@article {pmid41668114,
year = {2026},
author = {Ng, KP and Chong, JSX and Lussier, F and Therriault, J and Rahmouni, N and Savard, M and Stevenson, J and Pascoal, T and Gauthier, S and Rosa-Neto, P and Zhou, JH},
title = {Functional network phenotypes of mild behavioural impairment: cognitive effects moderated by amyloid.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41668114},
issn = {1758-9193},
support = {MOP-11-51-31; RFN 152985, 159815, 162303//Weston Brain Institute, Canadian Institutes of Health Research (CIHR)/ ; MOP-11-51-31 -team 1//Canadian Consortium of Neurodegeneration and Aging (CCNA)/ ; NIRG-12-92090, NIRP-12-259245//The Alzheimer's Association/ ; CFI Project 34874; 33397//Brain Canada Foundation/ ; Chercheur Boursier, 2020-VICO-279314//The Fonds de Recherche du Québec - Santé (FRQS)/ ; NMRC/OFLCG19May-0035, NMRC/CIRG/1485/2018, NMRC/CSA-SI/0007/2016, NMRC/MOH-00707-01, NMRC/CG/435 M009/2017-NUH/NUHS, CIRG21nov-0007, HLCA23Feb-0004 and OFIRG24Jul-0049//Singapore National Medical Research Council/ ; RIE2020 AME Programmatic Fund No. A20G8b0102//A*STAR, Singapore/ ; MOE-T2EP40120-0007 and T2EP2-0223-0025, MOE-T2EP20220-0001//Ministry of Education - Singapore/ ; Yong Loo Lin School of Medicine Research Core Funding//National University of Singapore/ ; },
abstract = {BACKGROUND: Mild behavioural impairment (MBI) is a neurobehavioural syndrome that represents an at-risk state for incident cognitive decline. No study to date has systematically investigated whole-brain within- and between- network functional connectivity (FC) disruptions in MBI and their effects on cognitive performance in dementia-free individuals. Hence, we sought to evaluate the whole-brain functional network phenotypes associated with MBI and its subdomains, and their relationships with amyloid and tau pathology in predicting future cognition and function in dementia-free older adults.

METHODS: We studied 203 dementia-free individuals aged between 55 and 90 years (77 males) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort with baseline functional MRI, amyloid-β [18 F]AZD4694 and tau [18 F]MK6240 PET imaging, and longitudinal neuropsychological assessments up to 32 months. Multivariate associations between MBI-Checklist (MBI-C) subdomain scores and whole-brain FC matrices were examined using partial least squares correlation. We then assessed how these MBI-related network phenotypes were associated with baseline and longitudinal changes in global cognition (via Montreal Cognitive Assessment (MoCA) scores) and functional performance (via clinical dementia rating (CDR) sum of boxes), and whether they interacted with baseline Alzheimer’s disease pathology (global amyloid uptake and tau temporal meta-region-of-interest uptake via PET) to influence future outcomes using linear regression models.

RESULTS: We identified an MBI-related functional network phenotype characterized by greater MBI severity and widespread dysfunctions particularly in higher-order networks. Greater expression of this phenotype was associated with poorer baseline global cognition, as well as greater functional impairment at baseline and over time. Further, baseline global amyloid uptake, but not temporal tau uptake, moderated the effects of baseline MBI-related FC disruptions on longitudinal global cognition changes in dementia-free older adults. Specifically, individuals with higher amyloid burden and greater MBI-related FC disruptions showed accelerated cognitive decline over time. In contrast, the MBI-C total score did not show independent or interactive effects with amyloid and tau burden on longitudinal cognitive and functional outcomes.

CONCLUSIONS: Our findings demonstrated a global MBI-related functional network phenotype in dementia-free individuals that was associated with impaired cognition and function. Moreover, this phenotype interacts with amyloid burden to accelerate cognitive decline, underscoring its relevance in preclinical Alzheimer’s disease.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-01980-2.},
}

@article {pmid41839479,
year = {2026},
author = {Jiao, Y and Zhang, T and Han, W and Zhang, L and Wang, M and Lyu, Z and Zhao, H and Wang, Z and Zhang, X and Guo, S and Hu, Y and Yang, Y and Fu, P},
title = {Multimodal topographic properties of white matter functional segregation in Alzheimer's disease: A simultaneous PET/MR study.},
journal = {European journal of radiology},
volume = {199},
number = {},
pages = {112782},
doi = {10.1016/j.ejrad.2026.112782},
pmid = {41839479},
issn = {1872-7727},
abstract = {OBJECTIVE: White Matter (WM) functional networks offer insight into the network processes underlying progression along the Alzheimer's disease (AD) continuum. Amyloid (Aβ) retention in WM regions, as measured by Aβ-PET, reflects WM integrity and is associated with cognition. This study used simultaneous PET/MR imaging to investigate topographic alterations in WM functional networks and Aβ-burden networks, aiming to provide objective neuroimaging evidence of white matter-related pathology in Alzheimer's disease.

METHODS: A total of 85 subjects were included in this study, including 42 patients with AD, 24 patients with Prodromal AD (PAD), and 19 age- and sex-matched healthy controls (HC). Cognitive assessments were collected along with clinical information, including the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Every enrolled subject underwent an integrated [18]F-Florbetapir ([18]F-AV45) PET/MR scan. High-resolution T1-weighted structural images, blood oxygen level dependent fMRI (BOLD-fMRI) and diffusion tensor imaging (DTI) data were acquired for all subjects. K-means clustering was utilized to obtain white matter functional networks (BWM) from BOLD-fMRI. Normalized Aβ standardized uptake value ratio (SUVR) was calculated within each BWM, with the whole cerebellum as the reference region. The group covariance matrix was generated by Pearson correlation to construct functional, structural, and Aβ retention networks. Topographic properties including the clustering coefficient, characteristic path length and global efficiency were calculated.

RESULTS: AD patients showed lower mean MMSE and MoCA scores than HC and PAD subjects (pcorrected < 0.001). In the functional network, higher characteristic path length and lower global efficiency were found in AD patients, compared with the PAD and HC groups (both p < 0.05). Higher characteristic path length and lower global efficiency were observed in the Aβ retention network of the AD group (all p < 0.05). Furthermore, the clustering coefficient was lower in AD patients (both p < 0.05). The AD group exhibited a significant difference in functional-Aβ retention coupling compared with the PAD group (p = 0.002) and the HC group (p < 0.001). No significant difference was found in the structural network.

CONCLUSION: We observed cognitive impairment in AD patients as compared with participants of the HC or PAD group. AD patients also showed higher characteristic path length and lower global efficiency in both functional and Aβ retention networks. These results may highlight the importance of the multimodal topographic properties of white matter functional segregation for early diagnosis and personalized management of AD.},
}

@article {pmid41839797,
year = {2026},
author = {Fallone, M and Sivananthan, M and Joseph, M},
title = {Donepezil for Korsakoff Syndrome.},
journal = {American journal of therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1097/MJT.0000000000002102},
pmid = {41839797},
issn = {1536-3686},
abstract = {BACKGROUND: Korsakoff syndrome is a neurocognitive disorder characterized by memory impairment and confabulation caused by severe or prolonged thiamine deficiency. It is preceded by a type of delirium called Wernickes Encephalopathy, which is reversible. However, once a patient progresses to Korsakoff syndrome, treatment options are limited because there are currently no FDA-approved medications for Korsakoff syndrome. Donepezil is an acetylcholinesterase inhibitor that has shown efficacy in Alzheimer disease and has been theorized to have benefit in other neurologic disorders as well. In this case, we present a patient with Korsakoff syndrome who had improvement in symptoms after starting donepezil.

DATA SOURCE: The information presented here is derived directly from the clinical records and observations of the patient under our care.

FINDINGS AND LIMITATIONS: The case presented here demonstrates improvement in cognition, motivation, and affect in Korsakoff dementia with the use of donepezil. Limitations of this case study and those alike include lack of generalizability, retrospective design, and absence of a control.

CONCLUSIONS: The off-label use of donepezil for Korsakoff syndrome in this case and others has been shown to be beneficial and well tolerated. Ultimately, larger studies are needed to determine safety and efficacy.},
}

@article {pmid41839802,
year = {2026},
author = {Xu, YR and Tao, Y and Lish, AM and Li, S and Ostaszewski, BL and Anderson, AK and Young-Pearse, T and Lawton, TL and Yang, HS and Walsh, DM and Yang, T and Selkoe, DJ},
title = {Novel Monoclonal Antibody Detects Small Aβ Oligomers More Sensitively Than Lecanemab in Alzheimer's Disease CSF, Serum and Culture Media.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78196},
pmid = {41839802},
issn = {1531-8249},
abstract = {OBJECTIVE: Aqueously diffusible oligomers of the amyloid β-protein (oAβ) are neurotoxic and play a role in neuronal dysfunction in Alzheimer's disease (AD). Accurate quantification of oAβ in brains and biofluids could be valuable for understanding and monitoring AD. In this study, we aimed to examine the ability of 2 antibodies to quantify diffusible oAβ in AD tissue and biofluids.

METHODS: Two oligomer preferring antibodies, 71A1 and lecanemab, were compared to quantify oAβ assemblies in AD brain tissue, cerebrospinal fluid (CSF), serum, and culture media of human neurons expressing Aβ-altering mutations.

RESULTS: Both antibodies recognized synthetic aggregates of Aβ and detected significantly elevated oAβ levels in aqueous extracts of AD versus control brain tissues. Only 71A1 sensitively quantified diffusible oAβ species in CSF, neuronal media, and serum.

INTERPRETATION: Whereas lecanemab is an effective plaque-clearing immunotherapy that robustly detects higher-order Aβ aggregates in AD brain, its preferred Aβ targets are present at very low levels in biofluids. Our results demonstrate that 71A1 detects low-n, diffusible Aβ oligomers that predominate in CSF, serum, and neuronal media that associate with AD-related pathology. Together, these findings indicate that Aβ oligomer populations distribute differently in brain tissue versus biofluids and inform the selection of assays for monitoring oligomers during AD progression and treatment. ANN NEUROL 2026.},
}

@article {pmid41839854,
year = {2026},
author = {Meng, J and Chen, C and Zhu, Z and Sun, Y and Huang, Y and Hu, K and Fu, J and Wu, L and Li, L and Bai, Y and Fei, T and Liu, Z and Li, C and Shen, Z and Liu, L and Li, C and Song, T and Liu, C and Poo, M and Liu, S and Lei, Y and Sun, Y},
title = {Single-cell spatial map of cis-regulatory elements for disease-related genes in the macaque cortex.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-70497-x},
pmid = {41839854},
issn = {2041-1723},
support = {No. T2422026//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Single-cell spatial transcriptomes have demonstrated molecular and cellular diversity in the brain, but gene regulatory mechanisms underlying transcriptomic profiles and disease pathogenesis remain largely unknown in primates. Here we performed single-nucleus Assay for Transposase-Accessible Chromatin followed by sequencing (snATAC-seq) for ~1.6 million cells from 142 cortical regions of two male cynomolgus monkeys (Macaca fascicularis), and identified distinct chromatin accessibility profiles of cis-regulatory elements (CREs) for various cell types. By integrative analysis with large-scale spatial transcriptome data, we found that these CREs showed laminar and regional preferences, with their regional accessibility exhibiting striking dependence on the region's hierarchical level. Cross-species comparison of snATAC-seq data revealed human/macaque-enriched layer-4 glutamatergic neurons and LAMP5/LHX6-expressing GABAergic neurons as well as human/macaque-biased CREs for genes related to neurodevelopment and psychiatric diseases. Importantly, risk single-nucleotide polymorphisms for many brain disorders strongly associated with human/macaque-biased CREs in glutamatergic neuronal types and those for Alzheimer's disease strongly associated with CREs exclusively in microglia. Our results provided the basis for understanding the spatial gene regulatory mechanisms underlying cellular diversity and disease pathogenesis in the primate cortex.},
}

@article {pmid41839929,
year = {2026},
author = {Marschner, RA and Ribeiro, RT and Gayger-Dias, V and Da Silva, VF and Wajner, SM and Gonçalves, CA},
title = {Increased type 3 deiodinase reduces hippocampal T3 signaling and is associated with cognitive impairment in a sporadic Alzheimer's disease animal model.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-43232-1},
pmid = {41839929},
issn = {2045-2322},
support = {171607/2023-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico , Brasil/ ; 302102/2022-1//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; },
}

@article {pmid41840186,
year = {2026},
author = {Düzel, E and Kreutz, MR},
title = {Maintaining and regaining episodic memory in Alzheimer disease: a circuit-based perspective.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {41840186},
issn = {1759-4766},
abstract = {Losing track of personal experiences is a defining feature of Alzheimer disease (AD), arising from the spread of AD pathology through the brain circuits that support episodic memory. In this Review, we explore strategies to improve the function of episodic memory circuits in AD by leveraging the optimized use of neural resources. We introduce the circuit utilization framework, which builds on evidence that synaptic dysfunction, maladaptive responses and deficient adaptive plasticity contribute to episodic memory impairment. The circuit utilization framework posits that by optimizing the utilization of circuit resources, episodic memory function can be partially regained. Our focus includes mitigation of hypoactive and hyperactive synaptic dysfunction, reduction of maladaptive processes and enhancement of brain and cognitive reserve. The circuit utilization framework is grounded in circuit-specific hypotheses that link the component processes of episodic memory to clinical symptoms of memory impairment and AD progression. Its overarching aim is to guide the development of interventions that support episodic memory in people with AD, complementing disease-modifying treatments such as anti-amyloid antibody therapies.},
}

@article {pmid41840280,
year = {2026},
author = {Zuliani, G and Cervellati, C and Zuin, M and Brombo, G},
title = {Why acetylcholinesterase inhibitors should be considered disease-modifying drugs for Alzheimer's disease?.},
journal = {Aging clinical and experimental research},
volume = {},
number = {},
pages = {},
doi = {10.1007/s40520-026-03353-z},
pmid = {41840280},
issn = {1720-8319},
}

@article {pmid41840283,
year = {2026},
author = {Yilmaz, U},
title = {[Magnetic resonance imaging in dementia].},
journal = {Radiologie (Heidelberg, Germany)},
volume = {},
number = {},
pages = {},
pmid = {41840283},
issn = {2731-7056},
abstract = {Magnetic resonance imaging (MRI) plays a pivotal role in the diagnostic work-up of dementia. In addition to excluding secondary and potentially treatable causes, MRI enables the identification of characteristic neuroanatomical patterns that support the differentiation between major dementia entities. In daily clinical practice, the diagnostic value of MRI relies primarily on systematic visual assessment and semiquantitative evaluation of regional atrophy patterns and accompanying vascular pathology. In recent years, automated morphometric analyses and artificial intelligence (AI)-based approaches have gained increasing attention. While these techniques promise objective quantification of structural brain changes, their clinical utility on an individual patient level remains limited. High interindividual variability of brain volumes, technical dependencies, and normative database issues restrict their diagnostic accuracy and may lead to overinterpretation of numerical results if used outside the appropriate context. This review provides a clinically oriented overview of MRI in dementia imaging. Emphasis is placed on pattern-based visual assessment, the role of established semiquantitative rating scales and a critical appraisal of automated morphometry. A practical imaging algorithm is proposed that integrates visual analysis, rating scales and quantitative tools in a structured manner. The aim is to highlight the realistic clinical value of MRI and to emphasize its role as an interpretative rather than a purely numerical diagnostic modality.},
}

@article {pmid41840318,
year = {2026},
author = {Paliwal, S and Bhardwaj, JS and Yang, CH and Taliyan, R},
title = {Unravelling Epigenetic Modulation via MicroRNA Delivery: A Therapeutic Frontier for Alzheimer's.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41840318},
issn = {1559-1182},
support = {BT/INF/22/SP42545/2021//Department of Biotechnology- BUILDER/ ; },
mesh = {*MicroRNAs/administration & dosage/genetics/metabolism ; *Alzheimer Disease/genetics/therapy ; Humans ; *Epigenesis, Genetic ; Animals ; *Gene Transfer Techniques ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is a common form of dementia that primarily affects the elderly population. Several signalling pathways, including Wnt/β-catenin and PI3K/Akt, are significantly affected, disrupting normal physiological processes such as neurogenesis, neuronal survival, neuroinflammation, and BBB disruption, all of which contribute to the progression of AD-like conditions. The current study seeks to investigate and evaluate the involvement of the PI3K-Akt and Wnt/β-catenin pathways in AD, as well as epigenetic regulators that may alter these pathways and be employed as a treatment to improve AD-like conditions. A class of epigenetic regulators known as miRNAs, or short non-coding RNAs, greatly affects gene expression by preventing translation or encouraging target gene destruction. This review will focus on how miRNAs affect Aβ peptide accumulation, hyperphosphorylated tau protein aggregation, and neuroinflammation. In addition, miRNA delivery through exosomes, a lipid nanoparticle, has also been explored in later sections. Our knowledge will assist in creating new miRNA-based therapeutics involving mimics/inhibitors and advance our understanding of how miRNAs control gene expression.},
}

*MicroRNAs/administration & dosage/genetics/metabolism
*Alzheimer Disease/genetics/therapy
Humans
*Epigenesis, Genetic
Animals
*Gene Transfer Techniques
tau Proteins/metabolism

@article {pmid41840320,
year = {2026},
author = {Rai, PK and Srivastava, V},
title = {Claustrum and Hippocampus Segmentation-Based Alzheimer's Disease Identification Model Using RoT-Kmeans and CoLU-CNN.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41840320},
issn = {1559-1182},
mesh = {*Alzheimer Disease/diagnostic imaging ; *Hippocampus/diagnostic imaging/pathology ; Humans ; Magnetic Resonance Imaging/methods ; *Claustrum/diagnostic imaging/pathology ; *Neural Networks, Computer ; Male ; Gray Matter ; Image Processing, Computer-Assisted/methods ; },
abstract = {Alzheimer's disease (AD) is a dementia disease that causes loss of cognitive functions. Also, it is a noncurable disease. However, early diagnosis and proper medication reduce AD's progression time. Yet, the prevailing AD diagnosis models did not concentrate on the claustrum in the brain, reducing the efficiency of the AD diagnosis. Thus, this framework proposes an effective AD identification model with claustrum segmentation based on Collapsing Linear Unit-Convolutional Neural Network (CoLU-CNN). Primarily, the resting state-functional Magnetic Resonance Imaging (rs-fMRI) is preprocessed. Then, Gray Matter (GM), White Matter (WM), Cerebrospinal Fluid (CSF), and the hippocampus are segmented. By using Rogers and Tanimoto-based K-means (RoT-Kmeans), the putamen edge is detected from the segmented GM to segment the claustrum. Likewise, the time-series extraction is performed from rs-fMRI, and network connectivity is generated by using Seed-Based Functional Connectivity (SBFC). Then, the network connectivity and segmented claustrum are mapped. Next, the features are extracted from the segmented and mapped images, and optimal features are selected by using Kent Map-based Wild Geese Optimization (KM-WGO). Lastly, the AD is classified by using CoLU-CNN. The experimental investigation stated that the proposed methodology attained 99% AD classification accuracy.},
}

*Alzheimer Disease/diagnostic imaging
*Hippocampus/diagnostic imaging/pathology
Humans
Magnetic Resonance Imaging/methods
*Claustrum/diagnostic imaging/pathology
*Neural Networks, Computer
Male
Gray Matter
Image Processing, Computer-Assisted/methods

@article {pmid41840370,
year = {2026},
author = {Gönüllü, S and Aydın, Ş and Çelik, H and Çelik, O and Küçükler, S and Topal, A and Akay, R and Yıldız, MO and Alım, B and Özdemir, S},
title = {Milk-derived miR-126-3p-loaded small extracellular vesicles attenuate amyloid-β-induced cellular stress in a neuroblastoma cell model.},
journal = {BMC neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12868-026-01002-9},
pmid = {41840370},
issn = {1471-2202},
}

@article {pmid41840418,
year = {2026},
author = {Burns, LH and Romero, A},
title = {Filamin A phosphorylation at S2152: A molecular switch fueling cancer and neurodegeneration.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-02806-2},
pmid = {41840418},
issn = {1478-811X},
}

@article {pmid41840770,
year = {2026},
author = {Clouston, SAP and Hanes, DW and Smith, DM},
title = {An exploration of sources of bias in population models of cognitive aging and accelerated decline: A prospective cohort study.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbag040},
pmid = {41840770},
issn = {1758-5368},
abstract = {OBJECTIVES: Epidemiologic models used to model cognitive aging and decline often rely on a linear random slopes model, though clinicians rely on accelerated cognitive decline for diagnosis. This study examined the extent to which accelerated versus linearized models of cognitive decline are biased by study design and analytic choices.

METHODS: Data on participants of the Health and Retirement Study (1998-2019) who completed cognitive monitoring and lacked cognitive functional limitations or a history of stroke at baseline were included. Episodic memory was measured as the outcome at each time-point. Experiments manipulated sample size, gaps between observations, and waves/participants, and the degree of censoring due to factors in the model, and the degree of cognitive functional limitations. The outcome was the degree of bias in rates of cognitive decline estimated by different models when compared with the full sample.

RESULTS: This study used data from 30,740 HRS participants followed 194,818 times and for 335,025.73 person-years of cognitive assessment. While linear models were often biased by relatively small changes in sample design, attrition, and analytic choices, quadratic models and nested nonlinear models provided results that were less biased. Nested nonlinear models were less biased than linear models across 4/5 experimental conditions and were less biased than quadratic models in 3/5 experimental conditions.

DISCUSSION: Linearized models of cognitive decline yielded high levels of bias that were sensitive to variations in study design and analytic choices. Results support shifting towards methods modeling accelerated decline in studies of cognitive aging and decline.},
}

@article {pmid41840857,
year = {2026},
author = {Biju, AP and Karim, F and Schafer, DM and Sison, SA and Liang, C and Head, E and Mukherjee, J},
title = {Measurement of Tau Protein and Aβ Amyloid Plaques in Postmortem Human Brains of Down Syndrome and Alzheimer's Disease by Using [[125]I]IPPI and [[125]I]IBETA Autoradiography.},
journal = {Synapse (New York, N.Y.)},
volume = {80},
number = {2},
pages = {e70044},
doi = {10.1002/syn.70044},
pmid = {41840857},
issn = {1098-2396},
support = {AG 077700/NH/NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/metabolism ; *Alzheimer Disease/metabolism/pathology/diagnostic imaging ; *Down Syndrome/metabolism/pathology/diagnostic imaging ; Autoradiography/methods ; Male ; Female ; Middle Aged ; *Plaque, Amyloid/metabolism/pathology/diagnostic imaging ; Iodine Radioisotopes ; Aged ; *Amyloid beta-Peptides/metabolism ; *Brain/metabolism/pathology/diagnostic imaging ; Aged, 80 and over ; },
abstract = {The accumulation of tau tangles and Aβ plaques are prominent neuropathologies that characterize Alzheimer's disease (AD) and Down syndrome (DS). Continuous developments of PET tracers as biomarkers can be supported by autoradiography to validate effectiveness and accuracy of binding properties that elucidate the pathophysiology of DSAD and AD. This in vitro comparative study evaluates [[125]I]IPPI binding to tau and [[125]I]IBETA binding to Aβ plaques in the frontal cortex (FCX) and temporal cortex (TCX) of postmortem human brain slices of AD (n = 5), DSAD (n = 5), and cognitively normal (CN) (n = 5) cases. With anti-tau and anti-Aβ immunostains confirming the presence of tau and Aβ plaques, [[125]I]IPPI and [[125]I]IBETA binding in autoradiographic images were significantly higher in DSAD and AD gray matter (GM) compared to CN. When comparing DSAD with AD, FCX and TCX GM binding was similar throughout DSAD and AD, except in FCX GM where there was 48% more [[125]I]IPPI binding in DSAD than AD. In vitro drug inhibition studies revealed that [[125]I]IPPI binding was significantly inhibited with increasing harmine concentrations (IC50 = 115 nM) in DSAD FCX and TCX, but KuFal194, a DYRK1A drug, minimally inhibited [[125]I]IPPI binding in the same cases. The GM/white matter ratios for DSAD ([[125]I]IPPI = 4.1, [[125]I]IBETA = 2.9) and AD ([[125]I]IPPI = 4.2, [[125]I]IBETA = 2.6) were significantly greater than CN ([[125]I]IPPI = 1.3, [[125]I]IBETA = 1.2). A positive correlation between [[125]I]IPPI and [[125]I]IBETA binding suggests a synergistic relationship between tau and Aβ plaque in DSAD and AD pathology. This study demonstrates that [[125]I]IPPI and [[125]I]IBETA may serve as novel radiotracers in both DSAD and AD to continue diagnostic investigations.},
}

Humans
*tau Proteins/metabolism
*Alzheimer Disease/metabolism/pathology/diagnostic imaging
*Down Syndrome/metabolism/pathology/diagnostic imaging
Autoradiography/methods
Male
Female
Middle Aged
*Plaque, Amyloid/metabolism/pathology/diagnostic imaging
Iodine Radioisotopes
Aged
*Amyloid beta-Peptides/metabolism
*Brain/metabolism/pathology/diagnostic imaging
Aged, 80 and over

@article {pmid41841008,
year = {2026},
author = {Peng, T and Zhang, Z and Ding, N and Zhang, J},
title = {Mechanistic Investigation of Exercise Interventions in Rodent Models of Alzheimer's Disease and Prospects for Clinical Translation.},
journal = {Neural plasticity},
volume = {2026},
number = {1},
pages = {e6718671},
doi = {10.1155/np/6718671},
pmid = {41841008},
issn = {1687-5443},
support = {2025023//Fundamental Research Funds for the Central Universities/ ; },
mesh = {*Alzheimer Disease/therapy/physiopathology/metabolism ; Animals ; Disease Models, Animal ; Gastrointestinal Microbiome/physiology ; *Physical Conditioning, Animal/physiology ; *Exercise Therapy/methods ; Humans ; Translational Research, Biomedical ; Mice ; Brain/metabolism ; Mice, Transgenic ; Neuronal Plasticity/physiology ; },
abstract = {Alzheimer's disease (AD) is a progressive and debilitating neurodegenerative disorder for which existing pharmacotherapies are inadequate to arrest pathological progression, highlighting the imperative to identify safe and effective nonpharmacological interventions. Exercise, as a multi-target therapeutic modality, has been shown to reverse multiple facets of AD-related neuropathology through diverse mechanisms. In this systematic review, we synthesize evidence on the effects of voluntary running, structured swimming, and modulation of the gut microbiota in transgenic murine models of AD. Exercise was found to ameliorate AD pathology by modulating amyloid precursor protein (APP) processing and β-amyloid (Aβ) production/clearance, restoring mitochondrial integrity and function, attenuating neuroinflammatory responses, enhancing synaptic plasticity, and upregulating neurotrophic factors. Moreover, exercise reshapes the intestinal microbiome and thereby modulates the gut-brain axis, further promoting neuroimmune homeostasis and cognitive resilience. Through RNA sequencing data analysis, key genes such as Tlr4, Cdc42, and F13a1 were identified, which may play significant roles in neuroimmune regulation and cognitive protection. By integrating multi-omics evidence, we propose a coordinated "exercise-microbiota-brain" mechanistic framework that offers theoretical support for personalized, exercise-based therapeutic strategies and translational applications in AD. We also emphasize the necessity of future studies combining exercise with complementary interventions to accelerate the clinical translation of multimodal therapeutic approaches.},
}

*Alzheimer Disease/therapy/physiopathology/metabolism
Animals
Disease Models, Animal
Gastrointestinal Microbiome/physiology
*Physical Conditioning, Animal/physiology
*Exercise Therapy/methods
Humans
Translational Research, Biomedical
Mice
Brain/metabolism
Mice, Transgenic
Neuronal Plasticity/physiology

@article {pmid41841031,
year = {2026},
author = {Peng, W and Xia, T and De Sousa Ribeiro, F and Bosschieter, T and Adeli, E and Zhao, Q and Glocker, B and Pohl, KM},
title = {Latent Causal Modeling for 3D Brain MRI Counterfactuals.},
journal = {Deep generative models : 5th MICCAI workshop, DGM4MICCAI 2025, held in conjunction with MICCAI 2025, Daejeon, South Korea, September 23, 2025, Proceedings. DGM4MICCAI (Workshop) (5th : 2025 : Taejon-si, Korea)},
volume = {16128},
number = {},
pages = {192-201},
pmid = {41841031},
abstract = {The number of samples in structural brain MRI studies is often too small to properly train deep learning models. Generative models show promise in addressing this issue by effectively learning the data distribution and generating high-fidelity MRI. However, they struggle to produce diverse, high-quality data outside the distribution defined by the training data. One way to address the issue is using causal models developed for 3D volume counterfactuals. However, accurately modeling causality in high-dimensional spaces is a challenge so that these models generally generate 3D brain MRIS of lower quality. To address these challenges, we propose a two-stage method that constructs a Structural Causal Model (SCM) within the latent space. In the first stage, we employ a VQ-VAE to learn a compact embedding of the MRI volume. Subsequently, we integrate our causal model into this latent space and execute a three-step counterfactual procedure using a closed-form Generalized Linear Model (GLM). Our experiments conducted on real-world high-resolution MRI data (1mm) provided by the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) demonstrate that our method can generate high-quality 3D MRI counterfactuals.},
}

@article {pmid41841751,
year = {2026},
author = {Guo, HH and Ou, HN and Yu, JS and Luo, ZR and Yau, SY and Tsang, HW},
title = {The Adiponectin-PP2A Pathway Confers Cognitive Benefits of Physical Exercise Against Chronic Stress-Induced Tau Hyperphosphorylation in the Hippocampus.},
journal = {Aging cell},
volume = {25},
number = {3},
pages = {e70447},
doi = {10.1111/acel.70447},
pmid = {41841751},
issn = {1474-9726},
support = {82072529//National Natural Science Foundation of China/ ; 2021KSYS009//Key Laboratory of Guangdong Higher Education Institutes/ ; 2022M720907//China Postdoctoral Science Foundation/ ; //Mental Health Research Center (MHRC) at Hong Kong Polytechnic University./ ; },
mesh = {Animals ; *Hippocampus/metabolism ; *tau Proteins/metabolism ; *Adiponectin/metabolism/genetics ; Mice ; *Physical Conditioning, Animal ; Phosphorylation ; *Cognition/physiology ; *Protein Phosphatase 2/metabolism/genetics ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; },
abstract = {Protein phosphatase 2A (PP2A) regulates Tau hyperphosphorylation in Alzheimer's disease (AD). This study hypothesized that exercise increases adiponectin levels, activating PP2A to reduce Tau hyperphosphorylation and enhance hippocampal plasticity. The study utilized adiponectin knockout (Adipo[-/-]) and hippocampal-specific PP2A knockdown (PP2A-KD) in mice with 3-week voluntary running and/or chronic stress to assess changes in Tau phosphorylation, adult neurogenesis, and cognitive performance. Running improved cognitive deficits and reduced Tau hyperphosphorylation in association with increased adiponectin levels and enhanced PP2A activity in stressed mice. Adiponectin deficiency impaired cognitive performance, increased Tau phosphorylation, and decreased PP2A activity. Mechanistically, adiponectin is dispensable for running to increase PP2A activity, reduce Tau hyperphosphorylation, and restore hippocampal neurogenesis, leading to cognitive improvement. Hippocampal-specific PP2A knockdown diminished the beneficial effects of running, indicating that PP2A is downstream of adiponectin's action. This study provides mechanistic insights into how exercise reduces AD-like neuropathology, emphasizing the critical role of the adiponectin-PP2A pathway in mitigating Tau hyperphosphorylation and suggesting a potential therapeutic target for AD through modulation of this pathway.},
}

Animals
*Hippocampus/metabolism
*tau Proteins/metabolism
*Adiponectin/metabolism/genetics
Mice
*Physical Conditioning, Animal
Phosphorylation
*Cognition/physiology
*Protein Phosphatase 2/metabolism/genetics
Male
Mice, Inbred C57BL
Mice, Knockout

@article {pmid41842176,
year = {2025},
author = {Zhang, Z and Huang, X and Wang, Y and Cao, Y and Wang, W and Huang, L and Shu, G and Liu, G},
title = {Loss-amplification-radiation coupling model of the mid-infrared signal propagating in demyelinated axons.},
journal = {Applied optics},
volume = {64},
number = {34},
pages = {10380-10387},
doi = {10.1364/AO.574928},
pmid = {41842176},
issn = {1539-4522},
mesh = {*Axons/physiology/pathology ; *Demyelinating Diseases/physiopathology ; *Infrared Rays ; Humans ; Myelin Sheath ; Computer Simulation ; *Models, Neurological ; },
abstract = {Many neurological disorders are associated with demyelination, leading to abnormalities in neural signal transmission. This study presents a loss-amplification-radiation coupling model for the transmission mechanisms of terahertz and infrared signals in demyelinated axons with disruption and rupture. Demyelinated axons are treated as dielectric antennas, and the radiation characteristics at different degrees of demyelination are investigated through simulations in the frequency range of 55-75 THz. The results indicate that radial demyelination tends to increase radiation more significantly than axial demyelination. The directivity and radiation efficiency reach 18.76 dBi and -1.17dB for severe demyelination (Ld/L>0.5 and td/t>0.5), respectively. Ruptured myelin axons can maintain signal transmission within a certain distance of less than 15 µm in the simulation. These results are consistent with previous studies and may enhance the understanding of mid-infrared signal propagation mechanisms in nerves, as well as contribute to research on diseases associated with demyelination, such as multiple sclerosis and Alzheimer's disease.},
}

*Axons/physiology/pathology
*Demyelinating Diseases/physiopathology
*Infrared Rays
Humans
Myelin Sheath
Computer Simulation
*Models, Neurological

@article {pmid41842662,
year = {2026},
author = {Sun, Y and Ji, M and Leng, M and Wang, Z},
title = {Effects and mechanisms of a mobile-based intelligent recommender system for dementia care on the psychological health of family caregivers: A secondary analysis of a randomized clinical trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261427705},
doi = {10.1177/13872877261427705},
pmid = {41842662},
issn = {1875-8908},
abstract = {BackgroundHealth recommender systems show promise in delivering remote support and improving coping among family caregivers of persons with dementia.ObjectiveTo evaluate the effectiveness of a mobile-based intelligent recommender system for dementia care (DCIRS) in enhancing psychological well-being among family caregivers and to explore the mechanisms underlying its effects.MethodsData from a randomized controlled trial (RCT) were used. Of the 250 eligible participants, 125 caregivers were randomly allocated to the intervention group (receiving DCIRS) and 125 to the waitlist control group. Outcomes, including benefit finding, depressive symptoms, self-efficacy, and coping styles, were assessed at baseline (T0), 6 weeks (T1), and 12 weeks (T2). Generalized estimating equations (GEE) was used to evaluate changes over time and between-group differences, while path analysis examined mediation pathways.ResultsAt 12 weeks, the intervention group showed significant within-group improvements in coping, self-efficacy, and benefit finding (all p < 0.05 for group × time interaction). Between-group analyses revealed greater reductions in depressive symptoms at T1 and T2, though the group × time interaction was non-significant (p = 0.393). Path analysis indicated that reduced depressive symptoms were mediated primarily by increased self-efficacy.ConclusionsThis DCIRS demonstrated the potential to reduce depressive symptoms and enhance benefit finding in caregivers of people with dementia. Strengthening self-efficacy and active coping styles should remain a core focus in digital health interventions, providing meaningful guidance to healthcare professionals in developing caregiver support program.},
}

@article {pmid41842683,
year = {2026},
author = {Lipnicki, DM and Vella, AS and Castro-Costa, E and Blay, SL and Lima-Costa, MF and Ritchie, K and Rolandi, E and Davin, A and Rossi, M and Kim, KW and Han, JW and Oh, DJ and Ding, D and Zhao, Q and Zhou, X and Chen, YC and Chen, JH and Sachdev, PS and , },
title = {Disturbing dreams and dementia incidence across diverse cohort studies: A COSMIC collaboration study.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.70046},
pmid = {41842683},
issn = {1440-1819},
support = {104-2314-B-002-038-MY3//National Science and Technology Council/ ; 107-2314-B-002-186-MY3//National Science and Technology Council/ ; 107-2314-B-002-230//National Science and Technology Council/ ; 108-2314-B-002-128-MY2//National Science and Technology Council/ ; 110-2314-B-002-068//National Science and Technology Council/ ; 110-2314-B-002-129-MY3//National Science and Technology Council/ ; R01AG057531/AG/NIA NIH HHS/United States ; APP1196150//National Health and Medical Research Council/ ; },
abstract = {AIM: Distressing dreams were previously reported to predict future all-cause dementia among predominantly white US participants aged 79-89 years, particularly in men. We investigated whether disturbing dreams (nightmares and bad dreams) were associated with all-cause and Alzheimer dementia (AD) among individuals aged 60-89 years from diverse international regions.

METHODS: Data were from six longitudinal cohort studies across Brazil, China, France, Italy, South Korea, and Taiwan (n = 10,238, 42.5% men). Cox regressions with a random effect for study investigated associations between disturbing dreams and incident dementia, with all participants and stratified separately by sex and baseline age. Analyses examined (i) any disturbing dreams and (ii) disturbing dreams at least once a week. Fully adjusted analyses included three studies with covariates for sleep problems, medications, mental and physical health, cognition, and APOE ε4 status.

RESULTS: Disturbing dreams were reported by 24.2% overall and all-cause dementia, and AD incidence was 10.8 and 5.3 per 1000 person-years, respectively. In fully adjusted analyses, having any disturbing dreams was associated with increased incidence of all-cause dementia among 60-69-year-olds (hazard ratio [HR] 3.93, 95% confidence interval [CI] 1.32-11.67). There were no significant effects for older individuals. In fully adjusted sex-stratified analyses, having disturbing dreams at least once a week was associated with AD only among men (HR 3.59, 95% CI 1.44-8.96).

CONCLUSIONS: We found some evidence for disturbing dreams being associated with incident all-cause dementia among individuals aged 60-69 years and with AD among men. The mechanisms potentially underlying these associations remain to be clarified.},
}

@article {pmid41842757,
year = {2026},
author = {Agnello, L and Dukic, L and Akvlediani, L and Zaninotto, M and , },
title = {Current practices and harmonization challenges in Alzheimer's disease biomarkers: an EFLM Committee: Harmonization Survey.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {41842757},
issn = {1437-4331},
abstract = {OBJECTIVES: Fluid biomarkers are central to the biological definition and diagnosis of Alzheimer's disease (AD). Despite international recommendations, substantial variability persists in laboratory practices. This survey, promoted by the Committee: Harmonisation (C:H) of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM), aimed to assess real-world laboratory practices for AD biomarker testing.

METHODS: An online survey was distributed to EFLM members. The questionnaire addressed pre-analytical, analytical, and post-analytical practices for cerebrospinal fluid (CSF) and blood-based AD biomarkers. Descriptive statistics were applied.

RESULTS: A total of 316 responses from more than 35 countries were collected. CSF remained the primary matrix for AD diagnostics, although blood-based biomarkers were increasingly implemented. Marked heterogeneity was observed across all phases of testing, including sample handling, assay platforms, biomarker panels, and decisional cut-offs. Cut-off values for core biomarkers varied widely, as well as harmonization of reporting unit and the adoption of SI units preventing a shared approach to interpreting the results.

CONCLUSIONS: Despite growing clinical adoption, AD biomarker testing remains highly heterogeneous. Coordinated international harmonization of pre-analytical procedures, analytical methods, and post-analytical interpretation, particularly for blood-based biomarkers, is urgently required to ensure reliable and comparable results.},
}

@article {pmid41842840,
year = {2026},
author = {Kortmann, E and Steinacker, P and Guthknecht, A and Weise, CM and Otto, M},
title = {Serum as an alternative to plasma for determining the ApoE4 phenotype using Pan-ApoE and ApoE4 chemiluminescent enzyme immunoassays.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {41842840},
issn = {1437-4331},
abstract = {OBJECTIVES: Since apolipoprotein E4 (ApoE4) is associated with therapy-related adverse effects of anti-amyloid-β monoclonal antibodies in Alzheimer's disease, such as amyloid-related imaging abnormalities, methods for determining the ApoE4 status are needed. The Lumipulse[®] ApoE4 and Pan-ApoE assays provide a practical approach, but they have so far been validated only in plasma.

METHODS: Plasma and serum obtained from a single blood draw from 157 patients were analyzed using ApoE4 and Pan-ApoE chemiluminescent enzyme immunoassays. The APOE genotype was determined by allele-specific quantitative polymerase chain reaction. Additional experiments assessed assay repeatability, intermediate precision, and sample stability under various storage conditions.

RESULTS: ApoE4, Pan-ApoE, and the resulting ApoE4/Pan-ApoE ratio showed minimal bias, strong positive correlation and linearity between plasma and serum. Using matrix-specific thresholds, plasma- and serum-derived ApoE4/Pan-ApoE ratios accurately classified the ApoE4 phenotypes in concordance with APOE ε4 genotypes. The assay demonstrated repeatability of <15 % and <5 % (day 1 and 2), with intermediate precision <10 % for both Pan-ApoE and ApoE4. Plasma and serum showed both comparable stability after multiple freeze-thaw-cycles and up to 120 h at 4 °C, while serum showed deterioration after 120 h storage at 20 °C.

CONCLUSIONS: Using matrix-specific thresholds, the ApoE4/Pan-ApoE ratio in plasma and serum accurately classified the ApoE4 phenotype in concordance with APOE ε4 genotypes. Serum and plasma showed comparable stability and precision. Thus, serum is a reliable alternative to plasma for measuring Pan-ApoE and ApoE4 with the Lumipulse assays. The use of serum expands sample availability, particularly in retrospective studies or when collected alongside cerebrospinal fluid.},
}

@article {pmid41843337,
year = {2026},
author = {Roy, KK and Mehta, DK and Das, R},
title = {Unrevealing possible mechanism of Riluzole, Salsalate and Nimodipine in Alzheimer's disease: multi-target network pharmacological perspective.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41843337},
issn = {1568-5608},
}

@article {pmid41843546,
year = {2026},
author = {Stingl, J and Guyette, FX and Drábek, T},
title = {Accidental Environmental Hypothermia in a Nonagenarian Resulting in Cardiac Arrest.},
journal = {Prague medical report},
volume = {127},
number = {1},
pages = {39-43},
doi = {10.14712/23362936.2026.6},
pmid = {41843546},
issn = {1214-6994},
mesh = {Humans ; Female ; *Heart Arrest/etiology/therapy ; *Hypothermia/complications/therapy ; Aged, 80 and over ; },
abstract = {Accidental hypothermia after environmental exposure and/or impaired thermoregulation resulting in significant decrease in body temperature and cardiac arrest (CA) is linked to 1,500 deaths annually in the United States. Hypothermic CA treatment has specific presentation and clinical features. With appropriate treatment, its survival can reach 27-70%, contrasting ~ 10% in medical CA. Majority of accidental hypothermic CA survivors recover with favourable neurologic outcome. An integrated, dedicated multi-disciplinary team-approach is essential to maximize the chances of survival. We report on a 91-year-old female who was found outside and unresponsive in freezing temperatures. During transport, she required bag-and-mask ventilation. An esophageal temperature recorded 24.5 °C. Shortly after rapid sequence intubation, she developed CA. She was successfully resuscitated with chest compressions, epinephrine, atropine, and two defibrillations. Due to persistent hypothermia and bradycardia, she was rewarmed using extracorporeal membrane oxygenation. Perioperative transesophageal echocardiography showed normal cardiac function. She was extubated the next day. She remained stable for the rest of her hospital stay without focal neurological deficits on serial examinations. However, her post-arrest stay was complicated by acute delirium, likely from underlying dementia, with a waxing and waning level of consciousness, confusion, agitation and hallucinations. She was discharged on post-operative day 5. Her long-term recovery was complicated by repeated aspiration pneumonias, and gradual decline of her mental status due to Alzheimer's dementia. She died approximately two years later at the age of 93. Thus, full neurologic recovery remains possible after CA induced by severe hypothermia from environmental exposure, despite extreme age and frailty.},
}

Humans
Female
*Heart Arrest/etiology/therapy
*Hypothermia/complications/therapy
Aged, 80 and over

@article {pmid41843743,
year = {2026},
author = {Madeline, V and Galvin, A and De Graaf, L and Engelhardt, J and Lebailly, P and Baldi, I},
title = {Farming exposures and Alzheimer's disease: cross-sectional analysis within the French AGRICAN cohort.},
journal = {Scandinavian journal of work, environment & health},
volume = {},
number = {},
pages = {},
doi = {10.5271/sjweh.4284},
pmid = {41843743},
issn = {1795-990X},
abstract = {OBJECTIVE: There is epidemiological evidence of an association between occupational pesticide exposure and cognitive impairment, but studies on the link with Alzheimer`s disease are scarce. We explored the association between agricultural exposures and Alzheimer`s disease in the AGRICAN cohort.

METHODS: We analyzed the relationship between doctor-diagnosed Alzheimer`s disease and life-long exposures separately among men and women with the following exposures: work on a farm, pesticide use in any job, growing specific crops (N=13) or rearing animals (N=5), pesticide use on these crops/livestock, with adjustment for age, education, smoking, alcohol consumption and body mass index.

RESULTS: Among 109 287 participants in the analysis, 818 (267 men, 551 women) were classified as Alzheimer`s disease cases. Increased risks were seen for work on a farm [men: odds ratio (OR) 1.81, 95% confidence interval (CI) 0.92-3.57; women: OR 1.58, 95% CI 0.94-2.86] or pesticide use in any job (men: OR 1.14, 95% CI 0.85-1.53; women: OR 1.42, 95% CI 1.10-1.85). Risks for crops and livestock were close to unity when compared with non-farmers, except for pigs (OR 1.38, 95% CI 1.01-1.89) and rapeseed among men (OR 1.45, 95% CI 1.00-2.11) and sunflower among women (OR 1.55, 95% CI 0.90-2.66). Using pesticides increased the risk among men especially for sheep/goats (OR 1.98, 95% CI 1.18-3.34), pigs (OR 1.80, 95% CI 1.19-2.74), potatoes (OR 1.47, 95% CI 1.03-2.10) and meadows (OR 1.54, 95% CI 1.14-2.08). Among women, risks associated with pesticide use on crops were generally elevated, reaching a two-fold increase for corn, rapeseed, sunflower, field peas and fruit growing.

CONCLUSION: Our results suggest that agricultural exposures may play a role in Alzheimer's disease among both men and women, with the highest risks associated with pesticide use in certain livestock and crop activities.},
}

@article {pmid41843801,
year = {2026},
author = {Ostenso, S and Birkeland, RW and Albers, E and Louwagie, KW and Iwan, A and Chesak, SS and Gaugler, JE},
title = {The TBI-AD/ADRD Caregiver Support Intervention (TACSI): Protocol of a Pilot Randomized Controlled Trial Evaluation of a Remote Intervention for Family Caregivers.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e81125},
doi = {10.2196/81125},
pmid = {41843801},
issn = {1929-0748},
mesh = {Humans ; *Caregivers/psychology/education ; Pilot Projects ; *Brain Injuries, Traumatic/psychology/therapy ; *Alzheimer Disease/therapy/psychology ; Male ; Female ; Social Support ; Middle Aged ; Adult ; },
abstract = {BACKGROUND: Across the United States, there are millions of informal (ie, unpaid) caregivers helping individuals with Alzheimer Disease/Alzheimer Disease and Related Dementias (AD/ADRD), traumatic brain injury (TBI), or both. TBI is a risk factor for developing, and often co-occurs with, AD/ADRD. In the next decade, more informal caregivers will have to navigate the complexities of the dual diagnosis of TBI and AD/ADRD. Currently, there is a paucity of interventions for caregivers dealing with this dual diagnosis. Our team designed the TBI-AD/ADRD caregiver support intervention (TACSI) as a support program to meet the needs of those providing care to individuals with dual diagnoses of TBI and AD/ADRD.

OBJECTIVE: This pilot randomized controlled trial (RCT) evaluates the preliminary efficacy and successful implementation of TACSI, a 6-session semistructured psychosocial and psychoeducational program, over a 6-month period.

METHODS: This pilot RCT uses an embedded mixed methods randomized controlled evaluation. Caregivers of individuals with a dual diagnosis of AD/ADRD and a history of TBI are randomly assigned to the TACSI (n=41) or a usual care control condition (n=39). Primary outcomes include perceived burden, caregiver relationship satisfaction, and caregiving mastery. Secondary outcomes include caregiver self-efficacy, well-being, and personal resources. Qualitative elements (up to 20 semistructured interviews at the conclusion of the 6-month evaluation and an open-response item at follow-up surveys) allow for better interpretation of quantitative results and understanding of TACSI's mechanisms of benefit.

RESULTS: Recruitment for the study was completed in October 2024. Survey collection and intervention were completed in June 2025. Data analysis will follow.

CONCLUSIONS: Having a dual diagnosis of AD/ADRD and a history of TBI is relatively common. However, there are currently no caregiver support interventions specific to this dual diagnosis. It is important to support these caregivers as they encounter the unique challenges of managing TBI and AD/ADRD. This pilot RCT will help determine if the TACSI program can help to increase caregiving skills and strategies and provide support to improve mood and reduce stress for caregivers of individuals with AD/ADRD and a history of TBI, and also determine if it is feasible to proceed to a full-scale RCT.},
}

Humans
*Caregivers/psychology/education
Pilot Projects
*Brain Injuries, Traumatic/psychology/therapy
*Alzheimer Disease/therapy/psychology
Male
Female
Social Support
Middle Aged
Adult

@article {pmid41843841,
year = {2026},
author = {Zagryadskaya, YA and Nesterov, SV and Mitkevich, VA and Kozin, SA and Kryuchkova, AK and Lomakina, GY and Karbyshev, MS and Bocharov, EV and Makarov, AA and Okhrimenko, IS},
title = {Beta-Amyloid Suppresses Mitochondrial ATP Production in Human Neuroblastoma Cells.},
journal = {Biochemistry. Biokhimiia},
volume = {91},
number = {2},
pages = {230-244},
doi = {10.1134/S0006297925602060},
pmid = {41843841},
issn = {1608-3040},
mesh = {Humans ; *Amyloid beta-Peptides/pharmacology/metabolism ; *Mitochondria/metabolism/drug effects ; *Adenosine Triphosphate/biosynthesis/metabolism ; *Neuroblastoma/metabolism/pathology ; Cell Line, Tumor ; Alzheimer Disease/metabolism ; },
abstract = {β-Amyloid peptides (Aβ), which play a crucial role in the pathogenesis of Alzheimer's disease by forming toxic oligomeric species, are known to affect mitochondrial function. In this study, luciferin-luciferase assay was used to assess changes in ATP production by mitochondria isolated from human neuroblastoma SH-SY5Y cells cultured in the presence of monomeric Aβ at a nanomolar concentration. ATP synthesis rates were measured in the presence of substrates specific for respiratory chain complexes I, II, and IV alongside inhibitors targeting the other complexes. Aβ significantly reduced both the rate of ATP generation and amount of ATP synthesized by mitochondria. This effect of Aβ on ATP synthesis did not result from a direct influence on the respiratory chain complexes I, II, and IV. Our findings provide insights into possible causes of mitochondrial dysfunction in neurons in Alzheimer's disease.},
}

Humans
*Amyloid beta-Peptides/pharmacology/metabolism
*Mitochondria/metabolism/drug effects
*Adenosine Triphosphate/biosynthesis/metabolism
*Neuroblastoma/metabolism/pathology
Cell Line, Tumor
Alzheimer Disease/metabolism

@article {pmid41843859,
year = {2026},
author = {Knopman, DS and Pike, JR and Griswold, M and Lu, Y and Gross, A and Mosley, TH and Windham, BG and Albert, MS and Walker, KA and Gottesman, RF and Sullivan, KJ and Yasar, S and Coresh, J and Burgard, S and Palta, P},
title = {Contingency of Plasma Dementia Biomarkers on Cognitive Profiles for Prognosis of Incident Dementia: The ARIC Study.},
journal = {Neurology},
volume = {106},
number = {7},
pages = {e214779},
doi = {10.1212/WNL.0000000000214779},
pmid = {41843859},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Biomarkers/blood ; Aged ; *Dementia/blood/diagnosis/epidemiology ; *tau Proteins/blood ; Prognosis ; *Cognitive Dysfunction/blood/epidemiology/diagnosis ; Incidence ; *Cognition/physiology ; Aged, 80 and over ; Alzheimer Disease/blood ; },
abstract = {BACKGROUND AND OBJECTIVES: Plasma biomarkers such as phospho-tau species are increasingly used in clinical practice for the diagnosis of Alzheimer disease (AD). Phosphorylated-tau at threonine 181 (p-tau181) values also provide prognostic information about incident dementia. Cognitive status similarly conveys prognostic information, but the relationship between plasma biomarkers for AD and cognitive status requires clarification.

METHODS: Participants from the Atherosclerosis Risk in Communities (ARIC) study who were adjudicated as free of dementia in 2011-2013 had plasma samples analyzed for p-tau181 and other biomarkers. Participants were surveilled for incident dementia through December 31, 2022. Cumulative incidence curves, Cox models, and Fine-Gray models were used to evaluate the independent and combined discriminatory accuracy of cognitive status and plasma biomarkers for incident dementia.

RESULTS: The sample comprised 1,577 ARIC participants (age 76.5 years, 60% women, 73% White, 27% Black). The risk of incident dementia was higher in persons with a baseline status of mild cognitive impairment (covariate-adjusted hazard ratio [HR] 2.94, 95% CI 2.61-3.33) compared with those who were cognitively unimpaired independent of biomarker status. The risk of dementia was also higher in persons with more abnormal concentrations of p-tau181 and other biomarkers independent of cognitive status. When age, cognitive status, and p-tau181 were included in the same models, the risk was attenuated relative to models where only cognitive status or plasma biomarkers were included. For continuous p-tau181 concentrations, the covariate-adjusted HR without cognitive status was 1.45 (95% CI 1.36-1.54), but when cognitive status was included, the HR decreased to 1.37 (95% CI 1.29-1.46). Models showed that when combined with age, p-tau181 alone, cognitive status alone, or the combination of p-tau181 and cognitive status had similar discriminatory accuracy.

DISCUSSION: Cognitive status and plasma biomarker concentrations convey independent but overlapping information about the risk of incident dementia. Although cognitive status and plasma p-tau181 have similar discriminatory accuracies, the far lower incidence rate of dementia in persons who are initially cognitively unimpaired highlights the importance of an accurate clinical diagnosis.},
}

Humans
Female
Male
Biomarkers/blood
Aged
*Dementia/blood/diagnosis/epidemiology
*tau Proteins/blood
Prognosis
*Cognitive Dysfunction/blood/epidemiology/diagnosis
Incidence
*Cognition/physiology
Aged, 80 and over
Alzheimer Disease/blood

@article {pmid41844011,
year = {2026},
author = {Wu, L and Dong, YT and Mu, X and Luo, X and Chen, ZJ},
title = {Integrative SMR prioritizes oxidative stress-related regulatory genes for Alzheimer's disease with brain-tissue validation.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {5},
pages = {100535},
doi = {10.1016/j.tjpad.2026.100535},
pmid = {41844011},
issn = {2426-0266},
abstract = {Oxidative stress (OS) plays a critical role in the pathogenesis of Alzheimer's disease (AD), yet its genetic and epigenetic regulatory mechanisms remain unclear. In this study, we applied a three-step summary-based Mendelian randomization (SMR) framework to integrate Alzheimer's disease (AD) GWAS summary statistics with peripheral-blood eQTL and mQTL datasets, and further evaluated brain-tissue relevance using GTEx v8 and AMP-AD resources. Across the three-step SMR analyses, we prioritized multiple OS-related candidate genes (e.g., CRLS1, PRKAA1, CYP2E1, GPX1, and APP) associated with AD risk, and brain-tissue analyses further highlighted KEAP1, SIRT1, and PRDX5 as region-relevant signals. Functional enrichment analyses highlighted critical pathways such as "Nrf2-mediated antioxidant response" and "PI3K-AKT signaling," emphasizing the roles of oxidative stress, mitochondrial function, and neuroinflammation in AD. Novel regulatory mechanisms were uncovered at methylation sites (e.g., cg20211653 associated with ABCA1), linking epigenetic regulation to transcriptional mechanisms and providing candidates for brain-tissue follow-up. This study provides new insights into the molecular underpinnings of AD, bridging genetic variation, epigenetic regulation, and transcription, and identifies potential therapeutic targets for mitigating oxidative damage and neurodegeneration.},
}

@article {pmid41844366,
year = {2026},
author = {Duan, J and Engelman, CD and Lu, Q and Kang, H},
title = {Comparison of Methods for Sensitivity Analysis of Heterogeneous Treatment Effects in Observational Studies and Application to Alzheimer's Disease and Cognitive Decline.},
journal = {Statistics in medicine},
volume = {45},
number = {6-7},
pages = {e70446},
doi = {10.1002/sim.70446},
pmid = {41844366},
issn = {1097-0258},
mesh = {Humans ; *Alzheimer Disease/therapy ; *Cognitive Dysfunction/therapy/etiology ; *Observational Studies as Topic/statistics & numerical data/methods ; Male ; Models, Statistical ; Female ; Treatment Outcome ; Sleep Wake Disorders/complications ; Treatment Effect Heterogeneity ; },
abstract = {In Alzheimer's disease (AD) research, many observational studies have shown that the effect of sleeping quality, a modifiable risk factor, on cognitive decline is heterogeneous, where some adults experience faster rates of cognitive decline compared to others. However, these effects are likely confounded by unmeasured confounders, and the sensitivity of these effects to unmeasured confounders may be heterogeneous, where one subgroup's treatment effect is more sensitive than that of another subgroup. Unfortunately, compared to the overall treatment effect, there are limited investigations about the sensitivity of heterogeneous treatment effects to unmeasured confounding. The paper presents and compares methods for sensitivity analysis of heterogeneous effects in observational studies based on Rosenbaum's model for sensitivity analysis. We show that, unlike the sensitivity analysis of the overall treatment effect, the sensitivity of heterogeneous treatment effects depends on the variation in the effect sizes across subgroups and the correction for multiple testing. The data analysis further supports our findings where the overall effect of sleep disturbances on cognitive decline is significant (p $$ p $$ -value = 5 . 55 × 1 0 - 5 $$ 5.55\times 1{0}^
{-5}
$$). Also, the effect is more severe among males (p $$ p $$ -value = 2 . 00 × 1 0 - 4 $$ 2.00\times 1{0}^
{-4}
$$) and insensitive to a moderate degree of unmeasured confounding. Finally, we offer an easy-to-use R software to carry out the sensitivity analyses for heterogeneous treatment effects.},
}

Humans
*Alzheimer Disease/therapy
*Cognitive Dysfunction/therapy/etiology
*Observational Studies as Topic/statistics & numerical data/methods
Male
Models, Statistical
Female
Treatment Outcome
Sleep Wake Disorders/complications
Treatment Effect Heterogeneity

@article {pmid41844374,
year = {2026},
author = {Suzuki, N and Yamakawa, H and Yoshihara, K and Niidome, K and Anan, K and Takaya, K and Kouki, K and Fujimoto, K and Ono, H and Izumi, T and Unemura, K and Ito, M and Hatta, T and Kido, Y and Horiguchi, N and Kusakabe, KI},
title = {Discovery of Highly Selective HDAC2 Inhibitors in Cells That Elevate Histone Acetylation In Vivo without Adverse Effects from Dual Inhibition of HDAC1 and 2.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c02022},
pmid = {41844374},
issn = {1520-4804},
abstract = {Alzheimer's disease impairs the cognitive domain of learning and memory through synaptic dysfunction. Memory formation requires gene expression to facilitate synaptic plasticity. When HDAC2 is inhibited, elevated histone acetylation promotes the gene expressions critical for synaptic plasticity and thus facilitates memory formation. However, simultaneous inhibition of HDAC1 and HDAC2 leads to hematologic toxicity. As the two isoforms have high homology, it is a challenge to identify selective HDAC2 inhibitors. Here, we report the development of novel cellular assays to determine HDAC2 potency and selectivity over HDAC1. Our HTS campaign using cellular assays for both isoforms identified 6 as a selective hit compound. With optimization efforts focusing on balancing cellular potency, selectivity, and mitigating BCRP recognition, we discovered compound 11, which exhibited significant in vivo efficacy in elevating histone acetylation levels and enhancing LTP. Importantly, 11 showed no significant hematological toxicity in human blood cells derived from simultaneous inhibition of HDAC1 and HDAC2.},
}

@article {pmid41844398,
year = {2026},
author = {Hou, Y and Huang, G and Liu, Y and Qiu, Y and Ye, P and Bi, L and Zheng, P and Xu, Y and Wu, S and Wei, C and Jin, H},
title = {Rescue of Cognitive Deficits in a Mouse Model of Alzheimer's Disease with a Novel Brominated P2 × 7 Receptor Antagonist.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00127},
pmid = {41844398},
issn = {1948-7193},
abstract = {P2 × 7 receptor (P2 × 7R) represents a promising therapeutic target for Alzheimer's disease (AD), given its marked upregulation in neuroinflammation and involvement in amyloid-β (Aβ) and tau pathology. Although several P2 × 7R antagonists with high central nervous system (CNS) penetration and cross-species activity have been developed, none have yet reached clinical use, underscoring the need for optimized agents suitable for chronic neurological conditions. In this study, we designed a series of brominated P2 × 7R antagonists based on a prominent antagonist Lu AF27139, among which the lead compound YH1 exhibited favorable lipophilicity, brain penetration, plasma stability, and receptor binding. In transgenic AD mice, YH1 treatment significantly alleviated cognitive deficits, reduced cerebral P2 × 7R expression, and decreased Aβ load. Using [18]F-GSK1482160 positron emission tomography (PET) imaging, we observed a significant decline of P2 × 7R binding, indicating that YH1-mediated cognitive improvement involves targeted suppression of P2 × 7R-driven neuroinflammation. These results establish a precision AD-oriented optimization of the Lu AF27139 scaffold, demonstrate measurable PK improvements, and provide the first PET-verified P2 × 7R target engagement in an AD model, supporting translational relevance.},
}

@article {pmid41844465,
year = {2026},
author = {Liu, J and Cao, F and Li, Z and Zeng, H and Zhou, M and He, Q and Jiang, W and Li, Y and Yan, J},
title = {Association between exogenous hormone use and dementia: A prospective cohort study and synthetic analysis.},
journal = {Maturitas},
volume = {208},
number = {},
pages = {108895},
doi = {10.1016/j.maturitas.2026.108895},
pmid = {41844465},
issn = {1873-4111},
abstract = {OBJECTIVES: To investigate the controversial association between exogenous hormone use (EHU) and dementia, with a focus on subtype-specific risks.

STUDY DESIGN: This prospective cohort study followed 273,069 women in the UK Biobank over 3,802,608 person-years, identifying 4,710 dementia cases.

MAIN OUTCOME MEASURES: Cox models assessed use of oral contraceptive (OC) and hormone replacement therapy (HRT) in relation to all-cause dementia, Alzheimer's disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD) across treatment durations. Subgroup analyses were stratified by age, ethnicity, APOE status, education, income, and reproductive factors. A systematic review was conducted to synthesize existing evidence.

RESULTS: In the cohort study, OC use was associated with reduced risks of all-cause dementia (HR 0.90, 95%CI 0.84-0.95), AD (HR 0.87, 95%CI 0.79-0.95), and VaD (HR 0.81, 95%CI 0.70-0.93), particularly after 4-14 years of use. HRT showed no significant association with increased dementia risk. Synthesized results largely corroborated these findings: OC use was associated with reduced risks of dementia (HR 0.90, 95%CI 0.89-0.92); and although four European studies reported a moderately increased AD risk after post-menopausal HRT use, neither cohort-based studies (HR 0.98, 95%CI 0.90-1.06) nor traditional case-control studies (OR 1.00, 95%CI 0.90-1.11) found an association between HRT and dementia.

CONCLUSIONS: Our combined evidence does not support an increased risk of dementia associated with OC use; similarly, no clear association was observed between HRT and increased dementia risk. Clinical decisions on EHU should be individualized, balancing overall benefits against potential risks.},
}

@article {pmid41833649,
year = {2026},
author = {Li, S and Guo, J and Wang, Y and Shi, D and Lian, X and Lu, J and Li, J},
title = {Inflammatory and metabolic pathways underlying the association between PM2.5 exposure and dementia.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {},
number = {},
pages = {127961},
doi = {10.1016/j.envpol.2026.127961},
pmid = {41833649},
issn = {1873-6424},
abstract = {Ambient PM2.5 exposure has been linked to dementia risk, while the underlying pathways remain unclear. This prospective cohort study was conducted in the UK Biobank, including 269,683 participants recruited at baseline between 2006 and 2010 and followed through September 1, 2023. Cox proportional hazards models were used to examine the association between annual average PM2.5 concentrations and incident dementia. Logistic regression analyses assessed the relationships between PM2.5 exposure and brain imaging characteristics. Structural equation modeling and causal mediation analysis were applied to investigate the potential mediating roles of lipid metabolites and inflammatory markers in the association between PM2.5 exposure and dementia risk. For each interquartile increase in PM2.5, the risk of all-cause dementia rose by 5% (p = 0.021), while the risk of Alzheimer's disease increased by 9% (p = 0.004). Mediation analyses indicated that lipid metabolites and inflammatory markers jointly accounted for 1.1%-3.5% of the observed associations. Neuroimaging results were consistent with these findings, showing associations with structural changes in the hippocampus and alterations in white matter microstructure. Among participants without the APOE ε4 allele, structural equation modeling further supported the presence of an inflammation-metabolism pathway linking PM2.5 exposure to dementia risk. Our findings suggest that PM2.5 may be involved in the development of dementia through interacting inflammatory and metabolic pathways, offering a more integrated biological interpretation of previously separate mechanistic observations.},
}

@article {pmid41833767,
year = {2026},
author = {Guo, Y and Li, X and Chen, Y and Li, Y and Cheng, Q and Jiang, Y and Tian, S and Yuan, B and Liu, Y and Hu, H and Li, S},
title = {Sarsasapogenin ameliorates Alzheimer's disease by dual inhibition of RIPK1-mediated necroptosis and pyroptosis.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112481},
doi = {10.1016/j.cellsig.2026.112481},
pmid = {41833767},
issn = {1873-3913},
abstract = {Sarsasapogenin (Sar), a natural bioactive steroidal saponin derived from Anemarrhena asphodeloides, has demonstrated significant neuroprotective effects in preclinical models of Alzheimer's disease (AD). However, its specific mechanism of action, particularly in modulating receptor-interacting protein kinase 1 (RIPK1)-mediated necroptosis and pyroptosis, remains underexplored. This study aimed to investigate Sar's therapeutic potential in AD by targeting RIPK1, a central regulator of programmed cell death. We employed biolayer interferometry (BLI), cellular thermal shift assays (CETSA), and drug affinity responsive target stability (DARTS) to confirm the binding of Sar to RIPK1. In vitro, we assessed the effects of Sar on RIPK1 activation, necroptosis, and pyroptosis in SH-SY5Y neuroblastoma and BV2 microglial cells using Western blotting, immunofluorescence, and cytokine assays. In vivo, the therapeutic efficacy of Sar was evaluated in the 5 × FAD transgenic mouse model, with behavioral analysis (Morris water maze) and histological assessments of brain tissue pathology. Sar demonstrated robust binding to RIPK1 (KD = 435 nM), enhancing its thermal stability and resistance to proteolytic degradation. Treatment with Sar significantly inhibited RIPK1 phosphorylation and downstream necroptotic and pyroptotic signaling in neurons and microglia. In the 5 × FAD mouse model, Sar markedly improved spatial memory performance, reduced amyloid-beta (Aβ) plaque deposition, and decreased neuroinflammatory and necroptotic markers in both the cortex and hippocampus. Sar is a promising natural RIPK1 inhibitor capable of concurrently mitigating both necroptosis and pyroptosis-two critical pathological processes underlying AD. These findings suggest that Sar may serve as a novel disease-modifying therapeutic for AD by regulating multiple pathways involved in neurodegeneration, offering new insights into the potential of natural products in AD treatment.},
}

@article {pmid41833832,
year = {2026},
author = {Zhang, W and Liu, T and Rong, X and Liu, H and Li, M},
title = {Sympathetic overactivity-induced type H endothelial cell senescence contributes to the impairment of vascularized osteogenesis by PKM2-mediated glycolysis in preclinical stages of Alzheimer's mice.},
journal = {Bone},
volume = {},
number = {},
pages = {117859},
doi = {10.1016/j.bone.2026.117859},
pmid = {41833832},
issn = {1873-2763},
abstract = {Alzheimer's disease (AD) is characterized by early-onset bone loss, yet the underlying mechanisms remain elusive. Here, we demonstrated that sympathetic hyperactivity drives vascularized osteogenesis impairment in preclinical AD through a novel PKM2-glycolysis-mediated bone vascular endothelial cell (EC) senescence pathway. Utilizing systematic transcriptome profiling complemented by in vitro functional assays and in vivo validation studies, we found that norepinephrine (NE)-induced PKM2 downregulation disrupts glycolytic flux, triggering mitochondrial dysfunction-induced senescence (MiDAS) in vascular ECs. This metabolic reprogramming of vascular ECs inhibits the differentiation of osteoprogenitors by reducing the secretion of pro-osteogenic factors. Pharmacological inhibition of β-adrenergic signaling or PKM2 activation rescues EC senescence and bone loss. Mechanistically, NE released by the sympathetic nerve suppresses c-Maf, a transcription factor critical for PKM2 expression, linking sympathetic activation to metabolic dysfunction. Furthermore, our results also showed that combination therapy with oryzanol (sympathetic modulator) and eldecalcitol (senolytic) synergistically restores vascularized osteogenesis by targeting both neurovascular and metabolic axes. These findings establish a pathogenic role for sympathetic hyperactivity in AD-related skeletal dysfunction and highlight a therapeutic strategy targeting EC senescence and glycolytic metabolism.},
}

@article {pmid41833859,
year = {2026},
author = {Carroll, T and Pfendler, D and Alhaj Arhayem, H and Thoma, R and Müller-Eigner, A and Straut, A and Johnson, GVW and Nehrke, K},
title = {Tunable tau expression in C. elegans neurons reveals that early-AD tau phosphorylation selectively impacts behavior and mitochondrial quality control.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107350},
doi = {10.1016/j.nbd.2026.107350},
pmid = {41833859},
issn = {1095-953X},
abstract = {Tau protein accumulates myriad post-translational modifications as Alzheimer's disease (AD) progresses, and early-disease tau modifications such as phosphorylation at threonine 231 (T231) likely play a key role in AD pathogenesis. Here, a series of "tunable tau" strains was developed in C. elegans to test the relative impact of tau pseudo-phosphorylation of T231 (T231E) compared to protein expression level as a driver of phenotypic penetrance and severity. Multiple copies of a cassette coding for pan-neuronal wildtype tau or T231E were inserted at a genomic safe harbor loci to create a repertoire of strains expressing tau from low to high levels. In stereotypical behavioral assays of locomotory activity, T231E selectively impacted phenotypic severity compared to wild-type human tau controls, which further tracked with age and tau expression level. However, deficits in associative memory were non-selective between tau and T231E. Moreover, genetic, pharmacologic, and molecular approaches indicated that mitophagy modulation could suppress T231E phenotypes. Additionally, a robust mitochondrial unfolded protein response (UPRmt) occurred in T231E, and loss of atfs-1, a transcription factor central to the UPRmt suppressed T231E toxicity. These results demonstrate that phenotypic severity is invariably associated with tau dosage, while early-AD relevant modifications can be causative drivers of selective deficits. Consistent with recent findings, enhancing mitophagy or suppressing potentially maladaptive consequences of persistent UPRmt induction can be beneficial. This provides a solid foundation for further interrogation into mitochondrial quality control disruption as a potential root cause for AD pathogenesis.},
}

@article {pmid41834054,
year = {2026},
author = {Chatanaka, MK and Soosaipillai, A and Cano, A and Orellana, A and Boada, M and Prassas, I and Morató, X and Diamandis, EP},
title = {Validation of human kallikrein 6 in the cerebrospinal fluid of patients with progressive and non-progressive alzheimer's disease: correlation with other biomarkers.},
journal = {Clinical proteomics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12014-025-09577-x},
pmid = {41834054},
issn = {1542-6416},
abstract = {BACKGROUND: Alzheimer's disease (AD) biomarkers in plasma and cerebrospinal fluid (CSF) are useful for disease diagnosis, prognosis, risk assessment and monitoring therapy response, as well as for uncovering altered disease pathways. Previously, we and others cloned a novel gene, KLK6, which encodes a serine protease of the kallikrein family. The protein (hK6) is highly expressed in the brain, spinal cord and cerebellum.

METHODS: To examine the correlation of hK6 concentration in CSF with various clinicopathological variables in AD, we used a quantitative ELISA system. The variables examined included patient age, sex, MMSE score, APOE status, amyloid β 1-42 (Αβ1-42), phosphorylated Tau 181 (p-Tau181), total Tau (t-Tau). Previously, using a cohort of Swedish and Norwegian patients, we established a positive correlation between CSF hK6 and age as well as the levels of core AD biomarkers in four groups of patients (cognitively normal, MCI without progression to AD, MCI with progression to AD within 2 years and AD dementia). In this investigation, our goal was to validate these previous data with a large and independent patient cohort from Spain.

RESULTS: We found that CSF hK6 is minimally or not affected by patient age and sex, but it significantly correlates with MMSE score and CSF Aβ1-42, p-Tau1811 and t-Tau.

CONCLUSIONS: We conclude that these correlations further support our previous findings and suggest that hK6 may be an additional biomarker for AD and may play some role in the pathogenesis of AD.},
}

@article {pmid41834096,
year = {2026},
author = {Brown, CA and Cousins, KAQ and Korecka, M and McGrew, E and Chen-Plotkin, A and Detre, JA and McMillan, CT and Lee, EB and Das, SR and Mechanic-Hamilton, D and Yushkevich, PA and Nasrallah, IM and Shaw, LM and , and Wolk, DA},
title = {Temporal Modeling of Amyloid and Tau Trajectories in Alzheimer's Disease Using PET and Plasma Biomarkers.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78194},
pmid = {41834096},
issn = {1531-8249},
abstract = {OBJECTIVE: This study aimed to compare positron emission tomography (PET) and plasma-based temporal modeling of amyloid and tau biomarkers in Alzheimer's disease.

METHODS: Longitudinal amyloid PET (n = 1,097, mean age ± SD = 72.5 ± 7.38 year, 51.4% male), [18]F-flortaucipir tau-PET (n = 230, 74.3 ± 7.18 year, 52.2% female), and Fujirebio Lumipulse plasma p-tau217 (n = 752, 72.8 ± 6.93 year, 51.3% male) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and University of Pennsylvania Alzheimer's Disease Research Center (Penn ADRC) were used to generate biomarker trajectory models using sampled-iterative Local approximation (SILA). SILA models using plasma p-tau217 were compared to amyloid and tau PET-based models to estimate amyloid and tau onset, and factors influencing tau onset and time from tau onset to dementia were evaluated for PET and plasma models.

RESULTS: Plasma and PET models generated similar results for estimated amyloid and tau onset, with stronger model agreement for tau (r = 0.88[0.86, 0.89], t = 57.4, p < 0.001) than amyloid (r = 0.75[0.72, 0.77], t = 37.4, p < 0.001) onset. Accuracy of estimated onset compared to actual onset was high within modality (mean absolute error [MAE] ≤ 2.03) with slightly greater error (MAE 3.09-3.42) when comparing across modalities (ie, plasma to PET). For both plasma and PET, earlier tau onset was associated with younger amyloid onset, female sex, and ≥1 apolipoprotein (ApoE) ε4 allele. Earlier dementia onset after tau was associated with later tau onset for both plasma and PET, while male sex was associated with shorter tau to dementia gap in plasma models.

INTERPRETATION: Temporal modeling of plasma biomarkers provides comparable information to PET-based models, particularly for tau onset age, and can serve as a widely accessible tool for clinical assessment of biological disease severity. ANN NEUROL 2026.},
}

@article {pmid41834385,
year = {2026},
author = {Bouhour, C and Konstantopoulou, S and Piton, T and Tingaud, M and Mauriello, C and Lory, K and Unschuld, PG and Bréchet, L},
title = {Family caregiver perspectives on administering home-based stimulation in patients with mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261429857},
doi = {10.1177/13872877261429857},
pmid = {41834385},
issn = {1875-8908},
abstract = {BackgroundWhile transcranial alternating current stimulation (tACS) shows therapeutic promise for neurological and psychiatric disorders when applied repeatedly, its potential is constrained by multiple laboratory visits.ObjectiveTraining caregivers to administer tACS at home could make therapy more practical, especially for vulnerable populations such as individuals with mild cognitive impairment (MCI). This study aimed to evaluate caregivers' perceptions and experiences of administering home-based tACS to MCI patients under remote clinical supervision.MethodsTwenty family caregivers (M age: 70 ± 12 years, 11 female) were trained to operate a six-electrode tACS device and administered 20 home-based sessions to MCI patients under real-time remote supervision. Quantitative ratings assessed caregivers' confidence, burden, and perceived benefits.ResultsCaregivers demonstrated high confidence in technical procedures (85-100% across tasks) and rated training as very satisfactory. The majority (85%) would feel comfortable administering tACS independently without remote support. Although most caregivers (70%) experienced daily life interference, nearly all (90%) would reuse the system. Clinically, 45% of caregivers observed patient benefits, and 57% of MCI patients believed sessions were beneficial. Effects on quality of life and memory were mixed, with some reporting mild deterioration, possibly reflecting natural disease progression or the double-blind design.ConclusionsCaregiver-administered home-based tACS proved feasible and acceptable among older caregivers (average age 70), despite daily life interference and mixed clinical perceptions. These findings support the expansion of caregiver-delivered protocols while emphasizing the importance of enhanced training and ongoing remote support to reduce the burden and optimize outcomes.Clinical trial registryhttps://clinicaltrials.gov/study/NCT05708001.},
}

@article {pmid41834394,
year = {2026},
author = {Yuan, M and Zhou, HY},
title = {CTAD 2025: Key trends redefining therapeutic and diagnostic strategies in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430764},
doi = {10.1177/13872877261430764},
pmid = {41834394},
issn = {1875-8908},
abstract = {This article synthesizes key themes emerging from the CTAD 2025 meeting, highlighting significant advances in Alzheimer's disease (AD) research and clinical practice. New disease-modifying approaches-ranging from next-generation anti-amyloid-β and anti-tau antibodies to small-molecule aggregation inhibitors and gene-based strategies-underscore a growing shift toward multi-target therapeutic frameworks. Blood-based biomarkers, such as p-tau217, p-tau181, glial fibrillary acidic protein, and neurofilament light, are nearing clinical readiness, while digital biomarkers and wearable technologies are enabling remote, continuous assessment of cognitive and physiological functions. Clinical trial design is increasingly oriented toward earlier disease stages and genetically or biomarker-defined high-risk groups, incorporating adaptive methodologies and real-world data to enhance efficiency and generalizability. Collectively, these developments signal an impending transition over the next two to three years from a centralized, cognitive scale-driven model of AD care to a more decentralized, biomarker-guided precision paradigm. CTAD 2025 thus marks a pivotal inflection point in the evolving structure of AD diagnosis and treatment.},
}

@article {pmid41834402,
year = {2026},
author = {Al-Hammadi, M and Fleyeh, H and Thomas, I},
title = {Gait and movement analysis for discrimination between people with dementia and healthy control persons based on pose estimation and machine learning.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430001},
doi = {10.1177/13872877261430001},
pmid = {41834402},
issn = {1875-8908},
abstract = {BackgroundDementia disorders are affecting millions of people globally, characterized by memory loss, communication difficulties, and motor function decline. Accurate and early dementia detection is crucial for effective management and treatment. Gait analysis offers a non-invasive method for dementia detection by identifying subtle changes in walking patterns that often precede cognitive symptoms.ObjectiveThis study aims to evaluate the clinical utility of video-based gait analysis using the Timed Up and Go (TUG) test under single and dual-task conditions (TUGdt) for distinguishing individuals with dementia disorders from healthy controls (HCs).MethodThe study implemented three machine learning models: Support Vector Machine (SVM), Logistic Regression (LR), and Random Forest (RF), to discriminate between persons with dementia and HCs. The dataset consists of a cohort of 64 people with dementia (47 with Alzheimer's disease) and 67 HCs. The participants performed the TUG test as a single and dual-task (TUGdt). In the TUGdt, participants performed the TUG test while simultaneously completing an additional cognitive task (i.e., animal naming (TUGdt-NA) or reciting months in reverse order (TUGdt-MB)).ResultsThe results showed that dual-task classification outperformed the single-task. The SVM algorithm achieved the highest accuracy in the TUGdt-NA task (accuracy of 87% ± 5.1 and recall of 86.6% ± 3.2) using 5-fold cross-validation and accuracy of 85.5% and recall of 89.5% using Leave-One-Out Cross-Validation (LOOCV) in the TUGdt-MB task.ConclusionsIn summary, video-based gait features effectively distinguish people with dementia from HCs, particularly under dual-tasking, offering cost-effective, automated, and non-invasive pre-screening to complement clinical assessments.},
}

@article {pmid41834411,
year = {2026},
author = {Yue, J and Carriquiriborde, V and Cheng, WH and Yildirim, T and Fan, J and Tok, S and Kelly, ML and Wellington, CL and Kent, BA},
title = {Repetitive Mild Traumatic Brain Injury Causes Neuronal Damage in the APP/PS1 Mouse Model of Alzheimer's Disease Without an Enduring Impact on Amyloid Pathology, Sleep, or Epileptiform Activity.},
journal = {Journal of neurotrauma},
volume = {},
number = {},
pages = {8977151261430301},
doi = {10.1177/08977151261430301},
pmid = {41834411},
issn = {1557-9042},
abstract = {Traumatic brain injury (TBI) is a known risk factor for Alzheimer's disease and related neurodegenerative diseases. Sleep disturbances and epileptiform abnormalities can appear after TBI and may contribute to the development of neuropathology. In this study, we characterized sleep, epileptiform activity, and neuropathology after repetitive mild traumatic brain injury (rmTBI) in a mouse model of Alzheimer's disease. We used the Closed Head Impact Model of Engineered Rotational Acceleration to deliver rmTBI or sham (control) treatment to 6-month-old APP/PS1 mice (N = 19). One month post-injury, we implanted electroencephalogram and electromyographic electrodes, recorded for 72 h, and then collected brain tissue and blood plasma. Our assessment of sleep architecture showed that time spent in vigilance state was not affected by the rmTBI 1 month post-injury; however, power spectra analysis showed a shift toward higher frequencies in the rmTBI group during non-rapid eye movement sleep. Epileptiform activity did not differ between sham and rmTBI. Compared with sham controls, the rmTBI group showed higher neurofilament light (NF-L), but not glial fibrillary acidic protein in blood plasma and no change in Aβ pathology. These results indicate sustained neurological injury in the APP/PS1 mice 1 month after rmTBI without affecting amyloid deposition in the brain. Our study suggests that rmTBI can induce neural injury without causing enduring sleep disruption, seizures, and exacerbation of amyloidosis in the APP/PS1 mouse model.},
}

@article {pmid41834535,
year = {2026},
author = {Luca, A and Luca, M and Ferri, R and Lanza, G and Serretti, A},
title = {Neuropsychiatric and behavioural correlates of sundowning in Alzheimer's disease.},
journal = {International journal of psychiatry in clinical practice},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/13651501.2026.2642681},
pmid = {41834535},
issn = {1471-1788},
abstract = {OBJECTIVES: The aims of this study were to estimate the frequency of 'sundown syndrome' (SS) in a large sample of patients with Alzheimer's disease (AD) and to assess its associated socio-demographic and clinical variables.

METHODS: Three hundred and sixty-one AD patients (age 78.4 ± 8.3 years) collected within the National Institute of Mental Health Genetics Initiative were included. A subsample was autopsy-confirmed. SS was identified within a caregiver-structured interview. Sociodemographic, clinical and neuropsychiatric features of sundowners and non-sundowners were compared by logistic regression.

RESULTS: One hundred eighty-five patients (51.2%) were sundowners. SS was positively associated with several neuropsychiatric symptoms (i.e., hallucinations, suspiciousness, wandering and aggression; all p-values < 0.01), and negatively associated with Mini-Mental State Examination and voluptuary habits (all p values < 0.05). Subsample analysis carried out in the autopsy group confirmed the findings.

CONCLUSIONS: SS is common in AD and is associated with several neuropsychiatric features and voluptuary habits. The identification of SS predictive factors may allow preventive and targeted therapeutic interventions.},
}

@article {pmid41834587,
year = {2026},
author = {Shimizu, K and Yasuda, S and Maeshima, H and Ichikawa, T and Baba, H},
title = {Serum Amyloid β Oligomer May Predict Treatment Response in Middle-Aged and Late-Life Patients With Depression.},
journal = {Neuropsychopharmacology reports},
volume = {46},
number = {2},
pages = {e70109},
doi = {10.1002/npr2.70109},
pmid = {41834587},
issn = {2574-173X},
mesh = {Humans ; Male ; Female ; *Amyloid beta-Peptides/blood ; Middle Aged ; Aged ; *Antidepressive Agents/therapeutic use ; *Major Depressive Disorder/drug therapy/blood ; *Peptide Fragments/blood ; Treatment Outcome ; Biomarkers/blood ; Adult ; Aged, 80 and over ; },
abstract = {AIM: Late-life patients with depression are reportedly less responsive to antidepressant treatment than younger patients. Additionally, patients who have depression comorbid with Alzheimer's disease (AD) and those with an amyloid β (Aβ) burden have shown a poor response to antidepressant treatment, suggesting that AD pathology may contribute to treatment resistance. A recent report indicated that Aβ oligomers in blood have increased in patients with AD and are associated with AD pathology. This study was performed to reveal the relationship between blood Aβ oligomers and the response to antidepressant treatment in middle-aged and late-life patients with depression.

METHODS: In this observational study, serum levels of Aβ40, Aβ42, and Aβ oligomers were evaluated in 80 inpatients with major depressive disorder aged ≥ 40 years. Depressive symptoms were assessed at admission (baseline) and after 4 weeks of treatment.

RESULTS: There were significantly fewer treatment responders among patients with than without serum Aβ oligomers (p = 0.016). Serum Aβ oligomers were found to influence the treatment response even after control for age, sex, number of depressive episodes, severity of depression, and Mini-Mental State Examination scores (p = 0.031).

CONCLUSIONS: These results suggest that serum Aβ oligomers may predict a poor response to antidepressant treatment in middle-aged and late-life patients with depression. Our findings also lead us to speculate that elderly patients with a poor treatment response may share AD-related pathophysiological features or neural vulnerability.},
}

Humans
Male
Female
*Amyloid beta-Peptides/blood
Middle Aged
Aged
*Antidepressive Agents/therapeutic use
*Major Depressive Disorder/drug therapy/blood
*Peptide Fragments/blood
Treatment Outcome
Biomarkers/blood
Adult
Aged, 80 and over

@article {pmid41834650,
year = {2026},
author = {Weise, CM and Abu-Rumeileh, S and Otto, M},
title = {From 'senile dementia' to non-vascular Alzheimer's synucleinopathy: the evolution of dementia classification.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag103},
pmid = {41834650},
issn = {1460-2156},
}

@article {pmid41834887,
year = {2026},
author = {Brühl, SM and Volk, HA and Rohn, K and Meyerhoff, N},
title = {Myoclonus in geriatric dogs and its association with canine cognitive dysfunction: an online survey.},
journal = {Frontiers in veterinary science},
volume = {13},
number = {},
pages = {1745264},
pmid = {41834887},
issn = {2297-1769},
abstract = {BACKGROUND: An increasing number of dogs are presented with suspected canine cognitive dysfunction (CCD), and a subset also exhibits myoclonus.

OBJECTIVES: Because CCD shares multiple pathological and pathophysiological features with Alzheimer's disease in humans, and myoclonus has been linked to neurodegenerative disorders in people, the aim of the study was to describe myoclonus in dogs with clinical signs of CCD.

MATERIAL AND METHODS: An anonymous online survey for owners of geriatric dogs (over 7 years of age), consisting of 46 questions, was conducted. The survey included items on signalment, the Canine Dementia Scale (CADES), and myoclonus. CCD was defined based on a CADES score of >8. It was available online in both German and English from April to June 2024.

RESULTS: Of the 401 participants, 148 dogs were excluded due their young age, under 7 years and incomplete CADES-Score. Among the remaining respondents, 89% of owners reported that their dog showed signs of CCD. Overall, 146/164 (89.0%) dogs exhibited both CADES-defined CCD and myoclonus. However, no statistical significance was found between the co-occurrence of CCD screen status and the presence of myoclonus (p = 0.45). Predominantly, myoclonus occurred spontaneously (72.6%, n = 119), stress-induced (15.2%, n = 25), and light-induced (11.6%, n = 19). Noise-induced and feeding-induced myoclonus were the least common trigger (3.0%, n = 5 each), as well as no answer given (0.6%, n = 1). Ten dogs had multiple trigger causes.

CLINICAL SIGNIFICANCE: Myoclonus was commonly co-reported alongside CADES-defined CCD by respondents. Although no statistically significant association between CCD and myoclonus was detected, CCD should be considered among the differential diagnosis in geriatric dogs presenting with myoclonus, particularly in the context of concurrent cognitive decline.},
}

@article {pmid41834908,
year = {2026},
author = {Baek, K},
title = {EEG alpha reactivity in cognitive aging and dementia: clinical implications and cholinergic mechanisms.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1665301},
pmid = {41834908},
issn = {1662-5161},
abstract = {Alpha reactivity-the attenuation of the alpha rhythms upon eye-opening-is a well-known phenomenon in electroencephalography (EEG). Altered alpha reactivity has increasingly been recognized as a potential biomarker for cognitive aging and various types of dementia. This mini-review synthesizes the existing literature on EEG alpha reactivity in older adults, highlighting its clinical implications and neurobiological underpinnings. Methodological issues in quantifying alpha reactivity are first addressed, including the choice of reactivity index, frequency bands, and spatial analysis methods. The review then summarizes evidence that alpha reactivity declines with healthy aging and is further reduced in dementia, especially Alzheimer's disease (AD) and Lewy body dementia (LBD). Importantly, distinct patterns of reduced alpha reactivity may aid in differential diagnosis. It has been reported that AD is often characterized by reduced alpha rhythm during eyes-closed rest, whereas LBD typically shows impaired alpha attenuation upon eye-opening. Neuroimaging and pharmacological studies suggest that alpha reactivity reflects cholinergic system integrity, particularly involving the nucleus basalis of Meynert and its projections to the visual cortex. In conclusion, EEG alpha reactivity is a promising, non-invasive biomarker of cognitive health and dementia subtypes. However, larger, harmonized, multimodal and longitudinal studies are needed to establish its diagnostic value and clarify its neurobiological mechanisms.},
}

@article {pmid41834915,
year = {2026},
author = {Kakkar, A and Singh, H and Jasoria, Y and Kumar, A and Chopra, S and Chopra, H and Mishra, AK},
title = {Bridging pathologies: Mechanistic insights into the diabetes-Alzheimer's nexus.},
journal = {EXCLI journal},
volume = {25},
number = {},
pages = {261-289},
pmid = {41834915},
issn = {1611-2156},
abstract = {Type 2 diabetes mellitus (T2DM) is increasingly recognized as a major risk factor for Alzheimer's disease (AD), with mounting evidence highlighting shared pathophysiological mechanisms. This review explores the intricate biological and molecular links between these two chronic disorders. Key overlapping pathways include impaired insulin signaling, chronic inflammation, oxidative stress, mitochondrial dysfunction, amyloid-beta (Aβ) accumulation, tau hyperphosphorylation, and the formation of advanced glycation end-products (AGEs). Disruption of insulin signaling in the brain contributes to synaptic loss and neurodegeneration, while systemic metabolic disturbances aggravate blood-brain barrier dysfunction and neurovascular damage. Emerging studies also underscore the role of antidiabetic treatments, especially newer agents targeting the gut-brain axis, in modulating AD progression. The review further examines preclinical models, clinical observations, and the development of biomarkers to improve early detection and intervention. Despite growing insights, challenges remain in translating mechanistic knowledge into effective therapies. A multidisciplinary approach integrating metabolic control and neuroprotective strategies is essential for addressing the comorbid burden of T2DM and AD. See also the graphical abstract(Fig. 1).},
}

@article {pmid41834979,
year = {2026},
author = {Li, Y and Chen, Y and Chen, S and Huang, X},
title = {[Aging-Associated Oral Microbiota Dysbiosis and Hypofunction: Their Role in Alzheimer's Disease Pathogenesis].},
journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition},
volume = {57},
number = {1},
pages = {56-64},
pmid = {41834979},
issn = {1672-173X},
mesh = {Humans ; *Alzheimer Disease/microbiology/etiology/physiopathology ; *Dysbiosis/complications/microbiology ; *Mouth/microbiology/physiopathology ; *Aging/physiology ; *Microbiota ; Amyloid beta-Peptides/metabolism ; Brain ; },
abstract = {Alzheimer's disease (AD), a multifactorial neurodegenerative condition, imposes a major burden on societies with aging populations. Recent research indicates that oral cavity health is a critical factor influencing AD pathology, making proactive investigation of this modifiable risk factor essential. This review proposes that aging-related oral microecological dysbiosis and oral hypofunction may promote AD progression by inducing or exacerbating systemic inflammation and disrupting the homeostasis of the "oral-gut-brain" axis. Moreover, each factor may worsen damage through distinct biological pathways: oral microbiota dysbiosis allows direct invasion of the central nervous system by oral pathogens, promoting amyloid β-protein (Aβ) deposition and Tau hyperphosphorylation, while chronic sensory deprivation from oral dysfunction triggers neuronal degeneration and adverse remodeling in key cognitive brain regions. This review aims to systematically elucidate the roles of oral microbiota dysbiosis and oral hypofunction in AD pathogenesis in the context of aging, clarify their underlying biological mechanisms, and explore the potential value of integrating oral cavity health management into comprehensive AD prevention and treatment strategies.},
}

Humans
*Alzheimer Disease/microbiology/etiology/physiopathology
*Dysbiosis/complications/microbiology
*Mouth/microbiology/physiopathology
*Aging/physiology
*Microbiota
Amyloid beta-Peptides/metabolism
Brain

@article {pmid41834991,
year = {2026},
author = {Wen, L and Zhang, Y and Nie, Y and Shen, H and Qin, Q and Qu, M},
title = {Discriminative Plasma Lipidomic Signatures of Dementia with Lewy Bodies and Alzheimer's Disease: A Targeted Mass Spectrometry and Machine Learning Approach.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {561999},
pmid = {41834991},
issn = {1176-6328},
abstract = {BACKGROUND: Dementia with Lewy bodies (DLB) exhibits a more aggressive progression and poorer prognosis than Alzheimer's disease (AD), yet clinical differentiation remains challenging. Dysregulated lipid metabolism, implicated in α-synuclein aggregation and neuroinflammation, may offer specific biomarkers for distinguishing DLB and AD.

METHODS: This cross-sectional study implemented targeted lipidomic profiling to comprehensively characterize plasma lipidomes in a cohort comprising 50 DLB patients and 56 AD patients. Five machine learning algorithms - least absolute shrinkage and selection operator (LASSO) regression, support vector machine (SVM), random forest (RF), recursive feature elimination (RFE), and stepwise regression - were systematically applied for biomarker discovery.

RESULTS: Significant alterations were observed in 7 lipid classes and 65 specific lipid species in DLB compared to AD. DLB plasma exhibited marked elevations in sphingolipids (total Cer, Hex1Cer, SM), lysophospholipids (LPC, LPE), phosphatidic acid (PA), alongside significant reductions in 45 triacylglycerol (TG) species compared to AD. Five machine learning algorithms consistently identified PA(16:0_16:0) and PA(16:0_20:4) as core discriminators between DLB and AD. The LASSO regression model demonstrated superior generalizability in the test set (AUC=0.916), selecting a 11-lipid panel dominated by PA species, alongside PC(18:0_20:4), ChE(22:4), Hex2Cer(d18:1_22:0), and PE species.

CONCLUSION: This first comprehensive targeted lipidomics study reveals distinct plasma lipid signatures differentiating DLB from AD, characterized by upregulated sphingolipids, lysophospholipids, and PA, and downregulated TG. Machine learning identified a 11-lipid biomarker panel, highlighting profound disturbances in glycerophospholipid metabolism. These findings provide novel molecular insights into DLB pathogenesis and a promising diagnostic tool for diagnosis.},
}

@article {pmid41835065,
year = {2026},
author = {Xiao, X and Yan, X and Liang, C and Yang, Y},
title = {Metabolic dysfunction and mitochondrial failure in Alzheimer's disease: integrating pathophysiology, clinical evidence and emerging interventions.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1772036},
pmid = {41835065},
issn = {1664-2295},
abstract = {Alzheimer's disease (AD) is a gradual and irreversible decline in the brain's ability to function which is not only signified by amyloid-beta plaques and neurofibrillary tangles but also by and metabolic and mitochondrial changes that have a negative impact on the classical neuropathological hallmarks. It is becoming increasingly clear that the central roles in the process of synaptic dysfunction, neuronal death and cognitive decline are played by the brain's impaired glucose utilization, insulin resistance, lipid metabolism alterations, and energy homeostasis disruption. Mitochondrial dysfunctions in AD comprising of oxidative phosphorylation defects, ATP production decrease, reactive oxygen species generation over and above the normal level, poor mitochondrial dynamics, and vacuolar-type H+-ATPase-mediated cell death are the factors that further worsen the situation and hence speed up the process of neuronal death and eventually, disease progression. The metabolic and mitochondrial disturbances have a two-way relationship with amyloid-beta and tau pathology, neuroinflammation, and oxidative stress, thus creating a self-sustaining cycle of neurodegeneration. Besides, clinical and neuroimaging studies, fluorodeoxyglucose positron emission tomography, cerebrospinal fluid biomarkers, and peripheral metabolic profiling all support the notion that metabolic impairment is an early and clinically relevant feature of AD very convincingly. Thus, the attention of the scientific community has turned more and more toward the approaches that use the metabolic and mitochondrial pathways as their target. The new treatments are coming, including insulin sensitizers, ketogenic and Mediterranean diets, mitochondrial-targeted antioxidants, exercise, metabolic modulators, and new drugs, all aimed at bringing back equilibrium to bioenergetics and letting neurons live longer. In this review, we have considered the current mechanistic insights, clinical evidence, and therapeutic advances related to metabolic dysfunction and mitochondrial failure in AD together and their potential as early biomarkers and modifiable targets for disease prevention and treatment that are highlighted.},
}

@article {pmid41835069,
year = {2026},
author = {Duan, H and Liu, J and Pan, X and Huang, T and Chen, X},
title = {Associations of modified triglyceride-glucose indices with risks of dementia subtypes and brain structure: a prospective cohort study.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1750736},
pmid = {41835069},
issn = {1664-2295},
abstract = {BACKGROUND: The associations of modified triglyceride-glucose (TyG) indices with risks of dementia subtypes and brain structural changes remain unclear. This study prospectively examines whether modified TyG indices, including TyG with body mass index (TyG-BMI) and TyG with waist circumference (TyG-WC), are associated with the risks of Alzheimer's disease (AD) and vascular dementia (VaD) and with structural brain alterations.

MATERIALS AND METHODS: This study analyzed 356,454 dementia-free participants from the UK Biobank. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) for incident AD and VaD. Restricted cubic spline (RCS) analyses assessed nonlinear relationships. Linear regression models evaluated associations between modified TyG indices and brain structures, including hippocampal volume and white matter hyperintensity (WMH) volume. Subgroup analyses and sensitivity analyses were performed to test robustness.

RESULTS: During follow-up, 2,594 AD and 1,386 VaD cases were identified. In fully adjusted Cox models, both TyG-BMI and TyG-WC showed clear dose-response patterns with dementia risk. Using Q5 as the reference, participants in the lowest sextile (Q1) had a 47% higher risk of AD for TyG-BMI (HR = 1.47, FDR-adjusted p < 0.001) and a 23% higher risk for TyG-WC (HR = 1.23, FDR-adjusted p = 0.019), while those in the highest sextile (Q6) also tended to have increased AD risk. By contrast, VaD risk increased with higher modified TyG levels, and participants in the highest sextile had 32 and 45% higher VaD risk for TyG-BMI and TyG-WC, respectively (TyG-BMI: HR = 1.32, FDR-adjusted p = 0.029; TyG-WC: HR = 1.45, FDR-adjusted p = 0.011). Multivariable-adjusted restricted cubic spline analyses confirmed significant nonlinear relationships, showing a broad U-shaped association of modified TyG indices with AD and a J-shaped association with VaD. Higher modified TyG indices were additionally linked to larger hippocampal volume but greater WMH burden. The associations remained robust in multiple sensitivity analyses.

CONCLUSION: Modified TyG indices show nonlinear, differential associations with AD and VaD risks, and are linked to structural brain alterations. These findings highlight the importance of metabolic health in dementia prevention and brain aging.},
}

@article {pmid41835547,
year = {2026},
author = {Kalidass, B and Kodiveri Muthukaliannan, G},
title = {In Silico Profiling of Phytochemicals for Modulating Amyloid Beta-Mediated Immune Regulation and Neuroinflammation in Alzheimer's Disease.},
journal = {ACS omega},
volume = {11},
number = {9},
pages = {14947-14963},
pmid = {41835547},
issn = {2470-1343},
abstract = {The etiology of Alzheimer's disease (AD) has been extensively studied for a long time, primarily associated with multifaceted mechanisms involving aggregation of amyloid beta, tau hyperphosphorylation, neuroinflammation, and immune regulation. Current therapeutics for AD are significantly targets to attenuate the cognitive decline by modulating neurotransmitters and diminishing aggregation of amyloid beta. However, these therapeutics fail to address the neuroimmune dysregulation that critically facilitates disease progressions. In this study, we have delineated the phytochemical potential to modulate the amyloid beta-triggered immune regulation through in silico approaches. Seventy three phytochemicals were selected from established anti-Alzheimer's plants through literature mining and sequentially administrated to pharmacodynamic and pharmacokinetic investigations. The draggable study has established 14 phytochemicals, and the compounds were further curated based on their molecular interactions with the hub-targets, enriched in the amyloid beta-driven immune regulation. AD-associated proteins were retrieved from different data sets such as GeneCards, DisGeNet, GEO, and Opentargets, and the intersecting targets were curated for downstream analysis. Functional annotation and network pharmacology analysis mapped APOE4, BACE1, TREM2, IL-1β, and TNF-α as key regulatory targets. The molecular interaction analysis revealed that genkwanin and kaempferol exhibited strong binding affinity and stable interactions with the hub-targets as a potent candidates to attenuate the immune regulation in AD. Further molecular mechanics/Poisson-Boltzmannsson-Boltzmann surface area and DFT analysis have revealed their thermodynamic stability and electronic reactivity, highlighting their potential efficacy in mitigating AD progression.},
}

@article {pmid41835939,
year = {2026},
author = {Negro, G and Poloni, C and Medici, V and Calatozzolo, C and Canazza, A and Ferrari, RR and Cutaia, C and Davin, A and Poloni, TE},
title = {Frontotemporal lobar degeneration complexity: atypical presentations and heterogeneous proteinopathies in five cases.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1774283},
doi = {10.3389/fnins.2026.1774283},
pmid = {41835939},
issn = {1662-4548},
abstract = {INTRODUCTION: Frontotemporal lobar degeneration (FTLD) encompasses heterogeneous clinical syndrome within the frontotemporal spectrum, where clinicopathological associations may be misleading. This case series illustrates clinicopathological variability and mismatches.

METHODS: A retrospective case series was conducted within the brain donation program at the Golgi Cenci Foundation. Cases presenting at onset with a frontotemporal-spectrum phenotype, longitudinal clinical data, and post-mortem neuropathological characterization were included.

RESULTS: Five cases (mean age at onset 65.4 years) were clinically diagnosed with major neurocognitive disorder due to frontotemporal dementia (FTD). Neuropathological examination revealed clinicopathological heterogeneity: two cases showed FTLD-TDP-A associated with GRN mutations, including a classic case and one with posterior (parieto-occipital) involvement; one non-fluent variant primary progressive aphasia (nfvPPA) case demonstrated FTLD-TDP-A with multiple co-pathologies; one semantic-variant-like case was driven by high Alzheimer's disease neuropathological changes; and one behavioral variant FTD-like case corresponded to frontal-variant Alzheimer's disease (fvAD) with extensive mixed pathology, including Lewy body disease, LATE-NC, and vascular pathology.

DISCUSSION: Findings indicate that clinical phenotypes are more influenced by the anatomical distribution of pathology than by the specific molecular substrate. Frequent coexisting proteinopathies and asymmetric involvement contribute to phenotypic variability, reinforcing the role of neuropathological examination of both hemispheres for accurate clinicopathological correlations and definitive etiological diagnosis.},
}

@article {pmid41836011,
year = {2026},
author = {Chakif, D and Furrer, J},
title = {The impact of nutritional, environmental, and lifestyle factors on neurological disorders: therapeutic implications and mechanistic insights.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1765786},
doi = {10.3389/fphar.2026.1765786},
pmid = {41836011},
issn = {1663-9812},
abstract = {Neurological disorders like Alzheimer's, Parkinson's, multiple sclerosis, and primary psychiatric conditions are complex, arising from a mix of genetic and modifiable risks. Growing evidence indicates that nutrition, environment, and lifestyle significantly influence disease development, progression, and treatment response. Nutrients such as vitamins, minerals, omega-3 fatty acids, and polyphenols affect neuroinflammation, oxidative stress, mitochondrial health, and neurotransmitter function. Dietary patterns like the Mediterranean and ketogenic diets offer protective benefits in clinical and experimental contexts. Meanwhile, environmental neurotoxicants-air pollution, heavy metals, pesticides, and endocrine disruptors contribute to neurodegeneration via oxidative damage, synaptic impairment, and epigenetic alterations. Lifestyle factors, such as physical activity, sleep, stress, and substance use, affect brain plasticity, neurogenesis, and metabolic health, thereby influencing disease progression over time. These factors often share common pathways such as oxidative stress, inflammation, vascular injury, mitochondrial dysfunction, and protein misfolding, underscoring the need for a comprehensive prevention and treatment strategy. Emerging therapies now incorporate personalized nutrition, lifestyle changes, and environmental risk mitigation alongside traditional drugs, supported by advances in multi-omics, digital health, and systems biology. Public health efforts to reduce neurotoxic exposure and encourage healthy habits further strengthen these approaches. This review summarizes existing mechanistic and clinical knowledge, with a focus on the potential of nutritional, environmental, and lifestyle interventions in neurological diseases. It also outlines the future research required to enhance precision neurology and strategies for brain health prevention.},
}

@article {pmid41836026,
year = {2026},
author = {Zhao, M and Qu, Y and Zhang, S and Zhang, M and Wang, H and Yang, Y and Xue, G and Hou, X and Yan, X},
title = {Multi-target intervention mechanisms and prospects of the traditional Chinese medicine Scutellaria baicalensis georgi in Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1707688},
doi = {10.3389/fphar.2026.1707688},
pmid = {41836026},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is one of the most prevalent central nervous system disorders affecting middle-aged and elderly populations. As a neurodegenerative disease, its primary clinical manifestations include memory impairment, cognitive dysfunction, and behavioral abnormalities. However, there are limited clinically available treatments for AD. Existing medications neither cure the disease nor halt its progression, and are often associated with significant side effects. Scutellaria baicalensis Georgi, with its long history of medicinal use, shows potential for treating central nervous system disorders. Modern pharmacological research has revealed its antioxidant, anti-inflammatory, antiviral, neuroprotective, and immunomodulatory properties. Its active metabolites, such as baicalin and baicalein, exert multi-target effects by simultaneously influencing Aβ production and aggregation, tau phosphorylation, and microglial activation, while also regulating brain-gut axis function. This systematic review examines the mechanisms of action of baicalin and baicalein, the active metabolites of Scutellaria baicalensis Georgi, in treating Alzheimer's disease, offering novel insights and research directions for modern medical approaches to Alzheimer's disease treatment.},
}

@article {pmid41836096,
year = {2026},
author = {Wang, G and Li, H and Zhang, S},
title = {Rethinking cervical deep lymphovenous anastomosis in Alzheimer's disease: problems and prospects.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1722759},
doi = {10.3389/fnagi.2026.1722759},
pmid = {41836096},
issn = {1663-4365},
abstract = {BACKGROUND: Deep cervical lymphovenous anastomosis (DCLVA) has been proposed as a novel surgical strategy to promote brain waste clearance in Alzheimer's disease (AD), inspired by advances in glymphatic and meningeal lymphatic research. Early reports suggested possible cognitive benefits, yet the scientific basis of this approach remains controversial.

DISCUSSION: This Perspective critically examines the mechanistic rationale, anatomical limitations, and methodological shortcomings underlying DCLVA. The pressure disparity between cervical lymphatic and venous systems challenges the physiological feasibility of the procedure, while existing studies lack randomized design, biomarker validation, and control for anesthesia-related confounding. Ethical and translational considerations further underscore the need for rigorous preclinical and clinical evaluation before any clinical adoption.

SUMMARY: While DCLVA reflects an innovative attempt to translate lymphatic biology into surgical therapy, its current theoretical and empirical foundation is insufficient. A shift toward mechanistic validation, objective imaging biomarkers, and non-invasive modulation of lymphatic function is warranted before DCLVA can be considered a viable therapeutic option for AD.},
}

@article {pmid41836504,
year = {2026},
author = {Alsulami, A and Bogdani, M and MacLean, E and Keene, CD and McGrath, S and Consortium, DAP and Latimer, CS and Moreno, JA},
title = {Alzheimer's Disease Neuropathological characterization of the dog brain and relationship to biofluid biomarkers and cognitive function.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8994620/v1},
pmid = {41836504},
issn = {2693-5015},
abstract = {Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a major global health challenge affecting more than 55 million people worldwide. AD is clinically defined by progressive cognitive decline and neuropathologically characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs). While transgenic rodent models have provided valuable mechanistic insights, they do not fully capture the spontaneous, age-related nature of human AD. In contrast, the companion dog develops naturally occurring age-associated cognitive decline and AD-like neuropathological features, including Aβ deposition and tau pathology, and behavioral impairments measurable by the validated cognitive scales, Canine Cognitive Dysfunction Rating (CCDR). However, the systematic application of human AD neuropathological criteria to canine brains has been limited. Objective The objective of this study was to apply established human neuropathological criteria (Thal, Braak, and CERAD) to aged canine brains and examine relationships among neuropathology, cognitive status, and plasma biomarkers. Methods Postmortem brain tissues from 24 client-owned senior dogs were evaluated using Thal phases for Aβ deposition, Braak-based regional assessment of tau pathology, and CERAD criteria for neuritic plaques. Neuropathological findings were integrated with antemortem owner-reported cognitive assessments and plasma biomarker measurements to evaluate the clinico-pathologic and biomarker associations. Results Senior dogs exhibited Aβ deposition consistent with early to intermediate Thal phases, variable and regionally restricted tau pathology, and an absence of neuritic plaques. Quantitative analysis demonstrated greater Aβ burden in cognitively impaired dogs compared with cognitively intact dogs, while age, but not cognitive score, was strongly associated with regional Aβ burden. Further, plasma glial fibrillary acidic protein (GFAP) levels showed a significant positive correlation with Aβ plaque burden, whereas the other plasma biomarkers assessed did not. Conclusion Senior dogs exhibit neuropathologic features consistent with early-stage AD-like pathology, characterized by Aβ deposition and limited tau pathology in the absence of neuritic plaques. These findings support the utility of the companion dog as a naturally aging model for investigating early AD-related pathological processes and evaluating translational biomarkers during preclinical disease.},
}

@article {pmid41836505,
year = {2026},
author = {Ma, T and Jester, H and Wang, X and Li, T and Suhocki, A and Zhou, X and Proud, C and Rosenblum, K},
title = {Suppression of neuronal eEF2K alleviates cognitive deficits and apathy-like behavior in APP/PS1 AD model mice.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8970895/v1},
pmid = {41836505},
issn = {2693-5015},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by synaptic failure, cognitive impairment and neuropsychiatric symptoms (NPS). Apathy is the most common NPS seen in AD patients, and its underlying mechanisms remain unknown. Here, we investigated the roles of neuronal eukaryotic elongation factor 2 (eEF2) phosphorylation (by its kinase eEF2K) in AD-associated cognitive deficits and NPS. We performed a series of experiments using a multidisciplinary approach including genetics, behavioral assays, synaptic electrophysiology, and unbiased proteomics. The results demonstrated that neuron-specific inhibition of eEF2K and eEF2 phosphorylation can alleviate cognitive deficits, synaptic plasticity impairments, and apathy-like behavior in aged APP/PS1 AD model mice. Our findings indicate the therapeutic potential of targeting the eEF2K signaling in the treatment of dementia and NPS in AD and related dementias (ADRDs).},
}

@article {pmid41836515,
year = {2026},
author = {Leitner, D and Kanshin, E and Balcomb, K and Askenazi, M and Suazo, J and Marta-Ariza, M and Schneider, J and Ueberheide, B and Drummond, E and Wisniewski, T},
title = {The Amyloid Plaque Proteomes of Alzheimer's Disease and Mild Cognitive Impairment.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9012095/v1},
pmid = {41836515},
issn = {2693-5015},
abstract = {Amyloid plaques contain numerous proteins in addition to amyloid beta in Alzheimer's disease (AD). Previous localized proteomics identified plaque-associated proteins in late-onset AD, early-onset AD, rapidly progressive AD, preclinical AD, and AD in Down syndrome, although most studies had smaller cohorts and focused primarily on severe pathology. The amyloid plaque proteome in mild cognitive impairment (MCI) has not been evaluated. We evaluated plaque proteomes in MCI and AD with comparisons to neighboring non-plaque tissue and control non-plaque tissue from ROSMAP (151 cases (n = 240 samples); control (n = 62), MCI (n = 36), AD (n = 53)). Tissue was microdissected from autopsy paraffin embedded temporal cortex and evaluated by label-free quantitative proteomics. We identified differentially abundant proteins with robust differences at a false discovery rate (FDR) < 5% and fold-change > 1.5 for 135 proteins in MCI and 156 in AD plaque tissue compared to neighboring non-plaque tissue, which included proteins described previously as well as novel proteins. Gene ontology (GO) term associations included increased inflammatory response and lysosome proteins in both MCI and AD, and decreased myelin proteins particularly in AD. Of plaque proteins altered in at least one disease group, many changed in the same fold-change direction (p < 0.0001, R [2] = 0.53) and there were 100 shared proteins in MCI and AD. In non-plaque tissue, there were 277 differentially abundant proteins in MCI and 177 in AD; associated with structural constituent of chromatin in MCI and negative regulation of DNA recombination and autolysosome in AD, with decreased proteins associated with actin-myosin filament in AD. Weighted gene correlation network analysis (WGCNA) identified proteins associated with pathology and demographics. We have conducted the most extensive proteomics of microdissected plaque proteomes in both MCI and AD. Our results provide insights into MCI and AD molecular mechanisms, novel biomarkers, and potential novel therapeutic targets.},
}

@article {pmid41836522,
year = {2026},
author = {Liu, A and Xing, L and Li, J and Yao, M and Song, J and Guo, W and Duan, P and Li, H},
title = {Traditional Chinese Medicine and Ferroptosis in Alzheimer's Disease: A Potential Therapeutic Approach.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {590868},
doi = {10.2147/DDDT.S590868},
pmid = {41836522},
issn = {1177-8881},
mesh = {*Ferroptosis/drug effects ; Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Medicine, Chinese Traditional ; *Drugs, Chinese Herbal/pharmacology/chemistry/therapeutic use ; Animals ; },
abstract = {Alzheimer's disease (AD) represents a prevalent neurodegenerative disorder associated with considerable morbidity and mortality. Currently, no therapeutic agents exist that can achieve a fundamental reversal or complete cure for this condition. Consequently, the identification of novel molecular targets and the development of innovative treatment modalities aimed at slowing progression and alleviating symptoms represent pressing priorities within AD clinical research. Ferroptosis, a regulated cell death process driven by intracellular iron dysregulation and excessive lipid peroxidation, is now recognized as a critical contributor to AD pathogenesis. Traditional Chinese medicine (TCM) has demonstrated beneficial outcomes in managing AD, and emerging evidence suggests its regulatory effects may extend to modulating ferroptotic pathways. This review summarizes and analyzes the therapeutic efficacy of various TCM strategies against AD, including herbal extracts, monomers (eg, alkaloids, terpenoids, glycosides, phenolic derivatives, quinones), compound formulas, and acupuncture. It highlights how these interventions target key ferroptosis-related axes-such as iron homeostasis, the system Xc-/GSH/GPX4 antioxidant system, and the Keap1/Nrf2/ARE pathway-to collectively address the pathological foundation of the disease. However, current evidence is predominantly preclinical, and the translational potential of TCM is constrained by challenges including blood-brain barrier penetration, pharmacokinetic profiles, standardization, and safety assessments. In conclusion, TCM exhibits substantial potential for both research and clinical application in AD by targeting and attenuating the ferroptosis pathway, offering promising avenues for disease modification and symptomatic relief.},
}

*Ferroptosis/drug effects
Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Medicine, Chinese Traditional
*Drugs, Chinese Herbal/pharmacology/chemistry/therapeutic use
Animals

@article {pmid41836608,
year = {2026},
author = {Yang, SJ and Lin, AA and Shen, H and Pappalardo, LW and Spychalski, GB and Rosario, J and Forsberg, LK and Grant, KM and Buser, JR and Savica, R and O'Bryant, S and Jones, DT and Dickson, DW and Reichard, RR and Nguyen, AT and Meaney, DF and Boeve, BF and Ross, OA and McLean, PJ and Issadore, D},
title = {Microfluidic nanomagnetically isolated neuron- and astrocyte-derived extracellular vesicles to differentiate Lewy body and Alzheimer's disease.},
journal = {Npj biosensing},
volume = {3},
number = {1},
pages = {19},
doi = {10.1038/s44328-026-00086-x},
pmid = {41836608},
issn = {3004-8656},
abstract = {Identifying plasma-based biomarkers that can accurately differentiate Lewy body disease (LBD) from Alzheimer's disease (AD) remains a major challenge. Extracellular vesicles (EVs), which carry molecular cargo from their parent cells and can cross the blood-brain barrier, offer a new path forward. We developed the multiplexed Track-Etch magnetic NanoPOre (mTENPO) platform, a highly parallelized microfluidic technology for cell-specific EV isolation, and demonstrated independent enrichment of GluR2+ (neuron-derived) and GLAST+ (astrocyte-derived) EVs from the antemortem plasma of 137 autopsy-confirmed LBD, AD, mixed pathology, and control subjects. By integrating miRNA sequencing of GluR2+ and GLAST + EV cargo with plasma measurements of Aβ40, Aβ42, tau, p-Tau181, and p-Tau231, we identified a multimodal 15-feature panel that more comprehensively reflects brain pathology than conventional biomarkers. Using tenfold cross-validation to mitigate overfitting, the panel achieved an accuracy of 0.95 and an area under the curve of 0.96 for distinguishing LBD versus AD.},
}

@article {pmid41836694,
year = {2026},
author = {Kumar, P and Waris, M and Rao, AR and Bajpai, S and Soni, N and Chakrawarty, A and Chatterjee, P and Dey, AB},
title = {Early Diagnosis of Cognitive Impairment in the Ageing Population: Determinants and Barriers.},
journal = {Indian journal of community medicine : official publication of Indian Association of Preventive & Social Medicine},
volume = {51},
number = {1},
pages = {52-57},
doi = {10.4103/ijcm.ijcm_402_24},
pmid = {41836694},
issn = {0970-0218},
abstract = {BACKGROUND: Diagnosis of cognitive impairment at an early stage is vital to the management of dementias like Alzheimer's disease. Recent studies have proven the benefits of multimodal interventions in patients with early stages of cognitive impairment. In this study, we evaluate the determinants of presentation of cognitive impairment at early and late stages in a tertiary center memory clinic.

STUDY DESIGN: A cross-sectional study.

METHOD: A total of 438 patients presenting with cognitive impairment were evaluated in the memory clinic. After ruling out reversible causes and pseudodementia, 294 patients were included for final analysis and classified as those with early disease (i.e., Subjective Cognitive Decline [SCD] and Mild Cognitive Impairment [MCI]) or major neurocognitive decline [MNCD]. A retrospective data analysis was done to evaluate the association of baseline characteristics (age, sex, education, region, occupation, and cardiovascular diseases) with the stage of presentation of cognitive decline.

RESULT: Patients presenting with an early-stage cognitive impairment (SCD and MCI) constituted 65% and MNCD was identified in 35% of the population. Demographic factors like female sex [OR: 1.99, 95% CI: 1.10, 3.56] and lower education [OR: 1.99, 95% CI: 1.15, 3.42] were significantly associated with late presentation MNCD.

CONCLUSION: Female patients and those with lower education are vulnerable to late presentation and can be an important target population for dementia screening. Increasing dementia awareness and care at the primary healthcare level may help in the early diagnosis and preventive interventions of dementia.},
}

@article {pmid41836758,
year = {2026},
author = {Li, X and Yu, Y and Li, S and Lin, X and Yang, C and Yang, Y and Wang, S and Zhou, M and Bao, Z and Sui, X and Feng, W and Yang, J and Zuo, D and Luo, Y and Wang, Y and Du, X},
title = {A high-throughput screening platform for acetylcholinesterase inhibitors using a genetically encoded acetylcholine fluorescent sensor.},
journal = {Frontiers in bioengineering and biotechnology},
volume = {14},
number = {},
pages = {1781867},
doi = {10.3389/fbioe.2026.1781867},
pmid = {41836758},
issn = {2296-4185},
abstract = {Acetylcholinesterase (AChE) is a crucial hydrolytic enzyme in the central nervous system, responsible for the rapid degradation of the neurotransmitter acetylcholine (ACh) in the synaptic cleft, thereby maintaining the balance between neuronal excitation and inhibition. AChE is not only the primary target of neurotoxic agents and organophosphorus pesticides but its aberrant activity is also closely associated with various neurodegenerative diseases such as Alzheimer's disease (AD) and myasthenia gravis. The efficient and rapid discovery and screening of AChE inhibitors hold urgent and significant value for chemical toxin detection, toxicological research, and drug development for neurodegenerative diseases. Addressing the limitations of existing methods, such as low biocompatibility, low detection throughput, relative operational complexity, and high cost, this study innovatively utilizes a genetically encoded biosensor to construct a stable cell line co-expressing the ACh probe and AChE, establishing a novel high-throughput screening method for AChE inhibitors. The results demonstrate that this method achieved to detect AChE inhibitors at micromole level. This method eliminates the need for purified enzymes and toxic chemical reagents (e.g., DTNB in Ellman's assay), significantly reduces cost (by approximately two orders of magnitude), and offers a simplified, rapid, and high-throughput compatible workflow for applications in neurotoxin detection and neurotherapeutic drug discovery.},
}

@article {pmid41836919,
year = {2026},
author = {Aguzin Parrilli, LJ and Belzunce, MA},
title = {Bias and generalizability of brain age prediction models: A multi-cohort evaluation with anatomical and interpretability insights.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
doi = {10.1162/IMAG.a.1164},
pmid = {41836919},
issn = {2837-6056},
abstract = {Brain age prediction from T1-weighted MRI and its associated brain age gap (BAG) has emerged as a promising neuroimaging biomarker for assessing deviations from normative aging. However, the robustness, bias, and interpretability of existing models across external datasets remain poorly understood, limiting clinical translation. In this study, we evaluated four publicly available brain age models (ENIGMA, DeepBrainNet, Pyment, and BrainAgeNeXt) across four independent MRI datasets (ADNI, UNSAM Long COVID, and two OpenNeuro cohorts), comprising 1,634 subjects with diverse demographic and clinical profiles. Models were tested using their original preprocessing pipelines, and performance was assessed using mean absolute error (MAE), mean error (ME), and BAG variability metrics, with additional analyses of biases related to age, dataset, ethnicity, and education. Interpretability was evaluated using Layer-wise Relevance Propagation, and anatomical correlates were explored using BrainChart-derived centile scores. Group-level comparisons were performed between cognitively normal (CN) individuals and patients with Mild Cognitive Impairment (MCI), Alzheimer's disease (AD), or Long COVID (LC). Models based on 3D convolutional neural networks (Pyment and BrainAgeNeXt) outperformed the DeepBrainNet 2D CNN and the ENIGMA ridge regression model in both accuracy (MAE: 3.9-3.7 vs. 6.2-12.4 years respectively) and stability (ASTD: 3.2-2.9 vs. 4.6-8.3 years). Dataset-specific BAG differences were largely explained by age distributions, whereas ethnicity showed a statistically significant but small effect on BAG in some models. Relevance maps highlighted the lateral ventricles as the most consistently relevant anatomical region, with additional cerebellar contributions emerging in older adults for BrainAgeNeXt. Group-level analyses confirmed elevated BAG in MCI and AD patients compared to CN, while no significant differences were observed in Long COVID participants. These findings suggest that, while BAG is a promising biomarker for group-level analyses, current models are required to address age and demographic biases to enable individual-level clinical application.},
}

@article {pmid41837280,
year = {2026},
author = {Mosconi, L},
title = {Women's midlife: the front line of Alzheimer prevention.},
journal = {The Journal of clinical investigation},
volume = {136},
number = {6},
pages = {},
doi = {10.1172/JCI199832},
pmid = {41837280},
issn = {1558-8238},
mesh = {Humans ; *Alzheimer Disease/prevention & control/metabolism/physiopathology ; Female ; *Menopause ; *Aging/pathology ; Risk Factors ; Middle Aged ; Estrogen Replacement Therapy ; },
abstract = {Nearly two-thirds of patients with Alzheimer disease (AD) are women, most of them postmenopausal. While sex differences in AD have historically been attributed to women's relative longevity, accumulating evidence challenges that view, pointing to female sex-specific biological underpinnings. In particular, neuroendocrine aging and the hormonal shifts that accompany the menopause transition have emerged as potentially modifiable AD risk factors in women. Yet, key neuroendocrine aging-related factors linked to increased AD and dementia risk, such as early menopause, premenopausal bilateral oophorectomy, frequent vasomotor symptoms, and midlife cognitive and mood disturbances, remain underinvestigated. Additionally, although a growing evidence base highlights the potential of menopause hormone therapy for AD prevention, particularly in women undergoing oophorectomy, progress remains hindered by a lack of clinical trials and biomarker-driven studies. This Review calls for a paradigm shift: from viewing AD risk as a byproduct of generalized aging to validating midlife neuroendocrine aging as a distinct window of vulnerability, and an opportunity for prevention. By 2050, over 1.2 billion women worldwide will be in or approaching menopause. The stakes are global, and the opportunity is urgent: to redefine AD prevention through sex-specific, time-sensitive, and biologically informed strategies that translate science into scalable, actionable care.},
}

Humans
*Alzheimer Disease/prevention & control/metabolism/physiopathology
Female
*Menopause
*Aging/pathology
Risk Factors
Middle Aged
Estrogen Replacement Therapy

@article {pmid41837285,
year = {2026},
author = {Gautier, O and Nguyen, TP and Gitler, AD},
title = {Decoding neurodegeneration one cell at a time.},
journal = {The Journal of clinical investigation},
volume = {136},
number = {6},
pages = {},
doi = {10.1172/JCI199841},
pmid = {41837285},
issn = {1558-8238},
mesh = {Humans ; *Neurodegenerative Diseases/genetics/pathology/metabolism ; *Single-Cell Analysis ; Animals ; *Neurons/metabolism/pathology ; *Transcriptome ; },
abstract = {Neurodegenerative diseases are characterized by protein misfolding and the selective vulnerability of specific neuronal subtypes. This selective vulnerability presents a paradox; most neurodegenerative disease genes are expressed broadly throughout the brain, and some ubiquitously, but only certain types of neurons are lost while others are resistant. The molecular basis for selective neuronal vulnerability has remained a mystery, but recent genomics technological innovations are starting to provide mechanistic insights. Here, we review how single-cell genomics techniques - single-cell transcriptomics, single-cell epigenomics, and spatial transcriptomics - advance our molecular understanding of selective vulnerability and neurodegeneration across Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington disease. Together, these approaches reveal the cell types affected in disease, define disease-associated molecular states, nominate candidate determinants of vulnerability and degeneration, and situate degenerating neurons within their local tissue context. Continued development and application of these techniques, including single-cell perturbation screens, will expand descriptive atlases of relevant cell types in health and disease and identify causal mechanisms, revealing the molecular basis of vulnerability and degeneration and informing therapeutic development.},
}

Humans
*Neurodegenerative Diseases/genetics/pathology/metabolism
*Single-Cell Analysis
Animals
*Neurons/metabolism/pathology
*Transcriptome

@article {pmid41837371,
year = {2026},
author = {Ackley, SF and La Joie, R and Caunca, M and Mukherjee, S and Choi, SE and Trittschuh, EH and Crane, PK and Hayes-Larson, E and , },
title = {Substituting Blood-Based Biomarkers for Imaging Measures in Alzheimer's Disease Studies: Implications for Sample Size and Bias.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag068},
pmid = {41837371},
issn = {1758-535X},
abstract = {BACKGROUND: Blood-based biomarkers for Alzheimer's disease (AD) pathology are appealing options in large population-based studies due to their low cost, minimal invasiveness, and feasibility of collection in non-clinical settings. Despite these benefits, blood-based biomarkers have lower test-retest reliability than neuroimaging measures like amyloid positron emission tomography (amyloid-PET) Centiloids; trade-offs in power and bias remain unexplored.

METHODS: We use data from Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) studies, which include both amyloid-PET and blood-based measures, to assess differences in statistical power, required sample size, and bias when replacing a neuroimaging measure with a blood-based measure. We use simulations parameterized based on these studies to show potential implications of using plasma p-tau 181 or p-tau 217, blood-based AD biomarkers, in place of Centiloids from amyloid-PET, when the biomarker is either the exposure or the outcome in an analysis of interest.

RESULTS: We demonstrated that substituting amyloid-PET Centiloids with a blood-based measure of p-tau can substantially reduce power, requiring 1.5 to 6.5 times the sample size to achieve 80% power compared to amyloid-PET. In addition, using a blood-based biomarker as the exposure can introduce significant regression dilution bias, attenuating estimated associations.

CONCLUSIONS: While blood-based biomarkers are lower cost and easier to collect than neuroimaging measures, their use as proxies for AD pathology may introduce substantial methodological challenges, depending on the p-tau isoform. Consideration of the sample sizes they necessitate and their potential for bias is critical for the design and interpretation of studies employing these biomarkers.},
}

@article {pmid41837374,
year = {2026},
author = {Kaufmann, CN and Yang, KH and Tseng, CI and Chang, G and Amjad, H and Albrecht, JS and Spira, AP and Gross, AL and Wickwire, EM and Malhotra, A},
title = {Using Observational Data to Investigate Cognitive Outcomes of Obstructive Sleep Apnea Treatment: A Scoping Review.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag078},
pmid = {41837374},
issn = {1758-535X},
abstract = {BACKGROUND: Prior research indicates a connection between obstructive sleep apnea (OSA) and cognitive deficits, prompting interest in whether OSA treatment can prevent or slow cognitive decline. Past clinical trials on OSA treatment and cognitive impairment have shown inconsistent results. However, observational data might help by examining more diverse populations and larger sample sizes, increasing the ability to detect subtle effects. Therefore, we reviewed literature to characterize studies evaluating cognitive outcomes from OSA treatment using observational study data.

METHODS: We conducted a scoping review of studies retrieved on PubMed and Embase. Studies were screened by title/abstract, and then full text, for inclusion. We extracted data characterizing data source, study design, population, sample size, follow-up time, treatments assessed, cognitive outcome variables, and key associations.

RESULTS: Of 3,655 unique articles obtained from PubMed and Embase, 13 met eligibility criteria. All were retrospective cohort studies. Ten studies evaluated positive airway pressure (PAP) therapies, one examined uvulopalatopharyngoplasty, and two evaluated any type of OSA treatment. No studies evaluated mandibular advancement devices. Cognitive outcomes assessed included dementia diagnosis (8 studies), and changes in cognitive performance (5 studies). Results from studies for most part found OSA treatment was associated with better cognitive outcomes, although effects varied in magnitude and statistical significance based on the data source, outcomes, and sample size.

CONCLUSIONS: Observational data has the potential to help evaluate cognitive outcomes from OSA treatment, but more studies are needed, especially for OSA therapies beyond PAP alone.},
}

@article {pmid41837502,
year = {2026},
author = {Huang, C and Han, Y and He, J and Ma, W and Chen, Y and Dong, Z and Cheng, X and Lu, C and Gu, X},
title = {Reactive astrocyte subpopulations with high Gfap and C4b expression in different Alzheimer's disease mouse models: Single-cell nuclear transcriptome analysis.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00789},
pmid = {41837502},
issn = {1673-5374},
abstract = {Understanding the cellular landscape underlying the heterogeneity of Alzheimer's disease and the cell type-specific molecular perturbations is essential for identifying novel, targeted therapeutic strategies. However, previous bulk transcriptomic studies have failed to capture the unique contributions of individual cell populations to the early pathogenesis of the disease, and the functional diversity of key cell types in driving Alzheimer's disease progression remains insufficiently characterized. In this study, we examined transcriptional changes in hippocampal tissue during early Alzheimer's disease stages in two mouse models of Alzheimer's disease: the apolipoprotein E4 knock-in and amyloid precursor protein/presenilin 1 mice. We performed single-cell nuclear transcriptome sequencing on hippocampal tissue from three 8-month-old amyloid precursor protein/presenilin 1 mice and one 6-monthold apolipoprotein E4 knock-in mouse, with one 6-month-old apolipoprotein E3 knock-in mouse serving as the control. Analyses of intergroup differential expression and functional enrichment indicated that Alzheimer's disease-associated genes in different cell types were involved in synapse-related pathways. When we re-analyzed astrocytes, we found a group linked to Alzheimer's disease that had high levels of Gfap and C4b, which was confirmed by immunofluorescence. Gene Ontology enrichment analysis indicated that this subpopulation may promote disease through RNA splicing. Further pseudotime trajectory and functional enrichment analyses showed that cells from different Alzheimer's disease mouse models had different development paths, functions, and gene expression patterns. Similar re-clustering and functional enrichment analyses of excitatory neurons uncovered a distinct excitatory neuron subpopulation that may affect Alzheimer's disease progression through mRNA processing and RNA splicing mechanisms. Gene set variation analysis further revealed functional differences between models within this subpopulation. Using single-cell sequencing, we identified a subgroup of astrocytes with high Gfap/C4b and a diseaserelated subgroup of excitatory neurons that are involved in RNA splicing. Together, these results provide a cellular and molecular basis for further research and a potential resource for future targeted treatments.},
}

@article {pmid41837517,
year = {2026},
author = {Dong, S and Wei, X and Rominger, A and Ni, R},
title = {Multimodal imaging-guided precise neuromodulation for Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01680},
pmid = {41837517},
issn = {1673-5374},
}

@article {pmid41837520,
year = {2026},
author = {Zhao, Y and Lei, J and Wang, Z and Yang, S and Zhao, Z and Xie, Y and Ran, J and Zang, G},
title = {Identification of novel biomarkers for Alzheimer's disease: A deep learning omics-based approach to drug pair discovery and exploration of potential therapeutic targets.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00989},
pmid = {41837520},
issn = {1673-5374},
abstract = {The understanding of Alzheimer's disease is shifting from a traditional focus on Aβ/tau pathology to an emerging consensus that positions immune dysregulation as a central synergistic driver in the early stages of the disease. However, the causal relationships between peripheral immune cells, plasma proteins, and Alzheimer's disease, as well as the mediating effects of plasma proteins on the disease, remain poorly understood. Moreover, there are no effective drug combination therapies targeting plasma proteins for Alzheimer's disease. This study investigated the causal associations between immune cells, plasma proteins, and Alzheimer's disease, with a focus on the role of Fc gamma receptor 3A in disease progression. Using a two-sample Mendelian randomization approach, we identified 59 plasma proteins and 65 immune cell types significantly associated with Alzheimer's disease. We performed data mining of a large Alzheimer's disease cohort and drug databases and established a biofactor-regulated neural network for rapidly screening and optimizing compound drug pairs. Among the immune cells, CD8+ T cells, particularly CD8+CD28+CD45RA. T cells, were found to have a protective effect against Alzheimer's disease. Furthermore, increased expression of Fc gamma receptor 3A (also known as CD16a, an activating receptors of NK cells) in plasma and the hippocampus correlated with enhanced CD8+ T-cell infiltration and accelerated Alzheimer's disease progression in 5×FAD mice. Mediation analysis revealed that Fc gamma receptor 3A mediates the effects of CD8+ T cells on Alzheimer's disease risk. Additionally, Fc gamma receptor 3A gene expression levels were significantly higher in patients with Alzheimer's disease compared with individuals with mild cognitive impairment and cognitively normal participants, as revealed by an analysis of the Alzheimer's Disease Neuroimaging Initiative database. These findings suggest that CD8+ T-cell infiltration and Fcγ receptor 3A expression play critical roles in the pathophysiology of Alzheimer's disease and may serve as therapeutic targets. Molecular docking analysis further identified 19 candidate drugs targeting Fcγ receptor 3A. This study proposes novel immune-based therapeutic strategies and introduces an omics-based intelligent drug discovery framework for repurposing existing drugs for the treatment of complex diseases. The key contributions of this study include the identification of potential immune-based therapeutic targets for Alzheimer's disease and demonstration of the utility of bioinformatics and drug repurposing approaches in addressing complex neurodegenerative diseases.},
}

@article {pmid41837529,
year = {2026},
author = {Cheung, CYM and Gera, R and Kar, AK and Linderoth, B and Eriksdotter, M and Mitra, S},
title = {Alzheimer's disease therapy: Neurotrophin-based regenerative approaches.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01462},
pmid = {41837529},
issn = {1673-5374},
abstract = {Neurotrophins are a class of proteins that maintain the health and phenotype of neuronal cells under normal physiological conditions. Nerve growth factor was the first neurotrophin to be discovered, supporting the survival and cholinergic phenotype of basal forebrain cholinergic neurons, which are crucial in maintaining cognitive function in healthy individuals. Nerve growth factor metabolism is altered in Alzheimer's disease and, along with the degeneration of basal forebrain cholinergic neurons and loss of cholinergic pathways in the affected brain, contributes to cognitive problems. These findings initiated the application of nerve growth factor supplementation as a regenerative strategy against Alzheimer's disease in the late 20th century. Later decades witnessed the development of drugs that support cholinergic activity, namely, cholinesterase inhibitors offering small but persisting cognitive benefits in Alzheimer's disease patients. Further developments in the Alzheimer's disease field have witnessed the rise of anti-amyloid immunotherapies that target the amyloid plaques in Alzheimer's disease brains in an attempt to reduce disease pathology. Over the years, several reports have appeared in support of or undermining the therapeutic claims of each strategy, while many other therapeutic approaches are being presently tested. In this narrative review, we present broader perspectives regarding cholinergic therapeutic strategies against Alzheimer's disease, highlighting aspects in the Alzheimer's disease field that need to be addressed, and propose future perspectives. We provide a special focus on neurotrophic molecules, especially on nerve growth factor, due to its close association with cognitive pathways and its relationship with cholinergic pathways, since cholinesterase inhibitors remain a widely used medication for Alzheimer's disease patients even after 30 years of research.},
}

@article {pmid41837530,
year = {2026},
author = {Righini, CM and Mantovani, DBA and de Paula Faria, D},
title = {Positron emission tomography of neuroinflammation in Down syndrome and Alzheimer's disease: Current status and future perspectives.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01403},
pmid = {41837530},
issn = {1673-5374},
}

@article {pmid41837537,
year = {2026},
author = {Sun, Y and Andrikopoulos, N and Ding, F and Ke, PC},
title = {An endogenous beta-endorphin corona confers neuroprotection against Alzheimer's amyloidogenesis.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01700},
pmid = {41837537},
issn = {1673-5374},
}

@article {pmid41837539,
year = {2026},
author = {Park, YJ and Li, H},
title = {Beyond the brain: How does Alzheimer's disease affect the body?.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01545},
pmid = {41837539},
issn = {1673-5374},
}

@article {pmid41837575,
year = {2026},
author = {Xu, C and Fu, J and Zhang, K and Wang, Y and Liu, X and Mubarik, S and Shi, W and Zhang, S and Wang, F},
title = {Waist circumference as a mediator in the association between sarcopenia and cognitive function.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261427037},
doi = {10.1177/13872877261427037},
pmid = {41837575},
issn = {1875-8908},
abstract = {BackgroundThere is a synergistic effect between sarcopenia and obesity, and they are important factors affecting cognitive function. It's essential to explore the complex relationship among the three.ObjectiveTo explore the mediating effect of waist circumference in the relationship between sarcopenia and cognitive function.MethodsA total of 5577 participants aged 60 years and older from CHARLS (China Health and Retirement Longitudinal Study) were included. Cognitive function was assessed via episodic memory and mental integrity. Sarcopenia status was diagnosed according to the criteria of the AWGS 2019. General linear regression models were applied to investigate the association between WC, sarcopenia, their combined effects and cognitive function. Mediation analysis was used to access the mediating effect of WC in the relationship between sarcopenia and cognitive function. The nonlinear association between WC and cognitive function was explored by using the restricted cubic spline model.ResultsAmong 5577 participants, the average cognitive score was 12.41. After controlling for confounding factors, participants with central obesity and severe sarcopenia had the worst cognitive scores (β = -3.22, 95%CI = -4.81, -1.61). WC mediated 16.95% of the association between sarcopenia and cognitive scores, and 9.26% of the association between severe sarcopenia and cognitive scores. The strongest positive association was found between WC and cognitive scores when WC was 96.74 cm in men.ConclusionsCentral obesity was associated with better cognitive function. However, central obesity accompanied by sarcopenia or severe sarcopenia was associated with lower cognitive function. There were significant differences in the mediating effect of WC between different sarcopenia status and cognitive function.},
}

@article {pmid41837588,
year = {2026},
author = {Pratap Swain, M and Mohanty, S and Gupta, N and Mukherjee, T and Kumar Singh, S and Pattnaik, A},
title = {Quercetin's Multifaceted Role in Alzheimer's Disease, Melanoma, and Tuberculosis: A Systematic Review with Preclinical Insights.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128404554251209100242},
pmid = {41837588},
issn = {1873-4286},
abstract = {INTRODUCTION: Quercetin, a polyphenolic flavonoid that is abundant in fruits and vegetables, demonstrates substantial antioxidant, anti-inflammatory, immunomodulatory, and anti-cancer properties. It has garnered attention for its therapeutic potential in tuberculosis (TB), melanoma cancer, and Alzheimer's disease (AD).

METHODS: Following PRISMA 2020 guidelines, a systematic review was conducted using PubMed, Scopus, and Web of Science databases (2000-2024). The focus was on approaches to improve bioavailability, with an examination of preclinical models, pharmacological mechanisms, and therapeutic outcomes.

RESULTS: Quercetin reduced β-amyloid aggregation (45-60%), improved cognitive performance by up to 50%, and mitigated oxidative stress by nearly 50% in Alzheimer's models. In melanoma, it promoted apoptosis, inhibited angiogenesis (45% reduction), and decreased tumor volume by 40-60% in preclinical studies. In TB models, quercetin enhanced macrophage autophagy (30% increase), decreased bacterial burden by 40-60% and synergistically improved the efficacy of rifampicin by 35-40%. Addressing its bioavailability challenge (<1% in native form), nanotechnology-based delivery systems increased quercetin's absorption up to 10-fold, with certain systems achieving absolute bioavailability improvements of 30-35%.

DISCUSSION: Preclinical findings consistently highlight quercetin's multitargeted role in modulating oxidative stress, inflammation, apoptosis, and immune responses across diverse disease models. However, discrepancies between experimental efficacy and clinical applicability are primarily due to its low systemic availability. Nanocarrier-based strategies, including liposomes, nanoparticles, and phytosomes, provide encouraging solutions, yet require robust clinical validation.

CONCLUSION: Quercetin demonstrates multifaceted therapeutic potential across AD, melanoma, and TB. However, clinical translation remains limited by poor bioavailability and a lack of large-scale clinical validations. Future directions should emphasize advanced drug delivery systems, combination therapies, and robust clinical trials to establish quercetin's role as a potent therapeutic agent.},
}

@article {pmid41837594,
year = {2026},
author = {Sivamaruthi, BS and Kesika, P and Chaiyasut, C and Mathew, TM and Alagarsamy, K},
title = {Probiotic Interventions and Cognitive Performance: Insights from Recent Clinical Trials.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128436386251216114724},
pmid = {41837594},
issn = {1873-4286},
abstract = {Probiotics, traditionally recognized for their role in gastrointestinal health, have recently been investigated for their potential influence on cognitive function through modulation of the gut-brain axis (GBA). This review summarizes the current clinical evidence and mechanistic insights on the role of probiotic interventions in mitigating cognitive decline and enhancing brain function, particularly in older adults and individuals with neuropsychiatric conditions. Cognitive impairments in the elderly, driven by neurodegeneration, vascular compromise, inflammation, and lifestyle factors, present significant challenges to public health systems. Several randomized controlled trials have demonstrated the beneficial effects of specific probiotic strains, such as Bifidobacterium breve A1, Lactiplantibacillus plantarum P8, and multispecies formulations, in improving memory, attention, and emotional regulation in populations with mild cognitive impairment, Alzheimer's disease, major depressive disorder, and schizophrenia. The cognitive improvements are linked to various mechanisms, including anti-inflammatory and antioxidant activities, modulation of neurotransmitter levels, maintenance of gut barrier integrity, and shifts in gut microbiota composition favoring beneficial taxa. However, not all interventions have yielded significant effects, suggesting strain-specific efficacy and interindividual variability in response. The present study discusses the limitations of existing studies and emphasizes the need for personalized approaches and rigorous, long-term clinical trials. Overall, probiotics show promise as adjunctive agents for preserving cognitive health and managing neurodegenerative and psychiatric disorders via modulation of the microbiota-GBA.},
}

@article {pmid41837598,
year = {2026},
author = {Ma, J and Liu, T and Liu, FZ and Shi, YJ},
title = {Mechanistic Insights into the Qingge Formula for the Treatment of Alzheimer's Disease: A Network Pharmacology and Molecular Docking Study.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128403988251202073700},
pmid = {41837598},
issn = {1873-4286},
abstract = {INTRODUCTION: Alzheimer's disease (AD) affects millions globally. This study explores the therapeutic mechanisms of Qingge Formula (QGF) against AD using network pharmacology and molecular docking.

METHODS: Active components and targets were identified via TCMSP, Swiss ADME, and GeneCards databases. PPI networks, GO, and KEGG analyses were performed, followed by molecular docking.

RESULTS: Core targets included PTGS2, EGFR, ESR1, STAT3, and SRC. GO identified 222 terms; KEGG revealed 65 pathways. Molecular docking revealed that the six key components bind to the core targets with energetically favorable conformations, among which SRC showed the highest affinity for all the Discussion: QGF likely modulates neuroinflammation, immunity, and synaptic plasticity pathways, with SRC as a crucial target.

CONCLUSION: QGF demonstrates multi-component, multi-target therapeutic potential against AD.},
}

@article {pmid41837602,
year = {2026},
author = {Onuki, K and Nishio, Y},
title = {Assessing professional caregiver burden related to patient agitation in dementia: A systematic review of measurement scales.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430767},
doi = {10.1177/13872877261430767},
pmid = {41837602},
issn = {1875-8908},
abstract = {BackgroundAgitation is a common behavioral and psychological symptom of dementia that places significant burden on caregivers. While its impact on family caregivers is well-documented, its effect on professional caregivers remains underexplored. Additionally, it is unclear whether existing caregiver burden scales adequately capture the International Psychogeriatric Association's (IPA) definition of agitation. Since agitation requires different treatment approaches than cognitive impairment, its distinct burden warrants further investigation.ObjectiveThis systematic review examined scales used to assess professional caregiver burden related to agitation in dementia.MethodsFollowing PRISMA guidelines, we searched MEDLINE, Embase, and ICHUSHI for English and Japanese articles published during January 1980-August 2024. Studies included professional caregivers, either exclusively or alongside informal caregivers. Key outcomes were the number and frequency of scales, target population, and agitation coverage within the scales.ResultsWe identified 52 articles: 22 focused exclusively on professional caregivers, and 30 included both types. Publications involving both caregiver types increased notably in the last decade. Across studies, 39 scales were used. The Zarit Burden Interview (n = 21) and Neuropsychiatric Inventory (n = 15) were most frequent. Sixteen scales targeted the general population; 11 each were designed for professional and informal caregivers, and one for both. Most scales did not fully reflect the IPA's definition of agitation. Scales for professional caregivers also included work-related factors like coworker conflicts and administrative workload.ConclusionsThere is a critical gap in validated scales to measure agitation-related burden in professional dementia caregivers. Specialized tools are urgently needed to assess this burden and guide support strategies.},
}

@article {pmid41837605,
year = {2026},
author = {Jiang, X and Lv, G and Xiong, X and Yuan, J and Kevin Lu, Z},
title = {Cost-effectiveness of traditional and novel neurotherapeutic agents for Alzheimer's disease: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430376},
doi = {10.1177/13872877261430376},
pmid = {41837605},
issn = {1875-8908},
abstract = {BackgroundSeveral monoclonal antibodies designed to slow cognitive and functional decline in individuals with early Alzheimer's disease (AD) have been recently approved. However, a comprehensive evaluation of the cost-effectiveness of all FDA-approved neurotherapeutic agents for AD remains lacking.ObjectiveThis study aimed to systematically review and analyze the incremental costs and effectiveness of currently available FDA-approved neurotherapeutic agents for AD to provide consolidated evidence on their economic value.MethodsA systematic review was conducted across PubMed, Embase, Cochrane CENTRAL, and Web of Science, adhering to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and PRISMA guidelines.ResultsTwenty-three articles were included. Most studies (74%) used a Markov model. Nearly half (48%) of studies were analyzed from both healthcare system and societal perspectives. Industry-funded studies made up 43%, while 39% were funded by non-profits, and 17% received no funding. Quality-adjusted life year (QALY) was the most common effectiveness measure (91%). At a willingness-to-pay (WTP) threshold of $100,000/QALY, all studies found memantine cost-effective, and more than half reported cost-effectiveness for donepezil, rivastigmine, and galantamine. Aducanumab, lecanemab, and donanemab were not cost-effective in any study. Under the WTP threshold of $150,000/QALY, value-based prices for aducanumab, lecanemab, and donanemab were estimated below $5,960, $15,700, and $33,700, respectively.ConclusionsTraditional symptom-targeting drugs were consistently cost-effective, whereas anti-amyloid therapies were not. Future independent cost-effectiveness analyses would benefit from head-to-head comparisons using real-world data and greater attention to disparities in dementia research.},
}

@article {pmid41837609,
year = {2026},
author = {Hu, S and Ge, J and Wang, G and Zhao, M and Lv, P and Wang, F and Guo, F and Huang, J and Guan, H and Ma, X and Xing, Z},
title = {Plasma biomarker changes following deep cervical lymphatic venous anastomosis: An exploratory study in Alzheimer's disease using single-molecule array technology.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431355},
doi = {10.1177/13872877261431355},
pmid = {41837609},
issn = {1875-8908},
abstract = {BackgroundDeep cervical lymphatic venous anastomosis (dcLVA) is a novel surgical approach for patients with Alzheimer's disease (AD). Its theoretical basis lies in the promotion of the clearance of large biomolecular metabolites in the central nervous system by unblocking the deep cervical lymphatic system. Currently, there is a lack of systematic and comprehensive research on biomarkers for monitoring disease progression and therapeutic efficacy in patients with AD after treatment. Single-molecule technology is applied widely in the field of medicine to detect trace amounts of proteins, especially for detecting the biomarkers related to neurodegenerative diseases such as AD.ObjectiveThis study presents the data of 30 AD patients who underwent dcLVA surgery and the results of analyzing AD biomarkers, exploring the efficacy of dcLVA treatment, and explores whether peripheral blood biomarkers could be used to monitor the treatment effects.MethodsUsing single-molecule technology to detect dynamic changes in blood biomarkers, combined with cognitive scores and Clinician's Interview-Based Impression of Change Plus (CIBIC-plus) data, a prognostic prediction model is constructed.ResultsThe results show that dcLVA surgery elevates peripheral blood amyloid-β (Aβ)42 levels which correlate significantly with the CIBIC plus score. The combination of Aβ42 and Aβ42/40 achieved the highest AUC (0.737) at 180 days post-surgery, showing good diagnostic performance and potential as a prognostic biomarker for dcLVA surgery.ConclusionsBy leveraging the dynamic changes of blood biomarkers, it is helpful to adjust the treatment plan in a timely manner, thereby achieving personalized treatment and improving the treatment effectiveness.},
}

@article {pmid41837631,
year = {2026},
author = {Kim, MG and Woo, SH and Kim, GW and Choi, HK and Kim, KK and Koo, BS},
title = {Efficacy and safety of Woohwangchungsimwon in combination with donepezil for behavioral and psychological symptoms of dementia in probable Alzheimer's disease: An assessor-blinded randomized controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431692},
doi = {10.1177/13872877261431692},
pmid = {41837631},
issn = {1875-8908},
abstract = {BackgroundWoohwangchungsimwon (WCW) is a traditional Korean herbal formula commonly used to treat anxiety and restlessness. However, its potential role in managing behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD) is unclear.ObjectiveThis study evaluated the efficacy and safety of WCW as an adjunctive treatment for BPSD in patients with mild probable AD already receiving donepezil.MethodsSeventy-four patients receiving donepezil 5 mg daily were randomized 1:1 into an intervention group (WCW add-on, n = 37) or a control group (no additional treatment, n = 37) for 24 weeks. The primary outcome was the change in BPSD measured using the Neuropsychiatric Inventory (NPI). Secondary outcomes were cognitive function and emotional and physical well-being, including depression, anxiety, insomnia, quality of life, and severity of dementia. Safety was assessed via adverse events and laboratory results.ResultsSixty-three participants were included. The WCW group demonstrated significantly improved total NPI scores versus controls, particularly in the irritability/lability subdomain. Analysis of covariance (ANCOVA) confirmed these findings in both the full analysis set (FAS) and per-protocol set (PPS). T-test and rank ANCOVA showed significance in the PPS and a trend in the FAS. The general quality of life dementia scale showed a trend toward improvement. No significant differences in adverse events or laboratory results were observed.ConclusionsWCW may be a safe and effective adjunctive therapy for BPSD in patients with mild probable AD. Future studies should adopt more rigorous designs and include patients with broader disease severity to enhance clinical applicability.Trial registrationThe trial was registered with the Clinical Research Information Service (CRIS) on December 10, 2020 (KCT0005669).},
}

@article {pmid41837641,
year = {2026},
author = {Gao, P and Chen, B and Xu, D and Wang, Q and Yang, M and Lin, G and Zhou, H and Huang, X and Zeng, Y and Liang, S and Li, J and Liu, Q and Yao, K and Xiao, Z and Zhong, X and Ning, Y},
title = {Differential effects of PSEN1 mutations (p.P117L with ataxia and p.P264L without ataxia) in early-onset Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430771},
doi = {10.1177/13872877261430771},
pmid = {41837641},
issn = {1875-8908},
abstract = {Presenilin 1 (PSEN1) plays a pivotal role in early-onset Alzheimer's disease (EOAD). The clinical phenotype of EOAD is typically marked by cognitive decline, with ataxia rarely reported. We identified mutations at different positions of PSEN1 in two Chinese patients with EOAD. Interestingly, one patient carrying the PSEN1 p.P117L mutation manifested symptoms of ataxia, while another patient harboring the PSEN1 p.P264L mutation did not exhibit any signs of this disorder. Computational analyses using PolyPhen-2, SIFT, Provean, and Mutation Taster predicted both mutations as pathogenic, while structural predictions using SOPMA, TMHMM 2.0, and PyMOL. Our findings expand the spectrum of atypical PSEN1-associated phenotypes.},
}

@article {pmid41837651,
year = {2026},
author = {Chen, YJ and Gaba, A and Yang, HW and Maher, M and Saxena, R and Li, P and Hu, K and Gao, L},
title = {Associations between polygenic risk scores for Alzheimer's disease and postoperative delirium risk.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430955},
doi = {10.1177/13872877261430955},
pmid = {41837651},
issn = {1875-8908},
abstract = {BackgroundPostoperative delirium (POD) affects up to a third of older surgical patients, leading to significant morbidity, mortality, and potential progression to Alzheimer's disease (AD). Polygenic risk scores (PRS) capture inherited susceptibility to complex diseases, but their relevance to POD is unclear.ObjectiveWe examined whether higher AD-PRS predict increased POD risk in patients without dementia and whether sleep burden modifies this relationship.MethodsThis study included 345 414 UK Biobank participants (mean [SD] age: 70.1 [7.9], range: 40.4-87.6 years; 54.0% women) to identify new-onset POD, using the International Classification of Disease-10 coding within three days of surgery. Participants with mild cognitive impairment, dementia, or dementia diagnosed within one year of POD were excluded. AD-PRS was calculated as a weighted sum of genetic variants, with scores divided into quartiles due to the absence of standardized thresholds. Covariates included demographics, comorbidities, and lifestyle factors. Cox proportional hazard models were used to evaluate the relationship between AD-PRS and POD risk.ResultsA total of 1610 POD cases were identified. Compared to Q1, individuals in Q3 (HR = 1.23, 95% CI [1.07-1.42], p < 0.01) and Q4 (1.35, [1.18-1.56], p < 0.001) had progressively higher POD risk. Findings were consistent across alternate POD definitions and subgroups defined by sleep burden, sex, age, cardiovascular risk, and inflammatory markers.ConclusionsHigher AD-PRS is independently associated with greater POD risk in adults without dementia. AD genetic susceptibility may help identify high-risk surgical patients and warrants validation in prospective perioperative cohorts.},
}

@article {pmid41837670,
year = {2026},
author = {Novas, M and Matos, MJ and Chai, CLL},
title = {The futility of the familiar: rethinking strategies for the development of small molecules for neurodegenerative disorders.},
journal = {Expert opinion on drug discovery},
volume = {},
number = {},
pages = {},
doi = {10.1080/17460441.2026.2646603},
pmid = {41837670},
issn = {1746-045X},
abstract = {INTRODUCTION: As life expectancy increases globally, the prevalence of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases continues to rise. Despite decades of intensive research and substantial investment, effective preventive or curative treatments remain unavailable. Much of the drug discovery efforts have focused on small-molecule therapeutics. However, these approaches have yielded limited clinical success. This lack of progress underscores the inherent complexity of neurodegenerative diseases and suggests that conventional drug discovery paradigms may be overly simplistic or fundamentally flawed.

AREAS COVERED: In this article, the authors explore the key challenges underlying the failure of small-molecule strategies in neurodegenerative research and discuss emerging avenues that may offer more promising therapeutic outcomes for brain disorders.

EXPERT OPINION: Conventional approaches in CNS drug discovery and development have not yielded disease-modifying CNS drugs. To be successful, it is important to rethink strategies, assays, animal models from scratch and redesign how R&D in CNS diseases should be carried out.},
}

@article {pmid41837671,
year = {2026},
author = {Youssef, H and Gatto, RG and Ghayal, NB and Petersen, RC and Jack, CR and Reichard, R and Dickson, DW and Whitwell, JL and Josephs, KA},
title = {Comparative effects of TDP-43-A and TDP-43-α on hippocampal subfields and amygdala nuclei.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261426494},
doi = {10.1177/13872877261426494},
pmid = {41837671},
issn = {1875-8908},
abstract = {Transactive response DNA-binding protein of 43 kDa (TDP-43) type-A is associated with frontotemporal lobar degeneration (FTLD). In primary age-related tauopathy (PART), TDP-type-α displays similar features to FTLD-TDP type-A. We compared antemortem MRI volumes of amygdala nuclei and hippocampal subfields between 16 PART-TDP-α and 12 FTLD-TDP-A autopsy-confirmed cases. Hippocampal tail and CA1 body volumes were smaller in PART-TDP-α group, which also had smaller lateral and central amygdala nuclei compared to FTLD-TDP-A group, but differences were non-significant after FDR correction. There is no evidence suggesting that TDP-43 type-A in FTLD affects hippocampal and amygdala volume loss differently than TDP-43 type-α in PART.},
}

@article {pmid41837676,
year = {2026},
author = {Ma, J and Zhou, S and Zhu, W and Tao, Y and Wang, W and Chen, X and Ye, W and Lu, Y and Gao, Z and Li, X and Li, X and Yu, Y},
title = {Periodontitis associated with multi-region brain functional alterations and cognitive impairment: A cross-sectional study in normal cognition, amnestic mild cognitive impairment, and Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261426906},
doi = {10.1177/13872877261426906},
pmid = {41837676},
issn = {1875-8908},
abstract = {BackgroundGrowing evidence links periodontitis to Alzheimer's disease (AD), yet the specific links between periodontitis severity gradients and brain functional alterations remain poorly understood.ObjectiveTo investigate brain functional alterations quantified by functional connectivity density (FCD) and regional homogeneity (ReHo) across periodontitis severity gradients, include microbiota measures as explanatory variables, and assess correlations between these functional alterations and cognitive impairment.MethodsClinical periodontal data, subgingival plaque, cognitive tests, and brain MRI data were collected from all 89 participants, including community-recruited normal cognition (NC) and patients with amnestic mild cognitive impairment (aMCI) and AD from a hospital neurology department. According to periodontal examination, participants were categorized into mild, moderate, and severe groups. FCD and ReHo were compared among different periodontal condition groups and subgroups. Correlation analyses were conducted to explore the relationship among FCD, ReHo, periodontal indices, and cognition.ResultsWith increasing severity of periodontitis, the FCD of bilateral middle frontal gyrus (MFG.R, MFG.L), right inferior frontal gyrus, triangular part (IFGtriang.R), and the ReHo of IFGtriang.R all decreased. These regions are commonly associated with executive control, working memory, and attention. These changes were more strongly correlated with overall periodontal inflammatory burden and cognitive performance than to the abundance of specific taxa in the subgingival plaque microbiota.ConclusionsPeriodontitis severity is associated with reduced prefrontal FCD/ReHo and cognitive decline, and these associations appear to be more strongly driven by overall periodontal inflammatory burden than by specific subgingival taxa.},
}

@article {pmid41837677,
year = {2026},
author = {Hoepel, SJW and Oryshkewych, N and Barnes, LL and Butters, M and Buysse, D and Ikram, MK and Lim, A and Wolters, FJ and Yu, L and Wallace, ML and Luik, AI},
title = {Multidimensional self-reported sleep health, cognitive decline, and risk of all-cause dementia: A population-based multi-cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261422263},
doi = {10.1177/13872877261422263},
pmid = {41837677},
issn = {1875-8908},
abstract = {BackgroundConsidering the multidimensional nature of self-report sleep health may improve identification of those at risk of accelerated cognitive decline and dementia.ObjectiveWe compared how composite measures of multidimensional sleep health relate to cognitive performance and the risk of dementia over time in older adults.MethodsSelf-reported indicators of sleep health domains (satisfaction, alertness, timing, efficiency, and duration) were measured in 7892 Rotterdam Study (RS) participants (mean ± SD age: 69.5 ± 8.9 years, 58.2% female) and 1601 Rush Memory and Aging Project and Minority Aging Research Project (MAP/MARS) participants (79.5 ± 7.9 years, 77.3% female). Sleep items were harmonized and used to derive a sleep health score (number of adverse sleep health items) and sleep health clusters (with latent class analysis). During follow-up, multiple cognitive tests were performed repeatedly and participants were followed for incident all-cause dementia. Relationships of sleep health with cognitive decline (linear mixed models) and risk of dementia (Cox proportional hazards models) were assessed in both samples, adjusting for covariates.ResultsThree sleep health clusters were identified: average sleep, inefficient sleep, and poor sleep. During follow-up of 10.6 ± 4.5 years in RS and 5.3 ± 2.9 years in MAP/MARS, 1148 (14.5%) and 286 (19.8%) participants developed dementia, respectively. Multidimensional sleep health scores and clusters were not significantly associated with accelerated cognitive decline or the risk of dementia in either sample (Hazard Ratios [HRs] between 0.72-1.15).ConclusionsFindings suggest composite measures of self-reported multidimensional sleep health need refinement to be useful in identifying older adults at risk of accelerated cognitive decline and dementia.},
}

@article {pmid41837733,
year = {2026},
author = {Madruga, E and Garcia-Rubia, A and Sanchez-Nuñez, C and Martinez-Gonzalez, L and Fernandez-Escamilla, AM and Lastres-Becker, I and Gil, C and Martinez, A},
title = {Brain Permeable SGK1 Inhibitors: A Promising Therapeutic Strategy for Neurodegenerative Diseases.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c03050},
pmid = {41837733},
issn = {1520-4804},
abstract = {A major challenge in modern medicine is developing new therapies for aging-related diseases such as neurodegenerative disorders, whose prevalence increases with longer life expectancy. Although kinase inhibitors have achieved clinical success, their development for central nervous system (CNS) disorders remains limited due to the complexity of kinase networks and poor blood-brain barrier (BBB) permeability. Serum/glucocorticoid-regulated kinase 1 (SGK1) participates in multiple signaling pathways but remains an underexplored target in neurodegeneration. Following a mixed ligand- and structure-based virtual screening, we have previously identified a brain-penetrant SGK1 inhibitor. A medicinal chemistry program based on hit expansion and optimization for BBB permeability reported here has generated a new family of SGK1 inhibitors as chemical probes that enable the investigation of SGK1's role in neurological disorders and serve as promising starting points for drug development. These findings highlight SGK1 as a potential therapeutic target for neurodegenerative diseases, such as Alzheimer's disease.},
}

@article {pmid41837772,
year = {2026},
author = {Yilmaz, A and Ashrafi, N and Guerra, Z and Goniwiecha, D and Saiyed, N and Gordevičius, J and Krinickis, K and Gabrielaite, M and Osentoski, T and Schumacher, N and Khan, S and Pai, A and Ruff, S and Maddens, ME and Imam, K and Monastero, R and Graham, SF},
title = {Salivary metabolomics for early detection of vascular contributions to cognitive impairment and dementia: Exploring microbiome dysbiosis and sex differences.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261423158},
doi = {10.1177/13872877261423158},
pmid = {41837772},
issn = {1875-8908},
abstract = {BackgroundVascular factors contribute to dementia in approximately 20 million individuals, notably in vascular contributions to cognitive impairment and dementia (VCI). However, the lack of specific molecular biomarkers to differentiate VCI from normal aging and Alzheimer's disease (AD) impedes early diagnosis and treatment.ObjectiveTo date the use of saliva for VCI diagnosis has not been previously reported. In this small proof-of-concept study, we aim to explore the feasibility of screening novel salivary diagnostic biomarkers for VCI.MethodsUsing both proton nuclear magnetic resonance ([1]H NMR) spectroscopy and liquid chromatography coupled with mass spectrometry (LC-MS) we biochemically profiled saliva samples collected from individuals with VCI (n = 26) and compared them with cognitively healthy controls (n = 37).ResultsOf the 167 salivary metabolites 56 of them are found to be at significantly different concentrations in the saliva of individuals with VCI as compared to controls. Subsequently, we developed predictive models capable of distinguishing VCI from controls with 0.92 accuracy. Moreover, sex-stratified analysis revealed the perturbation of different metabolic pathways in the saliva of individuals with VCI.ConclusionsThis study underscores the promising role of salivary metabolomics as a non-invasive tool for the early detection of VCI. Our findings suggest that oral microbiome dysbiosis may contribute to VCI pathogenesis, offering novel mechanistic insights. Given the accessibility of saliva, further validation of these robust salivary biomarkers could facilitate scalable, cost-effective screening for VCI, aiding in timely intervention strategies.},
}

@article {pmid41837773,
year = {2026},
author = {Zhang, W and Yao, G and Luo, Y and Sun, J and Fang, X and Wang, G and Wang, H and Xv, P and Wang, L and Liu, Y and Wang, H and Zhou, N},
title = {Self-perceptions of aging and depression among community-dwelling older adults: A moderated mediation model of physical function and motoric cognitive risk syndrome.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261427463},
doi = {10.1177/13872877261427463},
pmid = {41837773},
issn = {1875-8908},
abstract = {BackgroundDepressive symptoms in older adults have become a major public health problem. Interventions targeting physical function and motoric cognitive risk syndrome (MCR), a pre-dementia (such as Alzheimer's disease) syndrome, may offer promising new avenues for addressing this problem.ObjectiveWe aim to explore the relationship between self-perceptions of aging (SPA) and depression among community-dwelling older adults and analyze whether physical function plays a mediating role in this association and whether motoric cognitive risk syndrome (MCR) can moderate this mediating effect.MethodsFrom March to November 2023, 861 community-dwelling older adults in Xinxiang City, China were investigated for their SPA, depression, physical function and MCR status. Descriptive statistics, analysis of variance and correlation analysis were performed on the data, and Mplus8.3 was used to construct a moderated mediation model.ResultsSPA is positively correlated with depression, with physical function playing a mediating role between SPA and depression, accounting for 16.2% of the total effect. The results of the interaction term between SPA and MCR were significant (β = -0.089, p = 0.009), indicating that MCR moderates the relationship between SPA and physical function.ConclusionsThis study reveals the mediating role of physical function and the moderating role of MCR. It suggests that attention should be paid to the physical and mental management of community-dwelling older adults with negative self-perceptions of aging, reduce the risk of MCR, to prevent and alleviate the depressive symptoms.},
}

@article {pmid41837778,
year = {2026},
author = {Ortiz, BL and Scheffler, AW and Callahan, P and Shdo, S and Rijpma, MG and Antoniou, R and Hirst, R and Brown, LM and Rabinovici, G and Rosen, HJ and Gorno-Tempini, ML and Seeley, WW and Miller, BL and Possin, KL and Kramer, JH and Rankin, KP},
title = {Unveiling discrepancies in depression detection among persons with dementia: A comparative analysis of caregiver and self-report.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261422511},
doi = {10.1177/13872877261422511},
pmid = {41837778},
issn = {1875-8908},
abstract = {BackgroundDepression assessment in persons with dementia (PWD) often prioritizes caregiver report, with limited integration of self-report due to concerns about PWD insight.ObjectiveThis cross-sectional study examined discrepancies between self- and caregiver-reported depression in PWD and identified neuropsychiatric and diagnostic predictors of discordance.Methods402 PWD diagnosed with Alzheimer's disease (AD), behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), or progressive supranuclear palsy (PSP) self-reported depression using the Geriatric Depression Scale (GDS), while caregivers completed the Neuropsychiatric Inventory (NPI). Discrepancies were categorized as Concordant (agreement), Discordant Type 1 (self-reported depression denied by caregiver), or Discordant Type 2 (caregiver-reported depression denied by PWD).ResultsOne-third (33.8%) of dyads showed discrepancies: 66.2% were concordant, 10.2% Discordant Type 1, and 23.6% Discordant Type 2. PSPs had higher incidence of Type 1 discordance compared to AD (OR = 2.91, p < 0.05), while svPPAs were less likely to incur Type 2 discordance than AD (OR = 0.33, p < 0.01). Higher self-reported GDS Hopelessness, Withdrawal, and Worry predicted higher rates of Type 1 discordance, while lower Dysphoria predicted Type 2 discordance. Higher caregiver-reported NPI Apathy increased odds of Type 1 discordance (OR = 2.46, p < 0.05) and lower NPI Anxiety increased odds of Type 2 discordance (OR = 0.50, p < 0.01). Among cases with Type 1 discordance, caregivers often endorsed PWD apathy, irritability, agitation, or anxiety instead of depression.ConclusionsDiscrepancies in reporting depression in PWD can reflect underreporting by caregivers, not only denial by PWD. Integrating self-report, caregiver input, and clinical judgment may improve diagnostic accuracy for depression in PWD and improve care.},
}

@article {pmid41837780,
year = {2026},
author = {Mendoza-Franco, G and Rodríguez-Cruz, F and Estrada-Modesto, SS and Hérnandez González, EO and Boucard, AA and Meraz Ríos, MA and Basurto-Islas, G and Garcia-Sierra, F},
title = {Extracellular amyloid-β42 oligomers alter endo-lysosomal trafficking of Rab7- and Lamp-1-coated vesicles in cultured neuroblastoma cells.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261422415},
doi = {10.1177/13872877261422415},
pmid = {41837780},
issn = {1875-8908},
abstract = {BackgroundThe levels of soluble amyloid-β (Aβ)42 oligomers in the brains of patients with Alzheimer's disease (AD) are well-known to correlate with the extent of synaptic loss. However, the abnormal role of these oligomers in disrupting the balance of the endo-lysosomal pathways for substance degradation in AD brains and cellular models remains unclear.ObjectiveWe aimed to investigate whether extracellular Aβ42 oligomers alter the composition, distribution, and identity of vesicular components and impact the processing of substances involved in the endo-lysosomal pathways of protein degradation.MethodsWe overexpressed Rab7, Lamp-1, and β-1,4-galactosyltransferase-1 proteins in nondifferentiated SH-SY5Y cells. We then incubated these cells with extracellular Aβ42 oligomers, and evaluated the effects on the morphology, composition, and distribution of vesicular components in the endo-lysosomal pathway using super-resolution confocal microscopy. Additionally, we assessed the effects of Aβ42 oligomers incubation on the degradation and processing of endocytosed fluorescent transferrin in vivo.ResultsOur findings revealed that Aβ42 oligomers alter the distribution and identity of Rab7- and Lamp-1-coated vesicles, as well as the Golgi apparatus. This alteration resulted in the formation of disorganized vesicles carrying distinct surface markers of the endo-lysosomal pathway, without evident changes to the cytoskeleton. In vivo evaluation showed a delayed degradation of endocytosed fluorescent transferrin after incubation with Aβ42 oligomers.ConclusionsAβ42 oligomers may contribute to neuronal toxicity by inducing changes in the identity, distribution and balance of vesicular components associated with the endo-lysosomal pathway. This disruption impacts the processing and degradation of various materials that accumulate in the cytoplasm.},
}

@article {pmid41837791,
year = {2025},
author = {Sahoo, S and Padhy, AA and Shivani, K and Misra, A and Mishra, P},
title = {Ubiquitin signatures on aggregating proteins in neurodegeneration.},
journal = {Essays in biochemistry},
volume = {69},
number = {5},
pages = {},
doi = {10.1042/EBC20253046},
pmid = {41837791},
issn = {1744-1358},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Ubiquitin/metabolism ; Animals ; alpha-Synuclein/metabolism ; Ubiquitination ; Ubiquitin-Protein Ligases/metabolism ; tau Proteins/metabolism ; Protein Aggregates ; },
abstract = {The aberrant accumulation of misfolded proteins marked by cellular dysfunction and progressive neuronal loss is the hallmark of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. This review examines the pivotal role of ubiquitin modifications in altering the fate of aggregation-prone proteins such as tau, α-synuclein, mutant huntingtin, TAR DNA-binding protein 43 and superoxide dismutase 1. The ubiquitin signatures identified by their linkage types, chain architectures and site specificities emerge as a complex regulatory language that influences the clearance, aggregation or cellular propagation of these aggregating proteins. The dysregulation of other components of the ubiquitin association pathways, such as impaired E3 ligases and deubiquitinases, also contributes to the inefficient protein disposal and disease progression. Understanding how ubiquitin signatures alter the spatiotemporal dynamics of aggregating proteins is critical for advancing our knowledge of disease biology. Here, we focus on the role of ubiquitin modifications and their associated regulators affecting protein fate and neurotoxicity, and highlight the current therapeutic strategies targeting the degradation of aggregating proteins to uncover potential avenues for treating neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/metabolism
*Ubiquitin/metabolism
Animals
alpha-Synuclein/metabolism
Ubiquitination
Ubiquitin-Protein Ligases/metabolism
tau Proteins/metabolism
Protein Aggregates

@article {pmid41837796,
year = {2026},
author = {Ren, X and Zhang, X and Wang, W and Zhang, M and Bi, X and Peng, W},
title = {Exploratory evaluation of CAP1 and ROCK2 as candidate blood biomarkers for vascular cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261423568},
doi = {10.1177/13872877261423568},
pmid = {41837796},
issn = {1875-8908},
abstract = {BackgroundVascular cognitive impairment (VCI) is the second most common dementia etiology after Alzheimer's disease. However, plasma biomarkers of VCI remain insufficiently validated.ObjectiveWe aimed to identify plasma biomarker candidates for VCI by using integrated multi-omics analyses.MethodsWe prospectively recruited VCI patients and healthy controls (HCs), performed proteomic and metabolomic analyses with ELISA validation, and conducted plasma protein quantitative trait loci (pQTL)-based Mendelian randomization (MR) with VCI-related imaging phenotypes.ResultsProteomics identified 871 differentially upregulated proteins, in 8 VCI patients compared to 6 HCs. Proteins containing YWHAZ, CLDN5, VCL, TPM4, TLN1, CAP1, ITGB3, GP1BB, and ROCK2 were further investigated. ELISA validation conducted on another 8 VCI patients and 8 HCs showed levels of CAP1 (257.1 ± 51.48 versus 204.7 ± 27.47 ng/L, 95% CI: 8.19-96.68, p = 0.0235) and ROCK2 (10.10 ± 2.417 versus 7.555 ± 1.835 ng/mL, 95% CI: 0.24-4.84, p = 0.0328) were significantly higher in the VCI group. CAP1 expression demonstrated a significant association with glycolysis-related metabolites, particularly lactate and the complex glycolysis score, based on adjusted rank correlation analysis (panel-wise FDR < 0.05). MR analysis utilizing plasma pQTL data and vascular dementia and its imaging-derived phenotypes suggested no evidence for a causal effect in either direction.ConclusionsPlasma CAP1 and ROCK2 levels were observed elevated in individuals with VCI, with CAP1 showing metabolomic consistency in relation to glycolytic pathways. These findings provide preliminary exploratory signals suggesting that CAP1 and ROCK2 may merit further investigation in the context of VCI.},
}

@article {pmid41838033,
year = {2026},
author = {Ali, N and Alotaibi, FT and Babu, MA and Singh, TG and Tyagi, Y and Alotaibi, AN and Bansal, N and Puri, S},
title = {Developments on BACE 1 Inhibitors as Anti-Alzheimer Agents: A Perspective on Medicinal Chemistry-Based Advances.},
journal = {Archiv der Pharmazie},
volume = {359},
number = {3},
pages = {e70220},
doi = {10.1002/ardp.70220},
pmid = {41838033},
issn = {1521-4184},
support = {IMSIU-DDRSP2601//Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University (IMSIU)/ ; },
mesh = {*Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; Humans ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Structure-Activity Relationship ; Drug Development ; Molecular Structure ; },
abstract = {Alzheimer's disease (AD) is a progressive and complicated neurodegenerative disorder that mostly affects the elderly and is characterized by memory loss, cognitive dysfunction, accumulation of amyloid beta (Aβ) plaques, neurofibrillary tangles, and cholinergic deficits. Current therapies used for AD, such as acetylcholinesterase inhibitors and NMDA receptor antagonist memantine, can only provide temporary or symptomatic relief, but they do not stop or reverse the progression of the disease. Numerous pathogenic hypotheses have been proposed to explain this mechanism; however, the amyloid cascade hypothesis remains the most widely accepted theory, as it suggests that β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) plays a critical role in the generation of Aβ peptides. Therefore, BACE1 may be a key therapeutic target. This review primarily focuses on the key role of BACE1 in AD pathogenesis and describes the development of its inhibitors over three generations, explaining their structure, design, and pharmacological properties. While the first generation lacked brain penetration, the second-generation improved potency but encountered clinical trial failures due to adverse effects. The third generation of these drugs was designed to achieve a balance between efficacy, selectivity, and safety. Additionally, we review the promising molecules currently under clinical investigation, highlighting both their therapeutic potential and the challenges that remain in developing effective disease-modifying therapies for AD treatment.},
}

*Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism
Humans
*Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism
*Alzheimer Disease/drug therapy/metabolism
Animals
Structure-Activity Relationship
Drug Development
Molecular Structure