgery ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder with limited treatment options. Recent discoveries of the glymphatic system and meningeal lymphatic vessels (MLVs) have highlighted their critical role in clearing metabolic waste-including amyloid beta and tau proteins-from the brain. Dysfunction of these systems contributes to AD pathogenesis by impairing the clearance of neurotoxic proteins. Deep cervical lymphaticovenous anastomosis (dcLVA) is an innovative microsurgical technique designed to enhance cerebral waste drainage by anastomosing deep cervical lymphatic channels to adjacent veins. This narrative review synthesizes current evidence on the mechanisms, applications, and emerging perspectives of dcLVA for AD. Early studies suggest potential short-term improvements in cognitive scores and neuroimaging biomarkers after surgery, with an acceptable safety profile. However, the evidence is limited to small prospective cohorts and case reports, underscoring the need for larger, randomized controlled trials to validate its efficacy and long-term benefits. dcLVA represents a promising surgical intervention for select patients, particularly those with moderate-to-severe AD who have failed conventional pharmacotherapy, but it requires careful patient selection and further investigation. HIGHLIGHTS: This review proposes deep cervical lymphaticovenous anastomosis (dcLVA) as a mechanism driven surgery that may enhance clearance of amyloid beta (Aβ) and tau through the brain, meningeal, and deep cervical drainage pathways. Early human evidence from a single arm cohort and case reports suggests short term cognitive and imaging signals with acceptable perioperative safety. dcLVA is not recommended as a first line option for early Alzheimer's disease (AD) and may be considered for moderate to severe AD or for patients who are refractory to pharmacotherapy and have objective evidence of drainage impairment. Standardized patient selection and longitudinal imaging and biomarker monitoring are recommended, including Aβ and tau positron emission tomography (PET), diffusion tensor imaging (DTI) analysis along the perivascular space, and cerebrospinal fluid (CSF) or plasma panels. Systemic safety remains an important uncertainty, and future trials should include longitudinal surveillance of hepatic, renal, and hematologic function. Multicenter randomized controlled trials (RCTs) are urgently needed with 12 month Clinical Dementia Rating Sum of Boxes (CDR SB) as a primary endpoint, transparent reporting, and evaluation of combination strategies with anti Aβ therapies.},
}

Humans
*Alzheimer Disease/surgery
*Lymphatic Vessels/surgery
*Anastomosis, Surgical/methods
*Glymphatic System/surgery
Amyloid beta-Peptides/metabolism

@article {pmid41457120,
year = {2025},
author = {Jiang, T and Ma, W and Dong, W and Zhou, H and Mao, X},
title = {Ferroptosis-associated transcriptional factors in neurological diseases: molecular mechanisms and therapeutic prospects.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {41457120},
issn = {2092-6413},
abstract = {Ferroptosis, a newly discovered type of regulatory cell death with iron-dependent accumulation of lipid peroxides, is widely discussed in a plethora of neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and spinal cord injury. There are many preclinical and clinical evidences supporting the critical role of ferroptosis in these neurologic conditions, despite the molecular machinery by which ferroptosis modulates brain dysfunction remains uncharacterized. Transcription factors (TFs) are core components of the machinery that manipulates ferroptosis process genetically. Until now, there is no report on the summarization of role of ferroptosis-associated TFs in neurological diseases. Therefore, here we provided the basic knowledge regarding the regulation of TFs on ferroptotic processes including iron metabolism, antioxidant defense and lipid peroxidation. In addition, we also discussed the recent advances in our understanding of ferroptosis-related TFs in the emerging hallmarks of neurological diseases. The fact that Nrf2 activator RTA-408 is approved for clinical evaluation (phase 2 clinical trial) of its efficacy and safety in patients with Alzheimer's disease supports this notion. Future research on proteolysis-targeting chimera (PROTAC) and gene therapy holds promise for optimization of neurological disease treatment.},
}

@article {pmid41456743,
year = {2025},
author = {Sabrina, T and Federica, F and Zaira, B and Lucia, G and Manuela, M and Loredana, LP and Gloria, V and Antonella, F},
title = {INVESTIGATION OF DIPYRIDAMOLE-ELICITED SIGNALING IN THE BRAIN OF NIEMANN PICK TYPE C MICE: A MULTI-OMIC STUDY.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111708},
doi = {10.1016/j.brainresbull.2025.111708},
pmid = {41456743},
issn = {1873-2747},
abstract = {Niemann Pick type C1 (NPC1) is a rare, fatal disorder characterized by endo-lysosomal (EL) lipid accumulation that leads to damage of both peripheral organs and central nervous system, with cerebellum and hippocampus being particularly affected. Currently very few therapeutic options exist in Europe for NPC. In fact, miglustat is the only approved drug and L-acetylleucine was recently granted for marketing authorization by European Medicine Agency. Thus, the identification of new treatments is mandatory. We have previously demonstrated that dipyridamole (DIP), an approved medicine that is clinically employed as an antiplatelet agent, could rescue recognition memory and increase hippocampal expression of calbindin. On the contrary, the drug was unable to improve cerebellar-dependent motor function. In order to elucidate the mechanism of these region-specific changes induced by DIP, in this work we performed a multi-omic analysis of genes and proteins modulated by the treatment in the hippocampus and cerebellum of a mouse model of NPC1 (Npc1[-/-]). Our results revealed that DIP significantly affected various pathways in the hippocampus at protein level, but it had no significant impact on pathways in the cerebellum (either at gene or protein level). Interestingly, the most affected pathways in the hippocampus of Npc1[-/-] mice administered with DIP were those related to cGMP-PKG activation and to mitochondrial function. Our results paved the way to test DIP in experimental models of other neurodegenerative disorders, such as Alzheimer's disease that is similarly marked by hippocampal and mitochondrial dysfunctions.},
}

@article {pmid41456527,
year = {2025},
author = {Li, X and Ji, W and Wu, X and Cai, J and Zheng, M and Zhang, X and Liu, P and Wang, G and Li, X and Wang, S and Huo, Z and Wang, Q and Song, Z and Li, D and Zhou, S and Sun, H and Ma, X and Zou, L and Gao, W},
title = {Cerebralcare Granule® restores intracranial lymphatic drainage system to support proactive brain health in Alzheimer's disease models.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {150},
number = {},
pages = {157617},
doi = {10.1016/j.phymed.2025.157617},
pmid = {41456527},
issn = {1618-095X},
abstract = {BACKGROUND: Impairment of the intracranial lymphatic drainage system significantly contributes to Alzheimer's disease (AD) by facilitating the accumulation of neurotoxic amyloid-β (Aβ) and tau proteins. Restoring lymphatic function offers a promising preventive strategy against early-stage AD pathology.

PURPOSE: This study aimed to evaluate the effects and mechanisms of Cerebralcare Granule® (CG), a traditional Chinese medicine formula, on cognitive impairment and pathological markers in AD mouse models by modulating intracranial lymphatic clearance pathways.

METHODS: Six-month-old APP/PS1 transgenic mice and wild-type controls received oral administration of CG or donepezil for two months. Behavioral assessments included the Morris water maze, open field, Y-maze, novel object recognition, and passive avoidance tests. Immunohistochemistry, immunofluorescence, and Western blot analyses were used to assess Aβ deposition, glymphatic clearance, astrocytic aquaporin-4 (AQP4) polarization, meningeal lymphangiogenesis, and blood-brain barrier integrity. Tracer-based in vivo imaging confirmed improved CSF influx and efflux dynamics. Brain-penetrant compounds of CG were identified using UPLC-MS/MS, MALDI-TOF-MS imaging, and network pharmacology.

RESULTS: CG treatment significantly improved cognitive performance, reduced Aβ burden, enhanced glymphatic transport, and promoted meningeal lymphatic drainage in APP/PS1 mice. CG restored perivascular AQP4 polarization, improved cerebrospinal fluid-interstitial fluid exchange, facilitated waste removal to cervical lymph nodes, and protected the integrity of the blood-brain barrier. Major brain-penetrant compounds-paeoniflorin, rhynchophylline, and ethyl gallate-were found to target lymphatic signaling pathways (AQP4, VEGFC, VEGFR3, PROX1) effectively.

CONCLUSION: CG exerts protective effects against cognitive impairment and AD pathology by reinforcing the structural and functional integrity of the intracranial lymphatic drainage system, highlighting a novel therapeutic avenue for proactive brain health management in early-stage AD.},
}

@article {pmid41456355,
year = {2025},
author = {Haixia, T and Bo, X},
title = {Exercise impact on IRE1α signaling: Novel insights into Alzheimer's disease prevention and treatment.},
journal = {Biochemical and biophysical research communications},
volume = {797},
number = {},
pages = {153156},
doi = {10.1016/j.bbrc.2025.153156},
pmid = {41456355},
issn = {1090-2104},
abstract = {Endoplasmic reticulum stress (ERS) and its downstream signaling play a central role in neuroinflammation in Alzheimer's disease (AD). Among them, IRE1α, as a key sensor of ER stress, is a pivotal molecule connecting stress to inflammation. Its aberrant activation drives neuroinflammation, which in turn exacerbates Aβ deposition, Tau pathology, and cognitive decline. Therefore, targeting the IRE1α signaling pathway has become a potential strategy for AD intervention. Recent studies suggest that exercise can alleviate ER stress and directly or indirectly inhibit the excessive activation of IRE1α, thereby reducing its downstream inflammatory signals. This review aims to systematically elucidate the pathogenic mechanism of the IRE1α inflammatory signaling pathway in AD. It also focuses on exploring the evidence of the neuroprotective effect of exercise through regulating this pathway, providing new theoretical basis and direction for exercise-based prevention and treatment of AD.},
}

@article {pmid41455872,
year = {2025},
author = {Marei, HE},
title = {Epigenetic Editing in Neurological and Neuropsychiatric Disorders: Pioneering Next-Gen Therapeutics for Precision Gene Control.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {330},
pmid = {41455872},
issn = {1559-1182},
mesh = {Humans ; *Epigenesis, Genetic/genetics ; *Gene Editing/methods ; *Nervous System Diseases/genetics/therapy ; Animals ; *Mental Disorders/genetics/therapy ; *Genetic Therapy/methods ; *Precision Medicine/methods ; Epigenome Editing ; },
abstract = {Epigenetic editing has emerged as a promising approach in the treatment of neurological and neuropsychiatric disorders, enabling the precise and enduring modification of genes associated with these conditions. Interventions that focus on chromatin, such as programmable systems like CRISPR/dCas9, zinc-finger proteins, and TALEs linked to epigenetic effector domains, enable the modification of DNA methylation, histone modifications, and noncoding RNA control at specific loci. This work integrates current progress in understanding the epigenetic landscape of neurological neuropsychiatric disorders, highlighting the functions of DNA methylation (de novo vs maintenance, active versus passive demethylation), histone remodeling, and context-dependent gene regulation. We emphasize that the dysregulation of these processes is essential to diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and major psychiatric disorders. Innovative therapeutic approaches, including KRAB- and TET-based repressors, "hit-and-run" epigenome editing, and targeted noncoding RNA regulation, are analyzed alongside translational methodologies that utilize gene therapy vectors, nanoparticle delivery systems, and inducible expression mechanisms. We also examine proof-of-concept studies that demonstrate how to prevent gene expression and alter the transcriptional networks of diseased cells in living organisms. We identify current challenges, including off-target effects, delivery issues, inadequate understanding of long-term stability, and the need for reliable diagnostics, while highlighting the translational promise of combining epigenetic clearance with biogenesis and repair. This review is aimed at providing a comprehensive and critical examination of the molecular principles, therapeutic strategies, and translational obstacles associated with epigenetic editing in neurological and neuropsychiatric disorders, thereby facilitating the development of next-generation precision therapies.},
}

Humans
*Epigenesis, Genetic/genetics
*Gene Editing/methods
*Nervous System Diseases/genetics/therapy
Animals
*Mental Disorders/genetics/therapy
*Genetic Therapy/methods
*Precision Medicine/methods
Epigenome Editing

@article {pmid41455863,
year = {2025},
author = {Elbermawy, Y and El-Desouky, S and Arafa, RK and Elfarrash, S and Bassiouny, A},
title = {Synergistic Neuroprotection in Tauopathic Mice via Green-Synthesized Silver Nanoparticles Co-delivering Methylene Blue and Moringa oleifera.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {331},
pmid = {41455863},
issn = {1559-1182},
mesh = {Animals ; *Methylene Blue/pharmacology/administration & dosage/therapeutic use ; *Moringa oleifera/chemistry ; *Metal Nanoparticles/chemistry/administration & dosage ; *Silver/chemistry/pharmacology ; *Neuroprotective Agents/pharmacology/administration & dosage/therapeutic use ; *Neuroprotection/drug effects ; Mice, Transgenic ; Mice ; *Green Chemistry Technology/methods ; *Tauopathies/drug therapy/pathology/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Plant Extracts/administration & dosage/pharmacology ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited therapeutic options.Most current treatments target only a single pathogenic pathway. We developed an innovative green-synthesized silver nanoparticle formulation for the co-delivery of methylene blue (MB), a tau aggregation inhibitor, and Moringa oleifera (MO) extract, an antioxidant and anti-inflammatory agent. Silver nanoparticles act as multifunctional carriers, improving drug stability and brain delivery, yielding the combined formulation MOMB-Ag-NPs. MOMB-Ag-NPs were synthesized and characterized using ultraviolet-visible spectroscopy (UV-Vis), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and energy-dispersive X-ray (EDX) analysis. Homozygous P301S tau transgenic mice were assigned to four groups: saline (0.9%, i.p.), MB (4 mg/kg/day, i.p.), MO (260 mg/kg/day, oral), or MOMB-Ag-NPs (4 mg/kg/day MB equivalent, i.p.) for 60 days. In vitro GSK-3β inhibition assays and molecular docking analyses assessed mechanistic interactions. Neuroprotective efficacy was evaluated through survival, behavioral tests, immunohistochemistry, ELISA, and Western blotting. MOMB-Ag-NPs displayed spherical morphology (10-25 nm), high stability, and efficient MB encapsulation (EE 54.7%, DL 93.5%). Both MO and MB inhibited GSK-3β in vitro (IC50 = 9.41 and 65.77 µg/mL), corroborated by molecular docking. In vivo, MOMB-Ag-NPs significantly improved locomotor activity, and cognitive performance. Treated mice showed reduced astrogliosis, decreased pro-inflammatory cytokines (TNF-α, IL-6), enhanced autophagy (LC3β), increased antioxidant defenses (SOD), and differential modulation of the AKT/GSK-3β pathway. This study provides novel evidence that a green-synthesized MB and MO nanoformulation exerts synergistic neuroprotective effects in tauopathy mice, highlighting the translational promise of multitarget strategies for AD treatment.},
}

Animals
*Methylene Blue/pharmacology/administration & dosage/therapeutic use
*Moringa oleifera/chemistry
*Metal Nanoparticles/chemistry/administration & dosage
*Silver/chemistry/pharmacology
*Neuroprotective Agents/pharmacology/administration & dosage/therapeutic use
*Neuroprotection/drug effects
Mice, Transgenic
Mice
*Green Chemistry Technology/methods
*Tauopathies/drug therapy/pathology/metabolism
Glycogen Synthase Kinase 3 beta/metabolism
Plant Extracts/administration & dosage/pharmacology
tau Proteins/metabolism

@article {pmid41455134,
year = {2025},
author = {Du, O and Wu, YJ and Li, MY and Du, JR},
title = {The role of HMGB1 in central nervous system (CNS) diseases: mechanisms and therapeutic perspectives.},
journal = {Cytokine},
volume = {198},
number = {},
pages = {157099},
doi = {10.1016/j.cyto.2025.157099},
pmid = {41455134},
issn = {1096-0023},
abstract = {Central nervous system (CNS) diseases represent a major global health burden and are among the leading causes of disability and mortality worldwide. The pathological mechanisms underlying CNS disorders are complex and multifactorial, involving processes such as neuroinflammation, oxidative stress, neuronal damage, and synaptic dysfunction. High-mobility group box 1 (HMGB1), a member of the high-mobility group box (HMGB) protein family, is predominantly localized in the nucleus under physiological conditions, where it contributes to DNA repair, transcriptional regulation, and other cellular functions. However, in various CNS pathologies-including stroke, traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), glioblastoma (GBM), epilepsy, depression, multiple sclerosis (MS), and schizophrenia-HMGB1 is released or secreted into the extracellular space. There, it plays a key role in regulating neuroinflammation, cell death, cell migration, and tissue damage and repair, thereby contributing to disease pathogenesis and progression. HMGB1 not only functions as a critical regulator in the progression of CNS diseases but also serves as a biomarker for predicting poor clinical outcomes. Moreover, a growing body of evidence indicates that therapeutic strategies targeting HMGB1 can significantly alleviate pathological damage in various CNS disorders, highlighting its potential as a promising therapeutic target. This review comprehensively summarizes the structure, post-translational modifications, release mechanisms, and receptor systems of HMGB1, along with its roles and mechanisms in CNS diseases. It also discusses the potential of HMGB1 as a biomarker and examines emerging HMGB1-targeted therapeutic strategies, aiming to provide a theoretical foundation for the treatment and drug development of CNS disorders.},
}

@article {pmid41454738,
year = {2025},
author = {Takeda, T and Toritsuka, M and Tamakoshi, H and Iwata, N and Makinodan, M},
title = {Immune involvement in neuropsychiatric disorders: Insights from single-cell transcriptomic studies.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.70018},
pmid = {41454738},
issn = {1440-1819},
support = {JPMJMS239F-1-2//Moonshot Research and Development Program/ ; 21gm6310015h0002//Japan Agency for Medical Research and Development/ ; 21uk1024002h0002//Japan Agency for Medical Research and Development/ ; 21wm04250XXs0101//Japan Agency for Medical Research and Development/ ; 22gm1510009h0001//Japan Agency for Medical Research and Development/ ; 24gm1910004s0402//Japan Agency for Medical Research and Development/ ; 24wm0625510h0001//Japan Agency for Medical Research and Development/ ; 23H04173//Japan Society for the Promotion of Science/ ; 24K02386//Japan Society for the Promotion of Science/ ; },
abstract = {Neuropsychiatric disorders pose profound challenges to both research and treatment, largely due to their clinical heterogeneity and the limited understanding of their underlying biological mechanisms. While bulk RNA sequencing (bulk RNA-seq) has been widely used to study gene expression, it cannot resolve cell-type-specific signals or detect rare cellular subpopulations. In contrast, single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) have emerged as transformative technologies, enabling transcriptomic profiling at single-cell resolution. These approaches have revealed immunological alterations across a wide range of disorders. This review introduces recent findings from sc/snRNA-seq studies of immune-related mechanisms in psychiatric disorders-including schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder-as well as in neurological conditions such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple sclerosis, and anti-NMDA receptor encephalitis. While sc/snRNA-seq overcome averaging effects of bulk RNA-seq by resolving cell types, these methods still face challenges. We outline a roadmap that integrates bulk RNA-seq and sc/snRNA-seq to mitigate the remaining gaps.},
}

@article {pmid41454086,
year = {2025},
author = {Mi, X and Shan, K and Ye, X and Cheng, R},
title = {AAD-2004 through clearing H2O2 reduces astrocyte proliferation and promotes neural regeneration after spinal cord injury.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-33322-x},
pmid = {41454086},
issn = {2045-2322},
support = {ZKKY2023003//Zhejiang Medical Association/ ; 2024KY658//Scientific Research Program of Zhejiang Medical Technology/ ; },
abstract = {To assess the effect of AAD-2004 on spinal cord injury (SCI) and to explore its mechanism, we employed an in vitro model using OGD/R-challenged astrocytes to investigate the effects of AAD-2004 against cell death (terminal deoxynucleotidyl transferase dUTP nick-end labeling, tunel), oxidative stress (H2O2 level), and the expression of the key neuroprotective factor MAP2.AAD-2004[2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] is a hydrogen peroxide(H2O2) scavenger primarily used for the treatment of amyotrophic lateral sclerosis and Alzheimer disease that has demonstrated certain neuroprotective properties. In parallel, modified allen's method was adopted, further exploring the potential molecular mechanism in vivo. Based on these conditions, histological and behavioral analysis were performed by Nissl staining, basso mouse scale and footprint analysis. The level of molecules associated with glial scar formation, nerve regeneration, axonal regeneration and H2O2 level were analyzed using western blot, immunofluorescence staining and H2O2 kit. AAD-2004 significantly improved the movement function after SCI and inhibited the proliferation of astrocytes, thus preventing the formation of glial scar by inhibiting of H2O2. At the same time, AAD-2004 promoted nerve regeneration, and the effect was due to neuronal regeneration and axonal regeneration pathways. The expression levels of GFAP and vimentin were significantly downregulated in AAD-2004-treated, and the expression level of Ki67 and PH3 were downregulated. The mean fluorescence intensity of neuronal regeneration (Neun[+]and MAP2[+]) and axonal regeneration-related (NF[+] and GAP43[+]) were significantly upregulated after AAD-2004 treatment. Scavenging H2O2 level is a viable therapeutic strategy, and that AAD-2004 is prospective, and that scavenging H2O2 facilitated nerve regeneration and inhibited glial scar formation for SCI.},
}

@article {pmid41453655,
year = {2025},
author = {Basri, R and Al-Kuraishy, HM and Fawzy, MN and Alruwaili, M and Batiha, GE},
title = {PACAP: A promising disease-modifying target for Alzheimer's disease.},
journal = {Life sciences},
volume = {386},
number = {},
pages = {124176},
doi = {10.1016/j.lfs.2025.124176},
pmid = {41453655},
issn = {1879-0631},
abstract = {Alzheimer's disease (AD) is a significant public health threat, and current therapeutic approaches provide only minimal symptomatic benefit without slowing its progression. This review covers evidence for the expanding involvement of pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenous neuropeptide with significant and consistent neuroprotective properties in various experimental models of AD. We consolidate evidence that PACAP works via multiple pathways to negate primary pathological events in AD by shifting the metabolism of amyloid precursor protein from the amyloidogenic into non-amyloidogenic, inhibiting tau hyperphosphorylation, controlling neuroinflammation, and promoting synaptic plasticity. The reduced level of PACAP in clinical studies of AD patients supports its therapeutic relevance. Although concerns about PACAP pharmacokinetics and blood-brain barrier (BBB) penetration persist as serious obstacles, recent development of stable analogs and innovative delivery systems holds promise for circumventing these limitations. We also consider how established drugs (metformin, linagliptin, and statins) might provide a degree of neuroprotection in part-seeking through PACAP-related pharmacology. Taken together, the cumulative available evidence places PACAP not only as yet another promising therapeutic candidate but rather as a master regulator of neuroprotection, tackling AD's multifaceted nature. Restoration of PACAP signaling is a very distinct method to intervene in disease development, which offers immeasurable benefit in comparison to symptom relief treatment.},
}

@article {pmid41452714,
year = {2025},
author = {Zhang, J and Zhu, D and Hu, M and Pan, M and Chen, C},
title = {A Combination of Low-Dose Δ[9]-THC and Celecoxib as a Therapeutic Strategy for Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1206},
pmid = {41452714},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia in the elderly, and no effective therapies are currently available to prevent, treat, or halt its progression. Δ[9]-Tetrahydrocannabinol (Δ[9]-THC), the primary psychoactive compound in marijuana, has been considered a potential therapeutic agent, but clear evidence for its ability to prevent cognitive decline is lacking. Previous studies have demonstrated that Δ[9]-THC-induced cognitive impairments are associated with the induction of cyclooxygenase-2 (COX-2). In this study, we aimed to evaluate whether Δ[9]-THC alone or in combination with Celecoxib, a selective COX-2 inhibitor, could reduce neuropathology and improve cognitive function in AD model animals. We observed that Δ[9]-THC (3.0 mg/kg), either alone or with Celecoxib (1.0 mg/kg), significantly reduced Aβ and tau pathologies, enhanced synaptic marker expression, and prevented the onset of cognitive decline. Notably, the combination treatment produced greater improvements in spatial learning and effectively mitigated Δ[9]-THC-induced neuroinflammatory responses. Furthermore, Δ[9]-THC reversed or attenuated the dysregulated expression of synaptic and immune/inflammation-related genes and restored the downregulated expression of genes linked to AD observed in both AD patients and AD animal models, with greater efficacy when combined with Celecoxib in AD model mice. These findings suggest that the combination of low-dose Δ[9]-THC and Celecoxib holds promise as an early intervention strategy for preventing AD onset or treating mild cognitive impairment (MCI). Importantly, both Δ[9]-THC (in the form of Dronabinol and Nabilone) and Celecoxib are FDA-approved medications already in clinical use, supporting the strong translational potential of this combination therapy and its feasibility for rapid advancement to clinical trials to assess its efficacy in preventing or delaying AD onset in humans.},
}

@article {pmid41452429,
year = {2025},
author = {Heidari, Z and Zakaee, A and Vafadar, A and Alavimanesh, S and Charami, H and Jamali, Z and Jahromi, AH and Rakhsha, A and Savardashtaki, A},
title = {An overview of gene and cell therapy approaches for Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {10},
pmid = {41452429},
issn = {1573-7365},
mesh = {*Alzheimer Disease/therapy/genetics ; Humans ; *Genetic Therapy/methods ; *Cell- and Tissue-Based Therapy/methods ; Animals ; },
abstract = {Alzheimer's disease (AD), acknowledged as the leading cause of dementia, is defined by the accumulation of amyloid plaques and neurofibrillary tangles (NFTs) in the brain. This condition presents a significant challenge to global health due to its complex and multifaceted characteristics. Pharmacological treatments for AD mainly focus on relieving symptoms instead of addressing the fundamental progression of the condition. Currently, there are three cholinesterase inhibitors (ChEIs) that can be used for the treatment of AD: donepezil, rivastigmine, and galantamine, along with the N-methyl-D-aspartate (NMDA) receptor antagonist memantine. Although these medications can improve cognitive function and assist patients in their daily activities, it is crucial to understand that they do not halt the progression of the disease itself. Recently, innovative therapeutic strategies have been introduced for the treatment of this disease. Cell and gene therapies hold remarkable potential for the treatment of AD. Gene therapy, in particular, enables the precise modulation of AD-related genes, enhances neuroprotective factors, and mitigates the accumulation of amyloid plaques. Additionally, cell-based therapies utilizing mesenchymal stromal cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs) are designed to replace lost neurons, modulate immune responses, and restore functional neural networks. Together, these innovative techniques represent significant advancement in the treatment of AD, instilling hope for enhanced patient outcomes and a higher quality of life. In this review, we emphasize the innovative cell and gene strategies, along with in vitro and preclinical studies, that explore the potential of gene and cell-based therapies as treatments for AD.},
}

*Alzheimer Disease/therapy/genetics
Humans
*Genetic Therapy/methods
*Cell- and Tissue-Based Therapy/methods
Animals

@article {pmid41452267,
year = {2025},
author = {Cai, X and Huang, Y and Wang, T and Gao, J and Tang, Y and Zhu, C and Rong, S},
title = {Mesoporous PdPt Nanozymes with Target Peptides and Cascade Reactive Oxygen Species Scavenging for Boosting Alzheimer's Disease Treatment.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.5c17413},
pmid = {41452267},
issn = {1936-086X},
abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disease that has become a major health problem nowadays. Inhibiting the aggregation of amyloid-β (Aβ) peptides has made progress in AD treatments. Here, we synthesized mesoporous PdPt nanozymes to immobilize target peptide KLVFFAED for high-efficiency AD treatment. Thanks to the high surface area of the mesoporous nanospherical structure of PdPt nanozymes, lots of KLVFFAED were grafted with a concentration as high as 439.2 μg mL[-1], amplifying inhibition activity against Aβ aggregations. Importantly, the system has a pre-eminent photothermal property in the near-infrared region and exhibits the ability to photothermally disintegrate Aβ aggregates. Moreover, the integrated superoxide dismutase/catalase mimetic activity of PdPt nanozymes also achieves cascade reactive oxygen species (ROS) scavenging to alleviate oxidative stress and neuroglial damage, thus delaying the progression of AD. Therefore, the designed system can simultaneously block Aβ aggregation, destabilize Aβ fibrils, and clear ROS, which together enhance the therapeutic effects, providing important insights into the applications of nanozymes for AD therapy.},
}

@article {pmid41451887,
year = {2025},
author = {Lynch, SY and Jia, J and Miles, N and Boiser, J and Buhl, DL and Graff, O and Zadikoff, C},
title = {ABBV-552 in patients with mild Alzheimer's disease: a randomized phase IIb trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70994},
pmid = {41451887},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; Aged ; Female ; Middle Aged ; Aged, 80 and over ; Double-Blind Method ; Treatment Outcome ; Dose-Response Relationship, Drug ; Mental Status and Dementia Tests ; },
abstract = {INTRODUCTION: This proof-of-concept, dose-finding phase IIb trial evaluated treatment with ABBV-552 compared with placebo in participants with clinically diagnosed mild Alzheimer's disease (AD).

METHODS: Participants aged 50 to 90 years with a Mini-Mental State Examination score of 20 to 26 and a global Clinical Dementia Rating score of 0.5 to 1.0 were randomized 1:1:1:1 to placebo or ABBV-552 (1, 5, or 15 mg) daily. The primary endpoint was the change from baseline in the 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 14) at week 12.

RESULTS: Two hundred sixty-three participants were randomized. The least-squares mean difference (vs placebo) in change from baseline at week 12 in ADAS-Cog 14 total score (95% confidence interval) for ABBV-552 1 mg was -0.02 (-1.87, 1.83), nominal p = 0.9819; 5 mg, -0.42 (-2.25, 1.42), nominal p = 0.6545; 15 mg, 0.25 (-1.58, 2.08), nominal p = 0.7860. Treatment-emergent adverse events occurred in 48.5% of ABBV-552 recipients versus 42.2% in the placebo group; no safety concerns were identified.

DISCUSSION: ABBV-552 did not demonstrate a meaningful difference versus placebo on the primary endpoint.

HIGHLIGHTS: ABBV-552 is a small molecule that modulates the SV2A receptor in neurons ABBV-552 may enhance synaptic efficiency leading to improved cognition in patients with Alzheimer's disease (AD) Participants with mild AD were treated with either placebo, 1 mg, 5 mg, or 15 mg of ABBV-552 covering an estimated 35% to 80% SV2A receptor occupancy in a phase II randomized clinical trial Results failed to show efficacy over placebo as measured by ADAS-Cog 14 at week 12 ABBV-552 was generally safe and well tolerated.},
}

Humans
*Alzheimer Disease/drug therapy
Male
Aged
Female
Middle Aged
Aged, 80 and over
Double-Blind Method
Treatment Outcome
Dose-Response Relationship, Drug
Mental Status and Dementia Tests

@article {pmid41451871,
year = {2025},
author = {Yang, T and Huhe, H and Williams, SP and Kaur, S and Ay, YA and Davis-Gilbert, ZW and Cary, GA and Paisie, C and Butler, RR and Wiley, J and Betarbet, R and Fu, H and Duong, D and Seyfried, NT and Leal, K and Carter, GW and Edwards, A and Levey, AI and Capener, JL and Drewry, DH and Hossain, MA and Oh, HJ and Axtman, AD and Sukoff Rizzo, SJ and Longo, FM and , },
title = {PAK1 inhibitor NVS-PAK1-1 preserves dendritic spines in amyloid/tau exposed neurons and 5xFAD mice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71033},
pmid = {41451871},
issn = {1552-5279},
support = {//PhRMA Foundation/ ; //The SGC is a registered charity that receives funds from Bayer AG, Boehringer Ingelheim/ ; //NIH grants NIA U54AG065187/ ; //Applebaum Foundation Fund/ ; //Archer Fund/ ; //Jean Perkins Foundation/ ; },
mesh = {Animals ; *Dendritic Spines/drug effects/pathology/metabolism ; *p21-Activated Kinases/antagonists & inhibitors/metabolism ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism/toxicity ; Mice, Transgenic ; *Alzheimer Disease/pathology/metabolism/drug therapy ; *Neurons/drug effects/metabolism ; Hippocampus/drug effects/pathology ; Disease Models, Animal ; Mice ; Female ; Humans ; Dibenzazepines ; Pyrrolidines ; },
abstract = {INTRODUCTION: Synaptic spine loss in Alzheimer's disease (AD) contributes to cognitive decline. p21-activated kinase 1 (PAK1), a regulator of spine integrity, is aberrantly activated in AD. We investigated whether PAK1 inhibition might preserve dendritic spines in vitro and in vivo.

METHODS: Oligomeric amyloid beta (oAβ) or tau (oTau) were applied to hippocampal neurons ± NVS-PAK1-1, a selective PAK1 inhibitor. NVS-PAK1-1 was orally administered to 5xFAD mice. The effects of NVS-PAK1-1 treatment on PAK1 activity, spine density, and the proteome were assessed using phospho-PAK1 (pPAK1) western blotting, Golgi staining, and mass spectrometry for proteomic analyses.

RESULTS: NVS-PAK1-1 prevented oAβ and oTau-induced spine loss in vitro. In 5xFAD mice, NVS-PAK1-1 demonstrated brain exposure after oral administration and reduced PAK1 activation, prevented spine loss, and partially normalized synaptic proteomic signatures in females in absence of alterations in brain or plasma Aβ.

DISCUSSION: PAK1 inhibition enhances spine resilience in AD models, supporting its therapeutic potential.

HIGHLIGHTS: p21-activated kinase 1 (PAK1) inhibitors prevent oligomeric amyloid beta (oAβ) and oligomeric tau-induced spine loss and dendritic degeneration in cultured mouse hippocampal neurons. NVS-PAK1-1, a selective PAK1 inhibitor, protects against oAβ-induced spine loss in a dose-dependent manner (EC50 = 2 nM). Oral administration of NVS-PAK1-1 achieves brain penetration and bioavailability in normal CD-1 mice, and target engagement in 5xFAD mice. Chronic NVS-PAK1-1 treatment mitigates spine loss in the somatosensory cortex of 6-month-old 5xFAD female mice. Chronic treatment with NVS-PAK1-1 restores proteomic abundance of actin cytoskeleton and dendritic spine-associated proteins, including cofilin 2 and pyruvate dehydrogenase kinases, downstream of PAK1 in young 5xFAD female mice showing spine resilience. Clinical oncology trials with other PAK1 inhibitors support potential repurposing or novel compound development for Alzheimer's disease trials.},
}

Animals
*Dendritic Spines/drug effects/pathology/metabolism
*p21-Activated Kinases/antagonists & inhibitors/metabolism
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism/toxicity
Mice, Transgenic
*Alzheimer Disease/pathology/metabolism/drug therapy
*Neurons/drug effects/metabolism
Hippocampus/drug effects/pathology
Disease Models, Animal
Mice
Female
Humans
Dibenzazepines
Pyrrolidines

@article {pmid41451412,
year = {2025},
author = {Li, S and Qian, W and Zhang, Z and Chen, Y and Hou, X and Min, B and Zhou, H and Zhu, X and Ling, J and Yang, W and Cao, S},
title = {Comprehensive safety assessment of donepezil: pharmacovigilance analysis based on the FDA adverse event reporting system.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1655216},
pmid = {41451412},
issn = {1664-2295},
abstract = {BACKGROUND: Alzheimer's disease (AD) has a growing global prevalence, and the need for safe and effective treatments is urgent. Donepezil is commonly used therapeutic agents for AD but has safety controversies. The objective of this study was to thoroughly evaluate donepezil's adverse event profile using actual data.

METHODS: In this study, reports of donepezil-related adverse events were collected from the first quarter of 2004 to the fourth quarter of 2024 through the FAERS database. The association of donepezil-induced adverse events was disproportionality analyzed using Reporting odds Ratios (ROR) and Proportional Reporting Ratio (PRR) and Bayesian Confidence Propagation Neural Network (BCPNN) and Multi-item Gamma Poisson Shrinker (MGPS), among other methods.

RESULTS: A total of 26,120 ADRs with donepezil as the "first suspect" were retrieved during the reporting period. The most common AEs included nausea, vomiting, syncope, and dizziness, which were consistent with the labeling of the medication and clinical trials. Unintended major AEs such as fall, hypotension, tremor, cognitive disorder, mania, and the highest signal of pleurothotonus were also detected. The reports also collected were characterized by a high proportion of female patients (51.3%) and the time of AE induction within 30 days (41%).

CONCLUSION: Donepezil treatment needs to focus on cardiovascular and neurological adverse events, especially for women, elderly patients, or patients with co-morbidities, cardiac monitoring and dose adjustment should be strengthened. Clinics need to balance efficacy and risk, develop individualized dosing regimens, and explore novel therapeutic strategies to improve long-term safety.},
}

@article {pmid41450657,
year = {2025},
author = {Zhao, Y and Xi, E and Wang, Z and Gao, N and Sun, H and Zhu, G},
title = {Nanoamplifier Agents Transiently Rise the Metabolism of β‑Amyloid Peptide in Urine for the Early Diagnosis of Alzheimer's Disease.},
journal = {JACS Au},
volume = {5},
number = {12},
pages = {6169-6178},
pmid = {41450657},
issn = {2691-3704},
abstract = {Alzheimer's disease (AD) is the most common form of dementia without effective treatment. Therefore, early diagnosis for timely treatment and delayof the onset of AD are critical. At present, detecting β-amyloid (Aβ) in cerebrospinal fluid is still the most important clinical method. However, the invasive detection method is harmful and difficult to promote. Recent research has shown that Aβ was found not only in blood and cerebrospinal fluid, but also in urine, which could be used for noninvasive testing. Compared with blood/cerebrospinal fluid, the background proteins in urine are very low, but unfortunately the content of Aβ is even lower. Therefore, if the concentration of Aβ is increased with the background proteins maintained at the low level, urine could be an ideal noninvasive early detection target for AD. Gold nanoparticles (AuNP) with ultrasmall size (<6 nm) could be rapidly metabolized by the kidneys and excreted with urine, and easily regulated by the metabolic pathway between kidneys and liver by changing their size. After screening, we found 3 nm AuNP had the highest renal metabolic efficiency, and by modifying with kidney targeting peptides and Aβ antibody 6E10, the complex system (P6-Au) acted as a "Aβ-targeting renal metabolic carrier", which both metabolized rapidly through the kidneys and increased the concentration of Aβ in urine. After tail vein injection of P6-Au, the Aβ content in the urine of 5×FAD transgenic mice increased by more than 20 times within the next 24 h, which resulted in the diagnosis time being advanced from the ninth month to the fifth month and provided a new approach for early detection of AD.},
}

@article {pmid41450541,
year = {2025},
author = {Chen, C and Shao, Q and Zhou, S},
title = {Exploring the Mahuang Fuzi Xixin Decoction's mechanism for treating Alzheimer's disease using molecular docking and network pharmacology.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1688316},
pmid = {41450541},
issn = {1663-4365},
abstract = {OBJECTIVE: Explore the potential mechanism of Mahuang Fuzi Xixin Decoction (MFXD) in the treatment of Alzheimer's disease (AD) using network pharmacology, molecular docking approaches, and test its efficacy by in vitro experiments.

METHODS: Active components of MFXD were screened from TCMSP, BATMAN-TCM, and TCMID, with corresponding targets obtained from SwissTargetPrediction and TCMSP. AD-related differential genes were retrieved from GEO. Intersection targets were identified via Venn diagrams, followed by GO/KEGG enrichment analyses, PPI network construction, and molecular docking. In vitro validation experiments were carried out using PC12 cells induced by Aβ25-35 to simulate the pathological state of AD. For the detection of cell viability, the CCK-8 assay was employed to evaluate the protective effect of MFXD and its active components on damaged PC12 cells. Western blot analysis was used to determine the protein expression levels of key molecules involved in AD-related signaling pathways, including phosphorylated p-NF-κB p65, NF-κB p65, p-GSK-3β, GSK-3β, MMP-9, p-Tau, and Tau. Additionally, the ELISA was utilized to measure the secretion level of TNF-α in the supernatant of Aβ25-35-induced PC12 cells, so as to assess the anti-inflammatory effect of MFXD.

RESULTS: Thirty-seven active components and 230 targets of MFXD were identified, along with 4913 AD-related differentially expressed genes from GEO dataset GSE122063, yielding 47 intersection targets. GO annotation enriched these targets in processes like reactive oxygen species metabolism, components like extracellular matrix, and functions like neurotransmitter binding; several pathways were enriched in the KEGG analysis, such as TNF signaling pathway, calcium signaling pathway, and NF-κB signaling pathway. The intersection target PPI network identified MMP9, EGFR, FOS as core targets. Molecular docking results indicated that quercetin binds to the three core targets (MMP9, EGFR, FOS), while luteolin binds preferentially to EGFR and MMP9. In vitro, Aβ25-35-induced PC12 cells treated with quercetin/luteolin had concentration-dependent viability increases (all P < 0.001); 15% MFXD-containing serum restored viability to ≥ 95% (P < 0.001 vs. AD model, comparable to DHCL). Western blot showed AD model had elevated p-NF-κB p65/NF-κB p65, MMP9/β-actin, p-Tau/Tau and reduced p-GSK-3β/GSK-3β (all P < 0.05); MFXD reversed these (all P < 0.05), while DHCL only inhibited p-NF-κB p65/NF-κB p65. ELISA showed MFXD and DHCL both reduced AD model's TNF-α (all P < 0.001).

CONCLUSION: MFXD potentially exerts anti-AD effects through a multi-component, multi-target, multi-pathway approach. Its key active components (quercetin, luteolin) may act by modulating the core target MMP9. Also, MFXD can simultaneously regulate several pathways, such as the TNF signaling pathway, Calcium signaling pathway, and NF-κB signaling pathway, and target Tau protein-related pathology by restoring the phosphorylation level of GSK-3β to suppress abnormal hyperphosphorylation of Tau, and thereby alleviating pathological damage in AD.},
}

@article {pmid41449667,
year = {2025},
author = {Günaydin, C and Hackett, NR and Wakim, V and Sondhi, D and Kaminsky, SM and Crystal, RG},
title = {Prime Editing of Alzheimer's Disease High-Risk APOE4 Allele by Brain-Directed Adeno-Associated Virus Vectors.},
journal = {Human gene therapy},
volume = {},
number = {},
pages = {},
doi = {10.1177/10430342251401888},
pmid = {41449667},
issn = {1557-7422},
abstract = {Common variants of the apolipoprotein E (APOE) gene have a major impact on the risk of developing Alzheimer's disease (AD). Relative to homozygotes with the common E3 allele, the APOE4 variant (C112R) increases risk by 3.5-fold in E3/E4 heterozygotes and 15-fold in E4 homozygotes. Since the E3 and E4 alleles differ only by a single nucleotide, gene editing of E4 to E3 is a potential strategy to reduce AD risk in E4 homozygotes. Because the APOE pool in the brain is separate from systemic APOE, editing to treat AD would ideally be directed to the brain. Following in vitro optimization of prime editing guide RNAs, efficient prime editing expression cassettes were inserted into the adeno-associated virus (AAV) split-intein system and packaged into pairs of AAV vectors for in vivo editing. The AAV vectors were administered to human homozygous APOE4-targeted replacement mice (TRE4), and APOE4 to APOE3 editing efficiency was assessed after 4 weeks. The prime editing construct designated APOE3/4-3_10 was the most efficient at APOE4 to APOE3 conversion, both in liver following intravenous delivery and in brain following intrahippocampal delivery. To assess brain-wide editing, two AAV capsids were compared, including AAVrh.10 with administration either directly to the hippocampus or to the cerebrospinal fluid via the cisterna magna and AAV-CAP.B10 administered intravenously. Other than minor differences in APOE4/3-3_10 mediated E4 to E3 editing in the cerebellum, the different capsids and routes yielded similar editing efficacy throughout the brain. This may represent a candidate treatment to reduce the risk of AD.},
}

@article {pmid41448751,
year = {2025},
author = {Liu, S and Wang, L and Li, S and Xu, G},
title = {[Effects of 40 Hz light flicker stimulation on hippocampal-prefrontal neural activity characteristics during working memory tasks in Alzheimer's disease model rats].},
journal = {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi},
volume = {42},
number = {6},
pages = {1107-1114},
pmid = {41448751},
issn = {1001-5515},
mesh = {Animals ; *Alzheimer Disease/physiopathology/therapy ; *Memory, Short-Term/physiology/radiation effects ; *Prefrontal Cortex/physiopathology ; *Hippocampus/physiopathology/physiology ; Rats, Wistar ; Rats ; Disease Models, Animal ; Male ; *Photic Stimulation ; Maze Learning ; },
abstract = {40 Hz light flicker stimulation is deemed to hold considerable promise in the treatment of Alzheimer's disease (AD). However, whether its long-term effect can improve working memory and its related mechanisms remains to be further explored. In this study, 21 adult Wistar rats were randomly divided into the AD light-stimulation group, the AD group and the control group. AD models were established in the first two of these groups, with the light-stimulation group receiving long-term 40 Hz light flicker stimulation. Working memory performance across groups was subsequently evaluated using the T-maze task. To investigate the potential neural mechanisms underlying the effects of 40 Hz light stimulation on working memory, we examined changes in neuronal excitability within the hippocampus (HPC) and medial prefrontal cortex (mPFC), as well as alterations in inter-regional synchronization of neural activity. The findings demonstrated that prolonged 40 Hz light stimulation significantly improved working memory performance in AD model rats. Furthermore, the intervention enhanced the synchronization of neural activity between the hippocampus (HPC) and medial prefrontal cortex (mPFC), as well as the efficiency of information transfer, primarily mediated by theta and low-frequency gamma oscillations. This study provides theoretical support for exploring the mechanisms of 40 Hz light flicker stimulation and its further clinical application in the prevention and treatment of Alzheimer's disease.},
}

Animals
*Alzheimer Disease/physiopathology/therapy
*Memory, Short-Term/physiology/radiation effects
*Prefrontal Cortex/physiopathology
*Hippocampus/physiopathology/physiology
Rats, Wistar
Rats
Disease Models, Animal
Male
*Photic Stimulation
Maze Learning

@article {pmid41448509,
year = {2025},
author = {Kim, N and Jeon, JY and Seo, J and Lee, Y and Kim, HJ and Kim, JS},
title = {A Combined Model of Convolutional Neural Networks and Graph Attention Networks for Improved Classification of Mild Cognitive Impairment.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121674},
doi = {10.1016/j.neuroimage.2025.121674},
pmid = {41448509},
issn = {1095-9572},
abstract = {Mild cognitive impairment (MCI), a precursor of Alzheimer's disease (AD), underscores the importance of early diagnosis and treatment. With an aging global population, AD prevalence is rising, necessitating more precise diagnostic methods. Deep learning technology shows promise for MCI and AD classification, but existing convolutional neural network (CNN) and graph attention network (GAT) models have limitations in capturing brain structural features and detecting microlesions. To address these issues, we propose a novel approach combining a CNN and modified GAT model to improve MCI classification. Magnetic resonance imaging volume data were analyzed using a CNN, whereas cortical thickness data were modeled using a GAT, leveraging their complementary strengths. Preprocessing involved extracting brain's structural features via the CIVET pipeline, and t-SNE was used to visualize the data's high-dimensional distribution. Final classification was performed using a multilayer perceptron, integrating feature vectors from both models. Performance evaluation metrics included the area under the curve (AUC), F1-score, sensitivity, and specificity. The combined CNN-GAT model outperformed existing single-model approaches, particularly in MCI classification, effectively distinguishing subtle variations between normal aging and MCI. The combined CNN-GAT model improved MCI classification performance by addressing the limitations of existing approaches. By capturing brain structural features and inter-regional relationships, it offers significant potential for advancing early diagnosis and treatment strategies for neurodegenerative diseases. Future efforts will focus on enhancing performance through additional data optimization.},
}

@article {pmid41447429,
year = {2025},
author = {Chandrasekaran, A and Malek-Ahmadi, M and Decourt, B and Sabbagh, MN},
title = {Informant-Based Questionnaires in the Diagnostic Pathway for Screening of Cognitive Impairment.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {41447429},
issn = {2193-8253},
abstract = {Alzheimer's disease (AD) remains the most common form of dementia in elderly populations. Accurately diagnosing early forms of dementia and AD remains a significant clinical challenge, especially in fast-paced primary care settings. Informant-based questionnaires that rely on close caregivers of the patients, such as the Informant Questionnaire on Cognitive Decline in the Elderly, the Ascertain Dementia 8-Item, the Quick Dementia Rating System, and the Alzheimer's Questionnaire, have recently been shown to be a valuable supplement to current standards of diagnosis, such as performance-based tests. This review aimed to explore the key characteristics of various informant-based questionnaires and evaluate their efficacy in the medical setting. Analysis of each test demonstrated that informant-based assessments show a strong ability to detect cognitive impairment early on in its pathology and can highlight gradual decline over time, compared with the single-timeframe evaluations that performance-based tests provide. Informant-based questionnaires are also able to circumvent challenges associated with the patient's education level, language, and other cultural biases, thus making them useful in diverse populations. When used in conjunction with performance tests, informant-based tests can significantly streamline the diagnostic process for dementia and enhance management and treatment strategies. Further research is advised to effectively integrate these tests into routine clinical practice and establish a new standard of care.},
}

@article {pmid41446880,
year = {2025},
author = {van Brummelen, R and van Brummelen, AC},
title = {The role of neuro-supportive substances of natural origin in neurological conditions-A literature-based formulators' perspective.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1647092},
pmid = {41446880},
issn = {1664-2295},
abstract = {Products of natural origin are seldom tested up to a point of full acceptance, mainly due to a lack of financial viability for commercialization. Yet many come with a rich history of use and proof of concept testing. We investigated literature regarding the possible role and function of the best known of these nutraceuticals in relationship to three neurological conditions i.e. stroke, Alzheimer's - (AD) and Parkinson's disease (PD), and their potential as supportive therapies. Current studies suggest that citicoline has a neuroprotective effect in ischemic conditions, playing a role in the restoration of the barrier function of endothelial cells, activating repair mechanisms and possibly decreasing ischemic lesion size in stroke, as well as increasing dopamine availability in PD. Citicoline was also demonstrated to increase the levels of sirtuin 1 (SIRT1), thus reducing inflammation-leading to improved cognitive status and a better quality of life in cognitive impairment. N-Acetylcysteine (NAC) shows pro-cognitive effects, increasing glutathione (GSH) levels that are decreased in AD and PD patients, possibly decreasing neuroinflammation. Mechanistic studies indicate the potential neuroprotective and neurorestorative effects of resveratrol by its anti-inflammatory and anti-apoptotic activity, also increasing SIRT1 levels and promoting the outgrowth of neurite protrusions and synaptogenesis. Curcumin's anti-inflammatory effects via inhibition of interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) can potentially delay progression of PD. Some nutraceuticals, e.g., citicoline, show synergism in combination with current therapies. We propose a renewed, risk-benefit approach for inclusion of the investigated nutraceuticals with limited indications in certain neurological treatment regimens.},
}

@article {pmid41446876,
year = {2025},
author = {Sun, Y and Chen, D and Ye, Q and You, Z and Zhao, Z and Shi, J and Sun, H and Li, S and Xu, X and Xu, Y and Zhang, P and Tang, Z},
title = {Applications of Endovascular Brain-Computer Interface in Patients with Alzheimer's Disease.},
journal = {Research (Washington, D.C.)},
volume = {8},
number = {},
pages = {1049},
pmid = {41446876},
issn = {2639-5274},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting the elderly, leading to important impairments in cognitive function and the ability to live independently. This results in substantial disability and places an increasing burden on families and society. Currently, the therapeutic approaches adopted in clinical practice predominantly hinge upon cholinesterase inhibitors and the N-methyl-d-aspartate (NMDA) receptor antagonist memantine. Nevertheless, these medications merely alleviate symptoms and fail to tackle the pathological characteristics of AD. In recent years, monoclonal antibodies such as lecanemab and donanemab against β-amyloid (Aβ) have shown good efficacy in clinical practice for early-stage AD patients. However, the early diagnosis of AD remains a challenge. Against this backdrop, endovascular brain-computer interface (EBCI) offers an integrated solution for the early diagnosis and neuroregulatory treatment of AD patients, with minimal invasiveness. This review comprehensively examines the safety and feasibility of EBCI for AD patients, focusing on 3 major application areas: early diagnosis, deep brain stimulation targeting specific brain regions, such as the fornix and the basal nuclei of Meynert, and the use of external neurofeedback devices. Furthermore, we explore future development trends in this field, including miniaturization, integration, and the exploration of deep brain regions.},
}

@article {pmid41446471,
year = {2025},
author = {Masna, H and Konda, M and Ganti, L},
title = {Huntington's Disease Research Over Six Decades: Global Insights, Gaps, and Future Directions.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e97567},
pmid = {41446471},
issn = {2168-8184},
abstract = {Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by expanded cytosine-adenine-guanine (CAG) repeats in the huntingtin (HTT) gene. It leads to progressive decline in motor function, cognition, and behavior, often following a prolonged pre-symptomatic phase. Although research on HD has progressed, significant gaps remain in understanding its full impact, particularly in areas such as mental health, global collaboration, and early intervention. A bibliometric analysis was conducted using the Web of Science Core Collection to evaluate global research trends in HD and its testing from 1966 to 2025. A total of 1,515 publications were analyzed for authorship patterns, contributing countries, journal sources, and frequently occurring keywords. VOSviewer software v1.6.15 (Centre for Science and Technology Studies, Leiden University, The Netherlands) was used to visualize author networks and keyword co-occurrence. Publication activity peaked in 2014 and 2018, with 101 and 96 articles published, respectively. The United States emerged as the leading contributor to HD research, followed by European countries with fewer publications. Keyword analysis revealed strong associations between HD and other neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, as well as recurring terms related to genetic testing, brain anatomy, and animal models. Limited author collaboration was observed, with only a few dense research clusters present. This analysis highlights the growing body of research on HD, particularly in genetic mechanisms and therapeutic modeling. However, the concentration of research within a few countries and author groups suggests limited global collaboration. Emerging gaps include underrepresentation of mental health impacts, disparities in geographic research output, and narrow journal dissemination. Strengthening international cooperation and diversifying research focus could accelerate progress in diagnosis, treatment, and overall patient care.},
}

@article {pmid41446236,
year = {2025},
author = {Fredriksen, K and Joshi, SS and Chang, A and Li, L},
title = {High-density lipoprotein mimetic peptide 4F ameliorates APOE4-associated lipid dysfunction in primary and iPSC-derived astrocytes and cerebral organoids.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.16.694774},
pmid = {41446236},
issn = {2692-8205},
abstract = {APOE is the greatest genetic risk factor for late-onset Alzheimer's disease (AD). In humans, APOE has three isoforms: APOE2 (E2), APOE3 (E3), and APOE4 (E4); E4 increases AD risk, while E3 is neutral and E2 decreases risk. In the brain, APOE is predominantly produced by astrocytes, where it binds lipids to form HDL-like particles, and plays a central role in lipid homeostasis, Aβ clearance, and neuroimmune modulation. Its lipidation state is critical for function, with E4 being poorly lipidated compared to E2 and E3, contributing to the pathogenic effects of E4 while also offering a potential therapeutic target. We have previously demonstrated that the HDL-mimetic peptide 4F increases APOE secretion and lipidation in wild-type mouse astrocytes and counteracts the inhibitory effects of Aβ42. Here, we assessed the ability of 4F to mitigate E4-associated dysfunction using primary astrocytes from humanized E3 and E4 knock-in mice and isogenic human iPSC-derived astrocytes and cerebral organoids. Results showed that 4F enhanced APOE secretion and lipidation in both cellular and organoid models in the absence or presence of aggregated Aβ42. Compared to E3 astrocytes, E4 astrocytes were prone to Aβ42-induced inhibition of APOE secretion and lipidation and increased accumulation of lipid droplets. 4F treatment ameliorated the inhibitory effects of Aβ42 and reduced lipid droplet accumulation. These findings support the therapeutic potential of HDL-mimetic peptides for E4-associated dysfunction in AD.},
}

@article {pmid41446123,
year = {2025},
author = {Shao, B and Kula, B and Le, H and Venkhatesh, P and Katti, P and Marshall, AG and Chittaranjan, S and Thapilyal, S and Kalpana, NH and Nivedya, C and Roszczyk, A and Mobley, H and Killion, M and St John, E and Martin, P and Rodrigiuez, B and Hamilton, M and Bell, L and Wyckoff, SM and Moran, LA and Philips, M and Hubert, D and Tomeau, B and Afolabi, JM and Kirabo, A and Blanco, I and Reasonover, S and Drake, LE and Lippmann, ES and Evans, C and Santisteban, MM and Cheairs, TG and Mesenga, S and Wanjalla, C and Gaddy, J and McMillan, R and Perez, CPH and Paing, HH and Schafer, JC and Mobley, B and Berry, J and Crabtree, A and Kovtun, O and Goodwin, S and Lopez, EG and Dash, C and Dai, DF and Miller-Fleming, TW and Hinton, A and Smith, NA},
title = {The role of MICOS in modulating mitochondrial dynamics and structural changes in vulnerable regions of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.13.693635},
pmid = {41446123},
issn = {2692-8205},
abstract = {Mitochondrial contact site and cristae organizing system (MICOS) complexes are critical for maintaining the mitochondrial architecture, cristae integrity, and organelle communication in neurons. MICOS disruption has been implicated in neurodegenerative disorders, including Alzheimer's disease (AD), yet the spatiotemporal dynamics of MICOS-associated neuronal alterations during aging remain unclear. Using three-dimensional reconstructions of hypothalamic and cortical neurons, we observed age-dependent fragmentation of mitochondrial cristae, reduced intermitochondrial connectivity, and compartment-specific changes in mitochondrial size and morphology. Notably, these structural deficits were most pronounced in neurons vulnerable to AD-related pathology, suggesting a mechanistic link between MICOS disruption and the early mitochondrial dysfunction observed in patients with AD. Our findings indicate that the loss of MICOS integrity is a progressive feature of neuronal aging, contributing to impaired bioenergetics and reduced resilience to metabolic stress and potentially facilitating neurodegenerative processes. MICOS disruption reduced neuronal firing and synaptic responsiveness, with miclxin treatment decreasing mitochondrial connectivity and inducing cristae disorganization. These changes link MICOS structural deficits directly to impaired neuronal excitability, highlighting vulnerability to AD-related neurodegeneration. These results underscore the importance of MICOS as a critical determinant of neuronal mitochondrial health and as a potential target for interventions aimed at mitigating AD-related mitochondrial dysfunction.},
}

@article {pmid41445693,
year = {2025},
author = {Lee, S and Yin, L and Teopiz, KM and Wong, S and Han Le, G and Xiao, N and Stahl, S and Valentino, K and Ho, R and Zhang, MC and Greg Rhee, T and McIntyre, RS},
title = {Effects of glucagon-like peptide-1 receptor agonists on psychiatric disorders: a systematic review.},
journal = {Therapeutic advances in psychopharmacology},
volume = {15},
number = {},
pages = {20451253251396304},
pmid = {41445693},
issn = {2045-1253},
abstract = {Extant literature pertaining to the administration of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for Alzheimer's disease, Parkinson's disease, major depressive disorder, bipolar disorder, substance-, alcohol- and nicotine-use disorders, suggests promising efficacy beyond the current FDA-approved indications (e.g., type 2 diabetes mellitus, obesity). The implicated brain regions of the aforementioned mental disorders contain glucagon-like peptide 1 (GLP-1) receptors associated with improving cognitive and behavioral functioning. Therefore, we aimed to systematically review the treatment effects of GLP-1RAs in various neurocognitive and psychiatric disorders. Online databases including PubMed, OVID, MEDLINE, Embase, PsycINFO and Google Scholar, were searched from inception until October 1, 2024. Additional studies were identified from the reference lists of the included articles. 22 studies were identified, with a total of 186,847 participants included. Results reported that GLP-1RAs meaningfully improved cognitive and affective functioning (e.g., memory), which in some cases was sustained beyond exposure to the agent. Separately, multiple epidemiological studies reported that GLP-1RAs have protective effects, with a suggestion of decrease in the incidence of mental disorders. These results provides the impetus for large, long-term, randomized controlled trials for GLP-1 RAs for the treatment of various mental disorders. This review is not registered in PROSPERO or any other registry.},
}

@article {pmid41445644,
year = {2025},
author = {Li, R and Langford, O and Insel, PS and Sperling, RA and Raman, R and Aisen, PS and Donohue, MC},
title = {Divergent latent classes of cognitive decline in the A4 and LEARN studies.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.15.25342305},
pmid = {41445644},
abstract = {IMPORTANCE: Alzheimer disease biomarkers in cognitively unimpaired older adults are associated with later cognitive and clinical decline, yet substantial heterogeneity in the timing and rate of decline remains insufficiently characterized.

OBJECTIVE: To identify subgroups of cognitive decline among biomarker-defined cognitively unimpaired adults and determine baseline predictors of heterogeneity in preclinical Alzheimer disease progression.

Longitudinal data were drawn from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study, which enrolled amyloid-positive participants, and the parallel LEARN Study, which enrolled amyloid-negative individuals meeting all other A4 criteria. Participants completed baseline amyloid PET, plasma P-tau217, structural MRI, and serial cognitive assessments. Latent Class Mixed-Effects Models (LCMMs) were used to identify distinct cognitive trajectory classes. Associations between class membership and demographic, clinical, and biomarker characteristics were evaluated.

MAIN OUTCOMES AND MEASURES: The primary outcome was longitudinal change in the Preclinical Alzheimer's Cognitive Composite (PACC).

RESULTS: Three cognitive trajectory classes were identified: stable, slow decliners, and fast decliners. Higher plasma P-tau217, smaller hippocampal volume, and elevated tau PET were associated with greater odds of belonging to declining classes. Among amyloid-positive individuals, approximately 70% were classified as stable over the observed follow-up interval.

CONCLUSIONS AND RELEVANCE: Latent class modeling reveals marked heterogeneity in preclinical cognitive trajectories, even among individuals with biomarker evidence of Alzheimer pathology. The high proportion of stable individuals is consistent with the long presymptomatic interval. Identifying subgroups of decline may improve prognostic modeling and guide enrichment strategies for precision secondary prevention trials.},
}

@article {pmid41444683,
year = {2025},
author = {Weissmann, C and Castellanos, LCS and Montes, MM and Uruk, G and Youssef, H and Reichard, RR and Gatto, RG and Josephs, KA},
title = {4R-tau isoform induction via TDP-43 in neurons in response to insulin: converging signaling pathways with implications for neurodegenerative disease.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {258},
pmid = {41444683},
issn = {2051-5960},
support = {PIP Grant No. 11220210100589CO//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; UBACYT (Grant No. 20020220400291BA)//Universidad de Buenos Aires/ ; R01-AG37491//National Institute for Health Care Management Foundation/ ; R01 AG037491/AG/NIA NIH HHS/United States ; PICT 2020-01211//Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación/ ; },
mesh = {Animals ; *tau Proteins/metabolism ; *DNA-Binding Proteins/metabolism ; *Neurons/metabolism/drug effects ; Humans ; *Signal Transduction/drug effects/physiology ; *Insulin/pharmacology ; Protein Isoforms/metabolism ; HEK293 Cells ; Mice ; *Neurodegenerative Diseases/metabolism ; Phosphorylation/drug effects ; Cells, Cultured ; Cerebral Cortex/cytology/metabolism ; Mice, Inbred C57BL ; },
abstract = {Tau protein isoforms, regulated during development, are influenced by the nuclear factor TDP-43, which plays a crucial role in tau mRNA stability and exon 10 inclusion. Both tau and TDP-43 are prone to pathological phosphorylation and aggregation, with specific phosphorylated forms of TDP-43 linked to cytoplasmic mislocalization and alterations in the 3R/4R tau ratio as detected in different pathologies. In this study, we show that insulin treatment of embryonic mouse primary cortical neurons-cells that normally express only 3R-tau-induces the expression of 4R-tau, suggesting that metabolic signaling can influence tau isoform expression in a developmentally immature neuronal context. In addition, experiments in HEK293 cells revealed isoform-specific stabilization effects and showed that insulin promotes TDP-43 redistribution to the cytoplasm along with a phosphorylation pattern. These results underscore the complex interplay between TDP-43 and tau isoforms and metabolic signaling pathways that play a crucial role in their expression and localization with potential implications for understanding mechanisms of neurodegenerative disease onset and progression.},
}

Animals
*tau Proteins/metabolism
*DNA-Binding Proteins/metabolism
*Neurons/metabolism/drug effects
Humans
*Signal Transduction/drug effects/physiology
*Insulin/pharmacology
Protein Isoforms/metabolism
HEK293 Cells
Mice
*Neurodegenerative Diseases/metabolism
Phosphorylation/drug effects
Cells, Cultured
Cerebral Cortex/cytology/metabolism
Mice, Inbred C57BL

@article {pmid41444088,
year = {2025},
author = {Lynch, S},
title = {Addressing Cognitive Dysfunction: Education, Diagnosis, and Practical Care.},
journal = {The Veterinary clinics of North America. Small animal practice},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cvsm.2025.09.030},
pmid = {41444088},
issn = {1878-1306},
abstract = {Cognitive dysfunction syndrome (CDS) is a common, yet underdiagnosed, neurobehavioral disease of domestic animals. Much like its human counterpart, Alzheimer's disease, CDS is the result of neuronal loss and inflammatory changes in the central nervous system; however, the specific pathophysiology of the disease continues to be researched in efforts to advance diagnostics, prognosis, and treatment. Diagnosis is typically conducted by ruling out possibilities and using assessment tools, including the Canine Dementia Scale and the Canine Cognitive Dysfunction Rating Scale. Treatment is often most successful when a tailored, multimodal approach is initiated early in the disease progression.},
}

@article {pmid41442238,
year = {2025},
author = {Periyakoil, VS and Von Gunten, C and Kraemer, H},
title = {Virtual, Nurse-Led Early Primary Palliative Care Intervention (ELICIT) for Community-Dwelling Older Adults With Cognitive Impairment: Protocol for a Randomized Controlled Trial.},
journal = {JMIR research protocols},
volume = {14},
number = {},
pages = {e75082},
pmid = {41442238},
issn = {1929-0748},
support = {R01 AG062239/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Cognitive Dysfunction/nursing/therapy ; *Palliative Care/methods ; Aged ; Independent Living ; Male ; Female ; Aged, 80 and over ; Quality of Life ; Randomized Controlled Trials as Topic ; Primary Health Care ; },
abstract = {BACKGROUND: Although dementia is a serious illness that progresses over many years, little is known about the primary palliative care needs of individuals who have it, especially those living in the community.

OBJECTIVE: This trial aims to test the impact of a virtual, nurse-led early primary palliative care intervention (ELICIT) on older adults living in the community who are chronically ill and have a diagnosis of cognitive impairment or are at risk of it.

METHODS: A total of 200 community-dwelling older adults who were chronically ill and had varying degrees of cognitive impairment were recruited and randomized to either usual care or usual care + a virtual, nurse-led ELICIT. For both arms, we will track the number of participants who (1) report supportive care needs to the blinded evaluators and (2) complete conversations on goals of care and document advance directives and the Physician Orders for Life-Sustaining Treatment form in the electronic health record. We will also track their end-of-life resource use and the percentage of participants who receive goal-concordant care. Changes in Edmonton Symptom Assessment Scale, Patient Activation Measure, and Quality of Life in Alzheimer's Disease scores will be tracked and analyzed.

RESULTS: As of October 2025, we have recruited 200 participants. We are following all study participants on an ongoing basis to determine whether they received goal-concordant care at the end of life and their resource use patterns. We hypothesize that, compared to the usual care arm, more participants in the intervention arm will (1) express supportive care needs to the blinded evaluators, (2) complete goals of care conversations, document advance care planning, and (3) have higher levels of goal-concordant care and lower end-of-life resource use.

CONCLUSIONS: The identification of the primary palliative care needs of community-dwelling older adults who are chronically ill and have various levels of cognitive impairment will help refine the intervention and enable trained nurses to provide virtual early primary palliative care within the scope of nursing.},
}

Humans
*Cognitive Dysfunction/nursing/therapy
*Palliative Care/methods
Aged
Independent Living
Male
Female
Aged, 80 and over
Quality of Life
Randomized Controlled Trials as Topic
Primary Health Care

@article {pmid41441957,
year = {2025},
author = {Neve, V and Saqlain, S and Veeranjaneyulu, A and Karwa, P and Kapare, H and Yeralkar, K},
title = {Evaluation of the neuroprotective activity of Momordica dioica against aluminum chloride (AlCl3)-Induced alzheimer's disease in Wistar rats.},
journal = {Discover mental health},
volume = {5},
number = {1},
pages = {198},
pmid = {41441957},
issn = {2731-4383},
abstract = {Alzheimer's disease is a brain condition that slowly erodes a person's memory and cognitive abilities. It is caused by damage to brain cell, particularly in the hippocampus, a region crucial for memory. By 2050 worldwide no. of AD is going increases. Various therapeutic strategies have been explored for AD. The use of herbal products is one of the treatment regimens for AD. In this study, we examined how a herbal extract from Momordica dioica could potentially protect Wistar rats from AD caused by Aluminum chloride. Aluminum chloride (AlCl3) is widely used in preclinical studies to induce Alzheimer-like symptoms, as chronic exposure is known to promote oxidative stress, neuroinflammation, and cholinergic dysfunction-hallmarks of Alzheimer's disease pathology. A total of 86 Wistar rats were randomly assigned to nine experimental groups (n = 6-10 per group), including a normal control group and an Alzheimer's disease (AD) model group. One group treated with Donepezil (2.05 mg/kg), three groups treated with different doses of herbal extract of Momordica dioica (100, 200 and 400 mg/kg), and three groups treated with a combination of Donepezil and herbal extract of Momordica dioica (std + 100, std + 200 and std + 400 mg/kg). The aluminum chloride (17 mg/kg, p.o) was administered once daily for 7 days to induce AD. From the 8th day onward, the herbal extract of Momordica dioica was administered orally for 21 consecutive days at doses of 100, 200, and 400 mg/kg to groups 4, 5, and 6 respectively, as well as in combination with Donepezil (2.05 mg/kg) in groups 7, 8, and 9. This brought the total duration of the study to 28 days." Elevated Plus Maze and Forced Swim test was used for the behavioral assessment. After that, brain samples were collected for biochemical analysis. Herbal Extract significantly improved AlCl3-induced behavioral impairments and cognition deficits in Forced Swim Test, Elevated Plus Maze Test significantly with high dose. Then, herbal extract of Momordica dioica facilitated cholinergic activity via inhibiting acetylcholinesterase (AChE) activity. Besides, herbal extract of Momordica dioica decreased lipid peroxidation level & Nitrite level but enhanced levels of glutathione, Succinate dehydrogenase, Catalase and superoxide dismutase and results are more convincing with high dose. Histopathological analysis further confirmed reduced neuronal degeneration and better preservation of brain architecture, especially at higher doses of the herbal extract." The results suggested that herbal extract of Momordica dioica ameliorated AlCl3-induced cognitive and memory impairments, possibly through regulating AChE activity, suppressing oxidative stress. The herbal extract of Momordica dioica significantly improved behavioral impairments and cognition deficits, particularly at high doses. It facilitates cholinergic activity by inhibiting AChE activity and reduced oxidative stress. Overall, the conclusion states that the herbal extract may ameliorate and memory impairments associated with AD.},
}

@article {pmid41441560,
year = {2025},
author = {Clevenger, C and Jackson, WC and Stroud, J and Brubaker, M and Patel, M and Bucior, I and Bratlee-Whitaker, E and Brown, TM and Fehnel, S and Peschin, S and Cummings, J and Grossberg, G},
title = {Development and evaluation of the agitation in Alzheimer's screener for caregivers (AASC): a clinical tool to screen for agitation.},
journal = {Current medical research and opinion},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/03007995.2025.2606562},
pmid = {41441560},
issn = {1473-4877},
abstract = {OBJECTIVE: Although agitation is a common neuropsychiatric symptom in Alzheimer's dementia, it can be challenging to recognize and diagnose. Caregivers of individuals with Alzheimer's dementia are often the first to encounter agitation behaviors but may struggle to recognize and communicate symptoms to healthcare professionals (HCPs). Here, we describe the development and evaluation of the Agitation in Alzheimer's Screener for Caregivers (AASC), a practical screening tool to identify agitation symptoms and facilitate caregiver-HCP communication.

METHODS: The AASC was developed based on the International Psychogeriatric Association (IPA) criteria for agitation in cognitive disorders, input from multidisciplinary experts, and qualitative interviews with caregivers of patients with Alzheimer's dementia. Thereafter, a 2-phase quantitative evaluation study was conducted to refine the AASC and assess the predictive validity of the final tool against IPA criteria. Data were collected from caregiver-HCP dyads, where caregivers completed the AASC and HCPs used IPA criteria to inform their assessment of agitation.

RESULTS: A total of 226 caregiver-HCP dyads were quantitatively evaluated. The mean age of caregivers was 61 years; many were spouses/partners (46%), White (60%), and female (62%), providing an average of 60 h of care weekly (range: 9-168 h). Following initial assessment and refinement, the final AASC, evaluated in a subset of 105 dyads, showed a 73.3% agreement with IPA criteria, with sensitivity of 0.77, specificity of 0.70, and kappa and F1 scores of 0.47 and 0.71, respectively. Most patients were classified as having mild (41%) to moderate (37%) Alzheimer's dementia, while 22% had severe disease.

CONCLUSION: The AASC is a reliable, easy-to-use, 2-item screener for the presence and impact of agitation, in agreement with IPA criteria. The AASC supports caregivers and HCPs by providing an accessible framework for recognizing agitation throughout all stages of Alzheimer's dementia and prompting comprehensive assessment for diagnosis and appropriate treatment planning.},
}

@article {pmid41440958,
year = {2025},
author = {Rahmani, AR and Madani, SA and Aminov, E and Gogokhia, L and Bench, T and Kalogeropoulos, A},
title = {Heart Failure and Cognitive Impairment Through the Lens of the Gut Microbiome: A Narrative Review.},
journal = {Journal of personalized medicine},
volume = {15},
number = {12},
pages = {},
pmid = {41440958},
issn = {2075-4426},
abstract = {Heart failure (HF) affects over 55 million individuals globally, with prevalence projected to exceed 11 million in the United States by 2050 and is increasingly recognized as a systemic disorder extending beyond hemodynamic dysfunction to encompass profound alterations in neural and gut physiology. Cognitive impairment affects nearly half of HF patients and represents a major determinant of morbidity, self-care capacity, and mortality. Recent advances suggest that the gut microbiome serves as a pivotal intermediary in the heart-brain crosstalk, influencing neurocognitive outcomes through inflammatory, metabolic, and neurohumoral pathways. Dysbiosis in HF disrupts intestinal barrier integrity, facilitating translocation of endotoxins and microbial metabolites such as trimethylamine-N-oxide (TMAO), short-chain fatty acids (SCFAs), and bile acids, which in turn modulate neuroinflammation, cerebral perfusion, and neuronal signaling. The gut-heart-brain axis provides an integrative framework linking HF and cognitive impairment pathophysiology through dysbiosis-driven systemic inflammation and metabolite dysregulation. Gut-derived biomarkers and microbiome-targeted interventions represent promising strategies for detection of early alterations and precision treatment, highlighting the urge for prospective, multi-omics studies to establish causality and therapeutic efficacy. This review synthesizes current evidence connecting gut microbiome dysbiosis and metabolite alterations to both HF and cognitive impairment pathophysiology and proposes translational strategies for integrating microbiome-targeted therapies in HF patients with cognitive dysfunction.},
}

@article {pmid41438688,
year = {2026},
author = {Su, T and Li, Z and Yang, Y and Dai, Y and Li, Y and Zhao, H},
title = {In vitro 3D models of neuron-astrocyte interactions.},
journal = {Biochemistry and biophysics reports},
volume = {45},
number = {},
pages = {102400},
pmid = {41438688},
issn = {2405-5808},
abstract = {The pathological processes of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis) also include relationships between neuron and glia cells. Conventional two-dimensional (2D) cell cultures have limitations to mimic the microenvironment of cells inside living organisms because of flaws in intercellular relationships investigated using 2D cell cultures. Recent advances have introduced three-dimensional (3D) cell cultures that have the capability to create 3D cellular architecture to mimic advanced platforms for scientific inquiries into neurodegenerative diseases, simulating microenvironments inside living organisms.This review provides a brief overview of the development of in vitro 3D cell culture models of astrocytes and attempts to highlight the role of astrocytes in crucial pathophysiologic events occurring in 3D cultures. Studies have shown the use of in vitro 3D cultures to better represent the dual functions of astrocytes in neurodegenerative disorders. Looking ahead to the future, novel advances in microfluidics and multi-omics analysis promise to further improve 3D cultures and push forward new insights into neurological dysfunction to spark innovative advances for treatment strategies.},
}

@article {pmid41437993,
year = {2025},
author = {Fliri, A and Sostek, R and Kajiji, S},
title = {Protein swarm-based cause-effect analysis: effects of microRNAs on cooperation networks linking COVID-19 infections, atherosclerosis, and Alzheimer's disease.},
journal = {Frontiers in cardiovascular medicine},
volume = {12},
number = {},
pages = {1577844},
pmid = {41437993},
issn = {2297-055X},
abstract = {Well-being depends on the integrated operation of biological processes at all levels of system organization, from individual cells to tissues and organ systems, collectively sustaining homeostasis and optimal bodily functions. The regulation of cooperation among these processes is mediated by information flow within networks possessing diverse structural, functional, and temporal properties. Disruption in these networks is observed in conditions such as infections, inflammatory diseases, and cancer. To advance understanding of immune system roles and to elucidate mechanisms underlying health vulnerability during disease, we utilized proteomics data related to 4,800 diseases along with protein swarm-based cause-effect analyses to identify principles governing plasticity and self-organizing capabilities of immune systems. Our findings demonstrate that the precision of immune system functions is regulated by dynamic alterations in the topologies of cooperation networks that are partially modulated by microRNAs. Additionally, our analysis indicates that investigating the underlying causes of diseases through the study of cooperative network functions and their interactions with microRNAs-rather than concentrating exclusively on individual protein targets or microRNAs-provides significant insights for devising effective treatment strategies for infections, cardiovascular conditions, Alzheimer's disease, cancer, aging, and related health concerns.},
}

@article {pmid41436813,
year = {2025},
author = {Birnbaum, EM and Xie, L and Serrano, P and Rockwell, P and Figueiredo-Pereira, ME},
title = {BT-11 targets the LANCL2 pathway to attenuate cognitive deficits and hippocampal pathology in Alzheimer's transgenic rats.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-31514-z},
pmid = {41436813},
issn = {2045-2322},
support = {TL1-TR0002386//NIH Weill Cornell CTSC/ ; R01AG057555//NIH/NIA/ ; },
abstract = {Neuroinflammation is a key pathological hallmark of Alzheimer's disease (AD). Investigational and FDA approved drugs targeting inflammation already exist, thus drug repurposing for AD is a suitable approach. BT-11 is an investigational drug that reduces inflammation in the gut and improves cognitive function. BT-11 is orally active and binds to lanthionine synthetase C-like 2 (LANCL2), a glutathione-s-transferase, thus potentially reducing oxidative stress. We investigated the effects of BT-11 long-term treatment on the TgF344-AD rat model of AD. BT-11 (1) reduced spatial memory deficits, and hippocampal Abeta plaque load, and increased neuronal levels in males, and reduced microglia numbers in females, and (2) induced transcriptomic changes in signaling receptor, including G-protein coupled receptor pathways in both males and females, with changes in neurotrophic factors only in males. We detected LANCL2 in hippocampal nuclear and cytoplasmic fractions with potentially different post-translational modifications, suggesting distinct functions based on its subcellular localization. LANCL2 was present in oligodendrocytes, indicating a role in oligodendrocyte function. To our knowledge, these last two findings have not been reported. Overall, our data support that targeting LANCL2 with BT-11 improves cognition and reduces AD-like pathology potentially by modulating G-protein signaling. LANCL2's localization in oligodendrocytes suggest a possible role oligodendrocyte function that warrants further investigation. Our studies contribute to the field of new immunomodulatory AD therapeutics and establish LANCL2 as a promising therapeutic target meriting further mechanistic investigation.},
}

@article {pmid41435831,
year = {2025},
author = {Chaubey, K and Vázquez-Rosa, E and Tripathi, SJ and Shin, MK and Yu, Y and Dhar, M and Chakraborty, S and Yamakawa, M and Wang, X and Sridharan, PS and Miller, E and Bud, Z and Corella, SG and Barker, S and Caradonna, SG and Koh, Y and Franke, K and Cintrón-Pérez, CJ and Rose, S and Fang, H and Cintrón-Pérez, AA and Tomco, T and Zhu, X and Fujioka, H and Gefen, T and Flanagan, ME and Williams, NS and Wilson, BM and Chen, L and Dou, L and Cheng, F and Rexach, JE and Woo, JA and Kang, DE and Paul, BD and Pieper, AA},
title = {Pharmacologic reversal of advanced Alzheimer's disease in mice and identification of potential therapeutic nodes in human brain.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102535},
doi = {10.1016/j.xcrm.2025.102535},
pmid = {41435831},
issn = {2666-3791},
abstract = {Alzheimer's disease (AD) is traditionally considered irreversible. Here, however, we provide proof of principle for therapeutic reversibility of advanced AD. In advanced disease amyloid-driven 5xFAD mice, treatment with P7C3-A20, which restores nicotinamide adenine dinucleotide (NAD[+]) homeostasis, reverses tau phosphorylation, blood-brain barrier deterioration, oxidative stress, DNA damage, and neuroinflammation and enhances hippocampal neurogenesis and synaptic plasticity, resulting in full cognitive recovery and reduction of plasma levels of the clinical AD biomarker p-tau217. P7C3-A20 also reverses advanced disease in tau-driven PS19 mice and protects human brain microvascular endothelial cells from oxidative stress. In humans and mice, pathology severity correlates with disruption of brain NAD[+] homeostasis, and the brains of nondemented people with Alzheimer's neuropathology exhibit gene expression patterns suggestive of preserved NAD[+] homeostasis. Forty-six proteins aberrantly expressed in advanced 5xFAD mouse brain and normalized by P7C3-A20 show similar alterations in human AD brain, revealing targets with potential for optimizing translation to patient care.},
}

@article {pmid41434387,
year = {2025},
author = {Huang, X and Puri, R and Sun, D and Zhao, Y and Zhang, J and Huang, K and Wang, Y},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110031},
doi = {10.1002/alz70862_110031},
pmid = {41434387},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology ; *Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/physiopathology ; Female ; Male ; Aged ; Brain Mapping ; *Nerve Net/diagnostic imaging/physiopathology ; },
abstract = {BACKGROUND: Functional magnetic resonance imaging (fMRI) has emerged as a powerful modality for investigating brain activity, offering superior spatial resolution and a non-invasive means to probe functional connectivity. In the context of Alzheimer's disease (AD), studying these disruptions is crucial for understanding how functional connectivity changes in salient brain activation networks for different subtypes. This study compares asymptomatic and typical AD groups to identify early alterations in brain networks that may inform future diagnostic and therapeutic strategies.

METHOD: Three analytical pipelines were employed to characterize functional connectivity comprehensively from ADNI resting state fMRI data. The first pipeline parcellated the brain using functional atlases, then edge quantification through Graphical Lasso and group sparse covariance estimation, thereby capturing inter-regional dependencies, using Nilearn. The second pipeline used independent component analysis (ICA) to decompose the fMRI data into distinct spatial components; mutual information was then applied to quantify the statistical relationships among these components. The third pipeline utilized FSL to perform advanced brain decomposition techniques like ICA and dual regression to generate time series that were subsequently analyzed to discern significant connectivity patterns between asymptomatic and typical AD cohorts.

RESULT: Across all pipelines, heatmaps were generated to visualize regions of high and low brain activity, while network diagrams demonstrated varying levels of connectivity strength and hub distribution. For instance, when compared to typical AD, patients having asymptomatic AD have more regions with negative covariance. These regions are the right posterior temporal region, the default mode network. On the contrary, the regions with high positive connections or brain activity for typical AD are the auditory cortex, intraparietal sulcus, dorsal, ventral anterior cingulate cortex, and left lateral occipital complex. The posterior occipital region has strong negative connections with other regions of the brain in Typical AD.

CONCLUSION: This study underscores the utility of fMRI-based techniques for elucidating connectivity differences in asymptomatic and symptomatic stages of AD. By mapping out network-level alterations, the resulting brain graphs offer valuable insights into the pathophysiology of AD, highlighting regions and pathways that may be critical in the early detection and treatment of the disease, potentially in a clinical setting utilizing fMRI as a biomarker.},
}

Humans
*Alzheimer Disease/diagnostic imaging/physiopathology
*Magnetic Resonance Imaging/methods
*Brain/diagnostic imaging/physiopathology
Female
Male
Aged
Brain Mapping
*Nerve Net/diagnostic imaging/physiopathology

@article {pmid41434278,
year = {2025},
author = {Honarvar, F and Noronha, J and Gibicar, A and Tyrrell, P and Maralani, P and Fischer, C and Black, SE and Moody, AR and Khademi, A},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110217},
doi = {10.1002/alz70862_110217},
pmid = {41434278},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; *White Matter/diagnostic imaging/pathology ; Canada ; Biomarkers ; Cohort Studies ; *Alzheimer Disease/diagnostic imaging ; *Brain/diagnostic imaging/pathology ; Middle Aged ; *Cerebrovascular Disorders/diagnostic imaging ; Aged, 80 and over ; },
abstract = {BACKGROUND: Cerebrovascular disease (CVD) is a leading cause of mortality with a strong link to cognitive impairment and dementia. White matter lesions (WML) are prevalent in CVD and are early markers of vascular compromise, particularly in relation to intraplaque hemorrhage (IPH), an indicator of carotid artery plaque instability. As vascular disease represents a possible treatment window for dementia subjects, this study explores the relationship between hemispheric WML asymmetry and IPH utilizing a large multicenter cohort to find novel biomarkers of disease.

METHOD: FLAIR MRI scans of 264 subjects from the Canadian Atherosclerosis Imaging Network were categorized as IPH positive (IPH+) or IPH negative (IPH-) and WML biomarkers were automatically computed (Figure 1). Biomarkers related to WML prevalence (volume) and WML ischemia and progression (intensity) were extracted: ICV-normalized WML volume (WML-ICV), WML mean intensity (WML-Intensity), and WML intensity ratio (WML-IR). WML asymmetry was assessed via an asymmetry index measure (AIM). Linear mixed models and regression analyses were conducted, with adjustments for age, sex, scanner manufacturer, and stenosis, to evaluate associations between WML biomarkers and IPH status.

RESULT: IPH+ patients exhibited significant rightward asymmetry in WML-ICV (0.0032 ± 0.002, p < 0.05), WML-Intensity (7.26 ± 5.41, p < 0.05), and WML-IR (0.0271 ± 0.0204, p < 0.05); Table 1. IPH+ subjects (left, right or bilateral) had more lesions that were brighter in the right hemisphere. This trend was most pronounced in younger male patients (<65 years), suggesting a high-risk demographic. Regression analysis revealed IPH as a significant predictor of WML asymmetry, with stronger effects observed in subjects with IPH in the right carotid artery.

CONCLUSION: Previous studies suggest more injury in the right hemisphere for subjects with small vessel disease, and this work supports this finding. With rightward WML asymmetry being strongly associated with IPH, this could be reflecting a surrogate marker for overall vascular disease and its contribution to brain health and dementia. Automated WML biomarkers can be used to identify these high-risk patients and guide early interventions for subjects with vascular disease and dementia. Future work should validate these findings in larger, longitudinal datasets to enhance clinical applications.},
}

Humans
Male
Female
Magnetic Resonance Imaging
Aged
*White Matter/diagnostic imaging/pathology
Canada
Biomarkers
Cohort Studies
*Alzheimer Disease/diagnostic imaging
*Brain/diagnostic imaging/pathology
Middle Aged
*Cerebrovascular Disorders/diagnostic imaging
Aged, 80 and over

@article {pmid41434276,
year = {2025},
author = {Anda-Duran, I and Hwang, PH and Leverant, E and Emrani, S and Thompson, LI and Andersen, SL and Libon, DJ},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109843},
doi = {10.1002/alz70862_109843},
pmid = {41434276},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis/psychology ; Aged ; *Alzheimer Disease/diagnosis ; *Neuropsychological Tests ; Aged, 80 and over ; Middle Aged ; Memory, Short-Term ; },
abstract = {BACKGROUND: With the availability of monoclonal anti-body treatment for mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD), there is a need to screen and identify emergent disease as soon as possible. In a companion abstract, a panel of six novel outcome measures from the digital Trail Making Test-Part B (dTMT-B) was able to dissociate patients with mild cognitive impairment (MCI) versus normal cognition (NC). The current research fashioned an abbreviated dTMT-B test and assessed how well this test can dissociate patients with MCI versus NC; and relationships between paper/pencil neuropsychological tests.

METHOD: Using a digital neuropsychological battery of episodic and working memory tests, memory clinic patients (n = 58) were classified into groups presenting with MCI versus NC. An abbreviated dTMT-B test was created by examining behavior confined to approximately the first half of the test, i.e., target circle '1' through target circle 'F'. The panel of dTMT-B process metrics included (1) hit duration or time spent with the pen inside target circles; (2) distance or the length of an imaginary line connecting all targets; and (3) the velocity or the speed pen strokes were drawn.

RESULT: MCI patients were slightly older and less educated than NC patients; and scored lower on the MMSE. An ANOVA controlled for age, education, and sex found longer hit duration for MCI compared to NC patients (p < 0.004, η[2]= 0.204). No differences were found for total distance or pen stroke velocity. Partial correlations controlled for age, education, and sex found that longer hit duration inside target circles was associated with lower performance on tests measuring attention (WAIS-IV Digits Forward/ Trails A; r= -0.724, p < 0.001); working memory (WMS-IV Symbol Span/ letter fluency; r= -0.520, p < 0.007); and episodic memory (CVLT-9 Delay Free recall/ Recognition; r= -0.411, p < 0.037).

CONCLUSION: The engineering of the Trail Making Test- Part B onto the digital platform has resulted in a panel of new process-based metrics and potentially increases the versatility of this test. An abbreviated version of the test could easily be deployed to screen for emergent cognitive impairment.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis/psychology
Aged
*Alzheimer Disease/diagnosis
*Neuropsychological Tests
Aged, 80 and over
Middle Aged
Memory, Short-Term

@article {pmid41434222,
year = {2025},
author = {Heston, MB and Windon, CC and Hanna, L and Gatsonis, C and Carrillo, MC and Apgar, C and Dilworth-Anderson, P and Hillner, BE and March, A and Siegel, BA and Whitmer, RA and Wilkins, CH and Joie, R and Rabinovici, GD},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110237},
doi = {10.1002/alz70862_110237},
pmid = {41434222},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/diagnostic imaging/drug therapy ; Aged ; *Positron-Emission Tomography ; Aged, 80 and over ; Brain/diagnostic imaging ; Socioeconomic Factors ; *Cognitive Dysfunction/diagnostic imaging/drug therapy ; },
abstract = {BACKGROUND: Socioeconomic vulnerabilities and healthcare environment contribute to disparities in dementia assessment. Whether these affect dementia management, however, remains unclear. We used Imaging Dementia - Evidence for Amyloid Scanning (IDEAS) study data to compare the impact of amyloid PET on pharmacological management across social factors, patient comorbidities, and physician practice settings.

METHODS: We analyzed rates of pharmacological change in IDEAS participants with visually interpretable amyloid PET, completed pre- and post-PET case reports, social determinants (racioethnic identity of Asian, Black, Hispanic, or White, area deprivation index (ADI), living arrangement, education) and medical history. Outcomes included any change between pre-PET and post-PET visits in prescription of Alzheimer's disease (AD) drugs, and of non-AD drugs treating dementia risk factors or affecting cognition/mood/behavior. We used multilevel logistic regression with a random site intercept to test whether the probability of change in management associated with social determinants, race/ADI interactions with amyloid-positivity, comorbidities, and clinical setting, adjusting for demographics.

RESULTS: Among 10,904 cognitively impaired participants (Table 1), 90% were White, with 4.8% Hispanic, 3.1% Black, and 1.8% Asian representation. 10% resided in highly disadvantaged neighborhoods (ADI 9-10), 83% lived with ≥1 person, and 68% were educated past high school. Pre-FDR correction (adjusted P-values: Table 1), AD drug management change was associated with dyslipidemia (OR [95% CI]=0.88 [0.80-0.97], P unadj=.007), depression (0.87 [0.77, 0.97], P unadj=.014), and tobacco use (0.87 [0.77, 0.99], P unadj=.028). Non-AD drug management change was associated with depression (1.73 [1.51, 1.97], P unadj<.001), group practice (0.72 [0.56, 0.93], P unadj=.012) and ADI in amyloid-positive participants (0.68 [0.47, 0.98], P unadj=.04). Change rates were also associated with amyloid-PET status, impairment level, and etiology. Figure 1 summarizes change rates across social factors.

CONCLUSIONS: These results suggest amyloid status, cognitive impairment level, dementia etiology, and comorbidities may inform pharmacological decision-making. Clarifying dementia etiology with amyloid PET may, for instance, help clinicians optimize treatment plans to address undermanaged depression in cognitively impaired older adults. Further, socioeconomic disadvantage may limit clinical response to amyloid-positivity. Replication in New IDEAS and examination of Medicare claims will help elucidate whether disparities in pre-PET management and management changes are primarily driven by access barriers to assessment and healthcare.},
}

Humans
Female
Male
*Alzheimer Disease/diagnostic imaging/drug therapy
Aged
*Positron-Emission Tomography
Aged, 80 and over
Brain/diagnostic imaging
Socioeconomic Factors
*Cognitive Dysfunction/diagnostic imaging/drug therapy

@article {pmid41434193,
year = {2025},
author = {Ackley, SF and Flanders, M and Chen, R and Wang, J and Shah, SJ},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110201},
doi = {10.1002/alz70862_110201},
pmid = {41434193},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/drug therapy ; Male ; Female ; Positron-Emission Tomography ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Aged ; *Cognitive Dysfunction/diagnostic imaging/drug therapy ; Aniline Compounds ; Ethylene Glycols ; Mental Status and Dementia Tests ; Amyloid beta-Peptides/metabolism ; Brain/diagnostic imaging ; },
abstract = {BACKGROUND: Amyloid removal has been used as surrogate outcomes in clinical trials of Alzheimer's disease (AD) drugs, leading to approvals of aducanumab and lecanemab under the Accelerated Approval Program. While well-established epidemiologic and econometric methods exist to formally evaluate amyloid's validity as a surrogate outcome, their application has been hindered by restricted access to individual-level data from anti-amyloid drug trials. The newly available individual-level data from the A4 trial of solanezumab offers a unique opportunity to demonstrate how these untapped approaches can improve our understanding of the impact of amyloid removal on cognitive decline.

METHOD: We used data on 815 A4 study participants (Alzheimer's Clinical Trial Consortium A4/LEARN) with complete follow-up measures for florbetapir PET imaging and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score. We estimated cognitive change using the trajectory of the CDR-SB score over 4.5 years. Instrumental-variable (IV) methods were used to evaluate the causal effect of amyloid reduction on cognitive changes using randomization as an instrument for amyloid reduction. Causal mediation analysis was conducted to estimate the extent to which changes in amyloid mediated the cognitive effects of solanezumab. Analyses were adjusted for sex, APOE-ε4 carrier status, and baseline age, cognition, and amyloid.

RESULT: Average between-group differences in amyloid change and cognitive trajectory were -0.05 (SD 0.16) SUVr and 0.002 (SD 0.028) CDR-SB points per month, respectively. Non-linear effects of amyloid on cognition were not supported (Figure 1). The IV-estimated effect of a 1 SUVr reduction on monthly CDR-SB change was -0.041, 95% CI: (-0.096, 0.014) (Figure 2). Mediation analysis suggests that amyloid change mediates 23% of solanezumab's effect on cognitive change, 95% CI: (-125%, 253%) (Figure 2).

CONCLUSION: Using epidemiologic and econometric methods to analyze individual-level data from trials of amyloid-targeting drugs will improve our understanding of amyloid as a surrogate outcome for cognition. In this instance, results are imprecise because solanezumab did not effectively remove amyloid. However, reproducing these analyses using individual-level data from effective anti-amyloid trials has the potential to shape treatment strategies and inform use of surrogate outcomes in future approval processes.},
}

Humans
*Alzheimer Disease/diagnostic imaging/drug therapy
Male
Female
Positron-Emission Tomography
*Antibodies, Monoclonal, Humanized/therapeutic use
Aged
*Cognitive Dysfunction/diagnostic imaging/drug therapy
Aniline Compounds
Ethylene Glycols
Mental Status and Dementia Tests
Amyloid beta-Peptides/metabolism
Brain/diagnostic imaging

@article {pmid41434192,
year = {2025},
author = {Chan, T and Rahmouni, N and Zheng, Y and Gonçalves, MP and Therriault, J and Macedo, AC and Trudel, L and Socualaya, KMQ and Hosseini, SA and Hall, BJ and Wang, YT and Aumont, E and Arias, JF and Bezgin, G and Servaes, S and Hopewell, R and Hsiao, C and Vitali, P and Pascoal, TA and Zetterberg, H and Benedet, A and Rosa-Neto, P},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109923},
doi = {10.1002/alz70862_109923},
pmid = {41434192},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/cerebrospinal fluid/diagnosis/blood ; Female ; Male ; Aged ; Biomarkers/blood/cerebrospinal fluid ; *tau Proteins/blood/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Positron-Emission Tomography ; Cohort Studies ; Middle Aged ; Immunoassay ; Quebec ; Brain/diagnostic imaging/metabolism ; },
abstract = {BACKGROUND: With the anticipated arrival of disease-modifying treatments for Alzheimer's disease (AD) in Canada, integrating biomarkers into clinical practice is crucial to enhancing diagnostic accuracy and optimizing referrals for treatment. Lumipulse G1200 (Fujirebio) is a fully automated immunoassay instrument that streamlines the analysis of these biomarkers. In this study, we evaluated the diagnostic performance of Lumipulse G1200 plasma and CSF immunoassays in detecting AD pathology within a Quebec population cohort.

METHOD: Plasma and CSF samples of 102 participants from the TRIAD cohort (median age 67 years, 54% female) were analysed. Kruskal-Wallis with post hoc Benjamini-Hochberg false discovery rate (BH) correction compared the levels of biomarkers among the diagnostic groups. Discriminative performance for Aβ ([18]F-NAV4694) and tau ([18]F-MK6240) PET status was assessed using the area under the curve (AUC) of receiver operating characteristic (ROC). Amyloid PET global SUVR > 1.55 and tau PET metaROI SUVR>2.5STD of the young controls determined Aβ and Tau PET positivity, respectively. Spearman's correlation examined the association between plasma p-tau217 and p-tau181 with amyloid and tau PET SUVR.

RESULT: Plasma p-tau181 and p-tau217 were higher in individuals with clinical diagnosis of AD compared to the cognitively unimpaired (CU) or MCI not due to AD (MCI-). Plasma p-tau217 very strongly correlated with both Aβ and tau PET SUVR (ρ=0.805 and 0.797 respectively, p-value<2.2e-16), as compared to plasma p-tau181 (ρ=0.629 and 0.644 respectively, p < 4.097e-10). Both assays identified with comparable high accuracy elevated Aβ pathology (plasma p-tau217, AUC, 0.96, 95% CI: 0.92-1.00; p-tau181, AUC 0.88, CI 0.81- 0.96). However, plasma p-tau217 had higher discriminative performance than p-tau181 for tau PET (p-tau217, AUC 0.99, CI: 0.98-1.00; p-tau181, AUC 0.94, CI 0.89-0.98, DeLong's test p-value<0.01). CSF p-tau181, p-tau181/Aβ42 and Aβ42/40 had excellent discriminative performance for Aβ and tau PET positivity. Moreover, plasma p-tau217 had similar performance as CSF p-tau181 for predicting Aβ and tau PET positivity.

CONCLUSION: Lumipulse G1200 immunoassays showed excellent agreement with amyloid and tau PET. Their ease of use and high diagnostic accuracy make them strong candidates for clinical implementation.},
}

Humans
*Alzheimer Disease/diagnostic imaging/cerebrospinal fluid/diagnosis/blood
Female
Male
Aged
Biomarkers/blood/cerebrospinal fluid
*tau Proteins/blood/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid/blood
Positron-Emission Tomography
Cohort Studies
Middle Aged
Immunoassay
Quebec
Brain/diagnostic imaging/metabolism

@article {pmid41434191,
year = {2025},
author = {Condado, JG and Klinger, HM and Birkenbihl, C and Elorriaga, IT and Seto, M and Coughlan, GT and Properzi, MJ and Yang, HS and Erramuzpe, A and Rentz, DM and Schultz, AP and Chhatwal, JP and Johnson, KA and Cortes, JM and Sperling, RA and Hohman, TJ and Donohue, MC and Diez, I and Buckley, RF},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109903},
doi = {10.1002/alz70862_109903},
pmid = {41434191},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/pathology/genetics/metabolism ; Aged ; Magnetic Resonance Imaging ; *Brain/diagnostic imaging/pathology/metabolism ; tau Proteins/metabolism ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; Neuroimaging ; Longitudinal Studies ; *Cognitive Dysfunction/diagnostic imaging ; Cohort Studies ; *Aging/pathology ; Aged, 80 and over ; Biomarkers ; Middle Aged ; },
abstract = {BACKGROUND: BrainAge models estimate biological brain age based on neuroimaging data, providing a measure of brain health. This metric is particularly relevant in Alzheimer's disease (AD), where accelerated brain aging is exacerbated by β-amyloid (Aβ) and tau accumulation. We investigated the extent to which BrainAge moderates associations between AD biomarkers and longitudinal cognitive decline across two independent cohorts.

METHODS: We examined 1690 participants from A4/LEARN and 349 from HABS (Table 1). Using the Open-Source tool AgeML within each cohort, we built a BrainAge linear regressor model with 5-fold cross validation using MRI-T1 volumetric and FreeSurfer cortical thickness ROIs. We compared predicted ages with chronological age to create a BrainAgedelta. To avoid regressing out sex and APOEε4 variance, separate male/female models were built with data from APOEε4 non-carriers and applied to each cohort. We examined BrainAgedelta as a moderator of global neocortical Aβ-PET burden, temporal lobe Tau PET composite and p-tau217 associations with longitudinal PACC using linear mixed effects models. We adjusted for random intercepts and slopes, and baseline age, sex, years of education and APOEε4. In A4/LEARN we additionally adjusted for cumulative dose and treatment group using a spline model.

RESULTS: Higher levels of Aβ-PET, Tau-PET and p-tau217 at baseline was significantly correlated with higher BrainAgedelta (worse) (Figure 1). BrainAgedelta was directly associated with PACC trajectories in both cohorts. It also moderated the association between Aβ and Tau-PET and PACC trajectories such that higher BrainAgedelta was associated with faster cognitive decline with increasing levels of each biomarker. We found the same pattern of effects in p-tau217 limited only to the A4/LEARN sample but was trend-level in HABS (Figure 2).

CONCLUSIONS: BrainAgedelta is significantly associated with Aβ and tau burden and moderates their association with cognitive decline, supporting previous literature suggesting that BrainAge is a robust marker of brain health. Prioritizing individuals with worse BrainAge for clinical trials could not only effectively reduce screen fails (estimates forthcoming) but is a potentially feasible approach given that it can be calculated from a single T1-weighted MRI scan. These findings also highlight the importance of age-independent neurodegeneration patterns to contribute unique signal in models of brain health and pathological progression.},
}

Humans
Male
Female
*Alzheimer Disease/diagnostic imaging/pathology/genetics/metabolism
Aged
Magnetic Resonance Imaging
*Brain/diagnostic imaging/pathology/metabolism
tau Proteins/metabolism
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
Neuroimaging
Longitudinal Studies
*Cognitive Dysfunction/diagnostic imaging
Cohort Studies
*Aging/pathology
Aged, 80 and over
Biomarkers
Middle Aged

@article {pmid41434159,
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 = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109847},
doi = {10.1002/alz70862_109847},
pmid = {41434159},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging/metabolism/pathology ; *tau Proteins/cerebrospinal fluid/metabolism/blood ; Female ; Male ; *Apolipoprotein E4/genetics ; Aged ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Positron-Emission Tomography ; Biomarkers/cerebrospinal fluid ; Aged, 80 and over ; Brain/diagnostic imaging/metabolism ; Alleles ; Cross-Sectional Studies ; },
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
*Alzheimer Disease/genetics/diagnostic imaging/metabolism/pathology
*tau Proteins/cerebrospinal fluid/metabolism/blood
Female
Male
*Apolipoprotein E4/genetics
Aged
Amyloid beta-Peptides/metabolism/cerebrospinal fluid
Positron-Emission Tomography
Biomarkers/cerebrospinal fluid
Aged, 80 and over
Brain/diagnostic imaging/metabolism
Alleles
Cross-Sectional Studies

@article {pmid41434095,
year = {2025},
author = {Hu, M},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109822},
doi = {10.1002/alz70862_109822},
pmid = {41434095},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/diagnostic imaging/metabolism ; Aged ; Positron-Emission Tomography ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; Disease Progression ; Aged, 80 and over ; Biomarkers ; *Brain/diagnostic imaging/metabolism ; Apolipoprotein E4/genetics ; },
abstract = {BACKGROUND: Despite advances in Alzheimer's disease (AD) research, limited information exists regarding the absolute risk of mild cognitive impairment (MCI) in cognitively unimpaired (CU) individuals with abnormal AD biomarkers, particularly when accounting for competing risks of death. This knowledge gap is critical as the field addresses disease-modifying treatments targeting CU individuals with preclinical AD. We focus on the predictive value of AD amyloid stages defined by amyloid PET Centiloid values.

METHODS: We included 5,858 participants from the Mayo Clinic Study of Aging (MCSA) to evaluate AD amyloid stage as a predictor of clinical progression to MCI or dementia. The data includes long-term follow-up information on death and dementia beyond active study participation, which mitigates potential bias due to dropout. We predicted 10-year and lifetime risks of MCI and dementia, accounting for the competing risks of death, given amyloid PET stages, sex, APOE4 status, and baseline age. Results are based on a hidden Markov model.

RESULTS: AD amyloid staging based on amyloid PET Centiloid values was the strongest predictor of lifetime risk for MCI or for dementia (Figure 1). Higher Centiloid levels amplified age effects on the risk of MCI, whereas for dementia, amyloid stage effects surpassed age effects. For 10-year risk, age was the dominant factor, whereas for lifetime risk, amyloid stages had a greater influence. While smaller in magnitude than the effects of amyloid stages and age, APOE4 carrier status and (on average) male sex were also associated with increased risk of MCI and dementia. For a female APOE4 carrier at age 65, lifetime risk was 41%/61%/76% for low/moderate/high amyloid PET levels. The 10-year absolute risk for a female APOE4 carrier with high amyloid PET was 4%/29%/58% when assessed at starting ages 65, 75, and 85.

CONCLUSIONS: AD amyloid staging is a critical predictor of lifetime risk for cognitive impairment, underscoring its importance in guiding treatment decisions if interventions are approved for preclinical AD in the future. Effective patient evaluation should focus on biomarker-based amyloid staging rather than simple binary biomarker classification, with careful consideration of age, sex, and APOE4 status to ensure a comprehensive benefit-risk assessment for future therapeutic strategies.},
}

Humans
Female
Male
*Alzheimer Disease/diagnostic imaging/metabolism
Aged
Positron-Emission Tomography
*Cognitive Dysfunction/diagnostic imaging/metabolism
Disease Progression
Aged, 80 and over
Biomarkers
*Brain/diagnostic imaging/metabolism
Apolipoprotein E4/genetics

@article {pmid41434093,
year = {2025},
author = {Zammit, MD},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109931},
doi = {10.1002/alz70862_109931},
pmid = {41434093},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/blood/metabolism ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/metabolism ; Positron-Emission Tomography ; Middle Aged ; Amyloid beta-Peptides/metabolism ; Biomarkers/blood ; Adult ; *Down Syndrome/diagnostic imaging/metabolism ; Disease Progression ; Longitudinal Studies ; *Brain/diagnostic imaging/metabolism ; Aged ; },
abstract = {BACKGROUND: Characterizing the timing and progression of Alzheimer's disease (AD) biomarker positivity in Down syndrome (DS) and contrasting potential timing differences with neurotypical (NT) adults is needed to identify optimal anti-amyloid treatment windows in DS. This work uses temporal modeling to characterize tau accumulation using plasma pTau217 and Tau PET relative to amyloid accumulation using amyloid PET for DS and NT.

METHOD: 198 adults with DS from the ABC-DS and 172 NT adults from WRAP with available longitudinal Aβ PET, Tau PET and plasma pTau217 Lilly-Mesoscale immunoassay were included (Table 1). Aβ was quantified using Centiloids. Tau PET SUVRs were obtained from the Mesial Temporal and Universal CenTauR ROIs. A+ time was estimated using sampled iterative local approximation applied to longitudinal CL data. A Cox proportional hazards model was used to test differences in A+ onset age between DS/NT groups with A- participants right-censored at their last observation. Linear mixed-effects models (considering up to cubic polynomials) with random person-level intercepts were performed between estimated A+ time (predictor) and pTau217 and Tau PET for all participants. pTau217+ and Tau PET T+ onset times were extracted using inverse estimation of the LMEs.

RESULT: Following A+, DS revealed earlier pTau217 and Tau PET increases relative to NT (Figure 1). The Cox PH model indicated a significant difference in A+ risk between groups (p <0.001) with DS having 21.25[13.89, 32.51]-fold higher risk of becoming A+ over 5.5 years of follow-up (Table 1). pTau217+ and T+ in DS occurred nearly simultaneously (∼3-5 years after A+), while NT had greater time to pTau217+ and T+ and exhibited temporal latency between pTau217 and Tau PET onset (Figure 2).

CONCLUSION: Individuals with DS have earlier pTau217 and Tau PET progression following PET A+ compared to neurotypical adults. The early and simultaneous onset of these biomarkers in DS highlight the necessity for early AD interventions in this population. This work, combined with the upcoming DSAD clinical trials will help identify optimal treatment windows for these individuals.},
}

Humans
*tau Proteins/blood/metabolism
Male
Female
*Alzheimer Disease/diagnostic imaging/metabolism
Positron-Emission Tomography
Middle Aged
Amyloid beta-Peptides/metabolism
Biomarkers/blood
Adult
*Down Syndrome/diagnostic imaging/metabolism
Disease Progression
Longitudinal Studies
*Brain/diagnostic imaging/metabolism
Aged

@article {pmid41434085,
year = {2025},
author = {Dore, V and Bourgeat, P and Harada, R and Furumoto, S and Mulligan, RS and Xia, Y and Paranawithana, I and Laws, SM and Feizpour, A and Bozinovski, S and Huang, K and Lopresti, BJ and Ikonomovic, MD and Fripp, J and Okamura, N and Rowe, CC and Villemagne, VL},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109761},
doi = {10.1002/alz70862_109761},
pmid = {41434085},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism ; Male ; Female ; *Positron-Emission Tomography ; Aged ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; *Brain/diagnostic imaging/metabolism ; Monoamine Oxidase/metabolism ; Aged, 80 and over ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Middle Aged ; Radiopharmaceuticals ; },
abstract = {BACKGROUND: Monoamine Oxidase-B (MAO-B) is overexpressed in reactive astrocytes, playing a crucial role in neurodegeneration. Recently, increased binding of the PET MAO-B tracer [18]F-SMBT-1 has been shown in preclinical Alzheimer's disease (AD) stages. However, the regional distribution and effect on Ab of abnormal [18]F-SMBT-1 binding along the AD continuum remains unclear.

METHOD: 144 Cognitively Unimpaired (CU), 24 A+ Mild Cognitive Impairment (MCI), and 20 A+ AD subjects underwent PET imaging with [18]F-NAV4694, [18]F-MK6240, and [18]F-SMBT-1. Aβ and tau PET SUVR were transformed into Centiloid (CL) and CenTauR (CTR) using CapAIBL. A+ was defined as >15CL and T+ >14 CTR in the Meta-Temporal. SMBT-1 scans were spatially normalised using MR-based CapAIBL, scaled to the cerebellar cortex and several cortical regions sampled. The relationship between SMBT-1 binding and Aβ accumulation was assessed in a subset of 81 CU A-.

RESULT: Distinct regional [18]F-SMBT-1 binding was observed across brain regions (Figure 1). [18]F-SMBT-1 binding was higher in CU A+ compared to the CU A- in most regions, while binding in A+ MCI/AD either remained higher (in parietal/cingulate/occipital) or decreased (in frontal/caudate/putamen). Higher [18]F-SMBT-1 binding was also significant in CU A+ T- (n = 43) (Figure 2). In CU A- participants with high [18]F-SMBT-1 retention, significantly higher Ab accumulation rates were observed compared to low [18]F-SMBT1 (1.20CL/yr vs 0.01CL/yr, respectively, p = 0.001) (Figure 3). Furthermore, 92% of CU A- individuals with high [18]F-SMBT-1 were classified as Ab accumulators (58% in CU A-/low [18]F-SMBT-1).

CONCLUSION: Unlike fluid neuroinflammation markers, [18]F-SMBT-1 facilitates quantitative assessment of regional differences in reactive astrogliosis across the AD continuum, as well as longitudinal change. Elevated [18]F-SMBT-1 in CU A- predicted Ab accumulation, highlighting the potential of [18]F-SMBT-1 as a prognostic marker in early-stage AD while suggesting modulation of astrocytic function may be a target for AD prevention and treatment.},
}

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

@article {pmid41433909,
year = {2025},
author = {Arani, A and Przybelski, SA and Borowski, BJ and Senjem, ML and Cogswell, PM and Vemuri, P and Kantarci, K and Jack, CR},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109957},
doi = {10.1002/alz70862_109957},
pmid = {41433909},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Male ; Female ; Aged ; *Brain/diagnostic imaging ; *Neuroimaging/methods ; *Cognitive Dysfunction/diagnostic imaging ; },
abstract = {BACKGROUND: T2*-weighted imaging is of paramount importance for patient treatment eligibility and safety monitoring in anti-amyloid pharmaceutical clinical trials and clinical care. Recently with the adoption of multi-echo GRE (GRE) sequences, susceptibility weighted imaging (SWI), and quantitative susceptibility mapping (QSM) can be obtained in the same acquisition. In 2024, the QSM Consensus Organization Committee released a white paper recommending at least 1 mm isotropic voxel size for QSM. In clinical workflows microbleed detection is performed with higher in-plane resolution (0.5x0.5mm[2]), and large out-of-plane resolution (∼1.8mm), which was used in the ADNI4 protocol. In the CLARiTI protocol, a 1mm isotropic resolution was adopted. The objective of this work was to compare susceptibility estimates between the ADNI4 (0.5x0.5x1.8mm[3]) and CLARiTI (1mm[3]) protocols.

METHOD: The ADNI4 and CLARiTI QSM protocols were acquired on forty-seven subjects (33 cognitively unimpaired (CU), 14 cognitively impaired (CI), in the same scan session. The groups were defined by their Clinical Demential Rating (CDR) global score (CDR global = 0 for CU, and CDR global >= 0.5 for CI subjects). QSM images were generated using publically available software (STI Suite, UC Berkeley). Mean susceptibility values in atlas regions were compared.

RESULT: Significant group differences (CU vs. CI) were observed in the fusiform and middle occipital gyrus with the ADNI4 protocol, only in the rectus with the CLARiTI protocol (Figure 1). These three regions are small in size and closer to surface-air interfaces, which may have impacted estimation accuracy. However, in the substantia nigra and its sub-regions (pars compacta and pars reticulata), which shows increased susceptibility in Lewy body disease, the ADNI4 and CLARiTI protocols were in good agreement (r[2] > 0.9) (Figure 2).

CONCLUSION: Group differences were observed between the ADNI4 and CLARiTI QSM only in 3 small regions close to surface-air interfaces in this small dataset. The two techniques showed highly correlated (r[2] = 0.93) estimates in the substantia nigra, a region with high susceptibility due to iron deposition. Strong correlations between the two protocols are encouraging. Radiologists have historically preferred submillimeter in-plane resolution for microbleed detection, which is more time manageable with anisotropic imaging.},
}

Humans
*Alzheimer Disease/diagnostic imaging
*Magnetic Resonance Imaging/methods
Male
Female
Aged
*Brain/diagnostic imaging
*Neuroimaging/methods
*Cognitive Dysfunction/diagnostic imaging

@article {pmid41433812,
year = {2025},
author = {Shimony, H and Keefe, SJ and Sharifi, KJ and Okafor, JN and Joseph-Mathurin, N and Banks, JN and Hu, J and Jarman, S and Knopp, E and Paczynski, M and Lim, J and Venuto, A and Ghoshal, N and Snider, BJ and Flores, S and Benzinger, TLS},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110004},
doi = {10.1002/alz70862_110004},
pmid = {41433812},
issn = {1552-5279},
mesh = {Humans ; *Magnetic Resonance Imaging/methods ; Male ; *Alzheimer Disease/diagnostic imaging/pathology/drug therapy ; Female ; Aged ; *White Matter/diagnostic imaging/pathology ; *Brain/diagnostic imaging/pathology ; Middle Aged ; Gray Matter/diagnostic imaging/pathology ; Image Processing, Computer-Assisted ; },
abstract = {BACKGROUND: White matter hyperintensities (WMH) are known predictors of amyloid-related imaging abnormalities (ARIA) in patients undergoing anti-amyloid immunotherapy (AAT) for Alzheimer disease. WMHs and brain volumetric changes can potentially be captured by low-field magnetic resonance imaging (MRI) that imposes minimal safety risks to those with contraindicators to high-field MRI. We investigate the recently released FreeSurfer WMH-SynthSeg for volumetric and WMH lesion processing of low-field MRI and its comparability to 3T MRI.

METHOD: Low-field head MRI scans for 19 healthy controls and 23 patients undergoing AAT were acquired on a 0.064T Hyperfine SwoopÒ Portable MRI scanner. Treated patients also underwent a 3T MRI for ARIA screening by a clinical neuro-radiologist per treatment protocol. Volumetric measures of cortical grey matter, white matter, ventricles, and hippocampus were extracted from WMH-SynthSeg for low-field and FreeSurfer-7.4 for 3T MRI. WMH lesion probability maps were generated for all participants from WMH-SynthSeg. Linear regressions examined agreement between volumetrics for low-field and 3T MRI in treated patients without ARIA. Spatial localization of WMH lesions with ARIA pathology were visually assessed and compared with the clinical 3T scan. Finally, WMH volume measures were assessed amongst healthy controls and patients with and without ARIA using a pairwise Wilcoxon with Benjamini-Hochberg correction for multiple comparisons.

RESULT: Four patients were clinically identified as having ARIA with cerebral edema (ARIA-E) from 3T MRI. WMH-SynthSeg estimates of lateral ventricular, white matter, and cortical grey matter volumes agreed with 3T MRI but tended to be significantly underestimated for the hippocampus (Figure 1). WMH lesion probability maps aligned with known ARIA but failed to capture the entire area affected (Figure 2). While WMH volumes for healthy controls were significantly lower than those on AAT therapy, WMH volumes were not significantly different between AAT patients with and without ARIA-E (Figure 3).

CONCLUSION: WMH-SynthSeg provides comparable volumetric measures to 3T for large brain regions and can spatially capture known ARIA. However, in our small sample, these measures were not sensitive enough to fully identify areas of ARIA. Further development is needed to improve small region quantification and WMH lesion detection, particularly at low-fields.},
}

Humans
*Magnetic Resonance Imaging/methods
Male
*Alzheimer Disease/diagnostic imaging/pathology/drug therapy
Female
Aged
*White Matter/diagnostic imaging/pathology
*Brain/diagnostic imaging/pathology
Middle Aged
Gray Matter/diagnostic imaging/pathology
Image Processing, Computer-Assisted

@article {pmid41433800,
year = {2025},
author = {Lahiri, DK and Wang, R and Maloney, B and Ghetti, B and Nho, K and Farlow, MR and Saykin, AJ and White, FA and Sambamurti, K and Counts, SE},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110012},
doi = {10.1002/alz70862_110012},
pmid = {41433800},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/metabolism/diagnostic imaging ; *MicroRNAs/metabolism/genetics ; alpha-Synuclein/metabolism/genetics ; *Brain/metabolism/pathology ; Male ; Amyloid beta-Protein Precursor/metabolism/genetics ; Female ; Aged ; Repressor Proteins/metabolism/genetics ; Aged, 80 and over ; },
abstract = {BACKGROUND: The most common neurodegenerative disorders include Alzheimer's disease (AD), Lewy body and related dementias (ADRDs). Triggers of pathobiochemical changes in ADRDs remains unknown and appear numerous. Short non-coding RNAs, microRNA (miRNA), play a vital role in regulating biological and pathological processes leading to neurodegenerative diseases. Amyloid plaques, major hallmarks of AD, comprise abnormal aggregation of extracellular amyloid-β peptides (Aβ) derived from Aβ precursor protein (APP). Neurofibrillary tangles consist of filamentous hyper-phosphorylated tau proteins. Alpha-synuclein (SNCA) plays a critical role in the pathogenesis of Parkinson's and other synucleinopathies. Repressor Element 1-Silencing Transcription (REST) factor is altered in ADRDs. We studied the role of miR-153-3p in AD risk and in regulating levels of critical proteins. miR-153-3p reduced APP, SNCA and METHOD: We measured miR153 levels in non-cognitively impaired (NCI) and AD subject brain tissue samples from different recognized sources by qRT-PCR as described (Wang et al). We utilized autopsy brain tissues and ADNI participants' genotyping and performed association studies of miR-153-3p and its single nucleotide polymorphisms (SNPs) with AD risk, and nine endophenotypes. We used iPSC-derived neuronal cells, human cell lines and miRNA transfections to study the mechanism of miR-153-3p RESULT: Elevation of miR-153-3p is associated with a reduced probability of AD, while elevated REST associated with a greater likelihood of AD. MiR-153 gene SNPs are associated with nine AD-related endophenotypes. MiR-153-3p reduced REST, APP and SNCA 3'-UTR activities and respective protein levels. MiR-153-3p treatment altered REST and neuronal differentiation in iPSC-derived neuronal stem cells. RNA sequencing proteomics and interactome analysis revealed the role of miR-153-3p in axonal guidance.

CONCLUSION: With the increased emphasis on comorbidities of AD and other neurodegenerative diseases, we identified that miR-153-3p, as a master regulator, reduced a key group of neurodegeneration-related proteins. MiR-153-3p reduces APP, SNCA and REST expression, all pointing towards a therapeutic and biomarker potential in ADRDs. In addition to late-onset cases, we will profile miR153 in brain tissue samples from early-onset AD cases.},
}

Humans
*Alzheimer Disease/genetics/pathology/metabolism/diagnostic imaging
*MicroRNAs/metabolism/genetics
alpha-Synuclein/metabolism/genetics
*Brain/metabolism/pathology
Male
Amyloid beta-Protein Precursor/metabolism/genetics
Female
Aged
Repressor Proteins/metabolism/genetics
Aged, 80 and over

@article {pmid41433787,
year = {2025},
author = {Brown, CA and Taso, M and Das, SR and Hing, D and McGrew, E and Yushkevich, PA and Mechanic-Hamilton, D and Nasrallah, IM and Alsop, DC and Detre, JA and Wolk, DA},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110130},
doi = {10.1002/alz70862_110130},
pmid = {41433787},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Magnetic Resonance Imaging/methods ; *Alzheimer Disease/drug therapy/diagnostic imaging ; *Brain/diagnostic imaging/pathology/drug effects ; Middle Aged ; White Matter/diagnostic imaging ; Glymphatic System/diagnostic imaging ; Diffusion Magnetic Resonance Imaging ; },
abstract = {BACKGROUND: ARIA-E represents the greatest risk associated with anti-amyloid therapy (AAT) and is thought to be due to excessive inflammatory response resulting in FLAIR abnormalities on imaging and occasionally symptomatic manifestations. While FLAIR MRI monitoring for ARIA-E is now routinely performed, additional MRI contrast mechanisms could provide improved detection and mechanistic insights. We investigated perivascular spaces, microstructural alterations, and parenchymal water permeability in a real-world cohort receiving AAT using novel MRI techniques.

METHODS: Eight participants receiving AAT at the University of Pennsylvania underwent advanced imaging paired with clinical safety MRIs at baseline and during treatment. Advanced imaging sequences included multi-shell diffusion MRI to assess microstructure, an ultralong TE T2-weighted sequence to evaluate perivascular spaces structures, and a novel T2-saturation based water-exchange sequence. These sequences add <15 minutes to the MRI protocol and can be performed on clinical 3T scanners. We measured microstructure in a composite ROI consisting of cortical regions typically associated with high amyloid deposition as well as in global white matter. Water exchange was calculated specifically in regions that developed ARIA.

RESULTS: 2 patients developed ARIA-E after 2 months of treatment that prompted suspension of treatment: (1) mild symptomatic case that went on to develop mild ARIA-H at 3 months with resolution of ARIA-E, (2) moderate case that progressed to severe ARIA-E at 3 months. At baseline these individuals had lower Neurite Density Index (NDI) and Orientation Dispersion Index (ODI) compared to no ARIA (ARIA-) patients (Figure 1). At 2 months, they had marked increases in NDI and ODI that resolved by 3 months (Figure 2A). In contrast, there was gradual increase in water exchange and white matter free water fraction (FWF) at 2 and 3 months compared to ARIA- (Figure 2B). ARIA-E and ARIA-H is also readily visualized on water exchange sensitive maps (Figure 3). Quantification of perivascular volume is ongoing.

CONCLUSION: Measures of water diffusion and exchange enhance our understanding of ARIA with findings consistent with transient increases in cellularity at ARIA onset and prolonged increases in parenchymal water permeability and edema. Early results suggest microstructure could predict risk for future ARIA. Additional data collection continues.},
}

Humans
Male
Female
Aged
*Magnetic Resonance Imaging/methods
*Alzheimer Disease/drug therapy/diagnostic imaging
*Brain/diagnostic imaging/pathology/drug effects
Middle Aged
White Matter/diagnostic imaging
Glymphatic System/diagnostic imaging
Diffusion Magnetic Resonance Imaging

@article {pmid41433773,
year = {2025},
author = {Chiotis, K and Blazhenets, G and Eloyan, A and Maiti, P and Zhang, J and Touroutoglou, A and Kirby, K and Hammers, DB and Carrillo, MC and Dickerson, BC and Apostolova, LG and Rabinovici, GD},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110255},
doi = {10.1002/alz70862_110255},
pmid = {41433773},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/drug therapy/metabolism ; Male ; Female ; Positron-Emission Tomography ; tau Proteins/metabolism ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Amyloid beta-Peptides/metabolism ; Longitudinal Studies ; *Brain/diagnostic imaging/metabolism ; Middle Aged ; Aged ; Cognitive Dysfunction/diagnostic imaging/drug therapy ; },
abstract = {BACKGROUND: In clinical trials, monoclonal antibodies targeting Aβ pathology have shown strong target engagement, resulting in rapid Aβ clearance and a deceleration in rate of clinical decline. Now that these treatments are approved and implemented in clinical practice, we could assess their effects in observational studies involving these patients.

METHOD: We analyzed data from 20 participants with early-onset Alzheimer's disease (EOAD) in the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort, treated with Aducanumab (n = 4), Lecanemab (n = 15), or both (one transitioning from Aducanumab to Lecanemab). All participants had MCI or mild dementia at baseline, longitudinal Aβ and tau PET, as well as cognitive assessments, with at least one observation before and after treatment initiation. We applied piecewise regression with a knot at the treatment start, to evaluate changes in Aβ and tau PET burden and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. We compared the trajectories of treated participants with an untreated group (i.e., treated-untreated comparison) from LEADS, matched for age, sex, APOE ε4 genotype, pretreatment Aβ and tau PET load, CDR-SB, and follow-up duration, using a 1:3 matching design.

RESULT: The median treatment duration was 8 months (IQR=5-10). In the piecewise regression model, the treated group showed significant decreases in Aβ burden post-treatment (Δ=-52 Centiloids/yr, p <0.001) with widespread neocortical involvement (Figure 1). However, no significant inflection in tau burden (Δ=0 SUVR/yr, p = 0.58) or CDR-SB (Δ=0.3 units/yr, p = 0.57) trajectories was observed. In the treated-untreated comparison, the treated group showed a trend toward slower increases in CDR-SB scores post-treatment (ΔT=-1.8, p = 0.07) compared to the untreated group (Figure 2). Aβ levels significantly decreased in the treated group compared to the untreated group (ΔΤ=-8.5, p <0.001). No significant differences in tau trajectories were observed between groups (ΔT=0.4, p = 0.68), with both showing increases in cortical regions of interest.

CONCLUSION: We observed excellent target engagement, with piecewise regression models showing rates of Aβ clearance comparable to those seen in Phase 3 trials. The study was underpowered to detect cognitive benefits, which are limited over a short follow-up interval. These findings underscore the utility of observational studies with biomarker data in evaluating treatment efficacy, offering insights that complement traditional randomized trials.},
}

Humans
*Alzheimer Disease/diagnostic imaging/drug therapy/metabolism
Male
Female
Positron-Emission Tomography
tau Proteins/metabolism
*Antibodies, Monoclonal, Humanized/therapeutic use
Amyloid beta-Peptides/metabolism
Longitudinal Studies
*Brain/diagnostic imaging/metabolism
Middle Aged
Aged
Cognitive Dysfunction/diagnostic imaging/drug therapy

@article {pmid41433760,
year = {2025},
author = {Putcha, D and Properzi, MJ and Papp, KV and Johnson, KA and Sperling, RA and Rentz, DM and Amariglio, RE},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110248},
doi = {10.1002/alz70862_110248},
pmid = {41433760},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; Positron-Emission Tomography ; Neuropsychological Tests ; tau Proteins/metabolism ; *Cognitive Dysfunction/diagnostic imaging ; *Brain/diagnostic imaging/metabolism/pathology ; Aged, 80 and over ; Middle Aged ; Self Report ; Atrophy ; },
abstract = {BACKGROUND: The presence of Subjective Cognitive Decline (SCD) in cognitively unimpaired (CU) individuals represents a significant risk factor for progression from preclinical to the symptomatic stage of Alzheimer's disease (AD). Studies on SCD to date have focused on memory concerns as a risk factor for developing amnestic AD dementia. However, AD pathology underlies a heterogeneous phenotypic spectrum, including a visual variant of AD-Posterior Cortical Atrophy (PCA)-thought to comprise 5-15% of AD dementia cases. We do not yet have a method for identifying individuals at the preclinical stage of AD who go on to develop PCA.

METHOD: Self-report responses on the Everyday Cognition Scale (ECOG) from 253 CU participants (mean age = 72.1 ± 8.9) in the Harvard Aging Brain Study were analyzed. We explored associations between total participant responses on the visuospatial subscale, objective cognitive tests, and amyloid PET positivity. An exploratory whole-cortex tau PET general linear model was conducted to examine the association between subjective visuospatial decline and emerging tau burden in the neocortex.

RESULT: Four percent of participants (N = 9) endorsed "at least occasional problems" or more averaged across the 7-item ECOG visuospatial subscale. These individuals did not differ from the rest of the sample on age, sex, education, or MMSE. ECOG visuospatial scores across the whole CU group were unrelated to MMSE or objective visuospatial cognition. ECOG visuospatial scores were higher in PiB+ individuals compared to PiB- individuals (t = 3.4, p = 0.001). Subjective visuospatial concerns were associated with right-hemisphere predominant tau in temporoparietal and prefrontal cortices, largely overlapping with regions associated with subjective memory concerns and with tau epicenters reported in preclinical AD.

CONCLUSION: A subset of CU individuals endorsed subjective visuospatial decline, a cognitive domain that does not typically decline in healthy aging. The positive relationships observed between subjective visuospatial decline and biomarkers of amyloid and tau suggest that the ECOG can be a useful tool in capturing subtle visuospatial decline in addition to early memory concerns in preclinical AD. Developing methodology to predict the development of atypical AD variants has significant implications for optimizing early diagnosis and treatment of this disease.},
}

Humans
Male
Female
Aged
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
Positron-Emission Tomography
Neuropsychological Tests
tau Proteins/metabolism
*Cognitive Dysfunction/diagnostic imaging
*Brain/diagnostic imaging/metabolism/pathology
Aged, 80 and over
Middle Aged
Self Report
Atrophy

@article {pmid41433748,
year = {2025},
author = {Sun, X and Badachhape, AA and Reid, TE and Chin, J and Shulman, JM and Annapragada, A and Lowe, H and Toyang, N and Tanifum, E},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110120},
doi = {10.1002/alz70862_110120},
pmid = {41433748},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/diagnostic imaging/pathology ; *Microglia/metabolism/pathology ; *Magnetic Resonance Imaging/methods ; Humans ; Mice ; Liposomes ; Mice, Transgenic ; *Brain/diagnostic imaging/metabolism/pathology ; Disease Models, Animal ; Contrast Media ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; },
abstract = {BACKGROUND: Microglia-mediated neuroinflammation plays a pivotal role in the initiation and propagation of pathological markers of neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's disease (PD). CSF1-R signaling mediates microglial activation, proliferation, and survival; both CSF1-R upregulation and increased proliferation of microglia have been observed in AD patients. Imaging technologies that effectively profile reactive microgliosis in vivo have the potential to be diagnostic tools, facilitate patient stratification in clinical trials, and monitor treatment. There is currently no clinically approved tool to profile reactive microgliosis in vivo. We present a novel molecular imaging technique for neuroinflammation by targeting CSF1-R with MRI sensitive liposomes.

METHOD: Liposomes with DSPE-PEG-Caflanone as the targeting moiety, and Gd(III) DSPE-DOTA as the MRI contrast source were formulated using standard protocols. Caflanone is a potent CSF1-R ligand. In vitro nanoparticle cell uptake studies and blocking experiments with free Caflanone employing both human and mouse microglia cell lines were used to establish receptor-mediated internalization of the agent. Two AD mouse models (APP/PSEN1 and P301S) and one PD mouse model (A53TαS Tg) were used in in vivo MRI studies. Controls included wild type (WT) litter mates injected with the same agent. Mice were pre-scanned to establish a baseline followed by injection of the agent. Post-contrast scans were obtained at 4 days post-injection, followed by euthanasia, and brain removal for ex vivo immunohistochemical analysis.

RESULT: As shown in figure 1, in vitro cell assays showed internalization of the Caflanone labeled nanoparticles within 1.5 hours of exposure. Coincubation with increasing concentrations of free Caflanone resulted in diminished particle uptake at high concentrations of the free ligand. In vivo MRI demonstrated increased brain retention of the nanoparticles in transgenic mice compared to controls. Ex-vivo immunohistochemical analysis showed the nanoparticles in the cytosolic compartment of IBA1 reactive cells surrounding amyloid-β (Aβ) plaques in the APP/PSEN1 mouse model.

CONCLUSION: Results demonstrate precision delivery of Caflanone labeled liposomes bearing an MRI diagnostic payload to activated microglia in three different mouse models of neurodegenerative disorders. These nanoparticles can also deliver a therapeutic payload with similar precision, opening a new frontier for the development of both diagnostics and therapeutics for neuroinflammation.},
}

Animals
*Alzheimer Disease/diagnostic imaging/pathology
*Microglia/metabolism/pathology
*Magnetic Resonance Imaging/methods
Humans
Mice
Liposomes
Mice, Transgenic
*Brain/diagnostic imaging/metabolism/pathology
Disease Models, Animal
Contrast Media
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism

@article {pmid41433740,
year = {2025},
author = {Kotari, V and Holdridge, KC and Yaari, R and Williamson, MAM and Sims, JR and Shcherbinin, S},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110027},
doi = {10.1002/alz70862_110027},
pmid = {41433740},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/drug therapy/metabolism ; *Positron-Emission Tomography ; Double-Blind Method ; *tau Proteins/metabolism ; Male ; Female ; *Brain/diagnostic imaging/metabolism ; Aged ; },
abstract = {BACKGROUND: Preclinical Alzheimer's disease (AD) populations have evidence of elevated brain amyloid but are cognitively unimpaired. Most participants (95%) in solanezumab's preclinical AD trial, Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4), did not demonstrate elevated global tau accumulation at baseline. The ongoing TRAILBLAZER-ALZ 3 trial will assess the efficacy of donanemab in preclinical AD participants. Here, we characterize and compare all available baseline tau positron emission tomography (PET) scans from TRAILBLAZER-ALZ 3, A4, and the TRAILBLAZER-ALZ 2 (early, symptomatic AD) study.

METHODS: TRAILBLAZER-ALZ 3(NCT05026866) is a randomized, double-blind, placebo-controlled phase 3 trial. The study design was previously described. Baseline tau PET images were acquired using flortaucipir F 18 (FTP) as an optional sub-study. Scans were analyzed using an established image processing pipeline to evaluate global tau burden and regional tau patterns. Global burden was measured using AD-signature weighted neocortical standardized uptake value ratio (SUVR) relative to parametric estimate of reference signal intensity. Established SUVR cut points of >1.11 and >1.46 were utilized to quantitatively define positive FTP scan and high tau level, respectively. Regional tau patterns were assessed using multi-regional tau staging schemes.

RESULTS: Baseline FTP scans were assessed for N = 310 participants (n = 173 with Clinical Dementia Rating-Global Score, CDR-GS 0 [CDR0] and n = 137 with CDR-GS 0.5 [CDR0.5]). In the CDR0 and the CDR0.5 subgroups, 13.3% and 25.5% of participants, respectively, were tau positive (SUVR > 1.11; Figure 1). The medial and lateral temporal lobes had the highest regional baseline SUVRs for both subgroups. Average SUVRs for the CDR0 subgroup in medial temporal, lateral temporal, parietal, and frontal regions were 1.22, 1.18, 1.07, and 1.03, respectively, and 1.25, 1.24, 1.12, and 1.07 for the CDR0.5 subgroup, respectively (Figure 2).

CONCLUSIONS: Although CDR0.5 subgroup participants demonstrated higher mean FTP regional SUVR values compared with CDR0 participants, the baseline tau PET patterns in TRAILBLAZER-ALZ 3 are similar to other preclinical AD populations, even for participants in the CDR0.5 subgroup. Average regional baseline SUVR values support prior findings that tau deposition occurs sequentially from the medial temporal, lateral temporal, parietal, and frontal lobes. Additional regional analyses will be presented.},
}

Humans
*Alzheimer Disease/diagnostic imaging/drug therapy/metabolism
*Positron-Emission Tomography
Double-Blind Method
*tau Proteins/metabolism
Male
Female
*Brain/diagnostic imaging/metabolism
Aged

@article {pmid41433739,
year = {2025},
author = {Ridgway, GR and Nakajima, T and Torso, M and Hardingham, I and Khosropanah, P and Ohta, K and Aida, I and Chance, SA},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109939},
doi = {10.1002/alz70862_109939},
pmid = {41433739},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; Male ; Female ; Aged ; *Brain/diagnostic imaging/pathology ; *Diffusion Magnetic Resonance Imaging/methods ; Atrophy ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; Aged, 80 and over ; Magnetic Resonance Imaging ; },
abstract = {BACKGROUND: Measures of cortical microstructure from diffusion MRI (dMRI) have been shown to relate to amyloid pathology and to neuroinflammation, and can predict subsequent macrostructural atrophy (Torso et al., 2022, PMID:36281682). We have previously shown practicality of these methods using 1.5T MRI in a real-world hospital setting (Ridgway, Nakajima, et al., 2023, AAIC; jRCT1032210367). Anti-amyloid treatments such as Leqembi (Lecanemab) have been shown to reduce rates of clinical deterioration, but are associated with accelerated brain volume loss, which is presumed to be transient, but is not yet fully understood. We have commenced a study (https://jrct.niph.go.jp/en-latest-detail/jRCT1031240123) to explore the utility of dMRI measures to support early diagnosis and to track treatment response. Information on tissue microstructure is expected to add insights regarding volumetric atrophy or pseudoatrophy.

METHOD: Patients are recruited at National Hospital Organization Niigata National Hospital, with inclusion and exclusion criteria based on those of the approved drug Lecanemab. Amyloid positivity is confirmed with either amyloid PET or CSF Aβ42/40 ratio < 0.067. T1-weighted anatomical MRI (T1w) and dMRI (32-directions at b=1000 s/mm[2]) are acquired on a 1.5T Philips Ingenia MRI scanner and processed using FreeSurfer, FSL, and proprietary software to produce minicolumn-associated microstructural measures (AngleR, ParlPD and PerpPD[+]; McKavanagh et al., 2019, PMID:31355989).

RESULT: The study has enrolled 17 AD patients at the time of analysis, summarised in Table 1. Patients were scanned at baseline, and after 2, 3 and 6 months. 59 total scans were analysed, including 13 6-month scans. Figure 1 shows baseline associations of cognition (MMSE; lower scores worse) and cortical disarray (AngleR, higher values worse) with p-tau (higher values worse) for cases with CSF. Figure 2 shows regional associations of change in PerpPD+ with an overall improvement score that averaged MMSE, MMSE-DR, CDR-GS, CDR-SB and IADL.

CONCLUSION: We have introduced a promising real-world observational study that could shed light on the microstructural nature of amyloid-lowering treatment response and the debate about pseudo-atrophy. Microstructural imaging measures are sensitive treatment biomarkers that correlate with clinical changes. Future work with a larger dataset will investigate the potential prediction of clinical change using baseline cortical disarray measurements.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
Male
Female
Aged
*Brain/diagnostic imaging/pathology
*Diffusion Magnetic Resonance Imaging/methods
Atrophy
Amyloid beta-Peptides/cerebrospinal fluid
Middle Aged
Aged, 80 and over
Magnetic Resonance Imaging

@article {pmid41433733,
year = {2025},
author = {Is, O and Tan, J and Bergman, J and Wang, X and Tutor-New, FQ and Min, Y and Quicksall, Z and Atik, M and Reddy, JS and Gao, J and Tsai, W and Sotelo, KD and Nguyen, TT and Kanekiyo, T and Dickson, DW and Allen, M and Ertekin-Taner, N},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110127},
doi = {10.1002/alz70862_110127},
pmid = {41433733},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging ; *Microglia/metabolism ; *Adaptor Proteins, Signal Transducing/genetics ; Brain/metabolism ; Mutation, Missense ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) affects all brain cells and has complex genomic and immunological alterations. Previous research discovered missense AD risk or protective variants in microglial genes ABI3 and PLCG2, respectively. Expression levels of these genes are altered in AD and can influence microglial function. This study aims to uncover protective, and risk microglial molecular signatures associated with these variants to determine their role in microglial subtypes and states in AD by single cell expression and functional studies.

METHOD: We generated microglia-enriched snRNAseq data from donors harboring either AD protective PLCG2 or AD risk ABI3 missense mutations, or neither mutation. After standard snRNAseq QC, we performed differential expressed gene (DEG) analysis of all microglial cells between variant carriers and non-carriers using MAST. We defined protective signature as genes that are both down in ABI3 and up in PLCG2 mutation-carriers. In contrast, risk signature genes are up in ABI3 and down in PLCG2 mutation-carriers. We investigated the conservation of protective and risk signatures across multiple datasets, including scRNAseq data from iPSC-derived microglia cells carrying PLCG2 protective variant, snRNAseq data from AD-resilient donors, and data from AD and other diagnostic groups across multiple brain regions sourced from external datasets.

RESULT: We obtained snRNAseq profiles of 35,000 microglia from AD variant carriers. Our DEG analysis among all microglia cells provided 227 microglial protective and 293 risk signature genes defined by these variants. Using integrated analysis of multiple internal and external datasets, we further narrowed down these signatures. We determined that these high-confidence protective signature genes are downregulated in early AD, upregulated in late AD brains and positively-correlated with protective variant load in in vitro models. In contrast, risk signature genes are upregulated in early AD, downregulated in late AD and resilient donors. Risk signature expression is decreased with protective PLCG2 variant load, and altered with Aβ treatment in in vitro models.

CONCLUSION: Our study uncovers microglia specific protective and risk signatures associated with AD using sn/scRNAseq datasets from multiple sources and models. These findings nominate novel immune targets and pathways with implications for microglial function in health and disease, and ultimately therapeutic potential.},
}

Humans
*Alzheimer Disease/genetics/diagnostic imaging
*Microglia/metabolism
*Adaptor Proteins, Signal Transducing/genetics
Brain/metabolism
Mutation, Missense

@article {pmid41433721,
year = {2025},
author = {Chie, JAKHC and Persohn, SA and Pandey, RS and Simcox, O and Salama, P and Territo, PR},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110124},
doi = {10.1002/alz70862_110124},
pmid = {41433721},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism ; Male ; Female ; Aged ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; Retrospective Studies ; *Brain/diagnostic imaging/metabolism ; Fluorodeoxyglucose F18 ; Aged, 80 and over ; Cognitive Dysfunction/diagnostic imaging ; Cerebrovascular Circulation/physiology ; Middle Aged ; },
abstract = {BACKGROUND: Historically, clinical diagnosis of ADRD via medical imaging has largely focused on singular modalities late in the disease process to identify structural and/or functional changes; however, by this point, irreversible brain damage has occurred, thus resulting in a lack of sensitivity and specificity of the measure. Since treatment planning is often based on these readouts, outcomes are often compromised, leading to ineffective treatment responses. Recent preclinical data suggests that regional metabolic and vascular dysfunction (MVD) persist across the disease spectrum; however, few studies have explored these combined measures in ADRD. Therefore, we hypothesized that MVD may serve as a sensitive and early noninvasive diagnostic tool, and tested this in a retrospective clinical population spanning from CN to AD.

METHOD: Subjects from ADNI who were scanned with [18]F-FDG PET and ASL MRI within 180 days were included (N = 290; CN(91), MCI(116), AD(83), M/F(51.2/48.8%)). Cerebral blood flood (CBF) and images were generated from ASL images using ExploreASL. PET and CBF images were registered to the augmented MNI152+ Atlas. Mean intensities for unilateral 59 brain regions were ratioed to whole brain values, z-scores computed for each region (relative to CN), and were projected into Cartesian space. Statistical analysis of at-risk regions was evaluated using Student's t-test (p <0.05), and hierarchical clustering of at-risk regions was aligned with transcriptomic signatures and clinical cognitive assessments.

RESULT: Our findings suggest that disease progression follows an MVD pattern (Figure 1A), consistent with our preclinical work, illustrating the suitability of the approach for stage-dependent detection of at-risk brain regions. Moreover, clustered regions associated with memory, cognitive, and motor functions progress at different rates, where MCI subjects show both Type 1 (↓[18]F-FDG,↑CBF) and Type 2 (↑[18]F-FDG,↓CBF) uncoupling MVD (Figure 1B); where AD subjects showed prodromal (↑[18]F-FDG,↑CBF) and neuro-metabolic-vascular failure (↓[18]F-FDG,↓CBF) MVD phenotype (Figure 1C). Importantly, these changes aligned with transcriptomic and cognitive signatures.

CONCLUSION: Our findings show that MVD of the at-risk brain regions depends on sex, APOE status, age, and disease stage. Moreover, our data reveals that MVD patterns can provide a sensitive diagnostic tool for early diagnosis of ADRD, which may improve patient monitoring, stratification, and therapeutic testing.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism
Male
Female
Aged
Positron-Emission Tomography
Magnetic Resonance Imaging
Retrospective Studies
*Brain/diagnostic imaging/metabolism
Fluorodeoxyglucose F18
Aged, 80 and over
Cognitive Dysfunction/diagnostic imaging
Cerebrovascular Circulation/physiology
Middle Aged

@article {pmid41433535,
year = {2025},
author = {Joseph-Mathurin, N and Gong, K and Chen, G and Massoumzadeh, P and Strain, JF and Ibanez, L and Gordon, BA and Llibre-Guerra, JJ and Hassenstab, JJ and Perrin, RJ and Xiong, C and Bateman, RJ and McDade, E and Benzinger, TLS and Cruchaga, C},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109993},
doi = {10.1002/alz70862_109993},
pmid = {41433535},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/genetics/diagnostic imaging/pathology/cerebrospinal fluid ; Magnetic Resonance Imaging ; Middle Aged ; Biomarkers/cerebrospinal fluid ; Proteomics ; *White Matter/diagnostic imaging/pathology ; Aged ; *Brain/diagnostic imaging/pathology ; Adult ; },
abstract = {BACKGROUND: With the advent of disease-modifying treatment for Alzheimer disease (AD), identifying biomarkers for predicting risk for amyloid-related imaging abnormalities (ARIA), hemorrhagic or edema types, is of increased interest. ARIA are thought to be related to disruption of the blood-brain barrier as fibrillary amyloid is cleared from the brain. Molecular and cellular processes related to these events may inform future trials. We investigated proteomics related to abnormal neurovascular imaging phenotypes such as white matter hyperintensities (WMH) in autosomal dominant AD (ADAD), a relatively young population at risk for ARIA.

METHODS: Participants from the Dominantly Inherited Alzheimer Network observational study (nCarriers=290 and nNon-Carriers=183) were assessed for WMH and microhemorrhages using T2-FLAIR and T2*GRE MRI, and for CSF proteomics using the 7k Somalogic[®] platform. A subset (nCarriers=92 and nNon-Carriers=51) was evaluated for microhemorrhage incidence. WMH volumes were segmented with Triplanar U-Net ensemble network. Microhemorrhage count and incidence were classified as none, mild, moderate, or severe, based on current FDA recommendations. We performed differential abundance analyses to investigate proteins associated with WMH as a function of mutation status, accounting for age, APOE-e4 status, and sex, and significant proteins were further evaluated in pathway analyses and for associations with microhemorrhages.

RESULTS: Eight proteins were differently expressed in carriers with larger WMH volumes (Figure 1). The genes of seven proteins (e.g., neurofilament light-chain (NEFL), neurofilament heavy-chain (NEFH), matrix metalloproteinase 12 (MMP12), fibronectin-1 (FN1), periostin (POSTN)) were overly represented in vascular-related disorders such as subarachnoid hemorrhages, transient ischemic attack, or cerebrovascular diseases (Figure 2). CSF levels of NEFL, NEFH, MMP12, fibronectin1, and periostin differed as a function of CMH severity. Especially, NEFL and MMP12 were higher in carriers with severe CMH compared to those with none or mild CMH (Figure 3A). MMP12 levels were particularly high in participants having severe increase in microhemorrhages (Figure 3B). Carriers with high levels of MMP12 may more likely develop new microhemorrhages.

CONCLUSIONS: Our findings confirm the contribution of neurofilament light chain in disease processes and suggest a role for matrix metalloproteinase 12 in the development of microhemorrhages and especially severe case in ADAD.

FUNDING: K01AG080123, RF1-AG044546, UF1AG032438.},
}

Humans
Male
Female
*Alzheimer Disease/genetics/diagnostic imaging/pathology/cerebrospinal fluid
Magnetic Resonance Imaging
Middle Aged
Biomarkers/cerebrospinal fluid
Proteomics
*White Matter/diagnostic imaging/pathology
Aged
*Brain/diagnostic imaging/pathology
Adult

@article {pmid41433520,
year = {2025},
author = {Jiang, M and Joseph-Mathurin, N and Wang, Y and Gordon, BA and Cruchaga, C and Hassenstab, JJ and Ibanez, L and Li, Y and Perrin, RJ and Renton, AE and Wang, G and Xiong, C and Llibre-Guerra, JJ and Clifford, DB and Atri, A and McDade, E and Bateman, RJ and Benzinger, TLS and Wang, Q},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109981},
doi = {10.1002/alz70862_109981},
pmid = {41433520},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/drug therapy/pathology ; Pilot Projects ; Male ; *Diffusion Magnetic Resonance Imaging/methods ; Aged ; Female ; Antibodies, Monoclonal, Humanized/therapeutic use ; *Brain/diagnostic imaging/pathology ; Brain Edema/diagnostic imaging ; },
abstract = {BACKGROUND: Amyloid-Related Imaging Abnormalities (ARIA), characterized by vasogenic edema or sulcal effusions (ARIA-E) or hemorrhagic lesions (microhemorrhages, superficial siderosis, or, rarely, microhemorrhages) (ARIA-H), remain a significant challenge in monoclonal antibody (mAb) therapy for AD (1). Despite their clinical importance, the mechanisms underlying ARIA, particularly neuroinflammation, remain poorly understood. Advanced imaging techniques are crucial for elucidating these processes. Generalized diffusion basis spectrum imaging (g-DBSI), an advanced diffusion MRI method evolved from DBSI (2,3), can reveal microstructural changes linked to neuroinflammation and vasogenic edema in white and gray matter. This study aims to use g-DBSI to investigate the microstructural alterations linked to neuroinflammation and vasogenic edema during the development and recovery of ARIA-E in the context of mAb treatment.

METHOD: This pilot study included three participants from the DIAN-TU-001 trial who received Gantenerumab (4) and underwent longitudinal g-DBSI scans. ARIA assessment was conducted by a panel of trained neuroradiologists using an FDA grading scale and standardized structured reporting templates, as recommended by the American Society for Neuroradiology (5). Regions of interest (ROIs) were delineated on the FLAIR sequence in areas exhibiting ARIA-E. Within these ROIs, we quantified the g-DBSI-derived restricted ratio (RR, a putative marker of inflammation) and hindered ratio (HR, a putative marker of vasogenic edema).

RESULT: For the first participant, an elevated g-DBSI-derived RR and HR were observed one month before the onset of ARIA-E in the third participant compared to the 2-year follow-up g-DBSI (Figure 1A). For the second participant, the initial g-DBSI scan during ARIA-E onset showed elevated RR and HR, which decreased significantly in the follow-up scan two years later (Figure 1B). For the third participant, g-DBSI-derived RR and HR remained stable between 1- and 2-year follow-ups after the resolution of ARIA-E (Figure 1C).

CONCLUSION: Our findings suggest neuroinflammation's role in ARIA-E progression and demonstrate the potential of g-DBSI to detect microstructural changes before the onset of ARIA-E. This pilot study supports g-DBSI as a noninvasive imaging tool to monitor ARIA progression, providing insights into neuroinflammation and vasogenic edema. Further research with larger cohorts is necessary to further delineate and validate the potential clinical utility of g-DBSI.},
}

Humans
*Alzheimer Disease/diagnostic imaging/drug therapy/pathology
Pilot Projects
Male
*Diffusion Magnetic Resonance Imaging/methods
Aged
Female
Antibodies, Monoclonal, Humanized/therapeutic use
*Brain/diagnostic imaging/pathology
Brain Edema/diagnostic imaging

@article {pmid41433506,
year = {2025},
author = {Kim, S and Jung, W and Lee, SH and Suh, CH},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109684},
doi = {10.1002/alz70862_109684},
pmid = {41433506},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Magnetic Resonance Imaging/methods ; *Alzheimer Disease/diagnostic imaging ; Deep Learning ; Reproducibility of Results ; *Cerebral Hemorrhage/diagnostic imaging ; Middle Aged ; *Neuroimaging/methods ; *Brain/diagnostic imaging ; Aged, 80 and over ; },
abstract = {BACKGROUND: Microbleed detection is significant in anti-amyloid therapy (AAT) monitoring to evaluate amyloid-related imaging abnormalities (ARIA) severity (mild: ≤4, moderate: 5-9, severe: ≥10), which directly affects treatment decisions. Although T2*/GRE is recommended for the primary diagnostic imaging sequence of ARIA-H monitoring, the susceptibility-weighted imaging (SWI) sequence is known to be more sensitive to microbleeds. However, manual assessments are time-consuming and prone to reader variability. Deep learning-based automated detection systems can improve the efficiency and reliability of ARIA-H evaluations.

METHOD: 565 SWI MRI scans (2mm slice thickness) from Asan Medical Center were analyzed, comprising 429 positive and 136 negative cases. The mean age of the cohort was 71.9 ± 10.2 years (202 males, 363 females). A neuroradiologist with 14 years' experience labeled microbleeds that were defined as hypointense lesions ranging from 2 to 10mm in diameter on SWI. The dataset was split into training, validation, and test subsets at a 3:1:1 ratio. An Attention U-Net architecture with deep supervision was employed to handle the small size and morphological similarity of cerebral microbleeds. Model validation was performed using the Dice coefficient and the lesion-level Matthews correlation coefficient (MCC).

RESULT: A total of 114 test scans were evaluated (86 positive, containing 158 microbleeds, and 28 negative) using a 3 mm lesion center proximity threshold. The model detected 146 of 158 microbleeds, achieving an AUC of 0.872 (sensitivity=0.677, specificity=0.893). False-positive analysis revealed 103 occurrences in positive scans and 18 in negative scans. Patient-level metrics included 1.28 microbleeds per scan (95% CI: 1.02-1.54) and 1.06 false positives per scan (95% CI: 0.79-1.37), producing a minimal impact on the ARIA-H radiological severity classification standard (mild: ≤4 microbleeds, moderate: 5-9, severe: ≥10).

CONCLUSION: This study presents a robust automatic microbleed detection approach using SWI, facilitating ARIA-H assessment in diagnosis and severity categorization. Future work will involve multi-center external validation, supporting additional sequences, and incorporating additional ARIA-related factors for more comprehensive detection.},
}

Humans
Male
Female
Aged
*Magnetic Resonance Imaging/methods
*Alzheimer Disease/diagnostic imaging
Deep Learning
Reproducibility of Results
*Cerebral Hemorrhage/diagnostic imaging
Middle Aged
*Neuroimaging/methods
*Brain/diagnostic imaging
Aged, 80 and over

@article {pmid41433505,
year = {2025},
author = {Lui, KK and Wang, X and Lifset, ET and Heyworth, NC and Holloway, BM and DeYoung, PN and Malhotra, A and Sundermann, EE and Banks, SJ},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109805},
doi = {10.1002/alz70862_109805},
pmid = {41433505},
issn = {1552-5279},
mesh = {Humans ; Female ; Aged ; *Sleep Apnea, Obstructive/complications/cerebrospinal fluid/diagnostic imaging ; *Alzheimer Disease/diagnostic imaging/genetics ; Apolipoprotein E4/genetics ; tau Proteins/metabolism/cerebrospinal fluid ; *Inflammation/cerebrospinal fluid ; *Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging ; Biomarkers/cerebrospinal fluid ; Positron-Emission Tomography ; },
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) is thought to elevate Alzheimer's disease (AD) risk, possibly through an inflammatory mechanism. This may be particularly relevant for older women, who are underdiagnosed for OSA, express higher inflammatory responses and accumulate greater pathological tau in early AD stages than older men. APOE4 seems to worsen OSA's impact on AD risk; however, findings are mixed. This study examined APOE4's moderating role in how OSA symptoms relate to inflammation and tau pathology among older women with OSA from the Women: Inflammation and Tau Study (WITS).

METHOD: WITS recruits older women with mild cognitive impairment on the telephone Montreal Cognitive Assessment and elevated AD polygenic hazard scores and/or family history of dementia. Participants included 43 women (aged:71.9±4.1 years) with cerebrospinal fluid-derived inflammatory markers (IL-1β, IL-6, and TNF), MK-6240 tau PET data from a composite meta-temporal region of interest and the following OSA characteristics from a home sleep test: apnea-hypopnea index (AHI) and oxygen desaturation index (ODI). Following clinical guidelines, OSA was diagnosed with AHI≥5/hr. In women with OSA, multiple regression models analyzed OSA characteristics×APOE4 interactions on inflammatory markers and tau standardized uptake value ratio, controlling for age and body mass index (BMI).

RESULT: 29 women met OSA diagnosis (67%) with 27 unaware of this at screening (Table 1). In women with OSA, AHI and ODI significantly interacted with APOE4 to predict CRP (ps<0.04), whereby greater OSA severity related to elevated CRP levels in APOE4 carriers (AHI: p<0.05; ODI: p = 0.07). However, in non-carriers, higher AHI was associated with lower CRP (p = 0.04), while ODI was not associated with CRP (p = 0.24; Figure 1). Further, AHI and ODI significantly interacted with APOE4 status to predict tau (ps<0.04), such that greater OSA severity related to higher tau burden in only APOE4 carriers (ps<0.04) (Figure 2). There were no significant OSA severity×APOE4 interactions nor main effects of OSA severity on other inflammatory markers.

CONCLUSION: In women with OSA, APOE4 interacts with OSA severity to potentially precipitate a stronger inflammatory response and higher tau burden. Early diagnosis and treatment of OSA might mitigate AD risk, especially for older female APOE4 carriers.},
}

Humans
Female
Aged
*Sleep Apnea, Obstructive/complications/cerebrospinal fluid/diagnostic imaging
*Alzheimer Disease/diagnostic imaging/genetics
Apolipoprotein E4/genetics
tau Proteins/metabolism/cerebrospinal fluid
*Inflammation/cerebrospinal fluid
*Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging
Biomarkers/cerebrospinal fluid
Positron-Emission Tomography

@article {pmid41433495,
year = {2025},
author = {Bourgeat, P and Fripp, J and Gillman, AG and Cox, T and Feizpour, A and Xia, Y and Zisis, G and Goyal, MS and Tosun, D and LaMontagne, P and Benzinger, TLS and Barkhof, F and Farrar, G and Bollack, A and Sperling, RA and Morris, JC and Weiner, MSW and Villemagne, VL and Masters, CL and Rowe, CC and Dore, V},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110298},
doi = {10.1002/alz70862_110298},
pmid = {41433495},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism ; *Positron-Emission Tomography/methods ; Male ; Female ; *Deep Learning ; Aged ; *Brain/diagnostic imaging/metabolism ; },
abstract = {BACKGROUND: Centiloid quantification relies on a Standardised Uptake Value Ratio (SUVR) that could be subject to noise, spill-in, and specific binding in the reference region. We developed a novel deep learning method that learns scan-specific variability from longitudinal trends to correct SUVR quantification and then validated it in 7 large cohorts.

METHOD: 2,281 participants with 2+ visits in AIBL/ADNI (7,380 scans) had their Amyloid PET images spatially normalised and quantified using the Centiloid SPM8 pipeline. A deep learning network (DeepSUVR) was trained to predict a SUVR correction factor for each spatially normalised image, by penalising unexpected temporal changes based on the deviation from the Centiloid/Year vs mean Centiloid curve. Importantly, while the model requires longitudinal data for training, inference is performed on each visit independently. The model was trained using 5-fold cross-validation on ADNI+AIBL and evaluated on the out-of-fold AIBL+ADNI as well as OASIS3, AMYPAD, MCSA, HABS-HD and A4-LEARN studies (8,806 participants, 12,320 scans), comparing DeepSUVR with standard CL and when using a composite WCb+WM reference region for [18]F-Florbetapir.

RESULT: Fitting a bimodal Gaussian mixture on the baseline CL of each study, DeepSUVR improved the alignment of the first peak across all studies, as well as reducing their standard deviations (Figure 1A) with similar findings across tracers (Figure 1B). DeepSUVR CL had the strongest correlation between baseline CL and MMSE, best group separation between CDR 0/0.5/1 (Table 1A) and highest AUC against visual reads (Table 1B). DeepSUVR improved model fitness (Spearman rank) and inter-study model agreement in the longitudinal trajectories across studies in both training (Figure 2A) and testing cohorts (Figure 2B). DeepSUVR increased the effect size for the reduced rate of CL increase per year seen with treatment in the A4 study, while reducing the variability in the Amyloid negative subjects (Figure 2C).

CONCLUSION: Deep learning provides a significant advance in PET quantification of amyloid, outperforming standard methods both cross-sectionally and longitudinally in both observational and interventional studies. DeepSUVR improves the ability to harmonise large datasets and different PET tracers. This is particularly important for consistent decision making and when the outcome measure of an intervention is expected to be subtle such as altering the rate of accumulation.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism
*Positron-Emission Tomography/methods
Male
Female
*Deep Learning
Aged
*Brain/diagnostic imaging/metabolism

@article {pmid41433489,
year = {2025},
author = {Young, AL and Wijeratne, PA and Aksman, LM and Binette, AP and Strandberg, O and Oxtoby, NP and Altmann, A and Alexander, DC and Stomrud, E and Palmqvist, S and Mattsson-Carlgren, N and Vogel, JW and Hansson, O},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110838},
doi = {10.1002/alz70862_110838},
pmid = {41433489},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; Positron-Emission Tomography ; *tau Proteins/metabolism ; Female ; Male ; Aged ; Disease Progression ; *Brain/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Sweden ; Middle Aged ; Amyloid/metabolism ; },
abstract = {BACKGROUND: Amyloid and tau accumulation in Alzheimer's disease is known to be dynamic, with expected rates of accumulation varying depending on disease stage. Establishing the precise timeline of amyloid and tau accumulation and quantifying their dynamic progression is important for identifying an optimal intervention window and predicting treatment response.

METHOD: 960 individuals were selected from the Swedish BioFINDER-2 study with at least two tau-PET scans (Table 1; follow-ups were at 1 year (N = 66), 2 years (N = 924), 4 years (N = 335); 6 years (N = 60)). Two intersecting data subsets were selected: 773 individuals having at least two amyloid-PET scans for estimating amyloid duration, and 434 CSF-amyloid-positive individuals for comparison with timelines across the whole population. Regional tau-PET SUVR abnormality was computed in five established data-driven regions using mixture modelling. A novel explicit-duration version of the temporal event-based model (T-EBM) was used to determine the order and timeline of global amyloid-PET and regional tau-PET abnormality. The explicit duration approach accounts for censoring of an individual's first and last visit and handles arbitrary time intervals.

RESULT: The T-EBM inferred that tau accumulates in a Braak-like pattern (Figure 1a), estimating an average timeline of global amyloid and regional tau accumulation (Figure 1b) of around 20 years. Progression from stage 1 (amyloid) to stage 2 (entorhinal tau) was estimated to take 8 years on average, from stage 2 to stage 3 (temporal lobe tau) 5.5 years, and 2-3 years between each subsequent stage. The timeline was consistent in amyloid-positive individuals (most amyloid-negative individuals were stage 0 and did not influence the timeline). Figure 1c shows the number of individuals progressing between stages at follow-up. Individuals who progressed in stage (progressors) were older, had more advanced symptoms (diagnosis), more APOE4 alleles, worse MMSE scores, and were more frequently amyloid-positive compared to non-progressors (Table 2).

CONCLUSION: Amyloid accumulates slowly, after which tau spreads from the entorhinal cortex to the temporal lobe, initially at a slower pace before accelerating to a faster rate across the cortex. This data indicates that slower rates of accumulation would be expected at earlier stages. Work is ongoing validating these timelines in additional datasets.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
Positron-Emission Tomography
*tau Proteins/metabolism
Female
Male
Aged
Disease Progression
*Brain/diagnostic imaging/metabolism
*Amyloid beta-Peptides/metabolism/cerebrospinal fluid
Sweden
Middle Aged
Amyloid/metabolism

@article {pmid41433481,
year = {2025},
author = {Montalba, C and Aduluwa, H and Gracia, MF and Botwe, F and Maharjan, S and Mumuni, AN and Zeraii, A and Thairu, J and Zurakat-Aderibigbe, S and Adewo, A and Mokoena, K and Alfaro, A and Flores, G and Lim, T and Mach, M and Adebimpe, A and Taylor, R and Anosike, C and Anyanwu, B and Poloni, G and Abiodun, F and Dako, F and Anazodo, U},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109998},
doi = {10.1002/alz70862_109998},
pmid = {41433481},
issn = {1552-5279},
mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Alzheimer Disease/diagnostic imaging ; Developing Countries ; Brain/diagnostic imaging ; *Neuroimaging/methods ; Curriculum ; },
abstract = {BACKGROUND: In tandem with the ever-increasing aging population in low- and middle- income countries (LMICs), the burden of dementia is rising across LMICs. Magnetic resonance imaging (MRI) is essential in diagnosis to evaluate different dementia subtypes. However, most LMICs have limited access to MRI and lack trained MRI personnel to make accurate diagnoses. Here, we provide update on the Scan With Me (SWiM) training program [1] aimed at upskilling MRI radiographers from LMICs to optimize MRI acquisition on their limited infrastructure and produce high-quality images including advanced dementia MRI techniques.

METHOD: SWiM is a free train-the-trainer capacity-building initiative of the Consortium for Advancement of MRI Education and Research in Africa (CAMERA). SWiM implements RAD-AID's Teach-Try-Use strategy, which combines virtual learning resources, live expert case-based lectures, and hands-on vendor-led practical scanning sessions to train a team of radiographers who work together as a network to enhance their skills and collectively train others [2]. The curriculum (Figure 1) guides participants from basic to advanced brain imaging over 8 weeks. Two cases of patients with dementia, simulated from LMIC published case reports were used for as capstone projects. This guided participants to develop brain imaging protocols tailored from standards (e.g., ADNI) and optimized on their scanners for dementia imaging.

RESULT: The second program ran from August to September 2024, with special focus on dementia imaging and hands-on imaging sessions at 5 clinics in Kenya and Nigeria, and one trainer site in Chile. 96 radiographers from 29 imaging facilities in 18 LMIC countries received 70 hours of specialized training, observerships, and peer-to-peer engagements (Figure 2). Basic to advanced MRI techniques adapted from ADNI were acquired from the two African sites using optimized protocols (Figure 3). The LMIC-optimized scan protocols from participants are being curated and will be shared openly on protocols.io for others to use.

CONCLUSION: SWiM aims to establish a collaborative network of experts in imaging centers in LMICs, enabling them to collect robust datasets that can inform clinical care and support the development of imaging tools for advancing prevention and treatment strategies. [1] event.fourwaves.com/swim [2] Mumuni AN, et al.,. J Am Coll Radiol. 2024 21(8):1222-1234.},
}

Humans
*Magnetic Resonance Imaging/methods
*Alzheimer Disease/diagnostic imaging
Developing Countries
Brain/diagnostic imaging
*Neuroimaging/methods
Curriculum

@article {pmid41433476,
year = {2025},
author = {Burns, AP and Fortel, I and Zhan, L and Lazarov, O and Mackin, SR and Demos, AP and Bendlin, BB and Leow, A},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110111},
doi = {10.1002/alz70862_110111},
pmid = {41433476},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/diagnostic imaging/genetics/physiopathology ; Magnetic Resonance Imaging ; Apolipoprotein E4/genetics ; *Brain/diagnostic imaging/physiopathology ; *Cognitive Dysfunction/diagnostic imaging/genetics/physiopathology ; Longitudinal Studies ; Aged, 80 and over ; Diffusion Magnetic Resonance Imaging ; Disease Progression ; Sex Factors ; },
abstract = {BACKGROUND: Excessive neural hyperexcitation has been implicated in early cognitive decline and progression to Alzheimer's disease (AD). Restoring the balance between excitation and inhibition (E/I) with interventions like levetiracetam may offer clinical benefits, particularly for those at heightened risk. Recent cross-sectional studies suggest that female APOE-ε4 carriers may be especially vulnerable to hyperexcitation, but longitudinal evidence remains limited. We therefore investigated whether E/I dysregulation over time differs by sex and APOE-ε4 status in older adults who were cognitively unimpaired at baseline. Figure 1 illustrates the concept of early hyperexcitation preceding AD symptoms.

METHOD: We analyzed multimodal MRI data (resting-state functional MRI and diffusion-weighted imaging) from 106 older adults with at least one cognitively unimpaired scan and three or more longitudinal sessions. Most sessions were rated as clinically unimpaired (CDR = 0), though a subset transitioned to early mild cognitive impairment (CDR = 0.5 or 1). We applied an inverse Ising model regularized by empirical structural connectivity (Figure 2) to derive a whole-brain excitation-inhibition ratio (EIR). Linear mixed modeling tested whether EIR trajectory varied by sex, binary APOE-ε4 status, age at first scan, and time since first scan.

RESULT: A significant three-way interaction (Figure 3) indicated that female APOE-ε4 carriers demonstrate an elevated hyperexcitable EIR trajectory (p = 0.018). Pairwise comparisons further showed higher EIR slopes for female ε4 carriers compared to female non-carriers (p = 0.042). This effect remained significant after adjusting for age, time, and amyloid status, though it was somewhat diminished in participants with fewer longitudinal observations. Regional analyses focusing on default mode and limbic networks found higher baseline excitatory tone in females (p = 0.02), aligning with the global results.

CONCLUSION: These findings provide longitudinal support for a heightened susceptibility to hyperexcitation in female APOE-ε4 carriers, underscoring the importance of sex and genetic risk in preventive and therapeutic strategies for AD. Our multimodal approach integrating structural and functional network data highlights E/I balance as a promising biomarker and treatment target, with levetiracetam representing one potential intervention. Larger studies are needed to confirm how sex- and genotype-specific E/I dysregulation influences dementia risk and therapeutic efficacy.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/diagnostic imaging/genetics/physiopathology
Magnetic Resonance Imaging
Apolipoprotein E4/genetics
*Brain/diagnostic imaging/physiopathology
*Cognitive Dysfunction/diagnostic imaging/genetics/physiopathology
Longitudinal Studies
Aged, 80 and over
Diffusion Magnetic Resonance Imaging
Disease Progression
Sex Factors

@article {pmid41433469,
year = {2025},
author = {Biel, D and Steward, A and Dewenter, A and Dehsarvi, A and Zhu, Z and Roemer-Cassiano, S and Frontzkowski, L and Hirsch, F and Brendel, M and Franzmeier, N},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110180},
doi = {10.1002/alz70862_110180},
pmid = {41433469},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; Male ; Female ; tau Proteins/blood ; Biomarkers/blood ; Aged ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Longitudinal Studies ; Aged, 80 and over ; *Brain/diagnostic imaging/pathology ; Amyloid beta-Peptides ; },
abstract = {BACKGROUND: With the approval of anti-amyloid therapies in Alzheimer's disease (AD), surrogate biomarkers are urgently needed to monitor treatment effects that translate into clinical benefits. Candidate biomarkers, including amyloid-PET, tau-PET, plasma phosphorylated tau (p-tau), and MRI-assessed atrophy, capture core pathophysiological changes in AD. While cross-sectional biomarker assessments are critical for diagnosis and staging, biomarker change rates may better reflect disease dynamics, making them more suitable for monitoring treatment efficacy. Therefore, we determined which biomarker most effectively tracks cognitive changes in AD, identifying those best suited for efficient monitoring of disease-modifying treatments.

METHOD: We leveraged ADNI (N = 108) and A4 (N = 151) participants with longitudinal AD biomarker data (global amyloid-PET, temporal meta tau-PET, plasma p-tau217, MRI-assessed cortical thickness in the AD signature region) together with cognitive assessments (ADNI: MMSE, ADAS13, CDR-SB; A4: MMSE, PACC). Linear mixed models were used to calculate change rates for biomarkers and cognition. To test whether biomarker changes track cognitive decline, linear models were applied, to test biomarker change rates as a predictor of cognitive change rates. Standardized beta values from bootstrapped linear models were extracted to compare the strengths of correlations between biomarkers and cognitive decline. For non-parametric comparisons, 95% confidence intervals (CIs) of standardized beta values were compared. Models were controlled for age, sex, education, and baseline cognition, with ADNI models additionally adjusted for clinical status.

RESULT: In both cohorts, changes in temporal tau-PET, plasma p-tau217, and MRI-assessed cortical thickness were associated with cognitive decline (ADNI: Figure 1; A4: Figure 2). Amyloid-PET changes showed no significant association with cognitive changes (ADNI: Figure 1A+F+K; A4: Figure 2A+F). Bootstrapping confirmed that tau-PET, plasma p-tau217, and cortical thickness track cognitive decline, but not amyloid-PET (ADNI: Figure 1E+J+O; A4: Figure 2E+J). Overlapping CIs for tau-PET and plasma p-tau217 indicated comparable predictive accuracy.

CONCLUSION: Our findings demonstrate that tau-PET and plasma p-tau217 are robust biomarkers for monitoring cognitive changes, with plasma p-tau217 offering a cost-effective, scalable alternative for clinical use. Changes in amyloid-PET do not reliably reflect cognitive decline, limiting its utility as a treatment monitoring tool. Although cortical thickness correlates with cognitive changes, its application is limited by pseudoatrophy and volume loss induced by anti-amyloid antibody treatments.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
Male
Female
tau Proteins/blood
Biomarkers/blood
Aged
Magnetic Resonance Imaging
Positron-Emission Tomography
Longitudinal Studies
Aged, 80 and over
*Brain/diagnostic imaging/pathology
Amyloid beta-Peptides

@article {pmid41433464,
year = {2025},
author = {Binding, LP and Croitor, M and Parker, CS and Saguer, IL and Oxtoby, NP and Alexander, DC and Young, AL},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110289},
doi = {10.1002/alz70862_110289},
pmid = {41433464},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; *tau Proteins/metabolism ; Positron-Emission Tomography ; Male ; Female ; Aged ; *Brain/diagnostic imaging/pathology/metabolism ; Biomarkers ; Atrophy/pathology ; Disease Progression ; Aged, 80 and over ; },
abstract = {BACKGROUND: Mixed pathology is prevalent in Alzheimer's disease (AD) but difficult to detect in vivo as biomarkers for several additional pathologies are in their infancy. Cortical thickness (CT) atrophy reflects both tau deposition and additional pathologies (e.g., TDP-43). Specific biomarkers like tau-PET may help disentangle these contributions. We introduce Additional Pathology Inference (AddiPath), software designed to identify disease biomarker changes not explained by primary pathology, and apply it to identify CT changes unexplained by tau deposition on tau-PET.

METHOD: Paired tau-PET and CT data from 444 ADNI subjects across 8 bilateral meta-regions were analysed. Subtype and Stage Inference (SuStaIn) applied to tau-PET data identified tau pathology subtypes with distinct progression patterns. AddiPath was then applied to learn the relative contributions of tau and additional pathology to regional CT values. AddiPath simultaneously estimated a scaling parameter determining the contribution of the regional SuStaIn-predicted tau-PET value to changes in CT, and the regional progression pattern of the additional CT changes that were not explained by tau-PET. Regression analysis was utilised to analyse the effects of AddiPath stages on clinical variables of interest.

RESULT: SuStaIn revealed posterior, limbic, and cortical subtypes of tau deposition (Figure 1), AddiPath uncovered an additional pathology progression pattern (Figure 1) beginning in the entorhinal cortex, spreading to the medial temporal lobe, and then across the cortex. 84 individuals (50 mild cognitive impairment; 33 dementia; 1 control) were labelled by AddiPath as having additional pathology (Table 1). Increased AddiPath stages were associated with worse composite memory (p<0.001), language (p = 0.001) and executive function (p<0.001) scores. Greater tau-PET pathology stages correlated with CSF total tau (p <0.001) and tau-PET (p <0.001), but AddiPath stages did not (p = 0.860, p = 0.475), confirming that AddiPath-inferred additional pathology was unrelated to tau load (Figure 2).

CONCLUSION: We introduced AddiPath, a method for disentangling the contributions of additional pathology from primary pathology. AddiPath uncovered changes in CT not explained by tau deposition in the limbic lobe, possibly indicating TDP-43 deposition. This approach could improve patient selection for clinical trials and treatment stratification. Future work will replicate this finding across additional cohorts and test the applicability of AddiPath to other biomarkers.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
*tau Proteins/metabolism
Positron-Emission Tomography
Male
Female
Aged
*Brain/diagnostic imaging/pathology/metabolism
Biomarkers
Atrophy/pathology
Disease Progression
Aged, 80 and over

@article {pmid41433458,
year = {2025},
author = {Bublitz, EF and Hulle, CAV and Zylstra, H and Cronin, K and Cole, A and Johnson, KM and Rivera-Rivera, LA and Beckman, E and Eierman, AC and Wilson, RE and Chappell, RJ and Asthana, S and Gleason, CE and Zetterberg, H and Johnson, SC and Carlsson, CM},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109989},
doi = {10.1002/alz70862_109989},
pmid = {41433458},
issn = {1552-5279},
mesh = {Humans ; Male ; Aged ; *Alzheimer Disease/diagnostic imaging/drug therapy/genetics ; Middle Aged ; Female ; Magnetic Resonance Imaging ; Double-Blind Method ; Veterans ; *Brain/diagnostic imaging/drug effects ; *Eicosapentaenoic Acid/analogs & derivatives/therapeutic use ; Biomarkers/cerebrospinal fluid ; Apolipoproteins E/genetics ; Cerebrovascular Circulation/drug effects ; Genotype ; },
abstract = {BACKGROUND: Veterans are more likely to develop vascular disease and Alzheimer's disease (AD) than non-veterans. Icosapent ethyl (IPE), a form of the omega-3 fatty acid eicosapentaenoic acid, reduces risk for major adverse cardiovascular events and lowers triglycerides. Improvement in vascular health may also reduce the risk of developing AD. 4D flow MRI, using PCVIPR (phase contrast vastly undersampled isotropic projection), offers direct study of blood flow and arterial stiffness in the brain. PCVIPR imaging may help uncover the effects of IPE on cerebrovascular health, and the relationship with APOE genotype and cerebrospinal fluid (CSF) biomarkers.

METHODS: The Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid (BRAVE-EPA) study enrolled VA-eligible, cognitively unimpaired Veterans, ages 50-75, at the Veteran's Hospital in Madison, Wisconsin. The study was a randomized, double-blind, placebo-controlled clinical trial of 4 g daily IPE (Vascepa®) treatment for 18 months. Participants had PCVIPR MRI, APOE genotyping and levels of CSF vascular health/inflammation biomarkers assayed with the NULISAseq CNS disease panel. PCVIPR imaging was completed on a 3T GE x750 scanner at baseline, month 9 and month 18. Image analysis was done with the Quantitative Velocity Tool in MATLAB. The PCVIPR measurements analyzed were mean blood flow (MF), pulsatility index (PI) and total cerebral blood flow (CBF; cervical internal carotid arteries + basilar artery). Interactions between variables were assessed with a Mann-Whitney U test and using correlation analysis.

RESULTS: IPE treatment for 18 months did not significantly change MF, PI, or CBF measures (IPE: n = 41, placebo: n = 44; MF p-value range: 0.064-0.93; PI p-value range: 0.061-0.94; CBF p-value: 0.33). APOE ε4 carriers (n = 28) and non-carriers (n = 89) had similar baseline blood flow (MF p-value range: 0.16-0.92; PI p-value range: 0.055-0.98). In the full sample (n = 123), baseline CSF levels of vascular biomarkers were significantly correlated with baseline PI (p-value range: <0.0001-0.99; Figure 2). In contrast, few CSF vascular biomarkers were significantly correlated with MF (p-value range: 0.032-0.96; Figure 1).

CONCLUSION: IPE treatment did not significantly impact PCVIPR measures of cerebral blood flow. Baseline vascular CSF biomarker levels, but not APOE ε4 carrier status, significantly correlated with baseline PCVIPR measures of PI and to a lesser extent MF.},
}

Humans
Male
Aged
*Alzheimer Disease/diagnostic imaging/drug therapy/genetics
Middle Aged
Female
Magnetic Resonance Imaging
Double-Blind Method
Veterans
*Brain/diagnostic imaging/drug effects
*Eicosapentaenoic Acid/analogs & derivatives/therapeutic use
Biomarkers/cerebrospinal fluid
Apolipoproteins E/genetics
Cerebrovascular Circulation/drug effects
Genotype

@article {pmid41433446,
year = {2025},
author = {Yang, Q and Elyan, R and Pang, R and Kanekar, S and Will, J and Kalra, D and Eslinger, P and Karunanayaka, P and Wang, J},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109732},
doi = {10.1002/alz70862_109732},
pmid = {41433446},
issn = {1552-5279},
mesh = {Humans ; *Magnetic Resonance Imaging/methods ; Male ; Female ; Aged ; *Alzheimer Disease/diagnostic imaging/pathology ; Positron-Emission Tomography ; *Brain/diagnostic imaging/pathology ; *Cognitive Dysfunction/diagnostic imaging/pathology ; *Plaque, Amyloid/diagnostic imaging/pathology ; Amyloid beta-Peptides/metabolism ; Middle Aged ; },
abstract = {BACKGROUND: Diagnosis and treatment of AD relies on imaging of beta amyloid (Aβ) plaques in the brain using PET with radiotracer injection, and brain structural changes using MRI-two imaging modalities with extremely high costs. We have demonstrated that Aβ-plaques can be seen with MRI in high spatial resolution images in brain histological samples using a high field (7T and above), and with long acquisition times (7+ hours), which is too long for clinical human imaging studies. To address this technological challenge, we explored the feasibility of an MRI method (multiple-echo frequency-domain image contrast (MEFIC), which could improve signal-noise-ratio for high spatial resolution while optimizing T2* contrast, to image Aβ-plaques in living human brains at 3T.

METHOD: Eighteen mild cognitive impaired (MCI) and twelve normal (CN) subjects took part in the study. MEFIC images were acquired on a Siemens Prisma-Fit 3T scanner with a 64-channel head coil in a resolution of 0.4 x 0.4 x 0.7 mm[3] and scan time of 12:49. Aβ-PET scan was conducted on a Siemens Biograph mCT 20 PET/CT scanner with Florbetapir. Clinica software was used to calculate the standardized uptake value ratio (SUVr) with SUVr ≥ 1.11 as positive. PET and MEFIC images were co-registered in the patients' native space with SPM12.

RESULT: Figures 1-2 show evident correspondence between MRI-Aβ map (MEFIC) and the PET-Aβ (SUVr) map from one Aβ+ (MCI) and one Aβ- (CN) subjects. The prominent contrast between gray matter (GM) and white matter (WM) in the Aβ- subject was diminished in the Aβ+ subject mainly due to the Aβ load in the GM. MEFIC imaging provides a greater (10x) T2* contrast to noise ratio over conventional T2* imaging, which allows for high spatial resolution in-vivo brain imaging at 3T. There was a significant negative correlation between the Aβ-PET SUVr value and MEFIC signal in cortical GM (Figure 3).

CONCLUSION: We have shown that Aβ-plaque can be detected in T2* MRI images with MEFIC in the human brain at 3T. We have confirmed that MRI T2* in GM negatively correlates to SUVr of Aβ PET.},
}

Humans
*Magnetic Resonance Imaging/methods
Male
Female
Aged
*Alzheimer Disease/diagnostic imaging/pathology
Positron-Emission Tomography
*Brain/diagnostic imaging/pathology
*Cognitive Dysfunction/diagnostic imaging/pathology
*Plaque, Amyloid/diagnostic imaging/pathology
Amyloid beta-Peptides/metabolism
Middle Aged

@article {pmid41433433,
year = {2025},
author = {Sandell, R and Torok, J and Nagaragan, S and Ranasinghe, KG and Ma, D and Raj, A},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109738},
doi = {10.1002/alz70862_109738},
pmid = {41433433},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; Positron-Emission Tomography ; Male ; *tau Proteins/metabolism ; Female ; Aged ; *Brain/diagnostic imaging/metabolism/pathology ; Disease Progression ; Longitudinal Studies ; Cross-Sectional Studies ; Biomarkers ; Aged, 80 and over ; Cognitive Dysfunction/diagnostic imaging ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) affects 55 million people worldwide, with tau protein accumulation following distinct progression patterns. While tau traditionally follows Braak staging, in vivo tau-PET imaging reveals significant individual variability. Current modeling approaches either lack biophysical basis (statistical Event Based Models - EBMs) or require unavailable longitudinal data (biophysical Network Diffusion Models - NDMs).

METHOD: We developed a hybrid approach integrating EBMs and NDMs to create predictive individualized models of tau spread. We first applied an EBM to assign disease severity stages to 650 ADNI subjects (64 AD, 196 MCI, 390 controls) based on cross-sectional biomarker data, producing longitudinal biomarker trajectories from the diverse cohort. We then deployed an extended NDM (eNDM), which models pathological protein spread as a diffusive process on the brain's anatomical network. We fitted the model to the EBM-derived population-level trajectories and then to individuals' tau patterns by optimizing both tau's origin, or seed, and kinetic rate parameters controlling network-based spread and regional accumulation.

RESULTS: Individual seed optimization provided a better fit to subjects' empirical data (mean R=0.85, AIC=9,032) than individual parameter optimization (mean R=0.57, AIC=33,166) and benchmarks from prior studies (mean R=0.36-0.50). Model predictions were validated by a strong correlation to longitudinal data from 297 subjects with follow-up tau-PET scans (mean R=0.81). Analysis revealed that tau patterns show highest heterogeneity at disease onset and converge over time across subjects, challenging conventional assumptions of progressive divergence. Through covariance analysis and clustering, two distinct seeding archetypes were identified: entorhinal-dominant (typical AD) and diffuse temporal lobe patterns, suggesting multiple pathways of disease initiation.

CONCLUSION: Our hybrid modeling approach enables individual-level prediction of tau spread patterns from cross-sectional data, outperforming previous attempts. Integrating EBMs and NDMs leverages the strengths and tackles the limitations of each technique: EBMs provide longitudinal information, while NDMs generate a biophysical basis for pathology progression. Our findings suggest AD encompasses more diverse tau spread patterns than classical Braak staging, with heterogeneity stemming from distinct seeding sites that converge over time. This framework could guide personalized therapeutic strategies and be applied to other neurodegenerative diseases, potentially improving early diagnosis and treatment selection.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
Positron-Emission Tomography
Male
*tau Proteins/metabolism
Female
Aged
*Brain/diagnostic imaging/metabolism/pathology
Disease Progression
Longitudinal Studies
Cross-Sectional Studies
Biomarkers
Aged, 80 and over
Cognitive Dysfunction/diagnostic imaging

@article {pmid41433404,
year = {2025},
author = {Tazwar, M and Evia, AM and Ridwan, AR and Bennett, DAA and Schneider, JA and Arfanakis, K},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109757},
doi = {10.1002/alz70862_109757},
pmid = {41433404},
issn = {1552-5279},
mesh = {Humans ; Male ; *Magnetic Resonance Imaging ; Female ; Aged ; *Brain/pathology/diagnostic imaging ; *Alzheimer Disease/pathology/diagnostic imaging ; Aged, 80 and over ; Longitudinal Studies ; Cohort Studies ; *TDP-43 Proteinopathies/pathology/diagnostic imaging ; },
abstract = {BACKGROUND: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common pathologic finding in aged brain, however, definitive diagnosis of this disease is only possible at autopsy. This work aimed to develop a marker of LATE-NC based on in-vivo MRI features from a large group of community-based older adults.

METHOD: This study included ex-vivo MRI, in-vivo MRI, and pathology data from four longitudinal clinicopathological cohort studies of aging conducted at the Rush Alzheimer's Disease Center (ROS, Rush MAP, MARS, LATC). LATE-NC was evaluated based on pathologic TDP-43 inclusions in 8 brain regions and categorized into 4 stages (Figure 1). MRI data was processed to obtain fractional anisotropy (FA), deformation-based morphometry (DBM) measurements, and lobar volumes. To develop a marker of LATE-NC, we first trained a classifier to distinguish between advanced (stages 2-3) and early LATE-NC stages (stages 0-1) based on ex-vivo MRI features (N = 863). Our classifier used a two-level stacking model for training and cross-validation, where level-1 estimators generated risk scores based on single-modality features, and level-2 estimator (logistic regression) provided the final LATE-NC prediction score based on the combined risk scores. We then translated the classifier to in-vivo and validated it on a separate set of participants (N = 60) with in-vivo MRI and pathology data. The entire pipeline was packaged into an automated software container named MARBLE (MARker of Brain LatE).

RESULT: In the training group, the ex-vivo classifier demonstrated excellent performance, achieving an average AUC of 0.85±0.05 (sensitivity=78%, specificity=76%, balanced accuracy=77%) based on FA, DBM, and lobar volume features (Figure 2). In-vivo validation of MARBLE scores yielded an overall AUC of 0.76 in the test group. Additionally, ordinary least-squares regression revealed higher MARBLE scores with greater LATE-NC stages (p <0.001), controlling for antemortem interval (AMI) and scanners (Figure 3).

CONCLUSION: This study developed MARBLE, a novel, automated, in-vivo marker of LATE-NC based on MRI features. MARBLE was trained on ex-vivo MRI and pathology data from a large number of community-based older adults and showed decent performance in-vivo (AUC=0.76). While further validation is needed in independent cohorts, MARBLE has the potential to significantly contribute towards in-vivo diagnosis, monitoring, prevention, and treatment of LATE-NC.},
}

Humans
Male
*Magnetic Resonance Imaging
Female
Aged
*Brain/pathology/diagnostic imaging
*Alzheimer Disease/pathology/diagnostic imaging
Aged, 80 and over
Longitudinal Studies
Cohort Studies
*TDP-43 Proteinopathies/pathology/diagnostic imaging