@article {pmid42142451,
year = {2026},
author = {Razavi, A and Hou, J and Lin, SJ and Zhang, C and Kremen, WS and Fennema-Notestine, C and Elman, J and Holmans, P and Faraone, SV and Gaiteri, C and Hess, JL and Glatt, SJ},
title = {Predicted brain-regional gene expression patterns in individuals living with Alzheimer's disease.},
journal = {Neurobiology of aging},
volume = {166},
number = {},
pages = {29-40},
doi = {10.1016/j.neurobiolaging.2026.04.006},
pmid = {42142451},
issn = {1558-1497},
abstract = {Studying brain gene expression in Alzheimer's Disease (AD) remains difficult as postmortem brain is difficult to access, cannot be used to guide donor treatment, may be confounded by environmental factors before and after death, and is difficult to link to early AD states or disease progression. To circumvent these limitations, several studies have tested blood transcriptome biomarkers for AD. However, gene-expression levels in the blood have limited correlation with those in the brain. To evaluate the potential of monitoring Alzheimer's progression with peripheral data, we used transcriptome-imputation to identify brain-region-specific AD-associated gene-expression differences in cohorts with blood-based transcriptome data. This approach provides a high-resolution image of AD-associated molecular differences in the brains of individuals actively living with disease. We analyzed eight AD studies (777 AD cases, 779 cognitively unimpaired controls), imputing transcriptomes in 10 brain regions via the Brain Gene Expression and Network Imputation Engine (BrainGENIE). Hundreds of differentially expressed genes (DEGs) associated with AD were identified in nine brain regions, with anterior cingulate cortex and amygdala showing the most differential expression. AD-associated genes were enriched in pathways such as proteostasis, mitochondrial dysfunction, and immune activation. We observed significant yet moderate concordance between imputed AD-associated changes and those directly measured in the dorsolateral prefrontal cortex and cerebellum. These transcriptomic changes can guide future in vitro studies focused on pathogenesis or be targets of novel therapeutic development. In conclusion, we demonstrated the scope and utility of brain expression imputation from the peripheral transcriptome, laying the groundwork for biomarker discovery and prospective AD studies.},
}

@article {pmid42142504,
year = {2026},
author = {Abd-Eldayem, AM and Mohammed, RA},
title = {Riluzole in neuroinflammation and neurodegeneration: Mechanistic insights and experimental validation.},
journal = {Current opinion in pharmacology},
volume = {88},
number = {},
pages = {102632},
doi = {10.1016/j.coph.2026.102632},
pmid = {42142504},
issn = {1471-4973},
abstract = {Neuroinflammation and neurodegeneration are tightly interconnected processes that drive the progression of multiple central nervous system (CNS) disorders. Riluzole, a benzothiazole derivative approved for amyotrophic lateral sclerosis (ALS), has been widely investigated for its broader neuroprotective potential. Its actions include modulation of glutamatergic transmission through presynaptic inhibition and upregulation of excitatory amino acid transporters. Additionally, Riluzole inhibits voltage-gated sodium channels, thereby reducing neuronal hyperexcitability and excitotoxicity. Its anti-inflammatory properties are mediated through the suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and the attenuation of microglial activation, while its antioxidant effects involve the activation of the nuclear factor erythroid 2-related factor 2/heme Oxygenase-1 (Nrf2/HO-1) pathway and the preservation of mitochondrial function. These mechanisms have been supported by preclinical evidence across models of ALS, Alzheimer's disease (AD), Huntington's disease (HD), and spinal cord injury (SCI), with emerging clinical data supporting its broader therapeutic relevance. Although clinical findings remain limited and disease-specific, the mechanistic breadth of Riluzole continues to motivate interest in its potential utility across neuroinflammatory and neurodegenerative conditions. This review synthesizes recent advances in Riluzole pharmacology and outlines key considerations for future mechanistic and translational research.},
}

@article {pmid42142537,
year = {2026},
author = {Saido, TC},
title = {Animal models of Alzheimer's disease and related disorders.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {105069},
doi = {10.1016/j.neures.2026.105069},
pmid = {42142537},
issn = {1872-8111},
}

@article {pmid42142562,
year = {2026},
author = {Keramat, SA and Dao-Tran, TH and Nguyen, KH and Welch, A and Comans, T},
title = {Assessing the agreement between self- and proxy-reported responses for measuring health-related quality of life in people with dementia using the Alzheimer's Disease Five Dimensions instrument.},
journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jval.2026.04.011},
pmid = {42142562},
issn = {1524-4733},
abstract = {BACKGROUND: The level of agreement between utility values derived from self- and proxy-reports, assessed using the preference-based health-related quality of life (HRQoL) instrument, the Alzheimer's Disease Five Dimensions (AD-5D), remains unclear. We aimed to investigate the agreement between self- and proxy-reported HRQoL, measured using the AD-5D, a dementia-specific, preference-based HRQoL instrument.

METHODS: The data comprise 77 Australian dyads of people with dementia and their caregivers. The agreement between AD-5D utility values derived from self- and proxy-reports was analysed using a Bland-Altman plot. The ordinary least squares regression technique was employed to identify factors associated with the AD-5D utility value sets and to assess agreement between the resulting AD-5D utility values derived from self- and proxy-reports.

RESULTS: The mean AD-5D utility value derived from self-reports (0.667) was higher than the value derived from proxy-reports (0.523). The Bland-Altman plot shows that 7.79% of the differences in AD-5D utility values fell outside the limits of agreement. The regression results indicated that the AD-5D utility value derived from self-reports for people with dementia aged 80 years or older was, on average, 0.20 points lower (β = 0.20, SE = 0.10) than that for people with dementia aged less than 70 years.

CONCLUSION: Utility values derived from self-reports were higher than those derived from caregiver proxy-reports. While proxy reporting is a necessary alternative when self-reporting is not feasible, these perspectives are not interchangeable. Future economic evaluations should incorporate sensitivity analyses to account for this systematic 'proxy-gap'.},
}

@article {pmid42142620,
year = {2026},
author = {Shang, X and Chen, SY and Zhang, XY and Regina, I and Zhang, T and Luo, J and Yan, YZ and Qiao-yuanYao, and Tong, F and Pan, LH},
title = {Insulin in brain: The physiological functions and therapeutic insights for neurodegenerative diseases.},
journal = {Life sciences},
volume = {398},
number = {},
pages = {124468},
doi = {10.1016/j.lfs.2026.124468},
pmid = {42142620},
issn = {1879-0631},
abstract = {This review highlight the function of insulin in the central nervous system in addition to its role in the periphery. The cerebral distribution and mechanisms of insulin and its receptor isoforms are reviewed in detail. We emphasize the essential roles of insulin in the maintenance of cerebral glucose homeostasis, modulation of cognitive performance, regulation of appetite, promotion of cerebrovascular angiogenesis, and exertion of neuroprotective effects. We demonstrate how insulin resistance exacerbates characteristic neuropathological features in Alzheimer's disease (AD) and Parkinson's disease (PD), while insulin-based interventions ameliorate these pathologies through multiple mechanisms including increasing the activity of insulin-degrading enzyme, suppressing Aβ neurotoxicity, and reducing α-synuclein deposition. The review also systematically examines the neuroprotective effects of insulin sensitizers and their potential to reduce the risk of AD, while noting the complexity of their bidirectional regulatory role in PD, which warrants further investigation. Notably, intranasal insulin administration emerges as a promising non-invasive therapeutic approach that bypasses the blood-brain barrier via olfactory and trigeminal pathways, suggesting significant potential for cognitive enhancement and neuropathological mitigation. Nonetheless, it must be noted that the optimal dosage, long-term safety, and sustained efficacy of insulin therapy remain unclear, and the current evidence is derived primarily from preclinical studies or small-scale clinical trials. In summary, this review paper underscores the critical physiological roles of insulin in the brain and outlines novel therapeutic strategies for using insulin in the treatment of AD and PD.},
}

@article {pmid42142765,
year = {2026},
author = {Feng, Y and Zhang, C and Wei, Y and Liu, E and Sun, H and Flatt, P and Gault, V and Irwin, N and Hölscher, C and Hao, L and Zhang, Z},
title = {A novel bifunctional peptide predicted to target neuropeptide Y4 and GLP-1 receptors alleviates cognitive deficits in 5 × FAD mice by modulating cGAS-STING-mediated neuroinflammation.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118074},
doi = {10.1016/j.bcp.2026.118074},
pmid = {42142765},
issn = {1873-2968},
abstract = {Effective disease-modifying therapies for Alzheimer's disease (AD) remain limited. Glucagon-like peptide-1 receptor (GLP-1R) activation has shown neuroprotective potential in AD, whereas the neuropeptide Y/pancreatic polypeptide-Y4 receptor (NPY/PP-Y4R) axis has been implicated in central homeostasis and inflammatory regulation, although its role in AD remains insufficiently defined. Here, we evaluated a rationally designed bifunctional peptide predicted to target both NPY4R and GLP-1R in 5 × FAD mice and LPS-stimulated BV2 cells. In vivo, NPY4/GLP-1 improved spatial learning and memory, working memory, and exploratory behavior, and was accompanied by reduced hippocampal Aβ burden (P < 0.05), alleviated neuronal injury (P < 0.01), improved synaptic integrity (P < 0.01), and attenuated mitochondrial abnormalities (P < 0.01). These changes were associated with lower hippocampal levels of cytosolic mitochondrial DNA (mtDNA) (P < 0.05), cGAS (P < 0.05), STING (P < 0.05), and phosphorylated IRF3 (P < 0.01), together with decreased IL-1β (P < 0.05) and increased IL-10 (P < 0.05) expression. In LPS-stimulated BV2 cells, NPY4/GLP-1 similarly reduced STING-related signaling (P < 0.05) and inflammatory responses (P < 0.05). Co-treatment with the STING inhibitor C-176 provided additional support for the involvement of STING-associated inflammatory signaling under in vitro inflammatory conditions. Molecular docking suggested that NPY4/GLP-1 may interact with both NPY4R and GLP-1R, providing a structural rationale for its bifunctional design. Collectively, these findings indicate that NPY4/GLP-1 exerts beneficial effects in AD-related models and that these effects are associated with attenuation of mtDNA-cGAS-STING-related neuroinflammatory signaling. This study provides initial evidence supporting further evaluation of this novel bifunctional peptide as a candidate therapeutic strategy for AD.},
}

@article {pmid42143322,
year = {2026},
author = {Gröbner, LS and Pietrzik, CU},
title = {Transport pathways across the blood-brain barrier for waste clearance and drug delivery.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00812-7},
pmid = {42143322},
issn = {2045-8118},
abstract = {The blood-brain barrier (BBB) displays a highly organized and complex structure, which is important for maintaining brain homeostasis and protecting the brain from foreign molecules or pathogens. Receptor-mediated transcytosis (RMT) is one of the main delivery pathways across the BBB for molecules that cannot pass the barrier via, e.g. paracellular diffusion. For understanding the treatment options in neurodegenerative diseases such as Alzheimer´s disease (AD), it is important to investigate transport pathways and mechanisms at the BBB for a potential delivery of drugs, antibodies or other compounds across the BBB. This review provides an overview of the different transport variants across the BBB and how they can be targeted in order to promote internalization or secretion into or out of the brain. Therefore, we want to focus on two characterized proteins: the low-density lipoprotein receptor-related protein 1 (LRP1), which is a key mediator of amyloid β (Aβ) clearance from the brain during AD, and transferrin receptor 1 (TfR1), which is already used as a target for antibody-delivery into the brain. Additionally, this review discusses two other important proteins, which have been less frequently addressed in research regarding transport mechanisms: P-glycoprotein (P-gp) as another transporter at the BBB and proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-known regulator of cholesterol homeostasis which promotes the degradation of the low-density lipoprotein receptor (LDLR) and LRP1. For these four main proteins, we aim to highlight existing approaches for targeting or inhibiting the aforementioned receptors or proteins. The approaches enable a higher penetration of the BBB, a better distribution in the brain, and ultimately fewer side effects of antibodies or nanoparticles. Here, we include lecanemab, trontinemab, dual TfR/CD98hc shuttles, evolocumab and alirocumab, immunoliposomes and other nanoparticles targeting TfR1 or LRP1. We will further highlight approaches which differ from these common ideas and demonstrate the current state of the art regarding drug delivery and waste clearance across the BBB.},
}

@article {pmid42143738,
year = {2026},
author = {Budrovic, K and Gunstad, J and Hamrick, P},
title = {Formulaic and novel language dissociate in Alzheimer's clinical syndrome: evidence for the Dual-Process Model.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/13803395.2026.2674224},
pmid = {42143738},
issn = {1744-411X},
abstract = {INTRODUCTION: Spontaneous speech is commonly disrupted in persons with Alzheimer's disease (AD) and/or Alzheimer's clinical syndrome (ACS). Importantly, different aspects of speech (e.g. formulaic versus more novel or flexible speech) place different demands on distinct cognitive systems. Formulaic language may rely on automatized procedural processes, while more novel or diverse speech requires more flexible lexical-semantic processes associated with the subsystems of declarative memory. Given that AD/ACS are associated with impaired declarative processes and relatively spared procedural processes, we predicted that individuals with ACS may show increased reliance on formulaic language along with reduced diversity in speech.

METHOD: We analyzed the spontaneous speech of 81 individuals with ACS (aged 56-88) and 61 healthy controls (aged 47-80) who completed a picture description task using computational tools for the analysis of formulaic language (operationalized as proportion of frequent trigrams produced and mutual information score of trigrams) and novel language (operationalized as root type-token ratio, measure of textual lexical diversity, and semantic diversity).

RESULTS: Across all measures, individuals with ACS produced significantly more formulaic language than control participants and significantly less novel language than control participants, with small-to-medium overall model effect sizes. Machine learning classifiers trained on these patterns of formulaic and novel language distinguished between controls and individuals with ACS with reasonable accuracy, sensitivity, and specificity.

CONCLUSION: The spontaneous speech of individuals with ACS contains more formulaic language and less novel language than that of healthy controls, consistent with the Dual-Process Model. These differences may have clinical relevance and warrant further investigation. Keywords: Alzheimer's Disease, Alzheimer's clinical syndrome, formulaic language, lexical diversity, spontaneous speech.},
}

@article {pmid42144109,
year = {2026},
author = {Loukil, I and Vachon, A and Çaku, A and Plourde, M},
title = {Krill oil increase plasma omega-3 fatty acids more than fish oil in healthy adults: a double blind randomized controlled trial.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101346},
doi = {10.1016/j.ajcnut.2026.101346},
pmid = {42144109},
issn = {1938-3207},
abstract = {BACKGROUND: Omega-3 fatty acids (ω-3 FAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are recognized for their health benefits. However, their circulating levels after supplementation may be modulated by several factors, including sex, carriage of the apolipoprotein E4 allele (APOE4), and the chemical form of the supplement. Krill-oil delivers ω-3 FAs primarily as phospholipids (PL), whereas fish oil provides them as triglycerides (TG).

OBJECTIVE: To compare EPA and DHA concentrations after a supplementation with krill oil and fish oil and assess whether sex and APOE4 genotype modifies responses to supplementation.

METHODS: This double-blind, randomized clinical trial included 72 healthy adults (53 females, 19 males) matched for age and body mass index (BMI). Participants received 1.1 g/day ω-3 FAs through either krill oil (n=36) or fish oil (n=36) for 12 weeks. Plasma fatty acids were measured at baseline and at weeks 1, 2, 4, and 12 by gas chromatography-flame ionization detection. Differences in plasma ω-3 FAs concentrations by treatment, sex and APOE4 status, were analyzed.

RESULTS: Time-by-treatment interactions were significant for plasma delta over baseline concentrations of EPA (p = 0.0001) and DHA (p = 0.005), with krill oil resulting in ∼ 1.5-fold higher ΔEPA and ΔDHA compared to fish oil. The time-by-sex interaction was significant only for EPA (p = 0.026), with females having 1.5-fold greater increase than males at 12 weeks. Following supplementation with either krill oil or fish oil, APOE4 carriers had 3-fold and 1.6-fold higher EPA and DHA respectively, compared to baseline; however, these increases were not significantly different from those found in non-carriers.

CONCLUSIONS: Krill oil increased plasma ω-3 FAs more than fish oil, regardless of APOE4 genotype. Individuals with higher ω-3 FA requirements may achieve adequate enrichment with lower doses of krill oil compared to fish oil supplementation.

REGISTRATION NUMBER: NCT04279743. In https://clinicaltrials.gov.},
}

@article {pmid42144116,
year = {2026},
author = {Qiang, Q and Skudder-Hill, L and Toyota, T and Huang, Z and Wei, W and Adachi, H},
title = {Combination of CSF α-synuclein seed amplification assay and amyloid-β42 predicts cognitive decline in Parkinson's disease.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107452},
doi = {10.1016/j.nbd.2026.107452},
pmid = {42144116},
issn = {1095-953X},
abstract = {Cognitive impairment is a disabling non-motor feature of Parkinson's disease (PD). Cerebrospinal fluid (CSF) α-synuclein seed amplification assay (SAA) reflects Lewy body pathology, while reduced CSF amyloid-β42 (Aβ42) indicates Alzheimer's type co-pathology in PD. This study examined whether combined CSF α-synuclein SAA and Aβ42 status improves prediction of cognitive decline and dementia risk in PD. A total of 692 participants (145 controls and 547 individuals with PD) from the Parkinson's Progression Markers Initiative with available CSF α-synuclein SAA and Aβ42 measurements were included. Participants were classified into four biomarker-defined groups based on α-synuclein/amyloid (S/A) status: S - A- (n = 140), S - A+ (n = 67), S + A- (n = 307), and S + A+ (n = 178). At baseline, α-synuclein SAA positivity was highly prevalent in PD (87.2%). APOE ε4 carrier frequency differed significantly across groups (p < 0.001), with the highest prevalence in S - A+ (50.8%) and S + A+ (33.7%). The S + A+ group exhibited the lowest baseline cognitive scores, with intermediate deficits in S + A-. Longitudinally, S + A+ participants showed the steepest cognitive decline (p < 0.001), whereas the S + A- and S - A+ groups demonstrated more modest but significant declines. In multivariable Cox regression, each one-category increase in S/A status was associated with a higher hazard of dementia (HR = 2.72, 95% CI 1.80-4.08, p < 0.001). Combined CSF α-synuclein and Aβ42 stratification identifies subgroups at high risk for accelerated cognitive decline and dementia, offering a potential strategy to improve prognostic precision and clinical trial design in PD.},
}

@article {pmid42144205,
year = {2026},
author = {Ma, J and Yang, B and Jiang, X and Wang, L and Wei, W and Cao, Y and Li, H},
title = {Microglial senescence and epigenetic reprogramming in alzheimer's disease: An immunometabolic perspective.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {113177},
doi = {10.1016/j.exger.2026.113177},
pmid = {42144205},
issn = {1873-6815},
abstract = {Microglial senescence has emerged as a potentially important aging-related mechanism in Alzheimer's disease (AD), shaped in part by epigenetic reprogramming and closely coupled to immunometabolic dysfunction. While microglia initially mount adaptive responses to amyloid-beta (Aβ), tau, and tissue stress, persistent exposure to chronic neurodegenerative cues may drive subsets of microglia toward senescence-like states characterized by altered chromatin regulation, transcriptional remodeling, stable cell-cycle arrest, and a sustained senescence-associated secretory phenotype (SASP). These changes are accompanied by impaired phagocytosis, lysosomal and autophagic dysfunction, mitochondrial stress, and disrupted lipid handling, collectively weakening homeostatic surveillance and promoting a neurotoxic microenvironment. In turn, senescence-associated microglial dysfunction may contribute to amyloid and tau pathology, synaptic injury, neurovascular unit impairment, and chronic neuroinflammation across the AD continuum. In this review, we synthesize current evidence on the phenotypic and molecular features of senescent microglia, with particular emphasis on epigenetic and transcriptional reprogramming as an organizing framework linking aging, immune dysregulation, and metabolic vulnerability. We further discuss how senescent microglia relate to other disease-associated microglial states, and we highlight unresolved questions regarding causality, biomarker specificity, and the distinction between chronic activation and true senescence in human AD. Finally, we evaluate emerging therapeutic approaches-including senolytic strategies, microglial depletion-repopulation paradigms, and metabolic or epigenetic interventions-and discuss their opportunities, limitations, and translational challenges. Together, this perspective positions microglial senescence not as an isolated driver, but as a biologically relevant and potentially targetable component of the aging neuroimmune landscape in AD.},
}

@article {pmid42144627,
year = {2026},
author = {Bufi, AA and Papait, A and Ponsaerts, P and Silini, AR and Parolini, O},
title = {Mesenchymal stromal cells and neuroinflammation: a multimodal approach to neuroprotection and future therapeutic horizons.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42144627},
issn = {2047-9158},
support = {(Linea D1 OP)//Università Cattolica del Sacro Cuore/ ; 5x1000//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; },
mesh = {Humans ; *Mesenchymal Stem Cells ; *Mesenchymal Stem Cell Transplantation/methods/trends ; Animals ; *Neuroinflammatory Diseases/therapy/immunology ; *Neuroprotection/physiology ; *Neurodegenerative Diseases/therapy ; },
abstract = {As the global population ages, neurodegenerative and neuroinflammatory diseases are becoming a rapidly growing public health challenge, with available interventions remaining largely symptomatic and often only modestly affecting long-term disease progression. Therapies involving mesenchymal stromal cells (MSCs) have attracted substantial attention as a potential clinical therapeutic strategy across chronic central nervous system (CNS) disorders, due to their multifaceted ability to modulate immune response and confer neuroprotection. While initially explored for their multilineage differentiation potential, MSCs are now predominantly recognized for their paracrine functions, including secretion of soluble factors and extracellular vesicles. These acellular mediators induce diverse neuroprotective effects by attenuating neuroinflammation, stabilizing the blood-brain barrier, reprogramming glial and lymphocyte activity, and delivering regulatory microRNAs that modulate neuronal apoptosis and inflammatory gene networks. In this review, we summarize molecular evidence from in vitro and in vivo preclinical models, and early clinical investigations that demonstrate how tissue source and immunobiological plasticity shape the efficacy of MSCs. We further highlight emerging trends toward acellular MSC-derived therapies, offering a mechanistically versatile platform for therapeutic interventions for common neurodegenerative and neuroinflammatory disorders of the CNS, particularly Alzheimer's disease, Parkinson's disease and multiple sclerosis, a primary autoimmune demyelinating disorder.},
}

Humans
*Mesenchymal Stem Cells
*Mesenchymal Stem Cell Transplantation/methods/trends
Animals
*Neuroinflammatory Diseases/therapy/immunology
*Neuroprotection/physiology
*Neurodegenerative Diseases/therapy

@article {pmid42144687,
year = {2026},
author = {Zhao, Q and Yu, Y and Wang, F and Wang, Y and Shao, P and Zhao, L},
title = {TARDBP Mediates the MAP3K11/SLC3A2/GPX4 Axis in Alzheimer's Disease Rats by Enhancing KRAS mRNA Stability.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {10},
pages = {e71181},
doi = {10.1111/jcmm.71181},
pmid = {42144687},
issn = {1582-4934},
support = {HAB202113//Huai'an Natural Science Research Program/ ; },
mesh = {Animals ; Rats ; *Alzheimer Disease/metabolism/genetics/pathology ; PC12 Cells ; *RNA Stability/genetics ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics ; *Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Male ; Hippocampus/metabolism/pathology ; Disease Models, Animal ; Ferroptosis/genetics ; Amyloid beta-Peptides ; Reactive Oxygen Species/metabolism ; Iron/metabolism ; RNA, Messenger/genetics/metabolism ; Rats, Sprague-Dawley ; Signal Transduction ; },
abstract = {Ferroptosis is an emerging pathological mechanism in Alzheimer's disease (AD). The aim of the present study was to investigate the potential mechanisms by which TARDBP is involved in AD by promoting ferroptosis. An AD rat model was established by injecting homocysteine (Hcy). Memory function was assessed using the Morris water maze test and contextual fear conditioning test. Hippocampal neurons' morphology was observed by HE staining, and intracellular iron deposition in the hippocampus was evaluated by Perls' blue staining. PC12 cells were treated with 20 μM Aβ1-42 to establish an AD cell model in vitro. Cell viability was measured by MTT assay; LDH release, intracellular ROS levels and Fe[2+] concentrations were determined. The mRNA stability of KRAS was assessed by actinomycin D assay. Activation of the MAP3K11/SLC3A2/GPX4 pathway was assessed by Western blot. Treatment with Fer-1 or down-regulation of TARDBP improved memory function and reduced intracellular iron deposition in the hippocampus of AD rats. Furthermore, these interventions inhibited Aβ1-42-induced PC12 cell damage, ROS production and iron accumulation. Mechanistically, down-regulating TARDBP reduced the mRNA stability of KRAS, inhibited MAP3K11 expression and subsequently promoted the expression of SLC3A2 and GPX4. Conversely, up-regulation of KRAS reversed the protective effects induced by TARDBP knockdown in both AD rats and Aβ1-42-induced PC12 cells. TARDBP promotes the development of AD by enhancing the mRNA stability of KRAS, thereby mediating the MAP3K11/SLC3A2/GPX4 axis to induce ferroptosis.},
}

Animals
Rats
*Alzheimer Disease/metabolism/genetics/pathology
PC12 Cells
*RNA Stability/genetics
*Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics
*Proto-Oncogene Proteins p21(ras)/genetics/metabolism
Male
Hippocampus/metabolism/pathology
Disease Models, Animal
Ferroptosis/genetics
Amyloid beta-Peptides
Reactive Oxygen Species/metabolism
Iron/metabolism
RNA, Messenger/genetics/metabolism
Rats, Sprague-Dawley
Signal Transduction

@article {pmid42145047,
year = {2026},
author = {Jung, J and Kim, Y and Cirunduzi, AC and Yoon, S and Bang, S and Yang, SH},
title = {Multi-Target-Directed Ligands (MTDLs) as Potential Therapeutic Candidates Targeting Multiple Pathogenic Factor of Alzheimer's Disease.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {5},
pages = {e70919},
doi = {10.1002/cns.70919},
pmid = {42145047},
issn = {1755-5949},
support = {RS-2026-25481528//The National Research Foundation of Korea/ ; RS-2024-00350442//The National Research Foundation of Korea/ ; RS-2024-00411952//The National Research Foundation of Korea/ ; //Korea Environment Industry & Technology Institute (KEITI) through Technology Development Project for Safety Management of Household Chemical Products/ ; RS-2025-02223058//Korea Ministry of Environment (MOE)/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; Animals ; Ligands ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Molecular Targeted Therapy/methods ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia and a chronic neurodegenerative disorder in older adults. AD is not driven by a single factor but by the interaction of multiple pathological processes, including amyloid-β (Aβ) accumulation, tau hyperphosphorylation, and chronic neuroinflammation. Aβ aggregates into plaques that disrupt neuronal signaling, while hyperphosphorylated tau forms neurofibrillary tangles, leading to neuronal loss. These processes act synergistically to amplify toxicity. Persistent activation of microglia and astrocytes further promotes neuroinflammation, worsening Aβ and tau pathology.

CURRENT LIMITATIONS: Single-target therapies directed at Aβ or tau have shown limited clinical success and failed to alter disease progression, underscoring the complexity of AD.

OBJECTIVES: In response, multi-target-directed ligands (MTDLs) have emerged as a promising strategy. By simultaneously modulating several disease pathways, MTDLs can inhibit Aβ aggregation, reduce tau phosphorylation, and exert antioxidant and anti-inflammatory effects. This review summarizes recent progress on MTDLs, highlighting their mechanisms of action, representative drug candidates, and outcomes from preclinical and clinical studies.

CONCLUSIONS: Multi-target strategies have the potential to achieve more effective and disease-modifying outcomes than conventional approaches. A critical evaluation of their opportunities and challenges may guide future therapeutic development and the advancement of precision medicine for Alzheimer's disease.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology
Humans
Animals
Ligands
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Molecular Targeted Therapy/methods

@article {pmid42145109,
year = {2026},
author = {Saxena, P and Kothiyal, P and Ratan, P},
title = {Evaluation of neuroprotective effects of Pyracantha crenulata (D. Don) M. Roem against aluminium chloride induced memory impairment of rats.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/01616412.2026.2673060},
pmid = {42145109},
issn = {1743-1328},
abstract = {Pyracantha crenulata, traditionally used in Himalayan folk medicine, valued for enhancing vitality, mental clarity, and combating age-related cognitive decline due to its antioxidant constituents.

AIM: This study evaluated the neuroprotective effect of hydroalcoholic extract of P. crenulata against aluminium chloride (AlCl3)-induced Alzheimer's disease in rats.

MATERIALS AND METHODS: Alzheimer's pathology was induced using AlCl3, and rats were treated with P. crenulata extract (250 and 500 mg/kg) for 21 days. Cognitive and behavioural performance were assessed using the Morris Water Maze (MWM) and Elevated Plus Maze (EPM). Biochemical parameters, including oxidative stress markers (SOD), cholinesterase activity (AChE), and myeloperoxidase levels (MPO), were measured. Histopathological examination of the hippocampus and cerebral cortex was conducted.

RESULTS: Aluminium intoxication led to marked deficits in learning and memory, as evidenced by performance in the Morris Water Maze and Elevated Plus Maze tests. Treatment with P. crenulata extract significantly enhanced spatial and long-term memory in a dose-dependent manner, with the higher dose producing the most pronounced improvement.

CONCLUSION: The findings of this study highlight the notable neuroprotective effects of P. crenulata, demonstrated through modulation of biochemical parameters and suppression of amyloid precursor protein and Tau, key pathological hallmarks of Alzheimer's disease, further validated by histopathological evidence.},
}

@article {pmid42145110,
year = {2026},
author = {Wimo, A and Jönsson, L},
title = {[Health economic aspects of dementia].},
journal = {Lakartidningen},
volume = {123},
number = {},
pages = {},
pmid = {42145110},
issn = {1652-7518},
mesh = {Humans ; *Dementia/economics/diagnosis/epidemiology ; Sweden/epidemiology ; Cost-Benefit Analysis ; Health Care Costs ; Cost of Illness ; Quality of Life ; Alzheimer Disease/economics ; Life Expectancy ; },
abstract = {The societal costs of dementia in Sweden are very high: about SEK 90-100 billion per year. A purely demographic projection to 2050 gives a cost increase of about 80%. In addition to the costs, dementia also entails a loss of life expectancy for those with dementia and of quality of life for those affected and their relatives. At present, it is not possible to assess whether the antibody treatment against Alzheimer's disease is cost-effective in Sweden because no price is yet available. Blood-based biomarkers for Alzheimer's disease and other diagnostic methods, if included in the pricing basis for new drugs, can be a valuable addition to cost-effectiveness analyses.},
}

Humans
*Dementia/economics/diagnosis/epidemiology
Sweden/epidemiology
Cost-Benefit Analysis
Health Care Costs
Cost of Illness
Quality of Life
Alzheimer Disease/economics
Life Expectancy

@article {pmid42145180,
year = {2026},
author = {Zhang, Q and Li, W and Kundu, S and Long, Q},
title = {Knowledge-guided Bayesian biclustering model for omics data with noisy graphs.},
journal = {Biometrics},
volume = {82},
number = {2},
pages = {},
doi = {10.1093/biomtc/ujag070},
pmid = {42145180},
issn = {1541-0420},
support = {RF1AG063481/NH/NIH HHS/United States ; R01AG071174/NH/NIH HHS/United States ; },
mesh = {Bayes Theorem ; Humans ; *Models, Statistical ; Cluster Analysis ; Algorithms ; Computer Simulation ; Alzheimer Disease/genetics ; Data Interpretation, Statistical ; Gene Regulatory Networks ; Gene Expression Profiling ; Genomics/statistics & numerical data ; },
abstract = {Extracting biologically meaningful information from high-dimensional, heterogeneous omics data is one of the key challenges in many biomedical studies. Among various biomedical applications, disease subtyping is of particular interest due to its critical role in improving diagnosis and designing personalized treatments. To address this, biclustering has become a widely used statistical method for subtyping. Additionally, it has been demonstrated across various statistical learning methods that incorporating biological graph knowledge such as gene regulatory network can significantly enhance variable selection, prediction accuracy, and model interpretability. However, existing graph-guided methods, while often yielding promising results, tend to overlook potential misspecifications, such as false positive (FP) and false negative (FN) edges in the graphs. Ignoring this noise can lead to suboptimal identification of biclusters. Therefore, it is essential to develop biclustering methods that can effectively handle noisy graphs as well as provide biological insight. We propose a Bayesian denoising knowledge-guided biclustering method that enables to integrate multiple graphs simultaneously. The incorporated graphs, viewed as noisy variations of the underlying true graph, are de-noised through modeling of FP and FN errors. A Markov chain Monte Carlo algorithm is developed to estimate the biclusters. Extensive simulation studies and real data analyses, including gene expression and proteomics datasets of Alzheimer's disease, have been conducted to validate the superior performance of the proposed method.},
}

Bayes Theorem
Humans
*Models, Statistical
Cluster Analysis
Algorithms
Computer Simulation
Alzheimer Disease/genetics
Data Interpretation, Statistical
Gene Regulatory Networks
Gene Expression Profiling
Genomics/statistics & numerical data

@article {pmid42145345,
year = {2026},
author = {Prasad, S and Gupta, S and Omega Oraon, AP and Molina Recalde, AP and Cañarte Moreira, JJ and Moyano Salazar, GN and Torres Cañarte, PD and Racines Navas, CI},
title = {Blood - brain barrier breakdown and neurovascular unit failure in the progression of Alzheimer's disease.},
journal = {Bioinformation},
volume = {22},
number = {3},
pages = {1673-1678},
pmid = {42145345},
issn = {0973-2063},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder traditionally defined by amyloid-β deposition and tau pathology. Recent research highlights the role of blood-brain barrier (BBB) breakdown and neurovascular unit (NVU) dysfunction in disease initiation and progression. These factors contribute to neuroinflammation, cerebral hypoperfusion and impaired waste clearance. Despite this, the relationship between BBB integrity, NVU function and cognitive decline in AD remains inadequately understood. Data shows that blood-brain barrier disruption and neurovascular unit dysfunction are critical predictors of cognitive decline in Alzheimer's disease.},
}

@article {pmid42145602,
year = {2026},
author = {Clos-Garcia, M and Wretlind, A and Muk, T and Hooshmand, K and Simonsen, AH and Winchester, LM and Proitsi, P and Marioni, RE and Ahluwalia, TS and Kümler, T and Hasselbalch, SG and Legido-Quigley, C and , and , },
title = {Polyol pathway dysregulation in CSF links glucose metabolism to tau pathology independently of amyloid and genetic predisposition.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.06.26352559},
pmid = {42145602},
abstract = {Dementia affects approximately 60 million people worldwide, yet molecular mechanisms linking early neuropathological changes to clinical progression remain poorly understood. We performed targeted and untargeted metabolomics in plasma and cerebrospinal fluid (CSF) from 166 memory clinic patients spanning no cognitive impairment, mild cognitive impairment due to Alzheimer's disease (AD), AD dementia, and mixed AD-cerebrovascular dementia. Using a data-driven approach, we identified a CSF polyol signature characterized by elevated sorbitol, meso-erythritol, and d-glucose/erythritol ratio consistently associated with phosphorylated tau (pTau) and total tau (tTau), but not amyloid-β. This association was validated in an independent CSF metabolomics (n=687) and proteomics (n=737) cohorts. Structural equation modelling confirmed that polyol metabolites predict tau burden, with less than 3% attenuation following genetic adjustment, establishing a non-genetic, metabolically driven mechanism. These findings define a tau-dominant, amyloid-independent metabolic axis in neurodegeneration, implicating the polyol pathway as a potentially modifiable therapeutic target.},
}

@article {pmid42145614,
year = {2026},
author = {Morrison, C and Dadar, M and Zeighami, Y},
title = {Sex differentiated and domain specific patterns of longitudinal cognitive decline across subjective cognitive decline and amyloid positivity groups.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.06.26352563},
pmid = {42145614},
abstract = {BACKGROUND: Subjective cognitive decline (SCD) is associated with increased cognitive impairment and dementia. However, limited research has explored how amyloid (A) pathology contributes to these cognitive changes over time and whether these changes differ by sex.

METHODS: 1185 cognitively normal older adults (955 A-, 230 A+; 959 SCD-, 226 SCD+) from the National Alzheimer's Coordinating Center dataset were included. Linear mixed effects examined the interactions between SCD, sex, and amyloid positivity in predicting cognitive decline.

RESULTS: SCD+ and A+ individuals exhibited increased global cognition declines (p <.05), and A+SCD+ individuals showed the steepest decline in global cognition and function status (p <.05). A+ males exhibited increased functional deficits (p <.05), while A+SCD+ females exhibited increased language deficits (p <.05).

DISCUSSION: Our findings suggest that SCD and amyloid-positivity differentially impact global cognition, functional status, and language in males versus females, with important implications for clinical trials and therapeutic interventions.

HIGHLIGHTS: Few studies have explored the independent and joint effects of amyloid and sex in SCDSCD is associated with increased rates of global cognitive declineAmyloid positive females with SCD exhibit increased language declinesAmyloid positive males exhibit increased functional status declines.

RESEARCH IN CONTEXT: Systematic review: We reviewed the literature using traditional sources (e.g., PsycInfo, PubMed) and found that there are limited findings exploring longitudinal cognitive trajectories in people who are amyloid positive with SCD and whether these trajectories differ by sex.Interpretation: Our findings suggest that SCD and amyloid positivity jointly interact to influence global cognitive and functional declines. Females experience language deficits when they have both SCD and amyloid positivity whereas males with amyloid positivity exhibit increased functional deficits. Together these findings suggest that SCD status and amyloid positivity differentially impact females and males.Future directions: More research is needed using grouping amyloid, tau, neurodegeneration, and vascular pathologies together to explore the joint impact on cognitive change and conversion in people with SCD.},
}

@article {pmid42145619,
year = {2026},
author = {Sherva, R and Bayly, H and Zhang, R and Harrington, K and Mez, J and Miller, MW and Tsuang, D and Wolf, E and Zeng, Q and Le Guen, Y and Tejeda, M and , and , and , and Gaziano, JM and Panizzon, MS and Hauger, RL and Merritt, VC and Farrer, LA and Logue, MW},
title = {A Genome-wide Association Study of Alzheimer's Disease and Dementia in a Large Multi-ancestry Military Cohort Identifies Many New Dementia-Associated Loci.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.01.26352216},
pmid = {42145619},
abstract = {INTRODUCTION: Biobank-scale cohorts of individuals with genetic data and diagnoses of Alzheimer's disease and related dementias (ADRD) have facilitated the discovery of additional risk loci via meta-analysis, with existing cohorts assembled specifically for ADRD genetic discovery. Cross-ancestry meta-analyses have further elucidated the overall genetic architecture of these dementias. Here, we include for the first time the European ancestry (EA) and Hispanic ancestry (HA) subset of the VA Million Veterans Program (MVP) along with the African ancestry (AA) MVP participants in a meta-analysis with a large-scale EA and AA meta-analysis.

METHODS: Independent genome-wide association studies (GWASs) were conducted in MVP participants using four phenotypes derived from electronic medical records and surveys: ADRD, prescriptions for common dementia medications, and self-reported maternal and paternal history of dementia (dementia by proxy). These GWASs were repeated in the EA, AA, and HA cohorts. MVP ancestry-specific and cross-ancestry meta-analyses were conducted. These were then meta-analyzed with existing GWAS results. Functionality of the peak variants was explored using brain-derived gene expression data and co-localization analysis.

RESULTS: Apart from the APOE region, 17, 4, and 3 genome-wide significant (GWS) loci were observed in the MVP EA, AA, and HA meta-analyses, respectively. When we meta-analyzed these with consortium results, we observed 72 loci in the EA GWAS, and 62 lead loci in the cross-ancestry meta-analysis. While most of these loci were known, 27 genes/regions were identified containing variants surpassing genome-wide significance for the first time: 7 EA specific, 12 in the cross-ancestry meta-analysis, and 8 driven by AA and HA cohorts. Several of these are members of pathways containing established ADRD risk genes, and several of the peak SNPs showed evidence for eQTL effects on their respective genes. Several of the novel SNPs showed significant eQTL effects in brain-derived mRNA-seq experiments. Additionally, there was a significant differential expression of the novel gene PAX7 in ADRD cases and controls.

DISCUSSION: MVP represents a large and unique primarily male cohort comprised of US Veterans from a range of backgrounds with a unique set of environmental exposures. The results generated here demonstrate the utility of biobank level cohorts for AD genetic discovery. Furthermore, our discovery of ADRD genes was enhanced by the inclusion of MVP data that provided an increase of underrepresented ancestry groups in contrast to prior cross ancestry GWASs. The new AD risk loci identified present potential new targets for dementia treatment confirmed that future large-scale analyses of AD genetic risk and prediction will be enhanced by the inclusion of MVP data.},
}

@article {pmid42145631,
year = {2026},
author = {Ghanbarian, E and Zheng, L and Qian, T and Glover, CM and Sajjadi, SA and Corrada, MM and Grill, JD and , and Ezzati, A},
title = {CSF p-tau Predicts Asymmetric Hippocampal Atrophy in Cognitively Unimpaired Older Adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.26352391},
pmid = {42145631},
abstract = {BACKGROUND: Hippocampal atrophy is a core marker of neurodegeneration in dementia, particularly in Alzheimer's disease (AD). However, most studies focus on total hippocampal volume loss and overlook hemispheric asymmetry, which may reflect distinct biological processes. While tau pathology is closely linked to medial temporal lobe degeneration, it remains unclear whether tau is associated with asymmetric patterns of hippocampal atrophy.

METHODS: We analyzed 483 cognitively unimpaired participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with baseline cerebrospinal fluid (CSF) phosphorylated tau (p-tau181) and amyloid-β (Aβ42) measurements and longitudinal structural MRI data over 10 years of follow-up. Total hippocampal volume and hemispheric asymmetry, defined as the absolute difference between left and right hippocampal volumes (|L-R|), were quantified at each visit. Linear mixed-effects models assessed associations between baseline CSF biomarkers and longitudinal changes in hippocampal asymmetry, adjusting for demographic factors, APOE ε4 status, and baseline hippocampal volume.

RESULTS: Higher baseline CSF p-tau181 was associated with greater increases in hippocampal asymmetry over time (β = 1.20, SE = 0.43, p = 0.006). This association remained significant after additional adjustment for total hippocampal volume and baseline CSF Aβ42. CSF total tau was highly correlated with p-tau181 (Spearman's ρ =0.98, p < 0.001) and showed comparable associations with hippocampal measures. In contrast, baseline Aβ42 was not associated with subsequent changes in hippocampal asymmetry. Both p-tau181 and Aβ42 were associated with faster decline in total hippocampal volume. In amyloid-stratified analyses, p-tau181 was associated with increasing hippocampal asymmetry only among amyloid-negative individuals, whereas its association with total hippocampal atrophy was observed primarily in amyloid-positive individuals.

CONCLUSIONS: CSF p-tau181 is associated not only with overall hippocampal atrophy but also with progressive hemispheric asymmetry, suggesting that tau-related neurodegeneration may manifest as both magnitude and imbalance of tissue loss. These findings support hippocampal asymmetry as a complementary neuroimaging marker that may capture non-amyloid-related medial temporal lobe degeneration in cognitively unimpaired older adults.},
}

@article {pmid42145632,
year = {2026},
author = {O'Shea, DM and Galvin, JE},
title = {Comparative analyses of Alzheimer's disease blood biomarkers and cognitive domains.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.03.26352316},
pmid = {42145632},
abstract = {INTRODUCTION: Whether Alzheimer's disease (AD) blood biomarker-cognition associations differ across cognitive domains, analytic context, and biomarker modeling strategy in population-based cohorts is unclear.

METHODS: In 1,170 older adults from the Health and Retirement Study Harmonized Cognitive Assessment Protocol, we examined cross-sectional (2016) and prospective (2016-2022) associations of blood p-tau181, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and amyloid-β42/40 with memory, executive function, language, visuospatial ability, and global cognition using individual biomarker, principal components analysis-derived composite, and multibiomarker panel models.

RESULTS: Cross-sectionally, NfL and GFAP showed the broadest associations. Prospectively, p-tau181 was independently associated with memory and global cognition, whereas GFAP was associated with executive function, memory, and global cognition. P-tau181 also showed relative memory-versus-executive selectivity. The comparatively best-fitting modeling approach differed by cognitive domain and analytic context.

DISCUSSION: AD blood biomarker-cognition associations in community-dwelling older adults are domain-differentiated and context-dependent, supporting domain-specific outcomes and flexible biomarker modeling strategies.},
}

@article {pmid42145634,
year = {2026},
author = {Aguilar-Dominguez, P and Colceriu, CM and Holland, TM and Lockhart, SN and Masdeu, JC and Vasconcellos Neumann, LT and Snyder, HM and Baker, LD and Bejanin, A and Landau, SM and Arenaza-Urquijo, E},
title = {Association of neighborhood deprivation with Alzheimer's Disease pathology, brain structure, and cognition by race and ethnicity, sex, and APOE ε4 status.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.05.26352370},
pmid = {42145634},
abstract = {BACKGROUND: We investigated associations of neighborhood disadvantage with Alzheimer's Disease (AD)-related outcomes by biological and social factors in at-risk older adults.

METHODS: 1,880 U.S. POINTER participants with Area Deprivation Index (ADI) and cognition (PACC) were included. 868 had amyloid, tau PET, white matter hyperintensities (WMH), and/or gray matter volumes. We conducted exploratory, linear models testing ADI interactions with sex, race and ethnicity, and APOE ε4, adjusting for age and education.

RESULTS: "White/European American", "Hispanic/Latinx/Spanish" and "Others" showed lower cognitive scores with higher ADI, while "White/European American" showed the highest cognitive scores across ADI levels. APOE ε4 carriers from high-ADI areas showed higher WMH and tau, and "Hispanic/Latinx/Spanish" from more deprived areas showed higher WMH. Females from moderate-ADI areas showed higher tau. Amyloid burden was higher in APOE ε4 carriers from low-ADI areas.

CONCLUSION: Differential associations of ADI with AD-related outcomes across biological and social factors may reflect systemic health disparities and study design.},
}

@article {pmid42145636,
year = {2026},
author = {Lorenzi, M and Custo, A and Frisoni, GB and Garibotto, V},
title = {A data-driven Alzheimer's disease progression simulator for retrospective validation and prospective Phase III power design.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.03.26352317},
pmid = {42145636},
abstract = {Anti-amyloid immunotherapies have recently demonstrated the first significant slowing of cognitive decline in Alzheimer's disease (AD), yet clinical benefit varies markedly across drugs and scales with the completeness of amyloid clearance. Pharmacokinetic/pharmacodynamic (PK/PD) models are currently the standard tool for trial simulation, but they typically operate on single biomarkers and rely on drug-concentration assumptions, leaving the multi-scale cascade from amyloid clearance through tau, neurodegeneration, and cognition largely unmodelled. No existing framework has been jointly validated against the quantitative outcomes of multiple real-world phase III trials, spanning clearance kinetics, multi-modal biomarker trajectories, and statistical power. We present a trial simulation platform based on SimulAD, a disease progression model trained exclusively on longitudinal observational data from ADNI, with no access to trial-arm labels or drug-specific outcomes. SimulAD encodes intervention as piecewise amyloid clearance terms within a latent ordinary differential equation system that jointly governs amyloid, tau, structural MRI, and cognitive trajectories under the amyloid cascade hypothesis. We retrospectively simulated six landmark phase III anti-amyloid trials (TRAILBLAZER-ALZ2, CLARITY AD, EMERGE and ENGAGE, GRADUATE I and GRADUATE II) using a single trained model with trial-specific calibration limited to amyloid clearance kinetics. SimulAD reproduced published mean centiloid reductions within 5% error across all six trials and generated CDR-SB distributions broadly consistent with reported placebo and treated-arm outcomes. In a retrospective power analysis, calibrated simulations separated the three positive from the three null trials, with EMERGE near the decision boundary and ENGAGE and both GRADUATE trials below it. Across trials, higher amyloid-clearance rates were associated with larger calibrated clinical effects and lower estimated sample sizes. These results establish SimulAD as a valid disease-progression-centric trial simulator providing quantitative guidance on sample size planning and treatment kinetics optimisation that is grounded in the full multi-modal biomarker cascade of AD.},
}

@article {pmid42145643,
year = {2026},
author = {Cook, N and Zeng, Y and Yang, C and Jiang, Z and Wang, TC and Le Guen, Y and Cody, K and Johnson, M and Zhang, R and Merritt, VC and Hauger, RL and , and , and Koran, ME and Mormino, EC and Gordon, B and DeCasien, A and Andrews, S and Dumitrescu, L and Archer, D and Hohman, TJ and Pottier, C and Cruchaga, C and Sherva, R and Logue, M and Napolioni, V and Greicius, MD and Belloy, ME},
title = {An APOE *4-Informed Genomic Atlas of the X Chromosome in Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.05.26352461},
pmid = {42145643},
abstract = {The genetic contributions of the X chromosome to Alzheimer's disease (AD) remain poorly understood yet are expected to importantly shape sex differences in AD. We therefore performed large-scale X-chromosome-wide association studies (N=1,240,451), evaluating differential risk due to sex, APOE *4, and escape from X-chromosome inactivation, finding most X-linked loci appear relevant to female-biased AD etiology. In evaluating genetic pleiotropy with hormonal, lipid, and brain imaging traits, we discovered X-linked AD loci converged on white matter traits, particularly in the anterior corona radiata and splenium of the corpus callosum. Through brain-centric functional genomics analyses, we then nominated candidate causal genes, including 5 that appeared highly robust. Notably, we found the escape gene RBBP7 decreases AD risk in APOE *4 carriers likely through higher expression in excitatory neurons to counter tau-related neurodegeneration. Altogether, we provide an atlas of sex and APOE *4-informed candidate X-linked AD risk loci, genes, and mechanisms that will guide future studies.},
}

@article {pmid42145644,
year = {2026},
author = {Karlsson, L and Strandberg, O and Smith, R and Tang, W and Arvidsson, I and Åström, K and Oliveira Hauer, K and Janelidze, S and Stomrud, E and Palmqvist, S and Verghese, PB and Braunstein, JB and , and , and Klein, G and Shcherbinin, S and Jagust, WJ and Villeneuve, S and La Joie, R and Rabinovici, GD and Mattsson-Carlgren, N and Vogel, JW and Hansson, O},
title = {Generating synthetic tau-PET scans in Alzheimer's disease from MRI, blood biomarkers and demographics with deep learning.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.06.26352540},
pmid = {42145644},
abstract = {Tau protein aggregation in the brain is a hallmark of Alzheimer's disease (AD). Positron emission tomography (PET) is the only in vivo method to visualize tau pathology and estimate both its burden and regional distribution, but the use of tau-PET is constrained by high cost and limited accessibility. Here, we develop a deep learning model to synthesize tau-PET scans from more accessible data: structural magnetic resonance imaging (MRI), demographics, and when available, blood biomarkers. We included 5,191 participants across the AD continuum or with another neurological disorder from 13 cohorts (mean age 70 years, 51% female) and optimized a 3D U-Net neural network with residual and attention units for this task. In held-out test data, synthetic tau-PET reliably modeled tau burden, with correlations of R=0.77-0.86 with true tau-PET across individuals in common AD regions of interest. Spatial similarity between synthetic and true tau-PET was likewise high, with mean regional correlation of R=0.75. Synthetic scans also captured clinically meaningful prognostic information comparable to true tau-PET, including distinction between early (HR=12, p<0.001) and late (HR=45, p<0.001) stages of tau accumulation. These findings demonstrate that clinically informative synthetic tau-PET scans can be generated from widely available modalities using deep learning, potentially offering a scalable and cost-effective approach for estimating tau AD pathology in the brain.},
}

@article {pmid42145703,
year = {2026},
author = {Chen, F and Xue, M and Wang, H and He, H},
title = {Chronic two-photon microscopy reveals neuronal activity patterns in the cerebral cortex of an Alzheimer's disease mouse model.},
journal = {Biomedical optics express},
volume = {17},
number = {5},
pages = {2228-2241},
pmid = {42145703},
issn = {2156-7085},
abstract = {Chronic two-photon microscopy is used to investigate neuronal activity patterns in the primary visual cortex of Alzheimer's disease mice (5×FAD). We find that under resting conditions, individual AD neurons exhibit hyperactivity while the neuronal networks show rigid, hypersynchronous connectivity. Following precise optical stimulation of an individual neuron, the network hyperconnectivity is partially reduced. Morphological analysis of dendritic calcium signals reveals that AD neurons exhibit non-specific, widespread calcium propagation upon excitation and significantly increased dendritic length and branching density compared to WT mice, providing a potential link between single-neuron hyperactivity and network-level rigidity. These results demonstrate a hyperactive but rigid network phenotype in AD, providing a circuit-level explanation for early cognitive dysfunction.},
}

@article {pmid42145784,
year = {2026},
author = {Tamima, U and Gebril, HM and Hasan, MR and Quintero, MA and Aryasomayajula, A and Chengappa, D and Attarwala, I and Truong, BL and Moghe, PV and Uhrich, KE},
title = {Theranostic Nanoparticles for Fluorosensitive Visualization and Inhibition of Amyloid Beta-Induced Neuroinflammation.},
journal = {Particle & particle systems characterization : measurement and description of particle properties and behavior in powders and other disperse systems},
volume = {43},
number = {2},
pages = {e00220},
pmid = {42145784},
issn = {0934-0866},
abstract = {The emerging field of microglial therapies has significant potential to alleviate fibrillar amyloid beta (fAβ)-associated neuroinflammation, which exacerbates neurodegeneration in Alzheimer's disease (AD). New therapeutic strategies integrate with diagnostic capabilities to robustly elucidate the mechanisms and consequences of intervention. Amphiphilic macromolecules (AMs), comprising a hydrophilic sugar backbone, hydrophobic aliphatic side chains, and poly(ethylene glycol) (PEG) segments for enhanced stability, exhibit significant potential for biomedical applications due to their biocompatibility and self-assembled nanoscale structures. This study presents rhodamine B-tagged (Rh) AMs (Rh-AMs) that create stable nanoparticles (Rh-AM-NPs) with potential neurotherapeutic and diagnostic applications. Rh-AMs were successfully synthesized and validated using NMR, FTIR, UV-vis, and fluorescent spectroscopy. The ratio of labeled to unlabeled AMs necessary for Rh-AM-NPs formation was optimized via flash nanoprecipitation to confirm the minimum quantity required for direct visualization within cells. Using an in vitro BV2 microglial model, we demonstrated that Rh-AM-NPs exhibit multifunctional properties, suppressing the microglial inflammatory response and reducing microglial uptake of fAβ within a low-toxicity range, while simultaneously enabling in situ tracking of cellular interactions. This work validates a novel nanoplatform for combined AD therapy and diagnostics.},
}

@article {pmid42145981,
year = {2026},
author = {Hu, X and Li, G and Dai, K and Tang, S and Jin, X and Yang, W and Lu, T},
title = {Burden of dementia attributable to smoking among adults aged ≥40 years: A secondary dataset analysis of Global Burden of Disease 1990-2021 with projections to 2035.},
journal = {Tobacco induced diseases},
volume = {24},
number = {},
pages = {},
pmid = {42145981},
issn = {1617-9625},
abstract = {INTRODUCTION: Dementia persists as a critical global health challenge. Smoking is a modifiable behavioral factor associated with dementia, although improvements in healthcare have reduced dementia prevalence and mortality. Evaluating long-term changes in the smoking-attributable dementia burden provides a useful reference for informing and contextualizing dementia prevention efforts.

METHODS: This study is a secondary analysis of Global Burden of Disease (GBD) 2021 estimates. We examined smoking-attributable deaths and disability-adjusted life years (DALYs) for dementia among adults aged ≥40 years, across 204 countries and territories from 1990 to 2021. We assessed temporal trends using age-standardized rates and estimated annual percentage changes (EAPC), evaluated inequality across sociodemographic development levels, and projected the burden to 2035 using a Bayesian age-period-cohort (BAPC) model.

RESULTS: In 2021, the global burden of dementia attributable to smoking reached 1533214 DALYs (95% UI: 635494-3540712), representing an approximate twofold increase compared with 1990. However, the age-standardized DALY rate (ASDR) declined significantly over the same period, with an EAPC of -0.88 (95% CI: -0.92 - -0.83). Population growth and population ageing were the dominant contributors to the increase in DALYs, accounting for 112.17% and 26.02%, respectively, whereas epidemiological improvements partially offset the burden (-38.19%). In terms of regional variation, East Asia bore the heaviest absolute burden. BAPC projections indicated that despite continued declines in ASDR, smoking-attributable dementia DALYs are expected to keep increasing through 2035.

CONCLUSIONS: Despite declining age-standardized rates, the absolute burden of smoking-attributable dementia continues to rise, partly because reductions in smoking exposure are insufficient to counter demographic pressures from population ageing and growth. Persistent disparities across sociodemographic index groups further indicate that gains in tobacco control do not consistently translate into proportional reductions in dementia burden. Aligning tobacco control with ageing-responsive health system strategies will be essential to moderating future burden growth.},
}

@article {pmid42146216,
year = {2026},
author = {de Oliveira, TM and Pereira Bento, LD and Santos de Melo Wiermann, I and de Souza Fonseca, B and Tsui, GS and Pereira de Jesus, CJ and Sales, RO and Pereira Prado, MA and de Castro, MS and Reis Moura, JP and Gomes, EN and Bastos, LB and Lima Orsine, IC and de Souza Esteves, L and Silva Soares, MC and Falkoski, DL and da Silva, MP and de Oliveira, TA and da Silva, AM and Bechelane Maia, EH and Andrade Leite, FH and Valle, MS and de Carvalho, PB and Costa Vanessa Pereira Mendes, L and Taranto, AG and Moreira Damázio, LC},
title = {Integrative In Silico and In Vivo Evidence of Quercetin as a Multitarget Neuroprotective Agent in Alzheimer's Disease.},
journal = {ACS omega},
volume = {11},
number = {18},
pages = {27115-27127},
pmid = {42146216},
issn = {2470-1343},
abstract = {Alzheimer's disease requires therapeutic strategies targeting multiple pathological mechanisms. This study investigates the neuroprotective potential of quercetin using an integrated approach combining in silico modeling and in vivo validation. Computational analyses examined the binding behavior of quercetin toward three key enzymes implicated in disease pathophysiology: acetylcholinesterase, butyrylcholinesterase, and beta-secretase 1. Molecular dynamics simulations reveal consistent interaction patterns and stable binding profiles across independent trajectories. For experimental validation, Wistar rats with surgically induced Alzheimer's disease were orally treated with quercetin (30 mg/kg) for 5 weeks. Histological and immunohistochemical analyses of the hippocampus and subventricular zone evaluated neuronal density and astrocytic activation using glial fibrillary acidic protein and vimentin markers. Computational results supported the multitarget potential of quercetin through stable enzyme interactions. Consistently, in vivo assays demonstrated increased neuronal density and reduced astrocytic marker expression, suggesting a protective modulation of neuroinflammatory processes. These findings highlight quercetin as a promising scaffold for multitarget therapeutic strategies aimed at mitigating the progression of Alzheimer's disease.},
}

@article {pmid42146238,
year = {2026},
author = {Mishra, A and Satapathy, BS and Sahu, PK and Ghose, A and Paidesetty, SK},
title = {Epigenetic Modulation Is a Key Mechanism in Cognitive Deficit: Unveiling Garcinol as a Potent HAT Inhibitor in Improving Alzheimer's Disease.},
journal = {ACS omega},
volume = {11},
number = {18},
pages = {26129-26150},
pmid = {42146238},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a global concern. Conventional FDA-approved drugs mostly provide symptomatic relief but largely fail to address the underlying pathophysiology of AD. Further, chronic use of prescribed anti-AD drugs causes unpredictable, countless side effects, which thus evokes exploration for novel, safer, nontoxic, affordable, yet potent alternative modalities. Among various predicted pathophysiological hall marks in the progression of AD, aberrant histone acetylation has been identified as one of the major culprits, which leads to dysregulated gene expression and gradual neuronal degeneration. Thus, histone acetyl transferase (HAT) inhibitors are considered lucrative anti-AD agents. Active phyto constituents in recent times have occupied the center stage in addressing challenging neurodegenerative disorders in place of routine drug therapy. Garcinol (GL), a phytoactive constituent from Garcinia indica, possesses potent HAT inhibitory effect. Reports show that GL exhibits profound antioxidant, anti-inflammatory, anticancer, and neuroprotection effects. Neuroprotection of GL could be attributed to its ability to reduce oxidative stress and modulate important signaling pathways involved in neuronal degeneration. Present review unveils potentiality of HAT inhibitors in improving memory functions and neuroprotection; with a special focus on GL. Mechanical insights into activity of GL in ameliorating neurodegeneration have been discussed with rationalized evidence of various preclinical reports. Side by side, a portion has been devoted to update the trending drug delivery approaches investigated in recent times for GL toward improved pharmacological performance.},
}

@article {pmid42146335,
year = {2026},
author = {Lauderdale, K and Yan, Z and Mendiola, AS and Zhang, Y and Mallen, D and Nambiar, P and Brady, E and Miller, SR and Acevedo, RM and Cabriga, B and Jiang, F and Kaliss, N and Shen, K and Shin, J and Herbert, J and Ma, K and Ryu, JK and Agrawal, A and Schuck, R and Alzamora, MDPS and Sanz-Ros, J and Cobos, I and Stavenhagen, J and Kantor, AB and Ellisman, MH and Akassoglou, K and Palop, JJ},
title = {Therapeutic targeting of fibrin-microglia interactions ameliorates Alzheimer's disease-related hyperexcitability and brain network dysfunction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.01.722324},
pmid = {42146335},
issn = {2692-8205},
abstract = {UNLABELLED: Brain network dysfunction-including hyperexcitability, altered oscillations, and sleep disruption-is prominent in Alzheimer's disease (AD), but the contribution of vascular-neuroimmune processes to these alterations remains unclear. Here, we blocked the pro-inflammatory interaction of the blood protein fibrin with microglia using genetic (Fgg [γ390-396A] mice) and antibody-based (5B8 and THN392) strategies to test its role in AD-related network dysfunction. The 5xFAD model of AD exhibited network hyperexcitability associated with oscillatory slowing, sleep states, and disrupted sleep-circadian rhythms. These deficits were largely attenuated by blocking fibrin-microglia interactions in 5xFAD;Fgg [γ390-396A] mice. Notably, pharmacological interventions after disease onset with both anti-fibrin antibodies similarly attenuated these AD-related network deficits and behavioral abnormalities. We conclude that vascular-neuroimmune processes driven by fibrin-microglia interactions promote AD-related network dysfunction and that targeting the fibrin-microglia axis-currently under clinical evaluation with the humanized antibody THN391- represents a promising therapeutic strategy for AD. There is a companion manuscript submitted to bioRxiv (Yan et al., 2026). [110].

HIGHLIGHTS: Fibrin promotes AD-related network hyperexcitability and oscillatory slowing in 5xFAD miceFibrin promotes AD-related disruption of sleep and circadian rhythms in 5xFAD miceGenetic blocking of fibrin-microglia interactions rescues AD-related brain network dysfunctionAnti-fibrin antibodies (5B8 and THN392) show acute and chronic therapeutic benefit.},
}

@article {pmid42146347,
year = {2026},
author = {Capener, JL and Badillo-Martinez, A and Awada, B and Davis-Gilbert, ZW and Kramer, TW and Blair, CS and Bashore, FM and Al-Ali, H and Axtman, AD},
title = {Development of NanoBRET cellular target engagement assays in primary neurons for activating mutants of p21-activated kinase 1.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.03.722513},
pmid = {42146347},
issn = {2692-8205},
abstract = {The p21-activated kinases (PAKs) are a group of serine-threonine kinases central to multiple signaling pathways that govern cell survival and proliferation. Aberrant activity of PAK1, the most well characterized member of the PAK family, drives progression of several malignancies and brain disorders, including Alzheimer's disease and neurodevelopmental disorders. Despite growing interest in PAK1 as a drug target for these diseases, there is no assay to evaluate the intracellular target engagement of PAK1 inhibitors. To address this need, we developed first-in-class NanoBRET assays for wild-type PAK1 and a neurodevelopmental disorder-causing gain-of-function PAK1 mutant. Furthermore, we executed our novel PAK1 NanoBRET assay to evaluate target engagement of PAK1 inhibitors in primary hippocampal neurons. To the best of our knowledge, this is the first demonstration of a NanoBRET cellular target engagement assay in primary neurons, thereby increasing the relevance of our work by confirming PAK1 inhibitor binding to the aberrant form of the protein in primary neurons.},
}

@article {pmid42146356,
year = {2026},
author = {Riaz Rajoka, MS and Valladares, KN and Prairie, C and Li, W and King, P and Katz, J and Michalek, SM and Zhang, P},
title = {Porphyromonas gingivalis promotes lipid droplet-mediated microglial dysfunction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.03.722306},
pmid = {42146356},
issn = {2692-8205},
abstract = {Growing evidence supports a strong association between periodontitis and Alzheimer's disease (AD), yet the mechanisms linking these conditions remain poorly defined. In neurodegenerative disorders, including AD, microglia are often characterized by increased lipid droplet (LD) accumulation, heightened activation, and impaired function. In this study, we examined whether Porphyromonas gingivalis (Pg), a keystone periodontal pathogen, promotes LD accumulation in microglia and disrupts their function. We found that Pg infection induces robust LD accumulation in BV2 microglial cells and in microglia from Pg -infected App KI mice. This Pg -driven LD buildup was closely associated with elevated reactive oxygen species (ROS) production, impaired phagocytic ability, and altered activation. Notably, pharmacological inhibition of LD with a triglyceride synthesis inhibitor effectively reversed Pg -induced LD accumulation, mitigated ROS production, and restored phagocytic function, thus underscoring the critical role of lipid metabolism in regulating microglial function. These findings support a model in which, in the context of periodontitis, systemic dissemination of periodontal pathogens promotes LD accumulation in microglia, and this metabolic alteration exacerbates microglia dysfunction via a self-reinforcing cycle of excessive oxidative stress and impaired phagocytosis, potentially accelerating AD progression.},
}

@article {pmid42146366,
year = {2026},
author = {Lutz, MW and Man, Z and Zheng, Y and Venkatesan, S and Chiba-Falek, O},
title = {A diagnostic plasma omics-biomarker for Alzheimer's disease informed by microglial single-cell transcriptomics: A pilot study.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.721959},
pmid = {42146366},
issn = {2692-8205},
abstract = {BACKGROUND: The current biomarker framework for the diagnosis and staging of Alzheimer's disease (AD) relies mainly on neuropathological features; thus, its performance for diagnosis is limited prior to the initiation of neurodegeneration. Here, we leveraged transcriptomic data to develop a new framework for omic-informed blood-based diagnostic biomarkers for AD from early-stage.

METHODS: Microglial gene expression from single-nucleus (sn)RNA-seq data was analyzed via 6 statistical methods to identify candidate panels of genes predictive of AD. A total of 78 gene panels, 30-2000 genes in size, were selected and evaluated for their ability to distinguish AD patients from controls. Three top-ranked panels of 300, 50 and 30 genes were transferred to blood (monocyte) transcriptomic data obtained from living subjects via a graph-based mapping approach based on optimal transport statistics.

RESULTS: The 300-panel method resulted in an AUC of 0.7 and moderate accuracy (75%) in classifying AD; however, the accuracy in predicting cognitively normal patients was lower (53%). While the 300 genes provided high accuracy, inspection of the distribution of p values for the gene set revealed that the panel could be greatly reduced in size to capture the most significant differences between AD patients and cognitively normal individuals. The accuracy and specificity of the 50 and 30 panels demonstrated similar AUC values but improved the balance between the prediction of AD patients and normal controls. Specifically, the 50-gene panel resulted in an AUC of 0.7, with 65% AD accuracy and 71% normal accuracy.

CONCLUSIONS: Integrating multiomics datasets into the AD biomarker discovery pipeline offers a powerful modality to increase precision and comprehensiveness in AD research and clinical applications.},
}

@article {pmid42146419,
year = {2026},
author = {Cho, G and Kam, K and Chen, A and Mao, Y and Benveniste, H and Mecca, A and Valencia, DI and Martillo, KR and Chu, SS and Kumar, A and Bubu, OM and Osorio, RS and Ayappa, I and Liu, X and Miner, B and Varga, AW},
title = {Hypoxic burden predicts weaker coordination between brain pulsations and CSF flow independent of non-hypoxic arousals: Implications for glymphatic activity.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.25.720853},
pmid = {42146419},
issn = {2692-8205},
abstract = {OBJECTIVE: To examine whether hypoxic burden is distinctly associated with key drivers of glymphatic activity, independent of sleep fragmentation.

BACKGROUND: OSA is a robust risk factor for multiple neurodegenerative conditions, including Alzheimer's disease, with glymphatic impairment representing a potential mechanistic pathway. However, it remains unknown whether distinct pathological features of OSA, including hypoxic burden and sleep fragmentation, are differentially associated with the two key physiological drivers of glymphatic activity: (1) coordination between brain pulsations and CSF flow and (2) brain pulsation strength.

METHOD: Twenty-eight individuals with newly identified OSA and eight healthy individuals without OSA completed either in-lab polysomnography or WatchPAT, providing estimates of hypoxic burden, quantified as time spent below 90% oxygen saturation (T90), and sleep fragmentation, quantified as non-hypoxic respiratory effort-related arousals (RERAs). Participants also completed 7T resting-state fMRI to quantify the coordination between brain pulsations and CSF flow using gBOLD-CSF coupling (i.e., cross-correlation between g ray matter b lood o xygen level d ependent signal pulsations and CSF inflow) and brain pulsation strength using gBOLD amplitude. Hierarchical regression and Pearson correlations were used to examine associations between sleep measures and fMRI-derived metrics.

RESULTS: Greater T90 was associated with weaker gBOLD-CSF coupling, independent of age, sex, race, and RERAs (Table 2; β=0.07, p =0.008). T90 also significantly improved model-explained variance in gBOLD-CSF coupling (Table 2; ΔR [2] =0.20, p =0.008). Contrary to expectations, greater T90 was associated with higher gBOLD amplitude across the temporal lobe and multiple frontal and parietal regions. Within regions showing T90-linked elevations in gBOLD amplitude, higher gBOLD amplitude was not associated with stronger region-specific gBOLD-CSF coupling. This contrasted with regions not associated with T90, where higher gBOLD amplitude was associated with stronger gBOLD-CSF coupling (difference in β=0.0006, p<0.001). RERAs were not associated with gBOLD-CSF coupling and gBOLD amplitude throughout the cerebral cortex.

CONCLUSIONS: In OSA, hypoxic burden, rather than respiratory effort-related sleep fragmentation, may be the primary pathological feature associated with impaired brain pulsation and CSF dynamics, both of which are key drivers of glymphatic activity. These alterations may be most prominent in the temporal lobe, potentially reflecting its elevated metabolic demand and vulnerability to hypoxemia.},
}

@article {pmid42146439,
year = {2026},
author = {Xu, Z and Chen, W and Ren, W and Xu, T and Amaechina, S and Khan, R and Chen, Y and Province, M and Payne, P and Li, F},
title = {Interpreting Omics Data Analysis with Large Language Models for Disease Target and Drug Discovery.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.721768},
pmid = {42146439},
issn = {2692-8205},
abstract = {In biomedical scientific discovery, synthesizing prior knowledge from the literature is an essential component of interpreting numerical omics data analyses for disease target identification and drug discovery. Large language models (LLMs) alone can rapidly retrieve disease mechanisms from biomedical text, but text-only outputs are general and unreliable for target and drug prioritization without cohort-specific quantitative evidence. Herein, we propose a provenance-aware Text-to-Target framework that couples schema-constrained multi-model LLM retrieval with numeric omics data analysis. The key design is a modality-aware fusion step: candidates are partitioned into overlap-supported anchors, retrieval-only hidden hubs, and network-emergent novelty nodes, then propagated into staged hypothesis and strategy generation under topology constraints. We evaluate the model in Alzheimer's disease (AD) and pancreatic ductal adenocarcinoma (PDAC). In PDAC, the workflow produced a balanced 75-gene candidate universe and a 23-strategy portfolio, with significant DepMap support at both target level and strategy level. In AD, stricter candidate controls yielded a compact 34-gene universe and 14 strategies; under an expanded CRISPRbrain registry, both target-level axes were significant, with strong strategy-level enrichment. Across both diseases, final strategies preserved full provenance closure to the candidate pool, enabling end-to-end auditability from retrieval artifacts to validation outputs. These results support a transferable discovery architecture in which omics evidence constrains biological activity, LLM retrieval expands mechanistic search space, and network-aware fusion preserves interpretability. The framework provides a reproducible basis for dual-disease target prioritization and motivates continuous literature-mechanism concordance with agentic evidence-refresh loops.},
}

@article {pmid42146485,
year = {2026},
author = {Siebrand, CJ and Mayeri, Z and Brown, I and Andersen, JK and Walton, CC},
title = {In vitro comparison of Aβ-targeting SNIPR, synNotch, and TRUCK for cell-based drug delivery in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.29.721717},
pmid = {42146485},
issn = {2692-8205},
abstract = {Pioneering research is adapting chimeric antigen receptors (CARs) from oncology to Alzheimer's disease (AD) by targeting amyloid beta (Aβ). Newer synthetic receptor systems can go beyond, transforming cells into targeted biological drug factories that can couple Aβ detection to synthesis and secretion of genetically encoded therapeutics. Among candidate systems, T cells Redirected for Universal Cytokine Killing (TRUCK), synthetic Notch (synNotch), and Synthetic Intramembrane Proteolysis Receptors (SNIPR) have shown promise in oncology. Here, we adapt these platforms to AD using a shared Aβ-targeting binding domain derived from Aducanumab (Aduhelm), coupled to inducible expression cassettes driving identical transgenes: secreted Metridia luciferase (MetLuc) and a Lecanemab (Leqembi)-based chimeric human-mouse antibody (chLecanemab). To validate these systems in vitro , Jurkat clones expressing each receptor were treated with oligomer-enriched Aβ (AβO) to model AD, and receptor output was quantified by media MetLuc levels and chLecanemab colocalization with Aβ aggregates. For TRUCK systems, we show the Aβ-targeting CAR successfully activated Jurkat cells by flow cytometry. We also show that six Nuclear Factor of Activated T-cells (NFAT) tandem repeat response elements (6xNFAT) paired with either minimal interleukin-2, synthetic TATA box, or minimal cytomegalovirus promoters resulted in functional regulatory regions. Despite this, all TRUCK variants failed to significantly upregulate MetLuc in response to AβO. In contrast, both synNotch and SNIPR responded robustly to AβO, with SNIPR outperforming synNotch in both MetLuc and chLecanemab production. These findings establish SNIPR and synNotch as promising platforms for future research on cell-based targeted therapeutic delivery in AD.},
}

@article {pmid42146492,
year = {2026},
author = {Cordi, CV and Falkenberg, NG and Clark, GT and Allen, NG and Chuah, JR and Ulbrich, R and Herzog, AA and Lanka, M and Collins, EJ and Bentley, M and Dordick, JS and Jankowski, MS and Hurley, JM},
title = {Circadian disruption induces sex-specific Alzheimer's pathophysiology and immune cell reprogramming.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.721994},
pmid = {42146492},
issn = {2692-8205},
abstract = {UNLABELLED: Circadian disruption (CD) is increasingly recognized as a sex-specific risk factor for Alzheimer's disease (AD). However, the mechanisms linking CD to AD, and the role of biological sex in this interaction, are unclear. Immunometabolic regulation is extensively circadianly timed, has sex-specific phenotypes, and plays a role in AD. Therefore, we hypothesized that CD affects the timing of immunometabolism, contributing to the sex-specific effects of CD on AD. To demonstrate this, we subjected male and female APP/PS1 mice to chronic disruptive lighting to model circadian disruption, finding CD induced a female-specific reduction in amyloid plaque burden but an increase in the infiltration of peripheral macrophages into the brain. Concomitantly, we found macrophages exhibited CD-associated immune reprogramming, which in females led to altered immunometabolic timing, an increase of macrophages in the activated state, and elevated levels of reactive oxygen species (ROS), supporting a role for immunometabolism in the sex-specific effects of CD in AD.

HIGHLIGHTS: Circadian disruption reduces Aβ plaque load specifically in female micePeripheral immune infiltration correlates with reduced Aβ plaques in femalesCircadian disruption coordinates phasing of circadian immunometabolic proteinsIn females, circadian phase advancement correlates with increased ROS.},
}

@article {pmid42146512,
year = {2026},
author = {Bhattrai, A and Raikes, AC and Brinton, RD},
title = {Addition of humanized APP to humanized APOE mouse model reduces brain size and increases the ratio of cortical representation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.722764},
pmid = {42146512},
issn = {2692-8205},
abstract = {INTRODUCTION: Age, Apolipoprotein E4 (APOE 4) genotype, and biological sex are major risk factors for late-onset Alzheimer's disease (LOAD). Neuroimaging is central to its characterization, and preclinical mouse models enable controlled investigation of these factors. To date, humanized APOE 4 has not recapitulated LOAD-relevant brain phenotypes. Given the central role of amyloid precursor protein (APP) in LOAD pathogenesis, incorporating humanized APP (hAPP) alongside humanized APOE (h APOE) may therefore improve translational modeling of structural brain changes.

METHODS: Aged mice (mean age = 23.25 months) carrying murine (m) or humanized (h) APP and either murine Apoe or h APOE 3/3, h APOE 3/4, or h APOE 4/4 underwent in-skull ex vivo volumetric MRI. Regional volumes were quantified in absolute terms and relative to total brain volume (TBV). Linear models included APP type, APOE genotype, and sex, with FDR correction applied within contrasts.

RESULTS: Brain volumes were primarily determined by APP background, with hAPP globally reducing total and regional volumes relative to mAPP mice. Across hAPP models, h APOE 4/4 exhibited the greatest brain-wide reductions, which was mitigated by a single h APOE 3 allele. In contrast, mouse APP exerted modest effect in h APOE , with hAPOE4 carriers exhibiting greater total volume without regional specificity. After TBV adjustment, hAPP mice exhibited subcortical vulnerability with relative cortical preservation. Females exhibited larger brain volumes than males, independent of APP or APOE genotype.

DISCUSSION: These findings demonstrate that APP background is a primary driver of mouse brain volume, with hAPP producing global reductions amplified by the h APOE 4/4 genotype. In contrast, h APOE 4 effects in the mAPP background were modest and nonspecific, consistent with normative aging. Together, these results suggest that hAPP and h APOE 4 act synergistically, and that h APOE 4 alone is insufficient to recapitulate AD-relevant brain changes in mice. The hAPP/h APOE 4/4 model yields a brain-wide phenotype consistent with LOAD-associated volumetric patterns, whereas mAPP/h APOE models may better reflect non-pathological aging.},
}

@article {pmid42146521,
year = {2026},
author = {Shahani, N and Banerjee, R and MacMullen, C and Sharma, N and Habibi, M and Wasserman, HD and Noyes, NC and Zhao, P and Elgendy, B and Cameron, MD and Bannister, TD and Hegazy, L and Finck, BN and Davis, RL},
title = {Pharmacological rescue of mitochondrial dysfunction, neurite degeneration, and premature death of ALS and AD iPSC-derived neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.722019},
pmid = {42146521},
issn = {2692-8205},
abstract = {UNLABELLED: Mitochondrial (MT) dysfunction is a key driver of ALS pathology. Without a healthy MT system, motor neurons (MN) function at sub-optimal levels and die. In addition, other effects of ALS, like axon/dendrite degeneration, may occur from a pathophysiological cascade spurred by MT dysfunction. A phenotypic screen identified Dipyridamole (DPM), an FDA-approved and safe drug, as having extraordinary effects on ALS patient induced pluripotent stem cell (iPSC)-derived MNs. The drug prevented MT fragmentation, loss of MT content, impaired MT bioenergetics, axon/dendrite degeneration, and premature MN death, extending neuronal survival by more than fivefold. Importantly, its efficacy extended across iPSC-derived neurons representing two different familial forms of ALS (C9orf72, TDP43) and Alzheimer's disease (PSEN1), implying broad neuroprotection across ALS forms and other neurodegenerative diseases. DPM increased MT respiration and pyruvate uptake in a mechanism requiring the Mitochondrial Pyruvate Carrier (MPC), mechanistically explaining its biological activities. Thus, DPM is a promising drug to repurpose or refine for treating neurodegenerative diseases or other diseases that would benefit by augmenting pyruvate uptake into MT.

TEASER: Dipyridamole, an FDA-approved drug, restores mitochondrial function and protects neurons in ALS and Alzheimer's disease.},
}

@article {pmid42146576,
year = {2026},
author = {Bhaskar, U and Kos, MZ and Carless, MA},
title = {A Cell-Type-Resolved Meta-Analysis Reveals Glial DNA Methylation Changes Associated with Aging and Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.722662},
pmid = {42146576},
issn = {2692-8205},
abstract = {Epigenome-wide association studies implicate DNA methylation in the development and progression of Alzheimer's disease (AD). Although recent studies show that the epigenetics of non-neuronal cell types contribute to disease risk, the role of the methylome in individual glial cell types (i.e., astrocytes, oligodendrocytes) in biological aging and AD pathogenesis is unclear. In this study, we examined archived DNA methylation data across 13 cohorts and performed cell type deconvolution in silico to identify novel epigenetic signatures associated with aging and AD in glial cells. We observed pronounced age-associated methylation in astrocytes within the prefrontal cortex, whereas oligodendrocytes of the entorhinal cortex show the most differential methylation with AD status. Astrocytes, along with neurons, within the prefrontal cortex, emerge as key players in Braak stage-associated methylation, exhibiting strong concordance with previously reported associations at the brain tissue level. Age-associated changes in oligodendrocytes exhibit strong directional correlation with, and amplification of age-related effects with AD that affect neurodevelopmental processes, while AD-related methylation changes at age-associated sites in astrocytes diverge from those representative of normative aging processes. Our study expands on previous findings and reveals glial-specific methylation patterns associated with epigenetic aging and AD.},
}

@article {pmid42146583,
year = {2026},
author = {Shahin, S and Vit, JP and Rentsendorj, A and Fuchs, DT and Swerdlow, N and Gaire, BP and Robinson, E and Kissel, A and Hagerman, L and Williams, A and Ljubimov, AV and Hawes, D and Schneider, LS and Mirzaei, M and Black, KL and Koronyo, Y and Koronyo-Hamaoui, M},
title = {Sex-specific retina-brain signatures link ERα/ERβ imbalance with gliosis in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.722000},
pmid = {42146583},
issn = {2692-8205},
abstract = {Women face a twofold higher lifetime risk of Alzheimer's disease (AD) than men, yet the mechanisms underlying female-biased vulnerability and sex-specific disease signatures across the retina-brain axis remain unknown. By integrating clinicopathological and proteomic datasets from paired retinal and brain tissues from 182 donors, we identified sex-divergent molecular and pathological features across the AD continuum. Despite comparable retinal and cerebral amyloid and tau burdens between sexes, females exhibited a more severe neuroinflammatory-neurodegenerative phenotype with intensified gliosis and tissue atrophy, whereas males displayed a dominant vasculopathy, marked by increased retinal vascular Aβ 40 deposition, tight-junction disruption, and cerebral amyloid angiopathy. In females, this profile coincided with inflammation-associated estrogen receptor (ER)-α remodeling and reduced global and astrocytic-nuclear ER-β, which associated more strongly with cognitive decline than in males. These results indicate that comparable AD proteinopathy is associated with divergent downstream consequences across the retina-brain axis and identify astrocytic ERα/ERβ imbalance as a sex-linked glial mechanism associated with female vulnerability in AD.},
}

@article {pmid42146604,
year = {2026},
author = {Allen, NG and Cordi, CV and Llabre, JE and Chuah, J and Clark, GT and Kubik, AJ and Falkenberg, NG and Jankowski, MS and Cahill, RA and Herzog, AA and Chander, MS and Vashishth, D and Hurley, JM and Blaber, EA},
title = {Alzheimer's Disease and circadian disruption sex-specifically contribute to a loss of bone maintenance in APP/PS1 model mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.01.722089},
pmid = {42146604},
issn = {2692-8205},
abstract = {UNLABELLED: Alzheimer's Disease and Related Dementias (ADRDs) are linked to reduced bone integrity and increased fracture risk, but the mechanisms that underlie this risk remain poorly defined. Current research suggests that environmental factors, such as diet, sleep, and light exposure can modulate the brain-bone axis, increasing susceptibility to bone loss and fractures. Circadian disruption (CD) associated with ADRDs may exacerbate the effects of disease and aging in the bone. In particular, regulation of bone marrow progenitors may be acutely susceptible to disruption along this axis. Here, we explore the interplay among genetic and environmental factors that influence bone structure, marrow progenitor cell activity, and monocyte-derived macrophages. The APP/PS1 transgenic mouse model (AP) is used as an in vivo model of amyloid-beta deposition. High-resolution micro-computed tomography (μCT) identified sex- and genotype-specific responses in trabecular morphometry. Follow-up analysis with Raman spectroscopy (RS) found accumulation of non-enzymatic modifications of the organic matrix and notched three-point bending identified concomitant loss of bone toughness due to both CD and AP. Single-cell RNA sequencing (scRNA-seq) confirmed the presence of oxidative stress signals in the cellular populations of the bone marrow. We further mapped significantly differentially expressed genes (DEGs) from monocytes in the bone marrow to circadian-regulated proteins in monocyte-derived macrophages, revealing dysregulation of circadian timing in macrophages in vitro . These findings offer new insights into how environmental disruptions can exacerbate the progression of neurodegenerative disease and bone degradation.

LAY SUMMARY: Patients with Alzheimer's disease have an increased bone fracture risk, but the biological link between brain and bone disease is not well understood. Everyday factors such as altered light exposure (shift work, screens late at night, etc.) can worsen outcomes in the brain and skeleton. Using a mouse model of Alzheimer's disease, we found that both genetic risk and circadian disruption contribute to weaker bone and altered bone quality. We also identified inflammation and stress responses in bone marrow cells, suggesting that bone marrow may play a key role in linking brain disease to bone fragility.},
}

@article {pmid42146610,
year = {2026},
author = {Shiferaw, TG and Sarkar, S and Baker, KM and Wooldridge, RS and Binfet, HM and Prozapas, VN and Ogbu, CP and Schepmoes, AA and Attah, IK and Niemeyer, CS and Sprenger, KG and Hassell, JE and Eckel, RH and Melchior, JT and Bruce, KD},
title = {ApoE Lipidation State Directs Immunometabolic Reprogramming of Human Microglia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.722733},
pmid = {42146610},
issn = {2692-8205},
abstract = {INTRODUCTION: ApoE4 is the strongest genetic risk factor for Alzheimer's disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.

METHODS: Human microglia were treated with lipid-free or lipid-bound ApoE3 or ApoE4. Label-free live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet dynamics, mitochondrial morphology, and microglial phenotype.

RESULTS: ApoE4 treatment resulted in fewer but enlarged lipid droplets and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to lipid-free ApoE, which was exacerbated by lipid-free ApoE4.

DISCUSSION: These findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas lipid-free ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.},
}

@article {pmid42146614,
year = {2026},
author = {Lu, W and Caulfield, TR and Lee, E and Jeevaratnam, S and Wang, N and Bu, G and Kanekiyo, T and Li, Y},
title = {Discovery of a CI-994 derivative as a dual modulator of class I HDACs and Wnt/β-catenin signaling for Alzheimer's disease therapy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.721954},
pmid = {42146614},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is a multifactorial disease with mixed pathologies. Consequentially, drugs targeting multiple pathological processes may offer synergistic benefits. While histone deacetylase (HDAC) inhibitors have demonstrated efficacy in alleviating AD-related pathologies in animal models, the neuroprotective Wnt/β-catenin signaling pathway remains compromised in AD brain. CI-994 is a class I HDAC inhibitor containing N-(2-aminophenyl)-benzamide. Our recent studies indicate that CI-994 is also an activator of Wnt/β-catenin signaling by stabilizing Wnt co-receptor LRP6. We herein use CI-994 as a scaffold to develop novel potent dual modulators of class I HDACs and Wnt/β-catenin signaling for AD therapy. Our lead compound, W2A-28, selectively inhibits class I HDAC1, 2 and 3 with IC 50 values of 0.51 μM, 0.68 μM, and 0.22 μM, respectively, and shows no inhibitory activities on other HDACs. Furthermore, W2A-28 potently activates Wnt reporter activity with an EC 50 value of 1.61 μM in Wnt-3A-expressing HEK293 cells. As expected, activation of Wnt/β-catenin signaling by W2A-28 is associated with elevated LRP6 protein level. Importantly, W2A-28 displays excellent microsomal stability in both mouse and human liver microsomal stability assays, alongside high permeability and a lack of active efflux in MDR1-MDCKII models. Critically, W2A-28 treatment significantly enhances histone acetylation, activates Wnt/β-catenin signaling, and suppresses tau phosphorylation in AD patient-specific cerebral organoids carrying APOE ε4/ε4 or APOE ε3/ε4 with PSEN1 M146V mutation. Our findings position W2A-28 as a promising multi-target drug candidate for AD therapy.},
}

@article {pmid42146648,
year = {2026},
author = {Yan, Z and Mendiola, AS and Lauderdale, K and Kim, KY and Yong, Y and Leng, K and Bushong, EA and Schuck, R and Meyer-Franke, A and Agrawal, A and Traglia, M and Gill, N and Thomas, R and Keller, JN and Karvelas, N and Vasquez, MF and Ballard, DC and Madany, M and Simms, J and Guo, B and Tognatta, R and Alzamora, MDPS and Meza-Acevedo, R and Cabriga, B and Pierson, KN and Kourita, L and Han, K and Ryu, JK and Miller, BL and Elahi, FM and Ellisman, MH and Palop, JJ and Akassoglou, K},
title = {Resilience to neuronal hyperactivity and restoration of the neuroimmune interactome and decision-making by blocking fibrin in a model of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.01.722077},
pmid = {42146648},
issn = {2692-8205},
abstract = {UNLABELLED: Cerebrovascular pathology and neuronal network dysfunction are early features of Alzheimer's disease (AD) associated with neuroinflammation and cognitive decline, but the vascular and immune triggers of neuronal hyperactivity remain largely unknown. Here, we show that the blood coagulation protein fibrin disrupts microglia-neuron interactions, promoting neuronal hyperactivity in an AD mouse model. Genetic elimination of the fibrin inflammatory domain reduced neuronal hyperactivity, restored dynamic microglial interactions with active neurons and protected from high-risk decision making in 5XFAD mice. Leveraging the transcriptional signatures of microglia and inhibitory and excitatory neurons, a ligand-receptor atlas revealed fibrin-dependent disruption of innate immune and glutamatergic signaling between microglia and neurons in AD mice. Patients with AD also showed a correlation of cerebrospinal fluid (CSF) fibrinogen levels with biomarkers of inflammation, vascular and synaptic dysfunction. Thus, resilience to neuronal hyperactivity and restoration of the neuroimmune interactome by targeting fibrin may have therapeutic implications for Alzheimer's disease and related conditions.

HIGHLIGHTS: Vascular-microglia axis drives neuronal hyperactivityFibrin inflammatory activity disrupts the microglia-neuron interactomeMicroglia activation by fibrin impairs decision-making in AD miceSynaptic dysfunction and immune biomarkers correlate with CSF fibrinogen in AD patients.},
}

@article {pmid42146666,
year = {2026},
author = {Liu, Z and Ma, X and Ribas, RA and Medina, T and Quinones, S and Son, J and Wu, L and Ryan, AM and Shedlock, C and Ziani, B and Barco-Caiaffa, V and Rao, N and Wong, K and Titus, A and Larson, R and Vander Kooi, CW and Chandel, NS and Gentry, MS and Chen, L and Sun, RC},
title = {Metabolic Coherence of the Mouse Brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.07.723592},
pmid = {42146666},
issn = {2692-8205},
abstract = {The brain's metabolic demands are well established, but how metabolism is coordinated across anatomically distinct regions remains poorly understood. Here, using matrix-assisted laser desorption/ionization (MALDI) imaging integrated with the Allen Brain Atlas and optimal transport-based computational analysis, we map the spatial metabolome across twelve major mouse brain divisions. We define an optimal-transport-derived inter-regional metabolite similarity metric and refer to it as metabolic coherence. This structure is largely preserved in an amyloid mouse model of Alzheimer's disease despite widespread changes in individual metabolite and lipid levels. Individual metabolites and lipids shift in a coordinated manner across regions, sustaining inter-regional relationships even as absolute levels change in patterns indicative of mitochondrial dysfunction. To test whether the coherence metric is responsive to local intervention, we targeted the left hippocampus of mice from this model via lentiviral shHIF1α knockdown or neuronal AAV-mediated AOX expression. Both interventions were associated with metabolite normalization at the injection site. More importantly, normalization extended across distal regions sharing high metabolic similarity with the hippocampus and was accompanied by improved social memory in a single behavioral assay. Gene modulation and amyloid plaque reduction localized to the injection site.},
}

@article {pmid42146670,
year = {2026},
author = {Yang, Y and Gao, N and Sharma, N and Dai, S and Su, G and Dinga, R and Selvaggi, P and Krüger, J and Cai, Y and Liang, L and Liu, Z and Rutherford, S and Guo, T and Wolfers, T and , },
title = {Lamellar Normative Modelling of the Hippocampus Across the Human Lifespan.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.02.722431},
pmid = {42146670},
issn = {2692-8205},
abstract = {The hippocampus is a central hub of human memory and cognition and is closely associated with brain disorders. Studies have shown that it exhibits complex structural variation across the lifespan, yet the details of hippocampal morphology changes remain poorly understood. Here, we establish norms over the hippocampal geometry that resolve lamellar morphology and map lifespan trajectories across more than 27,000 individuals from 158 scanning sites. Hippocampal geometry shows spatially non-uniform developmental and ageing patterns across the lifespan, with lamellar thickness, width and length following dissociable trajectories. Across multiple brain disorders, this representation reveals localized and heterogeneous alterations beyond conventional subfield-level summaries, and uncovers a dichotomy in disease-associated patterns, with neurodegenerative conditions and schizophrenia showing predominant atrophy, whereas some other disorders exhibit focal or regionally selective hypertrophy. Transfer to a longitudinal Alzheimer's Disease Neuroimaging Initiative cohort further supports out-of-sample generalization of our approach and enables individual-level tracking and conversion risk stratification. Overall, this work establishes a population-scale geometric reference for the hippocampus, extends normative brain mapping from coarse regional phenotypes to anatomically organized subcortical structure, and enables anatomically grounded characterization of disease-related alterations and individual-level deviation mapping, providing a principled basis for understanding and stratifying brain disorders across the lifespan in health and disease.},
}

@article {pmid42146687,
year = {2026},
author = {Xu, FH and Duong-Tran, D and Huang, H and Saykin, AJ and Thompson, PM and Davatzikos, C and Zhao, Y and Shen, L and , },
title = {Gene-Modulated Network Diffusion for Improved Modeling of Amyloid- β Spread in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.722725},
pmid = {42146687},
issn = {2692-8205},
abstract = {Understanding the pathogenesis of amyloid- β pathology in Alzheimer's Disease (AD) proves to be a challenge. In this work, we expand upon the application of network diffusion models (NDM) to study pathophysiological spread of amyloid- β throughout white matter structural brain networks. We found that the NDM successfully recaptures subpopulation-level spatial patterns (Pearson's R=0.45-0.48, P FDR < 0.01) of amyloid- β deposition in the Alzheimer's Disease Neuroimaging Cohort at a regional level, but with drawbacks in mechanism interpretability. We then moved to an extended NDM framework (eNDM), including a protein synthesis term to better reflect the role of amyloid- β metabolism, as well as including regional vulnerability using spatial transcriptomics from the Allen Human Brain Atlas to modulate the region-level rate parameters of the synthesis term. The novel gene eNDMs exhibited significant performance increases in Pearson's correlation (Steiger's Z, P FDR < 0.10) over baseline NDM performance in mild cognitive impairment and AD groups using APOE, SORL1, and FGL2 for gene modulation. The results were robust and replicable when testing on an external cohort of the Alzheimer's Disease Sequencing Project. The study thus demonstrates the importance of regional genetic vulnerability, in conjunction with network diffusion mechanisms, in improving the modelling and prediction of amyloid- β pathophysiological spread.},
}

@article {pmid42146696,
year = {2026},
author = {Li, Y and Margoliash, J and Goren, A and Gymrek, M},
title = {The contribution of short tandem repeats to splicing variation in the human cortex.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.721407},
pmid = {42146696},
issn = {2692-8205},
abstract = {Splicing disruption has been implicated in a range of heritable phenotypes, including numerous psychiatric and neurological disorders. Recent studies have identified thousands of common genetic variants impacting splicing in brain and other tissues, but have focused largely on single nucleotide polymorphisms or short indels. Despite growing evidence that genetic variation at short tandem repeats (STRs) influences splicing, large-scale studies of STR-mediated splicing in brain have been limited by low sample sizes of available RNA-seq data or exclusion of certain classes of STRs, such as homopolymers which account for around half of all STRs. In this study, we leveraged deep RNA-seq and SNP array data from 336 human dorsolateral prefrontal cortex (DLPFC) samples collected by the Human Brain Collection Core (HBCC). We imputed 445,720 STRs into available genotype data and identified 51,343 unique STRs for which copy number is significantly associated with one or multiple alternative splicing events of nearby genes (spliceSTRs). We prioritized and characterized candidate causal spliceSTRs using three orthogonal fine-mapping strategies which identified 1,313 high-confidence fine-mapped spliceSTRs. Our analyses revealed strong associations between copy number of certain repeat units and binding of specific RNA-binding proteins (RBPs), including a previously known relationship between HNRNPL and AC repeat length, suggesting that the functional impact of some spliceSTRs may be mediated through their binding affinity for RBPs. Finally, co-localization analyses using summary statistics from genome-wide association studies (GWAS) for 6 brain-related disorders identified multiple signals that may be driven by spliceSTRs, including a previously identified GT n repeat that is a spliceSTR for PLEKHA1 associated with Alzheimer's disease as well as a newly identified AGG n spliceSTR in SEPTIN3 co-localized with schizophrenia. Together, our findings highlight the role of STRs in regulating alternative splicing in the human brain, suggest a general relationship between STR polymorphism and RBP-mediated splicing events, and support the hypothesis that splicing variation mediated by STRs plays a role in risk for brain-related disorders.},
}

@article {pmid42146852,
year = {2026},
author = {D'Amelio, C and Feroleto, C and Caligiuri, C and Li Puma, DD and De Chiara, G and Paoletti, I and Codazzi, C and D'Alelio, F and Miraglia, F and Pappalettera, C and Nucci, L and Frasca, F and Ventura, L and Manca, A and Morrone, M and Leone, L and Deriu, F and Morotti, M and Grassi, C and Vecchio, F and Podda, MV},
title = {EEG-motor correlation as early Alzheimer's disease index in herpes simplex virus type-1-infected mice.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag128},
pmid = {42146852},
issn = {2632-1297},
abstract = {Alzheimer's disease is a neurodegenerative disorder characterized by cognitive decline and memory impairment. Early treatment requires reliable tests to identify the initial manifestations for developing treatments that modify disease progression. Neuroinflammation has been implicated as a key driver of the onset and progression of Alzheimer's disease. Herpes simplex virus type-1 (HSV-1), a neurotropic virus that establishes latency within the central nervous system, has been associated with increased proinflammatory cytokines, cognitive impairment and Alzheimer's disease-like pathology in human and rodent brains. This study employed a murine model showing an Alzheimer's disease-related phenotype, induced by HSV-1 infection and recurrent reactivation through thermal stress, to investigate previously unexplored motor function impairments and their correlation with EEG changes predictive of Alzheimer's disease-like pathology. Mice were subjected to two (2×TS) or seven thermal stress (7×TS) HSV-1 reactivations to reproduce mild and severe cognitive impairments, respectively, and were tested for recognition memory using the Novel Object Recognition test and for spatial memory using the Y-maze test. Motor performance was assessed using grip strength and grid walking tests. Local field potential recordings, immunohistochemical, morphological and molecular analyses were performed to characterize the effects of HSV-1 on neural circuits. 2×TS HSV-1 mice showed a reduced preference index in Novel Object Recognition compared to mice receiving mock infection (i.e. vehicle inoculum), whereas 7×TS HSV-1 mice displayed severe cognitive decline across the different memory domains. Motor function was preserved after the second thermal stress but was impaired after the seventh thermal stress, with reduced forelimb force and increased foot faults starting from the fourth reactivation. Following the seventh reactivation, HSV-1 mice showed astrogliosis and phosphorylated Tau accumulation. In vivo, electrophysiological recordings revealed increased functional connectivity across frequency bands in 2×TS HSV-1 mice compared to controls, with negative correlations between total coherence and grip strength. Increased spine density in the frontal cortex of 2×TS HSV-1 mice supports early neuronal network alterations. From a translational perspective, we preliminarily evaluated comparable motor indices in healthy human participants, in patients with mild cognitive impairment, and in patients with Alzheimer's disease. As expected, both grip strength and dynamic balance were lower in patients with Alzheimer's disease compared to healthy and mild cognitive impairment subjects. Notably, grip strength was significantly reduced in mild cognitive impairment subjects, who displayed early motor impairment. Our findings highlight the potential of EEG-based biomarkers for early Alzheimer's disease detection and suggest motor indices as novel prognostic markers.},
}

@article {pmid42146858,
year = {2026},
author = {Core, LB and Froud, SA and Wastling, S and Jiang, J and Levett, BA and Mancini, L and Dymerska, B and Hardy, CJD and Zeidman, P and Warren, JD},
title = {Functional neuroanatomy of musical object processing in Alzheimer's disease and frontotemporal dementia.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag161},
pmid = {42146858},
issn = {2632-1297},
abstract = {Music, besides its emotional and social resonance, models a complex sensory environment exemplifying auditory objects corresponding to sources (musical instruments) and information streams (melodies). These musical dimensions can be variably preserved or blighted by neurodegenerative disease. Music is, therefore, an attractive way to investigate the neural mechanisms of sensory object processing in these diseases. Here, we assessed the functional neuroanatomy underlying the perceptual, semantic, and apperceptive processing of musical objects in Alzheimer's disease and temporal variant frontotemporal dementia. We studied 35 patients (20 Alzheimer's disease, 15 temporal variant frontotemporal dementia; 14 females; mean [standard deviation] age 70.3 [8.4] years) in relation to 25 cognitively healthy volunteers (16 females; age 69.5 [6.8] years). In a functional MRI experiment with sparse image acquisition to minimise the impact of scanner noise, participants passively listened to monophonic melodies. We varied timbre (same/change), timbre familiarity (natural/artificial instruments), melody familiarity (familiar/novel), and apperception (melodies with interpolated timbre changes); these manipulations allowed us to assess the functional neuroanatomical correlates of musical feature perception, melody familiarity, constancy, novelty, and instrument familiarity. Behavioural correlates were assessed in post-scan tasks and disease-related atrophy patterns using voxel-based morphometry of participants' structural scans. All contrasts were assessed at P < 0.05, corrected for multiple voxel-wise comparisons within pre-specified anatomical regions of interest. For timbre change perception, all participant groups demonstrated comparable temporo-parietal cortical activation anchored in planum temporale. For melodies, processing of semantic familiarity in all participant groups engaged a common network including supplementary motor area and inferior frontal gyrus, with reduced supplementary motor area activation in the Alzheimer's disease group compared with other groups, while melody novelty comparably engaged postero-medial cortical circuitry across groups. Apperceptive coding of melody constancy was associated with activation of the posterior superior temporal cortex in the healthy volunteers, but greater activation of the temporal polar cortex in the temporal variant frontotemporal dementia group than in healthy volunteers. For instrument familiarity, the temporal variant frontotemporal dementia group showed reduced activation of the temporal polar cortex, but increased activation of the anterior insula compared to healthy volunteers. Brain activation profiles were not influenced by behavioural performance on post-scan tasks and did not coincide with regional atrophy. Our findings delineate complex, differentiated functional neuroanatomical profiles of musical object processing in Alzheimer's disease and frontotemporal dementia, with implications for our understanding of the neural mechanisms that decode complex sensory environments and the design and evaluation of interventions in these diseases.},
}

@article {pmid42146883,
year = {2026},
author = {García-Alberca, JM and Mendoza, S and DE LA Guía, P and López DE LA Rica, M},
title = {Effectiveness of Souvenaid® combined with acetylcholinesterase inhibitors on caregiver burden in Alzheimer´s disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70262},
pmid = {42146883},
issn = {2352-8737},
abstract = {INTRODUCTION: The burden experienced by caregivers of Alzheimer´s disease (AD) patients is a complex and stressful situation influenced by distinct variables, such as the patient´s need for monitoring, social isolation, mental or physical health problems, or financial challenges. In additon, behavioral and psychological symptoms of dementia are strongly associated with caregiver experiences of burden.

METHODS: This was a 12-month, retrospective, single-center, real-world study to evaluate the effectiveness of the combined treatment with Souvenaid and acetylcholinesterase inhibitors (AChEI) compared to treatment with either AChEI alone or Souvenaid alone on caregiver burden, anxiety and depression in patients, and AD patients attending a memory clinic. Assessments were conducted using the Zarit Burden Interview (ZBI), the Beck Depression Inventory (BDI), the State Trait Anxiety Inventory-State (STAI-S), and the Neuropsychiatric Inventory-Caregiver distress scale (NPI-D). A mixed model for repeated measures was conducted to evaluate differences from baseline to month 12 between caregivers in the three treatment groups.

RESULTS: At 12 months, caregiver burden, depression, anxiety levels, and the emotional distress in the context of behavioral and psychological symptoms of dementia (BPSD) improved in caregivers in the Souvenaid plus AChEI group (n = 70) compared to those in the AChEI group (n = 84) and those in the Souvenaid group (n = 66).The mean change for the ZBI score was found to be significantly higher in the Souvenaid plus AChEI group than in the AChEI group (p < 0.001) and the Souvenaid group (p < 0.001). In addition, there was a significant difference in the mean change for the BDI, STAI-S, and NPI-D scores between groups, favoring the Souvenaid plus AChEI group over the AChEI and Souvenaid groups.

DISCUSSION: In addition to assessing patients' cognitive, behavioral, and daily functioning, it is recommended regular monitoring of caregiver burden while providing support for patients with dementia. The combined treatment with Souvenaid and AChEI may have a significant impact on caregivers' experience of burden.},
}

@article {pmid42146901,
year = {2026},
author = {Al-Ouran, R and Liu, C and Wang, L and Yu, Z and Wan, YW and Gu, C and Li, X and Cappuccio, G and Maletic-Savatic, M and Milosavljevic, A and Shulman, JM and Chen, H and Liu, Z},
title = {Latent Factor Modeling Reveals Unexpected Spatial Heterogeneity in Human Alzheimer's Disease Brain Transcriptomes.},
journal = {Computational and structural biotechnology journal},
volume = {35},
number = {1},
pages = {0108},
pmid = {42146901},
issn = {2001-0370},
abstract = {Alzheimer's disease is characterized by complex molecular and cellular heterogeneity, which complicates efforts to identify consistent biomarkers and therapeutic targets. To better characterize the heterogeneity, we applied latent factor modeling to RNA sequencing data from approximately 2,500 human Alzheimer's disease brain samples, uncovering underlying patterns in gene expression. These transcriptional groups demonstrated unique gene expression profiles related to synaptic and neuronal pathways, vasculature development, and protein folding and antigen processing. Notably, this latent factor reflects variation in spatial sampling. Adjusting for the latent factor improved the identification of differentially expressed genes in disease samples. This finding suggests that spatial heterogeneity is a pervasive driver of transcriptomic variation and has important implications for future studies of Alzheimer's disease and related neurological disorders.},
}

@article {pmid42147164,
year = {2026},
author = {Zafari, R and Kamroo, A and Taherkhani, T and Heidari-Foroozan, M and Nabizdeh, F and Aarabi, MH},
title = {DTI-ALPS Is Associated with Temporolimbic Amyloid but Not Plasma p-Tau181 Across the Alzheimer's Disease Continuum.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9382890/v1},
pmid = {42147164},
issn = {2693-5015},
abstract = {Background: Alzheimer's disease (AD) is the most common cause of dementia, characterized by progressive aggregation of misfolded proteins. Accumulation of amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) is the hallmark pathology of AD. Diffusion tensor imaging along the perivascular spaces (DTI-ALPS) has been proposed as an MRI marker related to perivascular diffusivity patterns and has been used in studies of neurodegenerative disease. Aims: This study investigates the association between the association between DTI-ALPS indices, regional amyloid-PET burden, and plasma p-tau181 across the AD spectrum. Methods: Data from 410 individuals was enrolled from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. DTI-ALPS was used as an imaging proxy related to perivascular diffusivity patterns. Results: Mean DTI-ALPS declined progressively from healthy controls to AD. Moreover, females reflected higher DTI-ALPS indices compared with males. No significant associations were observed between perivascular diffusivity patterns and plasma concentration of p-tau 181 in patients with cognitive decline. In contrast, the global cortical amyloid-PET SUVR was associated with the mean [β = -0.163] and right DTI-ALPS indices in the MCI group [β = -0.202]. Moreover, we observed stronger associations between DTI-ALPS index and amyloid-PET SUVR in the temporal pole cortex [β = -0.199], entorhinal cortex [β = -0.224], and parahippocampal gyrus in patients with MCI [β = -0.281]. Conclusions: Reduced DTI-ALPS indices were associated with increased temporolimbic amyloid deposition, particularly in individuals with MCI. These findings suggest DTI-ALPS-derived perivascular diffusivity as an imaging marker associated with amyloid burden in prodromal AD.},
}

@article {pmid42147167,
year = {2026},
author = {Armstrong, AM and O'Brien, EK and Fernandez, SM and Doré, V and Bourgeat, P and Shishegar, R and Maruff, P and Rowe, CC and Villemagne, VL and Initiative, TADN and Group, TAR and Porter, T and Laws, SM},
title = {Genetic variation in the glymphatic pathway predicts cognition and neurodegeneration in preclinical Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9444687/v1},
pmid = {42147167},
issn = {2693-5015},
abstract = {Background Impaired glymphatic clearance has been implicated in Alzheimer's disease (AD) through reduced clearance of amyloid-β (Aβ) and other metabolites from the brain. Mislocalisation of aquaporin-4 (AQP4), a water channel protein anchored to astrocytic endfeet by the dystrophin-associated complex (DAC), has been linked to increased Aβ accumulation, neurodegeneration and cognitive impairment. In animal models, genetic ablation of DAC subunits, leading to AQP4 mislocalisation, increases Aβ accumulation. Genetic variation in AQP4 has been examined in the context of AD, but variation in key DAC genes has not been systematically investigated in humans. This study examined whether variation within glymphatic pathway genes is associated with AD-related phenotypes in individuals on the AD trajectory. Methods Associations between genetic variation in glymphatic pathway-related genes (AQP4 and three DAC genes: DAG1 , DTNA , and SNTA1) and brain Aβ burden, cognition and regional brain volumes were analysed in two longitudinal cohorts of cognitively unimpaired older adults who were Aβ-positive or demonstrated ongoing Aβ accumulation. Linear regression models assessed cross-sectional and longitudinal outcomes within each cohort, followed by a meta-analysis. Pathway-based glymphatic genetic risk scores (G-GRS) were constructed to assess cumulative genetic impact. Results At the single-variant level, AQP4 , DTNA , and DAG1 showed significant associations with cognition, grey matter atrophy, and ventricular volume after correction for multiple testing. Variants in AQP4 (rs10502478 and rs10164026) were associated with differences in cross-sectional PACC scores. Whilst rs45556134 within DTNA was associated with grey matter atrophy. Further, six variants (rs13079082 DAG1 , rs8092794, rs17642885, rs7233779, rs78837792 and rs79500711 DTNA) were associated with cross-sectional ventricular volumes. At the polygenic level, higher G-GRS were associated with lower grey matter volume, faster grey matter atrophy, larger ventricular volumes and lower cognitive composite scores. Conclusions Variation within key glymphatic pathway genes is associated with early differences in cognition and neurodegeneration-related brain measures in cognitively unimpaired Aβ-positive older adults. These findings support a contributory role for glymphatic pathway dysfunction in early AD-related brain vulnerability and identify glymphatic pathway genetic risk as a potential marker for risk stratification. A limitation of this study is the absence of direct experimental measures of glymphatic clearance function, which will be required to confirm the functional impact of these genetic findings.},
}

@article {pmid42147188,
year = {2026},
author = {Chai, Y and Zhang, H and Kim, AS and Sun, Q and Chen, S and Ha, J and Kang, KW and Cen, H and Shin, JW and Park, G and Choi, J and Kim, M and Jahanshad, N and Thompson, PM and Chui, HC and Wang, DJ and Lim, DC and Joo, EY and Toga, AW and Kim, H},
title = {Multimodal Free-Water Imaging Links Cardiometabolic Risk to Periarterial Dysfunction and Amyloid Accumulation in Early Alzheimer's.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9374985/v1},
pmid = {42147188},
issn = {2693-5015},
abstract = {The brain's waste-clearance (glymphatic) system removes metabolic byproducts via periarterial influx, interstitial exchange, and perivenous efflux. Although dysfunction is implicated in Alzheimer's disease (AD), current imaging markers emphasize perivenous changes and may overlook earlier periarterial impairment. We developed a diffusion MRI framework to quantify periarterial fluid mobility, white matter free water, and perivenous integrity, and applied it to 546 cognitively normal adults (HCP-Aging) and 173 participants across the AD spectrum (ADNI). Periarterial mobility was reduced with higher cardiometabolic risk and amyloid positivity, particularly in AD-vulnerable regions. Free water increased with aging and metabolic burden, whereas perivenous dysfunction was most pronounced in AD. Combined measures predicted amyloid positivity and cognitive impairment (AUC = 0.82). Mediation analyses showed that blood pressure influenced cognition through periarterial dysfunction and amyloid burden. These findings support a staged, compartment-specific trajectory of glymphatic dysfunction, with early periarterial impairment representing a potential biomarker and therapeutic target.},
}

@article {pmid42147196,
year = {2026},
author = {Parker, D and Yi, E and Tang, W and Bamford, A and Taylor, L and Simmons, S and Meza, N and Tuteja, N and Avila, B and Chang, E and Bock, J and McMillan, L and Kim, S and Adams, J and Thomas, E and Jacobs, E and Yassa, M},
title = {Sex-specific immune-brain coupling in hippocampal circuits and Alzheimer's disease vulnerability.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9580437/v1},
pmid = {42147196},
issn = {2693-5015},
abstract = {Women face twice the lifetime risk of Alzheimer's disease (AD) compared with men. Inflammatory burden is widely implicated in AD, but whether sex-differentiated vulnerability is determined by cytokine levels or by the brain's sensitivity to those signals remains unclear. Here, we examined sex-specific associations between peripheral inflammatory markers, medial temporal lobe (MTL) white matter microstructure using NODDI diffusion MRI, and hippocampal-dependent memory in 121 cognitively unimpaired older adults. Women exhibited widespread alterations in MTL white matter microstructure relative to men. In women, peripheral cytokines (TNFα, IL-10) were associated with microstructural variation in hippocampal-prefrontal tracts, whereas these associations were absent in men. An indirect association between TNFα and memory through hippocampal cingulum neurite density was observed only in women. Despite these microstructural and coupling differences, cytokine levels were comparable between sexes, indicating that risk may be better captured by the coupling between peripheral immune signals and circuit integrity than by cytokine levels alone. These findings identify a sex-specific pattern of immune-brain coupling that reframes inflammatory risk in AD as a property of circuit-level sensitivity rather than overall inflammatory burden.},
}

@article {pmid42147211,
year = {2024},
author = {Prinz, A and Buerger, D and Krafft, J and Bergmann, M and Woll, A and Barisch-Fritz, B and Witte, K},
title = {Use of Immersive Virtual Reality in Nursing Homes for People With Dementia: Feasibility Study to Assess Cognitive, Motor, and Emotional Responses.},
journal = {JMIR XR and spatial computing},
volume = {1},
number = {},
pages = {e54724},
pmid = {42147211},
issn = {2818-3045},
abstract = {BACKGROUND: Physical activity interventions for people with dementia have shown promising effects in improving cognition and physical function or slowing disease-related decline. Immersive virtual reality (iVR), using head-mounted displays, facilitates realistic experiences by blurring the boundaries between VR and the real world. The use of iVR for people with dementia offers the potential to increase active time and improve dementia therapy and care through exercise interventions. However, the feasibility of using VR use in people with dementia, considering changes in motor, cognitive, psychological, and physiological parameters, remains insufficiently investigated.

OBJECTIVE: This study aims to investigate the feasibility of using iVR in people with dementia or mild cognitive impairment in nursing homes. Specifically, we examined changes in motor performance (balance and mobility), cognitive performance (global cognition and executive functions), emotional responses, and fear of falling using iVR.

METHODS: Utilizing a pre-post design, this study recruited 35 participants with mild-to-moderate dementia, assessed by the Mini-Mental State Examination (MMSE). Participants underwent a single session involving iVR exposure, with pre- and postexposure assessments and a feedback form, to exclude negative effects on cognitive and motor functions, mood, anxiety levels, and balance performance. The use of iVR involved 4 scenes, with a total length of 8 minutes. These scenes depicted a park with short and rather passive impressions presented as a 360° video in a head-mounted display. Before and after using the iVR, cognitive parameters were assessed using the Trail-Making Test A (TMT-A), motor parameters were assessed using the FICSIT-4 (Frailty and Injuries: Cooperative Studies of Intervention Techniques-4) and Timed-Up-and-Go (TUG) tests, and psychological parameters were assessed using the Dementia Mood Picture Test, State-Trait Anxiety Inventory, and Short Falls Efficacy Scale-International (Short FES-I). The Emotion Rating Scale and the duration of use were recorded during use, and a feedback questionnaire was completed afterward in addition to the posttests. Paired t tests and Wilcoxon tests were used to examine pre-post differences.

RESULTS: Of the 35 initial participants, 33 completed the study, which corresponds to a dropout rate of 6%. All 33 participants, who had a mean of 83.71 (SD 5.01) years, had dementia. They showed no statistically significant difference in cognitive and motor performance before and after iVR use. Thus, no negative effects on cognitive and motor functions, mood, anxiety levels, and balance performance were observed. The emotion rating scale also showed that 72% (n=24) felt joy and fun during iVR use, 100% (n=33) showed no emotions such as fear, sadness, or anger, and 93% (n=31) were attentive during iVR use.

CONCLUSIONS: The feasibility of using iVR for people with dementia can be rated positively. There were no changes in motor, cognitive, or emotional parameters that would increase the risk of falls or other negative emotional reactions during or after iVR use. Further studies are needed to investigate prolonged use in a more stimulating computer-generated environment and possible physical and cognitive tasks for people with dementia in nursing homes.

TRIAL REGISTRATION: German Clinical Trials Register DRKS00030616; https://drks.de/search/de/trial/DRKS00030616.},
}

@article {pmid42147337,
year = {2026},
author = {Li, Z and Chen, H and Li, X and Yang, A and Wang, X and Liu, S and Ning, X and Zhou, L and Zheng, F and Xun, F and Hu, B and Cui, Y and Yao, D and Gao, X and Xu, Z and Zhao, Q},
title = {Pharmacokinetics, distribution, metabolism, excretion and safety characterization of ZJCK-6-72: novel DYRK1A inhibitor with optimized brain exposure for Alzheimer's disease therapy.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1792258},
pmid = {42147337},
issn = {1663-9812},
abstract = {UNLABELLED: Developing effective drugs for Alzheimer's Disease (AD) is critically limited by insufficient brain exposure. To address this, structural optimization was employed to balance physicochemical properties and enhance blood-brain barrier (BBB) permeability, resulting in the development of ZJCK-6-72, a novel DYRK1A inhibitor. This study aims to comprehensively evaluate the drug-like properties and safety profile of ZJCK-6-72.

METHODS: A comprehensive in vitro and in vivo ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling of ZJCK-6-72 was conducted. Key assessments included pharmacokinetics, tissue distribution studies in rats, plasma protein binding assays, and metabolic stability testing. Additionally, acute toxicity was evaluated to determine the safety margin, and enzyme inhibition assays were performed to assess potential drug-drug interactions.

RESULTS: ZJCK-6-72 exhibited excellent oral bioavailability (78.03%) and extensive tissue distribution in rats. Notably, the compound demonstrated substantially enhanced brain penetration, with a brain-to-plasma ratio ranging from 1.92 to 4.63. The unbound brain-to-plasma partition coefficient (Kp, uu) was determined to be 3.50, significantly exceeding unity. Metabolic studies indicated a shift towards CYP1A2 and CYP2C19 mediated pathways, with concentration-dependent inhibition observed (IC50 ≈ 1.8 μM). The acute toxicity assessment revealed an LD50 of 233.9 mg/kg bodyweight.

DISCUSSION: The high Kp, uu value indicates that the efficient brain entry of ZJCK-6-72 is likely driven by active uptake mechanisms rather than simple passive diffusion, confirming its ability to effectively evade efflux transporters. Although the inhibition of CYP1A2 and CYP2C19 suggests a potential for mechanism-based auto-inhibition, the acute toxicity profile demonstrates an acceptable safety margin for therapeutic development.

CONCLUSION: ZJCK-6-72 displays an optimized pharmacokinetics profile characterized by superior unbound brain exposure. These findings support the potential of ZJCK-6-72 as a promising lead candidate for CNS-targeted AD therapy.},
}

@article {pmid42147344,
year = {2026},
author = {Geerts, H and Short, SM and Grant, A and van der Graaf, PH},
title = {Understanding quantitative effects of anti-amyloid therapies on tau biomarkers and functional outcome. Insights from a comprehensive mechanistic quantitative systems pharmacology study.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1813290},
pmid = {42147344},
issn = {1663-9812},
abstract = {INTRODUCTION: Anti-amyloid antibodies have the potential to become the standard of care in Alzheimer's Disease (AD) and large datasets from clinical trials allow the testing of predictive models on fluid biomarkers and functional outcomes. However, identifying an easily accessible biomarker to determine the time to switch to maintenance therapy, and identifying patient profiles with optimal cognitive benefit, are still unresolved issues in clinical practice.

METHODS: Predicted changes in monomers, oligomers, protofibrils and plaques were simulated using a well-validated Quantitative Systems Pharmacology model based on biophysical and biological assumptions of amyloid synthesis, aggregation and clearance. This model was combined with a previously calibrated computational neuronal network model of cognitive outcome in AD patients by introducing the effect of amyloid and tau oligomers on specific voltage- and ligand-gated ion channels, informed by preclinical studies.

RESULTS: The model accounted for 70% and 50% of the variance of clinically observed changes in plasma p-tau181 and Clinical Dementia Rating-Sum Of Boxes (CDR-SOB) respectively, in clinical trials of seven amyloid antibodies. We derived an antibody specific normalized decrease of plasma p-tau181 (-15% for donanemab, -45% for aducanumab and -75% for lecanemab) to determine trial duration for achieving central amyloid negativity. Using the concept of information processing bandwidth, the model suggests that anti-amyloid antibodies slow the cognitive worsening compared to placebo while at the same time lowering plasma p-tau181 levels by reducing neuronal firing. Finally, the model suggests that independently from the degree of amyloid reduction, the beneficial cognitive effect of treatment decreases with more advanced neuronal pathology and higher baseline tau-load. This provides a hypothesis for the impact of disease pathology and gender effect on functional outcomes with lecanemab and gantenerumab.

DISCUSSION: With further validation, this model has the capability to support optimization of clinical trial design for amyloid-tau combination therapy.},
}

@article {pmid42147463,
year = {2026},
author = {Saeed, F and Siepker, KL and Jang, S and Shahdadian, S and Liu, H},
title = {Cerebrovascular-CSF coupling measured by broadband near-infrared spectroscopy as a physiological marker of brain aging and Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1757765},
pmid = {42147463},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is strongly associated with cerebrovascular dysfunction and impaired glymphatic clearance. These dysfunctions may precede, contribute to, and interact bidirectionally with AD pathology, highlighting the importance of identifying physiological markers for the early detection of AD. Noninvasive approaches for assessing these processes and identifying early biomarkers remain limited. Cerebrospinal fluid (CSF) plays a central role in clearing neurotoxins from the brain, but current methods for quantifying CSF dynamics are invasive, costly, and not well suited for early detection of AD.

METHODS: Broadband near-infrared spectroscopy (bbNIRS) provides a promising alternative by enabling noninvasive measurement of total hemoglobin concentration (HbT) and CSF-related free-water fluctuations in the prefrontal cortex (PFC). In this study, we quantified cerebrovascular-CSF coupling using two-channel bbNIRS (2bbNIRS) in three groups: healthy young adults (YA; n = 26), healthy older adults (OA; n = 27), and early-stage AD patients (n = 16). Time series data of 7-min Δ[HbT] and CSF-related Δ[H2O]free dynamics were extracted and analyzed within three distinct infraslow oscillatory frequency (endogenic, neurogenic, and myogenic) bands. Linear correlation coefficients and slopes between Δ[HbT] and Δ[H2O]free signals were computed to quantify HbT-CSF coupling at each frequency band for each of the three groups, followed by statistical comparisons after Fisher transformation and ANOVA with Bonferroni correction.

RESULTS: The results showed that (1) HbT-CSF coupling was significantly stronger in the AD group than in healthy OA across all frequency bands, and (2) coupling exhibited clear age dependence, with YA showing the weakest prefrontal HbT-CSF coupling.

DISCUSSION: These trends may reflect age- and disease-related reductions in cerebrovascular elasticity and intracranial compliance. Enhanced coupling in the AD group may represent an early compensatory response to impaired CSF transport. Overall, this work demonstrates that 2bbNIRS offers a noninvasive, low-cost method for quantifying cerebrovascular-CSF interactions in the human PFC, with promising potential as a physiological marker of brain aging and early AD.},
}

@article {pmid42147618,
year = {2026},
author = {Sewell, DD and Kallenberg, G and Mandel, B and Mandvi, A and Asmus, L and Neel, IC and Heimler, G and Andrew, W and Lobatz, M},
title = {Enhancing Dementia Care in Primary Care: Impact of Targeted Training and Electronic Medical Record (EMR)-Integrated Algorithms.},
journal = {Cureus},
volume = {18},
number = {4},
pages = {e107031},
pmid = {42147618},
issn = {2168-8184},
abstract = {INTRODUCTION: The number of medical specialists whose training programs provide robust education in dementia diagnosis and treatment pales in comparison to the increasing number of individuals living with dementia. Primary care providers (PCPs) care for most older adults with cognitive concerns and dementia. Summarized here are the results of an effort to help PCPs care for these patients using targeted training and electronic medical record (EMR)-integrated clinical algorithms.

METHODS: Clinicians from two University of California San Diego Family Medicine Clinics completed assessments of dementia knowledge and comfort in caring for patients and family members impacted by dementia four times: enrollment, and approximately two, nine and 15 months after a three-component intervention: 1) training via four online educational modules (six hours total) on screening, evaluation, and care of patients with dementia; 2) integration of clinical algorithms into the EMR system and 3) access to mentoring from a more experienced peer.

RESULTS: Subjective assessment of comfort and competence of intervention group clinicians in working with patients with cognitive complaints significantly increased and was higher for intervention group PCPs than the comparison group PCPs. Evidence of completed AD8s (Eight-Item Informant Interview to Differentiate Aging and Dementia) at both clinics increased from baseline to post-intervention: 52.85% to 82.6% and 66.1% to 86.9%.

DISCUSSION: Training PCPs on dementia screening and diagnosis, and integration of algorithms into the EMR, improved clinician subjective competence and comfort in caring for patients with cognitive complaints and increased the AD8 completion rate. The small number of study participants mandates caution when interpreting these findings.},
}

@article {pmid42147722,
year = {2026},
author = {Choi, W and Jang, MH and Kim, C and Park, EY},
title = {Ultrasonic modulation of brain glymphatic transport: from observations to theranostic applications.},
journal = {Cancer drug resistance (Alhambra, Calif.)},
volume = {9},
number = {},
pages = {12},
pmid = {42147722},
issn = {2578-532X},
abstract = {The glymphatic system in the brain controls the cerebrospinal fluid (CSF) circulation and metabolic waste clearance, which is crucial for understanding the mechanisms and therapeutic opportunities of various brain pathologies. With the rapidly growing interest in its relationship with neurodegenerative conditions, including Alzheimer's disease, its underlying processes are still not fully understood and remain under active investigation. A representative finding is that the glymphatic flow is passively driven by factors such as vascular pulsation, and studies have been conducted to modulate the glymphatic system using external stimuli to enhance waste clearance or to leverage CSF pathways for delivering chemotherapeutic agents. Particularly, glymphatic flow modulation holds great potential for improving drug delivery to the brain via intrathecal administration as an alternative to conventional systemic delivery, which is restricted by the blood-brain barrier (BBB). This review focuses on ultrasound (US) techniques for glymphatic system modulation, with the aim of augmenting glymphatic flow and ultimately improving drug delivery for brain cancer therapy. Given the limited number of cancer-related studies in the field, we comprehensively review US-based glymphatic modulation research to date and identify their implications and future opportunities for brain cancer applications.},
}

@article {pmid42147774,
year = {2025},
author = {Kaholokula, JK and Buchwald, D and MacLehose, R and Look, M and de Silva, M and Worthington Antonio, JK and Desimone, K and Yoshimura, S and Dillard, A and Kenney, M and Kealiʻihoʻomalu, C and Purdy, M},
title = {The adaptation and evaluation of a culturally grounded lifestyle intervention to mitigate the risk of Alzheimer's disease and related dementias in Native Hawaiians and Pacific Islanders: A study protocol.},
journal = {SSM. Mental health},
volume = {7},
number = {},
pages = {},
pmid = {42147774},
issn = {2666-5603},
}

@article {pmid42147791,
year = {2026},
author = {Gould, B and Bulsari, S and Di Cesare, M},
title = {What needs to be addressed in caring for people living with dementia? A multi-faceted evidence on financial, psychological, and physical health issues in dementia care.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1790741},
pmid = {42147791},
issn = {2813-3919},
abstract = {BACKGROUND: Dementia is a progressive neurodegenerative condition with 60.2 million cases worldwide. The disease has financial, psychological, and physical health implications for people affected and their carers. There is a dearth of literature exploring financial issues experienced by carers and persons living with dementia beyond the loss of income, while psychological implications have been studied in silos, and physical health implications have mostly focused on sleep deprivation. Our study aims to provide multi-faceted evidence on all three issues experienced by persons living with dementia and their carers.

METHODS: Semi-structured interviews, congruent with the social constructivist framework, were administered, recorded on Microsoft Teams, and transcribed for eight carers, four persons living with dementia excepts, and one participant who was both a carer and a person living with dementia. Participants were recruited using a purposive sampling approach through the local community-led friendly cafe groups in Essex. Transcripts were anonymised, and thematic analysis was undertaken.

RESULTS: Responses of the carers revealed concerns about the future financial situation, the expenses on respite care, and replacing the household equipment. Psychological implications for carers included a change in role from partner to carer, resulting in loneliness, loss of friends, coping with the deterioration in behaviour of the person living with dementia except, and relentlessness of care. One major physical health implication identified was exhaustion and the need to extend physical support, such as lifting the person living with dementia from a fall. Persons living with dementia hardly expressed concerns on the financial implications, though they narrated denial of diagnosis, feeling of loss of independence, and the changes in behaviour associated with dementia, among the psychological implications. The physical implications of the persons living with dementia largely included physical deterioration. Other issues, including feeling at loss of access to information, post-diagnostic medical support, and designs of public toilets, were also elicited from the interviews.

CONCLUSION: Given the interdependent nature of the issues experienced by persons living with dementia and their carers, an integrated approach to post-diagnostic support for information dissemination, counselling, and training for carers could help reduce both the physical and mental burden of dementia on patients and carers.},
}

@article {pmid42148080,
year = {2026},
author = {You, J and Liu, Q and Li, X},
title = {Anti-Aβ3-10 monoclonal antibody 7B8 improves cognitive function and protects the blood-brain barrier in APP/PS1 mice by regulating the HMGB-1/RAGE/NF-κB pathway.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1781351},
pmid = {42148080},
issn = {1664-3224},
mesh = {Animals ; *Blood-Brain Barrier/drug effects/metabolism/immunology ; Mice ; Mice, Transgenic ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; *Alzheimer Disease/metabolism/drug therapy/immunology ; *Cognition/drug effects ; Amyloid beta-Protein Precursor/genetics ; NF-kappa B/metabolism ; Signal Transduction/drug effects ; HMGB1 Protein/metabolism ; Disease Models, Animal ; *Antibodies, Monoclonal/pharmacology ; Presenilin-1/genetics ; Receptor for Advanced Glycation End Products/metabolism ; Male ; Mice, Inbred C57BL ; Humans ; *Peptide Fragments/immunology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent dementia, is primarily underpinned by the amyloid cascade hypothesis. Passive Aβ immunotherapy effectively reduces cerebral Aβ deposition but is limited by severe side effects, including cerebral amyloid angiopathy (CAA), microhemorrhage, and amyloid-related imaging abnormalities (ARIA). Here, we investigated the efficacy and safety of a novel anti-A3-10 monoclonal antibody (7B8) in APP/PS1 double-transgenic mice, with a focus on its impacts on amyloid clearance, neuroinflammation, and blood-brain barrier (BBB) integrity.

METHODS: 7B8 was generated by immunizing mice with A3-10-KLH. Six-month-old APP/PS1 mice were intraperitoneally injected with 7B8 (10 mg/kg) weekly for 8 doses (7B8 group). Age-matched APP/PS1 mice treated with IgG and C57BL/6J mice served as negative and wild-type (WT) controls, respectively. One week after the final injection, behavioral tests were performed, followed by euthanasia for histological (left brain hemisphere) and biochemical (right brain hemisphere) analyses.

RESULTS: Compared with the IgG group, the 7B8 group exhibited significantly reduced cerebral Aβ deposition and improved cognitive function (both P < 0.05), comparable to the WT group. Notably, in these young 6-month-old APP/PS1 mice with early-stage amyloid deposition and minimal CAA pathology, 7B8 treatment did not increase microhemorrhage risk relative to the IgG control group (P > 0.05). Furthermore, 7B8 preserved vascular integrity by reducing perivascular Aβ40 deposition and smooth muscle actin damage, while enhancing endothelial cell fluorescence intensity (P < 0.05). At the molecular level, 7B8 upregulated vascular LRP-1 and BBB tight junction proteins (ZO-1, CLDN-5, Occludin), and downregulated RAGE expression (P < 0.05). It also suppressed microglial and astrocytic activation, reduced levels of IL-6 and cortical TNF-α, and inhibited the HMGB-1/RAGE/NF-κB signaling pathway (P < 0.05), without affecting global TNF-α or IL-1β levels.

CONCLUSION: 7B8 effectively alleviates cognitive impairment and clears cerebral and perivascular amyloid deposits in young APP/PS1 mice with early-stage AD pathology and minimal CAA, with no increased risk of microhemorrhage in this experimental setting. It also protects vascular structure and BBB integrity by inhibiting the HMGB-1/RAGE/NF-κB-mediated neuroinflammatory response. Given the limitations of evaluating CAA-related safety in young mice, future studies using mid-aged (12-15-month-old) APP/PS1 mice with prominent CAA will be conducted to fully characterize 7B8's safety profile. These findings highlight 7B8 as a promising candidate for safe and effective AD immunotherapy, providing new insights into the development of ARIA-minimizing strategies.},
}

Animals
*Blood-Brain Barrier/drug effects/metabolism/immunology
Mice
Mice, Transgenic
*Amyloid beta-Peptides/immunology/antagonists & inhibitors
*Alzheimer Disease/metabolism/drug therapy/immunology
*Cognition/drug effects
Amyloid beta-Protein Precursor/genetics
NF-kappa B/metabolism
Signal Transduction/drug effects
HMGB1 Protein/metabolism
Disease Models, Animal
*Antibodies, Monoclonal/pharmacology
Presenilin-1/genetics
Receptor for Advanced Glycation End Products/metabolism
Male
Mice, Inbred C57BL
Humans
*Peptide Fragments/immunology

@article {pmid42148083,
year = {2026},
author = {Li, L and Wang, S and Duan, L and Zhang, L and Yan, H and Chen, X and Tao, L and Gao, Y},
title = {Ferroptosis-immune crosstalk in CNS diseases: mechanisms and translational insights.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1807104},
pmid = {42148083},
issn = {1664-3224},
mesh = {*Ferroptosis/immunology ; Humans ; Animals ; *Central Nervous System Diseases/immunology/metabolism/etiology/pathology ; Iron/metabolism ; },
abstract = {Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation, which plays a pivotal role in regulating the inflammatory-immune microenvironment of central nervous system (CNS) diseases. Mounting evidence indicates that dysregulated iron metabolism and an imbalance in antioxidant defenses can induce ferroptosis in neurons and glial cells while simultaneously remodeling immune cell function, thereby establishing a bidirectional feedback loop that amplifies neuroinflammation and tissue damage. In neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), pro-inflammatory cytokines such as TNF-α and IL-1β released by activated microglia upregulate neuronal iron transporters (e.g., DMT1 and TfR1), promoting iron accumulation and ferroptotic cell death. In turn, damage-associated molecular patterns released from ferroptotic cells further potentiate immune activation, forming a self-amplifying cycle. In contrast, within the glioma microenvironment, CD8[+] T cell-derived IFN-γ suppresses SLC7A11 expression in tumor cells, leading to glutathione depletion and glutathione peroxidase 4 inactivation, thereby triggering ferroptosis and modulating anti-tumor immunity. Although targeting ferroptosis or neuroimmune pathways has shown therapeutic promise in mitigating neurological deficits and enhancing anti-tumor responses, the underlying mechanisms governing ferroptosis-immune crosstalk remain inadequately characterized. Herein, this review systematically summarizes the key biological characteristics of ferroptosis and immune responses, with particular emphasis on their interplay across major CNS disorders (i.e., AD, PD, ALS, multiple sclerosis, stroke, and glioma). Furthermore, we discuss emerging therapeutic strategies encompassing small molecules, immunomodulatory approaches, and nanotechnology-based interventions, highlighting the ferroptosis-immune axis as a promising therapeutic target for CNS diseases.},
}

*Ferroptosis/immunology
Humans
Animals
*Central Nervous System Diseases/immunology/metabolism/etiology/pathology
Iron/metabolism

@article {pmid42148242,
year = {2025},
author = {Khazaneha, M and Khadir, E and Motaghi, N and Arvan, H and Ebrahimi-Meimand, HA},
title = {Scientometric insights into neurology publications in Iran.},
journal = {Current journal of neurology},
volume = {24},
number = {1},
pages = {87-96},
pmid = {42148242},
issn = {2717-011X},
abstract = {Background: Undoubtedly, medical science has been born since the beginning of human creation. One of its important branches is neurology. Neurosciences in Iran, with a little delay from the first world, with the efforts of researchers, opened the way for the diagnosis and treatment of neurological diseases, and we reached the place where we are. Methods: In this bibliometric and scientometric study, we have evaluated the process of neurological science in Iran. By referring to the reliable indexes, we checked Web of Science (WoS), PubMed, and Scopus from 1963 onwards. We showed the published activities of Iranians in the form of charts and tables. Results: This study indicates the increasing growth of scientific studies in the field of neurology. In the field of neuroscience, the researchers are mostly aimed at the education and training of specialists and PhD students, and depending on the research facilities, as well as acquaintances and connections for the publication of articles. Diseases that have afflicted a large number of people causing them to suffer and limiting their activities, such as multiple sclerosis (MS), Alzheimer's, epilepsy, Parkinson's, and brain strokes have been the focus of researchers. Conclusion: Neurological studies have an increasing trend and can be divided into two basic sections, which are mainly done by neuroscientists and are based on the educational needs and training of specialists, but neurology studies and scientific publications are mainly done by neurologists and based on feeling the need and diseases in this field have been done.},
}

@article {pmid42148273,
year = {2026},
author = {Mughal, EU and Naeem, N and Cheema, AS and Othman, GA and Sadiq, A and Bayrak, S and Kılınç, N and Hawsawi, MB and Gomha, SM and Almaz, Z},
title = {Development of coumarin-sulfonate scaffolds for cholinesterase inhibition: experimental and computational studies toward Alzheimer's disease therapy.},
journal = {RSC advances},
volume = {16},
number = {28},
pages = {25819-25832},
pmid = {42148273},
issn = {2046-2069},
abstract = {The development of effective cholinesterase inhibitors remains a key strategy for the symptomatic management of Alzheimer's disease (AD); however, the identification of structurally versatile scaffolds capable of dual AChE/BChE inhibition remains limited. In this context, coumarin-sulfonate hybrids offer a promising framework for exploring structure-activity relationships due to their tunable electronic and steric properties. In the present study, a series of nine coumarin-sulfonate derivatives (1-9) were synthesized via a two-step procedure and evaluated for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using Ellman's assay. Among the tested compounds, derivative 3 (2,4,6-trimethylphenyl sulfonate) exhibited the highest inhibitory activity with IC50 values of 6.476 nM for AChE and 11.948 nM for BChE, indicating potent dual inhibition. Compound 2 also showed strong dual activity, whereas compound 5 displayed relatively higher selectivity toward BChE. Structure-activity relationship (SAR) analysis revealed that both electronic properties and steric bulk of the aryl sulfonate substituents significantly influenced enzyme inhibition. In addition, computational studies were performed to provide qualitative insights into ligand-enzyme interactions, supporting the experimentally observed activity trends. Overall, the results highlight coumarin-sulfonate derivatives as promising scaffolds for cholinesterase inhibition and provide a basis for further structural optimization toward AD-related targets.},
}

@article {pmid42148368,
year = {2026},
author = {Bailey-Taylor, MJ and Morrow, P and Hendrix, J and Galluzzi, KE and Sharafsaleh, G},
title = {Therapeutic Landscape of Early Symptomatic Alzheimer's Disease Translated into Everyday Practice for Geriatric Providers.},
journal = {Clinical interventions in aging},
volume = {21},
number = {},
pages = {585263},
pmid = {42148368},
issn = {1178-1998},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis ; Aged ; Cognitive Dysfunction/drug therapy ; Disease Progression ; Biomarkers ; },
abstract = {Alzheimer's disease (AD) accounts for 60-80% of all dementia cases. Recent advances in diagnostic biomarkers of early symptomatic AD (ie, mild cognitive impairment and mild dementia due to AD) and amyloid-targeting therapies (ATTs) have the potential to improve outcomes for patients with AD. Two ATTs (donanemab and lecanemab) are currently approved and available for use in the US. Both ATTs can slow disease progression as well as cognitive and functional decline in patients with early symptomatic AD. Treatment with ATTs is associated with specific safety concerns such as amyloid-related imaging abnormalities. Therefore, the benefit versus risk profile needs to be carefully considered when deciding whether to treat a patient with ATTs. This review aims to educate geriatric-trained health professionals regarding advances in the diagnosis and treatment of early symptomatic AD, including the optimal duration of treatment, management of adverse reactions, and patient counseling. It also discusses key considerations in care transitions and patient management in multidisciplinary settings to ensure continuous patient-centered care.},
}

Humans
*Alzheimer Disease/drug therapy/diagnosis
Aged
Cognitive Dysfunction/drug therapy
Disease Progression
Biomarkers

@article {pmid42148602,
year = {2026},
author = {Du, W and Wu, T and Fan, Y and Zhao, M},
title = {When copper turns killer: Decoding copper dyshomeostasis and cuproptosis in neurodegenerative pathogenesis and precision metal interventions.},
journal = {Neural regeneration research},
volume = {21},
number = {9},
pages = {3964-3976},
doi = {10.4103/NRR.NRR-D-25-00808},
pmid = {42148602},
issn = {1673-5374},
abstract = {Copper is an essential cofactor for neuronal metabolism, enzymatic functions, and neurotransmission. However, copper dyshomeostasis-induced redox activity makes the brain vulnerable to oxidative and proteostatic stress. Cuproptosis, a recently characterized form of programmed cell death, is triggered by copper binding to lipoylated enzymes of the tricarboxylic acid cycle, resulting in proteotoxic stress, mitochondrial dysfunction, and cell death. Given that mitochondria are central to copper handling and the primary site of cuproptosis, we examine mitochondrial pathways and key cuproptosis-related genes. We also assess disease-specific signatures of copper imbalance. In Alzheimer's disease, excess copper binds to amyloid-β, promoting aggregation and neurotoxicity. In Parkinson's disease, copper-bound α-synuclein fosters aggregation, while copper-driven redox cycling elevates reactive oxygen species. Cuproptosis worsens mitochondrial vulnerability in Parkinson's disease and impairs cellular stress responses in Huntington's disease. In amyotrophic lateral sclerosis, superoxide dismutase 1-related defects compromise antioxidant defenses alongside copper-dependent mitochondrial dysfunction. In prion diseases, copper facilitates prion protein misfolding and toxicity. Across these disorders, common features include mitochondrial dysfunction and cuproptosis hallmarks-such as enhanced protein lipoylation, elevated reactive oxygen species, impaired electron transport chain activity, fragile Fe-S clusters, and increased reliance on the tricarboxylic acid cycle-which collectively increase neuronal susceptibility to copper dyshomeostasis. Clarifying and understanding the critical roles of copper metabolism not only elucidates the pathogenesis of neurodegenerative diseases but also offers alternative therapeutic strategies. This review uniquely integrates the mitochondria-centered cuproptosis axis with copper dyshomeostasis across Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases, mapping convergent vulnerabilities to mechanism-grounded interventions and outlining testable translational routes.},
}

@article {pmid42148603,
year = {2026},
author = {Xu, Q and Lu, J and Zhang, Z and Xu, D and Guo, C},
title = {Deep learning-based cognitive impairment brain imaging analysis: New methods, new technologies, and new paradigms.},
journal = {Neural regeneration research},
volume = {21},
number = {9},
pages = {4135-4147},
doi = {10.4103/NRR.NRR-D-25-00332},
pmid = {42148603},
issn = {1673-5374},
abstract = {Cognitive impairment arising from ischemic stroke, Alzheimer's disease, and Parkinson's disease presents distinct structural and network-level alterations. Brain magnetic resonance imaging offers a non-invasive and high-resolution approach to assess these changes, while deep learning provides powerful tools for automated analysis. Given that accurate lesion delineation, precise localization of abnormal regions, and reliable disease classification are fundamental to clinical decision-making. This review aims to explore the application of deep learning techniques to brain magnetic resonance imaging analysis of cognitive impairments caused by these disorders, with a focus on three core tasks: lesion segmentation, object detection, and image classification. Recent widely accepted findings indicate that ischemic stroke studies have achieved state-of-the-art lesion segmentation performance, with optimized U-shaped convolutional network (U-Net) and hybrid convolutional neural network-transformer models reaching Dice scores up to 0.911 in delineating focal damage. Alzheimer's disease research has advanced classification and staging accuracy by more than 10% compared with unimodal baselines through three-dimensional convolutional neural network, Transformers, and multimodal fusion, enabling more precise detection of diffuse cortical atrophy. Parkinson's disease imaging, despite lacking overt structural lesions, has leveraged ResNet and Vision Transformer backbones to identify subtle and spatially distributed abnormalities, improving early-stage differentiation. Persistent challenges include the scarcity of large, high-quality annotated datasets, substantial inter-site variability, high annotation costs, and limited interpretability, hindering clinical integration. Addressing these barriers will require advances in federated learning to mitigate data scarcity while preserving privacy, domain adaptation techniques to reduce inter-site variability, automated annotation, and low-resource training strategies to lower labeling costs, and explainable artificial intelligence to improve interpretability, thereby ensuring model robustness, privacy, and transparency. This review highlights emerging methods, innovative technologies, and novel paradigms that are redefining brain imaging analysis in cognitive impairment. Mechanistically, deep learning improves cognitive impairment analysis by integrating hierarchical and multiscale spatial features, modeling long-range functional connectivity disruptions, and fusing structural with functional imaging to better represent network-level pathology. In conclusion, aligning network architectures with disease-specific imaging characteristics and task requirements can greatly enhance the accuracy, robustness, and generalizability of magnetic resonance imaging analyses for cognitive impairment. Future work should focus on multimodal fusion, structure-function coupling, cross-disease evaluations, and embedding artificial intelligence tools into clinical workflows to support early detection, individualized treatment planning, and large-scale clinical adoption.},
}

@article {pmid42148604,
year = {2026},
author = {Jin, S and Guo, B and Hao, W and Su, X and Zhang, T and Liu, C},
title = {Neuromodulation techniques targeting neurotransmitter dysfunction: Innovation in treatments for Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {21},
number = {9},
pages = {4157-4168},
doi = {10.4103/NRR.NRR-D-25-00582},
pmid = {42148604},
issn = {1673-5374},
abstract = {Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive decline, synaptic dysfunction, and neurotransmitter imbalance. Novel neuromodulation approaches, both non-invasive and invasive, show promising potential for restoring neural circuit integrity and improving cognition. This review aims to elucidate the relationship between neuromodulation, neural network circuits, and neurotransmitters. It systematically synthesizes recent advances in neuromodulation techniques, focusing on their ability to modulate four critical neurotransmitter systems: cholinergic, glutamatergic, GABAergic, and monoaminergic systems. Additionally, this review establishes a critical association between neurotransmitter regulation and synaptic plasticity mechanisms, proposing a novel "circuit-transmitter" triad framework for intervention. It represents the first systematic integration of the neurotransmitter regulation mechanisms of various neuromodulation techniques while evaluating their clinical viability for Alzheimer's disease intervention. Beyond established targets, this review identifies the hippocampus-thalamus axis, linked via direct entorhinal-thalamic projections, as a promising focus for ultrasonic neuromodulation research.},
}

@article {pmid42148948,
year = {2026},
author = {Li, X and Xiao, Y and Liu, F},
title = {Stevioside extends the healthspan and improves Alzheimer's disease and increases oxidative stress resistance via the mitochondrial unfolded protein response.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo00251j},
pmid = {42148948},
issn = {2042-650X},
abstract = {Increased evidence suggests that moderate activation of the mitochondrial unfolded protein response (UPR[mt]) can delay aging and ameliorate neurodegenerative pathologies. Stevioside (Ste), a natural zero-calorie sweetener extracted from Stevia rebaudiana, has gained global acceptance as a sugar substitute in the food industry. Accumulated studies indicate that stevioside exhibits a wide spectrum of biological effects, including anti-hyperglycemic, anti-hypertensive, anti-inflammatory, and antimicrobial activities. However, its potential roles in aging and neurodegenerative diseases remain poorly understood. In this study, the lifespan of Caenorhabditis elegans was found to be prolonged upon exposure to (1, 10, and 100 μM) stevioside in a dose-dependent manner. Furthermore, we found that stevioside extended the lifespan and healthspan in C. elegans via activation of the ATFS-1-mediated UPR[mt] pathway. Intriguingly, the amelioration of Alzheimer's disease-related phenotypes by stevioside was also mediated through the ATFS-1 pathway. Additionally, we found that stevioside increased the resistance of oxidative stress and reduced ROS levels and upregulated superoxide dismutase (SOD) activity in C. elegans via the ATFS-1 pathway. These results demonstrated that both the anti-aging and neuroprotective effects of stevioside in C. elegans required a functional ATFS-1-dependent mitochondrial unfolded protein response. Collectively, our work highlighted that stevioside might be a viable candidate for the prevention and treatment of aging and age-related diseases.},
}

@article {pmid42149101,
year = {2026},
author = {Ambi, A},
title = {The Copper-Gut-Brain Axis: A Triple Inflammatory Pathway Driving Neuroinflammation in Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0375},
pmid = {42149101},
issn = {2152-5250},
abstract = {Serum copper increases progressively with normal aging, yet its downstream consequences for the gut microbiome and neuroinflammation remain unexplored. Gut microbiota dysbiosis and elevated lipopolysaccharide levels are established features of Alzheimer's disease, and growing evidence indicates that this dysbiosis drives neuroinflammatory disease progression. Yet the upstream trigger initiating this dysbiosis remains unknown. We propose that age-related copper dyshomeostasis serves as this missing trigger. The redox-active copper content of ceruloplasmin increases across the adult lifespan, and copper is selectively toxic to anaerobic bacteria, preferentially affecting butyrate-producing genera including Faecalibacterium, Roseburia, and Coprococcus while sparing copper-resistant species. This selective toxicity is supported by animal studies demonstrating copper-induced elimination of butyrate producers with reversible gut barrier damage and by Wilson's disease cohorts showing consistent depletion of butyrate-producing genera due to elevated copper levels. The resulting dysbiosis creates a triple inflammatory pathway: butyrate loss compromises gut barrier integrity and removes histone deacetylase-mediated suppression of neuroinflammation; the increase of Gram-negative bacteria elevates lipopolysaccharide translocation through the compromised barrier; and impaired blood-brain barrier integrity reduces amyloid-β clearance. These three insults trigger microglial activation through NF-κB signaling, creating a 'triple hit' on a single transcription factor that may explain the magnitude of neuroinflammatory effects observed in Alzheimer's disease. This mechanism explains the increased acetate/butyrate ratio recently identified as a biomarker distinguishing Alzheimer's-related from non-Alzheimer's cognitive impairment (AUC 0.951), since copper disrupts microbial metabolic cross-feeding networks that convert acetate to butyrate. We present specific, falsifiable predictions that can be tested in human cohorts and propose copper as a novel upstream therapeutic target for Alzheimer's disease prevention.},
}

@article {pmid42149153,
year = {2026},
author = {El-Naggar, M and Al-Hussain, SA and Farag, B and Ebaid, MS and Alhilal, M and Zaki, MEA and Alhilal, S and Gomha, SM},
title = {Solvent-free synthesis of quinazolinone-chalcone hybrids and their evaluation as dual inhibitors of AChE and BuChE for alzheimer's disease.},
journal = {Die Naturwissenschaften},
volume = {113},
number = {3},
pages = {},
pmid = {42149153},
issn = {1432-1904},
support = {NBU-FFR-2026-80-04//Northern Borders University/ ; },
mesh = {*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry/therapeutic use ; *Alzheimer Disease/drug therapy/enzymology ; Acetylcholinesterase/metabolism ; Molecular Docking Simulation ; *Quinazolinones/chemistry/chemical synthesis/pharmacology ; *Butyrylcholinesterase/metabolism ; Humans ; *Chalcones/chemistry/chemical synthesis/pharmacology ; },
abstract = {A new set of quinazolin-4-one-based chalcones was prepared from 3-(4-acetylphenyl)-2- methylquinazolin-4(3H)-one (1) via a base-catalyzed Claisen-Schmidt condensation with substituted aromatic aldehydes. Synthesis was conducted using either a conventional NaOH/EtOH protocol or a solvent-minimized mechanochemical grinding approach. The grinding method delivered chalcones 3a-j and 5 in improved yields (85-94%) within 15-25 min, compared with 65-72% over 12-20 h for the solution method. Product structures were verified by spectroscopic and elemental analyses. The anti-Alzheimer's potential was investigated through molecular docking of the complete series to propose binding modes and prioritize candidates, followed by in vitro evaluation of the five top-ranked compounds (3e, 3f, 5, 3i, and 3 h) for AChE and BuChE inhibition relative to donepezil. In vitro assays revealed the following IC50 values for the compounds against AChE and BuChE: 3e (0.751 ± 0.023 µg/mL for AChE, 0.108 ± 0.003 µg/mL for BuChE), 3f (1.283 ± 0.039 µg/mL for AChE, 0.383 ± 0.01 µg/mL for BuChE), and 5 (2.148 ± 0.066 µg/mL for AChE, 1.212 ± 0.04 µg/mL for BuChE). These values suggest that 3e was the most promising dual inhibitor, outperforming donepezil in both AChE and BuChE inhibition. Docking outcomes agreed with the experimental trends, supporting this scaffold as a promising platform for dual cholinesterase inhibition. In silico ADMET assessment further indicated drug-like characteristics with predicted high oral bioavailability, supporting further lead optimization for Alzheimer's disease therapy.},
}

*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry/therapeutic use
*Alzheimer Disease/drug therapy/enzymology
Acetylcholinesterase/metabolism
Molecular Docking Simulation
*Quinazolinones/chemistry/chemical synthesis/pharmacology
*Butyrylcholinesterase/metabolism
Humans
*Chalcones/chemistry/chemical synthesis/pharmacology

@article {pmid42149299,
year = {2026},
author = {Morimoto, S and Takahashi, S and Okano, H},
title = {Human iPSC‑based translational and reverse translational research for neurodegenerative diseases: emphasis on ALS and key advances.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42149299},
issn = {1867-108X},
support = {JP21H05278, JP22K15736, JP25H00007//Japan Society for the Promotion of Science/ ; JP26K10434//Japan Society for the Promotion of Science/ ; JP26H02431//Japan Society for the Promotion of Science/ ; JP23bm1123046, JP23kk0305024, JP25ek0109811//Japan Agency for Medical Research and Development/ ; JP21wm0425009, JP22bm0804003, JP22ek0109616, JP23bm1423002, JP25wm0625519//Japan Agency for Medical Research and Development/ ; UBE Academic Foundation//UBE Academic Foundation/ ; the Kato Memorial Trust for Nambyo Research//the Kato Memorial Trust for Nambyo Research/ ; 2024A04//Japan Intractable Diseases Research Foundation/ ; Inamori Foundation//Inamori Foundation/ ; Kanagawa Institute of Industrial Science and Technology (KISTEC)e and Technology//Kanagawa Institute of Industrial Science and Technology (KISTEC)e and Technology/ ; Ono Medical Research Foundation//Ono Medical Research Foundation/ ; Nakatomi Foundation//Nakatomi Foundation/ ; },
abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) cause progressive loss of specific neuronal populations and currently lack curative therapies. Animal models and immortalized cell lines incompletely recapitulate human pathology and genetic heterogeneity, limiting drug discovery. Human induced pluripotent stem cells (iPSCs) provide a patient‑specific platform for disease modelling, drug screening and studying individual responses. Translational research (TR) uses iPSC models to identify candidate therapies that are subsequently tested in clinical trials, while reverse translational research (rTR) feeds clinical observations back to the bench by analyzing iPSCs derived from trial participants and integrating molecular data with patient phenotypes. This review summarizes recent advances in iPSC‑based TR and rTR for ALS and extends the discussion to other neurodegenerative diseases. Key clinical trials launched from iPSC screens-ropinirole, retigabine and bosutinib-are reviewed alongside emerging rTR efforts that use patient‑derived iPSCs to identify biomarkers and therapeutic mechanisms. We also survey iPSC models for AD, PD and HD, highlighting applications of three‑dimensional (3D) brain organoids and gene‑editing technologies. Finally, we discuss future directions for precision medicine, multimodal integration and technological challenges, with particular attention to how imaging biomarkers may complement iPSC-based TR/rTR frameworks in neurodegenerative diseases.},
}

@article {pmid42149354,
year = {2026},
author = {Jiang, G and Xie, G and Huang, L and Sun, S and Wang, Z and Zhang, Z and Xiao, T and Xiong, J},
title = {Novel Frameshift Variant in SORL1 Gene Identified in a EOAD Family Causes APP Sorting Dysfunction and Endolysosomal Swelling.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42149354},
issn = {1559-1182},
mesh = {Humans ; *Endosomes/metabolism/pathology ; *Frameshift Mutation/genetics ; *LDL-Receptor Related Proteins/genetics ; Female ; *Lysosomes/metabolism/pathology ; Pedigree ; *Membrane Transport Proteins/genetics ; HEK293 Cells ; *Amyloid beta-Protein Precursor/metabolism ; Male ; Protein Transport/genetics ; *Alzheimer Disease/genetics ; Middle Aged ; RNA, Messenger/genetics/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide. Rare, truncating variants in the sortilin-related receptor 1 (SORL1) gene are well established as high-risk factors for early-onset AD, although with incomplete penetrance. In this study, we identified a novel heterozygous frameshift variant in SORL1 (c.6152delA) in a Chinese family presenting with early-onset dementia characterized by progressive memory impairment and neuropsychiatric symptoms. The variant is extremely rare in gnomAD v4 and is predicted to introduce a premature termination codon. To investigate whether the truncated SORL1 transcript escapes nonsense-mediated mRNA decay (NMD) and to explore the potential cellular effects of residual truncated SORL1, the mutant SORL1 construct was expressed in SH-SY5Y cells and APPswe-expressing HEK293 cells. Additionally, SORL1 mRNA levels in the serum of the proband and her families were assessed by qRT-PCR. Confocal microscopy was used to examine amyloid precursor protein (APP) trafficking within early endosomes, late endosomes, and the trans-Golgi network, marked by EEA1, Rab7, and TGN46, respectively. Amyloid-β (Aβ40 and Aβ42) levels were quantified by ELISA. The results showed that SORL1 mRNA levels in the proband were reduced. And the SORL1 c.6152delA variant impaired the ability of SORL1 to retain APP within the Golgi-endosomal transport network, resulting in increased Aβ production. Overall, these findings indicate that the SORL1 c.6152delA frameshift variant is a significant risk factor for AD pathogenesis.},
}

Humans
*Endosomes/metabolism/pathology
*Frameshift Mutation/genetics
*LDL-Receptor Related Proteins/genetics
Female
*Lysosomes/metabolism/pathology
Pedigree
*Membrane Transport Proteins/genetics
HEK293 Cells
*Amyloid beta-Protein Precursor/metabolism
Male
Protein Transport/genetics
*Alzheimer Disease/genetics
Middle Aged
RNA, Messenger/genetics/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42149370,
year = {2026},
author = {Yamakuni, R and Seino, S and Yamaki, A and Shima, A and Ishikawa, H and Abe, M and Takano, H and Sawamoto, N and Sekino, H and Ishii, S and Fukushima, K and Ukon, N and Kasai, T and Narumoto, J and Hanakawa, T and Ito, H and , },
title = {Whole-brain histogram analysis and top 20% gray and white matter ratio of amyloid positron emission tomography: A comparison with the centiloid scale.},
journal = {Annals of nuclear medicine},
volume = {},
number = {},
pages = {},
pmid = {42149370},
issn = {1864-6433},
support = {18dm0307003//the Japan Agency for Medical Research and Development (AMED, www.amed.go.jp)/ ; JP23wm0625001//the Japan Agency for Medical Research and Development (AMED, www.amed.go.jp)/ ; },
abstract = {OBJECTIVE: To compare whole-brain histogram analysis (WBHA) of amyloid-β (Aβ) positron emission tomography (PET) using several magnetic resonance imaging (MRI)-based brain extraction (brain extraction tool [BET]) methods, to evaluate a novel quantitative analysis method, namely the Top 20% Gray and White Matter Ratio (GW-ratio), to determine appropriate thresholds, and to evaluate diagnostic performance in comparison with the Centiloid scale (CL).

METHODS: We analyzed structural MRI, [18]F-flutemetamol amyloid PET images, and dementia severity scores (Global Clinical Dementia Rating [G-CDR] and Mini-Mental State Examination [MMSE]) of 262 participants. For WBHA, BET was performed using structural MRI and three different BET software programs, namely High-Definition-BET (HD-BET), FMRIB Software Library (FSL), and Statistical Parametric Mapping (SPM). Skewness and mode-to-mean ratio (MMR) were measured using brain-extracted PET. The Top 20% Map was generated from SPM BET images, separated into gray and white matter voxels, and their ratio was calculated as the GW-ratio. The CL value was computed using structural MRI. Aβ-negativity or positivity was visually determined.

RESULTS: Skewness from three BET methods was strongly negatively correlated with CL. Skewness (HD-BET) showed the strongest correlation (R = -0.9043). Moreover, the GW-ratio strongly correlated with CL (R = 0.8332), whereas MMR, particularly MMR (FSL) (R = 0.2112), showed poor correlation. All indicators significantly distinguished Aβ-negative from Aβ-positive visuals. CL had the highest area under the curve (AUC, 0.9959), followed by skewness (HD-BET) (0.9927), Top 20% GW-ratio (0.9872), and skewness (SPM) (0.9779), with no statistical difference between CL and skewness (HD-BET) (P = 0.5763). Based on mean and SD values from 118 cognitively unimpaired (G-CDR = 0, MMSE ≥ 28) and visually Aβ-negative participants, 95% cut-off limits for Aβ-negative individuals without dementia symptoms were: CL ≤ 12.9, skewness (HD-BET) ≥ 0.1769, MMR (HD-BET) ≤ 0.9372, skewness (FSL) ≥ 0.1819, MMR (FSL) ≤ 1.9132, skewness (SPM) ≥ -0.0382, MMR (SPM) ≤ 1.1274, and GW-ratio ≤ 0.1079.

CONCLUSION: WBHA using MRI-based BET and GW-ratio showed strong correlations with CL and demonstrated a diagnostic performance comparable to that of CL.},
}

@article {pmid42149381,
year = {2026},
author = {Han, L and Xiong, X and Fan, M and Zhang, L and Gao, S and Li, R and Wang, X and Xiao, X and Huang, C and Yang, J},
title = {Early-Life Psychological Stress Impairs Spatial Learning and Memory in Rats by Altering the Hippocampal Proteome.},
journal = {Behavior genetics},
volume = {},
number = {},
pages = {},
pmid = {42149381},
issn = {1573-3297},
support = {82201342//National Natural Science Foundation of China/ ; xzy022023022//Xi 'an Jiaotong University Basic Research Student Project/ ; 2022PT-07//the Scientific Research and Sharing Platform Construction Project of Shaanxi Province/ ; },
abstract = {Early-life stress has been linked to anxiety, pessimism, and cognitive decline, all of which can have detrimental effects on individuals. One critical structure impacted by early-life stress is the hippocampus, which plays a vital role in regulating learning and memory functions. This study aims to elucidate the molecular mechanisms through which early-life psychological stress (ELPS) affects the learning and memory capabilities of the hippocampus in rats. In this study, ELPS model was applied on juvenile rats for 14 days. To evaluate the spatial learning and memory abilities of rats, the Morris Water Maze (MWM) test was adopted in this study. This study employed two-dimensional gel electrophoresis (2DE) and ultrahigh-performance liquid chromatographic-electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS) techniques to reveal the proteomic map of the rat hippocampus. Subsequently, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and direct protein-protein interaction (PPI) network construction were performed to identify the biological pathways associated with the differentially expressed proteins (DEPs). ELPS treatment induced age-dependent spatial cognitive deficits. In juvenile rats, ELPS caused mild impairments in spatial learning, as reflected by increased escape latency during specific training days, but did not affect spatial memory. In contrast, adult rats exhibited significant and robust impairments in both spatial learning and spatial memory, with longer escape latency across training days, fewer platform crossings, and reduced time and distance in the target quadrant. These findings demonstrate that ELPS-induced cognitive dysfunction is far more pronounced in adult animals, representing persistent and progressive spatial learning and memory deficits. After therapy, 71 proteins were found in the hippocampal region, including 10 DEPs across the juvenile and adult groups post-treatment. Subsequent pathway analysis indicated the involvement of 4 DEPs in various pathways, including Biosynthesis of amino acids, Prion disease, HIF-1 signaling pathway, Distal axon, Alzheimer disease, and Necroptosis pathways. Our study revealed significant proteomic changes in the hippocampus of rats as they transitioned from juveniles to adults, including 10 consistently differentially expressed proteins. These proteomic alterations correspond to the age-dependent spatial cognitive deficits induced by ELPS-mild spatial learning impairment in juveniles and more pronounced deficits in both spatial learning and memory in adults-collectively supporting the lasting effects of ELPS on spatial cognitive function.},
}

@article {pmid42149389,
year = {2026},
author = {Gautam, AS and Singh, RK},
title = {Chrysin Ameliorated Neurochemical and Behavioural Changes Mediated By Combined Exposure of Interleukin-17 A With Amyloid Beta1-42 in Mice.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42149389},
issn = {1557-1904},
mesh = {Animals ; *Amyloid beta-Peptides/toxicity/administration & dosage ; *Flavonoids/pharmacology/therapeutic use ; Mice ; *Interleukin-17/toxicity/administration & dosage ; Male ; *Peptide Fragments/toxicity/administration & dosage ; Mice, Inbred BALB C ; *Alzheimer Disease/metabolism/chemically induced/drug therapy ; Brain/drug effects/metabolism ; },
abstract = {Neuroinflammation is one of the major hallmarks of neurodegenerative diseases, including Alzheimer's disease (AD). Interleukin-17 (IL-17) cytokine and its downstream signaling have been shown to be implicated in preclinical and clinical models of AD. Moreover, the combination of recombinant IL-17 A with amyloid beta (Aβ1-42) has been shown to be involved in promoting neuroinflammation during AD pathology. Hence, it is speculated that IL-17 may exacerbate Aβ1-42-induced neuronal damage and inflammatory events in the brain. Although natural flavonoids have been reported to protect against neuroinflammation in AD, their role in IL-17 exacerbated Aβ1-42-induced responses has not been reported previously. The current research explored the ability of Chrysin in regulating the exacerbation of neuronal damage and inflammation during AD pathology induced due to the combination of recombinant mouse IL-17 A (rmIL-17 A) with Aβ1-42 in animals. Adult male BALB/c mice were exposed to intranasal Aβ1-42 (5 µg/10µL in phosphate-buffered saline (PBS)/animal) and rmIL-17 (4 µg/kg in 10 µL PBS/animal) from day 1 to day 14 on alternate days with therapeutic oral administration of Chrysin suspension (100 mg/kg) during the last 7 days. Oral treatment with Chrysin demonstrated significant protective effects in improving the memory functions of the animals, along with the modulation of neurodegenerative and neuroinflammatory signalling, microglial and astrocytic activation, and redox balance in the hippocampus and cortex areas of the animal brain tissues. These results supported the neuroprotective ability of Chrysin against the exacerbation caused by rmIL-17 A in Aβ1-42-induced AD in a mouse model.},
}

Animals
*Amyloid beta-Peptides/toxicity/administration & dosage
*Flavonoids/pharmacology/therapeutic use
Mice
*Interleukin-17/toxicity/administration & dosage
Male
*Peptide Fragments/toxicity/administration & dosage
Mice, Inbred BALB C
*Alzheimer Disease/metabolism/chemically induced/drug therapy
Brain/drug effects/metabolism

@article {pmid42149605,
year = {2026},
author = {Flanders, MD and Caunca, M and La Joie, R and Schneider, LS and Ackley, SF},
title = {Methodological Considerations for Quantile Aggregation in Alzheimer Disease Trials.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.1240},
pmid = {42149605},
issn = {2168-6157},
}

@article {pmid42149780,
year = {2026},
author = {Wen, S and Gao, Y and Miao, X and Deng, J and Zhou, Y and Ge, W and Bo, S and Zhang, W and Zhang, R and Hou, C and Ma, J and Jiang, J and Yang, S},
title = {GDAS: A Machine Learning-Driven Approach for the High-Throughput Identification of Disease-Associated Glycoforms.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.6c01321},
pmid = {42149780},
issn = {1520-6882},
abstract = {Glycosylation is a critical post-translational modification and a rich source of disease biomarkers, yet comprehensive, site-specific identification of glycosites and glycoforms at the proteome scale remains computationally intensive and time-consuming. Here, we present Glycoproteomics Data Analysis Software (GDAS), a high-throughput computational platform that enables rapid and confident identification of disease-specific glycoforms from mass spectrometry data. GDAS integrates an ultrafast open-search strategy (e.g., MSFragger-Glyco) with statistical filtering to efficiently reduce large proteome databases to a focused set of significantly regulated glycoproteins, thereby streamlining subsequent targeted N- and O-glycosylation analyses using specialized tools, including GlycReSoft and O-Pair. A dedicated final analysis module further integrates quantitative outputs through advanced statistical modeling and machine learning algorithms, including bootstrap or Bayesian inference, as well as XGBoost and random forest classifiers, to generate robust glycosylation scores for biomarker prioritization. Application of GDAS to published Alzheimer's disease data sets demonstrates its ability to capture biologically meaningful glycosylation alterations. GDAS is freely available at https://github.com/Yang-Lab-SUMC/GDAS.},
}

@article {pmid42149841,
year = {2026},
author = {Guu, TW and Li, WJ and Lee, SH and Hsu, CS and Chou, CN and Lack, L and Ma, WF},
title = {Facilitating the measurement and treatment of Behavioral and Psychological Symptoms of Dementia (BPSD) and understanding caregiver burden using wearable devices in Rural Taiwan-Protocol for a dyadic feasibility pilot study.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0342136},
doi = {10.1371/journal.pone.0342136},
pmid = {42149841},
issn = {1932-6203},
mesh = {Humans ; Pilot Projects ; *Caregivers/psychology ; Taiwan ; *Wearable Electronic Devices ; *Dementia/psychology/therapy ; Female ; Male ; Feasibility Studies ; Aged ; Quality of Life ; Surveys and Questionnaires ; Rural Population ; Alzheimer Disease/psychology ; Middle Aged ; Depression ; *Caregiver Burden/psychology ; Actigraphy ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) prevalence rises with societal ageing. In clinical care, behavioral and psychological symptoms of dementia (BPSD)-including depression, agitation/aggression, apathy, and sleep disturbance-worsen patients' quality of life and substantially increase caregiver burden, more significantly than the cognitive symptoms. Standard BPSD assessments rely on caregiver-rated questionnaires that are cross-sectional and may be biased when caregivers are themselves older adults. Device-based measures (e.g., research-grade wrist actigraphy) can provide objective longitudinal data and novel features. In parallel, therapeutic wearables may improve sleep and mood in adults, and might improve BPSD if accepted by people living with dementia.

METHODS: This dyadic pilot study will recruit 20 participants (n = 10 AD patients; n = 10 caregivers) from outpatient services and affiliated day-care/dementia hubs in rural Taiwan. Participants will wear Geneactiv continuously for 8 weeks and Re-Timer ≥30 min/day for 4 weeks. Device-based data will be processed with GGIR, a well validated R-package designed for processing accelerometer data. Questionnaire assessments include Pittsburgh Sleep Quality Index (PSQI), Neuropsychiatry Inventory Questionnaire (NPI-Q), Caregiver Burden Inventory (CBI), and a semi-structured interview based on the Taiwanese version of Quebec User Evaluation of Satisfaction with Assistive Technology (T-QUEST) at prespecified timepoints.

DISCUSSION: Wearable devices may facilitate the measurement and treatment of specific BPSD, as well as reduce caregiver burden. If proven feasible even in rural Taiwan where both digital and health literacy and resources are limited, this model will inform how device-based dementia care model can be considered and applied in the context of global ageing.},
}

Humans
Pilot Projects
*Caregivers/psychology
Taiwan
*Wearable Electronic Devices
*Dementia/psychology/therapy
Female
Male
Feasibility Studies
Aged
Quality of Life
Surveys and Questionnaires
Rural Population
Alzheimer Disease/psychology
Middle Aged
Depression
*Caregiver Burden/psychology
Actigraphy

@article {pmid42150247,
year = {2026},
author = {El-Mokaddem, OK and Elmasry, GF and Salama, A and Mansour, HM and Mahmoud, WR and Ghany, LMAA},
title = {Multi-target Triazole-Benzopyrone hybrids modulating cholinergic dysfunction, oxidative stress, and neuroinflammation through GFAP/NF-κB/APOE/NLRP3 axis in Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {315},
number = {},
pages = {118949},
doi = {10.1016/j.ejmech.2026.118949},
pmid = {42150247},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) is a degenerative neurological disorder characterized by a deterioration in cognitive abilities, especially memory and learning. The main aim of this study is to evaluate the effects of our agents on oxidative stress, neuroinflammation, cognitive function, and behavioral performance in an LPS-induced AD animal model and comprehensive in vitro and in vivo assays. The synthesized compounds, namely 4b, 5b, 6, 8a-d, and 11a-c, revealed acetylcholinesterase inhibitory activity (3.50-5.91 nM) superior to that of the reference drug donepezil (6.33 nM). The IC50 value of 11a the most active candidate was 3.50 nM against hAChE, with a significant reduction in amyloid-β accumulation by 70% compared to LPS-treated groups, it also reduced neuronal damage, as evidenced by histopathological analysis. Compared to LPS treated groups, 11a decreased brain GFAP, NLRP3, NF-κB, APOE and MDA by 76%, 65%, 48%, 75%, and 59% respectively while increasing GSH by 81%. Molecular docking simulation, along with 100 ns molecular dynamics (MD) simulations conducted on the AChE-ligand complexes, demonstrated favorable conformations of ligand-protein complex throughout the simulations, predicting a dual binding to the CAS and PAS regions of the enzyme which is consistent with kinetic studies against hAChE. Moreover, the chemical stability and reactivity of the drug-target complex were evaluated using global and local reactive descriptors. These findings suggested that compound 11a possessed promising potential as a multi-target lead compound for the development of anti-Alzheimer treatments based on cholinergic, amyloidogenic, and neuroinflammation, through GFAP/NF-κB/APOE/NLRP3 signaling axis.},
}

@article {pmid42150272,
year = {2026},
author = {Benfer, J and Tucker, GG and Zimmerman, S and Unroe, KT and Kusmaul, N and Cagle, JG},
title = {Resident, family, and staff perceptions of the 'Good Life' in nursing home dementia care.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {71},
number = {},
pages = {104099},
doi = {10.1016/j.gerinurse.2026.104099},
pmid = {42150272},
issn = {1528-3984},
abstract = {Providing high-quality care for nursing home residents with dementia is challenging due to staff turnover and complex care needs. This paper examines what constitutes 'good' days for residents, families, and staff. Guided by Gitlin's "Good Life" model, we conducted 46 telephone interviews with 11 residents with dementia, 19 family members, and 16 staff from seven nursing homes. Family or staff assisted residents during interviews. Data were analyzed thematically. Residents described better days as those with consistent daily routines and meaningful social interactions, particularly with staff. Family members reported better days when they felt reassured about the quality of care and could balance caregiving with other responsibilities. Staff defined better days as those in which residents' needs were met and high-quality care was delivered. Across groups, consistent routines and positive staff-resident interactions emerged as key contributors to well-being, highlighting opportunities to support residents, family and staff in nursing homes.},
}

@article {pmid42150345,
year = {2026},
author = {Frederiksen, KS and Boada, M and Frölich, L and Kramberger, M and Scarmeas, N and Vijverberg, E and Visser, PJ and Waldemar, G and Westman, E and Zetterberg, H and Engelborghs, S and Jessen, F},
title = {Class-level aggregation obscures clinically relevant heterogeneity in anti-amyloid antibody trials: comments on a Cochrane review by individual members of the EADC.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100598},
doi = {10.1016/j.tjpad.2026.100598},
pmid = {42150345},
issn = {2426-0266},
}

@article {pmid42150695,
year = {2026},
author = {Ouyang, X and Chia, RSL and Chai, YL and Chong, JR and Sim, MA and Jo, DG and Arumugam, TV and Sethi, G and Dawe, GS and Chen, CP and Lai, MKP},
title = {Peripheral biomarkers of neuroinflammation in Alzheimer's disease and vascular dementia.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118077},
doi = {10.1016/j.bcp.2026.118077},
pmid = {42150695},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD) and vascular dementia (VaD) are the two commonest causes of dementia in older adults and frequently coexist as mixed neurodegenerative-cerebrovascular pathology. Although AD is classically defined by amyloid-β (Aβ) deposition and tauopathy, and VaD primarily by hypoperfusion-associated small vessel disease, both conditions involve chronic, dysregulated neuroinflammation. Evidence suggests that neuroinflammation is not merely a downstream response to tissue injury, but actively participates in the bidirectional pathological loop linking Aβ aggregation, tau hyperphosphorylation, and vascular dysfunction. These interacting mechanisms represent a rich reservoir of accessible biomarkers that may serve as indicators of disease activity, prognosis, and therapeutic target engagement. This focused review summarises key neuroinflammatory mechanisms that support peripheral biomarker development in AD and VaD, with emphasis on glial activation markers, cytokines, chemokines, inflammasome-related molecules and emerging exosome-derived candidates. We further discuss the growing role of ultrasensitive immunoassay and multiplex platforms, including single molecule array and proximity extension assays, in enabling the detection of low-abundance blood-based biomarkers and multi-marker inflammatory signatures. Although current findings are promising, their clinical translation remains limited. Existing studies often report altered inflammatory marker levels without sufficient validation of their diagnostic, distinguishing, prognostic, or pharmacological utility. Moreover, generalisability is constrained by cohort heterogeneity, limited VaD-specific evidence, variable assay platforms, demographic and systemic confounders, and consequently the absence of harmonised clinical thresholds. We therefore evaluate the translational potential of single biomarkers and emerging multi-marker panels, while emphasising the need to distinguish biomarker readouts from druggable inflammatory pathways and to validate these approaches in well-phenotyped AD, VaD, and mixed dementia cohorts.},
}

@article {pmid42150890,
year = {2026},
author = {Zhang, K and Li, Y and Zou, J and Wang, S and Fausto, BA and Hu, L},
title = {Multi-Level Variable Selection Using a BART-Enhanced Mixed-Effects Framework.},
journal = {Statistics in medicine},
volume = {45},
number = {10-12},
pages = {e70593},
doi = {10.1002/sim.70593},
pmid = {42150890},
issn = {1097-0258},
support = {1R01HL159077/NH/NIH HHS/United States ; ME-2021C2-23685/PCORI/Patient-Centered Outcomes Research Institute/United States ; R01AG053961//National Institute on Aging of the National Institutes of Health/ ; },
mesh = {Humans ; Bayes Theorem ; Computer Simulation ; Cluster Analysis ; *Models, Statistical ; *Multilevel Analysis ; Statistics, Nonparametric ; Alzheimer Disease ; },
abstract = {Selecting important individual- and cluster-level predictors has become increasingly critical in healthcare research, where data often exhibit hierarchical structures due to collection from multiple clusters. Mixed-effects models, which account for within-cluster correlation and between-cluster heterogeneity, are a natural approach for multilevel variable selection. However, currently available variable selection methods for multilevel data are predominantly based on mixed-effects models that impose restrictive parametric assumptions, potentially limiting their utility when the underlying relationships are nonlinear or involve interactions. While nonparametric methods have shown promise for variable selection in non-clustered data, they have been much less studied in the multilevel setting. Moreover, nonparametric methods that explicitly account for multilevel structure have largely been designed for prediction, rather than for simultaneous selection of relevant covariates at both the individual and cluster levels. To address these limitations, we propose a flexible, fully Bayesian unified framework for simultaneous variable selection of both fixed and random effects. Our framework integrates the nonparametric flexibility of Bayesian Additive Regression Trees (BART) for fixed-effect predictor selection with a hierarchical Bayesian component that identifies random-effect predictors via covariance decomposition and permutation strategies. To address scenarios common in multilevel data, where cluster-level covariates are constant within clusters and can induce near-collinearity and instability in selection, we further propose a computationally efficient two-step procedure. This method disentangles the contributions of individual- and cluster-level predictors, thereby mitigating collinearity and improving stability in variable selection. Comprehensive simulation studies demonstrate the effectiveness and robustness of our proposed methods across diverse scenarios. We further illustrate the practical utility of these approaches by applying them to a multilevel Alzheimer's disease dataset.},
}

Humans
Bayes Theorem
Computer Simulation
Cluster Analysis
*Models, Statistical
*Multilevel Analysis
Statistics, Nonparametric
Alzheimer Disease

@article {pmid42150950,
year = {2026},
author = {Xie, Z and Su, J and Liao, T},
title = {From disease burden to care burden: Reconsidering Alzheimer's and Parkinson's disease estimates in East Asia.},
journal = {Journal of the Formosan Medical Association = Taiwan yi zhi},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jfma.2026.04.123},
pmid = {42150950},
issn = {0929-6646},
}

@article {pmid42151104,
year = {2026},
author = {Oberlin, LE and Solis-Urra, P and Sewell, KR and Collins, AM and Kang, C and Huang, H and Grove, G and Wan, L and Kramer, AF and McAuley, E and Burns, JM and Hillman, CH and Vidoni, ED and Marsland, AL and Kamboh, MI and Szabo-Reed, A and Rogers, RJ and Morris, J and Zeng, X and Karikari, TK and Jakicic, JM and Erickson, KI},
title = {Physical activity, aerobic fitness, and AD blood biomarkers: The IGNITE study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71484},
doi = {10.1002/alz.71484},
pmid = {42151104},
issn = {1552-5279},
support = {R01AG053952/NH/NIH HHS/United States ; K23MH129882/MH/NIMH NIH HHS/United States ; R35AG072307/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Female ; Aged ; *Biomarkers/blood ; Male ; Amyloid beta-Peptides/blood ; *Exercise/physiology ; *Alzheimer Disease/blood ; Positron-Emission Tomography ; tau Proteins/blood ; *Cardiorespiratory Fitness/physiology ; Brain/diagnostic imaging/metabolism ; Cohort Studies ; Peptide Fragments/blood ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; },
abstract = {INTRODUCTION: Physical activity (PA) and cardiorespiratory fitness (CRF) are associated with reduced risk of cognitive decline and dementia, yet their relationships with dementia-related pathophysiology remain unclear. In a community-dwelling older adult cohort, we examined associations between objectively measured PA, CRF, biomarkers of Alzheimer's disease (AD)-related pathology, and cognition.

METHODS: Participants (n = 648, 71% female, age 69.88 ± 3.75) completed a comprehensive cognitive evaluation, objective assessments of moderate-to-vigorous PA (MVPA) and CRF (VO2peak), and AD-related brain (positron emission tomography [PET] amyloid beta [Aβ]) and blood biomarkers (Aβ1-42/1-40, phosphorylated tau [p-tau]217, p-tau181, glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]).

RESULTS: Greater MVPA (β = -0.107; p = 0.013) and CRF (β = -0.114; p = 0.027) were associated with lower NfL, but not Aβ PET, p-tau217, Aβ1-42/1-40, or GFAP. Aβ positivity moderated the CRF-NfL relationship, with higher CRF linked to lower NfL specifically among Aβ-positive individuals. NfL mediated relationships between MVPA, CRF, and cognitive performance in select domains.

DISCUSSION: Neuroprotective benefits of PA may be conferred through mechanisms influencing neurodegeneration, particularly among those with emerging AD pathology.},
}

Humans
Female
Aged
*Biomarkers/blood
Male
Amyloid beta-Peptides/blood
*Exercise/physiology
*Alzheimer Disease/blood
Positron-Emission Tomography
tau Proteins/blood
*Cardiorespiratory Fitness/physiology
Brain/diagnostic imaging/metabolism
Cohort Studies
Peptide Fragments/blood
Glial Fibrillary Acidic Protein/blood
Neurofilament Proteins/blood

@article {pmid42151377,
year = {2026},
author = {Ma, D and Pabalan, C and Rajagopal, A and Akanksha, A and Interian, Y and Yang, Y and Raj, A},
title = {Predicting categorical and continuous Alzheimer's disease outcomes from a single MRI scan.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42151377},
issn = {2662-8465},
support = {R21AG087921//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG087302//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Deep learning (DL) has shown success in predicting Alzheimer's disease (AD) diagnosis, yet continuous measures such as cognitive assessment remain critical for richer prognosis, trajectory tracking and clinical trial enrichment. Current neurocognitive batteries are time-consuming, and the few DL models predicting cognition require expensive multimodal neuroimaging and longitudinal data. Although magnetic resonance imaging (MRI) is the most clinically accessible modality, on its own it struggles to capture AD heterogeneity in modern DL frameworks. We propose a multitask DL strategy integrating domain knowledge with large pretrained models to predict cognitive scores using only baseline MRI and demographics. By customizing loss functions and leveraging tissue segmentation-tuned latent representations as regularization features, our approach bypasses the need for longitudinal, multimodal or specialized neuroimaging data. This knowledge-informed multitask framework produces accurate diagnosis, segmentation and both current and future cognitive scores from a single baseline scan, with broad implications for early diagnosis, prognosis and clinical trial design.},
}

@article {pmid42141052,
year = {2026},
author = {Ruan, X and Lu, S and Fu, S and Ahn, J and Chen, F and Li, R and Wen, A and Wang, L and Onyema, E and Tang, V and Liu, H},
title = {A dynamic risk prediction framework for Alzheimer's disease and related dementias with interpretability.},
journal = {NPJ digital medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41746-026-02732-0},
pmid = {42141052},
issn = {2398-6352},
support = {3R01HG012748-02S2/HG/NHGRI NIH HHS/United States ; RR230020//Cancer Prevention and Research Institute of Texas Established Investigator Award/ ; R01AG072799-03//National Institute of Aging/ ; },
abstract = {Alzheimer's disease and related dementias (ADRD) develop years before symptoms emerge, making early prediction critical. Electronic health records (EHR) offer a scalable alternative to neuroimaging but are challenged by irregular encounters, data sparsity, and limited interpretability. We propose Gated Recurrent Unit with Decay & Attention (GRU-DA), which integrates GRU-D missingness modeling with RETAIN-style attention for interpretable risk monitoring. The model was trained on the University of Texas Physicians EHR (15,172 ADRD cases with 1:10 matched controls) and externally validated in the All of Us cohort. EHR data up to 10 years before diagnosis were used, with random follow-up initiation to reflect real-world encounters. Both GRU-DA and GRU-D outperformed competing models, particularly beyond 5 years of follow-up and achieved AUROC ~ 0.7 after 8.5 years. Prediction performance depended more on data availability than follow-up length: 1 year with 15% data availability (AUROC 0.75, Average Precision 0.5) was comparable to 7.5 years with 10% availability. For individual cases, GRU-DA produced stable risk predictions with some variability in timestep and feature-level attributions across folds. These results demonstrate EHR data can support dynamic ADRD risk monitoring up to 10 years before diagnosis, with effectiveness strongly influenced by data completeness.},
}

@article {pmid42141074,
year = {2026},
author = {Cai, C and Chong, YS and Liang, H and Hu, Y and Hu, Q and Chen, J and Sajikumar, S and Liu, F},
title = {Simvastatin rescues cognitive impairment in an Aβ1-42-induced model of Alzheimer's disease through the HDAC2-BDNF signaling pathway.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42141074},
issn = {1740-634X},
support = {2021J011433//Natural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation)/ ; 82201668//National Natural Science Foundation of China (National Science Foundation of China)/ ; MOH-000641-00//MOH | National Medical Research Council (NMRC)/ ; MOH-001883-00//MOH | National Medical Research Council (NMRC)/ ; },
abstract = {Statins, renowned for their efficacy in treating cardiovascular diseases, have emerged as potential therapeutic agents for the prevention of Alzheimer's disease (AD). Among them, simvastatin (SV) has attracted considerable attention for its reported cognitive benefits in AD. However, the precise mechanisms by which SV modulates spatial cognitive function in AD remain unclear. In the present study, we used an AD model induced through intracerebroventricular administration of Aβ1-42 in male C57BL/6 mice. The cognitive performance were assessed using the Morris Water Maze (MWM) test, the Y-maze and the Novel Object Recognition (NOR) test. HDAC2 and BDNF expression levels were analyzed by Western blotting. Chromatin immunoprecipitation (ChIP) assays were performed to examine histone H4 acetylation (Ac-H4K5) at Bdnf promoters. Our results showed that SV treatment reversed cognitive impairments induced by Aβ1-42. Aβ1-42 administration increased HDAC2 expression, reduced histone H4 acetylation, and decreased BDNF levels in the dorsal hippocampus (dHPC), all of which were restored by SV treatment. Notably, viral overexpression of HDAC2 abolished the beneficial effects of SV, underscoring the critical role of HDAC2 in mediating its actions. Furthermore, blockade of BDNF signaling using TrkB-Fc attenuated the behavioral improvements induced by SV. In addition, SV treatment ameliorated Aβ1-42-induced deficits in neurogenesis and long-term potentiation (LTP). Together, these findings highlight the therapeutic role of SV in AD through epigenetic and synaptic mechanisms, and support further investigation into its clinical applicability.},
}

@article {pmid42141084,
year = {2026},
author = {Shahat, EA and Ayoub, IM and Bakr, RO and Gad, HA and Eldahshan, OA and Singab, ANB},
title = {Comparative analysis of volatile composition and anticholinesterase activity of Egyptian Hedychium coronarium and Alpinia zerumbet using chemometric assessment of extraction techniques.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42141084},
issn = {2045-2322},
mesh = {*Zingiberaceae/chemistry ; *Alpinia/chemistry ; *Oils, Volatile/chemistry/pharmacology/analysis/isolation & purification ; *Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification ; Plant Leaves/chemistry ; Gas Chromatography-Mass Spectrometry ; Rhizome/chemistry ; *Plant Extracts/chemistry/pharmacology ; Antioxidants/pharmacology/chemistry ; Chemometrics ; Egypt ; },
abstract = {Hedychium coronarium and Alpinia zerumbet are rhizomatous plants belonging to the family Zingiberaceae. They are rich in essential oils. Hydrodistillation and headspace (HS) were employed for the extraction of the essential oils from the leaves and rhizomes of both plants. Essential oils were then analysed by GC/MS and the obtained results were subjected to chemometric analysis. The oil samples obtained by hydrodistillation were tested for their antioxidant and anti-cholinesterase activities using oxygen radical antioxidant capacity assay and colorimetric inhibition kit, respectively. Hydro-distilled oil from H. coronarium leaves showed the presence of forty-seven compounds (97.73%) compared to sixteen compounds (99.17%) in the HS volatiles. Meanwhile, hydro-distilled oil from H. coronarium rhizomes showed the presence of thirty-nine components (95.84%) compared to fifteen compounds (98.68%) in the HS volatiles with 1,8-cineole (41.69% and 58.41%) as the major component in both samples. A. zerumbet leaves oil showed the presence of nineteen compounds (94.54%) in the hydrodistilled oil and twenty-one compounds (99.53%) in the HS volatiles. Besides, the rhizomes hydrodistilled essential oil showed twenty-three compounds (91.85%) and sixteen compounds (100%) in the HS with 1,8-cineole (20.78% and 23.63%) representing the major component in both samples. Chemometric analysis of the results provided a clear and statistically robust discrimination between the hydrodistilled and headspace-isolated oil samples demonstrating that extraction method is a primary determinant of volatile profile. Principal component analysis score plot explained 75% of total variance and distinctly separated samples into four main clusters with key discriminating components β-pinene, and caryophyllene were the major responsible for the segregation of H. coronarium leaves by headspace and hydrodistillation extraction methods, respectively, besides, 1,8-cineole accounted for the discrimination of H. coronarium rhizomes extracted by hydrodistillation. Hierarchial cluster analysis (HCA) fully supported this classification, confirming consistent grouping patterns across both analyses. Importantly, A. zerumbet oils from both extraction methods clustered closely, indicating compositional stability, whereas H. coronarium samples showed strong method-dependent divergence. A. zerumbet rhizomes oil showed the strongest activity as anticholinesterase with IC50 of 0.54 ± 0.02 µg/mL while H. coronarium rhizomes showed the strongest antioxidant activity (10.06 ± 0.16 TE µM/L). H. coronarium leaves and A. zerumbet rhizomes showed anticholinesterase and antioxidant activities to such an extent that may make them a useful adjuvant in the treatment of cognitive diseases such as Alzheimer's.},
}

*Zingiberaceae/chemistry
*Alpinia/chemistry
*Oils, Volatile/chemistry/pharmacology/analysis/isolation & purification
*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification
Plant Leaves/chemistry
Gas Chromatography-Mass Spectrometry
Rhizome/chemistry
*Plant Extracts/chemistry/pharmacology
Antioxidants/pharmacology/chemistry
Chemometrics
Egypt

@article {pmid42141098,
year = {2026},
author = {Lu, L and Pichet Binette, A and Hristovska, I and Janelidze, S and Smets, B and Cumplido-Mayoral, I and Vasanthakumar, A and Milkovich, B and , and An, L and Ossenkoppele, R and Krish, V and Imam, F and Palmqvist, S and Vogel, JW and Stomrud, E and Hansson, O and Mattsson-Carlgren, N},
title = {Proteomic signatures of the APOE ε4 and APOE ε2 genetic variants and Alzheimer's disease.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42141098},
issn = {2662-8465},
support = {2025-2026-2024-2028//Region Skåne/ ; SG-231061717/ALZ/Alzheimer's Association/United States ; ZEN 24-I 069572/ALZ/Alzheimer's Association/United States ; },
abstract = {The APOE locus is the strongest genetic factor for Alzheimer's disease, with ε4 increasing and ε2 decreasing risk, yet the basis of these opposing effects remains unclear. Here we performed a multicohort proteomic analysis across plasma and cerebrospinal fluid in GNPC, BioFINDER-2, ADNI, UK BioBank, and PPMI. APOE-associated protein alterations are detectable before amyloid pathology and remain stable across age and disease progression. APOE2-associated proteins were enriched in pathways related to cellular maintenance and anti-inflammatory processes. By contrast, APOE4 showed a limited set of upstream mediators linked to cell-cycle and oligodendrocyte precursor cell biology, and a broader group of proteins reflecting vascular, immune, and proteostatic dysfunction shaped by downstream pathology. Comparative analyses highlighted allele-specific mediators and oppositely regulated proteins contributing to differential disease risk. Together, these findings reveal that APOE2 and APOE4 shape Alzheimer's disease risk through distinct molecular architectures and identify candidate biomarkers and targets for allele-specific interventions.},
}

@article {pmid42141120,
year = {2026},
author = {Wu, L and Akingbade, T and Nelson, PT and Wang, SJ and Xu, B},
title = {Molecular signatures and biomarker development for limbic-predominant age-related TDP-43 encephalopathy (LATE).},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42141120},
issn = {1432-0533},
support = {R03AG085058/NH/NIH HHS/United States ; R01NS118584/NH/NIH HHS/United States ; P30AG072958/NH/NIH HHS/United States ; R01AG067607/NH/NIH HHS/United States ; Duke-NCCU Collaborative Translational Research Award//Duke Clinical and Translational Science Institute/ ; Duke-NCCU Collaborative Translational Research Supplemental Award//Duke Clinical and Translational Science Institute/ ; 2023-TRG-0015//North Carolina Biotechnology Center Translational Research Grant/ ; },
mesh = {Humans ; *TDP-43 Proteinopathies/pathology/metabolism/diagnosis/genetics ; Biomarkers/metabolism ; *Limbic System/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; Dementia ; },
abstract = {Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a neurodegenerative disease marked by TDP-43 proteinopathy, affecting approximately one-third of individuals aged 80 and above. LATE neuropathological change (LATE-NC) is characterized by the accumulation of phosphorylated TDP-43 preferentially in the limbic system, with potential extension to the neocortex and other brain regions. Notably, the anatomic pattern of LATE-NC differs from that seen in frontotemporal lobar degeneration with TDP-43-immunoreactive inclusions (FTLD-TDP). LATE-NC can occur in a "pure" form but more commonly exists alongside other dementia-related comorbidities, including both degenerative and vascular pathologies. When those "mixed" pathologies are factored in, LATE contributes significantly to cognitive decline in human populations. However, LATE currently lacks a molecular-specific diagnostic method for definitive diagnosis in living people. There are new consensus-based guidelines for predicting the presence of either pure LATE-NC or LATE-NC combined with Alzheimer's disease neuropathologic change (ADNC). Aimed at developing more specific diagnostic methods, recent research efforts have been directed toward identifying unique features on neuroimaging and molecular signatures in biological fluids such as blood and cerebrospinal fluid to facilitate clinical diagnosis for LATE. This review discusses current progress in molecular understanding of LATE-NC, the search for biomarkers for LATE, and highlights key gaps that need to be addressed to advance early detection and improve patient management and clinical trial stratification.},
}

Humans
*TDP-43 Proteinopathies/pathology/metabolism/diagnosis/genetics
Biomarkers/metabolism
*Limbic System/pathology/metabolism
*DNA-Binding Proteins/metabolism
Dementia