@article {pmid42242445,
year = {2026},
author = {She, L and Li, M and Chen, F and Wu, X and Zhang, J and Jiang, W and Sun, Z and Li, L and Ren, J and Chen, D and Zhao, X and Liang, G},
title = {Microglial OTUD6A promotes neuroinflammation and Alzheimer's disease pathogenesis by deubiquitinating C/EBPβ.},
journal = {Pharmacological research},
volume = {230},
number = {},
pages = {108280},
doi = {10.1016/j.phrs.2026.108280},
pmid = {42242445},
issn = {1096-1186},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, neuroinflammation, and cognitive decline. Microglia, the brain's primary immune cells, play a central role in AD pathogenesis by driving neuroinflammatory responses. Deubiquitinating enzymes (DUBs) regulate microglial activation, but the role of the ovarian tumor domain-containing DUB OTUD6A in AD remains unclear. In this study, we demonstrate that OTUD6A is upregulated in microglia across multiple AD models, including Aβ-infused mice, 3 ×Tg mice, and APP/PS1 mice. Otud6a KO or microglia-specific knockdown Otud6a ameliorated cognitive deficits and reduced neuroinflammation in AD mice. Besides, OTUD6A binds to C/EBPβ by removing K48-linked ubiquitin chains at lysine 253 (K253), thereby leading to C/EBPβ accumulation and enhancing NF-κB signaling and proinflammatory cytokine production. Moreover, mutation of OTUD6A catalytic residue (C157A) abolished its deubiquitination activity, confirming its role in C/EBPβ stabilization. Furthermore, C/EBPβ knockdown reversed OTUD6A-mediated neuroinflammation, validating the microglial OTUD6A-C/EBPβ-NF-κB axis as a critical pathway in AD pathogenesis. Therefore, our findings highlight OTUD6A as a novel regulator of microglial activation and suggest that targeting this DUB could provide a therapeutic strategy to mitigate neuroinflammation in AD.},
}

@article {pmid42242486,
year = {2026},
author = {El-Dory, ST and Abd El-Fattah, AA and Sadik, NAH and Elbaz, EM},
title = {The neuroprotective effect of eugenol in aluminum chloride-induced Alzheimer's rats: Insights into the role of TLR4/MyD88/NF-kB and NLRP3 inflammasome/gasdermin D signaling pathways.},
journal = {Archives of biochemistry and biophysics},
volume = {},
number = {},
pages = {110885},
doi = {10.1016/j.abb.2026.110885},
pmid = {42242486},
issn = {1096-0384},
abstract = {Neuroinflammation, especially involving NLRP3 inflammasome, has been recognized as a fundamental pathology in Alzheimer's disease (AD). Therefore, inhibiting the NLRP3 inflammasome activity can slow the development of AD. Eugenol, a natural phenolic compound, is known to inhibit or modulate the inflammatory response. Therefore, this study focuses on scrutinizing the potential neuroprotective effect of eugenol via the NLRP3 signaling pathway in aluminum chloride (AlCl3) elicited AD rats. Rats were split into four groups: olive oil, eugenol (50 mg/kg), AlCl3 (100 mg/kg), and eugenol + AlCl3, where rats received eugenol orally 2 weeks before and concurrently with oral induction by AlCl3 for 12 weeks. Behavioral, histopathological, and biochemical analyses were performed. Significant behavioral dysfunction, aluminum accumulation and pronounced neuronal damage were observed in AD rats. These were associated with increased hippocampal nitric oxide (NO), malondialdehyde (MDA) and amyloid beta protein 1-42 (Aβ 1-42) along with diminished serum total antioxidant capacity (TAC) levels. In addition, activation of NLRP3 inflammasome pathway components concomitant with upregulation of the pyroptotic marker; gasdermin D (GSDMD) was observed. Nevertheless, eugenol administration significantly improved rats' behavioral and histological aberrations, reduced NO, aluminum, and elevated TAC levels. Eugenol modulated toll like receptor 4 (TLR4)/ myeloid differentiation primary response gene 88 (Myd88)/ nuclear factor kappa B (NF-kB) signal transduction pathway, leading to inhibition of NLRP3 inflammasome pathway, inflammatory cytokines as interleukin 18 (IL-18) and interleukin 1 beta (IL-1β) as well as GSDMD. Eugenol may exert neuroprotective effects against AlCl3-induced neurodegeneration by modulating NLRP3 inflammasome, pyroptosis, and TLR4/MyD88/NF-kB signaling pathways.},
}

@article {pmid42242586,
year = {2026},
author = {Wong, B and Payne, M and Silva, A and Kurniawan, E and Eidman, AS and Pizzo, D and Rajupalem, R and Lenk, GM and Paulo, JA and Khan, T and Eskelinen, EL and Gygi, SP and Brown, NG and Meisler, MH and Mendiola, AS and Gassaway, BM and Ferguson, CJ},
title = {Early-onset neuroinflammation drives neurodegeneration caused by lysosomal PI(3,5)P2 insufficiency.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107467},
doi = {10.1016/j.nbd.2026.107467},
pmid = {42242586},
issn = {1095-953X},
abstract = {Phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] is a lysosomal signaling lipid whose deficiency, caused by mutations in the PIKfyve complex subunits Fig. 4 or VAC14, underlies a spectrum of fatal neurologic diseases including Charcot-Marie-Tooth type 4 J (CMT4J) and amyotrophic lateral sclerosis (ALS). To map the molecular consequences of PI(3,5)P2 insufficiency in the brain, we performed quantitative proteomic and transcriptomic analyses of three mouse lines bearing distinct loss-of-function mutations in Fig. 4 or Vac14, examining the brain at the presymptomatic and end stages. Strikingly, profound neuroinflammation was already present at postnatal day 5 (before significant neurodegeneration), characterized by complement activation, interferon signaling, and parenchymal infiltration of peripheral myeloid cells and T-cells. Isolated mutant microglia exhibited a markedly pro-oxidative transcriptional state with elevated reactive oxygen species, a partly non-cell-autonomous phenotype, being present in microglia from mice with conditional Fig. 4 inactivation in just neurons and astrocytes. Comparison of early (P5) and late (P25) proteomics data revealed that PI(3,5)P2 insufficiency impairs developmental remodeling of the brain proteome: proteins typically upregulated during postnatal maturation failed to accumulate, implicating lysosomal function in neurodevelopment. We identify coordinated elevation of p53, Fas receptor, inflammatory caspases, Gasdermin D, RIPK1, and ZBP1, consistent with multifactorial inflammatory cell death with features of apoptosis, pyroptosis, and necroptosis. Many of the dysregulated proteins are encoded by genes mutated in lysosomal storage disorders, ALS, CMT, Alzheimer's and Parkinson diseases, extending the pathogenic relevance of PI(3,5)P2 insufficiency. Together, these findings establish that early neuroinflammation is a defining - and likely initiating - feature of neurodegeneration caused by disruption of lysosomal PI(3,5)P2.},
}

@article {pmid42242938,
year = {2026},
author = {Franklin, CE and Rosenberg, PB and Lyketsos, CG and Ismail, Z and Leoutsakos, JM},
title = {The Impact of Anticholinergic Burden on the Development of Mild Behavioral Impairment.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.05.008},
pmid = {42242938},
issn = {1545-7214},
abstract = {OBJECTIVE: Mild behavioral impairment (MBI) is a syndrome of late-life-onset persistent neuropsychiatric symptoms. Anticholinergic medication is commonly prescribed in older adults. Both MBI and anticholinergic exposure are associated with increased dementia risk. We sought to understand the association of anticholinergic burden (ACB) with MBI.

DESIGN, SETTING, PARTICIPANTS: We mapped ratings on the Neuropsychiatric Inventory Questionnaire to the MBI checklist (MBI-C) using an established algorithm to define MBI status in cognitively unimpaired individuals in the National Alzheimer's Coordinating Center database. We then assessed the association between time-varying ACB ratings and risk of incident MBI.

RESULTS: 4865 participants met inclusion criteria and were followed for a mean (SD) of 5.64 (3.92) years. ACB scores ranged from 0 to 11. 63.3% of participants had a score of 0, 27.7% had a score of 1-2, and 9% had a score of ≥3. Higher maximum total ACB score was associated with a higher likelihood of developing MBI (p ≤0.001). When assessed as a time varying covariate, ACB score was associated with incident MBI (HR 1.07, 95% CI 1.02-1.14, p = 0.010). This association remained significant when adjusted for 10-year mortality risk, age, sex, education, and race.

CONCLUSIONS: MBI risk should be considered when prescribing anticholinergic medication in older adults.},
}

@article {pmid42243086,
year = {2026},
author = {Stepanenko, OV and Sulatsky, MI and Gridasova, KG and Mikhailova, EV and Sulatskaya, AI and Stepanenko, OV},
title = {ATP binding to lysozyme and superfolder GFP amyloid fibrils induces aggregate remodeling and attenuates their cytotoxicity.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03186-9},
pmid = {42243086},
issn = {2058-7716},
support = {No. 23-74-10092//Russian Science Foundation (RSF)/ ; },
abstract = {The pathogenesis of neurodegenerative diseases such as Alzheimer's and Parkinson's, systemic and local amyloidoses is closely associated with amyloid fibril accumulation. Dysregulation of energy metabolism and a decline in the level of adenosine triphosphate (ATP), a key intracellular energy source and extracellular signaling molecule, contribute to the development of these pathologies. Despite the well-established role of ATP as a biological hydrotrope that prevents the initial aggregation of proteins, the impact of this nucleotide on the structure and properties of pre-formed (mature) amyloids is still poorly understood. In this study, we showed the ability of ATP to bind with affinity in the low-to-mid micromolar range to mature amyloids of lysozyme, which associated with hereditary lysozyme amyloidosis, and superfolder GFP, as model objects with unique properties, demonstrating a significant increase in the number of binding sites compared to native proteins. We demonstrated that this interaction induces declustering of both aggregate types, accompanied by fibril disordering specific to certain amyloidogenic proteins. Importantly, ATP-mediated fibril remodeling resulted in a significant reduction in their toxicity to mammalian cell lines, as well as a decrease in the aggregate resistance to chemical and thermal degradation. The obtained results reveal the complex nature of ATP's effects: while acting as an endogenous amyloid detoxification factor, it is also susceptible to sequestration in amyloid deposits due to its affinity in the low-to-mid micromolar range. Amyloid-associated ATP sequestration may lead to nucleotide deficiency and aggravation of amyloidosis.},
}

@article {pmid42243114,
year = {2026},
author = {Debnath, I and Duren, Z},
title = {Inference of spatial chromatin accessibility via integration of spatial transcriptomics and single-cell multi-omics data.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-73948-7},
pmid = {42243114},
issn = {2041-1723},
support = {R35GM150513//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R21DA060503//U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)/ ; },
abstract = {Integrating spatial transcriptomics, which maps gene expression location within tissues, with single-cell multi-omics data, profiling gene expression and chromatin accessibility (or other epigenomic data) for the same cell, offers powerful insights into gene regulation. However, commercially available kits for simultaneous spatial multi-omics profiling are currently unavailable, hindering widespread data generation. Here, we present ISON (Integrated Spatial Omics Network), a unified computational method for integrative spatial multi-omics analysis from single cell multiome data and spatial transcriptomics data. ISON accurately predicts chromatin accessibility profiles for spatial spots and reconstructs spatially resolved gene regulatory networks, demonstrating scalability in both time and memory. Importantly, ISON's chromatin accessibility prediction captures patterns consistent with cis- and trans- regulatory information and enables estimation of transcription factor (TF) activity at the spot level, distinguishing between TFs even within the same family, which is unique and is not present in approaches relying solely on chromatin accessibility data. The application of ISON to Alzheimer's disease data reveals disease- and age-specific spatially variable gene regulatory modules, highlighting its potential to uncover spatially organized mechanisms driving complex biological processes.},
}

@article {pmid42243151,
year = {2026},
author = {Gmelin, D and Ohlei, O and Aslam, MM and Junge, MP and Parkkinen, L and Mullin, K and Prokopenko, D and Lill, CM and Tanzi, RE and Dobricic, V and Bertram, L},
title = {GWAS on short tandem repeats identifies genetic mechanisms in Alzheimer's disease.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42243151},
issn = {2041-1723},
abstract = {GWAS typically focus on SNPs, often excluding complex genetic variants, such as short tandem repeats. Here, we report the results of GWAS analyses systematically assessing the role of short tandem repeats, both imputed and directly genotyped by whole genome sequencing, on risk for Alzheimer's disease in a large collection of ~330,000 individuals (3287 cases; 47,048 Alzheimer's disease-by-proxy cases, 283,111 controls) from the UK biobank. Using short tandem repeat genotype data, we identify 15 independent loci showing evidence for genome-wide significant association with Alzheimer's disease risk. While most identified loci had already been highlighted by SNP-based GWAS, we detect short tandem repeat-based signals near the genes SNX32 (chr. 11q13) and WSB1 (chr. 17q11). In addition, we delineate several other loci where short tandem repeats (and not SNPs) either represent the lead signal (ABCA7) or make substantial contributions to the SNP-driven associations (HLA-DRB1, MINDY/ADAM10, and APOE). Heritability analyses estimate that short tandem repeats account for at least 3% of the total phenotypic variance of Alzheimer's disease in this dataset. Aligning our top short tandem repeats with DNA methylation and transcriptome profiles from human brain samples suggests that several short tandem repeats may unfold their effects by impacting gene expression.},
}

@article {pmid42243402,
year = {2026},
author = {Moretto, E and Masato, A and Panzi, C and Lopes, AT and Stuart, S and De La-Rocque, S and Caso, MG and White, IJ and Harris, SS and Busche, MA and Schiavo, G},
title = {Aberrant tau accumulation caused by MAPT mutations induces early pathological changes in axonal transport that are rescued by p38α inhibition.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42243402},
issn = {1546-1726},
abstract = {Impairments in axonal transport have been implicated in the pathogenesis of tauopathies, including frontotemporal dementia and Alzheimer's disease, yet the underlying mechanisms and reversibility of these deficits are largely unknown. In particular, the impacts of tau mutations, phosphorylation and aggregation on axonal transport in vivo remain controversial. By using two-photon imaging of axonal transport of BDNF granules in the mouse cortex, we reveal that deficits in axonal transport arise in vivo at early stages of tau pathology, preceding tangle formation and neuronal death. Mechanistically, these impairments are caused by the enlargement of tau envelopes on microtubules, which act as functional barriers for transport. Crucially, these deficits are reversed by inhibiting MAPK p38α. Together, our work demonstrates that tau pathology causes reversible deficits in axonal transport in vivo, posing the basis for pharmacological interventions to restore the physiological flux of axonal organelles and cargoes in tauopathies.},
}

@article {pmid42243446,
year = {2026},
author = {Karami, M and Kebriaei, H and Ghassemi, F and Azadegan, H},
title = {Byzantine robust federated learning for heterogeneous brain MRI using multisignal gradient fingerprinting and adaptive trust aggregation.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-55855-5},
pmid = {42243446},
issn = {2045-2322},
abstract = {Federated learning enables collaborative training across institutions without centralizing patient data, but remains vulnerable to malicious clients and severe non-IID data heterogeneity. We propose a trust-aware federated learning framework for brain MRI that combines multi-signal gradient fingerprinting with adaptive aggregation to achieve Byzantine robustness. Each client update is characterized by a six-dimensional fingerprint (variational-autoencoder reconstruction error, cosine similarity to a server reference, peer similarity, gradient norm, sign consistency, and Monte Carlo Shapley contribution). A dual-attention module and a reinforcement-learning controller map these signals into trust weights and integrate with FedBN-P (Federated Batch Normalization with Proximal regularization), an optimizer co-designed for stability under heterogeneous and adversarial conditions. We evaluate on MNIST, CIFAR-10, Alzheimer's MRI, and the OASIS brain-MRI cohort (approximately 87 test samples, used strictly as proof-of-concept) under both standard and strengthened threat models (up to 40% malicious clients). Attack-specific ablation confirms a defense-in-depth design: VAE fingerprinting is the primary noise-attack defense (3.60 pp accuracy drop upon removal), Shapley values safeguard accuracy under scaling (10.16 pp drop), and reinforcement learning improves detection consistency under dynamic attack schedules. Three-seed paired-test validation further shows detection F1 outperforms FLTrust by up to 44 pp on Non-IID Gaussian noise; a white-box adaptive attacker degrades the detector but not model accuracy, confirming the layered design. End-to-end wall-clock overhead is + 8.8% over FedAvg with identical communication volume. The framework achieves F1 above 0.98 for gradient-scaling attacks while preserving accuracy under magnitude-preserving attacks where explicit detection remains limited. Multi-site validation on larger federated cohorts (e.g., ADNI, UK Biobank, FeTS) is required before any clinical-deployment claim can be made.},
}

@article {pmid42243535,
year = {2026},
author = {Arias, JF and Aumont, E and Therriault, J and Trudel, L and Margherita-Poltronetti, N and Thomas, E and Bezgin, G and Servaes, S and Wang, YT and Rahmouni, N and Macedo, A and Quispialaya, K and Hosseini, SA and Hall, B and Kunach, P and Jia, WL and Chan, T and Zheng, Y and Woo, MS and Mathotaarachchi, SS and Vitali, P and Pascoal, T and Iturria-Medina, Y and Montembeault, M and Rosa-Neto, P},
title = {Hemispheric lateralization of Tau associations with visual and verbal memory in Alzheimer's disease.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42243535},
issn = {1619-7089},
support = {LCF/BQ/EU21/11890154//'la Caixa' Foundation/ ; RFN 152985, 159815, 162303/CAPMC/CIHR/Canada ; MOP-11-51-31-team 1//Consortium canadien en neurodégénérescence associée au vieillissement/ ; 34874; 33397//Fondation Brain Canada/ ; 2020-VICO-279314//Fonds de Recherche du Québec - Santé/ ; },
abstract = {PURPOSE: Alzheimer's disease affects the brain in complex ways, and the location of tau tangles may influence specific types of memory problems. In this study, we examined how tau accumulation relates to verbal and visual memory performance, and whether these associations show a preference for one hemisphere of the brain over the other.

METHODS: We administered the Rey Auditory Verbal Learning Test (RAVLT) and its nonverbal analog, the Aggie Figures Learning Test (AFLT), to 132 cognitively unimpaired elderly participants and 44 cognitively impaired, amyloid-positive individuals from the Translational Biomarkers in Aging and Dementia cohort. All participants underwent [18 F]MK6240 tau PET, [18 F]AZD4694 amyloid PET, and structural MRI scans. We analyzed the data using region-of-interest and voxel-wise regression models, as well as correlation analyses.

RESULTS: Voxel-wise analyses showed that higher tau load in the right hemisphere was associated with worse visual memory, confirming a lateralized relationship. Left-hemisphere tau associations with verbal memory were observed at higher t-values. In regression models including both memory scores, visual memory remained significantly associated with tau on the right hemisphere (βAFLT~Rtau=-0.22, p=0.001; βRAVLT~Rtau=-0.1, p=0.13), whereas both visual and verbal memory remained significant on the left hemisphere (βAFLT~Ltau=-0.16, p=0.03; βRAVLT~Ltau=-0.14, p=0.04). These patterns were also reflected in Braak regions, except for Braak I, where only left tau-verbal and right tau-visual associations remained significant.

CONCLUSION: Our findings support lateralized associations between tau accumulation and memory deficits, with visual memory linked to right-hemisphere tau and verbal memory to left-hemisphere tau. This pattern is consistent with lateralization of memory functions observed in other neurological conditions and highlights the importance of considering hemisphere-specific tau pathology in Alzheimer's disease.},
}

@article {pmid42243549,
year = {2026},
author = {Lu, A and Chen, WT and Dalby, M and Sainz Garcia, D and Vanheusden, M and de Vries, LE and van Lieshout, V and Martirosyan, A and Craessaerts, K and Moonen, S and Zielonka, M and Chrysidou, I and Misbaer, A and Wolfs, L and Pavie, B and Swaab, D and Thal, DR and Huitinga, I and Rozemuller, A and Rohde, SK and Hulsman, M and Holstege, H and Balice-Gordon, R and Plath, N and Fiers, M and De Strooper, B},
title = {Human microglial transitions at the Aβ-tau inflection point associate with divergent pathways to dementia and resilience.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {42243549},
issn = {1546-170X},
support = {MR/Y014847/1//RCUK | MRC | Medical Research Foundation/ ; ERC-834682//EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))/ ; G065721N, G024925N//Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)/ ; 22-AAIIA-963171/ALZ/Alzheimer's Association/United States ; #73305095007//ZonMw (Netherlands Organisation for Health Research and Development)/ ; },
abstract = {Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics and single-nucleus RNA sequencing of the superior frontal cortex from octogenarians living with or without dementia and from cognitively intact centenarians with comparable Aβ accumulation. We identified six distinct tissue domains representing a spatial pathological continuum of AD, with a key inflection point marked by a shift from Aβ-associated inflammatory changes to tau-associated cellular programs. This transition was accompanied by a change in microglial states, from early inflammatory to late antigen-presenting phenotypes, termed early and late plaque-induced gene (PIG) programs. Resilient individuals showed distinct pathological patterns: octogenarians without dementia lacked late PIGs, whereas centenarians showed late PIG activation that was uncoupled from tau accumulation. Together, these findings highlight divergent resilience-associated mechanisms in human aging and position microglial state transitions at the Aβ-tau interface as candidate points of resilience with potential therapeutic relevance.},
}

@article {pmid42243620,
year = {2026},
author = {Wec, A and Wu, M and Scerpella, D and Zhang, Z and Peereboom, D and Colburn, JL and Nothelle, SK and Green, AR and Wolff, JL and Powell, DS},
title = {Documented follow-up to memory concerns reported at the Medicare Annual Wellness Visit.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71576},
doi = {10.1002/alz.71576},
pmid = {42243620},
issn = {1552-5279},
support = {//Consumer Health Information Technology to Engage and Support ADRD Caregivers/ ; R35AG072310//NIA/NIH/ ; T32AG066576//Health Services and Outcomes Research for Aging Populations National Institute on Aging/ ; //Research Training for the Care of Vulnerable Older Adults with Alzheimer's Disease and Related Dementias and Other Chronic Conditions Grant/ ; T32AG066598/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: The Medicare Annual Wellness Visit (AWV) may improve timely detection of Alzheimer's disease and related dementias (ADRD), yet little is known about the frequency of follow-up on patient-reported memory concerns during the AWV.

METHODS: We use electronic medical record (EMR) data from an academic health system to examine EMR-documented follow-up actions for patients with newly reported memory concerns on the AWV health risk assessment, including formal cognitive assessment or specialist referrals.

RESULTS: The 1411 patients with newly reported memory concerns were predominantly white (70%) and female (63%), with an average age of 78 (SD 7.5). At the AWV, few patients received a cognitive assessment (5.4%; n = 76), specialist referral (2.1%; n = 30), or both (0.4%; n = 6). In adjusted analyses, we did not observe statistically significant differences by sociodemographic characteristics.

DISCUSSION: This EMR-based study highlights an opportunity to better leverage the AWV to improve ADRD detection and care.},
}

@article {pmid42243744,
year = {2026},
author = {Efe, JJ and Anibor, E and Pandey, P and Sunday, OG and Innocent, DC and Anyakorah, PE and Emmanuel, OI},
title = {Blood-based biomarkers for early diagnosis of Alzheimer's disease: a current systematic review of diagnostic accuracy studies.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-05046-6},
pmid = {42243744},
issn = {1471-2377},
abstract = {BACKGROUND: Alzheimer disease (AD) is the most common cause of dementia in the world and its prevalence is increasing and it has important public health consequences. Early diagnosis remains challenging due to reliance on costly and invasive methods such as positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis. Blood-based biomarkers have emerged as a promising, less invasive alternatives to identify AD pathology, especially in the early and preclinical stages. This systematic review aim to evaluate the diagnostic accuracy of blood-based biomarkers for the early detection of Alzheimer's disease.

METHODS: An extensive literature search was performed in PubMed/MEDLINE, EMBASE, Scopus, Web of Science, and Cochrane Library on studies published since 2010 up to March 2026. The search strategies involved the use of Medical Subject Headings (MeSH), and free-text words associated with Alzheimer disease, blood-based biomarkers, and diagnostic accuracy. Peer-reviewed diagnostic accuracy studies focused on adult populations were included in line with PICO framework. The selection of studies was based on PRISMA guidelines and were critically appraised using QUADAS-2. Because of heterogeneity across the included studies, synthesis of findings was carried out using a narrative approach.

RESULTS: Six studies were included in this review. Diagnostic performance of phosphorylated tau biomarkers (p-tau181 and p-tau217) was consistently high (AUC up to 0.93), and glial fibrillary acidic protein (GFAP) also showed strong performance (AUC up to 0.87). Amyloid-β ratios (Aβ42/Aβ40) showed moderate to high accuracy, especially in preclinical detection, but had varying performance across assays (AUC 0.69-0.94). Neurofilament light chain (NfL) demonstrated moderate diagnostic value (AUC of up to 0.79) and was more predictive of progression than an early diagnosis. Combinations of biomarkers, especially those that included genetic variables like APOE genotype, were consistently more effective than individual biomarkers (AUC up to 0.92).

CONCLUSION: Biomarkers in blood, especially p-tau and GFAP, have a strong potential for early detection of Alzheimer disease, with their combination yielding better results. Although promising, assay variation and lack of standardisation hinder clinical translation. To facilitate their integration into standard diagnostic practice further large-scale validation and harmonisation effort is required.},
}

@article {pmid42243905,
year = {2026},
author = {Qian, L and Cui, M and Wu, M and Song, B and Wang, P and Wu, M and He, T and Zhang, B and He, Y},
title = {Tea-derived natural nanodrug simultaneously enables real-time fluorescent tracking and noninvasive treatment of neuroinflammation in Alzheimer's disease.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04642-5},
pmid = {42243905},
issn = {1477-3155},
support = {BK20240766//Natural Science Foundation of Jiangsu Province/ ; 22504095//National Natural Science Foundation of China/ ; 22393932//National Natural Science Foundation of China/ ; 2023M742532 and 2024T170625//China Postdoctoral Science Foundation/ ; 0002/2022/AKP, 0115/2023/RIA2//Macau University of Science and Technology Foundation/ ; 2023YFB3208202//National Key Research and Development Program of China/ ; },
abstract = {Neuroinflammation and glutamate-induced excitotoxicity are key drivers of synaptic dysfunction and cognitive decline in Alzheimer's disease (AD). However, chemically synthesized small-molecule drugs (e.g., memantine) often cause potential dose-dependent neurotoxicity, limited inflammation-targeting capability, and rapid systemic clearance, resulting in suboptimal therapeutic efficacy. Here, we introduce a tea-derived multifunctional natural nanodrug that enables real time fluorescence tracking and noninvasive treatment of neuroinflammation in AD. The natural nanodrug is derived from Pu-erh tea leaves, formulated with memantine and biomimetic vesicles for intranasal nebulized delivery. The tea-derived biomimetic nanodrug features intrinsic fluorescence, enabling real-time tracking at both cellular and tissue levels, with preferential colocalization in activated microglia and selective accumulation in neuroinflammatory brain regions. Remarkably, under matched nebulization conditions and nominal memantine loading, the tea-derived natural nanodrug shows an improved safety and efficacy relative to free memantine, significantly improving behavioral outcomes and reducing hippocampal damage. This noninvasive strategy enables efficient brain targeting and markedly restores hippocampal structure and cognitive performance in AD mouse models. Together, our study suggests new avenues and exciting opportunities for developing natural nanodrugs for noninvasively and precisely treating brain diseases including but not limited to AD.},
}

@article {pmid42243971,
year = {2026},
author = {Macedo, AC and Trudel, L and Hosseini, SA and Therriault, J and Aumont, É and Bezgin, G and Rahmouni, N and Stevenson, J and Tissot, C and Woo, MS and Servaes, S and Mitchell, S and Fernandez-Arias, J and Hall, B and Chan, T and Gonçalves, MP and Ferreira, PCL and Ferrari-Souza, JP and Bellaver, B and Lussier, FZ and Benedet, AL and Ashton, NJ and Zetterberg, H and Blennow, K and Tudorascu, DL and Zimmer, ER and Montembeault, M and Soucy, JP and Klostranec, J and Pascoal, TA and Vitali, P and Rosa-Neto, P},
title = {Tau extent outperforms tau load as a predictor of neurodegeneration in Alzheimer's disease.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00945-1},
pmid = {42243971},
issn = {1750-1326},
abstract = {BACKGROUND: In Alzheimer's disease (AD), tau pathology is more strongly linked to neurodegeneration than amyloid-β and better predicts brain atrophy. The spatial extent of tauopathy (SEOT) has shown promise as an earlier and more sensitive marker of AD severity than tau load, but how these complementary dimensions relate to neurodegeneration remains unclear. Here, we compared the in vivo associations of tau-PET extent versus load with cross-sectional and longitudinal neurodegeneration.

METHODS: We studied 367 participants across the healthy-aging to AD continuum (mean age 69.3 years; 61% female) from the TRIAD cohort who underwent [[18]F]MK-6240 tau-PET. Tau load was quantified as regional standardized uptake value ratio (SUVR), and SEOT as the proportion of abnormal voxels, within a temporal meta-region of interest (ROI) and a full-cortex ROI. Neurodegeneration markers included cortical thickness, hippocampal volume (HCV), medial temporal atrophy (MTA) visual ratings, plasma neurofilament light (NfL), and CSF total tau (t-tau). Cross-sectional associations were evaluated using multiple linear regression or covariate-adjusted Spearman correlations. We also compared local correlations of tau load and extent with cortical thickness across all cortical regions. Longitudinal predictive value for neurodegeneration was tested using linear mixed-effects models.

RESULTS: Cross-sectionally, all tau-PET metrics were significantly associated with neurodegeneration across imaging and fluid biomarkers. Full-cortex SEOT provided the best model fit for cortical thinning. SEOT outperformed tau load for associations with HCV and for predicting MTA, whereas SEOT and SUVR showed comparable associations with plasma NfL and CSF t-tau. Tau extent was equal or superior to tau load in its correlation with local cortical thickness across all cortical regions. Longitudinally, baseline full-cortex SEOT best predicted future cortical thinning, while temporal SEOT best predicted future hippocampal atrophy.

CONCLUSIONS: Across cross-sectional and longitudinal analyses, tau extent provided superior predictive value for imaging-based neurodegeneration compared with tau load. By enabling a spatially unbiased, whole-brain assessment of tau burden that accommodates heterogeneous topographies, SEOT represents a promising complementary tau-PET metric for staging and tracking disease progression in AD.},
}

@article {pmid42244018,
year = {2026},
author = {Li, Q and Chen, F and Zhan, R and Cong, W and Mu, S and Zhong, S and Liu, X and Zhao, D and Wang, Y and Zhao, C and Kang, K and Zhou, Z},
title = {Sleep disturbances and risk of Alzheimer's disease: a systematic review and meta-analysis of longitudinal cohort studies.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02102-8},
pmid = {42244018},
issn = {1758-9193},
support = {82071467//National Natural Science Foundation of China/ ; F16-206-9-01//Shenyang Population and Health Technical Critical Special Project/ ; 20180540150//Natural Science Foundation of Liaoning Province/ ; },
abstract = {BACKGROUND: Sleep is essential for healthy bodily functioning in many aspects, including physiology, psychology and cognition. Due to the reverse causation, it remains inconclusive whether sleep disturbances contribute to Alzheimer's disease (AD). The purpose of this meta-analysis was to investigate the association between sleep disturbances and AD risk.

METHODS: PubMed, Embase, and Web of Science were searched for longitudinal cohort studies until May 2025. Random-effects models were employed to pool risk ratios (RRs) with 95% confidence intervals (CIs).

RESULTS: Of the 2106 records, 31 studies from East Asia (23%), Europe (32%), and North America (45%) were eligible for inclusion, involving 13,109,323 participants. The pooled effect size showed that sleep disturbances were linked to higher risk of AD (RR 1.40, 95% CI 1.29 to 1.51), with the magnitude attenuated but still significant through multivariate adjustment (adj-RR 1.29, 95% CI 1.18 to 1.42). Similar effects persisted even after reducing effects of reverse causation, as implemented by stratified analysis on mid-life cohorts and longer follow-ups (5-15: RR 1.35, 95% CI 1.01 to 1.81; ≥ 15 years: RR 1.26, 95% CI 1.02 to 1.57). Dose-response analysis revealed a U-shaped correlation, with sleep duration < 6 or > 8 h associated with AD risk elevation. Neither baseline age, follow-up length, nor study quality significantly diluted the observed association.

CONCLUSIONS: This study adds to evidence that sleep disturbances are relevant to incident AD, even in mid-life cohorts and longer follow-ups, supporting sleep disturbances as a mid-life risk factor of AD.},
}

@article {pmid42244173,
year = {2026},
author = {Drew, KL and Zorec, R and Vardjan, N and Kreft, M and McKenna, MC},
title = {Brain Bioenergetics in Aging: Neurovascular and Neurometabolic Coupling and Fuels: 15th International Conference on Brain Energy Metabolism.},
journal = {Journal of neurochemistry},
volume = {170},
number = {6},
pages = {e70467},
doi = {10.1111/jnc.70467},
pmid = {42244173},
issn = {1471-4159},
support = {R13AG085950/AG/NIA NIH HHS/United States ; },
abstract = {This Preface introduces the Special Issue entitled, "Brain Bioenergetics in Aging: Neurovascular and Neurometabolic Coupling and Fuels," which is comprised of manuscripts contributed by invited speakers and program/organizing committee members who participated in the 15th International Conference on Brain Energy Metabolism (ICBEM) held on September 17-21, 2024, in Ljubljana, Slovenia. The conference covered the latest developments in research related to (i) coordination of neurometabolic and neurovascular coupling and homeostasis of energy metabolism in healthy aging and Alzheimer's disease, (ii) in vivo imaging modalities for study of neurometabolic and neurovascular coupling, (iii) mitochondrial and metabolic alterations and resilience in injured and aging brain, (iv) astrocyte metabolism in Alzheimer's and other neurodegenerative diseases, (v) microglial support of neuronal metabolism and role in neurodegeneration, (vi) neuronal mitochondria and disease, (vii) lipids and transporters in brain function, metabolism and Alzheimer's disease, and (viii) metabolic regulation of cognition. The special issue contains 19 manuscripts on these topics.},
}

@article {pmid42244184,
year = {2026},
author = {Guerrero, A and Galvis-Garrido, ND and Bocanegra, Y and Vásquez, D and Becerra, JC and Zuluaga, Y and Baena, A and Zubiri, V and Alzate, D and Osorio, L and Hincapié, L and Madrigal, L and García, G and Guzmán, C and Restrepo, F and Vidal, M and Martínez, L and Martínez, JE and Malotaux, V and Tristão-Pereira, C and Perez-Corredor, P and Vacano, GN and Lopera, F and Arboleda-Velasquez, JF and Quiroz, YT and Aguillon, D},
title = {Longevity and cognitive resilience in a Colombian family carrying the APOE ε2 variant.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261449392},
doi = {10.1177/13872877261449392},
pmid = {42244184},
issn = {1875-8908},
abstract = {APOE is the strongest genetic risk factor for late-onset Alzheimer's disease. Despite global efforts to promote resilience, delay cognitive decline, and slow aging, APOE ε2, one of the most robust resilience-associated variants, remains relatively underexplored in translational research. Exceptional longevity offers a window into cognitive trajectories. We present clinical, cognitive and neuroimaging data from five APOE ε2/ε3 siblings aged 94-105. Cognition ranged from normal to mild dementia. MRI showed less atrophy than expected for advanced age, and FDG-PET revealed preserved metabolism. Findings demonstrate APOE ε2-associated resilience in the oldest-old and offer insight into mechanisms of exceptional cognitive aging with potential translational relevance.},
}

@article {pmid42244193,
year = {2026},
author = {Deng, J and Li, S and , },
title = {Association of Alzheimer's disease blood-based biomarkers and visit-to-visit blood pressure variability: The HABS-HD study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261457455},
doi = {10.1177/13872877261457455},
pmid = {42244193},
issn = {1875-8908},
abstract = {BackgroundThe interplay between Alzheimer's disease (AD) and the cardiovascular system remains poorly understood. While vascular factors influencing AD have been studied, whether AD pathology conversely affects blood pressure regulation is unclear.ObjectiveThis study investigated whether baseline plasma AD biomarkers predict subsequent visit-to-visit blood pressure variability (BPV).MethodsThis prospective analysis included 470 community-based older adults from the Health and Aging Brain Study-Health Disparities (HABS-HD) cohort. Multiple linear regression models separately assessed associations between each baseline plasma AD biomarker (Aβ42/40 ratio, total tau, p-tau181, NfL) and follow-up BPV, with progressive adjustments for demographics, clinical diagnosis, cardiovascular risk factors, and mean blood pressure. In fully adjusted models, all plasma AD biomarkers were included simultaneously to adjust for potential mutual confounding and identify independent associations. Subgroup and sensitivity analyses were conducted.ResultsIn fully adjusted models, total tau remained independently associated with higher systolic blood pressure variability (β = 3.94, 95%CI: 1.00-6.87, p = 0.009). These associations were particularly prominent in males (β = 5.80, 95% CI: 1.66-9.95, p = 0.007), non-Hispanic White (β = 4.00, 95% CI: 0.12-7.88, p = 0.044), cognitively unimpaired individuals (β = 4.42, 95% CI: 1.14-7.70, p = 0.009), APOE ε4 non-carriers (β = 4.91, 95% CI: 1.42-7.70, p = 0.009), and individuals not using antihypertensive medication (β = 4.29, 95% CI: 0.71-7.87, p = 0.020). Sensitivity analyses confirmed robustness of findings.ConclusionsPlasma total tau independently predicts BPV, especially during pre-clinical AD stages. This finding reveals an important connection between AD pathology and vascular dysregulation, supporting the paradigm of AD as a systemic disorder and providing new directions for early risk identification and intervention.},
}

@article {pmid42244196,
year = {2026},
author = {Bożek, A and Dobosz, M and Miśkiewicz, M and Żurek, N and Miodońska, M and Zalejska Fiolka, J and Krupka Olek, M},
title = {Plasma p-tau217 and p-tau181 in middle-aged adults with mild cognitive impairment: The role of multimorbidity in an age-matched brief report.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261457132},
doi = {10.1177/13872877261457132},
pmid = {42244196},
issn = {1875-8908},
abstract = {Mild cognitive impairment (MCI) is an early stage of Alzheimer's disease-related neurodegeneration and may occur in midlife. The objective of the study was to assess associations between plasma p-tau217, p-tau181, cognition, and multimorbidity. We studied 236 MCI patients and 210 controls. Cognition was assessed using the Mini-Mental State Examination and Montreal Cognitive Assessment. Multimorbidity was defined as ≥2 chronic conditions, and comorbidity as coexisting diseases. MCI was associated with lower cognition, higher p-tau levels, and greater multimorbidity. Plasma p-tau217 correlated inversely with cognition. Plasma p-tau reflects early neurodegeneration, with multimorbidity contributing to cognitive decline.},
}

@article {pmid42244199,
year = {2026},
author = {Sozio, SJ and Sahai, A and Khalafi, M and Wang, X and Tanzi, E and Harvey, P and Maloney, T and Hojjati, SH and Zhou, L and Pahlajani, S and Butler, TA and Glodzik, L and Li, Y and Razlighi, Q and Kim, J and Goyal, P and Fossati, S and Chiang, GC},
title = {Poor R-wave progression associates with cerebral amyloid deposition: A potential link between heart and brain.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261449510},
doi = {10.1177/13872877261449510},
pmid = {42244199},
issn = {1875-8908},
abstract = {BackgroundAmyloid deposition is a key pathologic hallmark of Alzheimer's disease (AD). Since cardiac amyloidosis also involves abnormal amyloid accumulation, shared proteinopathy mechanisms may underlie both conditions.ObjectiveWe investigated whether brain amyloidosis on PET imaging is associated with electrocardiogram (EKG) findings of cardiac involvement by AD pathology.MethodsWe included 191 participants (mean age 66 ± 13.0 years) in our analysis, who underwent amyloid PET imaging and EKG within one year. EKG abnormalities (including low QRS voltage, poor R-wave progression (PRWP), bundle branch block, and sinus bradycardia) were assessed for associations with brain amyloid deposition, quantified in Centiloids, and cognitive function. A subset (n = 164) also underwent [18]F-MK6240 tau PET, and the relationship between these EKG abnormalities and tau deposition was also assessed.ResultsPRWP was associated with greater brain amyloid deposition (coefficient = 45 ± 12.15, p < 0.001) and worse cognition on the Clinical Dementia Rating scale (coefficient = 0.22 ± 0.098, p = 0.027). There was a trend for higher likelihood of cortical tau deposition with PRWP (odds ratio = 3.66, p = 0.05). Sinus bradycardia was associated with higher likelihood of cortical tau deposition (odds ratio = 2.81, p = 0.009). Other EKG abnormalities were not significantly associated with brain amyloid/tau deposition or cognition.ConclusionsPRWP and sinus bradycardia were found to be associated with AD pathology in the brain. These findings warrant further investigation into how cardiac electrophysiologic abnormalities may reflect a possible link between brain and cardiac pathologies or AD-associated cardiac dysfunction.},
}

@article {pmid42244245,
year = {2026},
author = {Finan, JM and Landes, SD and Turk, MA},
title = {Removing the Shroud: Revealing Cause of Death Patterns among Adults with Down Syndrome and Alzheimer's Disease.},
journal = {Journal of health and social behavior},
volume = {},
number = {},
pages = {221465261450455},
doi = {10.1177/00221465261450455},
pmid = {42244245},
issn = {2150-6000},
abstract = {Examination of cause of death patterns among disabled people is shrouded by death patterns in the general population. To remove this shroud, we focus on multiple causes of death (MCOD) comorbidity patterns between decedents with and without Down syndrome with Alzheimer's disease or unspecified dementia. Using 2005 to 2019 U.S. MCOD data, we examined comorbidity profiles of adults with (N = 7,936) and without (N = 4,593,118) Down syndrome using the broadest International Classification of Diseases (ICD-10) "List of 113 Selected Causes of Death" (selected cause groups) of death classification scheme as well as the ICD-10 "Specific Conditions" (specific causes). Comparison of these classification schemes revealed that the use of selected cause groups veiled comorbidities common among adults with Down syndrome-choking-related deaths, seizures and hypothyroidism. Results from this study underscore the necessity to change cause of death classifications schemes and/or the reporting of this information to account for differences and to mitigate data inequities.},
}

@article {pmid42244262,
year = {2026},
author = {Tariq, H and Khan, S and Shahid, H and Sohail, T and Noor, A},
title = {Multifunctional Nanoparticles for Theranostics of Protein Misfolding Diseases: A Systematic Review.},
journal = {Journal of biomedical materials research. Part B, Applied biomaterials},
volume = {114},
number = {6},
pages = {e70106},
doi = {10.1002/jbm.b.70106},
pmid = {42244262},
issn = {1552-4981},
abstract = {Protein misfolding disorders such as Parkinson's disease, Alzheimer's disease, islet amyloidosis, and several other diseases (amyloidosis) are characterized by the pathological accumulation of misfolded proteins that aggregate into toxic oligomers and fibrils. These misfolded proteins trigger oxidative stress, disrupt cellular homeostasis, and ultimately lead to tissue dysfunction. Overcoming the limitations of conventional strategies, multifunctional nanoparticles have emerged as a promising solution for simultaneously detecting, monitoring, and modulating pathogenic protein aggregates, offering a synergistic approach to addressing the multifaceted challenges of protein misfolding diseases. This systematic review examined 85 relevant studies published between 2010 and 2025, identified through PubMed searches. Only experimental studies reporting multifunctional or dual-functional nanoparticles for the theranostics of protein misfolding disorders were included. Data were narratively synthesized according to nanoparticle type, biomedical function, and therapeutic or diagnostic outcomes. The main findings suggest that multifunctional nanoparticles, including metallic, lipid, polymeric, carbon, silica, and hydrogel nanoparticles, can enable real-time monitoring, enhance imaging resolution, improve delivery of anti-amyloidogenic drugs, and mitigate oxidative stress and neuro-inflammation. Some strategies demonstrate potential to cross the blood-brain barrier, selectively bind amyloid aggregates, and provide synergistic theranostic effects. Among these, magnetic nanoparticles are superior because they possess intrinsic diagnostic capabilities and can be used for therapy simultaneously, eliminating the need for additional diagnostic agents. Their multifunctional nature offers several advantages for precision nano-theranostics in managing amyloidosis, though further translational studies are essential to establish scalability, safety, and long-term clinical applicability.},
}

@article {pmid42244340,
year = {2026},
author = {Bhardwaj, A and Benveniste, H},
title = {Amyloid-β-laden CSF turns guardian macrophages into collateral damage in Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag197},
pmid = {42244340},
issn = {1460-2156},
}

@article {pmid42244341,
year = {2026},
author = {Fox, GC and West, J and Rhodes, T and Poland, F and Birt, L and Handley, M and Wong, G and Moniz-Cook, E and Wolverson, E and Teague, B and Hackmann, C and Litherland, R and Hague, L and Alam, J and Sams, K and Mills, R},
title = {Recovery Colleges for post-diagnostic dementia support: The DiSCOVERY realist evaluation synopsis.},
journal = {Health and social care delivery research},
volume = {14},
number = {19},
pages = {1-36},
doi = {10.3310/GJCF2730},
pmid = {42244341},
issn = {2755-0079},
abstract = {BACKGROUND: Recovery Colleges offer peer-led, coproduced psychoeducational courses to support people to have meaningful lives. There is limited knowledge of their use in the context of dementia. This study used a realist programme theory approach to develop an in-depth understanding of how United Kingdom Recovery College dementia courses lead to outcomes for people with dementia, families and staff.

OBJECTIVES: To build knowledge through mapping Recovery College dementia courses across the United Kingdom; conduct a realist review of evidence; identify key components of effective Recovery College dementia courses within a realist programme theory; identify outcome measures for evaluating Recovery College dementia courses; understand diverse ethnic and cultural needs of people with dementia in accessing Recovery College dementia courses; and coproduce resources for implementing Recovery College dementia courses.

DESIGN AND METHODS: A mixed-methods design to examine what works for who and in what circumstances, coproduced with people with lived experience of dementia and staff from National Health Service Recovery Colleges and memory services. This involved: a United Kingdom-based staff survey of memory services and Recovery College dementia course provision, delivery and attendance; a realist review combining literature and stakeholder knowledge to build an initial programme theory; a realist evaluation using ethnographic observation within five case studies, realist interviews and documentary evidence, with analysis involving stakeholders using realist logic to explore causal processes operating in different contexts and intended and unintended outcomes (i.e. Contexts, Mechanisms and Outcomes); a scoping review of potential outcome measures for evaluation; and coproduced resources using three rounds of stakeholder workshops.

SETTING AND PARTICIPANTS: Set in United Kingdom National Health Service mental health organisations, staff recruitment from Recovery Colleges and memory services and people with dementia/families from Recovery Colleges.

RESULTS: Twelve (from 51) Recovery Colleges offered dementia-specific courses, and 210 memory service staff completed the survey. Thirty-five documents and discussions with 19 stakeholders (7 people with dementia, 2 family carers, 10 staff) informed the initial programme theory. A trusted person endorsing a course encouraged attendance. Shared coproduction values underpinned the success of setting up and running courses. Through co-facilitation of recovery-focused content by peer-tutors with well-developed facilitation skills, attendees appeared to mediate self-stigma, manage emotional uncertainty and make meaningful social connections in ways which engendered hope for the future. Course evaluation was challenging as people often left without completing a written survey. One attempt at pre and post course well-being measures failed to capture follow-up date.

LIMITATIONS: Four case sites were recruited, limiting diversity in course delivery methods and participant backgrounds. Numbers of people with dementia attending courses was lower than expected, raising questions about awareness and accessibility. Course evaluation was limited to standard feedback sheets. Sufficient data on coproduction processes and staff experiences were lacking, thus restricting refined theories about coproduction and its impact on practice.

CONCLUSIONS: Recovery-focused post-diagnostic courses can enable people with dementia to consider a hopeful future. Resources available may stimulate inclusivity and accessibility. The authenticity of peer tutors with dementia resonated with course attendees, and lived experience insights from people who were living positive lives with dementia is a key strength of this form of post-diagnostic support.

FUTURE WORK: Longer-term outcomes (e.g. hopefulness) for people with dementia attending recovery-focused courses is possible, but further validation of identified measures to address responsiveness, interpretability, inclusion of personal-recovery domains and cultural sensitivity for diverse populations is a pre-requisite.

FUNDING: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme as award number NIHR131676.},
}

@article {pmid42244445,
year = {2026},
author = {Fleming-Batayneh, VL and Helsel, BC and Ptomey, LT and Handen, BL and Mapstone, M and Petersen, M and Krinsky-McHale, SJ and Hom, CL and Minhas, D and Luo, W and Laymon, C and Lee, JH and Cohen, A and Ances, BM and Brickman, AM and Pulsifer, M and Rosas, HD and Lai, F and Zaman, SH and Head, E and Tudorascu, D and Price, J and Schmitt, F and Christian, BT and Okonkwo, O and Hartley, SL and , },
title = {Inflammation Associated With Obesity, Aging, and Amyloid Burden in Adults With Down Syndrome.},
journal = {Obesity (Silver Spring, Md.)},
volume = {},
number = {},
pages = {},
doi = {10.1002/oby.70229},
pmid = {42244445},
issn = {1930-739X},
support = {F31 AG085730/AG/NIA NIH HHS/United States ; K01 AG083130/AG/NIA NIH HHS/United States ; R01 AG070028/AG/NIA NIH HHS/United States ; U01 AG051406/AG/NIA NIH HHS/United States ; U01 AG051412/AG/NIA NIH HHS/United States ; U19 AG068054/AG/NIA NIH HHS/United States ; P50 HD105353/HD/NICHD NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; P50 AG005133/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; UL1 TR001857/TR/NCATS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; UL1 TR002366/TR/NCATS NIH HHS/United States ; U24 AG21886//National Centralized Repository for Alzheimer Disease and Related Dementias/ ; //NIHR Cambridge Biomedical Research Centre/ ; //Windsor Research Unit/ ; },
abstract = {OBJECTIVE: Adults with Down syndrome (DS) often show elevated systemic inflammation, but the association with obesity, aging, and Alzheimer's disease (AD) pathology is not well understood.

METHODS: Data were drawn from 188 nondemented adults with DS participating in the Alzheimer Biomarkers Consortium-DS (ABC-DS). Participants completed clinical assessments, blood draws, and neuroimaging. Plasma biomarkers included indicators of general, pro-, and anti-inflammation. Mixed linear models tested associations between BMI, age, PET-measured amyloid burden, and inflammatory biomarkers, adjusting for sex, trisomy type, and collection site. False discovery rate correction was applied.

RESULTS: The majority of the participants met criteria for obesity. Higher BMI was significantly associated with elevated levels of CRP, IL-6, TNF-α, B2M, IL-18, and slCAM-1 (p < 0.05). Older age was significantly associated with higher B2M (β = 1.22e + 05, p < 0.001). Amyloid burden was positively associated with IL-6 (β = 0.005, p = 0.037).

CONCLUSIONS: Obesity, aging, and amyloid burden relate to systemic inflammation in adults with DS. Obesity showed the strongest and most consistent associations, emphasizing the value of regular monitoring and weight management strategies to help reduce inflammation. Aging and early amyloid accumulation showed more limited links with systemic inflammation; future work should examine whether these processes are more closely related to biomarkers of neuroinflammation as AD progresses.},
}

@article {pmid42244486,
year = {2026},
author = {Yu, S and Gai, Y and Yang, Y},
title = {An effective method for modeling highly correlated interaction models with applications in Alzheimer's disease analysis.},
journal = {Statistical methods in medical research},
volume = {},
number = {},
pages = {9622802261457286},
doi = {10.1177/09622802261457286},
pmid = {42244486},
issn = {1477-0334},
abstract = {Interactions and correlations among features are essential in biology, as well as in other fields. This article introduces a novel approach for linear interaction models characterized by complex correlation structures. By integrating local linear approximation and Laplacian smoothing penalty with l1 or l1 and l2 penalties, our methods effectively estimate and predict highly correlated interaction models. Theoretical analysis confirms that both methods converge to an oracle solution within two iterations, demonstrating a rapid convergence rate. In simulation studies, our proposed methods outperform existing techniques in terms of prediction accuracy, estimation precision, and variable selection. When applied to protein microarray data for Alzheimer's disease analysis, they reveal substantial main and interaction effects with notably lower prediction errors. This highlights the potential of our methods as powerful tools for analyzing linear interaction models with intricate correlations, applicable across a wide range of biological research and other fields.},
}

@article {pmid42244540,
year = {2026},
author = {Jajoo, A and Maya-Martinez, M and Daskalakis, NP},
title = {Revealing the convergence of disease- and risk-associated circular RNAs in schizophrenia and bipolar disorder.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.24.725548},
pmid = {42244540},
issn = {2692-8205},
abstract = {Circular RNAs (circRNAs) remain an underexplored layer of transcriptomic regulation in psychiatric disorders. We quantified circRNA expression from 1,022 [518 neurotypical, 365 schizophrenia (SCZ) and 139 bipolar disorder (BIP)] postmortem cortex samples from PsychENCODE consortium cohorts and integrated these profiles with matched linear RNA and genotype profiles. We identified 23 SCZ-associated and 3 BIP-associated differentially expressed circRNAs (FDR<0.05; FDR-circDEG). We trained genetically regulated circRNA expression (circGReX) models using neurotypicals and applied them to SCZ and BIP GWAS to perform Transcriptomic Wide association analysis (TWAS) which identified 22 and 4 circGReX trait associations (circGTAs), respectively. Pathway enrichment of circDEGs and circGTAs implicated neuronal and synaptic processes for both disorders. In UK Biobank, circGReX-imaging associations were predominantly negatively correlated with SCZ and BIP circGTAs, but positively correlated with Alzheimer's disease circGTAs. circKLHL24 isoforms showed the most prominent imaging associations. Many co-expression modules containing our FDR-circDEGs were enriched for psychiatric and neurodegenerative risk genes, including our identified circGTAs, and these modules were enriched for cognitive and neurodevelopmental traits. To conclude, circRNAs represent a distinct regulatory layer in psychiatric disorders, linking genetic risk to synaptic biology, brain structure and cognition through disease-specific expression, TWAS prioritization, and imaging associations.},
}

@article {pmid42244569,
year = {2026},
author = {Shin, E and Kim, M and Soo, TJ and Espericueta, OT and Zolfaghari, E and Neel, MJ and Johnson, BA and Monuki, ES},
title = {Alzheimer's disease associations with increased Biondi body amyloid in hippocampal-associated choroid plexus epithelial cells and ependymal cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.25.727667},
pmid = {42244569},
issn = {2692-8205},
abstract = {To resolve discrepancies in the literature regarding the association between Alzheimer's disease (AD) and Biondi body (BB) amyloid in choroid plexus epithelial cells (CPECs), we investigated postmortem hippocampal paraffin blocks with and without a neuropathological diagnosis of AD (n=26-27 each). Similar to previous studies, age was associated with an increased fraction of hippocampal-associated CPECs bearing thioflavin S-positive BBs (p=0.004). In addition, we found that paraffin block storage time was associated with decreased BB detectability (p=0.038) while sex had no effect (p=0.577). Controlling for age, sex, and storage time, AD was associated with a near-significant increase in the BB-containing CPEC fraction (p=0.066) and a significantly greater load of BB-like amyloid in hippocampal-associated ependymal cells (p=0.032). The AD-BB association contrasts with our findings on choroid plexus from the atrium of the lateral ventricle, which lacked this association. We discuss potential explanations for the apparent discrepancy such as regional amyloid cross-seeding.},
}

@article {pmid42244587,
year = {2026},
author = {Nolin, SA and Aghamoosa, S and Rieter, WJ and Jones, A and Nietert, PJ and Benitez, A},
title = {Greater Amyloid Burden in Cognitive Networks in Preclinical Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.21.726909},
pmid = {42244587},
issn = {2692-8205},
abstract = {BACKGROUND: In preclinical Alzheimer's disease (pAD), regional patterns of amyloid-β (Aβ) deposition are well characterized but it is unclear how this process varies across functional networks.

OBJECTIVE: Determine how Aβ accumulation in functional networks ("network-amyloid burden" [NAB]) varies by age, network type (cognitive vs. non-cognitive), and Aβ status (Aβ+/Aβ-), and relates to cognition.

METHODS: 157 cognitively unimpaired adults (45-84 years; n=28 Aβ+ per neuroradiological read) underwent brain MRI, amyloid PET (18F-florbetapir), and neuropsychological testing. NAB was calculated as the mean standard uptake value ratio within 7 networks categorized as cognitive (fronto-parietal, default mode, ventral and dorsal attention, limbic) or non-cognitive (somato-motor, visual). Linear mixed models tested how NAB varies across age, networks (by type and each separately), Aβ status, and their interactions, and relationships between NAB and cognition.

RESULTS: NAB increased with age, most prominently in fronto-parietal and default mode networks. NAB was higher in cognitive than non-cognitive networks, and this difference was more pronounced in Aβ+ individuals. NAB was not significantly associated with cognition.

CONCLUSIONS: Cognitive brain networks are more vulnerable to amyloid accumulation with aging and in pAD than non-cognitive networks. Cognitive NAB may be useful for early detection and as a target for intervention in pAD.},
}

@article {pmid42244608,
year = {2026},
author = {Espericueta, NV and Neel, MJ and Wang, Y and Soo, TJ and Porahang, P and Goyokpin, FA and Salehi, RS and Khan, S and Lee, J and Maramica, NB and Flores, G and Kulkarni, A and Plaha, SS and Ghahremani, S and Huang, W and Smith, Q and Chang, P and Johnson, BA and Monuki, ES},
title = {Inducible lipid storage and steatosis in the human choroid plexus associated with age and adiposity.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.21.725559},
pmid = {42244608},
issn = {2692-8205},
abstract = {Cells that store lipids for other cells or organs can contain "giant" or large lipid droplets (LLDs) greater than 2 µm in diameter. In this study, human postmortem choroid plexus was evaluated for lipid droplets. Staining with hematoxylin and eosin (H&E), the lipophilic dye Oil red O, and anti-adipophilin antibodies established the presence of LLDs exceeding 10 µm in diameter in choroid plexus epithelial cells (CPECs). Manual annotation of H&E stains from 105 cases revealed a significant association between age and the percentage of CPECs containing LLDs (reaching up to 69%) and involving LLDs in our largest annotated category (>5 µm in diameter). The LLD association with age was replicated and extended to a total of 245 cases using a trained convolutional neural network, which further showed significant associations with body mass index at time of death (increasing with BMI), sex (higher in females >65 years old), and a near-significant association with Alzheimer's Disease (lower in AD). Like HepG2 and derived hepatocytes, excess fatty acids in culture media readily induced LLDs and steatosis in human embryonic stem cell-derived CPECs. Akin to hepatocytes for the human body, we propose that CPECs store lipids for the human brain and become steatotic in the setting of excess adiposity.},
}

@article {pmid42244657,
year = {2026},
author = {Kaipa, S and Zhai, T and Krishna Meka, SR and Moran-Losada, P and He, Z and Channappa, D and Oh, HS and Rutledge, J and Zeineh, M and Agudelo, A and Nair, R and Wilson, EN and Bandela, M and Raghuraman, K and Al-Rajhi, A and Akkiraju, A and Hwang, J and Longo, FM and Ramirez, V and Poston, K and Neretti, N and Khosla, S and Snyder, M and Wyss-Coray, T and Henderson, VW and Suryadevara, V},
title = {Plasma proteomics reveals divergent sex-specific senescence and bone biology signatures across neurodegenerative diseases.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.23.727339},
pmid = {42244657},
issn = {2692-8205},
abstract = {Neurodegenerative diseases are often accompanied by systemic comorbidities, including changes in bone health, but the molecular relationship between neurodegeneration, skeletal decline, and cellular senescence remains poorly understood. In this study, we investigated sex-specific changes in circulating bone- and senescence-related proteins across the spectrum of Alzheimer's disease(AD), Lewbody dementia(LB) and Parkinson's disease(PD). Plasma proteomic profiling was performed on samples from 408 participants deeply phenotyped for neurodegenerative diseases, followed by differential protein and pathway analyses. This study reveals sex-dependent alterations in bone and senescence-related circulating proteins in AD-related, PD and LB-related neurodegenerative diseases, providing insights into the complex relationship between neurodegeneration and bone health. Several candidate proteins were also associated with established plasma neurodegeneration biomarkers, particularly pTau181. Pathway analyses revealed shared mitochondrial and metabolic dysfunction across neurodegenerative diseases, with disease-specific features including vesicle trafficking disruption in AD and inflammatory-senescence pathways in LB, plus sex-divergent patterns in inflammatory signaling and bone-related pathways.},
}

@article {pmid42244694,
year = {2026},
author = {Vidal, JP and Myall, DJ and Pariente, J and Pitcher, TL and Roberts, RP and Cawston, EE and Le Heron, C and Anderson, TJ and Morgan, CA and Melzer, TR and Kirk, IJ and Tippett, LJ and Péran, P and Dalrymple-Alford, JC},
title = {Thalamic nuclei insights into Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.26.728015},
pmid = {42244694},
issn = {2692-8205},
abstract = {INTRODUCTION: Thalamic nuclei support multiple cognitive processes, yet their integrity in biologically-defined Alzheimer's disease (AD) remains unknown.

METHOD: Amyloid status was determined using PET Centiloids >24 in 1,327 participants from ADNI. Combined with clinical diagnosis, this yielded six groups: amyloid-negative or positive CN-MCI-dementia/AD. Thalamic nuclei volumes were extracted from T1-weighted MRI using the HIPS-THOMAS algorithm.

RESULTS: Large volume reductions in the anteroventral, mediodorsal, and pulvinar nuclei were observed in amyloid-positive MCI and AD. Reduced volumes were also evident in amyloid-positive CN, supporting preclinical AD. Adding the anteroventral nucleus improved cognitive status classification in Random Forest analyses. A phenotypic model integrating thalamic nuclei clearly distinguished amyloid-positive groups from amyloid-negative CN and reclassified non-AD patients with 68% of amyloid-negative MCI subjects as CN-like, and 27% of amyloid-positive CN as MCI-like.

DISCUSSION: Thalamic volumetry from conventional T1-weighted MRI enhances clinical insight into AD and provides a practical biomarker for disease intervention.},
}

@article {pmid42244738,
year = {2026},
author = {Amontree, M and O'Leary, J and Wonnenberg, P and Nelson, M and Conant, K},
title = {4-methylumbelliferone attenuates amyloid pathology and learning deficits in the APP/PS1 mouse model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.21.726929},
pmid = {42244738},
issn = {2692-8205},
abstract = {4-Methylumbelliferone (4-MU) inhibits hyaluronic acid (HA) synthesis and is currently approved in Europe for biliary spasm. 4-MU administration reduces perineuronal nets (PNNs), and enzymatic degradation of PNNs in mouse models of Alzheimer's disease (AD) attenuates memory impairment. Although 4-MU has therapeutic efficacy in rodent models of fibrosis and cancer, it has not been examined in an Alzheimer's model. Here, we evaluated the impact of long-term 4-MU treatment in the APP/PS1 amyloid mouse model. From three months of age, mice were on either a vehicle or 4-MU-supplemented diet for 70 days or 52 weeks. Short and long-term 4-MU treatment decreased the soluble parenchymal Aβ 1-42 /Aβ 1-40 ratio. Reductions in insoluble amyloid plaque were observed following 52 weeks of treatment. Extended 4-MU administration also reduced PNN intensity and ameliorated spatial memory deficits in APP/PS1 mice. These findings provide support for targeting brain extracellular matrix (ECM) as a therapeutic strategy for AD.},
}

@article {pmid42245015,
year = {2026},
author = {Kania, J and Zawar, I and Reyes, A and Williams, V and Sarkis, R and Punia, V and Williams, M and Ferguson, L and Arrotta, K and Busch, RM and Jones, J and Hermann, BP and McDonald, CR},
title = {Utility of the ADAS-Cog as a Cognitive Screening Tool in Older Adults with Epilepsy: A Multicenter Cohort Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.27.26354210},
pmid = {42245015},
abstract = {OBJECTIVE: Cognitive impairment is common among older adults with epilepsy, although efficient screening tools suitable for routine use are lacking. Here we examine, for the first time, the utility of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) as a screening tool to identify cognitive impairment in older adults with epilepsy.

METHODS: Participants included 83 adults (ages ≥ 55) with epilepsy from the Brain, Aging, and Cognition in Epilepsy (BrACE) study and 83 age-, sex-, and education-matched cognitively healthy controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI-3). All completed the ADAS-Cog and a comprehensive neuropsychological battery to identify cognitive phenotypes (intact vs impaired). Performance on individual ADAS-Cog items and the total score was assessed, and diagnostic efficiency statistics were determined.

RESULTS: Epilepsy participants (mean age=66.4 years) performed significantly worse across the ADAS-Cog total score and 8 of the 13 individual test items compared to controls. The largest effect sizes were observed on verbal learning and memory tasks, particularly word recall (d =0.87) and delayed word recall (d =1.06). An ADAS-Cog total score of ≥15 yielded optimal diagnostic efficiency (67.5% accuracy, 68.8% sensitivity, 66.7% specificity) for identifying cognitive impairment.

SIGNIFICANCE: The ADAS-Cog is sensitive to detecting cognitive impairment in older adults with epilepsy and may represent a scalable screening option in this population. Additional comparative studies in older epilepsy populations are needed to determine the sensitivity of this measure to longitudinal change, cross-cultural applicability, and availability across languages.

PLAIN LANGUAGE SUMMARY: Cognitive decline is common among older adults with epilepsy, although sufficient evidence supporting the use of screening tools to identify cognitive impairment in this population is lacking. The ADAS-Cog may be a useful screening option in epilepsy research and clinical care, although additional studies are needed to compare it with other cognitive screening tests and to confirm its applicability for clinical care and across cultures and healthcare settings.

KEY POINTS: □ ADAS-Cog, a tool widely used in Alzheimer's disease research, was used to detect cognitive impairment in older adults with epilepsy versus healthy controls.□ Largest deficits were in verbal learning and delayed recall, aligning with epilepsy-related memory vulnerability.□ ADAS-Cog was compared with the gold standard, the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE). An ADAS-Cog-13 cutoff ≥15 showed optimal accuracy for IC-CoDE-defined cognitive impairment.□ ADAS-Cog performance reliably distinguished IC-CoDE-impaired from intact participants within the epilepsy cohort.□ These findings support ADAS-Cog as a cognitive screening tool in aging epilepsy populations to identify neurodegenerative vulnerability.},
}

@article {pmid42245020,
year = {2026},
author = {Bazemore, K and Iqbal, T and Kuzma, AB and Grant, SFA and Schellenberg, GD and Wang, LS and Chesi, A and Jin, J and Naj, AC},
title = {Functionally informed annotation influences pathway-specific polygenic risk and disease inference in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.25.26353905},
pmid = {42245020},
abstract = {Pathway-specific polygenic risk scores (pathway-PRS) measure aggregate genetic risk across single nucleotide variants (SNVs) annotated to genes in a pathway of interest. In most applications, SNV-to-gene annotation is based on SNV position with respect to gene boundaries. This approach is ill-suited for incorporating non-coding SNVs, which can regulate gene expression over long distances and represent a large proportion of risk variants for Alzheimer's disease (AD). Here, we compare the performance of AD pathway-PRS across SNV-to-gene annotation strategies that integrate varying levels of functional genomic data, including adult brain chromatin interaction and expression quantitative trait loci (eQTL) data. In the UK Biobank (n=328,526), including AD cases defined by ICD-9/10 codes (n=3,043) and by family history of AD/dementia (n=38,589), we show that the annotation strategy integrating chromatin interaction and eQTL data consistently improves pathway-PRS performance. We replicate this finding in independent data from the Alzheimer's Disease Genetics Consortium (n=3,370). We further find that pathway-PRS associations with AD vary by annotation strategy and that power to detect sex-dependent and age-at-onset associations is increased with integrative annotation. Together, these findings support the use of functionally informed SNV-to-gene annotation for pathway-PRS construction and highlight the importance of applying multiple annotation strategies for robust inference.},
}

@article {pmid42245035,
year = {2026},
author = {Poulakis, K and Ioannou, K and Bezgin, G and Chiotis, K and Iturria-Medina, Y},
title = {Multimodal axes reveal individualized amyloid-β, tau, and neurodegeneration coupling in aging and Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.24.26353955},
pmid = {42245035},
abstract = {UNLABELLED: Can we decode Alzheimer's disease (AD) heterogeneity into a few portable axes that capture how amyloid-β, tau and neurodegeneration (A-T-N) spatially co vary in vivo? To answer this question, we built a pipeline that harmonizes longitudinal amyloid-β/tau PET and T1 MRI (gray matter) from ADNI cohort (12,430 images) with mixed effects modeling and then derived stage specific multimodal axes (mVCs) using linked component analysis, with robustness tested in simulations and external validation in the OASIS cohort (4,958 images). We identified a small set of multimodal axes that (i) recapitulate early tau weighted variation in cognitively unimpaired (CU) individuals, AD like A -T-N coupling in cognitively impaired (CI) individuals and atypical CU and CI participants with posterior (precuneus/occipitoparietal) and fronto insular/frontal weighted patterns, (ii) map onto domain specific cognition, APOE e4, and blood/CSF biomarkers of neurodegeneration, neuroaxonal injury and astrocyte activation, (iii) predict clinical transitions, (iv) generalize in an independent cohort, and (v) demonstrate modelling robustness to missing data, high dimensionality, and cross-cohort variability, enabling direct application of the extracted axes to new datasets for biomarker discovery and stratification. Multimodal axes provide a portable, interpretable layer for quantifying amyloid-β-tau-neurodegeneration coupling at the individual level, complementing current biomarker-based staging frameworks based on A-T-N status and tau PET topography, and can be computed on new datasets to aid clinical assessment and trial enrichment.

SIGNIFICANCE STATEMENT: We developed and validated a multimodal statistical pipeline to identify individualized patterns of association among core Alzheimer's disease biomarkers: amyloid-β deposition, tau accumulation, and neurodegeneration. Applied to longitudinal PET and MRI data, the approach revealed distinct, reproducible axes of biomarker coupling across cognitively unimpaired and impaired individuals, linked to cognitive performance and clinical progression. By providing subject -level scores that quantify how pathologies co-express across brain regions, this framework supports fine-grained biomarker discovery, improves interpretation of Alzheimer's disease heterogeneity, and can be extended to high -dimensional multimodal datasets in future biomarker studies.},
}

@article {pmid42245039,
year = {2026},
author = {O'Shea, DM and Wang, L and Lukacsovich, D and Zhang, W and Galvin, JE},
title = {MethylCog predicts six-year cognitive ability beyond blood-based ADRD biomarkers.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.26.26354133},
pmid = {42245039},
abstract = {INTRODUCTION: MethylCog is a 29-CpG blood DNA methylation (DNAm) proxy for general cognitive ability (g). Its incremental association with blood biomarkers of Alzheimer's disease and related dementias (ADRD) and prospective cognitive ability remains unclear.

METHODS: In the held-out test set from the original MethylCog study, we tested whether MethylCog explained baseline g beyond four ADRD blood biomarkers, and whether it predicted six-year follow-up g beyond baseline g and biomarkers.

RESULTS: MethylCog showed a stronger age-adjusted association with baseline g than individual biomarkers (r=.368 vs absolute r=.083-.162). MethylCog added 10.0% variance beyond all four biomarkers cross-sectionally (p<.001) and predicted six-year follow-up g in the biomarker-adjusted model (β=.108, p=.002). No individual ADRD biomarker independently predicted follow-up g.

DISCUSSION: MethylCog may provide cognition-related DNAm information complementary to blood-based ADRD biomarkers.},
}

@article {pmid42245054,
year = {2026},
author = {Lin, K and Sachdev, PS and Jiang, J and , },
title = {The Associations of Cerebral Blood Flow and White Matter Hyperintensities with Tau and Amyloid-beta Across the Alzheimer's Disease Spectrum.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.25.26354067},
pmid = {42245054},
abstract = {Although the associations between cerebrovascular dysfunctions and Alzheimer's disease are increasingly appreciated, the relationship of cerebral blood flow and white matter hyperintensities with tau and amyloid-β pathology remains unclear, particularly in the longitudinal context. This study investigated cross-sectional and longitudinal associations of cerebral blood flow and white matter hyperintensities with tau and amyloid-β pathology using multimodal imaging and blood biomarkers in 179 participants from the ADNI3 cohort. Participants underwent structural (T1-weighted, T2-weighted FLAIR) and arterial spin labelling perfusion MRI, tau and amyloid-β PET, and plasma assay tests for amyloid-β 42, amyloid-β 40, and phosphorylated tau-217. Tau from PET was negatively associated with cerebral blood flow both cross-sectionally and longitudinally in the posterior brain, independent of amyloid-β quantified from PET. Higher white matter hyperintensities volumes were associated with higher levels of tau and amyloid-β at baseline, but the associations were significantly attenuated after further adjusting for amyloid-β and tau, respectively. Plasma amyloid-β 42/40 ratio was negatively associated with white matter hyperintensity volumes both cross-sectionally and longitudinally. In conclusion, tau pathology showed spatially specific associations with cerebral hypoperfusion, independent of amyloid-β, particularly in posterior regions. The attenuation of associations of white matter hyperintensities with amyloid-β and tau after adjustment may reflect shared disease-related variance rather than distinct independent effects.},
}

@article {pmid42245064,
year = {2026},
author = {Zhang, X and Goudey, B and Laws, SM and Masters, CL and Baldwin, T and Faux, NG},
title = {Comparing Pathway-Informed Polygenic Risk Score Strategies: A multi-cohort evaluation of Amyloid-β.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.25.26354071},
pmid = {42245064},
abstract = {OBJECTIVE: To systematically evaluate pathway-informed polygenic risk score (PRS) strategies and determine which approaches most effectively leverage biological annotations for risk prediction, using brain amyloid-β (Aβ) positivity as a case study.

METHODS: We systematically benchmarked approaches for integrating pathway information into PRSs construction to predict brain Aβ positivity. Using two cohorts, the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 969) and Australian Imaging, Biomarkers and Lifestyle (AIBL, n = 251), we compared Apolipoprotein E (APOE) genetic risk score (GRS), clumping and thresholding (C+T) PRS, pathway-guided single nucleotide polymorphism (SNP) selection PRS, and pathway-specific PRSs ensembled via machine learning. Pathways were derived from manually curated literature or from pathway databases via Functional Mapping and Annotation (FUMA).

RESULTS: In cross-validation on the ADNI cohort, pathway-informed PRS using a narrow-set of pathways to guide SNP selection (PathPRS-SNP Lit without APOE locus) significantly outperformed the standard PRS model (median AUC = 0.742, p = 0.006) and the APOE locus model (median AUC = 0.736, p = 5.1 × 10 [-5]) based on the Mann-Whitney U test, achieving a median AUC of 0.763. This model showed enhanced ability to identify subgroups within the 10% lowest-and highest risk groups compared to the current standard of APOE locus alone (odds ratio = 0.67, 95% CI: 0.56-0.81; and OR = 13.23, 95% CI: 10.23-17.11), highlighting its clinical potential. Using a focused set l iterature-curated pathways outperformed using a broader set of database-derived pathways across configurations. When contrasting strategies for aggregating information across pathways, we observed that using pathways to guide selection of SNPs and then building a single PRS performed comparably to building PRS for each pathway and using machine learning (ML) to aggregate these, though the latter enabled pathway-level interpretability. S imilar trends were observed in the external AIBL validation dataset.

INTERPRETATION: Pathway-informed PRS can meaningfully improve genetic risk enrichment for Aβ positivity beyond APOE and standard C+T approaches, provided pathway definitions are carefully curated. The choice of pathway source has the strongest impact on predictive performance with aggregation strategies or ML model choice having far less impact. Our findings highlight the utility of literature-curated, pathway-informed PRSs for Aβ prediction and offer practical guidance for pathway-informed PRS construction in other polygenic traits.},
}

@article {pmid42245135,
year = {2026},
author = {Mao, Y and Sui, Z and Zhang, M and Ma, Y},
title = {Cognitive decline and reduced bone mineral density under the bone-brain axis: mechanistic insights and imaging evaluation strategies.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1799025},
pmid = {42245135},
issn = {1663-4365},
abstract = {Against the backdrop of an accelerating global aging population, the epidemiological correlation between cognitive impairment and osteoporosis has become increasingly prominent. These two conditions exhibit a profound pathological coupling mediated by the bidirectional regulatory network of the "bone-brain axis." The operation of this axis is rooted in an intricate neuro-skeletal signaling network involving hormonal dysregulation, systemic inflammatory cascades, and the aberrant regulation of core molecular pathways, such as Wnt/β-catenin and RANKL/OPG. Together, these factors synergistically drive the synchronized pathological progression of enhanced bone resorption and neurodegeneration. To address these complex pathological interactions, clinical evaluation strategies are undergoing a paradigm shift, transitioning from single-modality assessments toward the deep integration of multimodal imaging. By fusing cutting-edge technologies-including structural/functional MRI, molecular PET imaging (targeting Aβ and Tau deposition), and high-resolution peripheral quantitative computed tomography (HR-pQCT)-researchers can now comprehensively characterize the spatiotemporal patterns of bone microstructural degradation and brain functional evolution across scales ranging from the microscopic to the macroscopic. Prospectively, leveraging deep learning algorithms such as 3D-CNN to integrate multimodal biomarkers and construct risk-prediction models for bone-brain comorbidities will emerge as a pivotal pathway for achieving early precision screening and personalized preventive intervention for Alzheimer's disease (AD).},
}

@article {pmid42245283,
year = {2026},
author = {Miyahara, H and Riku, Y and Yano, K and Hidaka, Y and Tahara, D and Tahara, N and Moriyoshi, H and Akagi, A and Sone, J and Hashidate, H and Kakita, A and Iwasaki, Y},
title = {Unclassifiable senile plaques and extensive cerebral amyloid angiopathy involving spinal and bridging vessels in autopsied patients with Down syndrome.},
journal = {Free neuropathology},
volume = {7},
number = {},
pages = {12},
pmid = {42245283},
issn = {2699-4445},
abstract = {Background: Individuals with Down syndrome (DS) face markedly increased risk of premature aging and age-related pathological changes, particularly Alzheimer's disease (AD)-like neuropathology. By the fourth decade of life, virtually all individuals with DS develop the hallmark AD features such as senile plaques (SPs) and neurofibrillary tangles (NFTs). The aim of this study was to characterize the topographical distribution of cerebral amyloid angiopathy, the morphology of senile plaques, and the spectrum of co-existing aging-related proteinopathies in autopsied DS patients, with reference to age-matched and elderly controls. Methods: Nine autopsied DS patients (aged 0.5-68.0 years at death) were examined alongside age-matched controls. Immunohistochemical staining was performed for amyloid-β (Aβ), phosphorylated tau, α-synuclein, and phosphorylated TDP-43. In addition, silver impregnation using the Gallyas method and Congo red staining were performed. Aging-related pathologies were assessed using established criteria for NFTs, Aβ deposits, cerebral amyloid angiopathy (CAA), and other neurodegenerative changes. Results: All four DS patients aged ≥ 28 years (D6-D9) showed moderate-to-severe AD neuropathological changes, whereas none of five age-matched controls (23.1-68.4 years old) did. In DS patients with AD, unclassifiable SPs were predominant, and NFTs with both 3-repeat and 4-repeat tau were observed. The distribution and progression of the latter were similar to those of sporadic AD patients. CAA was observed in three DS patients and, owing to systematic sampling, could be documented in the spinal arteries and subdural/subarachnoid bridging vessels-sites not routinely evaluated in autopsy series of sporadic CAA. All three DS cases with CAA reached Thal stage 3 CAA, contrasting with a maximum of stage 2 in CAA-positive sporadic AD and elderly control cases. Notably, two of three DS patients with CAA had a documented clinical history of subdural hemorrhage (SDH); both showed marked cerebral atrophy at autopsy, precluding definitive attribution of SDH to CAA. The high frequency of SDH suggests increased hemorrhagic risk in DS patients due to extensive vascular amyloid deposition. Conclusions: This study demonstrates accelerated ADNC development in DS, with characteristic unclassifiable SPs and extensive CAA representing unique features that distinguish DS from common aging patterns. The clinical history of SDH in DS patients with CAA, together with the histological extension of CAA to subdural bridging vessels, may warrant attention when considering the vascular safety of emerging anti-amyloid therapies in this population. However, causality between CAA and SDH could not be established from the present autopsy data. These findings provide crucial insights into AD pathogenesis and highlight the importance of developing targeted therapeutic strategies while considering safety implications.},
}

@article {pmid42245290,
year = {2026},
author = {Yu, X and Yao, Q},
title = {Evaluating the Role of AI Assistants in Accelerating Neurodegenerative Disease Research: Opportunities and Translational Limitations.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {614952},
pmid = {42245290},
issn = {1176-6328},
abstract = {Neurodegenerative diseases including Alzheimer's disease and Parkinson's disease remain among the most challenging disorders to study, diagnose and treat. Despite rising prevalence with population aging, disease-modifying therapies remain scarce and research progress is hindered by biological complexity, patient heterogeneity, and incomplete experimental systems. Artificial intelligence (AI) has emerged as a transformative approach given the high-dimensional and multimodal data generated in this field. Traditional machine learning and deep learning have advanced imaging biomarker detection, disease trajectory prediction, drug target prioritization, and clinical data mining. More recently, foundation models and large language models (LLMs) have expanded AI from task-specific prediction tools to versatile assistants supporting literature retrieval, summarization, coding, data interpretation, and hypothesis generation. Although AI assistants promise to accelerate research workflows, their outputs are prone to dataset biases, poor interpretability, distribution shift, and hallucinations, which are particularly problematic in neurodegenerative research given subtle phenotypic variations, imperfect labeling, and protracted disease courses. This review evaluates the current applications of AI in neurodegenerative disease research, including drug discovery, biomarker identification, and multi-omics integration. We then discuss the transition from analytical AI models to general-purpose AI assistants and their potential to streamline scientific workflows. Critical limitations including bias, interpretability, reproducibility, and LLM hallucinations are highlighted, alongside ethical, regulatory and practical challenges. We argue that the most sustainable near-term model is human-AI collaboration rather than fully autonomous research, with its primary focus placed on research rather than clinical practice. Meaningful acceleration requires rigorous validation, transparent usage, and expert oversight to preserve scientific rigor and translational relevance.},
}

@article {pmid42245489,
year = {2026},
author = {Obafemi, BA and Barbosa, NV and Aschner, M and Adedara, IA and Rocha, JBT},
title = {Neuroprotective mechanisms of nutraceutical berberine: Preclinical evidence and future perspectives.},
journal = {Advances in neurotoxicology},
volume = {15},
number = {1},
pages = {417-455},
pmid = {42245489},
issn = {2468-7480},
abstract = {Despite currently available drugs for neurological disorders, the incidence of these diseases continues to rise with attendant morbidity, mortality and economic losses. The available treatments oftentimes focus more on either slowing down disease progression or ameliorating symptoms. According to the World Health Organization, some of these disorders, including Parkinson's disease and Alzheimer's diseases are among the leading causes of death globally. Identification of new compounds with neuroprotective properties is a fascinating line of research. Berberine, a plant-derived bioactive compound, of the alkaloid family, has been studied extensively for its neuroprotective properties in a wide range of models of neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, autism spectrum disorders, traumatic brain injuries and amyloid lateral sclerosis. Studies have shown that the neuroprotective property of berberine is linked to its ability to modulate several critical biochemical pathways and to regulate the concentrations and activities of important biomarkers that are both diagnostic and therapeutic targets for neurological disorders. This chapter provides insight into the biosynthesis, pharmacokinetics and neuroprotective mechanisms of berberine. Furthermore, ways to improve the utilization of berberine for its neuroprotective potentials such as combining it with other compounds or nanoparticle delivery are highlighted.},
}

@article {pmid42245509,
year = {2026},
author = {Wang, Z and Li, L and Dong, Y and Zhang, Y},
title = {The microbiota-tryptophan-brain axis in neurodegenerative diseases: pathogenic mechanisms, disease-specific roles, and translational therapeutics.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1820111},
pmid = {42245509},
issn = {1664-302X},
abstract = {The pathogenesis of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) is very complex. Recent studies have shown that gut microbiota and their metabolites play a key role in the progression of these diseases. Tryptophan (Trp) is an essential amino acid, which mainly produces a variety of biologically active compounds in the intestine through the metabolism of indole pathway, Kynurenine pathway (KP) and serotonin pathway, including indole derivatives, Kynurenine (KYN) and serotonin (5-HT). These metabolites affect the central nervous system (CNS) through the Microbiota-gut-brain axis (MGBA) and affect CNS in a variety of mechanisms, including immune regulation, neuroprotection and maintenance of intestinal barrier function. They are involved in key pathological processes such as neuroinflammation, oxidative stress and pathological protein aggregation. This paper systematically reviews the mechanism of the role of Trp metabolites derived from gut microbiota in NDDs, and explores their specific roles in AD, PD, Amyotrophic Lateral Sclerosis (ALS) and Huntington's disease (HD), and summarizes the potential therapeutic value of the current pathway strategy. These strategies include nutritional intervention, targeted microbiome therapy [such as probiotic and fecal microbiota transplantation (FMT)], and metabolite-derived drugs. Future research must clarify its dynamic mechanism in the human body, develop relevant biomarkers, and promote personalized prevention and treatment strategies through clinical transformation, so as to provide a new direction for early intervention and treatment of NDDs.},
}

@article {pmid42245579,
year = {2026},
author = {Brito, L and Faria, S and Leite, A and Pereira, MG},
title = {Quality of life and burden during the COVID-19 pandemic: a longitudinal study with family caregivers of persons living with Alzheimer's disease.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1662182},
pmid = {42245579},
issn = {1664-1078},
abstract = {INTRODUCTION: The COVID-19 pandemic intensified the challenges faced by family caregivers of persons living with Alzheimer's disease, potentially affecting their psychological, behavioral, and physiological well-being. Understanding how these processes evolve over time is critical for informing targeted interventions.

METHODS: A longitudinal study was conducted with 130 Portuguese family caregivers assessed at three time points over a 12-month period. Measures included quality of life (QoL), caregiver burden, psychological distress, forgiveness, health behaviors, caregiving competence, family stress, and heart rate variability (HRV). Linear mixed-effects models and mediation analyses were performed while controlling for caregiver age and dementia severity.

RESULTS: Physical QoL and health behaviors initially declined but subsequently demonstrated a trend toward recovery over time, whereas mental QoL showed a sustained decline. HRV, caregiving competence, and family stress increased throughout the study period. Forgiveness mediated the relationship between psychological distress and both caregiver burden and physical QoL, but not mental QoL. Health behaviors did not mediate the association between HRV and caregiver burden.

DISCUSSION: These findings highlight the dynamic and multifaceted nature of caregiving under prolonged stress conditions. Although caregivers demonstrated adaptive processes over time, the persistent decline in mental QoL underscores their continued psychological vulnerability. The mediating role of forgiveness suggests that it may serve as an important protective mechanism and a promising target for interventions aimed at improving caregiver well-being.},
}

@article {pmid42245780,
year = {2026},
author = {Saha, A and Shi, W and Elsharydah, MN and Schaffert, J and Kaufman, J and Leary, J and Jin, A and Almandoz, J and Lu, H and Thomas, BP},
title = {Blood-Brain Barrier Permeability Is Elevated in Type 2 Diabetes and Obesity: Associations with Cognitive Function and Metabolic Markers.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9698981/v1},
pmid = {42245780},
issn = {2693-5015},
abstract = {Background Type 2 diabetes (T2D) and obesity are established risk factors for Alzheimer's disease and related dementias, yet the cerebrovascular mechanisms linking metabolic dysfunction to cognitive decline remain poorly understood. Prior human studies relied on gadolinium-based methods to measure blood-brain-barrier (BBB) permeability to larger molecules (~ 550 Da), potentially underestimating subtle BBB disruption. This study aims to assess BBB water permeability in older adults with T2D and obesity using non-contrast WEPCAST MRI, and to evaluate associations between BBB integrity, metabolic markers, and cognitive function. Methods Twenty-eight older adults - 12 with T2D and obesity (BMI ≥ 30 kg/m[2]) and 16 age- and sex- matched controls - underwent WEPCAST MRI to quantify the BBB permeability measures: permeability-surface area product (PS), water extraction fraction (E) and global cerebral blood flow (CBF), along with T1-Weighted structural MRI acquisition. Cognitive function and fasting blood biomarkers were assessed in all participants. Associations between PS versus metabolic and cognitive function were examined using linear regression adjusted for age and sex. An additional adjustment for statin use was made for hemoglobin A1c (HbA1c) and lipid markers. Results T2D participants exhibited significantly elevated BBB water permeability (PS: P = 0.001, Hedges' g = 1.10) despite preserved CBF. Specifically, higher PS was associated with HbA1c (f[2] = 0.28, P = 0.016) and lower circulating cholesterol (total cholesterol: f[2] = 0.49, P = 0.003; LDL: f[2] = 0.45, P = 0.004; HDL: f[2] = 0.18, P = 0.053). The T2D group demonstrated lower scores across multiple domains including memory, attention, learning, executive function, and processing speed (g = 0.80-1.42). Higher PS was associated with poorer measures of executive function (P-values < 0.05). Conclusions Older adults with T2D and obesity exhibit elevated BBB water permeability, detectable by non-contrast WEPCAST MRI. Higher BBB water permeability was associated with higher glycemic burden and lower executive function, providing preliminary evidence that BBB permeability may serve as a novel imaging biomarker linking metabolic dysregulation to early cognitive vulnerability in T2D that follows a traditional "frontal-subcortical" pattern.},
}

@article {pmid42245785,
year = {2026},
author = {Manninen, E and Comrie, CJ and Serrano, GE and Beach, TG and Hutchinson, EB and Benjamini, D},
title = {Diffusion-relaxation MRI as virtual histology: separable microstructural signatures of AD pathology in ex vivo human brain.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9657671/v1},
pmid = {42245785},
issn = {2693-5015},
abstract = {Cognitive decline in Alzheimer's disease (AD) reflects progressive disruption of cellular and microstructural organization, yet the biological specificity of conventional MRI signals remains poorly understood. Multidimensional diffusion-relaxation MRI (MD-MRI) resolves sub-voxel tissue heterogeneity and may offer a framework for linking imaging signals to underlying neuropathology. We tested the hypothesis that neuronal, glial, and white matter pathologies in AD occupy separable regions of diffusion-relaxation space and generate spatially organized signatures associated with cognitive impairment. We integrated ex vivo MD-MRI with co-registered histology from 12 human donors spanning a range of Braak stages and pathological severity. Nested cross-validated elastic net models predicted voxelwise Aβ, pTau, microglia, and myelin burden from the multidimensional diffusion-relaxation density distribution. Regional associations were assessed across hippocampal subfields and white matter, and MRI-predicted pathology was related to ante-mortem Mini-Mental State Examination scores. Distinct diffusion-relaxation components were preferentially associated with different pathological markers, indicating separable microstructural signatures. MRI-derived predictions corresponded significantly with histological measures of myelin (ρ = 0.77), pTau (ρ = 0.62), and microglia (ρ = 0.61), with weaker correspondence for Aβ (ρ = 0.45). Regionally, predicted pathology recapitulated known patterns of selective vulnerability, with elevated pTau and microglial signal in hippocampal subfields and dominant myelin-associated signal in white matter (p < 0.0001). Higher predicted hippocampal pTau was strongly associated with worse cognitive performance (ρ = -0.88, p = 0.0014), with a moderate association in white matter (ρ = -0.66, p = 0.036). These findings demonstrate that AD-related pathological processes manifest as distinct, spatially organized diffusion-relaxation signatures, providing mechanistic insight into the microstructural basis of MRI contrasts. As clinically feasible MD-MRI protocols continue to emerge, translation of these signatures to in vivo imaging may enable more biologically informed assessment of neurodegeneration.},
}

@article {pmid42245790,
year = {2026},
author = {Hernández, AP and Dávila, EG and Espinosa, NR},
title = {Body mass index decline and cognitive trajectories in mild cognitive impairment: the role of maternal history of Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9696646/v1},
pmid = {42245790},
issn = {2693-5015},
abstract = {BACKGROUND: Maternal history of Alzheimer's disease (MH) has been associated with increased risk of Alzheimer's disease (AD), earlier onset, and distinct neurobiological features. In parallel, an anthropometric-metabolic phenotype characterized by body mass index (BMI) decline and unintentional weight loss has been described as an early feature preceding cognitive decline in the prodromal stages of AD.

OBJECTIVE: To investigate whether MH is associated with a distinctive anthropometric-metabolic and cognitive phenotype in individuals with mild cognitive impairment (MCI), focusing on longitudinal trajectories of body mass index (BMI), memory, and executive function.

METHODS: Participants with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed over up to 24 months of follow-up. Longitudinal changes in BMI, memory, and executive function were examined using repeated-measures ANOVA. MH, APOE4 status, age, sex, and conversion to AD were included as between-subject factors.

RESULTS: Among 397 participants with MCI, 270 (68%) remained clinically stable and 127 (32%) converted to AD during follow-up. APOE4 positivity was more frequent among converters. BMI declined over time, with a steeper reduction observed in individuals who converted to AD and in those with MH. MH was associated with differential longitudinal cognitive trajectories, characterized by subtle non-linear changes in memory performance and relative preservation of executive function. Changes in BMI showed modest associations with memory and executive function trajectories.

CONCLUSIONS: MH is associated with distinctive longitudinal patterns of anthropometric-metabolic and cognitive change in individuals with MCI. Incorporating maternal history may help refine phenotypic characterization in prodromal AD, supporting a more nuanced understanding of disease heterogeneity in the prodromal stages.},
}

@article {pmid42245791,
year = {2026},
author = {Nepal, P and Bashit, AA and Stewart, TC and Oakley, DH and Theodore, JZ and Hyman, BT and Makowski, L},
title = {Scanning X-ray microdiffraction studies of protein accumulation and tissue loss in thin sections of human brain tissue in Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9679677/v1},
pmid = {42245791},
issn = {2693-5015},
abstract = {Neurodegeneration in Alzheimer's disease is characterized by accumulation of pathological protein deposits including Aβ plaques, tau tangles and diffuse neuropil threads accompanied by wide-spread tissue loss. While dense protein deposits are readily observed by conventional methods, histology struggles to properly capture microscopic evidence of absences corresponding to tissue loss. This study demonstrates the use of scanning X-ray microdiffraction to quantitatively evaluate both protein accumulation and tissue loss in thin sections of human brain tissue across anatomical regions and stages of disease. We show that scanning small-angle microdiffraction can quantify the material properties of tissue through mapping the presence of sub-micron-sized "scattering voids", imaging a tissue attribute that is typically invisible and providing an alternative metric for tissue integrity. Correlation of x-ray data with images of silver-stained sections provided quantitative assessment of protein accumulation readily observed in densely stained features. Regions containing large and abundant scattering voids proved to be highly fragile and closely correspond to locations that were damaged during subsequent tissue processing. This work demonstrates the use of scanning microdiffraction for mapping the abundance of these voids in tissue, providing a detailed description of a phenomena that is typically invisible to histology and utilizing it to study tissue structure across multiple brain regions in diseased human tissue.},
}

@article {pmid42245798,
year = {2026},
author = {Ding, W and Si, C and Wang, L and Qiu, M and Xu, Z and Xu, L and Bao, R and Tang, X and Gong, J and Wu, J and Shao, Z and Zhang, T and Yang, F},
title = {Cholinergic Basal Forebrain Atrophy Accelerates Cognitive Decline via Cortical Thinning: The Moderating Role of Amyloid-β Pathology in Preclinical Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-6220536/v1},
pmid = {42245798},
issn = {2693-5015},
abstract = {Degeneration of the cholinergic basal forebrain (cBF) is a hallmark of early neurodegeneration in Alzheimer's disease (AD). While cBF atrophy has been linked to cognitive decline, the extent to which cortical thinning mediates this association, particularly in preclinical AD, remains unclear. Furthermore, the influence of amyloid-β (Aβ) pathology on these relationships warrants further investigation. This study analyzed longitudinal MRI and PIB-PET data from 230 cognitively normal older adults in the Harvard Aging Brain Study, with a mean follow-up of six years. FreeSurfer was used to quantify cBF volume and cortical thickness, while cognitive performance was assessed using the Preclinical Alzheimer Cognitive Composite-5 (PACC5). Linear mixed-effects models evaluated longitudinal associations between cBF atrophy, cortical thinning, and cognitive decline. Mediation analyses assessed whether cortical thinning mediated the relationship between cBF degeneration and cognitive decline, and the moderating effect of Aβ burden was examined. Progressive cortical thinning in multiple cognition-related regions was significantly associated with longitudinal cBF atrophy. Mediation analysis revealed that cortical thinning accounted for approximately 44% of the association between cBF degeneration and cognitive decline. These effects were more pronounced in Aβ-positive individuals, suggesting a synergistic interaction between amyloid pathology and cholinergic degeneration. These findings indicate that cBF atrophy accelerates cognitive decline by driving cortical thinning, with Aβ pathology further exacerbating these effects. This study enhances understanding of the structural mechanisms underlying cognitive decline in preclinical AD and highlights potential early intervention targets.},
}

@article {pmid42245826,
year = {2026},
author = {Gayathri, KB and Roy, S and Jyothish, K},
title = {Entropy estimation in acetylcholinesterase-donepezil interaction through topological indices: a graph theoretical perspective.},
journal = {Frontiers in chemistry},
volume = {14},
number = {},
pages = {1794525},
pmid = {42245826},
issn = {2296-2646},
abstract = {In this work, we investigate the molecular interaction between acetylcholinesterase (AChE) and the Alzheimer's medication donepezil using a graph-theoretical approach. We have presented the molecular graphs of AChE, donepezil, and their docked complex and calculated a set of degree-based topological indices, along with their respective Shannon entropy values. The entropy values measure the structural complexity and information content integral to each molecular graph. The study indicated a uniform growth of entropy for all indices in the docked complex over the unbound protein and ligand, signifying an enhancement in its topological disorder and edge-type variability with binding. It is interesting to see that indices such as the First Zagreb Index, Atom-Bond Connectivity Index, and Randić Index were successful in capturing this trend. This entropy-based assessment offers a solid and computationally efficient method for defining biomolecular interactions and providing insights into binding-induced structural reorganization. The results emphasize the value of topological entropy as a predictive tool for drug-target interaction profiling and structure-based drug design. Thus, the present study offers a computational approach to comprehend and forecast the energetics of a particular protein-ligand binding, which is a crucial objective in drug development and biophysical chemistry.},
}

@article {pmid42245911,
year = {2026},
author = {Yao, W and Wise, BL and Lin, YY and Fan, M and Xu, S and Ju, IS and Berg, JI and Silverman, JL and Loots, GG and Christiansen, BA},
title = {Brain and knee joint degeneration following anterior cruciate ligament injury in a mouse model of Alzheimer's disease.},
journal = {JBMR plus},
volume = {10},
number = {7},
pages = {ziag085},
pmid = {42245911},
issn = {2473-4039},
abstract = {Alzheimer's disease (AD) and osteoarthritis (OA) are 2 of the most common health conditions affecting the elderly. Recent studies in mice and humans have described an association between OA and AD, with prevalent OA increasing the risk of developing AD-like cognitive declines. In this study, we investigated brain and knee joint degeneration and neurocognitive dysfunction in a mouse model of AD (APP/PS1 double transgenic mice) in the presence or absence of OA induced by non-invasive ACL rupture. We hypothesized that OA would be associated with increased beta amyloid (Aβ) and phosphorylated tau (pTau) in the injured joint and brain and would be associated with accelerated cognitive decline in APP/PS1-Tg mice. Non-invasive knee injury was performed at 7 mo of age in male and female APP/PS1-Tg mice and non-transgenic (WT) littermates. Neurocognitive tests, including open field, novel object recognition, and Morris water maze, were performed 6 wk post-injury. Knees were also assessed at 6 wk post-injury to quantify OA, and Aβ, Tau, and pTau levels in the brain and knee joints. We found that female APP/PS1-OA mice had significantly more osteophyte formation than WT-OA mice, and significantly greater Aβ and pTau levels in the brain and knee joints than in WT or APP/PS1-Sham mice. These results provide insights about the pathoetiology of AD and OA and suggest possible common mechanisms connecting OA-associated inflammation to cognitive function. Identifying novel mechanisms of crosstalk between these 2 conditions could improve clinical care and quality of life for at-risk patient populations.},
}

@article {pmid42246108,
year = {2026},
author = {Ye, C and Deng, Z and Cong, S and Ran, C and Gong, T and Huang, S and Ma, T},
title = {Energy-Based Phase-Locking State Analysis in Brain State Identification.},
journal = {Human brain mapping},
volume = {47},
number = {8},
pages = {e70558},
doi = {10.1002/hbm.70558},
pmid = {42246108},
issn = {1097-0193},
support = {GuikeAD23026245//Guangxi Science and Technology Base and Special Talent Program/ ; 62106113//National Natural Science Foundation of P.R. China/ ; 62276081//National Natural Science Foundation of P.R. China/ ; 62466006//National Natural Science Foundation of P.R. China/ ; 2023A1515010792//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023B1515120065//Basic and Applied Basic Research Foundation of Guangdong Province/ ; GXWD20231129121139001//Shenzhen Science and Technology Program/ ; JCYJ20240813110522029//Shenzhen Science and Technology Program/ ; CJGJZD20230724093959002//Shenzhen Science and Technology Program/ ; },
abstract = {The human brain exhibits inherent multistability, with Energy Landscape Analysis (ELA) providing effective frameworks for investigating this property through BOLD signals. However, traditional amplitude-based approaches fundamentally neglect critical phase synchronization dynamics that mediate large-scale neural coordination, while existing phase-based methods like Leading Eigenvector Dynamic Analysis (LEiDA) lack thermodynamic formalism for state stability quantification. Here, we introduce Energy-based Phase-Locking State Analysis (EPLSA), a transformative computational framework that synergistically integrates instantaneous phase-coupling dynamics with rigorous energy landscape principles, addressing fundamental limitations of conventional methodologies. Comprehensive validation across two independent neuroimaging datasets (HCP and Natural Sleep) demonstrated EPLSA's marked superiority over LEiDA and conventional ELA in terms of test-retest reliability, task-specific brain state differentiation, and individual-level classification performance. To demonstrate the physiological and clinical utility of the proposed method, sleep-wake analysis was performed to reveal EPLSA's enhanced sensitivity to consciousness state transitions, identifying decreased primary state occupancy and increased minor state prevalence during sleep, with significantly reduced direct transition probabilities. Furthermore, application to patients with Alzheimer's disease using the OASIS-3 dataset identified shortened dwell time and occurrence frequency for the frontoparietal control network-default mode network (FPCN-DMN) co-activation state, and prolonged dwell time and occurrence frequency for the visual network-limbic network (VIS-LMN) co-activation state, with these metrics significantly correlating with cognitive impairment. By unifying phase-coupling and thermodynamic principles, EPLSA provides novel insights into neurodynamic mechanisms across cognitive tasks, consciousness states, and neurodegenerative conditions, offering a transformative analytical tool for investigating brain function in health and disease with particular promise for early detection and monitoring of neurological disorders.},
}

@article {pmid42246176,
year = {2026},
author = {Ramos de Jesús, C and Sabri, S and Sun, J},
title = {Capturing Early Aggregation Transitions of Disordered Tau by Covalent Footprinting Mass Spectrometry.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.6c00046},
pmid = {42246176},
issn = {1520-6882},
abstract = {Tau aggregation into β-sheet-rich fibrils is a defining pathological feature of Alzheimer's disease, yet the early conformational transitions that accompany tau aggregation, which are critical for understanding aggregation mechanisms and therapeutic intervention, remain poorly resolved due to the lack of a well-suited technique for this large intrinsically disordered protein (IDP). Here, for the first time, we captured dynamic conformational changes across full-length human tau 2N4R (441 residues) present as a heterogeneous mixture of post-translationally modified forms during a 72 h aggregation by diethyl pyrocarbonate (DEPC) covalent footprinting. Recombinant expression of fresh full-length human tau 2N4R, combined with optimized DEPC footprinting and complementary proteolytic digestion, enabled near-complete (93%) sequence coverage. Peptide-level kinetics revealed domain-specific behaviors, with the microtubule-binding domain (MTBD) exhibiting the most pronounced structural transitions. Residue-level analysis mapped these changes onto the fibril core, identifying early protection of residues from β4-β6 as an early nucleation event and progressive incorporation of adjacent MTBD strands during fibril maturation. In contrast, the N-terminal, proline-rich domain (PRD), and C-terminal region remained largely solvent-exposed throughout. Together, these results demonstrate that mass spectrometry-based covalent footprinting enables direct observation of early, dynamic conformational transitions in tau, complementing structural techniques that predominantly resolve mature aggregated states.},
}

@article {pmid42246690,
year = {2026},
author = {Totuk, O},
title = {CHMP2B p.Ala30Ser Variant in Biomarker-Confirmed Early-Onset Alzheimer Disease: A Potential Endolysosomal Disease Modifier.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000737},
pmid = {42246690},
issn = {1546-4156},
abstract = {Endolysosomal dysfunction has been increasingly implicated in the pathogenesis of neurodegenerative diseases. The charged multivesicular body protein 2B (CHMP2B) gene encodes a component of the endosomal sorting complexes required for transport (ESCRT-III), which regulates endosomal trafficking, multivesicular body formation, and autophagosome-lysosome fusion. Mutations in CHMP2B are classically associated with autosomal dominant frontotemporal dementia. Here, we report a 59-year-old woman with biomarker-confirmed Alzheimer disease (AD) (A+T+N+) carrying a heterozygous CHMP2B c.90C>T (p.Ala30Ser) variant identified by targeted exome sequencing after negative testing for APP, APOE, PSEN1, and PSEN2. The patient presented with progressive episodic memory impairment and spatial disorientation over 3 years. Brain MRI showed prominent posterior cortical atrophy, and cerebrospinal fluid biomarkers demonstrated decreased Aβ42 and elevated phosphorylated and total tau levels consistent with AD pathology. Dysfunction of CHMP2B-mediated endolysosomal pathways may impair intracellular protein degradation and influence tau clearance mechanisms. This observation suggests that rare variants in endolysosomal pathway genes may contribute to AD pathophysiology.},
}

@article {pmid42246933,
year = {2026},
author = {Wu, J and Tang, F and Lv, X and Wang, Y and Gao, F and Shen, Y and Cheng, Z and Shi, J},
title = {Multimodal Integration of Gait Dysfunction, Amyloid PET, and Plasma Biomarkers for Differentiating Etiological Subtypes in Mild Cognitive Impairment.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {6},
pages = {e70949},
doi = {10.1002/cns.70949},
pmid = {42246933},
issn = {1755-5949},
support = {XDB39000000//the Strategic Priority Research Program of the Chinese Academy of Sciences/ ; 202304295107020056//Anhui Provincial Key R&D Programs/ ; YD9100002033//Fundamental Research Funds for the Central Universities/ ; 2023AH053410//Natural Science Research Projects in Anhui Province Universities/ ; 202304295107020051//Anhui Provincial Clinical Medical Research and Translation Special Fund/ ; 2308085QH265//Natural Science Foundation of Anhui Province/ ; },
abstract = {OBJECTIVE: To investigate gait characteristics and plasma biomarkers in individuals with mild cognitive impairment (MCI) stratified by amyloid-β (Aβ) positivity on positron emission tomography (PET), and to evaluate the predictive value for Alzheimer's disease (AD)-related MCI.

METHODS: A total of 168 participants were enrolled, including 50 amyloid PET-negative MCI (MCI-), 51 amyloid PET-positive MCI (MCI+), and 61 cognitively normal (CN) individuals. Gait assessments were conducted using a multi-sensor motion analysis system during dual-task paradigms (cognitive load superimposed on locomotion). Plasma samples were analyzed for neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau at threonine 217 (p-tau217) via ultra-sensitive immunoassays.

RESULTS: Gait analyses identified 125 features, with 69 distinguishing MCI+ from CN and 36 differentiating MCI+ from MCI-. Receiver operating characteristic (ROC) analyses showed that dual-task gait under the countdown and animal-naming conditions (gait-countdown [GCD] and gait-animal naming [GAN]) discriminated MCI+ from CN with an AUC of 0.850. The combined models integrating GCD and GAN with plasma GFAP or p-tau217 yielded AUCs of 0.919 and 0.951, respectively. Similarly, GCD&GAN features demonstrated an AUC of 0.862 for distinguishing MCI+ from MCI-, with GFAP (AUC = 0.933) and p-tau217 (AUC = 0.986) enhancing predictive performance.

CONCLUSION: This study provides evidence that dual-task gait assessments, when combined with plasma biomarkers such as GFAP and p-tau217, may improve the discriminatory power for identifying AD-related MCI. The integration of biomechanical and molecular markers holds promise for advancing early detection strategies and therapeutic monitoring in AD.},
}

@article {pmid42246940,
year = {2026},
author = {Beaumont, S and Singh, T and Soares, LC and Salman, MM},
title = {Experimental models of cerebral small vessel disease: Physiological constraints, translational challenges and future directions.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP290165},
pmid = {42246940},
issn = {1469-7793},
support = {MR/W027119/1//Medical Research Council Career Development Award/ ; //British Heart Foundation (BHF)/ ; UK DRI-8203//UK Dementia Research Institute/ ; //UK DRI Ltd/ ; /MRC_/Medical Research Council/United Kingdom ; //BHF Centre of Research Excellence/ ; RE/24/130024//University of Oxford/ ; },
abstract = {Cerebral small vessel disease (cSVD) is a chronic, progressive cerebrovascular disorder and the second most common cause of dementia after Alzheimer's disease. It accounts for approximately 20% of strokes, including a quarter of ischaemic strokes and nearly half of vascular dementias, representing a growing clinical and socio-economic burden in ageing populations. Despite its prevalence, mechanistic understanding remains limited and disease-modifying therapies are lacking. A major obstacle is the difficulty of interrogating disease progression in vivo, as the small calibre and deep location of affected vessels restrict assessment. Experimental modelling has therefore been central to advancing cSVD research. Rodent models have provided insight into vascular dysfunction, white matter injury and blood-brain barrier (BBB) impairment, but differ from humans in cerebrovascular anatomy, cellular composition and disease trajectory. Emerging in vitro approaches, including three-dimensional cultures and microfluidic systems incorporating human vascular cells, offer improved experimental control and translational relevance, yet struggle to capture the slow progression of cSVD and its comorbidities such as hypertension and ageing. Most models therefore isolate pathological features rather than reproducing the integrated physiology of disease. In this review, we critically evaluate current in vivo, in vitro and in silico models of cSVD, highlighting their strengths and limitations. We identify the glymphatic system and brain clearance as underexplored but potentially unifying pathways linking vascular dysfunction, perivascular-space enlargement and impaired fluid clearance. Incorporating glymphatic elements into advanced models may address key mechanistic gaps. Improving physiological fidelity in cSVD modelling will be essential for robust target identification and development of effective therapies.},
}

@article {pmid42247062,
year = {2026},
author = {Dopke, P and Lehrner, J},
title = {Subjective and objective olfactory dysfunction and its screening value in patients with subjective cognitive decline, mild cognitive impairment, and Alzheimer's dementia.},
journal = {Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater},
volume = {},
number = {},
pages = {},
pmid = {42247062},
issn = {2194-1327},
abstract = {BACKGROUND: Due to an ageing population and increased life expectancy, Alzheimer's dementia (AD) is becoming increasingly important. Since AD is characteristically preceded by subjective cognitive decline (SCD) and mild cognitive impairment (MCI), innovative diagnostic tools and therapeutics are essential for diagnosis at an early stage. Olfactory dysfunction is commonly associated with cognitive decline, indicating its potential as a diagnostic marker.

OBJECTIVE: This study examined the association between olfactory function, evaluated with the Sniffin' Sticks Odor Identification Test (SS-OIT), and Assessment of Self-Reported Olfactory Functioning (ASOF) inventory across five cognitive subgroups (healthy controls [HC], SCD, non-amnestic MCI, amnestic MCI, and AD). Furthermore, this study investigated the utility of olfactory testing in screening for AD.

METHODS: This retrospective, single-center cross-sectional study was conducted at the Neurology Department of the Medical University of Vienna. The study included 958 participants during the period 2000-2023. Cognitive and olfactory functions were assessed using standardized neuropsychological and olfactory tools. Statistical analyses included descriptive measures, analysis of variance (ANOVA), model testing, and the receiver operating characteristic (ROC) methodology.

RESULTS: Olfactory performance declined with increasing cognitive impairment, with the strongest contrast showing an effect size of r = 0.51 between HC and AD. The SS-OIT (area under the ROC curve [AUC]: 75.3%) and Olfactory-Related Quality of Life subscale (ORQ; AUC: 64.8%) were identified as the most effective in distinguishing AD, with the following recommended cut-offs: SS-OIT ≤ 9; Subjective Olfactory Capability (SOC) ≤ 6; Self-Reported Capability of Perceiving Specific Odors (SRP) ≤ 4.10; and ORQ ≤ 3.67.

CONCLUSION: Olfactory functioning shows moderate reliability in distinguishing subgroups; nevertheless, the proposed cut-off values may be suitable for AD screening. Further studies are recommended to confirm our findings.},
}

@article {pmid42247187,
year = {2026},
author = {You, J and Yang, J},
title = {The bidirectional mechanistic links between Alzheimer's disease and cardiovascular disease.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {7},
pages = {},
pmid = {42247187},
issn = {1590-3478},
abstract = {BACKGROUND: Alzheimer's disease (AD) and cardiovascular disease (CVD) are two significant chronic diseases that have a profound impact on the health of the elderly globally. In recent years, an increasing body of research has suggested a potentially intimate association between the two. This review aims to comprehensively summarize the bidirectional pathological mechanisms between AD and CVD and explore their implications for clinical intervention and comorbidity management.

METHODS: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. English-language literature published between 1985 and 2025 was searched in the databases of Pubmed, Web of Science, Google Scholar, Embase, and Scopus. A total of 4,434 articles were initially identified, and 4,293 studies that did not meet the inclusion criteria were excluded. Eventually, 149 eligible articles were subjected to mechanism integration and a narrative review.

RESULTS: This review elucidates that ischemia-hypoxia, lipid metabolism disorders, systemic inflammatory responses, and blood-brain barrier dysfunction caused by chronic cerebral hypoperfusion constitute the four core pathways through which CVD promotes the incidence and exacerbation of AD. Conversely, mechanisms such as autonomic nervous system dysfunction, spillover of central inflammation to the periphery, adverse lifestyle changes, and cardiovascular side effects of therapeutic drugs are the main reasons why AD increases the risk of CVD.

CONCLUSION: The findings of this review suggest that AD is not merely a central nervous system disorder but also has a close bidirectional association with CVD through multiple mechanisms. Therefore, a thorough understanding of this "cardio-cerebral axis" mechanism is conducive to identifying early risks in the comorbid population, expanding intervention targets, and facilitating the translation and application of combined management strategies for AD and CVD in clinical practice.},
}

@article {pmid42247230,
year = {2026},
author = {Bojarski, LG and Jicha, GA and Coskun, EP and Schmitt, FA and Van Eldik, L and Abner, EL},
title = {Frontal Release Signs and Future Decline in Research Participants With Intact Cognition.},
journal = {JAMA network open},
volume = {9},
number = {6},
pages = {e2617060},
doi = {10.1001/jamanetworkopen.2026.17060},
pmid = {42247230},
issn = {2574-3805},
abstract = {IMPORTANCE: Frontal release signs (FRS) are primitive reflexes that regress with brain maturation and reappear in the setting of brain injury or neurodegeneration. Despite their association with dementia, the prognostic utility of this finding in the setting of early cognitive decline and preclinical disease is poorly understood.

OBJECTIVE: To evaluate the association of FRS with future cognitive decline in research participants.

This cohort study examined the presence of FRS (from 2005-2024) among research cohort participants with intact cognition or mild impairment at study baseline. The study used single-center data collection of longitudinal research cohort data through the Uniform Data Set at the University of Kentucky Alzheimer Disease Research Center (UK ADRC). Participants aged 70 years or older at first assessment were identified at baseline enrollment as having intact cognition or mild impairment based on consensus report and had at least 2 total annual assessments that included standard protocols involving assessment of FRS on neurological exam from the UK ADRC.

EXPOSURE: Participants were noted to be FRS positive or FRS negative.

MAIN OUTCOMES AND MEASURES: The main outcome of interest was incident dementia based on annual consensus diagnosis. Cause-specific hazard models were used to estimate the risk of transition to dementia when at least 2 FRS were present (FRS positive) at baseline vs when 0 or 1 FRS were present (FRS negative), and linear mixed models were used to investigate the association of baseline FRS positivity with cognitive performance over time.

RESULTS: A total of 873 participants (mean [SD] age, 76.9 [5.6] years; 527 female [60.4%]) were included, with a mean (SD) of 16.1 (2.8) years of education. The prevalence of FRS positivity at baseline was 59 of 672 participants (8.8%) with intact cognition and 48 of 201 participants (23.9%) with mild impairment. FRS positivity was associated with an increased risk of dementia for participants who were cognitively intact; in this group, 15 of 59 participants who were FRS positive (25.4%) progressed to dementia compared with 89 of 613 participants (14.5%) who were FRS negative (hazard ratio, 1.78; 95% CI, 1.02-3.09).

CONCLUSIONS AND RELEVANCE: This study's findings suggest that FRS may be a quick, noninvasive, and low-cost adjunct to neurological examination with prognostic utility in the earliest stages of cognitive decline.},
}

@article {pmid42247407,
year = {2026},
author = {Caute, A and Mirza, L and Mackintosh, B and Scherer, R and Joffe, V},
title = {Uses of assistive technology incorporating smart camera features in the rehabilitation of people living with disabilities: a scoping review.},
journal = {Disability and rehabilitation. Assistive technology},
volume = {},
number = {},
pages = {1-24},
doi = {10.1080/17483107.2026.2678548},
pmid = {42247407},
issn = {1748-3115},
abstract = {PURPOSE: The objective of this scoping review was to explore the use of assistive technology incorporating smart camera features in the rehabilitation of people living with disabilities.

MATERIALS AND METHODS: This review was conducted in accordance with the Joanna Briggs Institute methodology for scoping reviews. Articles were eligible if they considered assistive technology that incorporated at least one smart camera feature. Rehabilitation in any setting was considered. Research including participants of any age with any form of disability, both self-reported and diagnosed, was considered.

RESULTS: 25 studies were included in the final synthesis. Most studies investigated assistive technology for visual impairment (n = 23). The most explored devices were smartphones (n = 16) and/or smart glasses (n = 13). Most studies focused on text-to-speech (n = 22) and/or object recognition features (n = 15). One study focused on facial recognition for people with Alzheimer's disease and one on reading for children with dyslexia.

CONCLUSIONS: Assistive technology incorporating smart camera features has been used mainly in the rehabilitation of people living with visual disabilities. Reported rehabilitative outcomes included enhanced reading ability and improved daily living skills. However, there were technical limitations, usability issues and high financial costs associated with various devices.},
}

@article {pmid42247667,
year = {2026},
author = {Yu, J and Chen, Y and Bai, J and Zeng, J and Zhao, J and Fan, Y},
title = {Application of Focused Ultrasound in Alzheimer's Disease: A Bibliometric Analysis.},
journal = {The Journal of craniofacial surgery},
volume = {},
number = {},
pages = {},
pmid = {42247667},
issn = {1536-3732},
abstract = {OBJECTIVE: This study uses bibliometric analysis and knowledge mapping methods to systematically explore the emerging research frontiers and development trajectories of focused ultrasound (FUS) technology in the treatment of Alzheimer's disease (AD), and provides new clues and research directions for future research by exploring hotspots and new topics.

METHODS: A comprehensive literature search was conducted through the Science Citation Index Expanded Core Collection (WoSCC) database to identify relevant articles and reviews published between January 2014 and 2025 on the application of FUS technology in AD. For data analysis and visualization, we used VOSviewer software, CiteSpace, and the R package "bibliometrix" to conduct rigorous bibliometric analysis and build knowledge domain maps.

RESULTS: A total of 1531 papers involving 9220 contributors were identified between 2014 and 2025. The field demonstrated consistent growth (R2=0.9272), peaking in 2025 with 225 publications. China led in total output (475 papers), while the United States achieved the highest academic impact (12,965 citations, H-index: 56). The Chinese Academy of Sciences was the most prolific institution, whereas Harvard Medical School recorded the highest citation impact. The Journal of Alzheimer's Disease and Scientific Reports emerged as the leading publication venues, while Theranostics and Alzheimer's & Dementia provided high-prestige platforms. Tianfu Wang and Baiying Lei were the most productive authors, though Isabelle Aubert garnered the highest total citations. International collaboration analysis revealed a robust, multi-centric network anchored by the USA, China, Canada, and Italy. Co-citation analysis identified Leinenga G (2015) as the foundational study for ultrasound-mediated amyloid-beta clearance. Lipsman N (2018) marked a critical clinical inflection point, exhibiting a strong citation burst (17.3) that catalyzed a shift from preclinical models to human safety trials. Recent bursts extending into 2025 focus on multicenter clinical validation and long-term efficacy. Keywords analysis confirms that non-invasive blood-brain barrier (BBB) opening via microbubble-enhanced focused ultrasound (FUS) is the central research paradigm. Emerging frontiers have shifted from basic technical validation toward neuroinflammation, oxidative stress, tau pathology, and deep-learning-assisted diagnostics, reflecting an evolving focus on molecular mechanisms and precision neurosurgery.

CONCLUSIONS: Focused ultrasound technology has made significant progress in the field of Alzheimer's disease research and has become a research frontier with considerable therapeutic potential. With ongoing technological progress, the clinical translation of FUS is expected to bring new breakthroughs in AD treatment.},
}

@article {pmid42247782,
year = {2026},
author = {Kumar, S and Kumar, N and Krishnamurthy, S and Modi, G},
title = {Design, synthesis, and biological evaluation of novel multifunctional caffeic acid-piperazine derivatives for the management of Alzheimer's disease.},
journal = {Bioorganic & medicinal chemistry},
volume = {140},
number = {},
pages = {118704},
doi = {10.1016/j.bmc.2026.118704},
pmid = {42247782},
issn = {1464-3391},
abstract = {Alzheimer's disease (AD), the most prevalent form of dementia, is marked by progressive memory impairment, cognitive decline, reduced acetylcholine level, oxidative stress, amyloid-β (Aβ) aggregation, and disturbances in metal homeostasis. Our earlier work on caffeic acid-based multifunctional inhibitors prompted us to explore structure-activity relationships (SARs) to improve BChE cholinesterase inhibition while maintaining or enhancing the multifunctional activity of the previously identified lead molecule 12d. For this purpose, the glycinamide linker was rationally replaced with benzylpiperazine and glycinamide-piperazine, yielding six new series of derivatives. Comprehensive SAR analysis identified 7b as the most promising molecule, displaying markedly enhanced potency compared to caffeic acid and our earlier analog EJMC-12d. 7b exhibited approximate 3.6-fold improvement in BChE inhibition compared to EJMC-12d. While AChE inhibition of 7b was found to be comparable to EJMC-12d. The enzyme kinetic studies showed a mixed-type inhibitory mechanism for 7b at both AChE and BChE. Molecular docking studies also confirmed that 7b binds to the CAS and PAS sites of AChE. The DPPH assay on synthesized derivatives revealed strong antioxidant properties of 7b (IC50 = 4.89 ± 0.72 μM) compared to EJMC-12d (IC50 = 6.32 ± 0.15 μM).7b also showed efficient metal-chelating properties. 7b exhibited potent inhibitory activity against Aβ1-42 aggregation, as confirmed by the ThT fluorescence assay and validated by fluorescence microscopy. The PAMPA-BBB permeability assessment showed that 7b (Pe = 3.96 ± 0.38) can cross the blood-brain barrier. Cell viability studies with 7b in SH-SY5Y cells demonstrated cytocompatibility at higher doses. The neuroprotection studies against H2O2 and ROS generation confirmed that 7b exhibits strong antioxidant activity and a neuroprotective effect against oxidative stress. 7b was found to be safe in the acute toxicity studies at a higher dose of 500 mg/kg. In the in vivo Aβ-induced stereotaxic mouse model, 7b significantly restored spatial working memory. The overall findings highlighted 7b as a promising, efficacious, multifunctional candidate with significant therapeutic potential for AD. Despite this, there is scope for structural modifications in 7b to further improve the multifunctional properties. Overall, this scaffold demonstrates strong potential and can be further explored as a promising therapeutic candidate for AD management.},
}

@article {pmid42247843,
year = {2026},
author = {Chong, JR and Hilal, S and Venketasubramanian, N and Schöll, M and Ashton, NJ and Zetterberg, H and Chen, CP and Lai, MKP},
title = {Plasma brain-derived p-Tau217 outperforms other p-Tau species in detecting abnormal brain amyloid in an Asian cohort of older people with cerebrovascular disease burden.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100615},
doi = {10.1016/j.tjpad.2026.100615},
pmid = {42247843},
issn = {2426-0266},
abstract = {BACKGROUND: Plasma brain derived-p-Tau217 (BD-p-Tau217) may outperform total-p-Tau217 in detecting brain amyloid burden and warrants evaluation.

OBJECTIVES: To perform head-to-head comparison of plasma BD- as well as total-p-Tau181, p-Tau217 and p-Tau231 for detecting beta-amyloid positivity (Aβ+), evaluate reference ranges for Aβ+, and assess the prognostic utility of BD-p-Tau217 reference ranges.

DESIGN: Observational study.

SETTING: Participants recruited from memory clinics and the community in Singapore.

PARTICIPANTS: 213 participants, including 44 cognitively normal, 107 cognitively impaired no dementia, and 62 dementia (mean [SD] age, 73 [1] years; 121 females).

MEASUREMENTS: Amyloid status (Aβ- [n = 139] vs Aβ+ [n = 74]) was determined by positron emission tomography (PET). Plasma BD-p-Tau and total-p-Tau were measured using the NULISAseq™ CNS Disease Panel 120. The diagnostic performance for detecting Aβ+, reference ranges (three-range: 95% specificity/95% sensitivity); binary: maximizing Youden index), and the prognostic performance of p-Tau biomarkers were evaluated.

RESULTS: Plasma BD-p-Tau217 (AUC = 0.965) outperformed other BD- and total-p-Tau species in detecting PET Aβ+ (AUC = 0.823-0.937; all p ≤ 0.008). Using a three-range reference, BD-p-Tau217 achieved positive predictive value (PPV) and negative predictive value (NPV) of 90% and 97%, respectively. Proportion of participants in the intermediate-risk group was 7% (n = 14). Applying a binary reference, BD-p-Tau217 achieved both a specificity and sensitivity of 92%, with PPV and NPV of 86% and 96%, respectively. BD-p-Tau217-derived high-risk group exhibited faster cognitive decline than the low-risk group.

CONCLUSIONS: Risk stratification for PET Aβ+ based on plasma BD-p-Tau217 suggests superior diagnostic and prognostic utility, warranting further validation.},
}

@article {pmid42247844,
year = {2026},
author = {Zhang, C and Chen, X and Sun, Y},
title = {The growing burden of dementia in Asia: Comparative insights from Japan, China, and India.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100614},
doi = {10.1016/j.tjpad.2026.100614},
pmid = {42247844},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease and other dementias (ADODs) are increasingly becoming a major public health concern in rapidly ageing Asia. We compared the disease burden across Japan, China, and India at different demographic stages.

DESIGN: The Global Burden of Disease Study of 2023 was used to analyze the incidence, prevalence, mortality, and disability-adjusted life years (DALYs) in 1990-2023. Decomposition analysis identified drivers of DALYs trends. DALYs associated risk factors were quantified. The Auto-Regressive Integrated Moving Average model was used to predict future disease burden.

RESULTS: In 2023, China had the highest absolute burden, with age-standardized incidence and prevalence rates of 156.63 (95% uncertainty interval [UI]: 136.58-175.49) and 918.83(95% UI: 784.59-1,058.24) per 100,000, respectively. Japan recorded the highest age-standardized mortality rate (31.25 [8.47-71.42] per 100,000). India had the highest annual increase in mortality and DALYs, with estimated annual percentage changes of 0.91 (95% confidence interval [95% CI] 0.80-1.03) and 0.51 (0.45-0.56), respectively. Decomposition analysis revealed distinct drivers: Japan was dominated by epidemiological changes; China was driven by both aging and epidemiological changes; India was mainly due to population growth and epidemiological changes. Ambient particulate matter was the leading risk factor across all countries, though India faced a unique household air pollution burden. DALYs are predicted to increase in all three countries significantly by 2038.

CONCLUSIONS: The ADODs burden remains substantial, driven by distinct demographic and epidemiological factors in Japan, China, and India. Tailored strategies for prevention and management are essential to address the growing burden.},
}

@article {pmid42235756,
year = {2026},
author = {Shashwat, P and Kirthi, AV and Selvaraj, M and Karnwal, A and Dutta, J},
title = {Phytochemical Engineered Quantum Dots as Potential Therapy to Counter Alpha Synuclein aggregation in Parkinson's disease.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106194},
doi = {10.1016/j.neuint.2026.106194},
pmid = {42235756},
issn = {1872-9754},
abstract = {Parkinson's disease (PD) is a prevalent neurodegenerative disorder that critically impairs human health and presently lacks effective cellular-level therapeutic interventions. The disease is primarily characterized by pathological aggregation of misfolded α-synuclein in presynaptic neurons, leading to dopaminergic neuronal loss. The limited efficacy of current pharmacological treatments stems largely from challenges in crossing the blood-brain barrier. Recent studies suggest that nano-phytomedicine approaches offer promising alternatives for PD management. Specifically, phytochemical-engineered carbon quantum dots (CQDs) show potential to modulate key pathological processes, including α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, and neuronal degeneration. Evidence from related neurodegenerative models, such as Alzheimer's disease, reveals that multifunctional CQDs can scavenge reactive oxygen species, influence protein aggregation, and mitigate neurotoxicity. The synergistic integration of bioactive phytochemicals into CQDs could enhance drug bioavailability, pharmacokinetic properties, and cellular repair mechanisms while reducing toxicity. This review discusses the design strategies, therapeutic mechanisms, and biological interactions of phytochemical-engineered CQDs, emphasizing their potential as next-generation nanocarriers and intrinsic neurotherapeutic agents for PD treatment.},
}

@article {pmid42235884,
year = {2026},
author = {Jonany, V and Haslacher, D and Robinson, S and Sander, T and Zerfowski, J and Peekhaus, N and Krüger, P and Soekadar, SR},
title = {Single-trial assessment of gamma-frequency brain oscillations and their modulation using transcranial alternating current stimulation (tACS).},
journal = {Brain stimulation},
volume = {},
number = {},
pages = {103139},
doi = {10.1016/j.brs.2026.103139},
pmid = {42235884},
issn = {1876-4754},
abstract = {INTRODUCTION: Gamma-band oscillations (30-200 Hz) support cognitive functions such as memory, perception, and decision-making, which are often impaired in neuropsychiatric disorders including schizophrenia, Alzheimer's disease, and Parkinson's disease. These disorders show distinct gamma abnormalities that are promising targets for transcranial alternating current stimulation (tACS). However, phase-specific adaptation of stimulation to ongoing gamma activity has long been considered unfeasible due to the low signal-to-noise ratio (SNR) of non-invasive recordings and stimulation-related artifacts. Recent advances in quantum sensing now offer improved SNR, enabling phase-locked modulation of gamma oscillations.

METHODS: We tested whether gamma-frequency brain oscillations can be assessed at the single-trial level and modulated by amplitude-modulated tACS (AM-tACS) in a phase-specific manner. Using 16 optically pumped magnetometers (OPMs), we recorded 40 Hz auditory steady-state responses (ASSRs) in 19 participants during AM-tACS applied over the temporal lobe at randomly assigned phase lags relative to the ASSR. Participants judged the loudness of auditory stimuli, while occipital stimulation served as a control condition. We hypothesized that AM-tACS would alter ASSR latency, a measure of cortical synchronization, and loudness perception only when targeting the temporal lobe.

RESULTS AND CONCLUSION: AM-tACS modulated both ASSR latency (p < 0.05) and loudness perception (p < 0.05) in a phase-dependent manner during temporal but not occipital stimulation. Physiological and behavioral effects were correlated across participants in modulation strength (r = 0.613, p < 0.01), while an exploratory post-hoc analysis suggested that they are also linked in modulation phase (V = 5.38, p < 0.05). These findings establish the feasibility of single-trial assessment and phase-specific modulation of gamma oscillations, advancing adaptive closed-loop tACS approaches for neuropsychiatric disorders.},
}

@article {pmid42235964,
year = {2026},
author = {Luan, H and Chen, Z and Han, X and Wang, P and Sun, W and Gong, J and Li, S and Li, R and Xu, C and Wen, B and Lv, S and Yan, S and Wei, C},
title = {Neuronal Surface and Intracellular Antibodies in Mild Cognitive Impairment Due to Alzheimer Disease: Preserved Brain Metabolism on [18]F-FDG-PET.},
journal = {AJNR. American journal of neuroradiology},
volume = {47},
number = {6},
pages = {1664-1671},
pmid = {42235964},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Neuronal autoantibodies, which can mediate pathogenic mechanism in autoimmune encephalitis, are increasingly observed in mild cognitive impairment (MCI), yet their diagnostic or phenotypic implications in neurodegeneration remain unclear. This study aimed to evaluate the clinical and neuroimaging characteristics of antibody-positive MCI.

MATERIALS AND METHODS: This cross-sectional study included 97 patients diagnosed with MCI. Antibody was assessed by cell-based assays in both CSF and serum. Clinical features were systematically compared between antibody-positive and antibody-negative groups. Semiquantitative analyses of [18]F-FDG-PET and [11]C-Pittsburgh compound B ([11]C-PIB)-PET were performed among 20 amyloid-positive patients with MCI. All images underwent standardized preprocessing, with standardized uptake value ratios calculated using cerebellar gray matter as reference. Group-wise differences of whole-brain and ROI analyses (frontal, parietal, temporal, occipital lobes) were analyzed.

RESULTS: Neuronal antibodies were detected in 10 patients (10.3%), including anti-GABABR (n=1), anti-SOX-1 (n=3), anti-Ri (n=3), anti-Titin (n=3), and anti-Amphiphysin (n=1). Clinical profiles were highly comparable between groups; antibody-positive patients only demonstrated significantly higher abnormal tumor markers (P = .014). Compared with the antibody-negative group, the antibody-positive group exhibited relatively preserved metabolism on [18]F-FDG-PET (P = .035), predominantly in the right parietal lobe (P = .030). Further subregion analysis identified the right postcentral gyrus and supramarginal gyrus as focal hubs. No significant group differences were observed on [11]C-PIB-PET.

CONCLUSIONS: Antibody-positive MCI showed relatively preserved metabolism on [18]F-FDG-PET, despite indistinguishable clinical features. Identification of the antibody-positive group may provide novel insights into possible antibody-mediated pathogenesis in neurodegeneration.},
}

@article {pmid42236188,
year = {2026},
author = {Inagaki, N and Takei, Y and Kamoshida, J and Shimizu, S and Kosuge, H and Terasawa, M and Kiribayashi, K and Yazaki, Y and Satomi, K and Hayashi, T},
title = {Hypertrophic Cardiomyopathy and Sudden Cardiac Arrest Associated with a PSEN1 Variant: A Case Report.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {},
number = {},
pages = {},
doi = {10.2169/internalmedicine.7239-26},
pmid = {42236188},
issn = {1349-7235},
abstract = {A 46-year-old Japanese man with nonobstructive hypertrophic cardiomyopathy harboring a heterozygous PSEN1 c.367G>A (p.Glu123Lys) variant experienced sudden cardiac arrest due to ventricular fibrillation at 56 years of age. Although PSEN1 variants are primarily associated with early onset Alzheimer's disease, emerging evidence suggests a role in cardiomyopathy that is independent of the amyloid pathology. This case demonstrates a novel cardiac manifestation of presenilin 1 dysfunction. At the time of genetic diagnosis, the patient exhibited normal cognition, suggesting that cardiovascular manifestations may precede neurodegeneration. This report suggests an expansion of the phenotypic spectrum associated with PSEN1 variants and highlights the need for further investigation of potential cardiac manifestations in PSEN1 variant carriers.},
}

@article {pmid42236191,
year = {2026},
author = {Terayama, Y and Ishizuka, N and Maeda, T and Suzuki, N},
title = {Quantitative Assessment of Caregiver Quality of Life Across Dementia Severity Using a Utility-Weighted Scale Based on a Conjoint Analysis.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {},
number = {},
pages = {},
doi = {10.2169/internalmedicine.7345-26},
pmid = {42236191},
issn = {1349-7235},
abstract = {Objective Neurobehavioral symptoms of dementia substantially impair the quality of life (QOL) of caregivers. However, most caregiver burden instruments are ordinal and lack empirically derived symptom-specific weighting, limiting quantitative interpretation. This study aimed to develop a utility-weighted scale to quantitatively assess caregiver QOL impairment across the dementia severity levels. Methods Eleven dementia-related neurobehavioral symptoms were identified through a literature review and interviews with 115 dementia care professionals. Utility weights were estimated using a conjoint analysis based on the rankings of 27 hypothetical dementia profiles. The resulting Caregiver Quality of Life (CgQOL) scale was evaluated for reliability and validated in individuals with Alzheimer's disease using the Zarit Burden Interview (ZBI), Functional Assessment Staging Tool (FAST), and Mini-Mental State Examination (MMSE). Results A conjoint analysis revealed a clear hierarchy of symptom importance, with agitation having the highest relative importance (15.5%), followed by difficulties with toileting (12.1%) and sleep disturbances (11.7%). The total CgQOL scores ranged from 0 to 36.3. The scale demonstrated excellent inter-rater reliability (weighted κ=0.86) and internal consistency (Cronbach's α=0.998). CgQOL scores increased monotonically with advancing FAST stage and were negatively correlated with the MMSE scores. Moderate convergent validity was observed with the ZBI scores, thus indicating that the two instruments captured related but distinct aspects of the caregiver burden. Conclusion The CgQOL scale is a novel parametric utility-weighted instrument that quantitatively captures caregiver QOL impairment associated with dementia-related neurobehavioral symptoms and complements existing caregiver burden measures. This framework enables a more nuanced and quantitative evaluation of caregiver burden and may serve as a complementary tool to conventional scales in both clinical and research settings.},
}

@article {pmid42236229,
year = {2026},
author = {Cruz-Sanchez, A and Appings, R and LaDouceur, K and Inayat, M and Violi, F and Arruda-Carvalho, M},
title = {Ventral and Intermediate Hippocampus are Required for Object-in-Place Recognition Memory in Mice.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0105-26.2026},
pmid = {42236229},
issn = {2373-2822},
abstract = {Many behaviors that are essential for survival, such as retrieving food, finding shelter and locating predator cues, rely on forming effective associations between the identity and location of spatial elements. This identity-location association is commonly assessed in rodents using spontaneous object-in-place (OiP) recognition memory tasks. OiP recognition memory deficits are seen in autism spectrum disorder, schizophrenia, and are used to detect early onset of Alzheimer's disease. These deficits are replicated in animal models of neurodevelopmental, neurodegenerative and chromosomal disorders. The ventral hippocampus has been implicated in object recognition, but its contribution to OiP memory has not been established. Despite the broad adoption of mouse models in behavioral and systems neuroscience research for their ease of genetic manipulations, the neural correlates of OiP memory in mice remain unknown. Here we used chemogenetics to assess the contribution of the ventral and intermediate CA1 (vCA1 and iCA1, respectively) subregions of the hippocampus, as well as the medial prefrontal cortex (mPFC) and iCA1-mPFC projections to OiP memory in male and female C57BL/6J mice. We found that two-object OiP requires the activity of the vCA1 and iCA1, but not the mPFC or iCA1-mPFC connections. Our data identify a requirement for two hippocampal subregions in the successful assessment of OiP recognition memory in mice, expanding our understanding of the neural basis of spatial memory processing.Significance Statement Associations between the identity and location of spatial elements (what-where associations), underlie essential behaviors such as finding food, locating shelter and safely navigating the environment. Deficits in identity-location processing occur in patients with neurodevelopmental and neurodegenerative disorders, and are replicated in rodent models using object-in-place (OiP) recognition tasks. While mice have emerged as a widely used animal model to study the biological mechanisms underlying these disorders, nothing is known about the neural substrates of OiP memory in mice. Here we uncover a novel contribution of the ventral and intermediate hippocampal subregions to OiP performance, deepening our understanding of the neural signatures of spatial memory processing.},
}

@article {pmid42236351,
year = {2026},
author = {Hata, M and Miyazaki, Y and Takahashi, S and Ikeda, M},
title = {Temporal pattern of dementia with lewy bodies diagnostic labels around electroconvulsive therapy: A nationwide claims-based study.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100224},
doi = {10.1016/j.inpsyc.2026.100224},
pmid = {42236351},
issn = {1741-203X},
abstract = {BACKGROUND: Electroconvulsive therapy (ECT) is widely used for severe depression. Dementia with Lewy bodies (DLB) may initially present with depressive symptoms, and ECT may be administered in some patients during the course of the disease. However, the timing of DLB diagnosis in relation to ECT treatment has not been well characterized.

METHODS: We conducted a retrospective cohort study using a nationwide administrative claims database in Japan, including records from 564 acute care hospitals between April 2008 and March 2025. Analyses were restricted to patients with a mood disorder diagnosis (ICD-10 F30-F39) recorded in the same month as the first ECT session, and patients with both DLB and Alzheimer disease (AD) diagnostic codes were excluded. The primary analysis examined the timing of recorded DLB diagnostic labels relative to ECT initiation, with AD diagnoses analyzed as a comparator.

RESULTS: Among 3733 patients who underwent ECT, 71 met the analytic criteria for DLB. The median interval between ECT initiation and the first DLB diagnosis was 8 days prior to ECT initiation. Recorded DLB diagnostic labels occurred significantly more often within ±90 and ±180 days of ECT initiation than AD diagnoses, whereas AD diagnoses were distributed more broadly across the observation period.

CONCLUSION: Recorded DLB diagnostic labels showed a distinct temporal pattern around ECT initiation. Clinical evaluation associated with ECT may facilitate recognition of underlying DLB in patients presenting with severe psychiatric symptoms. Clinicians should remain attentive to evolving DLB when treating late-life treatment-resistant mood disorders with ECT, as recognition of DLB may occur several years after treatment initiation.},
}

@article {pmid42236499,
year = {2026},
author = {Kumar, D and Walhekar, V and Shenoy, KM and Kini, SG},
title = {In silico investigation of thiazole-semicarbazide hybrids as dual GSK-3β/Tau inhibitors for Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-55932-9},
pmid = {42236499},
issn = {2045-2322},
abstract = {AD is a widespread and debilitating neurodegenerative disorder, and existing treatments have demonstrated limited efficacy, emphasizing the need for novel therapeutic strategies. This study focused on the design of drug-like molecules with enhanced efficacy and minimized side effects by application of structure-based scaffold hopping and molecular hybridization strategies. Molecular docking was carried out on Glide module; Molecular dynamics simulation of 500 ns was executed employing Desmond and ADMET prediction was achieved by QikProp modules of Schrödinger. Through molecular docking studies targeting the GSK-3β and Tau enzymes, the compounds DVK5 and DVK11 were identified as promising inhibitors, showing favorable interactions within the active sites of these proteins, with docking energies of - 9.863 and - 8.994 kcal/mol, respectively. Molecular dynamics simulations further revealed that the DVK5 and DVK11 complexes exhibited stable interactions within the active sites of GSK-3β and Tau throughout a 500 ns simulation. Additionally, in silico ADMET analysis demonstrated that DVK10 exhibited an excellent human oral absorption rate of 75.175%, outperforming other compounds in the series. These findings strongly suggest the potential of DVK5 and DVK11 as dual inhibitors of GSK-3β and Tau, offering a basis for future drug development studies for the development of new lead compounds for AD treatment.},
}

@article {pmid42236609,
year = {2026},
author = {张, 宇 and 张, 静 and 徐, 思},
title = {Multiscale characterization and classification of Alzheimer's disease via integration of brain fingerprint radiomics and graph‑theoretical network metrics.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {42236609},
issn = {1432-1920},
abstract = {BACKGROUND: The rising prevalence of Alzheimer's disease (AD) associated with global population aging has become a critical health concern. Accurate and early diagnosis is essential for timely clinical intervention. Structural MRI-based radiomics and graph-theoretical modeling have recently provided new perspectives for identifying neurodegenerative changes.

OBJECTIVE: This study aimed to develop a unified framework integrating morphological brain fingerprinting and graph-theoretical network analysis to classify AD, mild cognitive impairment (MCI), and normal controls (NC), and to characterize the structural alterations across these distinct disease stages.

METHODS: High‑dimensional radiomic features were extracted from multiple AD‑related regions in structural MRI to construct individualized brain fingerprints. A graph structure was established using the inter‑regional correlation matrix, from which network metrics were derived to quantify topological connectivity, including node degree, clustering coefficient, and betweenness centrality. Support vector machine (SVM) and ensemble‑based classifiers were then employed to perform group classification and identify key imaging biomarkers.

RESULTS: In the AD vs NC classification, the model achieved the highest training accuracy (ACC = 0.9563), sensitivity (0.950), specificity (0.9625), and AUC = 0.995 (95% CI: 0.983-1.000); testing performance remained robust (ACC = 0.825, AUC = 0.935). For AD vs MCI and MCI vs NC, the training AUC were 0.972 and 0.952, while the testing AUC were 0.895 and 0.920, respectively. Feature mapping revealed a pattern of structural alteration, with the hippocampus, entorhinal cortex, and posterior cingulate showing significant abnormalities. Graph metrics indicated decreased integration efficiency and compensatory centrality increases within high-order cognitive networks.

CONCLUSION: The proposed fingerprint-graph integration framework enables multilevel quantification of AD‑related structural reorganization, offering interpretable and reliable classification performance. It provides a promising foundation for early diagnosis, individualized assessment, and precision‑oriented neurodegenerative research.},
}

@article {pmid42236747,
year = {2026},
author = {Yang, J and Li, J and Hou, X and Zheng, Y and Zhao, Z and Zhou, T and Jing, T and Kong, J and Zhang, G and Guo, Y},
title = {Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.},
journal = {npj aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41514-026-00424-3},
pmid = {42236747},
issn = {2731-6068},
support = {CSTB2023NSCQ-BHX0119//the Postdoctoral Science Founation Project of the Chongqing Natural Science Foundation/ ; C2024405023//the Natural Science Foundation of Hebei Province/ ; },
abstract = {Mitochondria are essential for neuronal energy production, cellular homeostasis, and overall neuronal function. Due to their high metabolic demands and limited regenerative capacity, neurons are particularly vulnerable to mitochondrial dysfunction, which leads to ATP depletion, excessive reactive oxygen species (ROS) production, and calcium imbalance-ultimately causing oxidative stress, metabolic disruption, and neuronal death. Mitophagy is a selective process that removes damaged mitochondria through the autophagy-lysosome pathway. As a key mechanism of mitochondrial quality control, mitophagy preserves energy production, limits oxidative damage, and maintains mitochondrial network integrity. This process is regulated by pathways such as PINK1-Parkin and receptor-mediated mechanisms involving BNIP3 and FUNDC1, all of which help sustain cellular health by preventing mitochondrial dysfunction. Impaired mitophagy is a common feature of several neurodegenerative diseases, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease, exacerbating mitochondrial damage and neuronal stress. Emerging therapeutic strategies that target mitophagy-ranging from pharmacological agents and gene therapies to dietary interventions-show promise in restoring mitochondrial quality and protecting neurons from degeneration. Nevertheless, challenges remain in translating these findings into effective clinical treatments. Mitophagy represents a critical mechanism for preserving neuronal integrity and offers a compelling target for innovative therapies against neurodegenerative disorders.},
}

@article {pmid42236894,
year = {2026},
author = {Lee, Y and Nam, H and Lee, JW and Ko, YJ and Kim, EJ and Ha, S and Kim, N and Koo, JW and Son, T and Kim, S and Yu, SW},
title = {A human telomerase reverse transcriptase-derived peptide GV1001 rescues neurodegeneration in a mouse model of Alzheimer disease.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {42236894},
issn = {2092-6413},
abstract = {GV1001 is a peptide consisting of 16 amino acids derived from the catalytic subunit of human telomerase reverse transcriptase. A recent phase II clinical trial in patients with Alzheimer disease (AD) showed that GV1001 effectively improved memory impairment with proven safety, leading to larger clinical trials. However, the mechanisms underlying therapeutic effects of GV1001 on AD remain elusive. Here, we report that GV1001 reduces amyloid plaque burden and rescues synaptic loss and memory deficits in 5xFAD mice by increasing microglial migration toward large amyloid plaques and amyloid β degradation. Single-cell RNA-sequencing revealed that GV1001 promoted the migratory and phagocytic phenotypes by modulating disease-associated microglial profiles. At the molecular level, through virtual target screening and docking simulation combined with peptide pulldown, we identified that bradykinin receptor 1 is the binding target of GV1001. Furthermore, we revealed that GV1001 facilitated microglial migration and amyloid β phagocytosis in an mTORC2-dependent manner. Collectively, our work demonstrates the amyloidolytic effects and the relevant in-depth signaling mechanism of GV1001 in microglia, suggesting GV1001 as a promising disease-modifying therapeutic agent for AD.},
}

@article {pmid42237024,
year = {2026},
author = {Dunot, J and Gandin, C and Truchi, M and Pirro, G and Moreno, S and Launay, A and Azoulay, B and Landra, H and Yishan, SM and Buée, L and Lebrigand, K and Pousinha, PA and Blum, D and Mari, B and Bethus, I and Willem, M and Marie, H},
title = {AETA peptide contributes to Alzheimer's disease signature of synapse dysfunction.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42237024},
issn = {1432-0533},
support = {ANR-15-IDEX-01//Agence Nationale de la Recherche/ ; ANR-21-ESRE-0052, ANR-10-INBS-09-02, ANR-10-INBS-09-03//Agence Nationale de la Recherche/ ; ANR-21-CE16-0032 APPYSYNAPSE//Agence Nationale de la Recherche/ ; ECO202106013670//Fondation pour la Recherche Médicale/ ; FR-24054T//Fondation Vaincre Alzheimer/ ; AAP SM 2018 Dossier 1795 and APP PFA 2024 Dossier 6479//French Association France Alzheimer/ ; (AAP 2015 AETAPHYS//French Fondation Alzheimer/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism/genetics ; Female ; Humans ; *Synapses/pathology/metabolism ; Male ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Hippocampus/pathology/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Mice, Inbred C57BL ; Neurons/metabolism/pathology ; Brain/pathology/metabolism ; Microglia/pathology/metabolism ; },
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by early synaptic dysfunction that precedes overt cognitive decline. While amyloid-β and Tau remain central to AD pathogenesis, molecular triggers of synapse weakening remain unclear. Here, we investigated AETA, a novel brain-secreted peptide derived from amyloid precursor protein (APP), as a potential mediator of synapse dysfunction in AD. We previously identified AETA as a unique modulator of NMDA receptor activity in the healthy brain; however, its role in AD etiology was yet to be explored. Post-mortem analyses of human hippocampal and prefrontal cortex tissues revealed significantly elevated AETA levels in AD patients, particularly in females. To further explore the contribution of AETA to AD synaptic pathology, we analyzed a new mouse model, the AETA-m mouse, exhibiting chronically increased brain AETA expression. Hippocampi of female AETA-m mice displayed an increase in the number of astrocyte and microglia, but no overt neuroinflammation. RNA sequencing of female AETA-m hippocampi revealed alterations in synaptic gene expression that closely paralleled those observed in vulnerable human AD brain regions, most notably in the hippocampus. These two phenotypes were absent in males. Functionally, hippocampal neurons from AETA-m mice displayed impaired NMDA receptor signaling, dendritic spine loss, and memory deficits especially in females, mirroring early AD-associated synaptic dysfunction. Together, these findings identify AETA as a novel key contributor of synaptic vulnerability in AD and associated memory processing, especially in females. Targeting AETA signaling may therefore offer new therapeutic avenues for preventing or mitigating synaptic and cognitive decline in AD.},
}

Animals
*Alzheimer Disease/pathology/metabolism/genetics
Female
Humans
*Synapses/pathology/metabolism
Male
*Amyloid beta-Protein Precursor/metabolism/genetics
*Hippocampus/pathology/metabolism
Mice
Mice, Transgenic
Disease Models, Animal
Mice, Inbred C57BL
Neurons/metabolism/pathology
Brain/pathology/metabolism
Microglia/pathology/metabolism

@article {pmid42237039,
year = {2026},
author = {, and , and , and , and , and , and , and , and , },
title = {Consensus meta-analysis of genome-wide association studies for Alzheimer's disease and related dementias.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {42237039},
issn = {1546-1718},
abstract = {To better characterize the genetic architecture underlying Alzheimer's disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, of which 16 are new and 56 are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 new) requiring further external validation. A polygenic score combining the effects of ADRD loci other than APOE was primarily associated with AD rather than non-AD pathology. Individuals in the tenth decile of the score exhibited a twofold increased risk of presenting with Braak neurofibrillary tangles stage of >4 and moderate-to-severe neuritic amyloid plaque pathology at death compared to individuals in the median score group. In conclusion, our study validated a large number of loci associated with the risk of clinically diagnosed AD, while further investigations are required to confirm the impact of the other loci on AD clinical diagnosis and of each locus on AD pathology.},
}

@article {pmid42237143,
year = {2026},
author = {Lambert, E and Gelle, C and Leclerc, V and Freire-Regatillo, A and Liefooghe, L and Barois, N and Malfoi, T and Hermant, X and Demiautte, F and Gallienne, I and Lafont, F and Amouyel, P and Blary, K and Kuenen, S and Najdek, C and Verstreken, P and Siedlecki-Wullich, D and Yger, P and Lambert, JC and Kilinc, D and Dourlen, P},
title = {BIN1 gain-of-function in the presynaptic compartment leads to isoform-specific synaptotoxicity.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02103-7},
pmid = {42237143},
issn = {1758-9193},
support = {#6473//Association France Alzheimer/ ; #328 ADhesion//Association France Alzheimer/ ; ANR-11-LABX-01 LabEx DISTALZ//Agence Nationale de la Recherche/ ; ANR-23-CE14-0064 TAUFUNALZ//Agence Nationale de la Recherche/ ; 3DMiniBrain//EU Joint Programme - Neurodegenerative Disease Research/ ; AARG-22-926152/ALZ/Alzheimer's Association/United States ; P-21-03626//French Renatech Network/ ; The BIN1-Tau neurotoxic link in Drosophila//Fondation Vaincre Alzheimer/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is associated with strong genetic predisposition and early synaptic loss that correlates with cognitive decline. While genetic determinants are thought to contribute to synaptic vulnerability, their precise role in AD pathogenesis at the synaptic level remains unclear. BIN1, a major AD susceptibility gene, is expressed in multiple isoforms, but isoform-specific effects at synapses have not been well defined.

METHODS: We investigated the impact of human BIN1 isoforms on synaptic structure and function using Drosophila and mammalian models. In flies, we overexpressed human BIN1 isoforms in retinal photoreceptor neurons and motoneurons, assessing synaptic function by electrophysiology and ultrastructural analyses. Morphological changes at neuromuscular junctions were also quantified. For both readouts, Rab11 modulation was tested as a potential rescue strategy. To determine conservation in mammals and distinguish presynaptic versus postsynaptic roles, we overexpressed BIN1 isoform 1 selectively in presynaptic or postsynaptic compartments of rat hippocampal neurons cultured in microfluidic devices. We assessed structural and functional connectivity using immunofluorescence and microelectrode arrays.

RESULTS: Gain-of-function of BIN1 isoform 1, but not isoforms 8 or 9, induced early loss of synaptic transmission in Drosophila photoreceptor neurons indicating BIN1iso1 synaptotoxicity. Structural analyses revealed accumulation of abnormally large vesicles in photoreceptor terminals, resembling BIN1-induced endosomal defects in cell bodies. Moreover, Rab11 gain-of-function prevented BIN1iso1 synaptotoxicity, suggesting that it originates from endosomal trafficking defects. In motoneurons, BIN1iso1 overexpression induced synapse remodelling, altering bouton morphology, including increased bouton number, reduced bouton size, and formation of satellite boutons. Rab11 modulation was additive to BIN1 isoform 1 effects, suggesting a distinct mechanism. In rat hippocampal neurons, BIN1 isoform 1 decreased synaptic connectivity only when overexpressed presynaptically, a finding confirmed by microelectrode array recordings.

CONCLUSIONS: Our findings demonstrate that BIN1iso1 exerts isoform-specific, presynaptic disruption during synapse development and maintenance that compromises synaptic integrity across species. BIN1iso1 synaptotoxicity may contribute to early synapse loss observed in AD and provides mechanistic evidence that genetic determinants such as BIN1 predispose synapses to failure. These results highlight BIN1iso1 as a potential target for therapeutic strategies aimed at preserving synaptic function in AD.},
}

@article {pmid42237182,
year = {2026},
author = {Sadleir, KR and Gomez, KP and Chandra, S and Ley, ML and Khatri, AW and Guo, J and Xue, Y and Cepko, CL and Vassar, R},
title = {Neuronal overexpression of Nrf2 reduces dystrophic neurites in 5XFAD Alzheimer's disease model mice.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02097-2},
pmid = {42237182},
issn = {1758-9193},
support = {5R25GM121231//National Institutes for Health/ ; F30AG079577//National Institutes for Health/ ; NIA R21AG059157//National Institutes for Health/ ; NIA R01AG030142//National Institutes for Health/ ; },
abstract = {BACKGROUND: The hallmark lesions of the Alzheimer's disease (AD) brain are amyloid plaques consisting of the β-amyloid protein and neurofibrillary tangles comprised of hyperphosphorylated, aggregated tau protein, which both cause neuronal dysfunction and loss. One goal of neuroprotective therapies is to maintain normal neuronal function and survival in the presence of toxic pathologies such as plaques and tangles. A potential neuroprotective target is nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, which regulates the expression of many antioxidant and detoxification genes. Nrf2 mRNA is decreased in AD brains, and deletion of the Nrf2 gene causes increased BACE1 and Aβ production and worsened cognitive deficits in amyloid pathology mouse models. Overexpression of Nrf2 in astrocytes has been shown to be protective against neurodegeneration, but the role of Nrf2 is neurons is unclear.

METHODS: We overexpressed Nrf2 from birth in neurons of 5XFAD amyloid pathology model mice using AAV8, hypothesizing that neuronal Nrf2 overexpression decreases cortical neuron loss and reduces plaque load by decreasing BACE1 levels. We quantified protein levels by immunoblot and neuropathology by immunofluorescent staining, using two-way ANOVA to measure differences between genotypes and AAV treatments. To assess genetic changes, we performed bulk mRNA seq.

RESULTS: While neuronal overexpression of Nrf2 in 5XFAD mice did not prevent neuronal loss as measured by NeuN labeling, decrease neuroinflammation by Iba1 or GFAP labeling, or reduce amyloid load by Aβ antibody or methoxy-XO4 staining, we show that increased Nrf2 expression reduces BACE1 protein levels, especially in swollen axonal dystrophic neurites around amyloid plaques. Other proteins that accumulate in dystrophic neurites were also reduced, indicating decreased dystrophic neurites overall. Immunoblot analysis suggested increased autophagy was unlikely to play a role, while bulk mRNA sequencing indicated changes in lipid metabolism and microtubule stability may have contributed to reduced dystrophic neurite formation.

CONCLUSIONS: Dystrophic neurites impair action potential conductance and contribute to tau seeding and spreading. Their reduction by neuronal Nrf2 overexpression may protect neurons against these pathologic changes. Further study of the mechanisms by which Nrf2 reduces dystrophic neurites may lead to therapeutic strategies that can limit neuritic damage caused by cerebral amyloid accumulation.},
}

@article {pmid42237205,
year = {2026},
author = {Wang, Q and Mei, J and Li, S and Zhang, G and Qiu, J and Li, X},
title = {GGAs: Regulation of Multiple Sorting Pathways and Potential Association With Human Diseases.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {11},
pages = {e71215},
doi = {10.1111/jcmm.71215},
pmid = {42237205},
issn = {1582-4934},
support = {ZR2022MH244//Natural Science Foundation of Shandong Province/ ; ZR2021QC039//Natural Science Foundation of Shandong Province/ ; 82301629//National Natural Science Foundation of China/ ; },
abstract = {Golgi-localized gamma-ear-containing Arf-binding proteins (GGAs) are a family of monomeric clathrin adaptors that function in intracellular vesicle trafficking. The three GGA family members-GGA1, GGA2 and GGA3-were first identified as sorting adaptors almost simultaneously by independent research groups in 2000. It is now well established that GGAs exert broad functions in intracellular sorting pathways. Moreover, GGAs have been shown to participate in diverse cellular processes including cell survival, migration and invasion, and are proposed to be potentially associated with multiple human disorders, such as Alzheimer's disease, cancers and type 2 diabetes mellitus. In this review, we briefly summarize the current knowledge regarding the roles of GGAs in intracellular vesicle trafficking, discuss the regulatory mechanisms underlying their functions, and speculate on their potential implications in human diseases. These findings may help us understand how GGAs participate in the pathogenesis of human diseases and, in the future, how to intervention the diseases via GGA-targeted strategies.},
}

@article {pmid42237401,
year = {2026},
author = {Nicholson, L and Tang, SJ and Karra, T and Abouelatta, H and Strittmatter, SM},
title = {Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer's knock-in mouse phenotypes.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00946-0},
pmid = {42237401},
issn = {1750-1326},
support = {none//Kavli Institute for Neuroscience, Yale School of Medicine/ ; R01034924/NH/NIH HHS/United States ; P30AG066508//National Institutes of Health,United States/ ; },
abstract = {BACKGROUND: Metabolic dysfunction contributes to the risk and progression of Alzheimer's disease (AD), yet the cellular mechanisms linking impaired insulin signaling and systemic metabolic stress to brain dysfunction remain incompletely defined.

METHODS: We examined the impact of chronic high-fat, high-sugar (HFHS)-induced insulin resistance on metabolic parameters, spatial learning and memory, and in vivo glial activation and neuropathology in Alzheimer's disease knock-in mice expressing human mutant APP and wild-type (WT) tau. Single-nucleus RNA sequencing was performed to resolve cell-type-specific transcriptional responses.

RESULTS: HFHS-diet induced weight gain, hyperglycemia, and glucose intolerance in WT and AD knock-in mice as compared to control diet-fed mice. However, impaired spatial learning was observed only in AD knock-in mice on the HFHS diet, even though there was no greater amyloid-β deposition or tau phosphorylation than in control diet AD knock-in mice. Transcriptomic profiling revealed that HFHS-fed AD mice engaged a distinct glial program, which we termed the metabolic impairment in neurodegeneration (MinD) state, characterized by upregulation of genes involved in synaptic targeting and trans-synaptic signaling shared across microglia, astrocytes, and oligodendrocytes. In parallel, we identified selective induction of the transcription factor Meis2 in cortical Layer 2 inhibitory neurons, which exhibited HFHS-diet transcriptional remodeling enriched for pathways regulating vesicle release, synaptic organization, and membrane excitability. These coordinated glial and neuronal transcriptional changes were associated with reduced inhibitory synapse density in HFHS-fed AD mice.

CONCLUSION: Diet-induced insulin resistance in AD knock-in mice is associated with coordinated glial and inhibitory neuron transcriptional remodeling and cognitive impairment, without alteration of the classical amyloid and tau pathology present in the AD mice fed a lean diet. These findings define cellular programs linking systemic insulin metabolic dysfunction to cortical circuity vulnerability in AD.},
}

@article {pmid42237406,
year = {2026},
author = {Oltra, J and Ištvánfyová, Z and Kalpouzos, G and Ekström, I and Hagman, G and Kivipelto, M and Laukka, EJ},
title = {Alzheimer's disease and cerebrovascular biomarkers in relation to odor identification in a naturalistic clinical cohort.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02073-w},
pmid = {42237406},
issn = {1758-9193},
abstract = {INTRODUCTION: Olfactory deficits, especially in odor identification (OID), have been linked to Alzheimer's disease (AD), likely due to regional proteinopathy and atrophy in the olfactory brain circuit. Their cognitive and biological correlates across the clinical spectrum, particularly in individuals with no evident cognitive impairment, have been underexplored. This examination is relevant because many individuals of this group will not progress to dementia, and olfactory deficits may reflect ongoing pathological processes and could enrich risk stratification.

METHODS: We analyzed data from a cohort of 233 subjective cognitive impairment (SCI, n=152), mild cognitive impairment (MCI, n=50), and AD dementia (n=31) individuals from the Karolinska University Hospital Memory Clinic (Solna, Sweden). We examined the association of performance on the 16-item Sniffin' Sticks OID test (free and total [free or cued] identification scores) with a range of markers: cognitive performance, cerebrospinal fluid biomarkers, AD- and olfactory-related brain volumes, and white matter hyperintensities volume. We performed correlation analyses, generalized additive models, and threshold regressions, adjusted for sociodemographic factors and APOE status.

RESULTS: OID performance was better in SCI compared to MCI and AD. Aβ42/40 ratio was positively associated with OID in SCI and AD, with APOE ε4 carriers driving this association in SCI. Hippocampal volume was positively associated with OID in AD. Higher volume of white matter hyperintensities was negatively associated with OID in MCI. The relationships of OID with Aβ42/40 and hippocampal volume were linear in the whole cohort. Worse verbal episodic memory performance was associated with lower OID scores only in the AD group. Free OID showed a broader and stronger pattern of associations with episodic memory and biomarkers compared with total OID. Threshold regression between free OID and Aβ42/40 identified a subthreshold value (<0.94) above the clinical cutoff (<0.86), capturing nine non-demented individuals within the gray zone between these cutoffs.

CONCLUSIONS: Our findings support an association between amyloid levels and olfactory performance in the AD spectrum, underscoring the potential of smell tests as cost-effective tools in multimodal stratification frameworks. In dementia stages, medial temporal atrophy accompanied by memory impairment may be the main correlate of olfactory deficits.},
}

@article {pmid42237481,
year = {2026},
author = {Zhang, Y and Sun, J and Cui, Y},
title = {Reticulophagy limits Alzheimer's disease pathology through FAM134B-dependent APP clearance.},
journal = {Autophagy},
volume = {},
number = {},
pages = {},
doi = {10.1080/15548627.2026.2684514},
pmid = {42237481},
issn = {1554-8635},
abstract = {Selective autophagy maintains organelle and proteome homeostasis through receptor-mediated degradation of damaged membranes and aggregation-prone proteins. Although autophagy dysfunction and endoplasmic reticulum (ER) abnormalities are prominent features of Alzheimer's disease (AD), whether reticulophagy directly contributes to amyloid precursor protein (APP) turnover has remained unclear. We identify FAM134B/RETREG1 as a specific receptor that recognizes ER-localized APP and promotes its lysosomal degradation through LC3-dependent reticulophagy. In AD patient samples and 5XFAD mice, epigenetic repression of FAM134B limits TFEB/TFE3-dependent transcription, resulting in impaired ER turnover, APP accumulation, and exacerbated amyloid pathology. Restoration of wild-type, but not LIR-mutant, FAM134B rescues reticulophagy, reduces APP and Aβ accumulation, preserves neuronal integrity, and improves cognition in 5XFAD mice. These findings establish impaired reticulophagy as an upstream pathogenic mechanism in AD and highlight FAM134B-mediated ER turnover as a potential therapeutic strategy for limiting amyloidogenic APP accumulation.},
}

@article {pmid42237659,
year = {2026},
author = {Biberoglu, K and Tacal, O},
title = {Tramiprosate, the Active Agent of ALZ-801, Modulates Amyloidogenic APP Processing and Tau Phosphorylation in a Cellular Model of Alzheimer's Disease.},
journal = {Drug development research},
volume = {87},
number = {4},
pages = {e70330},
doi = {10.1002/ddr.70330},
pmid = {42237659},
issn = {1098-2299},
support = {TSA-2022 19725//Hacettepe Üniversitesi/ ; //Hacettepe University Scientific Research/ ; },
abstract = {ALZ-801, a valine-conjugated prodrug of tramiprosate, has recently been evaluated in a Phase III trial as a potential Alzheimer's disease (AD)-modifying therapy. Tramiprosate reduces misfolding of amyloid beta (Aβ) monomers and inhibits oligomer formation. In the present study, we investigated tramiprosate's effects on amyloidogenic processing of amyloid precursor protein (APP) and tau phosphorylation using the N2a-APPSwe cell line as a cellular model of AD. Tramiprosate decreased levels of secreted Aβ40 and Aβ42 in a dose-dependent manner without affecting cell viability. It also reduced the levels of APP, β-site APP cleaving enzyme 1 (BACE1), and presenilin 1 C-terminal fragment (PS1-CTF) in this cellular model, indicating that tramiprosate may modulate amyloidogenic APP processing at multiple steps, thereby reducing Aβ production. Additionally, tramiprosate decreased tau phosphorylation at Ser202/Thr205 and Ser396/Ser404 in a dose-dependent manner while total tau level remained unchanged. Increased phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9, without altering total GSK-3β levels, suggests that GSK-3β inhibition underlies the decrease in tau phosphorylation at these sites. As a result, tramiprosate's impact on both amyloidogenic APP processing and tau phosphorylation reveals its potential to modify AD.},
}

@article {pmid42237690,
year = {2026},
author = {Cullen, AE and Winder, NR and Lee, B and Krishna Kumaran, S and Arora, N and Wolf, JR and Henson, GD and Woltjer, RL and Walker, AE},
title = {Deletion of Robo4 worsens neuroinflammation in a mouse model of Alzheimer's disease.},
journal = {Physiological reports},
volume = {14},
number = {11},
pages = {e70950},
doi = {10.14814/phy2.70950},
pmid = {42237690},
issn = {2051-817X},
support = {R01AG064016//HHS | National Institutes of Health (NIH)/ ; P30AG066518//HHS | National Institutes of Health (NIH)/ ; TL1TR002371//Oregon Health and Science University (OHSU)/ ; },
abstract = {Declines in vascular integrity are potential contributors to Alzheimer's disease (AD) as these result in increased blood-brain barrier permeability and, consequently, accelerate neuroinflammation and cognitive impairment. Roundabout guidance receptor 4 (Robo4) is primarily expressed in endothelial cells and stabilizes the vasculature, thereby potentially protecting the brain in AD. To study the effect of Robo4 on neuroinflammation and cognitive function in the context of AD, we compared Robo4 knockout and wild-type mice crossed with mice with and without AD mutations (APP/tau) from heterogeneous age and sex groups. We found that knockout of Robo4 led to greater astrocyte activation, as demonstrated by GFAP content, but this effect depended on the brain region studied. The knockout of Robo4 also led to greater activated microglia, as assessed by Iba1 content, but only in the presence of AD-related mutations. We found that AD mutations, but not Robo4 mutations, were associated with cognitive dysfunction, as measured by a nest-building test. Lastly, there was a non-statistically significant trend toward Robo4 deletion being associated with greater arterial stiffness. In summary, these results demonstrate that Robo4 impacts neuroinflammation and arterial stiffness; however, the impact on neuroinflammation is dependent on the presence/absence of AD-related mutations and the brain region examined.},
}

@article {pmid42237848,
year = {2026},
author = {Ching, KH and Keating, S and Zeng, B and Espinosa, DA and Stack, E and Wall, S and Beyer, S and Wade, J and Tam, A and Cunningham, O and Chowdhury, R and Zhang, Y and Morales, J and Abdiche, Y and Leighton, PA and Darmanin Sheehan, A and Harriman, W},
title = {Generation of human sequence antibodies in OmniChicken against the highly conserved mammalian target BDNF using three distinct discovery workflows.},
journal = {mAbs},
volume = {18},
number = {1},
pages = {2672771},
doi = {10.1080/19420862.2026.2672771},
pmid = {42237848},
issn = {1942-0870},
abstract = {Generation of antibodies against highly conserved mammalian targets remains a substantial challenge in the therapeutic antibody space. Naïve and synthetic libraries address this need through rounds of in vitro affinity maturation. In vivo affinity matured antibodies from hyperimmunization often fail to generate diverse repertoires against conserved targets. Phylogenetically distant species offer an alternative strategy to obtain in vivo affinity-matured antibodies against conserved targets. We used OmniChicken, a transgenic chicken that expresses fully human heavy and light immunoglobulin genes, to generate antibodies against brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family that is dysregulated in chronic pain syndromes and neurological diseases such as Alzheimer's disease. Mature BDNF is 100% conserved between humans and mice. Following immunization of a cohort of OmniChickens, splenocytes were screened using three discovery workflows: Gel Encapsulated Microenvironment (GEM) and xPloration®, which are both single B cell screening platforms, and phage display. In total, we isolated 110 unique antibodies representing 29 unique VH and 32 unique VL lineages, many of which overlapped across the three platforms. Assessment of immunogenicity, including T cell epitope content and "humanness" showed that the cohort compared favorably with a clinical reference set, while biophysical analysis was consistent with good developability characteristics. EC50s were comparable to a benchmark clone, R3bH01, previously developed from a wild-type chicken. Finally, an ELISA-based IC50 assay identified clones from each platform with neutralizing activity. Overall, all three discovery workflows identified diverse lineages of antibodies with desirable developability properties and functionally relevant binding characteristics.},
}

@article {pmid42238091,
year = {2026},
author = {Dütsch, L and Dietzel, N and Keefer, A and Laininger, L and Schwab, S and Ganslandt, T and Graessel, E and Kolominsky-Rabas, PL},
title = {Uncovering sex patterns in BPSD among home-care patients: longitudinal findings from a population-based registry - digital dementia registry Bavaria.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1810510},
pmid = {42238091},
issn = {1664-0640},
abstract = {BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are core features of Alzheimer's disease and related dementias. Previous research suggests possible sex differences in the prevalence and severity of BPSD; however, findings remain inconsistent. Moreover, most existing studies are cross-sectional and focus on institutionalized populations, while evidence from home-dwelling individuals is highly limited. As many people with dementia live at home for a substantial part of the disease trajectory, longitudinal analyses in this setting are essential.

METHODS: This study used data from the population-based, prospective Digital Dementia Registry Bavaria (digiDEM Bayern). A total of 368 home-dwelling individuals with mild cognitive impairment or mild to moderate dementia were included. BPSD were assessed at baseline and after 12 months using the Neuropsychiatric Inventory (NPI). Sex differences over time were examined using a mixed ANOVA, with age, educational level, and dementia severity included as covariates.

RESULTS: Overall, NPI scores showed a descriptive increase over the 12-month follow-up period. Men showed higher mean NPI scores than women at both measurement points. In unadjusted analyses, a significant main effect of time and a between-subjects effect of sex were observed. However, no significant interaction between sex and time was found. After adjusting for age, education, and dementia severity, neither time effects nor sex differences remained statistically significant.

CONCLUSION: The findings suggest that sex differences in BPSD among home-dwelling individuals with dementia are not explained by sex alone. BPSD may be largely influenced by underlying demographic and clinical factors such as age, educational level, and dementia severity. This study highlights the importance of considering these covariates when examining BPSD and underscores the value of longitudinal, population-based research in home-care settings to better inform future dementia care strategies.},
}

@article {pmid42238355,
year = {2026},
author = {Krishna, D and Pandey, AC and Nilesh, S and Ananda, S and Singh, JA and Singh, A},
title = {Mind-Body Interventions as Modulators of Neural Connectivity and Cognition in Individuals at Risk for Alzheimer's Disease: A Systematic Review.},
journal = {Annals of neurosciences},
volume = {},
number = {},
pages = {09727531261441080},
pmid = {42238355},
issn = {0972-7531},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia worldwide, contributing to nearly 60%-70% of dementia cases. Current pharmacological treatments provide limited symptomatic relief and minimal efficacy in altering disease progression, highlighting the need for complementary interventions. Mind-body practices such as yoga and meditation are increasingly explored for preserving cognitive abilities and reducing neurodegenerative risk.

SUMMARY: This systematic review evaluated randomized controlled trials investigating yoga, meditation, and related mind-body interventions on cognitive and neural health in individuals with normal cognition, mild cognitive impairment, or subjective memory decline. Following PRISMA guidelines, studies published up to March 2025 were reviewed. Findings showed improvements in memory, attention, executive functions, mood, and quality of life. Neurobiological benefits included preservation of hippocampal volume, improved functional connectivity, increased brain-derived neurotrophic factor levels, and reduced neuroinflammation markers. However, methodological limitations such as small sample sizes and short intervention durations were common.

KEY MESSAGE: Mind-body interventions show promising cognitive and neurobiological benefits in populations at risk of AD. Yoga and meditation may serve as feasible, cost-effective complementary approaches alongside conventional therapy. Larger long-term clinical trials are needed to establish standardized protocols and sustained therapeutic effectiveness.},
}

@article {pmid42238423,
year = {2026},
author = {Zeng, X and Farinas, MF and Nafash, MN and Smirnov, DS and Lopresti, BJ and Matan, C and Tudorascu, DL and Berman, SB and Sweet, RA and Shaaban, CE and Snitz, BE and Kofler, JK and Nadkarni, NK and Aizenstein, HJ and Ikonomovic, MD and Pascoal, TA and Villemagne, VL and Kamboh, MI and Cohen, AD and Lopez, OL and Karikari, TK},
title = {CNS-selective plasma p-tau217 accurately captures Alzheimer's disease pathology and progression.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.18.26353208},
pmid = {42238423},
abstract = {Blood-based biomarkers have expanded access to biologically supported diagnosis of Alzheimer's disease (AD), particularly through measurement of amyloid-beta (Aβ) and phosphorylated tau species [1-3] . Among these, plasma tau phosphorylated at threonine 217 (p-tau217) is currently the leading biomarker recommended by clinical guidelines [4-6] . However, circulating p-tau217 originates from both central nervous system (CNS) and peripheral tissues [7] , potentially limiting specificity, particularly in individuals with common age-related comorbidities [8] . Here we report a next-generation biomarker, brain-derived p-tau217%, which quantifies the proportion of circulating tau that is CNS-derived and phosphorylated at threonine 217. Across neuropathologically defined, Aβ- and tau-neuroimaging-characterized, and memory clinic cohorts, brain-derived p-tau217% consistently identified AD pathology and clinical AD with larger effect sizes, higher discriminative accuracy, and improved sensitivity and specificity, outperforming conventional non-CNS-selective plasma p-tau217, p-tau217/Aβ1-42 and p-tau217% alternatives as well as brain-derived-p-tau217 alone. Furthermore, the CNS-selective biomarker demonstrated more robust prediction of future clinical progression in individuals followed for up to two decades. Importantly, diagnostic performance remained high in older adults with diabetes and cardiovascular disease, populations in which standard p-tau217 showed reduced specificity. Moreover, superiority extended to comparisons against multiple CNS disease-related proteins in targeted proteomic analyses. These findings establish plasma brain-derived p-tau217% as a biologically grounded and clinically robust biomarker that advances molecular definition, detection, and prognosis of Alzheimer's disease.},
}

@article {pmid42238428,
year = {2026},
author = {Ferreira-Atuesta, C and Schubert, KM and Tai, XY and Noain, D and Skwarzynska, D and Wyss, MT and Schreiner, SJ and Jung, HH and Hedden, T and Zelano, J and Marson, T and Lip, GYH and Mbizvo, GK and Galovic, M},
title = {Sodium channel blockers are associated with reduced dementia risk in late-onset unexplained epilepsy.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.20.26353714},
pmid = {42238428},
abstract = {Late-onset unexplained epilepsy is a potential harbinger of dementia, likely driven by network hyperexcitability that facilitates amyloid-β release and tau propagation. Dampening this activity with antiseizure medications offers a potential disease modifying strategy, yet whether specific agents differentially alter this neurodegenerative trajectory remains unknown. Here, we emulated a target trial using global real-world federated data on patients with late-onset unexplained epilepsy to compare dementia risk across antiseizure monotherapies. Using data from over 75 million adults aged 55 years or older, we found that sodium channel blockers were associated with a 27% lower hazard of incident all-cause dementia (hazard ratio = 0.73, 95% confidence interval 0.61- 0.88) and 34% lower hazard of Alzheimer's disease (hazard ratio = 0.66, 0.49 -0.88), compared with levetiracetam/brivaracetam. While the class effect was protective, individual agents such as phenytoin, carbamazepine, and lamotrigine showed divergent safety and efficacy profiles. We replicated these findings in both a Down syndrome cohort and the external National Alzheimer's Coordinating Center dataset. Our results suggest that targeting neuronal excitability with sodium channel blockers is associated with lower risk of dementia, prioritizing the repurposing of these agents for dementia prevention trials.},
}

@article {pmid42238441,
year = {2026},
author = {Szujewski, C and Shepherd, TM and Ghesani, M and Ponisio, M and Lavely, W and Schramm, G and Bollack, A and Aron, B and Lemberskiy, G and , },
title = {MR-Guided PET Denoising and Resolution Enhancement Improves Visual Interpretation and Preserves Quantitative Behavior Across Amyloid Tracers.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.14.26353149},
pmid = {42238441},
abstract = {BACKGROUND: Amyloid- β PET provides critical biomarker data for Alzheimer's disease diagnosis and anti-amyloid therapy evaluation, yet low spatial resolution and partial volume effects result in decreased interpretability, particularly in cases with low or borderline cortical amyloid burden. While quantitative metrics (SUVr, Centiloid) aid in interpretation of amyloid burden, disagreement between visual reads and quantitative burden does occur, further blurring the line between positive or negative scans. We evaluated whether a vendor-neutral MR-guided PET denoising and resolution enhancement method (MRG) that uses Bowsher regularization improves image interpretability and reader performance while preserving established quantitative biomarkers across multiple amyloid tracers, leading to increased concordance among visual reads and quantitative metrics.

METHODS: Standard (STN) and MRG PET images were compared for four tracers ([ [18] F]AV-45 ([ [18] F]florbetapir, FBP), [ [18] F]florbetaben (FBB), [ [18] F]flutemetamol (FMM), and [ [11] C]Pittsburgh compound-B (PiB)) collectively from 24 MRI and 33 PET scanners. Quantitative equivalence was assessed by comparing Standardized Uptake Value ratio (SUVr) and Centiloid scores. In three of the four tracers (FBP, FBB, FMM), visual-quantitative concordance (AUC) and reader performance were evaluated in a blinded multi-reader study by four highly experienced brain PET readers who assessed image quality, artifact severity, reader confidence, and binary amyloid positivity.

RESULTS: Across all tracers, MRG preserved quantitative SUVr and Centiloid metrics relative to STN (R [2] > 0.90 for all tracers) without introducing bias to the SUVr metric. Concordance between visual reads and quantitative burden measures significantly improved with MRG. In the multi-reader study, MRG resulted in significantly higher image quality, lower artifact burden, and greater reader confidence compared to STN (p < 0.0001). Reader accuracy increased from 0.89 to 0.94, and the false-negative rate decreased from 0.08 to 0.04. Crucially, improvements in reader confidence, accuracy, and the reduction in false negative reads were most pronounced in cases with low amyloid burden near the threshold of visual positivity.

CONCLUSIONS: MRG denoising and resolution enhancement improved perceived image quality, reader confidence, and accuracy for amyloid PET while preserving standard quantitative behavior across tracers. By improving cortical definition in visually challenging low-burden cases without disrupting established SUVr/Centiloid behavior, MRG may reduce visual-quantitative discordance and support more confident amyloid PET interpretation near the threshold of positivity.},
}

@article {pmid42238464,
year = {2026},
author = {Leung, YY and Marcora, EM and Naj, A and Patel, T and Sedgwick, K and Katanic, Z and Corces, RM and Wang, LS and Mayeux, RC and Goate, AM and Farrer, L and Schellenberg, GD and Kunkle, B and Vardarajan, BN},
title = {Comprehensive adjudication identifies 111 high-confidence loci for Alzheimer's disease and related dementias.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.14.26353247},
pmid = {42238464},
abstract = {BACKGROUND: The Alzheimer's Disease Sequencing Project Gene Verification Committee developed a systematic framework to adjudicate genetic evidence for AD and related dementias, addressing wide variation in association quality.

METHODS: Phase 1 established tiered criteria by evaluating 23 nominated loci across study designs. Phase 2 applied this framework to 29 large-scale genome-wide studies published since 2015, tiering 163 unique loci.

RESULTS: Phase 1 yielded 17 high-confidence loci (12 linked to specific genes), and Phase 2 identified 111 high-confidence loci/genes with replicated associations across ancestries and convergent single-variant/variant-set evidence. Prioritized loci highlight APP processing, microglial immunity, and lipid metabolism pathways, including genes not captured by existing resources like Agora or Open Targets. Summarized results can be viewed at https://topgenes.niagads.org/.

CONCLUSION: This rigorously adjudicated catalog represents the most comprehensive AD/ADRD genetics resource to date, providing a foundation for functional validation and therapeutic discovery with broad applicability to complex diseases.},
}

@article {pmid42238467,
year = {2026},
author = {Tong, B and Cao, T and Duong-Tran, D and Davatzikos, C and Thompson, P and Andrew, S and Fornito, A and Shen, L and , },
title = {Geometric brain signatures of Alzheimer's disease progression and subtypes.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.14.26353211},
pmid = {42238467},
abstract = {Alzheimer's disease (AD) patients suffer from consequential diagnostic delay due to the lack of accessible biomarkers. They also show different responses to treatments due to disease heterogeneity and progression. Here, we developed a novel framework to identify disease progression and subtypes by using geometric brain signatures derived from multiple neuroimaging modalities, including [ [18] F]-Florbetapir (AV45) Positron Emission Tomography (PET), [ [18] F]-Fludeoxyglucose (FDG) PET, and structural Magnetic Resonance Imaging (MRI). These signatures were derived by decomposing corresponding maps of amyloid-beta levels, metabolic activity, and cortical thickness in terms of the fundamental, resonant modes--eigenmodes--of cortical geometry, each tied to a specific spatial resolution scale. Our results showed that geometric eigenmode-based features identified trajectories of disease progression, quantified as pseudotime, in distinct subtypes. The disease progression trajectories and subtypes are identified with high stability and are highly related to biological and cognitive measures. These performances are superior to those obtained using conventional localised features and remain robust across datasets, indicating that geometric signatures of brain structure and function can be used to uncover new markers of AD diagnosis and prognosis that are missed by conventional localisation approaches.},
}

@article {pmid42238474,
year = {2026},
author = {Liu, C and Wang, A and Sun, H and Luo, K and Qian, S and Li, Y and He, X and De Jager, P and Bennett, D and Wang, M and Cruchaga, C and , and Wang, G and Morgante, F},
title = {A Multi-Context Regulome-Wide Association Atlas for Genetic Studies of Aging Brain Disorders.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.15.26353329},
pmid = {42238474},
abstract = {Genome-wide association studies have identified risk loci for aging brain disorders, but mechanistic interpretation depends on linking these loci to genes and to the tissues, cell types, and molecular modalities in which those genes act. Here we introduce FunGen-xQTL Multi-Brain (FGMB), a multi-context regulome-wide association atlas for transcriptome-wide association studies (TWAS) built from molecular datasets assembled by the ADSP Functional Genomics Consortium. FGMB provides cis -genetic prediction models for 17,375 protein-coding genes across 36 molecular datasets, 18 contexts, and 3 regulatory modalities, yielding more than 293,000 imputable gene-level or splice-event models. FGMB evaluates eight established and newer Bayesian or multivariate prediction methods, including cross-context models that borrow information across tissues and cell types. Applied to Alzheimer's disease, FGMB identified 327 TWAS associations and used joint fine-mapping of variants and predicted molecular traits to prioritize 146 gene-molecular-trait pairs, distinguishing regulatory associations from linkage disequilibrium (LD) hitchhiking.},
}

@article {pmid42238522,
year = {2026},
author = {Contreras, JA and Ortega, NE and Hayes, CA and Pa, J and , and , and , },
title = {Intersectional effects of race/ethnicity, sex, and APOE4 on plasma inflammatory profiles in Hispanic and non-Hispanic white adults.},
journal = {Brain, behavior, & immunity - health},
volume = {54},
number = {},
pages = {101256},
pmid = {42238522},
issn = {2666-3546},
abstract = {BACKGROUND: Despite known links between inflammation and Alzheimer's disease (AD), little is understood about how inflammatory processes vary across racial/ethnic and sex groups, particularly in relation to the major genetic risk factor apolipoprotein E ε4 (APOE4), whether these differences contribute to AD disparities among understudied Hispanics.

OBJECTIVE: This study investigated the interactive effects of race/ethnicity, sex, and APOE4 status on plasma inflammatory markers (IL-5, IL-6, IL-10, TNF-α). Secondary analyses examined whether these inflammatory markers were associated with cognitive performance and plasma AD-related biomarkers.

METHODS: Cross-sectional baseline data from the Health & Aging Brain Study - Health Disparities (HABS-HD) were analyzed in a multiethnic cohort of 1348 non-Hispanic white (NHW) (56.9% women, 27.4% APOE4 carriers) and 1420 Hispanics (66% women, 17.6% APOE4 carriers). Linear regression models examined main and interaction effects between race/ethnicity, sex, and APOE4 on plasma inflammatory markers, adjusting for age, education, BMI, and vascular comorbidities. Follow-up models tested associations with plasma AD biomarkers (Aβ42/40, pTau181) and cognition.

RESULTS: Significant three-way interactions were observed for IL-10 (p = 0.012) and at trend-level for IL-5 (p = 0.056), with the highest inflammatory levels in Hispanic men who are APOE4 carriers. No consistent associations emerged between inflammatory markers and global cognition or plasma AD biomarkers. An IL-10 × race/ethnicity interaction was associated with language performance (p = 0.035), though this did not survive correction for multiple comparisons.

CONCLUSION: Inflammatory responses to APOE4 differ by race/ethnicity and sex, with Hispanic men showing elevated IL-10 and IL-5. While associations with cognition and AD biomarkers were limited, these findings highlight intersectional heterogeneity in inflammatory profiles that may contribute to understanding biological pathways underlying AD disparities. Longitudinal studies are needed to determine whether these cytokines predict future cognitive decline or AD pathology.},
}

@article {pmid42238675,
year = {2026},
author = {Almikhlafi, MA},
title = {Neuroinflammation at the Crossroads of Neurodegeneration: The Roles of Microglia and Astrocytes in Parkinson's Disease, Alzheimer's Disease, and Multiple Sclerosis.},
journal = {Neurosciences (Riyadh, Saudi Arabia)},
volume = {31},
number = {2},
pages = {89-107},
pmid = {42238675},
issn = {1319-6138},
abstract = {Neuroinflammation plays a critical role in the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review explores the underlying mechanisms of neuroinflammation, with a focus on the roles of microglia, astrocytes, peripheral immune cell infiltration, and cytokine release. The complex interplay between oxidative stress and chronic inflammation accelerates neurodegeneration, contributing to disease progression. Microglial activation, initially protective, becomes harmful when sustained over time, driving chronic inflammation. Similarly, astrocytes once considered passive are now recognized for their active involvement in both inflammatory and neuroprotective responses, depending on their activation state. Prolonged activation of microglia and astrocytes compromises blood-brain barrier integrity, facilitating immune cell infiltration and amplifying inflammatory cascades, thereby worsening neuronal damage. We also detail the molecular mediators of the vicious cycle linking oxidative stress and chronic inflammation, including redox-sensitive transcription factors and mitochondrial dysfunction. Furthermore, the reviewed mechanisms highlight a pathogenic feedback loop, wherein oxidative stress and neuroinflammation fuel each other through NF-κB and Nrf2 pathways, suggesting that dual-target therapeutic strategies may be most effective. This review synthesizes evidence to propose that the failure to resolve neuroinflammation, driven by a self-reinforcing loop between oxidative stress and glial dysfunction, represents a critical, targetable node common to PD, AD, and MS.},
}

@article {pmid42238745,
year = {2025},
author = {Ghafoori, S and Shalbaf, A},
title = {Detecting Mild Cognitive Impairment to Alzheimer's Disease Progression by fMRI Using Convolutional Neural Network and Long-short Term Memory.},
journal = {Basic and clinical neuroscience},
volume = {16},
number = {6},
pages = {1051-1066},
pmid = {42238745},
issn = {2008-126X},
abstract = {INTRODUCTION: Mild cognitive impairment (MCI) is the stage that occurs before Alzheimer's disease (AD), and there is a high risk of progression to AD. However, this progression is not guaranteed, and there is a chance of remaining at this stage. This study aimed to diagnose possible AD progression among patients with MCI using a combination of resting-state functional magnetic resonance imaging (fMRI), clinical assessment, and demographic information for starting treatments in case of progression or reducing medical expenses in case of future stability.

METHODS: Deep learning (DL) methods, including three-dimensional convolutional neural networks (CNN) and long short-term memory (LSTM) networks, were used in this study. The models were developed using 266 samples from 81 MCI subjects, with an average of five years between baseline and the last timepoint.

RESULTS: The results showed that the best validation scores were achieved by the CNN-LSTM model after integrating clinical attributes, with an accuracy of 92.47%.

CONCLUSION: The proposed algorithm demonstrated high performance in predicting MCI-to-AD progression, indicating the potential of DL approaches for processing fMRI data and the efficiency of data type integration.},
}

@article {pmid42238754,
year = {2025},
author = {Zamani, J and Talesh Jafadideh, A},
title = {Predicting the Conversion From Mild Cognitive Impairment to Alzheimer's Disease Using Graph Frequency Bands and Functional Connectivity-based Features.},
journal = {Basic and clinical neuroscience},
volume = {16},
number = {6},
pages = {1113-1130},
pmid = {42238754},
issn = {2008-126X},
abstract = {INTRODUCTION: Accurate prediction of the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is crucial for disease management. Machine learning techniques have demonstrated success in classifying AD and MCI cases, particularly using resting-state functional magnetic resonance imaging (rs-fMRI) data.

METHODS: This study utilized rs-fMRI data from the ADNI, involving 142 patients with stable MCI (sMCI) and 136 with progressive MCI (pMCI). Graph signal processing was applied to filter rs-fMRI data into low-, middle-, and high-frequency bands. Connectivity-based features were derived from both filtered and unfiltered data, resulting in a comprehensive set of 100 features, including global graph metrics, minimum spanning tree (MST) metrics, triadic interaction metrics, hub tendency metrics: and number of links. Feature selection was enhanced using particle swarm optimization (PSO) and simulated annealing (SA). A support vector machine (SVM) with a radial basis function (RBF) kernel and a 10-fold cross-validation setup were employed for classification.

RESULTS: The proposed approach achieved high accuracy with a reduced number of features selected via PSO, specifically five features. With these features: the SVM achieved 77% accuracy, 70% specificity, and 83% sensitivity. The identified features were as follows, (mean of clustering coefficient, mean of strength)/radius/(mean eccentricity, and modularity) from low/middle/high frequency bands of the graph.

CONCLUSION: This study highlights the efficacy of the proposed framework in identifying individuals at risk of developing AD using a parsimonious feature set. This approach holds promise for advancing the precision of MCI-to-AD progression prediction, aiding early diagnosis and intervention strategies.},
}