@article {pmid42853296,
year = {2026},
author = {Zhao, J and Bai, Y and Wang, C and Guo, P and Wang, Z and Du, G and Liu, A},
title = {Fraxetin Ameliorates Cognitive Impairment in STZ-Induced Mice: Involvement of Suppressed Microglial Hyperactivation and Improved Mitochondrial Dysfunction.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42853296},
issn = {1557-1904},
support = {2025177//Tianjin Municipal Research Project on Integrated Traditional Chinese and Western Medicine/ ; 2021-I2M-1-028//CAMS Innovation Fund for Medical Sciences/ ; 82574701//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Mice ; *Microglia/drug effects/metabolism ; *Mitochondria/drug effects/metabolism ; *Streptozocin/toxicity ; Male ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Coumarins/pharmacology/therapeutic use ; Mice, Inbred C57BL ; },
abstract = {Therapeutic for Alzheimer's disease (AD) remains a pressing medical challenge in the field of neuroscience. Natural compounds with structural diversity and multi-target regulatory properties have attracted increasing attention for the treatment of complex neurodegenerative disorders. ‌Fraxetin, previously identified through computer-aided virtual screening, C. elegans assays, and in vitro cellular models as a potential anti-AD natural compound, was further investigated in this study using established in vivo and in vitro systems to evaluate its efficacy in ameliorating cognitive function and elucidate underlying mechanisms. A sporadic AD mouse model was established by intracerebroventricular injection of STZ (3 mg/kg). Fraxetin (3, 10, and 30 mg/kg/day, po.) was administered until the mouse sacrifices. Cognitive performance was evaluated using the novel object recognition, passive avoidance, and Morris water maze tests. STZ induced cerebral energy metabolism disturbances accompanied by mitochondrial dysfunction, neuroinflammation, oxidative stress, neuronal and synaptic loss, and cholinergic system impairment. ‌Behavioral tests confirmed that fraxetin ameliorated cognitive deficits in STZ-induced mice. Further studies revealed that fraxetin preserved mitochondrial structural integrity and enhanced mitochondrial biogenesis, accompanied by upregulation of the Sirt1/PGC-1α/Nrf1/TFAM pathway. In parallel, fraxetin attenuated microglial overactivation and neuroinflammatory responses. Consistently, in LPS-stimulated BV2 microglial cells, fraxetin inhibited nitric oxide and inflammatory mediator release, which was associated with modulation of the TLR2/MYD88/NF-κB signaling pathway, while restoring cellular bioenergetic status, indicating coordinated regulation of inflammation-associated metabolic dysfunction. Importantly, fraxetin attenuated neurodegenerative alterations in STZ-treated mice, as evidenced by reduced neuronal loss and synaptic degeneration. These effects were associated with activation of the BDNF/TrkB/ERK/CREB neurotrophic pathway and inhibition of acetylcholinesterase activity, supporting preservation of synaptic and cholinergic function. This study provides experimental evidence supporting fraxetin as a promising natural multi-target candidate for the intervention of AD.},
}

Animals
Mice
*Microglia/drug effects/metabolism
*Mitochondria/drug effects/metabolism
*Streptozocin/toxicity
Male
*Cognitive Dysfunction/chemically induced/drug therapy/metabolism
*Coumarins/pharmacology/therapeutic use
Mice, Inbred C57BL

@article {pmid42853396,
year = {2026},
author = {Oberstein, TJ},
title = {[Anti-amyloid antibodies against Alzheimer's disease : Lecanemab and donanemab in practice-Clinical importance, patient selection and safety management].},
journal = {Der Nervenarzt},
volume = {},
number = {},
pages = {},
pmid = {42853396},
issn = {1433-0407},
abstract = {Lecanemab and donanemab are the first disease-modifying therapies for early Alzheimer's disease. These humanized IgG1 antibodies promote the clearance of aggregated amyloid-beta peptides and, in the pivotal CLARITY AD and TRAILBLAZER-ALZ 2 trials, significantly delayed cognitive and functional decline, with an approximately 30% relative risk reduction for the clinical stage progression; however, the clinical meaningfulness remains contested: critics point to the small between-group difference in relation to the total score. This is weighed against the first disease-modifying effect and the first pharmacotherapy for mild cognitive impairment due to Alzheimer's disease. A prerequisite is the biological diagnosis: the reference standard is cerebrospinal fluid (CSF) and amyloid positron emission tomography (PET), potentially complemented in the future by blood biomarkers such as plasma p‑Tau217. Amyloid-related imaging abnormalities (ARIA) are the key adverse event, manageable through patient selection, ApoE-ε4 genotyping and magnetic resonance imaging (MRI) monitoring. The indications and follow-up belong in specialized centers.},
}

@article {pmid42853420,
year = {2026},
author = {Salvadó, G and Groot, C and Wisse, LE and Vogel, JW and Beach, TG and Serrano, GE and Reiman, EM and Schneider, JA and Bennett, DA and Ossenkoppele, R and Hansson, O},
title = {Global and regional amyloid-β in explaining APOE-ε4 and sex associations with medial temporal tau: a neuropathology study.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42853420},
issn = {1432-0533},
support = {101061836//European Union's Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie action/ ; AARF-22-972612//Alzheimer's Association Research Fellowship/ ; A2024007F//BrightFocus Foundation/ ; AF-980942, AF-994514, AF-1012218//Alzheimerfonden/ ; AF-1010833//Alzheimerfonden/ ; ZonMW; project number: 10510022110010//Dementia Fellowship grant from Zorg Onderzoek Nederland - Medische Wetenschappen/ ; WE.03-2024-06//Alzheimer Nederland Early Career Grant/ ; KAW2020.0239//SciLifeLab & Wallenberg Data Driven Life Science Program/ ; 2024-03642//Swedish Research Council/ ; 2022-00775 and 2018-02052, 2021-02219//Swedish Research Council/ ; StG-101221737/ERC_/European Research Council/International ; ADG-101096455/ERC_/European Research Council/International ; U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610 and P30AG072980/AG/NIA NIH HHS/United States ; P30AG10161, P30AG72975, R01AG17917, R01 AG015819, U01 AG072572, U01 AG046152, and R01AG075927/AG/NIA NIH HHS/United States ; 211002//Arizona Department of Health Services/ ; 4001, 0011, 05-901 and 1001//Arizona Biomedical Research Commission/ ; R01AG083740/AG/NIA NIH HHS/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ERAPERMED2021-184//ERA PerMed/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse/ ; AF-980907, AF-994229//Swedish Alzheimer Foundation/ ; FO2021-0293, FO2023-0163//Swedish Brain Foundation/ ; 1412/22//Parkinson foundation of Sweden/ ; WASP/DDLS22-066//WASP and DDLS Joint call for research projects/ ; 2025-2026-2024-2428//Bundy Academy at Lund University/ ; 2022-Projekt0080, 2022-Projekt0107//Swedish federal government under the ALF agreement/ ; },
mesh = {Humans ; Female ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; Male ; *Temporal Lobe/pathology/metabolism ; Aged ; *Apolipoprotein E4/genetics ; *Alzheimer Disease/pathology/genetics/metabolism ; Aged, 80 and over ; *Sex Characteristics ; Cohort Studies ; },
abstract = {The medial temporal lobe (MTL) is a key region in Alzheimer's disease (AD) pathogenesis, affected early by tau pathology. While female sex and APOE-ε4 are two known risk factors that affect tau levels, whether these factors drive tau in the MTL via amyloid-dependent or amyloid-independent mechanisms remains unclear. We investigated these relationships in two large neuropathological cohorts comprising 2550 participants from the Religious Orders Study/Memory and Aging Project (ROS/MAP; n=1587, main cohort) and Arizona Study of Aging and Neurodegenerative Disorders (AZSAND; n=963, replication cohort) covering the whole AD continuum. Neuropathological assessments of global neocortical and regional MTL amyloid-β burden were used to determine the extent to which amyloid-β pathology mediated associations of APOE-ε4 carriership and sex with MTL tau burden. In both cohorts, APOE-ε4 carriership and female sex were associated with significantly greater MTL tau pathology (all p<0.001). Adjustment for global amyloid-β attenuated but did not eliminate these associations (p≤0.024). However, after jointly accounting for global and MTL amyloid-β burden, the association between APOE-ε4 and MTL tau was no longer significant in either cohort (p≥0.19), whereas the association between female sex and MTL tau remained robust (p≤0.004). Models incorporating both global and regional MTL amyloid-β explained substantially more variance in MTL tau burden than models including only global amyloid-β, and results were replicated when further adjusting for diagnostic group or neocortical tau burden. These findings suggest that APOE-ε4 and female sex influence MTL tau accumulation through partially distinct pathogenic pathways, supporting an additional contribution of regional amyloid-β to the APOE-ε4-associated MTL tau burden while implicating additional amyloid-independent mechanisms in female vulnerability to tau accumulation.},
}

Humans
Female
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism
Male
*Temporal Lobe/pathology/metabolism
Aged
*Apolipoprotein E4/genetics
*Alzheimer Disease/pathology/genetics/metabolism
Aged, 80 and over
*Sex Characteristics
Cohort Studies

@article {pmid42853677,
year = {2026},
author = {Yaman, Ü and Gustavsson, E and Lee, J and Ugolini, H and Macpherson, H and Mumford, P and Wiseman, F and Hardy, J and Salih, DA},
title = {Protocol for genome-wide differential methylation using long-read DNA sequencing in the cortex of a mouse model of Alzheimer's disease.},
journal = {STAR protocols},
volume = {7},
number = {4},
pages = {104827},
doi = {10.1016/j.xpro.2026.104827},
pmid = {42853677},
issn = {2666-1667},
abstract = {Third-generation sequencing enables direct detection of genome-wide 5-methylcytosine without bisulfite conversion. Here, we present a protocol for generating long-read DNA sequencing from mouse cortex and performing genome-wide differential methylation analysis. We describe steps for high-molecular-weight DNA extraction, data generation, and downstream analysis. We demonstrate the workflow in the App[NL-G-F] mouse model of amyloid pathology and provide a reproducible pipeline that links modified-base BAM (modBAM) files to annotated differentially methylated regions and functional enrichment results.},
}

@article {pmid42853714,
year = {2026},
author = {O Apos Connor, MK and Frank, B and Noah, HH and Harrington, SK and Metcalf, EE and DeCaro, R and Vives-Rodriguez, A and Hagan, B and Atlas, S and Hurley, L and Turk, KW and Budson, AE},
title = {Informant Presence Fails to Enhance Alzheimer's Diagnosis in Complex Veteran Cases.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1},
doi = {10.1159/dem/aciag009},
pmid = {42853714},
issn = {1421-9824},
abstract = {INTRODUCTION: Informant reports are thought helpful for Alzheimer's disease (AD) diagnosis. We hypothesized that informants would improve diagnostic accuracy, operationalized as agreement between clinical impression and amyloid PET (aPET) findings.

METHODS: This study was a retrospective analysis of 168 Veterans referred for aPET due to diagnostic uncertainty or atypical presentation (Mage=69.3, SD=5.8). We examined the association between diagnostic accuracy and presence of an informant, patient's MoCA score, and informant type.

RESULTS: We found no evidence that informant presence was associated with diagnostic accuracy (OR = 0.92, 95% CI 0.48, 1.72), that this association varied by patient cognitive status as measured by MoCA (interaction OR = 1.13, 95% CI 0.97, 1.33), or that diagnostic accuracy differed by informant type (spouse/partner: OR = 1.23, 95% CI 0.55, 2.79; other: OR = 0.91, 95% CI 0.29, 2.71).

CONCLUSION: Our findings suggest informant presence does not necessarily enhance diagnostic accuracy for complex AD presentations. This highlights the continued value of aPET imaging in complex clinical presentations.},
}

@article {pmid42853744,
year = {2026},
author = {Zheng, Y and Ye, X and Zhang, J and Huang, Z and Tian, X and Mao, H},
title = {DeMorph: A Decoupled Deformation Model with Anatomical Guidance for Predicting Longitudinal Brain Atrophy.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2026.3737688},
pmid = {42853744},
issn = {2168-2208},
abstract = {Modeling the longitudinal progression of brain atrophy in Alzheimer's Disease (AD) is critical for early diagnosis and prognosis, but remains challenging for existing generative models. Current methods either fail to preserve anatomical integrity or treat progression as an entangled process, where changes from normal aging are inseparably fused with AD pathology. This fundamentally limits their scientific utility. To address this, we propose DeMorph, a novel deformation-based framework that explicitly disentangles and accurately predicts longitudinal brain MRI changes. Our transformer-based architecture features two key innovations: (1) a Decoupled Feed-Forward Network (D-FFN) for separate aging and pathology deformation pathways; and (2) a Multi-Scale Anatomical Guidance Cross-Attention (MS-AGCA) module, which explicitly injects anatomical priors to ensure spatially precise and biologically plausible disentanglement. Extensive experiments on four datasets (ADNI, OASIS-3, AIBL, and an inhouse dataset) demonstrate that DeMorph achieves stateof- the-art performance in both image similarity and anatomical accuracy. Crucially, we validate the success of our framework through robust bidirectional counterfactual synthesis, demonstrating the ability to controllably induce and remove a quantitatively plausible, AD-specific pathological effect.},
}

@article {pmid42853952,
year = {2026},
author = {Hirbawi, J and Zaretsky, A and Zhu, H and Goshtchevsky, U and Dey, G and Merquiol, E and Siddiqui, AA and Cohen, I and Blum, G and Cohen, E},
title = {A neuronal GPCR modifies neuropeptide signaling to suppress proteostasis in distal tissues.},
journal = {Science advances},
volume = {12},
number = {41},
pages = {eady6048},
pmid = {42853952},
issn = {2375-2548},
mesh = {*Proteostasis ; Animals ; *Signal Transduction ; *Neurons/metabolism ; *Neuropeptides/metabolism/genetics ; *Receptors, G-Protein-Coupled/metabolism/genetics ; Caenorhabditis elegans/metabolism/genetics ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Proteolysis ; Gene Knockdown Techniques ; },
abstract = {The proteostasis network (PN) safeguards the integrity of proteins by promoting various cellular activities. However, with aging, the PN's competence declines and aggregated proteins accrue within cells. This process underlies the development of neurodegenerative disorders such as Alzheimer's and Huntington's diseases. While the PN functions within cells, proteostasis is regulated across the organism by intertissue communication, which is partially governed by neurons. We previously found that reducing the expression of gtr-1, which encodes a neuronal heterotrimeric guanine nucleotide-binding protein-coupled receptor, mitigates the toxicity of the Alzheimer's disease cause, Aβ peptide. Here, we investigated the mechanism that is acted upon the knockdown of gtr-1 and found that it differentially modulates gene expression profiles, including of neuropeptide-coding genes, and dissimilarly modifies protein aggregation in worms that express distinct proteotoxic proteins. The knockdown of gtr-1 also enhances protein degradation. These findings highlight the roles of neuropeptides as organismal coordinators of proteostasis in the face of distinct proteotoxic challenges.},
}

*Proteostasis
Animals
*Signal Transduction
*Neurons/metabolism
*Neuropeptides/metabolism/genetics
*Receptors, G-Protein-Coupled/metabolism/genetics
Caenorhabditis elegans/metabolism/genetics
*Caenorhabditis elegans Proteins/metabolism/genetics
Proteolysis
Gene Knockdown Techniques

@article {pmid42854044,
year = {2026},
author = {Wen, P and Liu, W and Li, Y and Liao, M and Qin, H and Ye, J and Deng, Z and Cui, S and Zhao, Y and Wang, X and Huang, Y and Tang, H and Qin, H and Wang, K and Qin, Q},
title = {Tobacco-attributable burden of alzheimer's disease and other dementias in China and ASEAN: Temporal trends and projections - an observational study based on GBD 2021.},
journal = {Medicine},
volume = {105},
number = {41},
pages = {e50974},
doi = {10.1097/MD.0000000000050974},
pmid = {42854044},
issn = {1536-5964},
mesh = {China/epidemiology ; *Alzheimer Disease/epidemiology/mortality/etiology ; Humans ; *Dementia/epidemiology/mortality/etiology ; *Cost of Illness ; Disability-Adjusted Life Years ; Male ; Female ; },
abstract = {This study aimed to systematically analyze the disease burden of Alzheimer's disease and other dementias (ADOD) attributed to tobacco in China and ASEAN countries from 1990 to 2021, and predict the disease burden in the next ten years to characterize the disparities in disease burden between the 2 sides, and to conduct a preliminary exploration of factors that may be associated with these disparities. Data on ADOD deaths, mortality, DALYs and DALY rates attributed to tobacco in China and ASEAN countries were extracted from GBD 2021, and the trend of disease burden was analyzed using Joinpoint regression model. R software was used for data analysis and visualization, and Joinpoint regression model was used to calculate the APC of each indicator; the disease burden attributable to tobacco in China and ASEAN countries was analyzed through the SDI; and the ARIMA was used to predict ADOD from 2022 to 2035. In China, the number of ADOD deaths (1990: 8126.47, 95% CI: 1822.19-22,577.84), mortality rate, DALYs, and DALY rate attributable to tobacco all exhibited significant and sustained upward trends from 1990 to 2021, and consistently exceeded the corresponding levels in the other ten ASEAN countries. The APC for mortality and DALY rates showed a significant increase in China and most ASEAN countries, with particularly rapid increases in mortality in China, Thailand, Cambodia, and Indonesia. Correspondingly, the DALY rate rose in most countries, indicating a growing overall disease burden. An exception was Myanmar, where the burden decreased. The burden of tobacco-attributable ADOD was consistently higher among males than females in all countries. Analysis based on SDI revealed a lower and more stable disease burden in high-SDI areas, whereas medium- and low-SDI countries demonstrated an upward trend. ARIMA model projections for 2022-2035 suggest that while mortality trends are diverse, an increasing trend is anticipated in most countries. The disease burden of ADOD attributable to tobacco use has continued to rise in China and ASEAN countries. This trend suggests a potential role for tobacco control in the prevention of ADOD, and also points to the value of strengthening tobacco regulation and paying early attention to cognitive interventions.},
}

China/epidemiology
*Alzheimer Disease/epidemiology/mortality/etiology
Humans
*Dementia/epidemiology/mortality/etiology
*Cost of Illness
Disability-Adjusted Life Years
Male
Female

@article {pmid42854182,
year = {2026},
author = {Atri, A and Apostolova, LG and Iwata, A and Wessels, AM and Atkins, A and Lu, M and Ye, W and Ryan, S and Doty, EG},
title = {Clinical Meaningfulness of Donanemab in Early Symptomatic Alzheimer Disease: Data From the Randomized Phase 3 TRAILBLAZER-ALZ 2 Trial.},
journal = {Neurology. Clinical practice},
volume = {16},
number = {6},
pages = {e200663},
doi = {10.1212/CPJ.0000000000200663},
pmid = {42854182},
issn = {2163-0933},
}

@article {pmid42854385,
year = {2026},
author = {Ye, BS and VandeVrede, L and Jeon, S and Lee, S and Choi, M and Jeon, S and Shin, NY and Charters, B and Plastini, M and Kang, S and Rim, JH and Lim, JB},
title = {Clinical and biomarker predictors of α-synuclein seeding in cognitive impairment and motor parkinsonism.},
journal = {Parkinsonism & related disorders},
volume = {153},
number = {},
pages = {108956},
doi = {10.1016/j.parkreldis.2026.108956},
pmid = {42854385},
issn = {1873-5126},
abstract = {Dopamine transporter (DAT) imaging and α-synuclein seed amplification assay (SAA) are biomarkers for Lewy body disease (LBD). We aimed to identify clinical and biomarker factors associated with SAA positivity in patients with cognitive impairment and frequent motor parkinsonism. Dual-phase DAT positron emission tomography (PET) scans, cerebrospinal fluid (CSF) phosphorylated-tau/β-amyloid ratio (PTAR) measurement, and SAA were performed in 108 patients, including 99 with motor parkinsonism. Diagnoses, which were not mutually exclusive, included normal pressure hydrocephalus (NPH, N = 60), Alzheimer's disease (AD, N = 53), dementia with Lewy bodies (DLB, N = 43), vascular cognitive impairment (VCI, N = 23), progressive supranuclear palsy (N = 3), and semantic variant primary progressive aphasia (N = 1). We investigated clinical and biomarker factors associated with SAA positivity, including clinical diagnoses, clinical features, striatal DAT uptake, and log-transformed PTAR (LN-PTAR), and examined whether SAA positivity was associated with dopaminergic degeneration and regional perfusion measured by dual-phase DAT PET. SAA was positive in 50 patients (46.3%), including 30 of 43 (69.8%) with DLB and 47 of 99 (47.5%) with motor parkinsonism. Seven (14.0%) SAA-positive patients showed normal DAT uptake. Among clinical diagnoses, DLB and AD were associated with a higher likelihood of SAA positivity, whereas NPH and VCI were associated with a lower likelihood. Among clinical features, cognitive fluctuations and rapid eye movement sleep behavior disorder were independently associated with SAA positivity. Among biomarker measures, lower posterior putamen DAT uptake and a higher LN-PTAR were independently associated with SAA positivity. SAA positivity was associated with lower posterior putamen DAT uptake on delayed-phase DAT PET but not with perfusion changes on early-phase DAT PET. These findings suggest that SAA provides complementary information to clinical diagnosis and DAT imaging for evaluating possible LBD, particularly in patients with biomarker evidence of coexisting AD pathology.},
}

@article {pmid42854446,
year = {2026},
author = {Gasik, RE and Thierry, AD and Thorpe, RJ},
title = {Allostatic load measurement and cognitive function among midlife and older Black and White adults in the health and retirement study.},
journal = {Psychoneuroendocrinology},
volume = {194},
number = {},
pages = {108032},
doi = {10.1016/j.psyneuen.2026.108032},
pmid = {42854446},
issn = {1873-3360},
abstract = {Allostatic load (AL), a composite of biological measures, is frequently used to capture the physiological burden of chronic stress and is associated with cognitive decline. Black Americans are more likely to develop Alzheimer's disease and related dementias than White Americans, but racial disparities in the AL-cognition relationship have been under explored. Additionally, AL is not consistently measured in literature. The aim of this research was to examine racial variation of the AL-cognition relationship using various AL scoring methods. Data were from the 2006-2016 waves of the Health and Retirement Study, and the sample included 29,809 person-waves of White adults and 7612 person-waves of Black adults. Cognitive function was measured using a modified Telephone Interview for Cognitive Status (mTICS). AL calculation methods included quartile, z-score, and clinical cut-offs. Each measure defined biomarker levels as either high risk or low risk. For 'one-tailed' measures, higher values indicated higher risk for all biomarkers except HDL, for which lower values indicated higher risk. For quartile and z-scores, additional two-tailed measures were calculated which define risk at both unusually low and high biomarker levels. Mixed models were run examining both within-person and between-person change in allostatic load measures in relation to cognitive function. Two-tailed measures more strongly predicted cognitive function both within- and between-persons than traditional quartile or clinical cut-offs, particularly in the Black sample. Findings suggest that nonlinear relationships should be given greater consideration when examining AL, particularly in diverse populations of older adults.},
}

@article {pmid42854589,
year = {2026},
author = {Rawson, G and Howard, ME and Pase, MP and Jackson, ML},
title = {Obstructive sleep apnoea and Alzheimer's disease pathology: a review of plausible pathological mechanisms and potential modifying impact of hypertension.},
journal = {Sleep medicine},
volume = {149},
number = {},
pages = {109307},
doi = {10.1016/j.sleep.2026.109307},
pmid = {42854589},
issn = {1878-5506},
abstract = {Alzheimer's Disease (AD) is estimated to account for up to 75% of all dementia cases, of which there is a global prevalence of 50 million. There are no curative treatments available for AD dementia, therefore, early identification of risk factors is paramount. Up to 40% of all dementia cases may be attributable to modifiable risk factors. One such risk factor is poor sleep. Obstructive sleep apnoea (OSA) is a common sleep disorder characterised by repeated upper airway collapse, contributing to intermittent hypoxaemia and sleep fragmentation. Hypertension is frequently comorbid with OSA and is an established risk factor for dementia, with recent literature exploring potential mechanistic contributions to AD pathogenesis. Despite current literature exploring associations between OSA and hypertension on AD individually, little research has investigated the potential combined impact of these two pervasive disorders. To this end, this review will synthesise existing literature investigating potential pathogenic mechanisms between OSA and AD, including oxidative stress and altered sleep architecture. Further, shared pathophysiological consequences of OSA and hypertension will be reviewed in the context of AD to highlight the potential for effective management in mid-life to preserve neurological and cognitive health in late life.},
}

@article {pmid42854625,
year = {2026},
author = {Jansen, R and Arndt, P and Brüggemann, J and Dörner, M and Mattern, H and Meuth, SG and Lee, JI and Gliem, M and Schreiber, S},
title = {Exploratory synergistic diagnostic value of CSF neurofilament light chain and topographic cortical atrophy in differentiating cerebral amyloid angiopathy from Alzheimer's disease - a pilot study.},
journal = {Journal of the neurological sciences},
volume = {491},
number = {},
pages = {126200},
doi = {10.1016/j.jns.2026.126200},
pmid = {42854625},
issn = {1878-5883},
abstract = {BACKGROUND: Differentiating Cerebral Amyloid Angiopathy (CAA) from Alzheimer's disease (AD) in vivo is challenging due to overlapping amyloid pathology and limited availability sensitivity of hemorrhagic markers in memory clinic settings. We investigated whether integrating regional cortical atrophy with cerebrospinal fluid (CSF) neurofilament light chain (NfL), a marker of axonal injury, might have a diagnostic value.

METHODS: In this pilot study (n = 30, n = 12 CE and n = 18 probable CAA), cortical thickness was quantified via FreeSurfer MRI analysis and standardized into regional Z-scores. We applied a hypothesis-driven dual-region approach (entorhinal cortex vs. precuneus). Classification was performed using firth's penalized logistic regression because of sample size and validated via Leave-One-Out Cross-Validation (LOOCV).

RESULTS: AD exhibited widespread atrophy involving both medial temporal (entorhinal) and posterior parietal (precuneus) structures. In contrast, probable CAA presented with relative temporal preservation despite posterior involvement. CSF NfL was numerically higher in CAA (median 2830 pg/ml) than in AD (2105.5 pg/ml). A combined model (entorhinal, precuneus, and CSF NfL) achieved the highest in-sample discrimination (AUC = 0.86, 95% CI: 0.64-1.00), while LOOCV yielded an AUC of 0.61.

CONCLUSION: The multimodal integration of temporal neurodegeneration and axonal injury captures the divergent pathophysiological signatures of AD and CAA, serving as an exploratory, hypothesis generating pathophysiological profile rather than a generalized diagnostic algorithm.},
}

@article {pmid42854699,
year = {2026},
author = {Trouvé, R and Verstreken, P and Hoekstra, MMB},
title = {Tau phosphorylation from neuronal adaptation to Alzheimer's disease.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.08.032},
pmid = {42854699},
issn = {1097-4199},
abstract = {Tau phosphorylation is classically associated with neurodegeneration, yet similar phosphorylation patterns emerge during physiological states and acute stress responses. How these overlapping patterns of phosphorylated Tau (pTau) relate to neuronal adaptation and Alzheimer's disease pathology remains unresolved. We synthesize findings from human to rodent and fly brains and from neuronal cell models, across neurodevelopment, sleep, hibernation, cellular stress, and disease. Across these contexts, pTau changes are associated with altered Tau localization and functions involving synaptic transmission, mitochondrial activity, RNA metabolism, and genomic integrity. Physiological and acute stress responses are generally transient and reversible, whereas aging, repeated stress, and amyloid-β-associated stress can promote persistent pTau accumulation, impaired clearance, aggregation, and neurodegeneration. We propose that pathological Tau phosphorylation reflects dysregulation of a shared adaptive response rather than activation of an entirely distinct pathway. The critical determinants may be phosphorylation persistence, subcellular localization, proteoform composition, and the capacity to restore Tau homeostasis.},
}

@article {pmid42854778,
year = {2026},
author = {Nguyen, NH and Le, HT and Thi Nguyen, NT and Nguyen, TT and Vo, GV},
title = {Polysaccharide-based drug conjugates and related delivery systems for Alzheimer's disease: from molecular design to translational challenges.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.10.010},
pmid = {42854778},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) presents distinct extracellular, intracellular and vascular delivery targets, yet brain exposure of candidate therapeutics remains difficult to establish. This narrative review compares hyaluronic acid, chitosan, cyclodextrin, dextran, alginate and pectin systems by construct architecture, route, blood-brain barrier (BBB) evidence, cargo release and biological response. The literature includes covalent drug conjugates, loaded or coated carriers, host-guest complexes and intrinsically active polymers; evidence from one category cannot validate another. Clinical programs involving intravenous hydroxypropyl-β-cyclodextrin and a transferrin-receptor antibody shuttle provide context, but do not establish BBB transport for the conjugates reviewed. We examine how polymer size and degradation influence immune safety, particularly chitosan-associated NLRP3 activation and context-dependent responses to hyaluronic acid fragments. We distinguish endothelial or whole-brain signal from parenchymal active-drug exposure, and discuss payload-specific endosomal escape. Advancement requires a defined construct, quantitative target-site exposure, target engagement, comparison with free drug and a matched carrier, and route-appropriate safety data.},
}

@article {pmid42854795,
year = {2026},
author = {Aumont-Rodrigue, G and Picard, C and Sarty, I and Savard, M and Poirier, J and , },
title = {Scavenger receptors associate with Alzheimer's pathology, cholesterol metabolism and synaptic dysfunction.},
journal = {Neurobiology of disease},
volume = {230},
number = {},
pages = {107641},
doi = {10.1016/j.nbd.2026.107641},
pmid = {42854795},
issn = {1095-953X},
abstract = {This study investigated relationships between cerebrospinal fluid (CSF) scavenger receptors and early Alzheimer's disease (AD) pathology in cognitively unimpaired older adults at elevated familial risk, with complementary analyses in autopsied frontal cortex. In the PREVENT-AD cohort, CSF levels of the scavenger receptors MSR1, SCARB2, and SCARF2 were examined in relation to AD biomarkers and synaptic proteins. Complementary analyses, with the same scavenger receptors, used frontal cortex tissue from the Douglas-Bell Canada Brain Bank and targeted sterol/oxysterol mass spectrometry. Linear regression, longitudinal mixed-effects models, pathway enrichment, and mediation analyses were performed. Higher CSF concentrations of MSR1, SCARB2, and SCARF2 were strongly associated with synaptic markers (SNAP25, SYT1, GAP43), with SCARB2 showing the strongest relationships. Associations with Tau biomarkers (t-Tau and p-Tau181) were consistently stronger than those with Aβ species, and baseline receptor levels correlated with longitudinal increases in p-Tau181 over up to 12 years. In autopsied cortex, MSR1 was increased and SCARF2 decreased in AD, while APOB, MSR1 and SCARB2 were associated specific oxysterol levels. Proteomic enrichment linked APOB to vascular and extracellular matrix pathways, whereas scavenger receptor-associated proteins were enriched for synaptogenesis, myeloid activation, and MAPK/phosphorylation signaling. Mediation analyses showed by correlation that scavenger receptors, particularly SCARB2, partially or fully mediated numerous associations between Tau biomarkers and synaptic markers (SNAP25, SYT1 and GAP43). These findings identify MSR1, SCARB2, and SCARF2 as potential integrators of lipid, immune, and synaptic processes in early AD and highlight SCARB2 as a possible mediator of Tau-associated synaptic vulnerability, supporting further mechanistic and cell type-specific investigation.},
}

@article {pmid42855152,
year = {2026},
author = {Gerson, G and Nogueira, GN and Teixeira, MJ},
title = {Plasma p-tau217 as a biomarker for Alzheimer's disease: diagnostic and prognostic value in clinical and population-based studies.},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {10},
pages = {1-8},
pmid = {42855152},
issn = {1678-4227},
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; Biomarkers/blood ; *tau Proteins/blood ; Prognosis ; Predictive Value of Tests ; Sensitivity and Specificity ; Phosphorylation ; Reproducibility of Results ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia worldwide, and blood-based biomarkers are emerging as accessible diagnostic tools. Plasma phosphorylated tau at position 217 (p-tau217) has shown promise in early detection.

OBJECTIVE: To evaluate the diagnostic accuracy, prognostic value, and applicability of plasma p-tau217 in AD compared with other biomarkers.

METHODS: We conducted an integrative review on the PubMed, Scopus, Embase, and Cochrane Library databases (2018-2024). Eligible observational and diagnostic studies assessing p-tau217 in plasma were included. Study selection and quality assessment followed the Standards for Reporting of Diagnostic Accuracy (STARD) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

RESULTS: We analized 9 studies involving more than 6 thousand participants analyzed. Plasma p-tau217 demonstrated high accuracy (area under the curve [AUC]: 0.86-0.94) for detecting tau and amyloid pathology, outperforming p-tau181. It was effective in diverse populations, asymptomatic individuals, and primary care settings. Longitudinal data suggest predictive value for cognitive decline.

CONCLUSION: Plasma p-tau217 is a reliable and non-invasive biomarker for AD, with applications in diagnosis, prognosis, and treatment monitoring. Standardization and multicenter validation are necessary before clinical implementation.},
}

Humans
*Alzheimer Disease/diagnosis/blood
Biomarkers/blood
*tau Proteins/blood
Prognosis
Predictive Value of Tests
Sensitivity and Specificity
Phosphorylation
Reproducibility of Results

@article {pmid42855713,
year = {2026},
author = {Zhang, X and Li, W and Sun, Z and Wang, X and Song, C and Wang, X and Niu, Y and Wei, D and Zhang, W and Zhang, G and Zhang, B and Wang, L and Liu, Z and Zhao, J and Jiang, W},
title = {Advantage of cerebellar intermittent theta-burst stimulation in Alzheimer's disease (ACT-AD): study protocol for a multicenter, randomized, double-blind, sham-controlled trial.},
journal = {Trials},
volume = {27},
number = {1},
pages = {},
pmid = {42855713},
issn = {1745-6215},
support = {2024LC2419//Clinical Research Program of the Fourth Military Medical University/ ; },
mesh = {Humans ; Double-Blind Method ; *Alzheimer Disease/therapy/physiopathology/psychology ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; Treatment Outcome ; *Cerebellum/physiopathology ; *Theta Rhythm ; *Transcranial Magnetic Stimulation/methods/adverse effects ; Time Factors ; Female ; Aged ; Cognition ; Male ; Magnetic Resonance Imaging ; China ; Electroencephalography ; },
abstract = {INTRODUCTION: The cerebellum plays a crucial role in cognitive processing and thus presents a promising therapeutic target for Alzheimer's disease (AD). This trial aims to evaluate the efficacy and safety of long-term, neuronavigated cerebellar intermittent theta burst stimulation (iTBS) in patients with AD.

METHODS AND ANALYSIS: The ACT-AD trial is a multicenter, randomized, double-blind, sham-controlled study involving 100 participants with mild-to-moderate AD across 4 centers in China. Participants will be randomized to receive either cerebellar iTBS or sham stimulation for 4 weeks (daily sessions), followed by 8 weeks of weekly maintenance sessions. The primary outcome is the change in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score from baseline to week 12. Secondary outcomes include additional clinical scales. Exploratory outcomes include electroencephalogram (EEG), blood biomarkers and magnetic resonance imaging (MRI). Statistical analysis will follow intention-to-treat principles using mixed models for repeated measures (MMRM).

DISCUSSION: The ACT-AD trial will assess the efficacy and safety of long-term, neuronavigated cerebellar iTBS in treating patients with mild-to-moderate AD.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT06669182. Registered on 31 October 2024.},
}

Humans
Double-Blind Method
*Alzheimer Disease/therapy/physiopathology/psychology
Multicenter Studies as Topic
Randomized Controlled Trials as Topic
Treatment Outcome
*Cerebellum/physiopathology
*Theta Rhythm
*Transcranial Magnetic Stimulation/methods/adverse effects
Time Factors
Female
Aged
Cognition
Male
Magnetic Resonance Imaging
China
Electroencephalography

@article {pmid42855737,
year = {2026},
author = {La, Y and Yuan, J and Chen, J and Lv, K and Wang, X and Gao, Q and Wang, Y and Wang, C and Xu, B and Yang, Y and Zhang, J},
title = {The glymphatic-lymphatic axis: known pathways, open questions, and emerging roles in neurodegeneration.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42855737},
issn = {2047-9158},
support = {LY24H090006//Natural Science Foundation of Zhejiang Province/ ; 82571418//National Natural Science Foundation of China/ ; 32530027//National Natural Science Foundation of China/ ; 2024C03098//Key Research and Development Program of Zhejiang Province/ ; },
mesh = {Humans ; *Glymphatic System/metabolism/pathology ; *Neurodegenerative Diseases/pathology/metabolism/physiopathology ; Animals ; *Lymphatic Vessels/metabolism/pathology ; *Brain/metabolism ; Lymphatic System ; Cerebrospinal Fluid/metabolism ; },
abstract = {The discovery of the glymphatic system and meningeal lymphatic vessels has transformed our understanding of brain fluid homeostasis and central-peripheral communication, highlighting the critical role of cerebrospinal fluid in brain clearance. While substantial progress has been made in defining the structural components and physiological regulators of brain clearance, major uncertainties remain regarding (1) how these systems interact as an integrated physiological network, (2) how they fail in disease, and (3) whether they can be therapeutically manipulated. In this review, we first summarize the anatomical and physiological organization of the glymphatic-lymphatic axis, with particular emphasis on its regulatory mechanisms in light of rapid advances in this field. We then discuss how the glymphatic-lymphatic axis functionally integrates with peripheral immune and metabolic systems and describe how impairment of these clearance pathways is associated with the accumulation of pathological proteins, neuroinflammation, and vascular dysfunction and may contribute to the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Finally, we discuss emerging therapeutic strategies and biomarkers targeting the glymphatic-lymphatic axis. By redefining the central-peripheral crosstalk, the glymphatic-lymphatic axis provides a unifying framework for understanding brain clearance, neurodegeneration, and future therapeutic interventions.},
}

Humans
*Glymphatic System/metabolism/pathology
*Neurodegenerative Diseases/pathology/metabolism/physiopathology
Animals
*Lymphatic Vessels/metabolism/pathology
*Brain/metabolism
Lymphatic System
Cerebrospinal Fluid/metabolism

@article {pmid42855813,
year = {2026},
author = {Alten, B and Gokcal, E and Sperling, RA and Shirzadi, Z and Chhatwal, JP and Gurol, ME and Kasner, SE and Greenberg, SM and Cucchiara, BL},
title = {Centrum Semiovale Perivascular Spaces Predict First Hemorrhagic Lesion in Asymptomatic Amyloid-Positive Individuals.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78388},
pmid = {42855813},
issn = {1531-8249},
abstract = {OBJECTIVE: Identification of cerebral amyloid angiopathy (CAA) before its hemorrhagic manifestations remains limited. We aimed to determine whether severe enlarged perivascular spaces in the centrum semiovale (EPVS-CSO) identify a prehemorrhagic stage of sporadic CAA by predicting the first appearance of CAA-related hemorrhagic lesions or incident cognitive decline in amyloid-positive, cognitively unimpaired, hemorrhage-free older adults.

METHODS: We performed a secondary analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial, a phase 3 randomized study in cognitively unimpaired, amyloid-positive older adults. Participants with baseline hemorrhagic lesions were excluded. Baseline EPVS-CSO severity was dichotomized as severe versus nonsevere. Severe basal ganglia EPVS, more closely associated with hypertensive small vessel disease, was evaluated as a topographical negative-control exposure. The primary outcome was incident strictly lobar cerebral microbleeds or cortical superficial siderosis. The secondary outcome was longitudinal cognitive trajectories measured by the Preclinical Alzheimer Cognitive Composite.

RESULTS: Among 932 participants (mean age 71.7 ± 4.8 years; 61.3% female), 101 (10.8%) had severe EPVS-CSO at baseline. Over a median follow up of 5.1 years (IQR 3.3-5.5 years), 33.7% of those with severe EPVS-CSO developed incident CAA-related hemorrhagic lesions compared with 13.6% of those with nonsevere EPVS-CSO (adjusted HR 2.85, 95% CI 1.91-4.25; p < 0.0001). Severe basal ganglia EPVS was not associated with incident hemorrhagic lesions (adjusted HR 0.87, 95% CI 0.35-2.18; p = 0.77). Severe EPVS-CSO was not associated with early cognitive differences, and participants who developed incident hemorrhagic lesions showed more pronounced cognitive decline.

INTERPRETATION: These findings identify severe EPVS-CSO as a strong predictor of first appearance of CAA-related hemorrhagic lesions in amyloid-positive individuals, supporting integration of amyloid biomarkers into magnetic resonance imaging-based Boston criteria. Identifying markers of the transition of CAA from a nonhemorrhagic to a hemorrhagic stage provides a potential foundation for approaching primary prevention of CAA-related hemorrhage. ANN NEUROL 2026.},
}

@article {pmid42855977,
year = {2026},
author = {Bosco, N and Cappellato, V and Micalizzi, E},
title = {Negotiating Care Over Time: A Systematic Review of Alzheimer's Disease Caregiving Through a Life Course Approach.},
journal = {Sociology of health & illness},
volume = {48},
number = {8},
pages = {e70280},
doi = {10.1111/1467-9566.70280},
pmid = {42855977},
issn = {1467-9566},
mesh = {Humans ; *Alzheimer Disease/nursing ; *Caregivers/psychology ; Adaptation, Psychological ; *Negotiating/psychology ; },
abstract = {The global ageing of the population has significantly increased the demand for long-term informal care, particularly in the context of Alzheimer's disease (AD). Although research on caregiver burden and coping strategies is extensive, limited attention has been paid to the temporal evolution of caregiving roles and their intersections with caregivers' life trajectories. This systematic review, conducted across literature published between 2004 and 2024, examines how the life course perspective has been applied in sociological research on family caregiving for people with AD, aiming to analyse the interplay between caregiving timing, biographical transitions, and socio-institutional contexts. The selected studies reveal that caregiving is not a static or homogeneous role but evolves across the life span, shaped by transitions, linked lives and structural conditions. Adopting a life course perspective enhances the understanding of caregiving as a dynamic and socially embedded process. This approach underscores the need for policies that are temporally sensitive, culturally reflexive and capable of supporting caregivers across different life stages.},
}

Humans
*Alzheimer Disease/nursing
*Caregivers/psychology
Adaptation, Psychological
*Negotiating/psychology

@article {pmid42855983,
year = {2026},
author = {Khan, Y and Naeem, MU and Naqvi, SF and Fatima, B and Hussain, R and Uddin, H and Aziz, T and Binsaleh, AY and Al-Hoshani, N and Alwabsi, HA},
title = {Design, synthesis, and biological evaluation of pyrimidine linked fused thiazole-isoxazole conjugates as dual cholinesterase inhibitors for Alzheimer's disease.},
journal = {Zeitschrift fur Naturforschung. C, Journal of biosciences},
volume = {},
number = {},
pages = {},
pmid = {42855983},
issn = {1865-7125},
abstract = {Alzheimer's disease (AD) affects over 55 million individuals worldwide, yet approved pharmacotherapies remain limited to symptomatic relief. Dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) offers a validated approach to restoring cholinergic tone. However, structurally differentiated inhibitors with favorable selectivity profiles are critically needed. Here, we report a series of pyrimidine clubbed thiazolo[4,5-c]isoxazole framework that functions as potent dual cholinesterase inhibitors with low-micromolar activity against both AChE and BuChE. Lead compound-1 demonstrated IC50 values of 6.19 ± 0.60 μM (AChE) and 8.64 ± 0.91 μM (BuChE) showing promising performance over the reference donepezil (AChE IC50 = 19.38 ± 0.98 μM, BuChE IC50 = 27.54 ± 1.34 μM). Furthermore, structure-activity relationship analysis identified electron-withdrawing (p-CF3, p-F, o,p-Cl, p-NO2) and electron-donating (-OH) aryl substituents as principal modulators of inhibitory potency. Moreover, molecular docking against human AChE and BuChE crystal structures revealed dual engagement of the catalytic anionic site and peripheral anionic site through hydrogen-bonding and π-π stacking interactions. In silico ADMET profiling confirmed electronic reactivity and drug-likeness of lead compounds. These findings establish pyrimidine-clubbed thiazolo[4,5-c]isoxazole as a mechanistically grounded scaffold with translational potential for next-generation anti-Alzheimer therapeutics.},
}

@article {pmid42856097,
year = {2026},
author = {Lopez-Esquibel, N and Bettcher, BM and Gunn-Sandell, LB and Gonzalez, ME and Carlson, NE and Unger, JR and Holden, SK and Greher, MR and Lum, HD},
title = {Patient and care partner perspectives of a teleneuropsychology intervention: a mixed-methods evaluation.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/13854046.2026.2742406},
pmid = {42856097},
issn = {1744-4144},
abstract = {OBJECTIVE: While neuropsychological evaluations by telehealth are a valid alternative to face-to-face (FF) visits, teleneuropsychology has not been widely adopted. We explored patient and care partner perspectives on acceptability, appropriateness, feasibility, and use of teleneuropsychology to evaluate possible Alzheimer's disease.

METHODS: Using mixed methods, we evaluated patient and care partner's quantitative surveys and qualitative interviews after two neuropsychology modalities: Teleneuropsychology or FF. Surveys included acceptability, appropriateness, and feasibility measures, and the Unified Theory of Acceptance and Use of Technology questionnaire. Median scores and interquartile ranges were compared. Interviews focused on implementation outcomes and intention to use. Qualitative analyses identified salient themes, which were integrated with quantitative findings.

RESULTS: Patients and care partners (94 and 93% non-Hispanic white) reported similar positive (median score = 4.0 on a 5-point scale) ratings for Teleneuropsychology and FF. Interviews found that benefits of Teleneuropsychology were support for care partner involvement, minimization of logistical demands, reduced travel burden, and increased comfort within a patient's home. Benefits of FF included increased interpersonal connection, improved communication with the provider, and less stress with technology. Some patients tended to prefer FF, while some care partners tended to prefer Teleneuropsychology.

CONCLUSIONS: Patients and care partners in this homogeneous sample indicated that both modalities were acceptable, appropriate, and feasible. Although quantitative ratings were similar, the "appropriate" choice for a particular patient and care partner dyad seemed to be a personalized consideration of tradeoffs that they navigated together. When Teleneuropsychology is adopted, attention to preferences and feasibility among diverse patients is needed.},
}

@article {pmid42856127,
year = {2026},
author = {Grant, RA and Park, LHE and Wahl, D and LaRocca, TJ},
title = {Apigenin Improves Healthspan and Protects Against Alzheimer's Disease-Associated Proteotoxicity in C. elegans.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.23.753917},
pmid = {42856127},
issn = {2692-8205},
abstract = {Apigenin is an abundant, bioactive phytochemical with reported therapeutic potential and neuroprotective effects in a variety of age-related disease models. However, the extent to which apigenin may promote healthspan and protect against neurodegeneration-associated proteotoxicity has not been thoroughly investigated, and the biological processes/mechanisms that underlie its protective effects remain unclear. To determine if apigenin increases healthspan, we performed lifespan assays in conjunction with measures of aging-relevant physiological function in wild-type C. elegans . We found that chronic exposure to apigenin extended median lifespan and improved multiple readouts of healthspan, including pharyngeal pumping, locomotor activity, and age-related macromolecular damage accumulation. Additional analyses of transgenic reporter strains and transcriptomic profiling (RNA-seq) indicated that apigenin primarily modulated redox-sensitive stress signaling and pathways associated with cellular homeostasis in aging animals. Finally, in transgenic C. elegans strains expressing the pathological Alzheimer's disease-associated proteins amyloid-beta or tau, we found that apigenin had similar beneficial effects on lifespan, healthspan, and proteotoxicity-associated functional impairments. Together, our results support apigenin as a potential healthspan-promoting intervention that acts in part through reductions in oxidative stress-associated signaling, with beneficial effects that extend to models of Alzheimer's disease-associated proteotoxicity.},
}

@article {pmid42856154,
year = {2026},
author = {Zhan, Y and Yan, B and Zhang, A and Kellis, M and Sun, N},
title = {ProxiNet transfers spatially learned cellular proximity to dissociated single-cell transcriptomes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.25.754372},
pmid = {42856154},
issn = {2692-8205},
abstract = {Spatial transcriptomics reveals cellular organization within intact tissues, whereas dissociated single-cell RNA sequencing provides broad transcriptomic coverage but loses information about cellular proximity and neighborhood structure. Here, we developed ProxiNet , a spatially supervised framework that learns transcriptomic signatures of pairwise cellular proximity from spatial reference datasets and transfers these relationships to dissociated single-cell transcriptomes. ProxiNet predicted cellular proximity across brain regions and spatial technologies, including zero-shot cross-technology transfer, and gradient-based attribution identified genes and broader transcriptional programs associated with proximity predictions. In spatial datasets with known coordinates, ProxiNet-derived cellular neighborhoods recovered reproducible tissue organization and anatomical structure, providing independent spatial validation of the inferred proximity relationships. Applying the spatially calibrated model to dissociated scRNA-seq revealed heterogeneous cellular neighborhoods with distinct cell-type compositions and candidate communication programs. In an Alzheimer's disease dataset, ProxiNet further identified age-associated remodeling of inferred neighborhoods, including an AD-associated neighborhood at 8 months characterized by distinct astrocyte and neuronal transcriptional states and candidate intercellular communication programs. Together, these results establish pairwise cellular proximity as an interpretable and transferable representation for extending spatially learned tissue organization to dissociated single-cell transcriptomes.},
}

@article {pmid42856250,
year = {2026},
author = {Traxler, L and Borgogno, O and Champion, K and Herdy, JR and Dzieciatkowska, M and Reisz, JA and Petrosyan, A and Siler, C and Anderson, CC and Gorostieta-Salas, E and Lucciola, R and Galasko, D and Gage, FH and D'Alessandro, A and Mertens, J},
title = {Nuclear acetyl-CoA accumulation drives reversible RBP hyperacetylation and transcriptome-wide splicing shifts in age-equivalent Alzheimer's disease neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.26.754222},
pmid = {42856250},
issn = {2692-8205},
abstract = {UNLABELLED: Metabolic alterations and dysregulated alternative RNA splicing are central layers of Alzheimer's disease (AD) pathogenesis, yet whether and to what extent these changes are mechanistically linked in adult human neurons in the aging brain remains unclear. To assess this, we generated induced neurons (iNs) by direct conversion of fibroblasts from sporadic AD patients and age-matched control donors. Fibroblast-derived iNs retaining donor-specific aging signatures have been shown to display several AD-related phenotypes. Metabolomic analysis revealed that AD iNs divert citrate toward ATP-citrate lyase (ACLY)-dependent citrate-to-acetyl-CoA flux, which drives increased nuclear levels of the high-energy metabolite acetyl-CoA. Acetyl-proteomics showed that acetyl-CoA accumulation leads to widespread hyperacetylation of RNA-binding proteins (RBPs) and splice regulators, suggestive of a direct mechanistic link between a metabolic shift and RNA processing. Indeed, single-cell long-read RNA sequencing identifies splicing alterations in AD-relevant transcripts whose isoform usage mirrors changes observed in post-mortem AD cortex samples. Subcellular acetyl-CoA imaging reveals that inhibition of ACLY enzymatic activity selectively reduces nuclear acetyl-CoA levels, and further improves citrate metabolic flux, normalizes RBP acetylation, and re-establishes a normal neuronal splicing landscape in AD iNs. Together, these findings reveal a nuclear acetyl-CoA-RNA processing axis that links age- and disease-related metabolic alterations to alternative splicing dysregulation in AD, and identify neuronal nuclear acetyl-CoA production as a causal and reversible node for restoring metabolic and RNA homeostasis in aging human AD neurons.

HIGHLIGHTS: Sporadic Alzheimer's disease (AD) patient-derived directly induced neurons (iNs) shift metabolism toward nuclear acetyl-CoA production via ATP-citrate lyase (ACLY).Elevated nuclear acetyl-CoA causes hyperacetylation of RNA-binding proteins (RBPs).Patient iNs show pathogenic RNA splicing patterns similar to post-mortem AD brains.Inhibition of ACLY normalizes neuronal acetyl-CoA metabolism and restores RNA splicing homeostasis.},
}

@article {pmid42856312,
year = {2026},
author = {Mukherjee, S and Barthélemy, NR and Atri, T and Li, Y and Yen, D and He, Y and Coyle, R and Ovod, V and Franklin, EE and Xiong, C and Wang, G and Xu, J and Farsad, H and Mummery, CJ and Masters, CL and Sanchez-Valle, R and Masellis, M and Hsiung, GR and Guthier, S and Lah, JJ and Berman, SB and Roberson, ED and Surti, G and Honig, LS and Clarnette, R and Vitali, P and Ringman, J and Bird, TD and Brooks, WS and Fox, NC and Suzuki, K and Black, SE and Levin, J and Farlow, MR and Chhatwal, J and Aggarwal, NT and Jucker, M and Frosch, MP and Kofler, JK and White, C and Keene, CD and Chen, J and Glass, J and Gearing, M and Ryan, NS and Aguillón, D and Supnet-Bell, C and Gordon, BA and Benzinger, TLS and Sims, J and Yaari, R and Bittner, T and Klein, G and Delmar, P and Morris, JC and Llibre-Guerra, J and Clifford, DB and Karch, CM and McDade, E and Perrin, RJ and Bateman, RJ and , and , },
title = {Gantenerumab reduces brain amyloid-β proteoforms: Biochemical evaluation in dominantly inherited Alzheimer disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.22.26363432},
pmid = {42856312},
abstract = {UNLABELLED: Therapeutic strategies targeting amyloid-β (Aβ) in Alzheimer disease (AD) include antibodies directed against fibrillar amyloid plaques or soluble amyloid-β (Aβ) species, yet how these approaches reshape brain pathology remains poorly understood. Postmortem neuropathological assessment is crucial for evaluating the degree of Aβ removal, providing information and context that fluid biomarkers and positron emission tomography (PET) alone cannot, and guiding development of more effective disease modifying therapies for AD. In this study, using high resolution mass spectrometry we quantitatively measured Aβ and tau proteoforms in postmortem brain tissue homogenates to evaluate the impact of long-term treatment with anti-Aβ monoclonal antibodies gantenerumab or solanezumab in a clinical trial of dominantly inherited Alzheimer disease (DIAD). Symptomatic DIAD participants who had been treated for ∼ 4 years with anti-Aβ monoclonal antibodies (gantenerumab, n=4 or solanezumab, n=4) were compared with untreated, symptomatic DIAD mutation carriers (n=40) and with age-relevant non-DIAD controls with modest or no plaque pathology (n=18). Consistent with antemortem Aβ-PET findings in the clinical trial, gantenerumab-treated participant samples showed significantly lower levels of specific Aβ proteoforms (Aβ 42 , Aβ 40) in the insoluble plaque associated pool (range: 60-80 % reduction); they also showed lower levels of post-translationally modified Aβ proteoform Aβ 3pGlu in both the insoluble and soluble pool, compared to untreated DIAD participants, but without reaching the levels found in non-DIAD controls. Samples from gantenerumab-treated participants also showed regionally lower amounts of insoluble phosphorylated tau species (pT181, pT205, pT208) and MTBR tau species (354-369, 306-317, 299-317) without apparent differences in insoluble total tau levels. In contrast, brain tissue samples from solanezumab-treated participants did not show significant differences overall in soluble or insoluble levels of Aβ and tau proteoforms in comparison to those from non-treated DIAD individuals. These findings support that amyloid targeting treatment (ATT) with gantenerumab, an antibody that targets fibrillar Aβ, can remove insoluble Aβ from the DIAD brain and also mitigate "downstream" biochemical and pathophysiological changes associated with AD.

KEY SUMMARY: Question: How do amyloid targeting treatments (ATT) affect the Alzheimer disease (AD)-related brain pathologies of soluble and aggregated amyloid-β and tau proteoforms in postmortem tissue?Background: Extracellular amyloid plaques and neurofibrillary tangles (NFTs) are the primary pathological hallmarks of AD. For the past three decades, active and passive immunization against cerebral amyloid-β (Aβ) has constituted one of the primary avenues of disease-modifying intervention in AD. Recently, passive immunizations using anti-Aβ targeting antibodies have demonstrated slowing of cognitive decline in sporadic AD and possibly in dominantly inherited AD (DIAD). In these clinical trials, target engagement has been inferred from Aβ-positron emission tomography (PET) and/or biofluid biomarkers during life. However, to confirm evidence of target engagement more directly, identify which pathological proteoforms are affected, quantify the dose dependent treatment effects of these treatments, and begin to evaluate their putative downstream effects on AD pathophysiology, quantitative biochemical comparisons of amyloid plaques and tau pathology (soluble and insoluble Aβ and tau species) in postmortem brain tissue of treated and untreated AD are needed.Findings: In this study, using high resolution mass spectrometry we measured the soluble and insoluble Aβ and tau proteoforms in the postmortem brain tissue homogenates from DIAN-TU-001 trial participants who were symptomatic and had been treated for ∼ 4 years with gantenerumab (n=4) or solanezumab (n=4), two antibodies that bind to insoluble and soluble Aβ, respectively. Intervals between treatment discontinuation and death ranged from 5 months to 3 years. Comparisons were made with postmortem brain tissue samples from untreated, symptomatic DIAD participants of the DIAN-Obs study (n=40) and from age-relevant, cognitively normal, non-DIAD controls with or without only modest burdens of diffuse Aβ plaques (n=18). Consistent with antemortem Aβ-PET findings in the clinical trial, gantenerumab significantly decreased specific Aβ (Aβ 42 , Aβ 40) proteoforms in the insoluble plaque associated pool (range: 60-80% reduction) compared to the untreated DIAD participants, but without reaching the levels found in the non-DIAD controls. Samples from gantenerumab treated participants also showed significantly lower amount of post-translationally modified Aβ (Aβ 3pGlu) and regionally lower insoluble phosphorylated tau species (pT181, pT205 and pT208), without apparent differences in insoluble total tau levels. In contrast, solanezumab treatment did not show significant effect on the soluble or insoluble levels of Aβ and tau proteoforms in comparison to samples from non-treated DIAD individuals. Significance: These findings support that ATT with gantenerumab, an antibody that targets fibrillar Aβ, can remove insoluble Aβ from the DIAD brain and also mitigate "downstream" biochemical and pathophysiological changes associated with AD.},
}

@article {pmid42856336,
year = {2026},
author = {Alsolami, S and Wang, M and Sabedot, TS and Singh, U and Kirk, B and Mitchell, L and Hernandez, M and Skvir, N and Bowman, C and Oiwa, K and Agarwal, R and Mahmoudi, M and Cuoco, MS and MacDonald, E and Cranston, S and Lucciola, R and Boassa, D and Herdy, JR and Jones, JR and Yoshikiyo, K and , and Mertens, J and Martinez-Trujillo, J and Jaremko, L and Murphy, GJ and Gage, FH},
title = {An age-preserving neuronal iSpheroid platform for modeling human aging and Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.30.755853},
pmid = {42856336},
issn = {2692-8205},
abstract = {UNLABELLED: Aging is the strongest risk factor for Alzheimer's disease (AD), yet existing human neuronal models either erase age-associated features during reprogramming or fail to recapitulate three-dimensional organization of human neuronal tissue. Here, we establish directly induced neuronal spheroids (iSpheroids), a scalable three-dimensional platform generated by direct conversion of primary fibroblasts without pluripotency. iSpheroids generate long-lived, electrophysiologically active neurons from young, unimpaired aged, and sporadic AD donors while preserving donor-specific epigenetic age. Single-nucleus RNA sequencing revealed approximately 96% of cells acquired a neuronal identity and were distributed across multiple neuronal states, including a diversity of neurons. The platform supports incorporation of astrocytes and microglia and generation from non-human primate fibroblasts. AD iSpheroids spontaneously recapitulated neuronal degeneration, amyloid-β accumulation, progressive Tau pathology, and metabolic dysfunction. Integrated proteomic, metabolomic, and lipidomic profiling distinguished physiological aging from AD and revealed disease-associated metabolic remodeling. Oxaliplatin shifted AD iSpheroids toward oxidative metabolism, whereas a multi-compound screen identified trametinib as a modulator of inflammatory and age-associated programs.

HIGHLIGHTS: - Direct conversion generates age-preserving, functional human neuronal iSpheroids.- iSpheroids recapitulate molecular and pathological hallmarks of AD.- Multi-omics distinguishes physiological neuronal aging from AD.- Pharmacological screening identifies reversible metabolic and inflammatory phenotypes.},
}

@article {pmid42856350,
year = {2026},
author = {Petrican, R and Fornito, A and John, A and Pendered, S},
title = {Regional similarity to male-typical brain architecture links childhood ADHD to neurophysiological aging in later adulthood.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.27.754764},
pmid = {42856350},
issn = {2692-8205},
abstract = {Identifying early life biomarkers of suboptimal aging trajectories could help design interventions to delay or even prevent the onset of pathological conditions in older adulthood. To address this issue, we capitalize on evidence that the prevalence rates and presentation of neurodevelopmental and neurodegenerative conditions tend to vary between males and females, thereby raising the possibility that processes involved in sexual differentiation could help connect brain maturation and aging outcomes. Here, we focus on attention deficit hyperactivity disorder (ADHD), a neurodevelopmental condition with male-biased prevalence, and examine the relevance of its genetic risk and functional brain profile to aging outcomes. We analyzed multimodal data from a child sample enriched in ADHD cases and a neurologically intact adult sample. Among 6-to-12-year-olds (N =522), genetic vulnerability to pathological aging, indexed via polygenic risk scores (PRSs) for Alzheimer's Disease (AD), predicted ADHD diagnosis across sexes, regardless of psychiatric history and PRSs for multiple disorders (including ADHD). Irrespective of age, boys and girls diagnosed with ADHD showed preferential alignment with male-, rather than female-, typical functional connectivity patterns in metabolically active transmodal areas which are enriched in 5-HT 2,4 , D1, and mGLU5 receptors. In an independent sample aged 36-90 years (N = 345), the ADHD brain profile correlated with higher levels of testosterone, physiological markers of reproductive aging and poorer performance on AD-relevant cognitive tasks among older individuals of either sex. Our results imply that neurodevelopmental conditions could provide insights into vulnerability to suboptimal aging trajectories and could help guide early interventions targeting at-risk individuals.},
}

@article {pmid42856359,
year = {2026},
author = {Petrican, R and Fornito, A},
title = {Alignment with sex-typical brain architecture: Links to mood pathology, sex hormones and transcriptomics of neurodegenerative conditions.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.27.754773},
pmid = {42856359},
issn = {2692-8205},
abstract = {Understanding the mechanisms that underpin the pervasive sex bias in risk for specific psychiatric and neurodegenerative conditions could substantially advance efforts promoting personalized medicine. As a first step towards addressing this issue, we applied imaging transcriptomics and multivariate analysis techniques to data from an adolescent sample enriched in anxiety/depression cases, a child sample enriched in attention deficit hyperactivity disorder (ADHD) cases, and adult patients with treatment resistant major depressive disorder (MDD). We tested whether, across sexes, alignment with female-typical, rather than male-typical, patterns of neural functional connectivity (FC) would relate to a diagnosis (adolescent sample) or severity of symptoms (adult sample) associated with internalizing disorders, which tend to be more often diagnosed in females. To provide preliminary evidence on its functional specificity, we compared the sex-aligned FC profile that distinguished neurotypical adolescents from those diagnosed with depression/anxiety against the sex-aligned FC patterns that distinguished neurotypical children from those diagnosed with ADHD. All the analyses controlled for age within each sample and sex. Finally, we examined the spatial overlap between the sex-aligned FC profile linked to an internalizing diagnosis in adolescence and the transcriptomic maps of genes that show sex-dependent dysregulation in neurodegenerative conditions. Across sexes, increasing alignment with female-typical FC patterns, from sensory-perceptual to default mode regions, discriminated between typically developing and anxious/depressed teens and tracked longitudinal fluctuations in depressive symptoms within adult MDD patients. The identified internalizing-related gradient showed a negative correlation with risk for ADHD in the child sample. The brain regions most strongly aligned with female-, rather than male-, typical FC in depression/anxiety overlapped the spatial expression profiles of genes linked to gonadal hormone synthesis, as well as genes dysregulated in female autism spectrum disorder (ASD) and male neurodegenerative conditions, specifically, Alzheimer's Disease (AD), Huntington's Disease (HD) and Multiple Sclerosis (MS). The brain areas most strongly aligned with male-typical, rather than female-typical, FC patterns overlapped the transcriptomic maps of genes related to androgen and estrogen receptors, as well as of genes dysregulated in male ASD and female neurodegenerative conditions (i.e., AD, HD, MS). Our results raise the possibility that the link between mood pathology and neurodegeneration could reflect a partial, regional reversal of sex-normative functional brain profiles.},
}

@article {pmid42856370,
year = {2026},
author = {Tang, S and Younes, K and Penukonda, E and Hausle, I and Thropp, P and Lupo, JM and Tosun, D and , },
title = {Examining the Clinical Utility of Deep Learning Models for Perivascular Space Segmentation in Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.27.26363725},
pmid = {42856370},
abstract = {Open-source deep learning models promise scalable quantification of MRI-visible perivascular spaces (PVS), an emerging marker of glymphatic dysfunction in Alzheimer's disease (AD). Whether these models remain valid when applied to heterogeneous AD cohorts and preserve ground-truth derived biological associations has not been established. We benchmarked five open-source nnU-Net-based PVS segmentation models (nnU-Net T1, nnU-Net T1+FLAIR, mcPVS-Net, MedNet-PVS, ADNI-PVS-Net) against manual labels in 60 multi-site ADNI-3 participants balanced across cognitively unimpaired, mild cognitive impairment, and AD dementia, and in 12 publicly available scans from the VAscular Lesions object-level and segmentatiOn (VALDO) challenge. We evaluated overall, voxel, object, and lesion-wise Dice; stratified performance by region, diagnosis, scanner, PVS severity, and white matter hyperintensity (WMH) burden; and tested whether model-derived PVS burden reproduced ground-truth derived associations with AD-related biomarkers. Despite high internal performance, all models showed a specialist-generalist trade-off: the AD-trained ADNI-PVS-Net achieved highest internal performance (overall Dice = 0.58±0.14) but degraded most externally (Dice ≤ 0.11), while MedNet-PVS and mcPVS-Net generalized externally (Dice 0.27-0.30) but systematically misestimated PVS burden. Models were relatively robust across scanner and diagnosis but inconsistent across PVS severity, and some misclassified up to 32% of WMH as PVS. Notably, only AD-trained models reproduced the expected PVS-amyloid biomarker relationship; other models returned a null result, despite comparable or superior Dice scores. These findings show that internal segmentation accuracy and external generalizability alone do not guarantee downstream inferential validity. Careful model selection and cohort-specific validation against manual labels should precede clinical inference in AD.},
}

@article {pmid42856420,
year = {2026},
author = {Geng, Z and Montembeault, M and Coulombe, V},
title = {Diagnostic Utility of Multi-Domain Language Measures Across the Alzheimer Disease Continuum.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.28.26364143},
pmid = {42856420},
abstract = {OBJECTIVES: Alzheimer's disease (AD) progresses from a cognitively unimpaired stage through mild cognitive impairment (MCI) to dementia. Because language impairment often emerges before dementia, it is a candidate marker of disease stage. Yet the standard batteries of large AD research cohorts rely on a narrow set of tests that mainly evaluate the lexical-semantic domain (i.e., picture naming and verbal fluency), leaving other language domains, such as semantic memory, phonology, morphosyntax, and single-word reading, rarely assessed. We evaluated the diagnostic utility of standard and specialized language tests for distinguishing amyloid-positive MCI and dementia of the Alzheimer's type (DAT) from healthy controls (HC) and from each other.

METHODS: We included 286 participants from the National Alzheimer's Coordinating Center (125 HC, 53 MCI Aβ+, 108 DAT Aβ+) assessed with three standard tests from UDSv3 (semantic fluency, letter fluency, and Multilingual Naming Test [MINT]) and nine specialized tests from the FTLD Module (regular and irregular word reading, semantic word-picture matching, semantic associates, Northwestern Anagram Test - Short Form [NAT-S], Northwestern Naming Battery noun and verb naming, sentence repetition, and sentence reading). For each test, the area under the receiver operating characteristic curve (AUC) was computed for DAT vs. HC, MCI vs. HC, and DAT vs. MCI, and AUCs were compared between tests with DeLong's test.

RESULTS: Eight of 12 measures reached acceptable discrimination (AUC ≥ .700) for DAT vs. HC, five for MCI vs. HC, but only semantic fluency and NAT-S for DAT vs. MCI. Semantic fluency showed the highest discrimination in each contrast, though it did not significantly outperform the NAT-S for MCI vs. HC or DAT vs. MCI. MINT, letter fluency, and irregular word reading reached clinically meaningful accuracy in distinguishing MCI and DAT from HC, but not DAT from MCI. The remaining specialized tests reached it only for DAT vs. HC, or not at all. In a post hoc regression, adjusting for cognitive flexibility and working memory attenuated group differences; the DAT difference was no longer significant, whereas the MCI difference remained significant.

DISCUSSION: Semantic fluency was the strongest single language marker across the AD continuum. Among specialized tests, NAT-S was the most informative, challenging the view that syntax is spared in early AD. Its performance was partly explained by executive function, mainly in DAT, whereas a residual morphosyntactic component remained in MCI, and several specialized tests were limited by ceiling effects. Clinically, the NAT-S may complement semantic fluency for staging, and specialized tests may help characterize heterogeneous language profiles in MCI and DAT.},
}

@article {pmid42856437,
year = {2026},
author = {Harris, AS and Rouse, JA and Guo, G and Fernandez-Maestre, I and Pal, S and Oh, B and Li, S and See, WY and Anderson, A and Gewolb, J and Soethout, M and Habel, J and Utama, R and Vakoc, CR and Amor, C},
title = {CAR T cell targeting of inflammatory myeloid progenitors in the bone marrow remodels border-associated macrophages and reverses cognitive aging.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.27.754777},
pmid = {42856437},
issn = {2692-8205},
abstract = {Aging is associated with progressive neuroinflammation and cognitive decline, yet the cellular sources that sustain this process and whether they can be targeted peripherally remain unclear. Here, we identify inflammatory border-associated macrophages (BAMs) as key drivers of neuroinflammation in aging and show that their therapeutic and prophylactic elimination through intrathecal CAR T cell therapy restores cognitive performance in mouse models of aging and Alzheimer's disease. Furthermore, targeting of aged inflammatory bone marrow myeloid progenitors through either intravenous CAR T cells, which do not infiltrate the brain, or through transplantation of CAR T-treated progenitors is sufficient to reduce neuroinflammation and cognitive impairment. These findings reveal that bone marrow myeloid progenitors harbor a heritable inflammatory transcriptional state that is transmitted to their BAM progeny, driving neuroinflammation and cognitive deterioration, and conserved in human aging. Critically, this proinflammatory state is marked by the upregulation of surface proteins, enabling precise peripheral CAR T cell targeting of these progenitors for long-lasting therapeutic effects in cognitive aging.},
}

@article {pmid42856516,
year = {2026},
author = {Wang, N and Dang, L and Chang, W and Qi, H and Ban, J and Guo, H and Tang, S},
title = {Non-pharmacological interventions for cognitive function improvement in patients with Alzheimer's disease: a best evidence summary.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1888519},
pmid = {42856516},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Cognitive Training ; Cognitive Enhancement ; *Cognition ; Music Therapy ; },
abstract = {OBJECTIVE: This study aimed to systematically retrieve, analyze, and synthesize evidence on non-pharmacological interventions to improve overall cognitive function in patients with Alzheimer's disease (AD), providing evidence-based references for selecting and optimizing these interventions.

METHODS: This review followed the PRISMA-ScR guidelines and the JBI scoping review framework. The evidence-based question was developed using the PIPOST framework. Databases and professional platforms were systematically searched from inception to January 30, 2026, using the "5S" model. Included studies were quality-appraised; eligible evidence was extracted, synthesized, graded, and assigned recommendation levels.

RESULTS: Following a strict literature screening strategy, a total of 15 studies were included, comprising 1 guideline, 7 expert consensus reports, 6 systematic reviews, and 1 randomized controlled trial. A total of 18 best evidence items were summarized and categorized into six dimensions: cognitive training (CT) and digital therapy, neuromodulation techniques, exercise interventions, lifestyle and reminiscence therapy interventions, music and sensory stimulation, and acupuncture and combined interventions.

CONCLUSIONS: This study consolidated the best evidence on non-pharmacological interventions to improve overall cognitive function in patients with Alzheimer's disease, providing references for clinical practice. Clinical healthcare professionals should select appropriate interventions based on the actual clinical scenarios and individual patient conditions, and strengthen quality control during implementation.},
}

Humans
*Alzheimer Disease/therapy/psychology
Cognitive Training
Cognitive Enhancement
*Cognition
Music Therapy

@article {pmid42856517,
year = {2026},
author = {Pinamonti, M and Moretto, M and Pieperhoff, L and Arunachalam, P and Barkhof, F and Wink, AM and Lorenzini, L and Veronese, M},
title = {Normative Modeling of Molecular-Enriched Functional Connectivity for Detecting Deviations from Healthy Brain Aging.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.28.754989},
pmid = {42856517},
issn = {2692-8205},
abstract = {INTRODUCTION: Inter-individual variability in adult brain aging can obscure early pathological alterations and is only partly represented by population-average or scalar brain-aging measures. We combined Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) with normative modeling (NM) to derive spatially resolved, molecularly informed deviation scores for dopamine transporter (DAT)-, norepinephrine transporter (NET)-, and serotonin transporter (SERT)-enriched resting-state functional connectivity (FC). We first evaluated whether these normative models could be transferred to independently processed external data through local calibration and then explored whether the resulting deviation profiles differed with cerebral amyloid burden in cognitively unimpaired older adults.

METHODS: Hierarchical Bayesian regression (HBR) models with a sinh-arcsinh likelihood (SHASHb) were estimated separately for 204 cortical molecular-enriched FC features in 4,152 healthy adults (18.0-89.8 years) from seven publicly available neuroimaging datasets and evaluated in a held-out healthy test set. Pretrained models were locally adapted to three Amyloid Imaging to Prevent Alzheimer's Disease Prognostic and Natural History Study (AMYPAD-PNHS) acquisition batches using cognitively unimpaired, amyloid-negative participants (global Clinical Dementia Rating (CDR) = 0; Centiloid (CL) < 10). The independent primary comparison contrasted participants with intermediate amyloid burden (10 ≤ CL < 30; n = 111) and amyloid-positive participants (CL ≥ 30; n = 66); secondary analyses tested linear associations with continuous CL within participants with CL ≥ 10.

RESULTS: Of 204 normative reference models, 199 (97.5%) met the predefined diagnostic criteria; median held-out explained variance (EXPV) was 0.174. Of 612 feature-by-batch transfers, 541 (88.4%) met the strict transfer-diagnostic criteria. In the primary false discovery rate (FDR)-controlled regional analysis, DAT-enriched right caudal middle frontal cortex showed lower locally standardized deviation scores in the intermediate-amyloid-burden group than in the amyloid-positive group (adjusted difference = -0.582, q = 0.016). DAT extreme-deviation burden was also greater in the intermediate-amyloid-burden group (difference = 0.032, q = 0.044). The right frontal effect was reproduced with model-native scores across the three acquisition batches (pooled standardized effect = -0.698, q = 0.010). No NET- or SERT-enriched regional difference between these two groups survived FDR-correction, and no regional or subject-level linear association with continuous CL values survived FDR-correction in the CL ≥ 10 group.

CONCLUSION: NM can provide spatially resolved reference distributions of molecular-enriched FC that are deployable in independently processed external data when local adaptation, calibration, and feature-level transfer diagnostics are incorporated. The AMYPAD-PNHS application identified modest, spatially selective, and molecular-system-specific categorical differences during a cognitively unimpaired stage of amyloid accumulation, while continuous analyses within CL ≥ 10 did not support linear association. These findings support a methodological basis for distributed application of molecular-enriched normative models and motivate independent and longitudinal evaluation of their biological relevance.

KEY POINTS: Hierarchical normative models characterized 204 regional DAT-, NET-, and SERT-enriched FC features across 4,152 healthy adults; 199/204 models met the predefined normative-reference-model diagnostic criteria.Local hierarchical adaptation enabled the pretrained normative models to be applied to independently processed AMYPAD-PNHS data without centralized reprocessing of the target raw images or explicit feature-level harmonization; 541/612 feature-batch transfers met the strict transfer criteria.In cognitively unimpaired AMYPAD-PNHS participants, the exploratory amyloid application identified a spatially selective DAT-enriched right frontal difference and greater DAT extreme-deviation burden in the intermediate-amyloid-burden group than in the amyloid-positive group. No FDR-corrected regional NET or SERT differences between these groups and no FDR-corrected linear associations with continuous CL were identified.},
}

@article {pmid42856537,
year = {2026},
author = {Brown, BRP and Li, X and Grasty, MR and Miranker, AD and Gürsoy, G},
title = {Integrating CSF and EV Proteomes Enhances Biomarker Discovery by Capturing Shared Variation Across Compartments.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.30.754912},
pmid = {42856537},
issn = {2692-8205},
abstract = {Cerebrospinal fluid (CSF) contains brain derived proteins that can be leveraged as biomarkers for Alzheimer's disease (AD) and other neurodegenerative diseases. However, converting protein intensities to a disease signal remains a challenge because physiology driven changes to the localization of proteins across CSF subcompartments are obscured when CSF is analyzed alone. Where subcompartment data, such as that from extracellular vesicles (EVs), are also measured, separate but parallel analyses of EVs and CSF can obscure their shared disease signal. Here, we present an integrated matrix factorization approach that combines proteomic signals from matched CSF and phosphatidylserine exposed EVs and nanoparticles (EV ps). In a ROS/MAP cohort of 48 participants, integrating CSF and EV ps signals improved biological concordance across compartments and increased the number of candidate proteins distinguishing participants with AD from controls. Notably, the joint signal identified as many brain-related biomarker candidates as studies using substantially larger cohorts. By demonstrating that integration of CSF and EV ps proteomes maximizes information from limited samples, this framework offers a path toward more efficient biomarker discovery across two compartments increasingly leveraged in neurodegenerative disease research.},
}

@article {pmid42856593,
year = {2026},
author = {Zheng, L and Ghanbarian, E and Albarrán Morillo, C and Younes, K and Glover, CM and Rabin, LA and Grill, JD and Ewers, M and Sajjadi, SA and Ezzati, A and , and , and , },
title = {Tau-PET subtype modifies the association between plasma p-tau217 and memory in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.25.26363629},
pmid = {42856593},
abstract = {INTRODUCTION: Plasma p-tau217 is associated with Alzheimer's disease pathology and memory performance, but its implications for memory may depend on fibrillar tau topography. We examined whether tau-PET subtype modified the association between plasma p-tau217 and memory.

METHODS: We analyzed 396 amyloid-positive, tau-positive participants spanning cognitively unimpaired, mild cognitive impairment, and dementia stages from six cohorts with tau-PET and plasma p-tau217; 301 had harmonized memory data. Tau-PET subtypes were derived using data-driven disease progression modelling. Primary cross-sectional models tested subtype×p-tau217 interactions for memory, adjusting for age, sex, education, APOE ε 4 status, and cohort. Secondary and exploratory analyses examined latent global cognition, non-memory measures, and longitudinal cognitive change.

RESULTS: Three tau-PET subtypes were retained: limbic-predominant, medial temporal lobe (MTL)-sparing, and posterior-predominant. Cross-sectionally, MTL-sparing participants had lower plasma p-tau217 than the other subtypes. The association between higher plasma p-tau217 and worse memory differed by subtype (interaction p =0.002) and was stronger in MTL-sparing (B =-0.191, p <0.001) than in limbic-predominant (B =-0.07, p =0.002) and posterior-predominant participants (B =-0.07, p <0.001). The interaction remained significant after additional adjustment for diagnostic group (p =0.015). This pattern also persisted after additional adjustment for PET tau burden, amyloid Centiloids, or plasma Aβ42/40; none of these biomarkers showed comparable subtype modification. Subtype modification was also observed for a global cognitive composite (interaction p =0.004) and subsequent memory decline in an exploratory analysis conditioned on baseline memory (interaction p =0.016).

DISCUSSION: Tau-PET subtype modified the p-tau217-memory association, suggesting that the cognitive implications of plasma p-tau217 may vary with tau topography.},
}

@article {pmid42856599,
year = {2026},
author = {Krishingner, T and Fausett, SR},
title = {A New Soaking Protocol to Live Stain C. elegans with Proteostat Dye Reveals Global Patterns of Stress-Induced Protein Aggregation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.30.755777},
pmid = {42856599},
issn = {2692-8205},
abstract = {Protein aggregates are a diverse array of intra- and extracellular structures containing misfolded proteins with limited macromolecular movement. Protein aggregation is induced by aging and cellular stress and is a hallmark of neurodegenerative diseases including Huntington's, Alzheimer's, and Parkinson's. Fluorescent tools to visualize global protein aggregation in whole organisms are, therefore, important for screening genes and compounds that may reduce or alter protein aggregation in connection with improved health outcomes. Fluorescent probes that report low fluidity structures in cells, such as molecular rotor dyes, are gaining popularity and overcome certain limitations of targeted markers such as tagged proteins or antibodies. However, permeability has been a key barrier preventing widespread use of such probes in whole organisms, including in C. elegans . To achieve visualization of non-specific protein aggregates in whole C. elegans nematodes without the need for strain engineering, we have developed a simple soaking protocol. Our protocol overcomes the permeability limitations of the commercially available molecular rotor dye, Proteostat, enabling widespread labeling of protein aggregates in live and post-fixed worms. Here, we present our novel approach and demonstrate quantification of protein aggregates in multiple tissues to detect differences in protein aggregation due to both genotype and treatment effects. We also outline anticipated future applications for this protocol, including its adaptation for other dyes, as well as limitations and special considerations for its use.},
}

@article {pmid42856607,
year = {2026},
author = {Onken, MD and Cooper, JA},
title = {The Alzheimer's Disease-associated gene CD2AP regulates permeability of endothelial cells and transendothelial migration of immune cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.01.755982},
pmid = {42856607},
issn = {2692-8205},
abstract = {Variants at the CD2AP locus, which encodes a branched-actin regulator, are associated with late-onset Alzheimer's disease (AD), and CD2AP-deficient mice show increased blood-brain barrier (BBB) permeability. CD2AP is enriched in endothelial cells, but its function there is poorly understood. In endothelium, branched actin networks maintain cell-cell junctions and are also required for immune cells to cross through individual endothelial cells (transcellular transendothelial migration, TEM). We previously showed that the Arp2/3 activators N-WASP and WAVE2 contribute to these processes, but the capping protein (CP)-interacting proteins involved are unknown. Here we tested whether CD2AP, a CP-interacting protein recruited to cell-cell contacts, regulates both junction integrity and TEM. In primary human microvascular endothelial cells, shRNA knockdown of CD2AP increased TNFα-induced monolayer permeability, measured by transendothelial electrical resistance, and altered VE-cadherin junction morphology. Unexpectedly, on soft hydrogels the same knockdown reduced TEM of NK-92 MI cells, lowering the proportion of transcellular events. Thus, loss of CD2AP weakens the endothelial barrier yet impairs a distinct, actin-dependent route of immune-cell passage. These findings suggest that CD2AP risk variants may affect the BBB through more than permeability, and they identify endothelial immune-cell trafficking as a testable link between CD2AP and AD.},
}

@article {pmid42856764,
year = {2026},
author = {Krokidis, MG and Sagar, R and Mustapic, M and Papatheodorou, MC and Exarchos, TP and Lyketsos, CG and Vlamos, P and Kapogiannis, D and Mahairaki, V},
title = {APOE4 differentially alters lipid composition in extracellular vesicles from hiPSC-derived neurons of Alzheimer's disease patients.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1917428},
pmid = {42856764},
issn = {1663-9812},
abstract = {BACKGROUND: The Apolipoprotein E4 (APOE4) is the most significant genetic risk factor for late-onset Alzheimer's disease (AD), but the cellular mechanisms by which it increases vulnerability remain poorly understood. Lipids play a crucial role in membrane organization, vesicle trafficking, and inflammatory signaling in the brain. Increasing evidence suggests that changes in lipid metabolism might serve as a connection between genetic risk and neurodegeneration. Extracellular vesicles (EVs) reflect the lipidomic composition of their parent cell offering a window into lipidomic alterations that may be tracked in living humans over time. Given high variability in human samples, we sought to define APOE4-related lipidomic EV signatures in a controlled human cellular system.

METHODS: We studied EVs secreted by four replicates of human-induced pluripotent stem cell (iPSC)-derived glutamatergic neurons from two healthy individuals (APOE2/E3 and APOE4/4) and two patients with AD (APOE3/3 and APOE4/4). Targeted lipidomics enabled quantitative profiling of hundreds of individual lipid species across major lipid classes. Univariate and multivariate analyses were applied to identify lipid alterations associated with APOE genotype and AD status.

RESULTS: APOE4 was associated with differences in lipid composition in neuronal EVs from both healthy and AD donors, suggesting that APOE4 influences EV lipid composition regardless of AD. Additionally, APOE4/4 carriers with AD exhibited clear, species-specific lipid imbalances. Lower levels of ganglioside GM3 and higher of phosphatidylserine emerged as consistent contributors to the APOE4-associated AD lipid signature, alongside alterations in dihydrosphingomyelin and phosphatidylinositol species linked to membrane integrity, endolysosomal function, and inflammatory pathways. These lipid species were among the strongest variables distinguishing healthy and AD APOE4/4 samples in multivariate analyses.

CONCLUSION: These findings specify lipidomic changes in AD related to the APOE4 genotype, and support a model by which APOE4 creates a lipid profile that becomes selectively dysregulated in AD. By identifying specific lipid species associated with APOE4 and AD, this work provides further evidence that distinct lipidomic signatures are associated with both APOE4 and AD. These findings may contribute to the identification of lipid-based biomarkers and support future investigations into genotype-informed therapeutic strategies, although validation in larger, independent cohorts is required.},
}

@article {pmid42856767,
year = {2026},
author = {Farzana, S and Arian, A and , and , and Ahsan, H},
title = {Evaluating Patient Representation Strategies for Early Prediction of Alzheimer's Disease and Related Dementias from Longitudinal EHRs.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10988118/v1},
pmid = {42856767},
issn = {2693-5015},
abstract = {The neurodegenerative processes underlying Alzheimer's disease and related dementias (ADRD) begin years before clinical diagnosis, motivating scalable approaches for earlier identification. Electronic health records (EHRs) provide longitudinal clinical information for early ADRD prediction but are sparse, temporal, and hierarchical, and alternative EHR representations encode these characteristics differently. We systematically evaluated how EHR representation and temporal distance from diagnosis influence ADRD prediction and whether representation-specific performance generalizes across health systems. Using All of Us EHRs, we compared interpretable count-based representations with pretrained clinical foundation-model representations at clinically meaningful lead times across multiple ADRD case definitions. Count-based models achieved the strongest overall discrimination and calibration. Performance generally declined with increasing prediction horizons, while differences between representations narrowed; at 36 months, pretrained representations achieved comparable AUROC (0.719 versus 0.738) with higher sensitivity and F1 at a fixed operating threshold. Temporal feature attribution showed greater model reliance on healthcare-utilization indicators at longer horizons and increasing importance of cognitive phenotypes, including amnesia and mild cognitive impairment, nearer diagnosis. Zero-shot evaluation on independent UChicago Medicine EHRs showed substantial performance degradation across representations, demonstrating challenges in cross-institutional transportability. These findings characterize representation-dependent tradeoffs in early ADRD prediction across temporal horizons and healthcare systems.},
}

@article {pmid42856786,
year = {2026},
author = {Li, X and Qi, H and Zhang, X and Jin, X and Xu, J and Ma, J},
title = {Comparative effects of six exercise modalities on global cognitive function in Alzheimer's disease, Parkinson's disease, and mild cognitive impairment: a systematic review and network meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1877537},
pmid = {42856786},
issn = {1664-2295},
mesh = {Humans ; *Cognitive Dysfunction/therapy/psychology/rehabilitation ; *Parkinson Disease/therapy/psychology/rehabilitation ; *Alzheimer Disease/therapy/psychology/rehabilitation ; *Exercise Therapy/methods ; *Cognition/physiology ; Cognitive Enhancement ; *Exercise ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD), and mild cognitive impairment (MCI) are commonly accompanied by cognitive decline. Although exercise is recommended as a non-pharmacological strategy, the comparative effects of different exercise modalities on global cognition remain uncertain.

OBJECTIVE: To compare six exercise modalities-aerobic exercise (AE), mind-body exercise (MBE), resistance training (RT), multi-component exercise (MCE), flexibility training (FT), and functional training (FTr)-for global cognitive function in people with AD, PD, or MCI, and to explore dose-related associations.

METHODS: PubMed, Embase, the Cochrane Library, and Web of Science were searched from inception to January 26, 2026. Randomized controlled trials (RCTs) were synthesized using a frequentist random-effects network meta-analysis (NMA) with standardized mean differences (SMDs) and 95% confidence intervals (CIs). Treatment rankings were summarized using SUCRA. Subgroup analyses, meta-regression, diagnosis-related sensitivity analyses, and CINeMA certainty assessments were also performed.

RESULTS: Twenty-eight trials involving 1,993 participants were included. Compared with control group (CG), AE [SMD = 0.47, 95% CI (0.18, 0.77)], MBE [SMD = 0.79, 95% CI (0.46, 1.11)], RT [SMD = 1.50, 95% CI (0.77, 2.23)], MCE [SMD = 0.83, 95% CI (0.26, 1.40)], and FTr [SMD = 0.83, 95% CI (0.13, 1.53)] improved global cognition, whereas FT showed no clear effect [SMD = -0.20, 95% CI (-1.27,0.87)]. RT ranked first, followed by MCE, FTr, MBE, AE, and FT. Heterogeneity was substantial (τ[2] = 0.23; I[2] = 80%), although no statistically significant global incoherence was detected. RT remained first after the exclusion of AD, PD, or MCI studies. Studies lasting more than 12 weeks, delivered 3-5 times per week, and using sessions of 31-60 min showed favorable pooled effects, but subgroup interaction tests and meta-regression were not significant. Certainty of evidence ranged from low to very low.

CONCLUSION: AE, MBE, RT, MCE, and FTr may improve global cognition in people with AD, PD, or MCI. RT showed the largest effect estimate and the most favorable ranking. However, substantial heterogeneity and sparse evidence for several modalities limit firm conclusions. Exercise selection should be individualized, and dose-related findings require confirmation in adequately powered comparative trials.},
}

Humans
*Cognitive Dysfunction/therapy/psychology/rehabilitation
*Parkinson Disease/therapy/psychology/rehabilitation
*Alzheimer Disease/therapy/psychology/rehabilitation
*Exercise Therapy/methods
*Cognition/physiology
Cognitive Enhancement
*Exercise

@article {pmid42856930,
year = {2026},
author = {Shaw, S and Warren, SL and Teng, C and Huynh, J and Ahmed, R and Piguet, O and Whitton, AE and Irish, M},
title = {Early anhedonia distinguishes behavioral variant frontotemporal dementia from Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70501},
pmid = {42856930},
issn = {2352-8729},
abstract = {INTRODUCTION: Differentiating behavioral variant frontotemporal dementia (bvFTD) from Alzheimer's disease (AD) remains challenging due to overlapping early behavioral and cognitive features. Anhedonia has emerged as a promising clinical marker, yet its multidimensional nature and temporal emergence across dementia syndromes remain unclear.

METHODS: Anticipatory and consummatory components of anhedonia were assessed in bvFTD and AD using the Temporal Experience of Pleasure Scale. Event-based modeling was applied in each group to stage the probabilistic emergence of anticipatory and consummatory anhedonia dimensions relative to apathy and cognitive symptoms.

RESULTS: Relative to controls, bvFTD showed marked loss of pleasure across anticipatory and consummatory components, whereas AD showed selective anticipatory anhedonia in the context of preserved consummatory pleasure. Event-based modeling placed consummatory and anticipatory anhedonia dimensions as early features of bvFTD occurring prior to overt cognitive changes. In contrast, for AD, anhedonia was probabilistically more likely to arise at later stages of the disease sequence, subsequent to cognitive decline.

DISCUSSION: These findings highlight consummatory anhedonia as an early, clinically informative marker of bvFTD and support the value of multidimensional hedonic assessment for improving dementia differentiation.},
}

@article {pmid42856984,
year = {2026},
author = {Ferreira, NV and Bertola, L and Paradela, RS and Ciciliati, AM and Silva, CM and Grinberg, LT and Pasqualucci, CA and Paes, VR and Ferriolli, E and Naslavsky, M and Leite, RP and Suemoto, CK},
title = {Social determinants of health modify the association of Alzheimer's disease pathology with cognitive abilities but not of apolipoprotein E-ε4 with Alzheimer's disease pathology.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70462},
pmid = {42856984},
issn = {2352-8729},
abstract = {INTRODUCTION: Apolipoprotein E (APOE) -ε4 and social determinants of health (SDoH) are major Alzheimer's disease (AD) risk factors, yet whether SDoH modify the relationship between APOE-ε4, AD pathology, and cognition remains unclear.

METHODS: Using Biobank for Aging Studies (BAS) data, we assessed APOE-ε4 using polymerase chain reaction (PCR), AD pathology using immunohistochemistry, and cognitive abilities using Clinical Dementia Rating - Sum of Boxes (CDR-SB).

RESULTS: In 1,193 individuals (mean [SD] age 73.4 [13.0] years; 50.1% women; 65.4% White), APOE-ε4 carriers had higher odds of AD pathology (odds ratio [OR]: 3.95, 95% confidence interval [CI]: 2.85; 5.51; p < 0.001), and AD pathology was associated with poorer cognition (β = 8.07, 95% CI: 7.47; 8.67; p < 0.001). SDoH modified this pathology-cognition association (p = 0·002), which was stronger in the unfavorable (β = 9.09, 95% CI: 8.00; 10.19, p < 0.001) versus the favorable SDoH profile (β = 6.39, 95% CI: 5.42; 7.37; p < 0.001). SDoH did not modify the APOE-ε4-pathology association (p = 0.806), and no race effect modification was observed.

DISCUSSION: AD pathology was more strongly associated with poorer cognition in unfavorable SDoH profiles, highlighting SDoH as targets for AD prevention.},
}

@article {pmid42857015,
year = {2026},
author = {Zheng, Y and Hong, L and Wu, L and Chen, X and Hu, Q and Chen, L and Ni, X and Zhuang, X and Yin, L},
title = {Effects of 12-week 24-form Tai Chi on cognitive function, cerebral perfusion, and vascular function in postmenopausal women with mild cognitive impairment: an exploratory randomized controlled trial.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1880915},
pmid = {42857015},
issn = {1663-4365},
abstract = {BACKGROUND: Postmenopausal women are at increased risk of mild cognitive impairment (MCI). Vascular and cerebrovascular dysfunction may contribute to this increased vulnerability. Tai Chi has been shown to benefit cognitive function, but its effects on cerebrovascular health in this high-risk population remain poorly defined. This study aimed to evaluate the impact of a 12-week Tai Chi intervention on cognitive performance, cerebral perfusion, and circulating vasomotor and Alzheimer's disease (AD)-related biomarkers in postmenopausal women with MCI.

METHODS: This single-center, parallel-group, open-label exploratory randomized controlled trial was conducted from June 2023 to September 2024 in Fuzhou, China. Forty postmenopausal women with MCI were randomized in a 1:1 ratio using block randomization to either a 12-week supervised 24-form Tai Chi program or a health education control group. Primary and secondary outcomes included Montreal Cognitive Assessment (MoCA) total and domain-specific scores, cerebral blood flow in cognition-related brain regions, circulating vasomotor factors, and serum AD-related biomarkers.

RESULTS: Compared with the health education control group, the Tai Chi group showed greater improvement in MoCA total score (β = 4.95, p < 0.001) and in delayed recall (β = 1.50), visuospatial/executive function (β = 1.10), and attention (β = 1.05) (all p < 0.001). Tai Chi was also associated with greater increases in global and regional CBF, including a significant group-by-time interaction for global CBF (β = 15.29, p < 0.001), as well as increased plasma NO (β = 10.41, p < 0.001), a lower ET-1/NO ratio (β = -0.97, p = 0.004), and greater reductions in circulating T-tau (β = -255.45, p < 0.001), P-tau (β = -135.67, p < 0.001), and Aβ1-42 (β = -169.41, p < 0.001). No intervention-related adverse events occurred.

CONCLUSION: A 12-week program of standardized 24-form Tai Chi was associated with improvements in overall cognitive performance as assessed by the MoCA in postmenopausal women with MCI. These cognitive changes were accompanied by increased cerebral perfusion, a more favorable vasomotor profile, and reductions in circulating AD-related biomarkers. Tai Chi appears to be a feasible and well-tolerated non-pharmacological intervention for this vulnerable population.

CLINICAL TRIAL REGISTRATION: ChiCTR2300068871.},
}

@article {pmid42857127,
year = {2026},
author = {Green, ZD and O'Bryant, SE and Johnson, LA and Burns, JM and Vidoni, ED and Morris, JK},
title = {Metabolic dysfunction associates with neuroimaging measures of brain structure and connectivity.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1889255},
pmid = {42857127},
issn = {1662-4548},
abstract = {INTRODUCTION: Metabolic syndrome (MetS) and insulin resistance are established risk factors for Alzheimer's disease (AD) and have been linked to alterations in brain structure and function, including within the Default Mode Network (DMN).

METHODS: Here, we examined associations between metabolic dysfunction, brain structure, and DMN functional connectivity using data from the Health and Aging Brain Study: Health Disparities (HABS-HD) cohort. Participants were classified as being cognitively unimpaired (CU; n = 1,045; mean age = 66.1 years; 65% female), or having mild cognitive impairment (MCI; n = 186; mean age = 66.5 years; 52% female) or dementia (n = 76; mean age = 69.0 years; 47% female).

RESULTS: Across diagnostic groups, cortical thickness in AD-vulnerable regions varied by both cognitive status and HbA1c grouping, with the strongest effects observed in the CU cohort. HbA1c grouping was also associated with white matter microstructure, including stepwise reduc tions in fractional anisotropy of the anterior corona radiata across glycemic cat egories (normoglycemia > prediabetes > diabetes) in CU individuals. Functional connectivity of the posterior DMN (pDMN) showed main effects of both cognitive status and HbA1c grouping. Using a continuous index of cardiometabolic risk (MetS-Z), pDMN connectivity decreased linearly with increasing cardiometabolic burden in the CU cohort, whereas other DMN subnetworks exhibited positive associations with MetS-Z.

DISCUSSION: These findings suggest network-specific associations between cardiometabolic risk and DMN organization that are detectable in indi viduals with MCI, a clinical state preceding dementia, as well as in some degree within cognitively unimpaired individuals. Longitudinal analyses are needed to determine whether metabolic dysfunction predicts divergent trajectories of DMN connectivity over time.},
}

@article {pmid42857161,
year = {2026},
author = {Torrigiani, EG and Cianca, D and Gaetani, L and Nardi, G and Paolini Paoletti, F and Chiasserini, D and Parnetti, L and Gammaitoni, L and Neri, I and Bellomo, G},
title = {Application of unsupervised and supervised machine learning approaches to blood-based biomarkers of Alzheimer's disease in a memory clinic cohort.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1922577},
pmid = {42857161},
issn = {1663-4365},
abstract = {INTRODUCTION: Blood-based biomarkers (BBMs) are promising tools to facilitate biological diagnosis of Alzheimer's Disease (AD). Establishing reliable cutoffs for BBMs represents a major issue for real-world implementation and the investigation of combined BBM approaches is limited. Our aim is to test different machine learning (ML) models for BBMs interpretation with respect to established gold-standard in vivo biomarkers, i.e., cerebrospinal fluid (CSF) biomarkers, to enhance their standalone and combined diagnostic value for AD.

METHODS: We selected 434 patients who referred to Perugia University Hospital for perceived cognitive decline with available CSF A β 42/40, pTau181 and tTau and plasma Aβ42, Aβ40, pTau217, pTau181 and NfL. Multiple unsupervised clustering algorithms for cutoff determination and supervised classification models were compared for the prediction of AD defined by a CSF A[+]/T [+] profile.

RESULTS: Different unsupervised clustering models obtained cutoffs with high performances in predicting an AD CSF profile (accuracy > 0.85). Each combination of cutoffs was tested, the best ones achieving A[+]/T[+] CSF profile prevalences > 0.9 in BBM-positive subgroups. The best supervised ML models achieved accuracies up to 0.88 in 10-fold cross-validation.

DISCUSSION: Our results prove that clustering approaches can help in identifying reliable BBMs cutoffs for AD diagnosis even in the absence of CSF gold standard reference and that ML approaches combining multiple BBMs can strongly enhance their diagnostic accuracy.},
}

@article {pmid42857391,
year = {2026},
author = {Shankar, A and Kryza-Lacombe, M and Insel, PS and Harris, E and Kassel, MT and Goldstein, L and Krystal, AD and Landau, SM and Tosun, D and Butters, MA and Aisen, P and Raman, R and Toga, AW and Jack, CR and Nelson, JC and Mackin, RS},
title = {Depression severity and sleep efficiency's associations with amyloid burden are additive but dependent on underlying genetic risk in late life depression.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70478},
pmid = {42857391},
issn = {2352-8729},
abstract = {INTRODUCTION: Evidence linking late-life depression (LLD) to amyloid beta (Aβ) burden remains mixed, possibly in part due to limited examinations of the confounding role of comorbid sleep disturbance and the moderating role of the apolipoprotein E (APOE) ɛ4 gene.

METHODS: We analyzed 110 older adults (ages 65-88, 66% female) with LLD to jointly model depression severity and sleep disturbance's relationship with Aβ, and to examine the moderating role of APOE ɛ4 genotype.

RESULTS: Depression severity, sleep efficiency, and sleep duration did not demonstrate a direct relationship with Aβ; however, a significant APOE ɛ4 moderation effect occurred for depression severity and sleep efficiency. In APOE ɛ4 carriers only, higher depression severity and lower sleep efficiency were associated with greater total Aβ burden and indicated greater likelihood of reaching clinical cutoffs for amyloid positivity. The effects of depressive symptoms and sleep efficiency were statistically unique and additive. Exploratory analyses demonstrated APOE ɛ4 also moderated the effect of lifetime duration of untreated depression on increased Aβ.

DISCUSSION: Depression severity and sleep efficiency's relationship with Aβ may be dependent on the presence of the APOE ɛ4 allele. This, among other individual differences, may partially explain mixed findings examining LLD as a risk factor for Alzheimer's disease. Furthermore, these findings do not suggest that the relationship between depression severity and amyloid is explained by the confounding role of sleep duration or sleep efficiency.},
}

@article {pmid42857403,
year = {2026},
author = {Agosta, F and Cecchetti, G and Ghirelli, A and Spinelli, EG and Rugarli, G and Pisano, S and Coraglia, F and Gajate, AMS and Vezzulli, P and Calloni, S and Canu, E and Castelnovo, V and Gilioli, A and Tripodi, C and Freri, F and Bianchi, A and Panzacchi, A and Pepe, G and Falini, A and Chiti, A and Filippi, M},
title = {Residualized occipital amyloid burden and plasma biomarker profiles in relation to ARIA-E during anti-amyloid treatment.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70401},
pmid = {42857403},
issn = {2352-8729},
abstract = {INTRODUCTION: Amyloid-related imaging abnormalities with edema (ARIA-E) represent the main safety concern of anti-amyloid monoclonal antibodies. Whether regional amyloid topology refines ARIA-E risk in real-world practice remains unclear.

METHODS: We analyzed 31 treatment courses in early Alzheimer's disease under European Medicines Agency labeling. Residualized occipital amyloid burden was defined as observed occipital standardized uptake value ratio (SUVR) minus occipital SUVR predicted from global composite SUVR in an expanded baseline positron emission tomography derivation sample (n = 53). Associations with ARIA-E and baseline plasma biomarkers were assessed.

RESULTS: ARIA-E occurred only in the elevated occipital amyloid group: 4/13 treatment courses, versus 0/18 low or comparable courses (Fisher exact p = 0.055). All ARIA-E events involved posterior regions. The elevated pattern showed higher baseline glial fibrillary acidic protein (GFAP), phosphorylated tau (p-tau)181, and p-tau217 levels, whereas amyloid beta 42/40 did not differ between groups. A GFAP + p-tau217 model showed exploratory discrimination of the elevated phenotype (area under the curve: 0.76).

DISCUSSION: Disproportionate occipital amyloid burden may identify a biologically vulnerable subgroup requiring validation in larger cohorts.},
}

@article {pmid42857419,
year = {2026},
author = {Ghirelli, A and Cecchetti, G and Spinelli, EG and Samanes Gajate, AM and Rugarli, G and Pisano, S and Zamboni, IAL and Canu, E and Castelnovo, V and Sibilla, E and Gilioli, A and Tripodi, C and Freri, F and Panzacchi, A and Pepe, G and Chiti, A and Filippi, M and Agosta, F},
title = {Regional amyloid-PET clearance dynamics and anti-Aβ monoclonal antibody therapy: a preliminary real-world study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70448},
pmid = {42857419},
issn = {2352-8729},
abstract = {INTRODUCTION: Amyloid positron emission tomography (PET) is the reference biomarker for treatment target engagement in anti-amyloid beta (Aβ) therapies in early symptomatic Alzheimer's disease (AD), yet global metrics may mask a regional heterogeneity of amyloid clearance.

METHODS: We report real-world longitudinal amyloid-PET data from 26 patients treated with lecanemab or donanemab for 6 months. Global Centiloids and regional standardized uptake value ratios (SUVRs) were quantified at baseline and 6 months and examined according to treatment, clinical diagnosis, and clinical stage.

RESULTS: Amyloid removal was regionally heterogeneous. Patients with mild cognitive impairment showed greater cortical amyloid reduction than those with mild dementia, while early- and late-onset AD exhibited comparable clearance. Frontal, anterior cingulate, and parietal regions showed the largest SUVR reductions, whereas the occipital cortex and temporal mesial cortex were consistently spared, including in patients reaching global amyloid-PET negativity.

DISCUSSION: Early amyloid clearance following anti-amyloid treatment is regionally heterogeneous and incompletely captured by global PET measures.},
}

@article {pmid42857445,
year = {2026},
author = {Ledesma-Aparicio, J and Caro-Gómez, LA and Padilla-Godínez, FJ and Hernández-González, O and Soto-Rojas, LO and Reyes-Grajeda, JP and Arias-Carrión, O and Palomero-Rivero, M and Bertrand, B and Munoz-Garay, C and Guerra-Crespo, M},
title = {Tau protein in Parkinson's disease: advances in phosphoproteomics and molecular dynamics simulations.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1841131},
pmid = {42857445},
issn = {1663-4365},
abstract = {Tau dysregulation, particularly abnormal phosphorylation, is increasingly implicated in Parkinson's disease (PD) and in the pathogenic interaction between Tau and α-synuclein. This review proposes an integrated PD-focused workflow connecting phosphoproteomic discovery, structural modeling, computational drug discovery, and experimental validation. Phosphoproteomic analyses of post-mortem brain tissue, biofluids, and patient-derived dopaminergic neuronal models can identify candidate Tau phosphosignatures associated with vulnerable brain regions, α-synuclein pathology, genetic background, or clinical progression. Molecular dynamics simulations can then evaluate how these signatures alter Tau conformation, microtubule binding, aggregation-prone motifs, membrane association, and pathogenic protein interactions. The resulting structural information can guide ensemble docking, chemoinformatics, and artificial intelligence approaches to prioritize conformer-selective ligands and regulatory targets. Candidate biomarkers should subsequently be validated in independent and longitudinal PD cohorts, whereas therapeutic candidates require mechanistic and functional validation in PD-relevant experimental models before clinical translation. This iterative framework may help distinguish mechanistically relevant Tau phosphoconformers from nonspecific phosphorylation changes, support biomarker-based patient stratification, and focus therapeutic development on structurally defined pathological states. Because much of the available structural evidence derives from Alzheimer's disease and other tauopathies, direct validation in PD remains essential. By linking PD-derived and disease-relevant molecular evidence with atomistic mechanisms and therapeutic prioritization, this workflow may support biomarker-informed strategies aimed at restoring Tau homeostasis and disrupting pathogenic Tau-α-synuclein interactions.},
}

@article {pmid42857586,
year = {2027},
author = {Zhang, Y and Li, H and Fan, Y},
title = {Discovering Heterogeneous Neurodegenerative Disease Patterns From MRI Data for Improved Prediction.},
journal = {Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention},
volume = {16894},
number = {},
pages = {160-170},
pmid = {42857586},
abstract = {Neurodegenerative diseases exhibit substantial heterogeneity, complicating both diagnosis and prognosis. Identifying clinically meaningful subtypes is crucial for understanding disease mechanisms and improving diagnostic precision and prognostic accuracy. Existing subtyping approaches primarily rely on unsupervised learning of patient data for capturing inter-individual variability, but they may fail to uncover subtypes that are directly informative for diagnosis or prognosis. To address this limitation, we propose a novel mixture-of-experts (MoE) framework that integrates predictive modeling with subtype discovery. Unlike traditional subtyping methods, our approach learns a router to assign individuals to specialized expert networks, each corresponding to a distinct subtype, for improving predictive accuracy. By coupling subtype identification with prediction, the proposed MoE framework encourages the discovery of subtypes that are not only statistically distinct but also clinically informative. We evaluate the framework on a real-world dataset of mild cognitive impairment (MCI) subjects and a semi-simulated dataset, demonstrating superior performance in predicting progression from MCI to Alzheimer's disease while revealing distinct, clinically meaningful MCI subtypes. Code is available at https://github.com/Kateridge/MoESubtyping.},
}

@article {pmid42853241,
year = {2026},
author = {Mugikura, S and Mori, N and Satake, M and Chiba, I and Taira, M and Koyama, T and Onuma, T and Saito, T and Takase, M and N Motoike, I and Hidaka, T and Otsuki, A and Orui, M and Obara, T and Nagami, F and Nakaya, N and Ogishima, S and Kumada, K and Katsuoka, F and Koshiba, S and Taki, Y and Shimizu, R and Kuriyama, S and Ohneda, K and Izumi, Y and Fuse, N and Hozawa, A and Kinoshita, K and Yamamoto, M},
title = {Accelerated hippocampal atrophy in APOE ε4 homozygotes and females: Longitudinal findings from the Tohoku Medical Megabank MRI study.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {42853241},
issn = {1432-1920},
support = {JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; JP21km0105001, JP21km0105002, JP23dm0307003h0006, JP24tm0524003h0002//the Reconstruction Agency; the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Japan Agency for Medical Research and Development (AMED)/ ; 24K06543, 25K10609//JSPS KAKENHI/ ; 24K06543, 25K10609//JSPS KAKENHI/ ; JP 25tm0524003h0003//Medical Research and Development (AMED)/ ; JP23dm0307003h0006//Medical Research and Development (AMED)/ ; },
abstract = {PURPOSE: The apolipoprotein E ε4 allele is a major genetic risk factor for Alzheimer's disease, but its longitudinal effect on hippocampal atrophy is unclear. Selective hippocampal atrophy, defined as greater hippocampal volume (HpV) loss relative to total brain volume (TBV), is an early marker of preclinical Alzheimer's disease. We examined age-related effects of APOE ε4 on longitudinal hippocampal atrophy in a large population-based cohort.

METHODS: We analyzed MRI data from 9,453 adults in the Tohoku Medical Megabank MRI Study, including 5,774 participants with follow-up MRI after a mean interval of 4.7 years. Cross-sectional analyses used linear regression to assess HpV and TBV, adjusting for age, sex, APOE genotype, and intracranial volume. Longitudinal analyses assessed HpV-Ratio and TBV-Ratio, defined as the second MRI volume divided by the first volume, using regression models including age, sex, APOE genotype, MRI interval, and interaction terms between age and APOE genotype and between age and sex. Montreal Cognitive Assessment (MoCA) scores obtained at the second MRI were included to assess effects independent of cognition.

RESULTS: No significant APOE genotype effects were observed in cross-sectional analyses. Longitudinally, ε4/ε4 carriers showed greater decline in HpV-Ratio than ε3/ε3 and ε3/ε4 carriers, and females showed lower HpV-Ratio than males. No APOE genotype or sex main effects were observed for TBV-Ratio. Interactions between age and APOE genotype and between age and sex demonstrated age-related acceleration of HpV-Ratio decline in ε4/ε4 carriers and females, and these effects persisted after adjustment for MoCA scores.

CONCLUSION: APOE ε4 homozygosity and female sex accelerate selective hippocampal atrophy in population-based cohorts.},
}

@article {pmid42853245,
year = {2026},
author = {Wang, D and Weedor, JG and Weah, NM and Koda, S and Quayon, CM and Pan, W and Yu, Y},
title = {The ACOD1-itaconate axis in anti-neuroinflammation and protection against neurodegenerative diseases.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261495587},
doi = {10.1177/13872877261495587},
pmid = {42853245},
issn = {1875-8908},
abstract = {Chronic neuroinflammation mediated by activated microglia constitutes a central pathogenic mechanism underlying neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Despite substantial progress in elucidating disease mechanisms, effective disease-modifying therapies remain elusive. Recent investigations have identified the aconitate decarboxylase 1 (ACOD1)-itaconate axis, a mitochondrial enzyme-metabolite pathway, as a critical immunometabolic checkpoint that regulates inflammation across diverse pathological contexts. This pathway exerts immunomodulatory effects through multiple mechanisms, including succinate dehydrogenase inhibition, nuclear factor erythroid 2-related factor 2 activation via Kelch-like ECH-associated protein 1 alkylation, and suppression of the NOD-like receptor protein 3 inflammasome. Emerging evidence has demonstrated that ACOD1-derived itaconate and its cell-permeable derivatives modulate neuroinflammation, preserve synaptic integrity, and ameliorate cognitive deficits in preclinical models of neurodegenerative diseases. This review critically synthesizes current evidence on the ACOD1-itaconate axis in central nervous system pathology, with particular emphasis on its roles in AD, PD, MS, and metabolic cognitive dysfunction. We further summarize the mechanistic insights and therapeutic potential of targeting this pathway in neuroinflammation-driven cognitive impairment. Additionally, this review uniquely integrates infection-induced and diet-induced cognitive impairment models and provides a critical perspective on translating this pathway from the bench to the bedside.},
}

@article {pmid42853248,
year = {2026},
author = {Low, S and Zheng, H and Moh, A and Liu, JJ and Liu, S and Ang, K and Lim, Z and Tang, WE and Sum, CF and Subramaniam, T and Lim, SC},
title = {Association between urinary metabolomics and cognitive performance in Asians with type 2 diabetes.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493174},
doi = {10.1177/13872877261493174},
pmid = {42853248},
issn = {1875-8908},
abstract = {BackgroundThere is an ongoing quest for novel biomarkers which may serve as therapeutic targets in cognitive impairment, alongside a growing appreciation of urinary metabolomics as a promising non-invasive approach to identify metabolic signature of Alzheimer's disease and other causes of dementia.ObjectiveWe studied whether urine metabolomics were associated with mild cognitive impairment (MCI) and cognitive performance in a diabetic milieu.MethodsWe implemented a cross-sectional study on 1053 patients who had Type 2 diabetes (T2D). Urinary metabolites were quantitated by nuclear magnetic resonance (NMR). We evaluated cognitive performance by administering Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Criteria for mild cognitive impairment (MCI) were met if patients scored > 1.5 standard deviations (SDs) less than the mean RBANS score for total index or any of the cognitive domains.ResultsThe average age was 65.1 ± 7.9. Four metabolites were associated with RBANS total score after multiple testing correction by Benjamini-Hochberg (BH) procedure in the adjusted analyses: sucrose (β = -1.17 (95%CI -1.71, -0.62)), 4-hydroxyhippurate (β = -0.92 (-1.42, -0.42)), trans-aconitate (β = -0.93 (-1.46, -0.40)), and tryptophan (β = -0.82 (-1.33, -0.32)). Sucrose was associated with MCI (OR = 2.19 (1.44, 3.32). Sucrose, trans-aconitate, 4-hydroxyhippurate, and 4-deoxythreonate were associated with delayed memory. Hypoxanthine, sucrose and tryptophan were related to visuo-spatial/constructional function.ConclusionsOur study identified several urinary metabolites which were differentially linked to cognitive performance in T2D. Future investigations are warranted to confirm the findings.},
}

@article {pmid42853249,
year = {2026},
author = {Kim, H and Kim, J and Choi, H and Kim, YS},
title = {Benzodiazepine use, incident dementia and Alzheimer's disease, and progression to severe dementia: A nationwide Korean cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261492672},
doi = {10.1177/13872877261492672},
pmid = {42853249},
issn = {1875-8908},
abstract = {BackgroundThe association between benzodiazepine (BZD) use and dementia risk remains controversial owing to conflicting observational findings and incomplete adjustment for confounders.ObjectiveTo examine the association between BZD use and incident dementia, including Alzheimer's disease (AD), and to determine whether BZD use accelerates progression to severe dementia, using nationwide claims data with detailed comorbidity adjustment.MethodsWe conducted a matched cohort study using Korean National Health Insurance Service data, comparing 132,805 BZD users with 132,805 age- and sex-matched controls. Incident dementia (AD [F00], vascular dementia [F01], and other subtypes) was defined by ≥3 diagnostic claims within one year, and severe cases by national special-registration codes. Hazard ratios (HRs) were estimated using Cox models adjusted for the Charlson Comorbidity Index (CCI) and clinical covariates.ResultsDementia incidence was 382.4/100,000 person-years in BZD users versus 280.7 in controls. BZD users had higher multimorbidity (CCI ≥7: 42.5% versus 26.5%) and psychiatric comorbidity (e.g., anxiety disorders: 42.6% versus 2.7%). After full adjustment, the HR for overall dementia attenuated from 1.43 to 1.15 (95% CI, 1.09-1.22), with similar attenuation for AD and severe dementia. The risk of progression from dementia to severe dementia was not increased among BZD users (adjusted HR, 0.98; 95% CI, 0.84-1.14), with no dose- or duration-response observed.ConclusionsBZD use showed only a modest association with incident dementia, largely attributable to the higher multimorbidity burden among users, and was not associated with accelerated progression to severe dementia.},
}

@article {pmid42853281,
year = {2026},
author = {Tyrovolas, S and Portella, MJ and Usall, J and Cambra-Martí, MR and Callén, A and Haro, JM and Núñez, C and Stephan-Otto, C},
title = {Greater temporo-occipital gray matter volume and frontoparietal cortical thickness in post-menopausal women: a UK Biobank study.},
journal = {Brain structure & function},
volume = {231},
number = {8},
pages = {},
pmid = {42853281},
issn = {1863-2661},
support = {AR202102//Parc Sanitari Sant Joan de Déu/ ; CD20/00142//Sara Borrell/ ; },
mesh = {Humans ; Female ; *Gray Matter/anatomy & histology/diagnostic imaging ; *Postmenopause ; Middle Aged ; Magnetic Resonance Imaging ; *Temporal Lobe/anatomy & histology/diagnostic imaging ; Aged ; United Kingdom ; Adult ; *Occipital Lobe/anatomy & histology/diagnostic imaging ; *Parietal Lobe/anatomy & histology ; Organ Size ; UK Biobank ; },
abstract = {Menopause is a critical transitional stage in women's lives, yet evidence on its impact on brain structure remains inconsistent, and large-sample neuroimaging studies are limited. Here, we applied whole-brain morphometry techniques to evaluate differences between pre- and post-menopausal women in terms of gray matter volume, cortical thickness and cortical gyrification. We processed and analyzed T1-weighted brain scans of 4098 women (1033 pre-menopausal; 3065 post-menopausal) from the UK Biobank. Post-menopausal women exhibited greater gray matter volume than pre-menopausal women primarily in the right temporal lobe, encompassing the amygdala and the hippocampus, and extending to the left temporal lobe and occipital regions. Post-menopausal women also exhibited greater cortical thickness in the frontal lobe and the supramarginal gyrus, whereas no differences in cortical gyrification were observed. These findings were consistent across multiple sensitivity analyses addressing age differences, peri-menopausal status, and other potential confounds. The spatial pattern of differences between post-menopausal and pre-menopausal women considerably overlaps with regions affected early in Alzheimer's disease, such as the medial temporal lobe and the supramarginal gyrus. Our findings of larger gray matter volume and greater cortical thickness in post-menopausal women may reflect compensatory mechanisms. Speculatively, these findings align with the biphasic model of brain structural changes in Alzheimer's disease. Further research with longitudinal designs is required to elucidate the exact mechanisms underlying the brain structural differences associated with menopause.},
}

Humans
Female
*Gray Matter/anatomy & histology/diagnostic imaging
*Postmenopause
Middle Aged
Magnetic Resonance Imaging
*Temporal Lobe/anatomy & histology/diagnostic imaging
Aged
United Kingdom
Adult
*Occipital Lobe/anatomy & histology/diagnostic imaging
*Parietal Lobe/anatomy & histology
Organ Size
UK Biobank

@article {pmid42847312,
year = {2026},
author = {Leppänen, L and Lehtonen, A and Aaltonen, M and Aho, K and Kivisild, A and Ullgren, A and Rinnankoski, I and Soppela, H and Haapasalo, A and Portaankorva, AM and Hartikainen, P and Katisko, K and Solje, E and Krüger, J},
title = {Comorbidities and health-care use prior to early-onset Alzheimer's disease: A population-based case-control study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71831},
pmid = {42847312},
issn = {1552-5279},
support = {//The Finnish Medical Foundation/ ; //Finnish Alzheimer's Disease Research Society/ ; //Finnish Brain Foundation/ ; //The Swedish Dementia Foundation/ ; //The Foundation for Geriatric Diseases at Karolinska Institutet/ ; //Uulo Arhio Foundation/ ; 360445//The Research Council of Finland/ ; 360451//The Research Council of Finland/ ; //Wihuri Foundation/ ; //Jane and Aatos Erkko Foundation/ ; //The State Research Funding/ ; //The Finnish Cultural Foundation/ ; //Päivikki & Sakari Sohlberg Foundation/ ; //Sigrid Juselius Foundation/ ; },
mesh = {Humans ; Female ; *Alzheimer Disease/epidemiology/diagnosis ; Male ; Case-Control Studies ; Comorbidity ; Finland/epidemiology ; Aged ; Age of Onset ; Aged, 80 and over ; Prevalence ; Middle Aged ; },
abstract = {INTRODUCTION: We examined whether comorbidities and health-care use differ between individuals later diagnosed with early-onset Alzheimer's disease (EOAD) and matched controls during the 15 years preceding diagnosis.

METHODS: This population-based case-control study included 407 EOAD patients diagnosed at two Finnish university hospitals (2010-2021), and 4035 age- and sex-matched controls. Prior diagnoses and health-care visits were obtained from nationwide registers.

RESULTS: EOAD patients had higher prevalence of vertigo (5.9% vs. 2.1%, p < 0.001), depression (5.7% vs. 2.3%, p < 0.001), headache (4.9% vs. 1.6%, p < 0.001), delirium (1.5% vs. 0.1%, p < 0.001), brain injuries (2.9% vs. 0.9%, p = 0.002), thyroid disorders (2.5% vs. 0.8%, p = 0.008), alcohol-related disorders (3.4% vs. 1.4%, p = 0.009), epilepsy (2.2% vs. 0.7%, p = 0.009), strokes (4.4% vs. 2.0%, p = 0.008), and otorhinolaryngologic diseases (5.2% vs. 2.9%, p = 0.027) 1-5 years before diagnosis. Only otorhinolaryngologic diseases (4.7% vs. 2.1%, p = 0.036) differed 6 to 10 years prior, whereas no differences were seen 11 to 15 years before diagnosis. Hypertension and dyslipidemia showed no between-group differences. Health-care use increased markedly from year before EOAD diagnosis.

DISCUSSION: EOAD is preceded by recognizable patterns of morbidity and increased health-care use, which may support earlier detection.},
}

Humans
Female
*Alzheimer Disease/epidemiology/diagnosis
Male
Case-Control Studies
Comorbidity
Finland/epidemiology
Aged
Age of Onset
Aged, 80 and over
Prevalence
Middle Aged

@article {pmid42847328,
year = {2026},
author = {Tee, M and Gutierrez, J and Cui, J and Chiang, E and Venketasubramanian, N and Chen, C and Petr, J and Mutsaerts, HJMM and Hilal, S},
title = {Association of stenosis and arterial remodeling with cerebral hemodynamics and cognition.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261494130},
doi = {10.1177/13872877261494130},
pmid = {42847328},
issn = {1875-8908},
abstract = {BackgroundAssociations between intracranial stenosis, arterial remodeling, cerebral hemodynamics, including cerebral blood flow (CBF) and arterial transit time (ATT), white matter hyperintensities (WMH), and cognition remain unclear.ObjectiveThis study investigates the relationships between MRA-derived vascular parameters, cerebral hemodynamics, WMH burden, and cognition. We hypothesized that greater stenosis or remodeling is associated with impaired hemodynamics, increased WMH burden, and poorer cognition.MethodsCross-sectional study of 452 memory clinic patients (median age 74 [IQR 68-78], 53% female) who underwent 3T MRI with time-of-flight MRA and pseudo-continuous ASL. Automated quantification derived global stenosis and brain arterial remodeling (BAR) scores. CBF and spatial coefficient of variation (sCoV) assessed hemodynamics; WMH volume from FLAIR; cognition from a validated neuropsychological battery. Structural equation modelling (SEM) evaluated associations, adjusting for demographics and cardiovascular risk factors.ResultsHigher sCoV was associated with higher BAR (β = 0.14, 95% CI:0.06-0.23). WMH was associated with stenosis (β = 0.20, CI:0.12-0.28) and BAR (β = 0.07, CI:0.001-0.140). Lower CBF (β = -0.26, CI:-0.36 to -0.15) and higher sCoV (β = 0.27, CI:0.17-0.36) were associated with greater WMH burden. Higher BAR was associated with better global cognition (β = 0.07, CI:0.00-0.14). SEM indicated indirect associations with cognition via WMH and CBF.ConclusionsVascular remodeling and stenosis are associated with cerebral hemodynamics, WMH, and cognition, with CBF and WMH as potential mediators, underscoring the importance of vascular health in Alzheimer's disease. These direct and indirect associations are not mutually exclusive: higher BAR was associated with better cognition directly, while also relating to poorer cognition indirectly through greater WMH burden and perfusion heterogeneity.},
}

@article {pmid42847329,
year = {2026},
author = {Hu, G and Liu, Y and Zhang, M},
title = {Multisystem aging discordance and cognitive decline in Chinese older adults: A longitudinal study from CHARLS.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261494123},
doi = {10.1177/13872877261494123},
pmid = {42847329},
issn = {1875-8908},
abstract = {BackgroundMultisystem aging discordance may represent an early risk factor for cognitive decline, but prospective evidence in Chinese older adults is limited.ObjectiveWe constructed a blood-based Aging Discordance Index (ADI) and examined its 3-year association with cognitive function in a nationally representative Chinese cohort. ADI was derived from five routine biomarkers (creatinine, total cholesterol, C-reactive protein, mean corpuscular volume, and glycated hemoglobin).MethodsData were from the China Health and Retirement Longitudinal Study (CHARLS). ADI was calculated as the standard deviation of age-adjusted Z-scores. Cognitive function was assessed via orientation, calculation, drawing, and equated word recall in 2018 data. Survey-weighted linear regression adjusted for baseline cognition, sociodemographic, lifestyle, and clinical covariates.ResultsAmong 1688 participants aged ≥60 years, higher ADI was independently associated with worse 3-year cognitive performance (fully adjusted β = -0.336, 95% CI: -0.598 to -0.075, p = 0.011) and greater cognitive decline (β = -0.326, 95% CI: -0.575 to -0.077, p = 0.010). To address potential bias due to loss to follow-up, we further applied linear mixed models (LMM) with random intercepts in an expanded sample of 2912 participants, which utilizes all available repeated measures. The ADI × time interaction remained significant (β = -0.346, 95% CI: -0.580 to -0.112, p = 0.004), confirming the robustness of the primary findings against attrition bias.ConclusionsA simple blood-based index of multisystem aging discordance independently predicts cognitive decline in Chinese older adults. ADI may offer a practical, low-cost tool for early risk stratification in community settings.},
}

@article {pmid42847330,
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 = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493984},
doi = {10.1177/13872877261493984},
pmid = {42847330},
issn = {1875-8908},
abstract = {BackgroundIn preclinical Alzheimer's disease (pAD), regional patterns of amyloid-β (Aβ) deposition are well characterized but have not been systematically compared across functional networks.ObjectiveDetermine how Aβ accumulation in functional networks ("network-amyloid burden" [NAB]) varies by age, network type (cognitive versus non-cognitive), and Aβ status (Aβ+/Aβ-), and relates to cognition.Methods157 cognitively unimpaired adults (45-84 years; n = 28 Aβ+ per neuroradiological read) underwent brain MRI, amyloid PET ([18]F-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.ResultsNAB 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.ConclusionsCognitive 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 {pmid42847333,
year = {2026},
author = {Cheng, CH and Lu, H},
title = {A randomized pilot trial of non-flickering 40 Hz light stimulation: EEG activity and cognitive outcomes in cognitively normal older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261494219},
doi = {10.1177/13872877261494219},
pmid = {42847333},
issn = {1875-8908},
abstract = {BackgroundGamma-frequency (40 Hz) sensory stimulation is a promising non-pharmacological approach for modulating neural activity and cognitive function in aging and Alzheimer's disease. However, conventional flickering stimulation is often poorly tolerated, and evidence for non-flickering approaches remains limited.ObjectiveTo evaluate the neurophysiological and cognitive effects of 4-week (28-session) non-flickering 40 Hz light stimulation in cognitively normal older adults.MethodsIn this randomized, double-blind, active-controlled pilot trial, 33 cognitively normal older adults were assigned to receive either non-flickering 40 Hz light stimulation (n = 17) or a 70 Hz active-controlled condition (n = 16) over four weeks. Per-protocol analyses were conducted in 29 participants who completed the intervention. Resting-state electroencephalography (EEG) was acquired at baseline, immediately after the first intervention session, and after completion of the 4-week intervention. Neuropsychological assessments were performed at baseline and after the intervention. Prespecified primary outcomes were resting-state gamma-band power spectral density (PSD) and functional connectivity (FC).ResultsNo significant between-group differences were observed in resting-state gamma-band PSD or FC following either one-session or 28-session intervention. Unadjusted secondary analyses suggested potential improvements in selected episodic memory measures in the 40 Hz group. Exploratory analyses further identified a positive association between improvements in visuospatial memory and increases in occipital-temporal FC. Both interventions were well tolerated.ConclusionsA 28-session non-flickering 40 Hz light stimulation was well tolerated and may improve selected episodic memory measures in cognitively normal older adults. Although no measurable group-level EEG effects were observed, the exploratory cognitive findings warrant further investigation in larger randomized trials.ClinicalTrial.gov (ID: NCT06715995) https://clinicaltrials.gov/expert-search?term=NCT06715995.},
}

@article {pmid42847459,
year = {2026},
author = {Balverde-Caballero, FB and Pérez-Tur, J and Cardona, F},
title = {A Hierarchical Framework for In Vitro Models of Alzheimer's Disease.},
journal = {WIREs mechanisms of disease},
volume = {18},
number = {5},
pages = {e70015},
pmid = {42847459},
issn = {2692-9368},
support = {CB06/05/1123//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas ISCIII. Ministerio de Ciencia, Innovación y Universidades/ ; },
mesh = {*Alzheimer Disease/pathology/metabolism ; Humans ; Animals ; Induced Pluripotent Stem Cells/metabolism/pathology ; Neurons/pathology/metabolism ; *Models, Biological ; Organoids/pathology/metabolism ; },
abstract = {Alzheimer's disease (AD) remains a major global health challenge, with a high rate of clinical trial failures often attributed to the limited translational predictive value of traditional experimental models. In vitro systems, ranging from induced pluripotent stem cell (iPSC)-derived neurons to complex three-dimensional (3D) organoids, have emerged as promising alternatives to investigate disease mechanisms in a controlled experimental setting. However, their rapid expansion has generated fragmented nomenclature and heterogeneous classification schemes. In this systematic review, we propose a hierarchical framework that categorizes in vitro AD models according to their architectural complexity and the biological questions they are designed to address. We organize these platforms into four progressive tiers: genetically defined iPSC-derived cell-autonomous models, stimulus-based reductionist models, interaction-dependent neuron-glia co-cultures, and advanced multicellular 3D or neurovascular platforms. Our findings indicate that low complexity models (Tier 1 and Tier 2) are particularly suited to dissect cell-intrinsic genetic drivers and acute toxic signaling, but they often fail to capture the chronic multicellular feedback loops and vascular dysfunction characteristic of AD. In contrast, high-complexity systems (Tier 3 and Tier 4), including organ-on-chip platforms and vascularized organoids, provide the spatial and physiological context necessary to model neuroinflammation and network-level degeneration, although they present greater technical variability. Finally, we propose an integrative hierarchical strategy that aligns model selection with specific pathological questions. By linking cellular complexity with mechanistic objectives, this framework provides a structured roadmap to improve experimental rigor, facilitate cross-study comparability, and support the development of more predictive experimental models for AD.},
}

*Alzheimer Disease/pathology/metabolism
Humans
Animals
Induced Pluripotent Stem Cells/metabolism/pathology
Neurons/pathology/metabolism
*Models, Biological
Organoids/pathology/metabolism

@article {pmid42847522,
year = {2026},
author = {Donlin-Asp, PG and Clayton, EL},
title = {Synaptic Proteostasis in Health and Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {10},
pages = {e70565},
pmid = {42847522},
issn = {1471-4159},
support = {309570/Z/24/Z/WT_/Wellcome Trust/United Kingdom ; ARUK-SRF2022A-005//Alzheimer's Research UK/ ; //CureSynGAP/ ; 571/ALZS_/Alzheimer's Society/United Kingdom ; //Simons Initiative for the Developing Brain/ ; },
mesh = {Humans ; *Proteostasis/physiology ; *Synapses/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Autophagy/physiology ; *Neurons/metabolism/pathology ; Proteotoxic Stress ; },
abstract = {Neurons rely on tightly coordinated mechanisms of protein synthesis and degradation to maintain cellular homeostasis, a process known as proteostasis. Given their highly polarised and compartmentalised nature, regulation of proteostasis is especially important at neuronal synapses, which are spatially distant from the soma yet require rapid on-demand adaptation of the synaptic proteome. Neurons meet their demand for synaptic proteostasis through localised mRNA transport and translation, alongside specialised pathways for protein degradation. Recent advances reveal that thousands of transcripts localise to distal neuronal compartments and that their distribution may be shaped by RNA stability, RNA dynamics, and organelle-hitchhiking transport mechanisms. In parallel, processes such as synaptic autophagy and endolysosomal trafficking are crucial for maintaining synaptic structure and neurotransmission. Disruptions in these finely balanced mechanisms are a common underlying feature of various neurological disorders, including fragile X syndrome, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. This overview highlights key milestones and remaining questions in synaptic proteostasis, focusing on how local protein synthesis and degradation work together to preserve synaptic integrity and how their dysregulation can lead to disease.},
}

Humans
*Proteostasis/physiology
*Synapses/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
Autophagy/physiology
*Neurons/metabolism/pathology
Proteotoxic Stress

@article {pmid42847555,
year = {2026},
author = {Lopez, FV and Erani, F and Bangen, KJ and Coughlin, DG and Galasko, D and Thomas, KR},
title = {Subjective Cognitive Concerns and Cognitive Trajectories in Parkinson's Disease: Biomarker Impact.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
pmid = {42847555},
issn = {2328-9503},
support = {//Michael J. Fox Foundation for Parkinson's Research/ ; AARG-22-723000/ALZ/Alzheimer's Association/United States ; K23 NS122038/NH/NIH HHS/United States ; P30 AG062429/NH/NIH HHS/United States ; RF1 AG082726/NH/NIH HHS/United States ; },
abstract = {OBJECTIVE: To examine the relationship of subjective cognitive concerns (SCC) with biomarkers of Alzheimer's disease (AD), neurodegeneration, and Parkinson's disease (PD) and domain-specific cognitive trajectories among cognitively unimpaired persons with de novo PD.

METHOD: Cognitively unimpaired participants with SCC (n = 294) and without SCC (n = 857) from the Parkinson's Progression Markers Initiative underwent neuropsychological testing, lumbar puncture, and dopamine transporter (DaT) single-photon emission computed tomography (SPECT). Multiple regression analyses examined SCC associations with biomarkers of AD (CSF phosphorylated-tau181/amyloid-beta42 [p-tau181/Aβ42]), neurodegeneration (CSF neurofilament light [NfL]), and PD (DaT-SPECT in contralateral putamen). Linear mixed effects models examined 5-year cognitive trajectories (working memory, category fluency, learning and memory, visuospatial functioning, processing speed) by SCC status and the extent to which biomarkers of AD, neurodegeneration, and PD moderated these associations.

RESULT: At baseline, the SCC group had higher p-tau181/Aβ42 (FDR-adjusted p = 0.004) than the No SCC group, while NfL and DaT-SPECT did not differ. Relative to the No SCC group, the SCC group exhibited faster decline in learning (FDR-adjusted p = 0.016), delayed recall (FDR-adjusted p = 0.016) and working memory (FDR-adjusted p = 0.016). AD and PD-related biomarkers moderated cognitive trajectories: SCC in combination with (1) higher CSF p-tau181/Aβ42 was related to steeper declines in working memory (FDR-adjusted p = 0.032); and (2) lower DaT-SPECT was related to steeper declines in delayed recall (FDR-adjusted p = 0.032).

INTERPRETATION: SCC is related to AD biomarkers and accelerated cognitive decline in the earliest stages of PD. SCC may serve as an early marker of cognitive risk, especially among persons with greater AD- or PD-related burden.},
}

@article {pmid42847638,
year = {2026},
author = {Schneider, RB and Skibinski, G and Fiske, B and Kopil, CM and Merchant, K and Simuni, T},
title = {Considerations for therapeutic targets for clinical trials in biomarker-characterized prodromal Parkinson's disease populations.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X261493297},
doi = {10.1177/1877718X261493297},
pmid = {42847638},
issn = {1877-718X},
abstract = {Parkinson's disease (PD) is a growing public health problem and biologically targeted therapeutics (BTTs) that slow disease progression are urgently needed. However, the development of effective BTTs is challenging as PD is a clinically defined syndrome with pathobiological heterogeneity and the pathobiological process begins many years before the onset of clinically detectable motor symptoms. Testing BTTs in a biomarker-defined population at an earlier stage in the disease course, before a clinical PD diagnosis, may be the key to achieving this objective. The recent emergence of biological definitions of neuronal α-synuclein disease (NSD) and research frameworks for staging disease represent the first step towards testing BTTs in biomarker-defined prodromal populations. While biomarker-defined populations are essential for implementing precision therapeutic approaches, selecting and prioritizing BTTs for testing in early-stage populations is also critical, and requires consideration of biological relevance, safety, and operational feasibility. Here, in preparation for such studies, we review the landscape of publicly available PD BTTs organized by mechanistic pathways and targets, and summarize scientific, safety, and operational considerations relevant to early-stage, biomarker-defined trials targeting NSD participants prior to PD clinical diagnosis. Recognizing that there are shared biological mechanisms across neurodegenerative disorders, we complement this review of the PD therapeutic target landscape with a review of publicly available Alzheimer's dementia and amyotrophic lateral sclerosis BTTs and provide a comprehensive list of agents for reference.},
}

@article {pmid42847732,
year = {2026},
author = {O'shea, DM and Disla, S and Gosling, AE and Valdelamar, GA and Ioana Tolea, M and Galvin, JE},
title = {Limitations of current neuroprotective therapies in dementia with Lewy bodies.},
journal = {Expert review of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1080/17512433.2026.2742316},
pmid = {42847732},
issn = {1751-2441},
abstract = {INTRODUCTION: Dementia with Lewy bodies (DLB) is characterized by progressive cognitive, neuropsychiatric, motor, autonomic, and sleep impairment. Pharmacological interventions developed with disease-modifying intent have entered clinical testing, but their biological rationale and adequacy of evaluation remain uncertain.

AREAS COVERED: This structured narrative review appraises pharmacological interventions developed with disease-modifying intent in DLB, focusing on biological rationale, central nervous system (CNS) exposure and target engagement, and whether trials adequately tested neuroprotection or altered clinical progression. PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies published from January 2023 through 29 July 2026, with trial and registry reconciliation continuing through 30 July 2026. Twelve DLB trials evaluated interventions targeting endosomal signaling, kinase-related proteostasis, autophagy-lysosomal function, cellular bioenergetics, oligomer-associated synaptic injury, or neurotrophic signaling. No completed trial established neuroprotection or disease modification. Interpretation was limited by biological heterogeneity, Alzheimer disease co-pathology, incomplete CNS target-engagement evidence, short treatment duration, small samples, and endpoints unable to distinguish symptomatic effects from altered progression.

EXPERT OPINION: Future trials should prioritize biomarker-supported diagnosis, prospective co-pathology assessment, demonstrated CNS exposure and target engagement, and longer follow-up combining clinical and mechanism-linked outcomes.},
}

@article {pmid42847983,
year = {2026},
author = {Cattaldo, S and Scarpina, F and Prina, E and Piterà, P and Milesi, A and Sabattini, E and Bigoni, M and Azzaro, C and Pradotto, LG and Mauro, A and Priano, L},
title = {Cerebrospinal fluid surfactant protein-G in neurodegenerative dementia: A comparative study with idiopathic normal-pressure hydrocephalus.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487596},
doi = {10.1177/13872877261487596},
pmid = {42847983},
issn = {1875-8908},
abstract = {BackgroundSurfactant protein G (SP-G) is a recently characterized protein potentially involved in cerebrospinal fluid (CSF) dynamics. Its role in human neurodegenerative dementia remains unknown.ObjectiveTo investigate the potential clinical relevance of CSF SP-G levels in neurodegenerative dementia (ND; including Alzheimer's disease [AD] and frontotemporal dementia [FTD]), idiopathic normal-pressure hydrocephalus (iNPH), vascular dementia (VaD), and clinical controls (CTR).MethodsCSF SP-G levels were quantified in 94 individuals: 35 with ND (11 AD + 24 FTD), 19 with iNPH, 13 with VaD, and 27 CTR. Group differences were analyzed using ANOVA with post hoc tests. ANCOVA was performed to adjust for age.ResultsCSF SP-G levels differed significantly among groups in the primary analysis (ANOVA: F(3,90) = 3.862, p = 0.012), with higher levels in iNPH compared with ND (p = 0.012) and CTR (p = 0.026). No significant differences were observed between ND, VaD, and CTR groups. After adjustment for age, the group effect was no longer significant (F(3,89) = 2.253, p = 0.088).ConclusionsThis is the first study to investigate CSF SP-G levels in neurodegenerative dementia. Our findings suggest that SP-G is more closely related to altered CSF physiology in iNPH than to neurodegenerative pathology, although the influence of age indicates that these observations should be interpreted with caution. SP-G may represent a candidate marker of CSF homeostasis and fluid dynamics. Larger, age-matched studies integrating SP-G with established CSF biomarkers and neuroimaging are needed to clarify its diagnostic and pathophysiological significance.},
}

@article {pmid42847994,
year = {2026},
author = {Chen, Y and Emam, KAF and Yue, S and Tian, J and Wang, T and Park, A and Mishra, S and Deep, G and Wang, ZJ and Du, H and Guo, L},
title = {Disrupted synaptic vacuolar H+-ATPase renders synaptic vulnerability to Alzheimer's disease.},
journal = {JCI insight},
volume = {11},
number = {19},
pages = {},
doi = {10.1172/jci.insight.202983},
pmid = {42847994},
issn = {2379-3708},
mesh = {*Alzheimer Disease/pathology/metabolism/genetics/enzymology ; Animals ; *Vacuolar Proton-Translocating ATPases/metabolism/genetics ; Humans ; Mice ; Synaptic Transmission ; Female ; *Synapses/pathology/metabolism ; Brain/pathology/metabolism ; Male ; Disease Models, Animal ; *Synaptic Vesicles/metabolism ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Aged ; Mice, Transgenic ; },
abstract = {Defective synaptic transmission is a prominent pathology that underlies cognitive deficits in Alzheimer's disease (AD), highlighting the need to elucidate molecular mechanisms of synaptic failure. Vacuolar H+-ATPase (V-ATPase), a proton-pumping enzyme, is essential for synaptic vesicle acidification and neurotransmitter loading. However, whether SV-associated V-ATPase is vulnerable to AD remains unclear. Here, using SV-rich fractions from postmortem brain tissues, we identified SV-associated V-ATPase deficits, including decreased enzymatic activity, impaired complex assembly, and altered expression of its key subunits in AD. SV-associated V-ATPase dysfunction was further associated with pathological and clinical characteristics of AD. Genetic downregulation of the V-ATPase V1D subunit, a component reduced in AD brains, disrupted V-ATPase proton transport and impaired SV acidification. Further experiments using 5×FAD mice, which exhibited AD-like SV-associated V-ATPase deficits, demonstrated the deleterious impact of V-ATPase dysfunction on SV acidification and synaptic transmission including presynaptic neurotransmitter release. In addition, ex vivo studies identified amyloid β-induced oxidative stress as a driver of V1D loss and V-ATPase disassembly, linking AD pathology to SV-associated V-ATPase dysfunction. These findings indicate that SV-associated V-ATPase dysfunction contributes to synaptic failure and cognitive deficits in AD. Therapeutic avenues to mitigate V-ATPase dysfunction have the potential to attenuate synaptic failure for the management of AD.},
}

*Alzheimer Disease/pathology/metabolism/genetics/enzymology
Animals
*Vacuolar Proton-Translocating ATPases/metabolism/genetics
Humans
Mice
Synaptic Transmission
Female
*Synapses/pathology/metabolism
Brain/pathology/metabolism
Male
Disease Models, Animal
*Synaptic Vesicles/metabolism
Oxidative Stress
Amyloid beta-Peptides/metabolism
Aged
Mice, Transgenic

@article {pmid42848122,
year = {2026},
author = {Nimbalkar, J and Shinde, R},
title = {Plant-derived phytochemicals for Alzheimer's disease: mechanisms of action, experimental evidence, and therapeutic perspectives.},
journal = {Journal of natural medicines},
volume = {},
number = {},
pages = {},
pmid = {42848122},
issn = {1861-0293},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cholinergic deficits, amyloid-beta accumulation, tau hyperphosphorylation, oxidative stress, neuroinflammation, and synaptic dysfunction, which collectively contribute to cognitive decline and neuronal loss. Conventional pharmacotherapies provide symptomatic relief but largely target single pathological pathways, highlighting the need for multi-targeted approaches. Herbal therapeutics have emerged as promising complementary or alternative interventions, offering multifaceted mechanisms that simultaneously modulate key disease processes. Preclinical studies, including in vitro and animal models, indicate that extracts of medicinal plants, including Bacopa monnieri (aerial parts), Ginkgo biloba (leaves), Curcuma longa (rhizomes), and Withania somnifera (roots), may enhance cognitive function, exert neuroprotective effects, attenuate oxidative stress and inflammation, and modulate amyloid and tau pathology. However, clinical evidence remains limited, heterogeneous, and inconclusive, with existing studies reporting variable effects on memory, attention, executive function, and global cognition and generally providing only preliminary evidence of safety and efficacy. This translational gap is further influenced by poor bioavailability and brain delivery of several phytoconstituents, variability in herbal preparations, inadequate standardisation, differences in dosing and study design, and the scarcity of adequately powered, long-term clinical trials. Emerging approaches, including nanotechnology-based delivery systems, rational combinations with conventional therapeutics or complementary herbal agents, and personalised interventions based on genetic and metabolic characteristics, may improve therapeutic precision and clinical translation. Integrating mechanistic insights with experimental and clinical evidence may help identify the most promising herbal candidates while defining their translational limitations. This review synthesises current evidence and future directions, providing a framework for advancing herbal interventions in AD.},
}

@article {pmid42848243,
year = {2026},
author = {Song, H and Du, M and He, H and Zhang, R and Fan, F and Xie, S and Zhang, J and Li, T and Qu, C and Zhang, J},
title = {Maresin1 Improves Angiogenesis and Cognitive Function by Regulating Perivascular Macrophages in Rats with Chronic Cerebral Hypoperfusion.},
journal = {Neurochemical research},
volume = {51},
number = {5},
pages = {},
pmid = {42848243},
issn = {1573-6903},
support = {2025AFD143//the Enshi Innovation and Development Joint Fund Project/ ; 82071210//Innovative Research Group Project of the National Natural Science Foundation of China/ ; 2021YFC2500102//National Key Research and Development Program of China/ ; PTXM2020006//the Zhongnan Hospital of Wuhan University Medical Science and Technology Innovation Platform Support Project/ ; PTYX2024024//the Hubei Provincial Clinical Research Center for Dementia and Cognitive Impairment/ ; },
mesh = {Animals ; *Macrophages/drug effects/metabolism ; Male ; Rats, Sprague-Dawley ; *Docosahexaenoic Acids/pharmacology/therapeutic use ; Specialized Pro-Resolving Mediators ; *Cognition/drug effects/physiology ; Rats ; *Brain Ischemia/drug therapy ; *Angiogenesis/drug effects/physiology ; Cerebrovascular Circulation/drug effects/physiology ; Signal Transduction/drug effects ; },
abstract = {Population aging imposes a substantial dementia burden. Chronic cerebral hypoperfusion (CCH) serves as a crucial early pathological basis for Alzheimer's disease (AD) and Vascular Dementia (VaD). Our previous studies have demonstrated that macrophage-derived docosahexaenoic acid metabolite Maresin1 can ameliorate CCH-induced cognitive impairment, though the underlying angiogenesis-related mechanisms remain to be elucidated. We developed a rat model of chronic cerebral hypoperfusion using the bilateral common carotid artery occlusion surgical approach. Cognitive improvements and angiogenic mechanisms by Maresin1 were systematically evaluated using behavioral assessments, immunofluorescence techniques, Western blotting (WB), ELISA, and cerebral blood flow measurements via laser Doppler. Our findings revealed that Maresin1 administration significantly ameliorated CCH-induced cognitive deficits, promoted hippocampal angiogenesis and enhanced cerebral perfusion. Further analysis showed significant enhancement of IGF-1/p-Akt/VEGF/eNOS signaling pathway activation by Maresin1, and the increased VEGF expression was predominantly mediated by perivascular macrophage (pvMΦ) activation. Depletion of pvMΦ using clodronate liposomes suppressed the VEGF upregulation and cognitive improvement mediated by Maresin1. Our research demonstrates that IGF-1/p-Akt/VEGF pathway activation in pvMΦ plays a crucial role in Maresin1-mediated angiogenesis in CCH rats.},
}

Animals
*Macrophages/drug effects/metabolism
Male
Rats, Sprague-Dawley
*Docosahexaenoic Acids/pharmacology/therapeutic use
Specialized Pro-Resolving Mediators
*Cognition/drug effects/physiology
Rats
*Brain Ischemia/drug therapy
*Angiogenesis/drug effects/physiology
Cerebrovascular Circulation/drug effects/physiology
Signal Transduction/drug effects

@article {pmid42849086,
year = {2026},
author = {Ali, SK},
title = {Re-evaluating the neuroprotective landscape of Nigella sativa: Molecular mechanisms, nanomedicine, and clinical translation.},
journal = {Current opinion in pharmacology},
volume = {91},
number = {},
pages = {102676},
doi = {10.1016/j.coph.2026.102676},
pmid = {42849086},
issn = {1471-4973},
abstract = {Nigella Sativa (NS) L., commonly known as black seed, and its major bioactive compound, thymoquinone (TQ), have long been used in traditional medicine and have recently gained increasing attention as potential neuroprotective agents. TQ exerts pleiotropic effects within the central nervous system through several interconnected mechanisms, including activation of the Nrf2/HO-1 antioxidant pathway, inhibition of NF-κB-mediated neuroinflammation and NLRP3 inflammasome signaling, and regulation of the mitochondrial Bax/Bcl-2/caspase-3 apoptotic pathway. These effects have been reported in diverse preclinical models of neurodegeneration and neurotoxicity, including amyloid-β-, 6-hydroxydopamine-,1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and rotenone-induced neuronal injury, global and focal cerebral ischemia-reperfusion, pentylenetetrazole- and status epilepticus-associated seizures, and toxicant- or trauma-related brain injury. However, the clinical translation of native TQ is limited by its poor aqueous solubility, rapid systemic metabolism, and restricted penetration of the blood-brain barrier. These challenges have stimulated the development of nanomedicine-based delivery systems, including solid lipid nanoparticles, PLGA/chitosan nanoparticles, and mesoporous silica nanocarriers, which are designed to improve TQ stability, brain availability, and therapeutic performance. A limited number of controlled human studies have reported potential benefits of NS seed or oil preparations on memory, attention, mood, and pediatric seizure frequency, with generally acceptable tolerability at conventional doses. Nevertheless, substantial variability in reported rodent oral median lethal dose (LD50) values, together with carrier-specific organ toxicity reported for some nanoformulations (renal and hepatic changes with silica-based carriers), underscores the need for formulation- and exposure-specific safety assessment. Overall, current evidence positions NS and thymoquinone as promising but predominantly preclinical neuroprotective candidates. Their potential applications in Alzheimer's disease, Parkinson's disease, ischemic stroke, and epilepsy remain hypothesis-generating and will require validation through pharmacokinetically optimized formulations and adequately powered clinical trials.},
}

@article {pmid42849148,
year = {2026},
author = {Freischmidt, A and Weishaupt, JH},
title = {Update on somatic mutations in major neurodegenerative diseases: mutational signatures in neurons and mosaicism.},
journal = {Current opinion in genetics & development},
volume = {101},
number = {},
pages = {102549},
doi = {10.1016/j.gde.2026.102549},
pmid = {42849148},
issn = {1879-0380},
abstract = {Somatic mutations in major neurodegenerative diseases are poorly understood, but research over the past 2 years provides valuable insights. Single-cell whole-genome sequencing of vulnerable neurons in Alzheimer's disease and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) revealed excess accumulation of single-nucleotide variant signatures and two-bp deletions independent of pathogenic protein aggregation. Increased oxidative DNA damage and possibly impaired DNA damage repair pathways may explain more pronounced signatures in patients. Ultra-deep sequencing of disease-associated genes in relevant tissues in ALS/FTD identified a subset of sporadic patients carrying mosaic variants that cause disease when present in the germline, but the pathogenicity of such mosaic variants at low allele frequencies is unclear. Research on somatic variants in Parkinson's disease remains underrepresented in the literature.},
}

@article {pmid42849166,
year = {2026},
author = {Sarwar, S and Mehmood, T and Abbasi, GR},
title = {Region-wise chemometric framework for identifying FTIR functional-group signatures associated with cholinesterase inhibition.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 2},
pages = {109474},
doi = {10.1016/j.compbiolchem.2026.109474},
pmid = {42849166},
issn = {1476-928X},
abstract = {Two key therapeutic targets in the treatment of Alzheimer's disease are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Understanding the molecular characteristics associated with cholinesterase inhibition is important for the development of new inhibitors. In this study, a chemometric framework integrating Fourier Transform Infrared (FTIR) spectroscopy, Principal Component Analysis (PCA), and region-wise Partial Least Squares Regression (PLSR) was applied to explore spectral-response relationships in newly synthesized flurbiprofen hydrazide and hydrazone derivatives. The dataset comprised 27 compounds with 1868 spectral variables covering the 4000-400 cm[-1] region and experimentally determined AChE and BuChE inhibition activities. Following SNV preprocessing, PCA was used to characterize spectral variability and define five major spectral domains: O-H/N-H, C-H, carbonyl/amide, C-O/C-N, and fingerprint regions. Region-wise PLSR models were evaluated using 5-fold cross-validation based on RMSECV and MAE-CV, with Y-randomization providing an additional assessment of the observed modeling performance. Among the investigated regions, the C-H stretching domain (3000-2800 cm[-1]) showed the most favorable relative cross-validated performance for both AChE (RMSECV = 5.49; MAE-CV = 4.02) and BuChE (RMSECV = 5.09; MAE-CV = 5.13). Y-randomization further supported the response-related performance of the C-H region, particularly for BuChE. Regression coefficient profiles provided additional spectral information for interpreting the response-related variation across the investigated regions. Overall, the FTIR-PCA-PLSR framework provides an interpretable approach for comparative assessment of spectral domains and for generating chemically testable hypotheses regarding cholinesterase inhibition in the investigated flurbiprofen derivative series.},
}

@article {pmid42849193,
year = {2026},
author = {Del Percio, C and Lizio, R and Noce, G and Carpi, M and Lopez, S and Carducci, F and De Bartolo, M and Afragola, AP and Soricelli, A and Salvatore, M and Giubilei, F and Güntekin, B and Yener, G and Massa, F and Arnaldi, D and Famà, F and Pardini, M and Ferri, R and Lanuzza, B and Stocchi, F and Vacca, L and Coletti, C and Infarinato, F and Marziali, S and Marizzoni, M and Taylor, JP and Hanoğlu, L and Yırıkoğulları, H and Frisoni, GB and Cuoco, S and Cappiello, A and Barone, P and Bonanni, L and Biundo, R and Cauzzo, S and Fiorenzato, E and Antonini, A and De Pandis, MF and D'Antonio, F and Bruno, G and Babiloni, C},
title = {Association among white matter lesions, rsEEG rhythms, amyloid tau markers, and cognitive status in mild cognitive impairment patients.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {193},
number = {},
pages = {2112432},
doi = {10.1016/j.clinph.2026.2112432},
pmid = {42849193},
issn = {1872-8952},
abstract = {OBJECTIVE: Abnormalities in posteriorly dominant resting-state eyes-closed electroencephalographic (rsEEG) alpha rhythms are associated with cerebrospinal fluid (CSF) tau neuropathology and Mini-Mental Status Examination (MMSE) score, reflecting global cognition, in patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD). The present study examined the relationships between white matter cerebrovascular lesions (WMLs) and CSF amyloid-tau markers, posterior rsEEG alpha rhythms, and cognitive status in patients with MCI-AD versus those with mild cognitive impairment not due to Alzheimer's disease (MCI-noAD).

METHODS: An international database provided clinical, demographic, CSF amyloid-tau, rsEEG, and magnetic resonance imaging (MRI) datasets for 68 MCI-AD and 44 MCI-noAD patients. The WMLs were segmented from T2-weighted and FLAIR MRI images. Cortical rsEEG sources at individual delta, theta, and alpha frequencies were estimated using eLORETA freeware.

RESULTS: In MCI-AD patients, greater WMLs were not associated with increased AD neuropathology, greater alterations in rsEEG alpha or other source activities, or worse MMSE scores. In contrast, higher WMLs were associated with lower MMSE scores in patients with MCI-noAD.

CONCLUSIONS: These results suggest that WMLs had a limited role in prodromal AD, while it affects global cognitive status in patients with MCI-noAD.

SIGNIFICANCE: These findings highlight the stage-dependent, region-specific, and pathology-specific nature of cerebrovascular-neurodegenerative interactions. The limited role of WMLs in MCI-AD may indicate that synergistic neurotoxic effects between vascular burden and AD pathology require more advanced disease stages or higher thresholds of vascular burden to manifest clinically.},
}

@article {pmid42849557,
year = {2026},
author = {Shrirame, D and Tatode, A and Dabhade, D and Taksande, J and Taksande, B and Kakade, O and Umekar, M},
title = {Intermittent Fasting as a Therapeutic Strategy in Alzheimer's Disease: Understanding of Brain-Derived Neurotrophic Factor Modulation.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {115522},
doi = {10.1016/j.physbeh.2026.115522},
pmid = {42849557},
issn = {1873-507X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease with amyloid-beta (Aβ) plaques, tau tangles, neuroinflammation, and oxidative stress, and it causes cognitive impairment and neuronal loss. The pharmacological treatment is of limited effectiveness, therefore the interest in novel approaches such as intermittent fasting (IF). IF, a nutritional regimen of periodic caloric restriction, has shown a potential to modulate neurodegenerative alterations by metabolic and molecular mechanisms. This review presents the implications of IF in the etiopathogenesis of AD, specifically in controlling brain-derived neurotrophic factor (BDNF). BDNF is a major neurotrophin that plays a key role in synaptic plasticity, neuronal survival, and cognition. Evidence indicates that BDNF is drastically decreased in AD, therefore enhancing disease progression. IF enhances BDNF expression via mechanisms such as improved mitochondrial function, increased ketone body production, and reduced systemic inflammation. Preclinical studies indicate that IF not only upregulates BDNF but also alleviates key AD pathologies, including Aβ deposition and tau hyperphosphorylation. Additionally, clinical data highlight the cognitive benefits of IF and its role in modulating metabolic health, although studies specifically linking IF, BDNF and AD in humans remain limited. This review underscores the need for further research to determine optimal IF protocols and clarify its long-term impact on AD progression. IF's ability to modulate BDNF and other neuroprotective pathways positions it as a promising non-pharmacological intervention for AD management. By bridging metabolic health and neuroprotection, IF offers potential therapeutic synergy for mitigating AD's complex etiopathogenesis.},
}

@article {pmid42849643,
year = {2026},
author = {Chen, R and Sun, X and Wu, T and Tao, L and Zhao, L and Zhong, X and Zhang, Q and Yan, Q and Lu, S and Song, Z and Song, D and Li, L and Niu, J and Yang, H and Teng, Y and Zou, J},
title = {CXCL16-driven neutrophil extracellular traps promote osteoporosis in APP/PS1 mice by disrupting bone remodeling.},
journal = {Bone},
volume = {},
number = {},
pages = {118126},
doi = {10.1016/j.bone.2026.118126},
pmid = {42849643},
issn = {1873-2763},
abstract = {Patients with Alzheimer's disease (AD) often exhibit abnormal bone loss alongside cognitive impairment. However, the mechanisms linking these two conditions remain insufficiently understood. We first employed amyloid precursor protein/presenilin 1 (APP/PS1) mice as the experimental model and demonstrated that they exhibit significant bone loss concurrent with cognitive impairment. Subsequently, we analyzed public datasets for AD and osteoporosis (OP) and identified CXC chemokine ligand 16 (CXCL16) as a shared hub gene between the two diseases. Transcriptomic sequencing further showed increased CXCL16 expression in the femoral tissue of APP/PS1 mice. Immunoblot analysis of brain and bone tissues, together with serum enzyme-linked immunosorbent assay (ELISA), verified the systemic elevation of CXCL16. These findings suggest that CXCL16 may link cognitive impairment with bone loss in APP/PS1 mice. In vitro experiments showed that CXCL16 did not directly affect the differentiation of bone marrow mesenchymal stem cells or bone marrow-derived macrophages. Instead, CXCL16 acted through neutrophils by promoting their migration and potentiating PMA-stimulated neutrophil extracellular trap (NET) formation. Conditioned medium from NET-producing neutrophils inhibited osteogenic differentiation and promoted osteoclastogenesis. In APP/PS1 mice, antagonism of CXCR6, the cognate receptor for CXCL16, with ML339 improved trabecular bone microarchitecture and osteogenic activity and alleviated cognitive impairment. Degradation of NETs with deoxyribonuclease I (DNase I) produced similar effects. Collectively, these results implicate CXCL16-associated enhancement of NET formation in AD-related skeletal deterioration and highlight the CXCL16-NETs pathway as a possible intervention target for maintaining bone homeostasis.},
}

@article {pmid42849896,
year = {2026},
author = {Tavakoli, M and Dadgostar, M and Green, JR and Salat, DH and Arnold, SE and Connaghan, KP and Richburg, B and Barnett, NV and Tkeshelashvili, M and Eshghi, M},
title = {Remote Identification of APOE-ε4 Carrier Status in Cognitively Normal Adults via Speech Acoustics: Cross-Sectional Observational Study.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e89830},
doi = {10.2196/89830},
pmid = {42849896},
issn = {2561-326X},
mesh = {Humans ; Cross-Sectional Studies ; *Apolipoprotein E4/genetics/analysis ; Aged ; Female ; Male ; Adult ; Middle Aged ; Aged, 80 and over ; *Heterozygote ; *Speech Acoustics ; *Cognition/physiology ; Speech/physiology ; },
abstract = {BACKGROUND: Apolipoprotein E ε4 (APOE-ε4), the strongest genetic risk factor for late-onset Alzheimer disease (AD), is associated with early neuromotor vulnerability that may precede measurable cognitive decline. Because speech integrates fine neuromotor processes, acoustic analysis could offer a sensitive, noninvasive marker of preclinical effects.

OBJECTIVE: This study aims to determine if speech acoustics distinguish cognitively normal APOE-ε4 carriers from noncarriers, and to assess which speech tasks provide optimal classification performance.

METHODS: In this cross-sectional observational study, 80 cognitively normal adults aged 41 to 89 years (22 APOE-ε4 carriers and 58 noncarriers) completed sustained phonation, oral diadochokinetic syllable repetition, passage reading, and spontaneous-speech tasks. Speech samples were collected remotely using participants' personal devices and processed to extract 88 acoustic features from the extended Geneva Minimalistic Acoustic Parameter Set. Task-specific random forest classifiers were developed to distinguish APOE-ε4 carriers from noncarriers. A genetic algorithm was used to select informative features, and model performance was evaluated using leave-one-participant-out cross-validation. Performance metrics included balanced accuracy, accuracy, precision, sensitivity, specificity, F1-score, and receiver operating characteristic area under the curve (ROC-AUC).

RESULTS: Spontaneous speech produced the strongest classification performance, with balanced accuracy of 0.84, accuracy of 0.89, sensitivity of 0.73, specificity of 0.95, F1-score of 0.78, and ROC-AUC of 0.75. Performance was lower for sustained phonation (F1-score=0.69), diadochokinetic syllable repetition (F1-score =0.70 for /ba/ and 0.64 for /pa/), and passage reading (F1-score=0.61). Combining recordings across tasks reduced performance (F1-score=0.53), indicating that task-specific acoustic patterns were more informative than pooled data.

CONCLUSIONS: Automated analysis of task-specific acoustic speech features, particularly spontaneous speech, internally distinguished cognitively normal APOE-ε4 carriers from noncarriers. These findings support further validation of speech acoustics as a low-burden digital biomarker of preclinical AD risk and suggest that spontaneous-speech tasks may be especially well suited for future remote and longitudinal assessment.},
}

Humans
Cross-Sectional Studies
*Apolipoprotein E4/genetics/analysis
Aged
Female
Male
Adult
Middle Aged
Aged, 80 and over
*Heterozygote
*Speech Acoustics
*Cognition/physiology
Speech/physiology

@article {pmid42850105,
year = {2026},
author = {Calafate, S and Mancuso, R},
title = {Sleep-dependent microglial functions in Alzheimer's disease.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.09.005},
pmid = {42850105},
issn = {1878-108X},
abstract = {Sleep is a fundamental regulator of brain homeostasis, yet how distinct brain cell types contribute to this process remains poorly understood. Microglia, the resident immune cells of the central nervous system, actively regulate neuroinflammatory tone, metabolic waste clearance, and synaptic remodeling, thereby contributing to neural circuit maintenance and proteostasis. Delineating the different functions played by microglia during specific brain states, such as sleep, represents an active area of research. In this article, we review a growing literature supporting the notion that sleep dynamically shapes microglial functional outputs. We further suggest that the failure of the sleep-microglia axis may represent an important component of the molecular framework of Alzheimer's disease (AD), contributing to disease progression. Finally, we discuss preclinical and clinical evidence suggesting that sleep-targeting interventions may modulate AD pathology, and highlight the possibility that restoring sleep physiology could recalibrate microglial homeostatic functions and slow disease progression.},
}

@article {pmid42850312,
year = {2026},
author = {Hou, Y and Li, Y and Zhang, P and Lorincz-Comi, N and Gohel, D and Fan, F and Qiu, Y and Yang, J and Chen, X and Song, W and Yang, X and Tan, Z and Liu, Z and Fang, X and Rivera Paz, I and Martin, W and Feng, Y and Zhou, Y and Xu, J and Dou, L and Border, J and Zhang, H and Mazique, JN and Hwang, SH and Roman, RJ and Babak, T and Bekris, L and Karavani, E and Danziger, M and Rosen-Zvi, M and Haines, JL and Yu, H and Hammock, BD and Leverenz, JB and Pieper, AA and Cummings, J and Cheng, F},
title = {Alzheimer's disease target and drug discovery by leveraging multiomics and electronic health data.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42850312},
issn = {1546-1726},
support = {U01AG073323//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R35AG71476, R25 AG083721-01//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG072959//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1NS133812//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
abstract = {Despite prolific genomic data from individuals with Alzheimer's disease (AD), translation into treatments has lagged. Here we applied Mendelian randomization to multiple AD genome-wide association studies and functional multiomics datasets to nominate druggable targets, identifying 19 targets for individuals of European ancestry and 7 for African ancestry. This included epoxide hydrolase 2 (EPHX2), for which we identified a protective missense variant (p.Arg287Gln). Experiments in induced pluripotent stem cell-derived neurons and cerebral organoids from patients with AD validated the protective role of p.Arg287Gln via reduced levels of EPHX2 and phosphorylated tau (pTau-181). Pharmacological inhibition of EPHX2 improved cognitive performance in the 5xFAD mouse model of AD. Finally, by leveraging electronic health data from 111,680 patients with mild cognitive impairment, we identified 12 drugs associated with reduced AD incidence, including trazodone (targeting ADRA1A) and baclofen (targeting GABBR1). Thus, integrating multiomics data, functional validation and electronic health data identifies new approaches for treating AD.},
}

@article {pmid42850455,
year = {2026},
author = {Padovani, A and Altini, M and Bellelli, G and Bozzali, M and Brignoli, O and Cagnin, A and Cherubini, A and Iannacci, M and Lodi, R and Logroscino, G and Marra, C and Nicora, C and Parretti, S and Sacco, A and Spadin, P and Zappia, M},
title = {Organizing healthcare delivery in the era of disease-modifying therapies for Alzheimer's Disease: an Italian RAND/UCLA consensus.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {11},
pages = {},
pmid = {42850455},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/therapy/diagnosis ; Italy ; *Delivery of Health Care/organization & administration ; Consensus ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) poses a growing clinical and organizational challenge, requiring coordinated, multidisciplinary care models. In Italy, significant regional variability in resources and access to diagnostic services persists, while the implementation of community-based care models, the expanding role of biomarkers, and the advent of disease-modifying therapies (DMTs) further highlight the need for a more coordinated and equitable dementia care network.

OBJECTIVE: Develop system-level recommendations to optimise the organisation of AD care delivery in Italy in anticipation of DMTs introduction.

METHODS: Using the RAND/UCLA Appropriateness Method, a multidisciplinary panel rated 55 statements across nine domains, evaluating appropriateness in two rounds and priority of implementation in a third round.

RESULTS: Consensus was achieved for all statements, with high appropriateness and priority ratings. The statements outline a regional, network-based model organised across territorial services, Spoke and Hub centres, with formal governance responsible for pathway definition and monitoring. Referral pathways from primary care are based on cognitive and frailty assessment, with non-frail patients referred to Spoke for clinical, neuropsychological and neuroradiological evaluation. Patients potentially eligible for DMTs are referred to Hub centres, where diagnostic confirmation is completed and multidisciplinary teams assess treatment eligibility. When authorised, Hub centres are responsible for DMTs prescription and administration. The statements emphasise the need for standardised neuropsychological and neuroradiological protocols for amyloid-related imaging abnormalities (ARIA) monitoring, alongside the progressive adoption of plasma biomarkers, telemedicine, and structured communication with patients and caregivers.

CONCLUSION: This consensus provides a pragmatic framework to support the reorganisation of AD care in Italy, ensuring that every patient is directed to the most appropriate level of care across a flexible regional network.},
}

Humans
*Alzheimer Disease/therapy/diagnosis
Italy
*Delivery of Health Care/organization & administration
Consensus

@article {pmid42851057,
year = {2026},
author = {Chen, S and He, M and Huo, Y and Xing, F and Gao, Y and Dai, Y and Gao, N and Yin, S},
title = {[Research progress on the correlation mechanism between innate immune imbalance and Alzheimer's disease based on Drosophila model].},
journal = {Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology},
volume = {42},
number = {10},
pages = {931-937},
pmid = {42851057},
issn = {1007-8738},
mesh = {Animals ; *Immunity, Innate ; *Alzheimer Disease/immunology ; Disease Models, Animal ; Humans ; *Drosophila melanogaster/immunology/genetics ; Signal Transduction ; },
abstract = {Innate immune dysregulation is a common pathological basis for the development and progression of both infectious diseases and various chronic diseases. Drosophila melanogaster, owing to its highly conserved immune system, well-established genetic manipulation tools, and intact in vivo physiological environment, has become an important model for studying human immune-related diseases. This article systematically reviews the latest research progress on the Drosophila model regarding the "infection-innate immune dysregulation-Alzheimer's disease (AD)" axis. Studies using Drosophila models have shown that Gram-positive bacteria and fungi activate the Toll pathway, while Gram-negative bacteria activate the immune deficiency (Imd) pathway, leading to innate immune dysregulation; all of the above pathogen infections are associated with the pathological progression of AD. Peripheral immune dysregulation can mediate cross-organ inflammatory transmission through the gut-brain axis and the oral-gut-brain axis, thereby contributing to the exacerbation of AD pathological damage. The Drosophila tumor necrosis factor α (TNF-α) homolog Eiger, via activation of the tumor necrosis factor-c-Jun N-terminal kinase (TNF-JNK) pathway, mediates peripheral-immune-driven remote central neuroinflammation. These findings suggest that precise regulation of the innate immune system is critical for maintaining organismal homeostasis, and its dysregulation serves as a link between infectious diseases and AD. The Drosophila model provides a unique perspective for dissecting the pathological progression of "infection-innate immune dysregulation-AD," laying a theoretical foundation for AD intervention strategies targeting immune pathways, the gut-brain axis, and the oral-gut-brain axis, and also offering a reference for translational research on innate immunity-related diseases. It should be noted that the above conclusions are mainly based on mechanistic studies in the Drosophila model, and their extrapolation to human AD still requires further validation.},
}

Animals
*Immunity, Innate
*Alzheimer Disease/immunology
Disease Models, Animal
Humans
*Drosophila melanogaster/immunology/genetics
Signal Transduction

@article {pmid42851103,
year = {2026},
author = {Zhang, L and Lin, P and Zhang, Y and Lin, Z},
title = {Clinical Value of Neuropsychiatric Scales in the Preliminary Identification of Frontotemporal Dementia from Alzheimer's Disease.},
journal = {Journal of the College of Physicians and Surgeons--Pakistan : JCPSP},
volume = {36},
number = {10},
pages = {1344-1349},
doi = {10.29271/jcpsp.2026.10.1344},
pmid = {42851103},
issn = {1681-7168},
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; *Frontotemporal Dementia/diagnosis/psychology ; Female ; Male ; Cross-Sectional Studies ; *Activities of Daily Living ; *Neuropsychological Tests ; Caregivers/psychology ; Middle Aged ; Aged ; Diagnosis, Differential ; *Psychiatric Status Rating Scales ; Sensitivity and Specificity ; China ; ROC Curve ; },
abstract = {OBJECTIVE: To provide a reference for the clinical differentiation of behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) by analysing differences in scores across various neuropsychiatric scales and their relationships with activities of daily living and caregiver burden.

STUDY DESIGN: A cross-sectional study. Place and Duration of the Study: Department of Neurology, the Affiliated Hospital of Putian University, Putian, China, from January 2024 to March 2025.

METHODOLOGY: Data from the Mild Behavioural Impairment Checklist (MBI-C), Neuropsychiatric Inventory (NPI), Frontal Behavioural Inventory (FBI), Activities of Daily Living (ADL) scale, and Zarit Caregiver Burden Interview (ZBI) were collected from patients with bvFTD and AD. t-test or chi-square test was used to analyse differences in the scores between the two groups. Pearson's correlation analysis was conducted to examine the relationship between ADL and ZBI scores and MBI-C, NPI, and FBI scores. ROC curve analysis was used to evaluate the sensitivity and specificity of the MBI-C, NPI, and FBI scales. The AUC values were calculated and compared.

RESULTS: The bvFTD group exhibited significantly higher MBI-C, NPI, and FBI scores than the AD group (p <0.05). Emotional problems, lack of motivation, disinhibition, speech disorders, impaired judgment, lack of self-awareness, inattention, stubbornness, and incontinence were all more pronounced in the bvFTD group. ADL and ZBI scores were positively correlated with MBI-C, NPI, and FBI scores in both groups. The FBI scale had an AUC value of 0.85, with sensitivity and specificity of 81.82% and 74.71%, respectively, when the score exceeded 20.5.

CONCLUSION: The MBI-C, NPI, and FBI scales can quickly and effectively distinguish bvFTD from AD, with the FBI scale having the highest diagnostic value. Neuropsychiatric disturbances in patients with bvFTD and AD reduce their daily living abilities and increase their caregiver burden.

KEY WORDS: Behavioural variant frontotemporal dementia, Alzheimer's disease, Mild behavioural impairment checklist, Neuropsychiatric inventory, Frontal behavioural inventory.},
}

Humans
*Alzheimer Disease/diagnosis/psychology
*Frontotemporal Dementia/diagnosis/psychology
Female
Male
Cross-Sectional Studies
*Activities of Daily Living
*Neuropsychological Tests
Caregivers/psychology
Middle Aged
Aged
Diagnosis, Differential
*Psychiatric Status Rating Scales
Sensitivity and Specificity
China
ROC Curve

@article {pmid42851117,
year = {2026},
author = {Powell, WR and Melcher, EM and Otte, RC and Lim, S and Etter, L and Pfaff, A and DeWitt, A and Lee, ARS and Ketchum, FB and Salamat, MS and Bradfield, CA and Goutman, SA and Zuelsdorff, ML and Bakulski, KM and Rissman, RA},
title = {Association between early-life farming exposure and Alzheimer's disease neuropathological burden.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71904},
doi = {10.1002/alz.71904},
pmid = {42851117},
issn = {1552-5279},
support = {R21AG079277//National Institute on Aging Awards/ ; R01AG070883//National Institute on Aging Awards/ ; P30AG062715//National Institute on Aging Awards/ ; R01AG079303//National Institute on Aging Awards/ ; P30AG066530//National Institute on Aging Awards/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/epidemiology ; Female ; Male ; *Brain/pathology ; *Agriculture ; *Environmental Exposure/adverse effects ; Aged ; Adolescent ; Risk Factors ; Child, Preschool ; Infant ; Child ; Aged, 80 and over ; Middle Aged ; Infant, Newborn ; Neuropathology ; },
abstract = {BACKGROUND: Farming populations may face a disproportionate share of adverse exposures influencing Alzheimer's disease (AD), yet farming data are rarely connected to cohorts with characterized AD neuropathology. Whether early-life exposure is related to AD neuropathology is limited.

METHOD: Brain donors from two Alzheimer's Disease Research Centers (N = 1035; between 1986-2018) were included. US Census records were used to identify those with early-life farming exposure (birth to 17 years old) and examined alongside AD neuropathology assessments.

RESULT: Early-life farming exposure (≈ 17% of donors) was associated with 60% higher odds of AD neuropathological burden (odds ratio = 1.60, 95% confidence interval: 1.09-2.35) adjusting for age, sex, and year of death.

CONCLUSION: Findings suggest exposure to farming early in life is linked to increased levels of AD neuropathology. Deeper occupational and residential phenotyping is needed to identify the potential multiple, overlapping risk pathways, which may include cumulative and sensitive life stage exposure to chemical toxicants, hearing loss, and psychosocial hazards.},
}

Humans
*Alzheimer Disease/pathology/epidemiology
Female
Male
*Brain/pathology
*Agriculture
*Environmental Exposure/adverse effects
Aged
Adolescent
Risk Factors
Child, Preschool
Infant
Child
Aged, 80 and over
Middle Aged
Infant, Newborn
Neuropathology

@article {pmid42851120,
year = {2026},
author = {Han, X and Hu, R and Ping, X and Chen, J and Liu, J and Liu, Z and Jin, X and Gao, X and Lin, M and Zhao, Y and Wang, N},
title = {Diffusion MRI reveals amyloid plaque-associated cellular signatures through spatial transcriptomic integration.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71908},
doi = {10.1002/alz.71908},
pmid = {42851120},
issn = {1552-5279},
support = {RP210099//Cancer Prevention and Research Institute of Texas/ ; //The UT System Rising STARs (Science and Technology Acquisition and Retention) Award/ ; //Ralph W. and Grace M. Showalter Research Trust Fund/ ; R01 NS125020//Foundation for the National Institutes of Health/ ; },
mesh = {Animals ; *Diffusion Magnetic Resonance Imaging/methods ; *Plaque, Amyloid/diagnostic imaging/pathology/genetics ; Spatial Transcriptomics ; *Alzheimer Disease/diagnostic imaging/pathology/genetics ; *Brain/pathology/diagnostic imaging ; Mice ; Disease Models, Animal ; Microglia/pathology/metabolism ; Mice, Transgenic ; Oligodendroglia/metabolism/pathology ; Neurons/pathology/metabolism ; Neural Networks, Computer ; Transcriptome ; },
abstract = {INTRODUCTION: Amyloid plaque deposition is a defining feature of Alzheimer's disease (AD), yet how plaque-associated cellular alterations are reflected in noninvasive imaging remains unclear.

METHODS: We integrated high-resolution diffusion magnetic resonance imaging (dMRI) with spatial transcriptomics (ST) in an AD mouse model. Spatial correlations were assessed across the whole brain and in disease-control and plaque-non-plaque comparisons. Neural network models were trained to predict AD-associated cell types from dMRI metrics.

RESULTS: dMRI metrics showed moderate spatial correlations (r = -0.41 to 0.36) with oligodendrocyte- and neuron-related gene expression. Disease-control comparisons revealed region-specific MRI-derived microstructural alterations aligned with transcriptional changes in microglia, astrocytes, oligodendrocytes, and neurons. Plaque-rich regions exhibited distinct diffusion and susceptibility signatures associated with oligodendrocyte and microglial expression. Neural networks predicted spatial distributions of AD-associated cell types with 80%-86% accuracy.

DISCUSSION: dMRI captures plaque-associated cellular pathology and supports biologically informed interpretation of imaging contrasts in AD.},
}

Animals
*Diffusion Magnetic Resonance Imaging/methods
*Plaque, Amyloid/diagnostic imaging/pathology/genetics
Spatial Transcriptomics
*Alzheimer Disease/diagnostic imaging/pathology/genetics
*Brain/pathology/diagnostic imaging
Mice
Disease Models, Animal
Microglia/pathology/metabolism
Mice, Transgenic
Oligodendroglia/metabolism/pathology
Neurons/pathology/metabolism
Neural Networks, Computer
Transcriptome

@article {pmid42851142,
year = {2026},
author = {Aqeel, A and Bashir, F and Asad, M and Asad, A and Jafar, S and Yasir, M},
title = {Rational modification of olive derived 4-ethylguaiacol into a BBB-permeable acetylcholinesterase inhibitor via molecular docking, DFT, and molecular dynamics: a computational approach to alzheimer's drug discovery.},
journal = {SAR and QSAR in environmental research},
volume = {},
number = {},
pages = {1-37},
doi = {10.1080/1062936X.2026.2740626},
pmid = {42851142},
issn = {1029-046X},
abstract = {Alzheimer's disease (AD) affects more than 55 million people worldwide, yet no disease-modifying therapy has been approved. Here, 23 phytochemicals from Olea europaea (olive) were evaluated using a multi-filter pipeline comprising ADME/drug-likeness screening, BBB permeability assessment, molecular docking, DFT analysis, and MD simulations. This is the first computational study of olive phytochemicals targeting AChE to use BBB permeability as an explicit screening filter, addressing the CNS penetrance gap that limits translation of prior in silico hits. ADME screening (through SwissADME) identified three Lipinski-compliant, BBB-permeable candidates. Among these, 4-ethylguaiacol exhibited the strongest AChE binding (-7.0 kcal/mol) and a favorable HOMO-LUMO energy gap (6.09 eV), indicating moderate chemical reactivity and stability. Structure-guided optimization of 4-ethylguaiacol using RDKit led to the design of AM-11; 4-ethyl-5-(1-hydroxycyclopropyl)-2-methoxyphenol, whose C-5 hydroxycyclopropyl group forms direct hydrogen bond with catalytic residue, Ser203. AM-11 showed improved binding affinity (-7.9 kcal/mol), stable RMSD throughout a 100 ns MD simulation, and a predicted LD50 of 720 mg/kg (Class IV), a better acute toxicity profile than donepezil (505 mg/kg). These findings position AM-11 as a as a computational lead for a BBB-permeable AChE inhibitor scaffold requiring experimental validation, and the pipeline as a reproducible framework for phytochemical-based lead optimization in AD.},
}

@article {pmid42851145,
year = {2026},
author = {Han, SW and Park, YH and Pyun, JM and Bice, PJ and Bennett, DA and Oveisgharan, S and Saykin, AJ and Kim, S and Nho, K},
title = {Proteomic dysregulation associated with cerebral amyloid angiopathy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71901},
doi = {10.1002/alz.71901},
pmid = {42851145},
issn = {1552-5279},
support = {P30 AG010161/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; U01 AG072572/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; R01 AG075959/AG/NIA NIH HHS/United States ; R01 AG082348/AG/NIA NIH HHS/United States ; R01 AG081951/AG/NIA NIH HHS/United States ; R01 AG057739/AG/NIA NIH HHS/United States ; R01 AG070883/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; R01 LM013463/LM/NLM NIH HHS/United States ; T32 AG071444/AG/NIA NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; U01 AG068057/AG/NIA NIH HHS/United States ; U01 AG072177/AG/NIA NIH HHS/United States ; U19 AG074879/AG/NIA NIH HHS/United States ; R01 AG019771/AG/NIA NIH HHS/United States ; R01 AG068193/AG/NIA NIH HHS/United States ; R01 LM012535/LM/NLM NIH HHS/United States ; //National Research Foundation of Korea/ ; RS-2024-00461936//Ministry of Science and ICT, Republic of Korea/ ; RS-2025-25426019//Ministry of Science and ICT, Republic of Korea/ ; },
mesh = {*Cerebral Amyloid Angiopathy/pathology/metabolism/cerebrospinal fluid ; Humans ; *Proteomics ; *Brain/pathology/metabolism ; Alzheimer Disease/pathology ; Female ; Male ; Biomarkers/cerebrospinal fluid ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Cerebral amyloid angiopathy (CAA) is characterized by impaired vascular amyloid-β clearance, distinct from Alzheimer's disease (AD), underscoring the need to clarify its molecular basis for predicting therapy-related amyloid-related imaging abnormalities.

METHODS: We analyzed post-mortem brain proteomics from Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) and cerebrospinal fluid (CSF) proteomics from Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify CAA-associated proteins and network modules, delineate their biological processes and cellular origins, and determine their diagnostic performance.

RESULTS: Proteomics analysis identified 30 proteins as associated with CAA severity, enriched in pathways distinct from AD pathology, with 11 replicated in ADNI. Two CAA-associated modules were enriched for microglial vesicle transport and astrocytic potassium-ion homeostasis. Pseudotime analysis demonstrated a molecular trajectory aligned with increasing CAA severity. Three proteins (RCSD1, FRZB, AKAP6) improved CAA classification beyond demographics and APOE ε4.

DISCUSSION: This integrative proteomics analysis identifies distinct, reproducible molecular signatures of CAA, revealing glia-mediated pathways and promising biomarkers for CAA detection and therapy-related risk assessment.},
}

*Cerebral Amyloid Angiopathy/pathology/metabolism/cerebrospinal fluid
Humans
*Proteomics
*Brain/pathology/metabolism
Alzheimer Disease/pathology
Female
Male
Biomarkers/cerebrospinal fluid
Aged, 80 and over

@article {pmid42851166,
year = {2026},
author = {Hwang, J and Figueredo, LF and Valencia, DI and Tolbert, TM and Hamada, E and Zhou, L and Gills, JL and Ruiz, J and Martillo, KR and Chu, SS and Kumar, A and Blessing, EM and Bubu, OM and Parekh, A and Kam, K and Mullins, AE and Rapoport, DM and Ayappa, I and Osorio, RS and Varga, AW},
title = {Longitudinal associations of rapid eye movement (REM) sleep and slow-wave sleep with plasma Alzheimer's disease biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71910},
doi = {10.1002/alz.71910},
pmid = {42851166},
issn = {1552-5279},
support = {R01 AG066870/AG/NIA NIH HHS/United States ; R01 AG080609/AG/NIA NIH HHS/United States ; R01 AG056031/AG/NIA NIH HHS/United States ; R01AG056531//NIH/ ; T32 HL160511/HL/NHLBI NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //American Thoracic Society (ATS)/ ; ASPIRE Fellowship//American Thoracic Society/ ; AARFD-24-1306796/ALZ/Alzheimer's Association/United States ; T32 HL160511/HL/NHLBI NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Sleep, REM/physiology ; Aged ; *Amyloid beta-Peptides/blood ; *Alzheimer Disease/blood/physiopathology ; Biomarkers/blood ; Female ; Male ; *Sleep, Slow-Wave/physiology ; Polysomnography ; *Peptide Fragments/blood ; Longitudinal Studies ; Aged, 80 and over ; Middle Aged ; Disease Progression ; Cross-Sectional Studies ; },
abstract = {INTRODUCTION: Data on how sleep architecture relates to progression of plasma Alzheimer's disease biomarkers remains limited.

METHODS: Sixty-four cognitively unimpaired older adults (ages 55-90) underwent plasma collection twice 2.6 years apart and polysomnography proximate to the first plasma collection. Plasma amyloid beta (Aβ) 42 and 40 were measured via mass spectrometry.

RESULTS: Frontal slow-wave activity (SWA) was inversely associated with plasma Aβ42/40 at cross-section in bivariate analysis and in a covariate-adjusted model. In comparison, low rapid eye movement (REM) sleep percentage was associated with a large longitudinal decline in annualized blood-based Aβ42/40. In exploratory analyses, the association between low REM sleep percentage and faster decline in Aβ42/40 ratio was stronger in the amyloid-positive group.

DISCUSSION: In cognitively unimpaired older adults, non-REM SWA correlates with cross-sectional amyloid load, whereas REM sleep may predict accelerated amyloid accumulation in preclinical stage, suggesting both may serve as early biomarkers and modifiable interventional targets.},
}

Humans
*Sleep, REM/physiology
Aged
*Amyloid beta-Peptides/blood
*Alzheimer Disease/blood/physiopathology
Biomarkers/blood
Female
Male
*Sleep, Slow-Wave/physiology
Polysomnography
*Peptide Fragments/blood
Longitudinal Studies
Aged, 80 and over
Middle Aged
Disease Progression
Cross-Sectional Studies

@article {pmid42851167,
year = {2026},
author = {Chen, Y and Li, F and Zhang, J and Wei, M and Ni, J and Li, T and Yao, L and Tian, J and Shi, J},
title = {Spatiotemporal heterogeneity and dynamic evolution of microglial glucose metabolic reprogramming in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71909},
doi = {10.1002/alz.71909},
pmid = {42851167},
issn = {1552-5279},
support = {BZY-JMZY-2022-002//Beijing University of Chinese Medicine/ ; 82074362//National Natural Science Foundation of China/ ; 8240154297//National Natural Science Foundation of China/ ; //Clinical Research and Achievement Commercialization Capacity Improvement Pilot Project of Beijing University of Chinese Medicine/ ; DZMG-JBZX-25001//Dongzhimen Hospital/ ; },
mesh = {*Microglia/metabolism ; *Alzheimer Disease/metabolism/pathology ; Humans ; Metabolic Reprogramming ; *Glucose/metabolism ; Animals ; Oxidative Phosphorylation ; *Brain/metabolism/pathology ; Energy Metabolism ; Glycolysis ; },
abstract = {Alzheimer's disease (AD) is accompanied by persistent disturbances in brain energy metabolism, and microglial glucose metabolic reprogramming constitutes an important link among pathological protein deposition, neuroinflammation, and impaired clearance. This review examines these metabolic changes across disease stages, brain regions, and plaque-associated microenvironments and proposes a dynamic state-composition model. In this model, microglia in different metabolic states coexist, and their relative proportions and spatial distribution change as AD progresses. In early disease or during active phagocytosis, some microglia show enhanced glycolytic and oxidative phosphorylation (OXPHOS) programs. Under persistent pathological stress, increased glucose uptake may not translate into effective energy production and can coexist with inflammation and impaired lipid metabolism. In late disease, microglia with reduced metabolic capacity and impaired phagocytosis become more prevalent. However, higher expression of OXPHOS-related genes in some microglial states associated with tau pathology does not necessarily indicate improved mitochondrial respiration. These population-level patterns do not imply that individual microglia follow a fixed sequence of metabolic changes. Longitudinal cell tracking and microglia-specific metabolic flux measurements are needed to test this model and inform interventions tailored to disease stage and microglial state.},
}

*Microglia/metabolism
*Alzheimer Disease/metabolism/pathology
Humans
Metabolic Reprogramming
*Glucose/metabolism
Animals
Oxidative Phosphorylation
*Brain/metabolism/pathology
Energy Metabolism
Glycolysis

@article {pmid42851168,
year = {2026},
author = {Whitwell, JL and Bhaskaran, JG and Satoh, R and Graff-Radford, J and Machulda, MM and Lowe, VJ and Mielke, MM and Dickson, DW and Tzeng, SC and Bui, J and Verghese, PB and West, T and Venkatesh, V and Josephs, KA},
title = {Plasma eMTBR-tau243 as a disease biomarker across Alzheimer's disease clinical phenotypes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71898},
doi = {10.1002/alz.71898},
pmid = {42851168},
issn = {1552-5279},
support = {R01-AG50603/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnostic imaging/pathology ; *tau Proteins/blood ; Female ; Biomarkers/blood ; Positron-Emission Tomography ; Male ; Aged ; Phenotype ; Amyloid beta-Peptides/metabolism ; Phosphorylation ; Aged, 80 and over ; Brain/diagnostic imaging/metabolism ; },
abstract = {INTRODUCTION: The concentration of endogenous tau microtubule-binding region containing residue-243 in plasma (eMTBR-tau243) has been proposed to be a sensitive biomarker of tangle pathology in Alzheimer's disease (AD). We assessed eMTBR-tau243 and phosphorylated tau217 (p-tau217) with tau and Aβ-positron emission tomography (PET) across different AD clinical phenotypes.

METHODS: Plasma eMTBR-tau243, p-tau217, and the ratio of non-phosphorylated to phosphorylated tau217 (%p-tau217) were measured in 20 Aβ-PET positive AD patients representing four clinical phenotypes and 10 cognitively unimpaired controls. Plasma levels were correlated with PET, demographic and cognitive variables.

RESULTS: Plasma eMTBR-tau243, p-tau217, and %p-tau217 levels were greater in AD than controls, with greatest levels observed in motor-predominant AD. Plasma biomarker levels correlated with cortical flortaucipir-PET uptake; eMTBR-tau243 correlations were strongest. In AD, eMTBR-tau243 levels were undetectable in patients with mild/focal flortaucipir-PET uptake (45%). Only eMTBR-tau243 correlated with cognition.

DISCUSSION: Plasma eMTBR-tau243 may be an excellent biomarker for tau deposition and cognition in AD across different phenotypes.},
}

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

@article {pmid42851206,
year = {2026},
author = {Fernandez, S and Dempsey, DA and Chaudhuri, S and Huang, YN and Park, T and Liu, S and Unverzagt, FW and Gao, S and , and Wilcock, DM and Yang, J and Rebholz, CM and Risacher, SL and Saykin, AJ and Nho, K},
title = {MIND diet-related plasma proteins are associated with Alzheimer's disease risk.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71884},
doi = {10.1002/alz.71884},
pmid = {42851206},
issn = {1552-5279},
support = {//National Institute on Aging (NIA)/ ; P30AG010133//National Institutes of Health (NIH):/ ; P30AG072976//National Institutes of Health (NIH):/ ; R01AG019771//National Institutes of Health (NIH):/ ; R01AG057739//National Institutes of Health (NIH):/ ; U19AG024904//National Institutes of Health (NIH):/ ; R01AG068193//National Institutes of Health (NIH):/ ; T32AG071444//National Institutes of Health (NIH):/ ; U01AG068057//National Institutes of Health (NIH):/ ; U01AG072177//National Institutes of Health (NIH):/ ; U19AG074879//National Institutes of Health (NIH):/ ; R01LM012535//National Institutes of Health (NIH):/ ; R01 LM013463//National Library of Medicine (NLM) NIH/ ; R01LM012535//National Library of Medicine (NLM) NIH/ ; R01 HL153178//National Heart, Lung, and Blood Institute (NHLBI), NIH/ ; 75N92022D00001//NHLBI, NIH, Department of Health and Human Services/ ; 75N92022D00002//NHLBI, NIH, Department of Health and Human Services/ ; 75N92022D0000375N92022D00004//NHLBI, NIH, Department of Health and Human Services/ ; 75N92022D00005//NHLBI, NIH, Department of Health and Human Services/ ; U01HL096812//NIH (NHLBI, NINDS, NIA and NIDCD)/ ; U01HL096814//NIH (NHLBI, NINDS, NIA and NIDCD)/ ; U01HL096899//NIH (NHLBI, NINDS, NIA and NIDCD)/ ; U01HL096902//NIH (NHLBI, NINDS, NIA and NIDCD)/ ; U01HL096917//NIH (NHLBI, NINDS, NIA and NIDCD)/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/prevention & control ; Female ; Male ; *Diet, Mediterranean ; *Blood Proteins/analysis ; Proteomics ; *Dietary Approaches To Stop Hypertension ; Aged ; Risk Factors ; },
abstract = {INTRODUCTION: Adherence to the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet is associated with reduced dementia risk, but underlying mechanisms remain unclear.

METHODS: Plasma proteomics (SomaScan 7k) from 206 Indiana Alzheimer's Disease Research Center participants were analyzed using network analysis to identify modules associated with MIND diet scores. Diet-related hub proteins were then investigated for associations with Alzheimer's disease (AD) phenotypes and as potential diet-AD outcome mediators. Validation analyses were conducted in the Atherosclerosis Risk in Communities study (n = 10,228) and Global Neurodegeneration Proteomics Consortium (n = 3,723) datasets.

RESULTS: Higher MIND diet scores were associated with lower AD odds (odds ratio = 0.75, p = 0.01) and lower plasma neurofilament light chain levels (β = -0.07, p = 0.02). Two proteins, MCTS1 and cytidylate kinase, were associated with MIND diet and AD risk, and may mediate their relationship (p[a × b < 0] ≥ 0.95). Validation analyses supported the MCTS1 finding.

DISCUSSION: Vascular-related biological mechanisms may underlie associations between diet and dementia risk.},
}

Humans
*Alzheimer Disease/blood/prevention & control
Female
Male
*Diet, Mediterranean
*Blood Proteins/analysis
Proteomics
*Dietary Approaches To Stop Hypertension
Aged
Risk Factors

@article {pmid42851222,
year = {2026},
author = {Sankar, G and R, I and Umasankar, H},
title = {Therapeutic role of deferasirox loaded niosomes against aluminium-maltolate induced Alzheimer disease: A study in Swiss albino mice.},
journal = {The Indian journal of medical research},
volume = {164},
number = {4},
pages = {550-558},
doi = {10.25259/IJMR_3060_2025},
pmid = {42851222},
issn = {0971-5916},
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/pathology ; *Deferasirox/administration & dosage ; Mice ; Oxidative Stress/drug effects ; Male ; Humans ; Liposomes/chemistry/administration & dosage ; Brain/drug effects/pathology ; Aluminum/toxicity ; Neuroprotective Agents ; Reactive Oxygen Species/metabolism ; Disease Models, Animal ; Organometallic Compounds/toxicity ; Maze Learning/drug effects ; Aluminum Compounds/toxicity ; Pyrones ; },
abstract = {Background and objectives Aluminium, a common component in underarm deodorants, has been reported to increase oxidative stress when present in the bloodstream, and chronic exposure is considered a potential risk factor for Alzheimer disease. This study investigates the neuroprotective and chelating effects of deferasirox (DFX) and its niosome-based formulation (DFX-NS) against aluminium-maltolate (Almal)-induced neurotoxicity in mice. Methods Thirty male Swiss albino mice were randomly assigned into five groups: Control, Almal, Standard (STD), DFX, and DFX-NS. For 21 d, all groups except the control received Almal to induce neurotoxicity, followed by respective treatments for an additional 21 d. After the treatment period, cognitive function was assessed using behavioral tests such as the Morris Water Maze and Y Maze. An in vitro MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed on SH-SY5Y cells to evaluate the neuroprotective potential of DFX. In vivo analyses-including elemental analysis (ICP-MS), histopathology, oxidative stress parameters [Reactive Oxygen Species (ROS), Malondialdehyde (MDA), Catalase (CAT)], urine analysis, and protein estimation (Bradford assay)-were performed on the brain, which was isolated after cervical dislocation. Results The results obtained shows that the Deferasirox has optimum capacity to chelate the aluminium ions in the brains of the Alzheimer-diseased swiss albino mice. Though, the evidence obtained were not fully conclusive, but still the results from the niosomes group shows effective treatment option for the Alzheimer disease caused by the aluminium exposure. Interpretation and conclusions The efficacy of DFX and DFX-NS in reducing aluminium-induced neurotoxicity and oxidative stress in the brain proves that DFX could be a possible candidate for treating Alzheimer's patients linked with metal toxicities.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced/pathology
*Deferasirox/administration & dosage
Mice
Oxidative Stress/drug effects
Male
Humans
Liposomes/chemistry/administration & dosage
Brain/drug effects/pathology
Aluminum/toxicity
Neuroprotective Agents
Reactive Oxygen Species/metabolism
Disease Models, Animal
Organometallic Compounds/toxicity
Maze Learning/drug effects
Aluminum Compounds/toxicity
Pyrones

@article {pmid42851246,
year = {2026},
author = {Bianco, CR and Rabaneda-Lombarte, N and Fatima, H and Celedon, J and Oakley, DH and Arnold, SE and Kivisäkk, P and Serrano-Pozo, A},
title = {Associations between plasma biomarker levels and quantitative postmortem neuropathologic measures in Alzheimer's disease and related dementias.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71883},
doi = {10.1002/alz.71883},
pmid = {42851246},
issn = {1552-5279},
support = {P30 AG062421/AG/NIA NIH HHS/United States ; R21AG087072/AG/NIA NIH HHS/United States ; R01AG089349/AG/NIA NIH HHS/United States ; BEVP36A7461//Fundación Ramón Areces Research Fellowship/ ; AARG-24-1309896/ALZ/Alzheimer's Association/United States ; ABA-25-1373553/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/pathology/blood ; *Biomarkers/blood ; Female ; *tau Proteins/blood ; Male ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; Aged ; *Brain/pathology ; Plaque, Amyloid/pathology ; Aged, 80 and over ; Amyloid beta-Peptides/blood ; Longitudinal Studies ; Autopsy ; Astrocytes/pathology ; *Dementia/pathology/blood ; Neurons/pathology ; },
abstract = {INTRODUCTION: Validation of Alzheimer's disease blood-based biomarkers (BBMs) has relied largely on amyloid beta (Aβ) and tau positron emission tomography (PET), with limited quantitative neuropathologic correlation studies. We examined associations between BBMs and quantitative postmortem neuropathology in 124 participants from the Massachusetts Alzheimer's Disease Research Center (MADRC) Longitudinal Cohort Study.

METHODS: Plasma phosphorylated tau 217 (p-tau217), p-tau181, total tau (t-tau), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured using the Meso Scale Discovery platform and correlated with postmortem quantitative measures of Aβ plaques, AT8[+] pTau neurons, cortical thickness, and GFAP[+] astrocytes across the temporal, frontal, and occipital lobes.

RESULTS: Plasma p-tau217 strongly associated with Aβ plaques (especially neuritic) and AT8[+] neurons. Associations were weaker for p-tau181 and t-tau. NfL associated only with lower cortical thickness. GFAP correlated with Aβ plaques, AT8[+] neurons, and cortical and white matter GFAP[+] astrocytes. Plasma p-tau217 and GFAP mediated the association between Aβ plaques and AT8[+] neurons.

DISCUSSION: These findings support BBM biological specificity and utility for in vivo characterization of distinct neuropathologic processes.},
}

Humans
*Alzheimer Disease/pathology/blood
*Biomarkers/blood
Female
*tau Proteins/blood
Male
Glial Fibrillary Acidic Protein/blood
Neurofilament Proteins/blood
Aged
*Brain/pathology
Plaque, Amyloid/pathology
Aged, 80 and over
Amyloid beta-Peptides/blood
Longitudinal Studies
Autopsy
Astrocytes/pathology
*Dementia/pathology/blood
Neurons/pathology

@article {pmid42851352,
year = {2026},
author = {Tran, ML and Kim, K and Kim, JU and Choi, YY and Do, J and Lee, KH and Seok, JW},
title = {Low-density lipoprotein cholesterol modulates amyloid-related entorhinal vulnerability and episodic memory performance in older adults.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1933036},
pmid = {42851352},
issn = {1663-4365},
abstract = {INTRODUCTION: Cerebral amyloid-beta (Aβ) burden does not fully explain variation in Alzheimer's disease (AD)-related brain structure and episodic memory. We examined whether circulating low-density lipoprotein cholesterol (LDL-C) modifies the cross-sectional statistical association between Aβ burden, the entorhinal cortex (EC) thickness and episodic memory performance.

METHODS: Cross-sectional data from 1,253 individuals in the Gwangju Alzheimer's Disease and Related Dementias cohort (798 cognitively normal, 425 mild cognitive impairment, 30 AD dementia) were analyzed. Primary conditional-process models were adjusted for age, sex, education, body mass index, and HbA1c; clinical diagnosis was examined in sensitivity analyses. HC3 heteroskedasticity-consistent inference was used for the focal interaction, and indirect associations were estimated using 10,000 bootstrap resamples.

RESULTS: Greater Aβ burden was associated with lower EC thickness (β = -0.0863, p = 0.0012), and EC thickness was positively associated with episodic memory (β = 0.3809, p < 0.001). The unconditional indirect statistical association was supported (β = -0.0329, 95% bias-corrected bootstrap CI [-0.0647, -0.0072]). LDL-C modified the Aβ-EC association (β = -0.0937, HC3 SE = 0.0332, 95% CI [-0.1589, -0.0285], p = 0.0049), although the incremental explanatory magnitude was small (ΔR[2] = 0.0082). The conditional Aβ-EC association was unsupported at approximately 66 mg/dL LDL-C (β = 0.0263, p = 0.583), not statistically supported at approximately 100 mg/dL (β = -0.0639, p = 0.060), and negative at 138 mg/dL (β = -0.1648, p < 0.001). The index of moderated indirect association was supported (β = -0.0357, 95% bias-corrected bootstrap CI [-0.0637, -0.0119]); conditional indirect associations were most clearly supported at higher LDL-C levels. A similar interaction was observed for non-HDL cholesterol, suggesting that the pattern may reflect a broader atherogenic lipid context.

CONCLUSION: Circulating LDL-C was associated with modest heterogeneity in the cross-sectional Aβ-EC relationship, with more clearly negative conditional associations observed at higher LDL-C levels. Longitudinal studies are needed to determine the temporal and clinical relevance of these findings.},
}

@article {pmid42851448,
year = {2026},
author = {Mishra, P and D, S and Jain, PR and Sharma, A and J C, K},
title = {Alzheimer's detection using quanvolutional neural networks with federated training.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1904876},
pmid = {42851448},
issn = {1662-4548},
abstract = {Alzheimer's disease detection from MRI data is challenging because of subtle anatomical patterns, high-dimensional image data, and privacy constraints associated with centralized medical-data training. We propose a hybrid quantum-classical federated learning framework using a frozen four-qubit quanvolutional front-end. The 128 × 128 grayscale MRI images are divided into 2 × 2 patches, and quantum features are pre-extracted using a fixed circuit implemented in PennyLane. The resulting features are classified using trainable classical dense layers implemented in TensorFlow/Keras. Federated training is performed across five non-IID clients using FedAvg and FedNova over ten communication rounds, with dynamic local epochs of 5-30 and batch size 32. Expectation-Value Local Differential Privacy (EV-LDP) is also evaluated. The proposed FedNova-DQ framework achieved a final global accuracy of 0.923, compared with 0.921 using FedAvg. The centralized QCNN achieved 0.891 accuracy compared with 0.872 for the classical CNN baseline. Under EV-LDP with ϵ = 2.0, the model maintained 90.85% accuracy. At K = 200 clients, FedNova achieved 90.15% accuracy compared with 82.15% for FedAvg. The frozen quantum front-end eliminates quantum-parameter communication and decouples quantum feature extraction from federated communication rounds while maintaining strong classification performance under heterogeneous client distributions.},
}

@article {pmid42851539,
year = {2026},
author = {Lei, Q and Liu, Q},
title = {Global trends, research hotspots, and clinical evidence mapping of music therapy interventions for cognitive impairment: a bibliometric and visualization analysis from 2006 to 2026.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1917320},
pmid = {42851539},
issn = {1664-1078},
abstract = {BACKGROUND: Cognitive impairment is an important public health issue in ageing societies. Music therapy, as a safe and accessible non-pharmacological intervention, has been increasingly used in the management of cognitive impairment. However, the overall research pattern, evolution of research hotspots, and features of clinical evidence in this field have not been systematically reviewed. This study aimed to analyze the current status, major topics, and development trends of research on music therapy interventions for cognitive impairment from 2006 to 2026.

METHODS: A stratified multi-database search strategy was used. The Web of Science Core Collection (WoSCC) served as the main data source. Bibliometric and visualization analyses were performed using Bibliometrix, CiteSpace, and VOSviewer. The Scopus database was also used to cross-validate key findings. In addition, randomized controlled trials (RCTs) retrieved from PubMed were analyzed to further assess the clinical evidence base.

RESULTS: A total of 835 publications were included from WoSCC. From 2006 to 2025, the annual number of publications increased steadily, with an average annual growth rate of 13.35%. The publication output reached its peak in 2025, and the exponential model showed a good fit to the growth trend (R [2] = 0.913). The United States, China, the United Kingdom, and Australia were the leading contributing countries, while institutions such as the University of Melbourne made notable contributions. The main research topics focused on dementia, music therapy, Alzheimer's disease, quality of life, and cognitive dysfunction. Over time, research hotspots have extended toward cognitive improvement, long-term care, and neuroplasticity-related mechanisms. A total of 250 RCTs were identified from PubMed, indicating a growing body of clinical evidence.

CONCLUSION: Research on music therapy interventions for cognitive impairment has shown continuous growth. Core topics mainly involve cognitive function, behavioral symptoms, quality of life, and care support. Mechanistic studies, especially those related to neuroplasticity, have become an important research frontier. Future studies should place greater emphasis on high-quality clinical research, clarify the mechanisms of music therapy, and promote its precise application and clinical translation.},
}

@article {pmid42851564,
year = {2026},
author = {Brink, D and Theart, R and Loos, B},
title = {Differential autophagy cargo engagement in amyloid-β-induced neuronal toxicity.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1913175},
pmid = {42851564},
issn = {1662-4548},
abstract = {Neurodegenerative diseases are characterized by progressive neuronal loss and the accumulation of misfolded proteins. In Alzheimer's disease, several pathogenic protein species, including amyloid precursor protein, amyloid beta, tau, phosphorylated tau, and alpha-synuclein, are known substrates of macroautophagy. However, the extent to which macroautophagy selectively engages these proteins for degradation under conditions of proteotoxic stress remains poorly understood. Here, the contribution of specifically macroautophagy to the degradation of amyloid precursor protein, amyloid beta, tau, phosphorylated tau, and alpha-synuclein was investigated using an amyloid precursor protein overexpression model. Mouse neuroblastoma N2A cells stably expressing the human Swedish amyloid precursor protein mutation were treated with butyric acid for 24 and 48 h to produce increasing proteotoxicity and molecular pathology. Autophagic flux was assessed using bafilomycin A1 and protein abundance quantified by western blotting. Confocal microscopy and colocalization analysis was performed to examine intracellular protein localization and recruitment to the autophagy compartment. Amyloid precursor protein overexpression and autophagosome/lysosome fusion inhibition elicited distinct protein-specific responses, with phosphorylated tau showing highest accumulation and autophagic recruitment. In contrast, tau and amyloid precursor protein exhibited moderate increases, while alpha-synuclein and amyloid beta showed differential and limited responses upon macroautophagy inhibition. Collectively, these findings suggest that the autophagy molecular machinery does not engage uniformly with Alzheimer's disease-associated proteins but may be characterized by a highly differential cargo engagement under amyloid precursor protein-driven proteotoxic stress. Phosphorylated tau emerged as the earliest and most prominent protein to be target to the autophagy compartment, highlighting its potential importance in disease progression and therapeutic intervention.},
}

@article {pmid42851601,
year = {2026},
author = {An, X and Wei, C and Cao, M and Xu, J and Yu, W and Ren, Z},
title = {MAPK3 as a ferroptosis driver in excitatory neurons in Alzheimer's disease: from genetic causal inference to in vivo functional validation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1868908},
pmid = {42851601},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and ferroptosis-an iron-dependent form of regulated cell death-has been increasingly implicated in AD-related neuronal loss. However, the causal relationship between specific ferroptosis-related genes and AD, particularly within defined neuronal subtypes, remains incompletely understood.

METHODS: We integrated two-sample Mendelian Randomization (MR) with single-cell expression quantitative trait locus (eQTL) analysis, followed by in vivo validation using AAV9-c-fos-mediated MAPK3 knockdown in APP/PS1 transgenic mice and in vitro validation using siRNA-mediated MAPK3 silencing in Aβ-treated HT22 neurons.

RESULTS: MR analysis of large-scale genetic datasets identified seven ferroptosis-related genes with causal associations with AD. Single-cell eQTL MR prioritized MAPK3 as a significant risk factor specifically within excitatory neurons. AAV9-c-fos-mediated MAPK3 knockdown in APP/PS1 mice significantly ameliorated cognitive deficits in the Morris water maze. Mechanistically, MAPK3 knockdown inhibited aberrant CaMKII phosphorylation, activated the Nrf2-GPX4 antioxidant axis (upregulation of GPX4, HO-1, and FTH1; downregulation of ACSL4 and KEAP1), and reestablished the Bax/Bcl-2 equilibrium, thereby reducing both ferroptosis and apoptosis. These effects were reproduced in Aβ-treated HT22 neurons following siRNA-mediated MAPK3 silencing.

DISCUSSION: Our findings identify MAPK3 in excitatory neurons as a potential causal link between genetic risk and AD pathogenesis, bridging population-level genetic risk and cellular vulnerability. Targeting the MAPK3-CaMKII-Nrf2 axis may represent a promising, cell-type-specific therapeutic strategy for AD.},
}

@article {pmid42851615,
year = {2026},
author = {Ohara, M and Ishigaki, S and Watts, JK and Yamada, K and Ikezu, T and Ikezu, S},
title = {Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {41},
pmid = {42851615},
issn = {3059-4944},
abstract = {Neurodegenerative disorders have diverse etiologies from monogenic mechanisms such as toxic gain-of-function mutation in subsets of amyotrophic lateral sclerosis (ALS) to multifactorial cascades exemplified by Alzheimer's disease (AD), which feature proteostasis failure, neuroinflammation, mitochondrial dysfunction, or age-associated cellular stress. While small molecules can modulate downstream pathways, nucleic acid therapeutics (NATs) target defined RNA sequences to directly reduce pathogenic gene expression, correct or shift isoform usage via splice modulation, and tune disease-relevant networks, positioning them as promising therapeutic modalities for neurodegenerative disorders. Recent clinical applications of NATs in the central nervous system (CNS) have made significant progress by optimized chemistries, improved tolerability, and established intrathecal administration routes, supporting sustained target engagement in relevant neural and glial compartments. This review summarizes three major NAT platforms-antisense oligonucleotides, small interfering RNAs, and aptamers-by highlighting their mechanisms of action, design principles to enhance their biodistribution, durability, and safety, and emerging novel delivery strategies for CNS targeting. We further discuss emerging translational opportunities across ALS, AD, polyglutamine disorders, prion diseases, and synucleinopathies by integrating disease biology with therapeutic rationale, and by summarizing regulatory approvals, ongoing clinical trials, and next generation NATs in preclinical development.},
}

@article {pmid42851655,
year = {2026},
author = {Luo, Y and Dai, N and Qiao, Y and Zheng, T and Zhang, Y and Zhang, Y and Yu, H and Cao, H and Zhang, A and Li, M and Li, Y and Yang, N and Wang, T and Zhou, J and Li, X},
title = {A collaborative multi-view fusion framework with Deep Forest for multi-class diagnosis of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1888587},
pmid = {42851655},
issn = {1663-4365},
abstract = {OBJECTIVE: A key aspect of diagnosing Alzheimer's disease (AD) is identifying mild cognitive impairment (MCI), a sensitive transitional stage between normal cognition (NC) and AD. We divided AD disease progression into three stages: NC, MCI, and AD according to severity. We used CoopLearning to integrate multi-view medical data with a Deep Forest (DF) classifier to classify three stages of AD to aid diagnosis.

METHODS: We used data from the Alzheimer's Disease Neuroimaging Initiative database. The research variables were divided into five views: demographic information, biological sample information, relevant scale information, pixel identification, and magnetic resonance imaging regional information. We compared CoopLearning for feature selection and fusion, least absolute shrinkage and selection operator cross-validation (LassoCV) for single-view feature selection, and LassoCV for multi-view feature selection. The fused data were processed using Synthetic Minority Oversampling Technique (SMOTE), SMOTETomek, and SMOTE Edited Nearest Neighbors (ENN) methods to achieve class balance. The balanced data were then applied to multiple classifiers, such as DF, Random Forest, etc., for performance evaluation.

RESULTS: Multi-view feature selection and fusion using CoopLearning, multi-view feature selection, and single-view overall feature selection using LassoCV identified 20 features from five views. Applying these results to the classifier revealed that model performance was optimal when using SMOTEENN in conjunction with CoopLearning multi-view feature selection and the DF classifier (Accuracy = 0.9898, multi-class area under the receiver operating characteristic curve = 0.9997).

CONCLUSION: Collaborative multi-view fusion substantially improved direct multi-class classification across the AD continuum. Integrating clinical and neuroimaging data with Deep Forest may provide a robust and interpretable framework for early auxiliary diagnosis and disease-stage stratification in Alzheimer's disease.},
}