@article {pmid42925933,
year = {2026},
author = {Wang, T and Ji, Y and Liu, S and Wu, H and Gu, L and Guo, M and Wang, P and Xu, G},
title = {Multimodal evidence associated with 20Hz rTMS in AD: neuroaxonal injury reduction, neural oscillatory rebalancing, and multilayer network integration.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116536},
doi = {10.1016/j.bbr.2026.116536},
pmid = {42925933},
issn = {1872-7549},
abstract = {High-frequency repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to enhance cognitive function in patients with Alzheimer's disease (AD), but the neurobiological mechanisms associated with neuroaxonal injury, neural oscillatory dynamics, and large-scale network reorganization remain unclear. In this study, we first conducted a randomized, sham-controlled trial with 16 patients with AD to evaluate the efficacy of DLPFC-targeted rTMS, followed by a single-arm multimodal cohort study of 30 patients to explore potential neurobiological mechanisms through cognitive assessments, blood biomarkers, EEG oscillatory activity, and multiplex brain network analysis. In Stage 1, the sham group showed no significant pre-post changes in MMSE or MoCA scores (MMSE: Z = -0.738, Cohen's r = 0.26; MoCA: Z =-0.853, Cohen's r = 0.30). The active rTMS group showed improvements in MMSE (Z = -2.124, Cohen's r = 0.75) and MoCA (Z = -2.108, Cohen's r = 0.75). In stage 2, rTMS was associated with improvements in MMSE (Z = -2.863, Cohen's r = 0.523) and MoCA (t = -6.137, Cohen's r = 0.752) scores. Biomarker analyses indicated a significant decrease in NfL concentrations (Z=-2.371, Cohen's r=0.484). EEG recordings revealed a decrease in delta power in the left temporal lobe (t=2.158, Cohen's r=0.372) and increases in beta power in the right parietal lobe and gamma power in the temporal lobe (beta: Z=-2.088, Cohen's r=0.381; gamma: Z=-2.129, Cohen's r=0.389). Network analysis showed reduced modularity and enhanced global efficiency across theta, alpha, and beta bands, accompanied by increased degree of overlap in frontal, parietal, and occipital regions. Importantly, MoCA improvement correlated with gamma-band global efficiency (R=0.389, P=0.034) and multilayer clustering coefficients in the left frontal and right occipital regions (R=0.478, P=0.008; R=0.398, P=0.029). Overall, rTMS exposure was associated with cognitive improvements in patients with AD, together with changes in neurodegeneration-related biomarkers and EEG network organization. These findings suggest that cognitive changes following rTMS may be associated with oscillatory modulation and large-scale network remodeling. TRIAL REGISTRATION: Registration number: ChiCTR2500095949; Registration Date: 2025-01-15.},
}

@article {pmid42926064,
year = {2026},
author = {Marick, A and Hemachandra Reddy, P and Manna, PR},
title = {Restoration of StAR-governed neurosteroids with all-trans retinoic acid in alleviating cognitive deficits in a humanized amyloid-β knock-in mouse model of late-onset Alzheimer's disease: New insights into therapeutics.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106280},
doi = {10.1016/j.neuint.2026.106280},
pmid = {42926064},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disorder of the elderly characterized by cognitive decline that involves diverse pathological processes. Aging, modulating neuronal instability, is the primary risk factor AD, resulting in dementia, for which a crucial neuropathological feature is the accumulation of amyloid-β (Aβ) plaques wherein suppression of neurosteroids plays important roles. Neurosteroidogenesis gradually decreases during aging, and the regulation of neurosteroid biosynthesis is mediated by the steroidogenic acute regulatory (StAR) protein. We demonstrate that treatment with all-trans retinoic acid (atRA, 20 mg/kg, 12-weeks) in humanized Aβ knock-in (hAbKI) mice (11-month old) resulted in increases in hippocampal StAR and sex neurosteroid (estradiol-17β/(E2) in females and testosterone in males) levels, when compared with controls. Elevated StAR and sex neurosteroid levels were associated with reductions in not only Aβ accumulation but also toxic soluble Aβ1-40 and Aβ1-42 peptides in both sexes, emphasizing an inverse correlation between neurosteroidogenesis and AD pathogenesis. Notably, atRA was capable of ameliorating cognitive impairments in both female and male hAbKI mice, as evaluated by Morris Water Maze analyses. These findings provide insights into the mechanistic events by which atRA restores neurosteroid instability, reduces neurotoxicity, and alleviates cognitive impairments in sex-specific hAbKI mice, demonstrating that retinoid therapy could serve as a novel target for the management of AD-related dementia for healthy aging.},
}

@article {pmid42926367,
year = {2026},
author = {Kowash, Z and Lim, J and Annalora, AJ and Wang, H and Cui, JY},
title = {Triple-Omics Analysis Unveiled the Neuroprotective Mechanisms of Akkermansia muciniphila in an Environmental Exposure-Linked Mouse Model of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.30.755812},
pmid = {42926367},
issn = {2692-8205},
abstract = {UNLABELLED: Cadmium (Cd) is an emerging environmental risk factor for cognitive decline and Alzheimer's disease, and few interventions limit its effects on the brain. Akkermansia muciniphila , a human gut commensal, is neuroprotective through mechanisms that remain unclear. Building on our finding that A. muciniphila prevented Cd-induced memory deficits without reducing brain Cd burden (Wang et al., 2026a), we tested whether it reprograms Cd-disrupted hippocampal RNA regulation. Male C57BL/6J mice received A. muciniphila (1×10[9] CFU, oral gavage, 5 days/week) before and throughout 9 weeks of 3 mg/L CdCl2 exposure; hippocampi were analyzed by RNA-seq, m[6]A epitranscriptomic profiling, and rMATS-based alternative-splicing analysis. Cd disrupted hippocampal neuropeptide signaling, neuronal excitability, and synaptic plasticity. Co-exposure with A. muciniphila reversed signatures enriched for Nrf2-centered cytoprotective signaling and opposed m[6]A and splicing changes across more than a thousand genes, largely without changes in total mRNA abundance. Restored events converged on machinery governing local translation, calcium-dependent plasticity, and synaptic transmission. Projected onto predicted protein structures, most introduced a premature termination codon predicted to trigger nonsense-mediated decay or edited short loop and linker segments rather than rebuilding folded domains, regulation largely invisible to gene-level expression analysis. Among these, paired events amplifying semaphorin-plexin signaling, an axis linked to oligodendrocyte injury and memory consolidation, were reversed. These findings identify restoration of hippocampal transcript fate and splice-isoform selection as a mechanism potentially underlying A. muciniphila -mediated protection against Cd neurotoxicity, and establish post-transcriptional RNA regulation as a gut-brain target for mitigating environmentally driven neurotoxicity.

IMPACT STATEMENT: Cadmium is a widespread environmental contaminant associated with cognitive decline and Alzheimer's disease, and few interventions are available to limit its effects on the brain. This study shows that supplementation with the gut commensal Akkermansia muciniphila reverses Cd-induced changes in hippocampal m⁶A methylation and splice-isoform selection, largely without altering total transcript abundance. These results identify post-transcriptional RNA regulation as a gut-brain target for mitigating environmentally driven neurotoxicity, and show that conventional gene-expression analysis alone would miss most of the protective response.},
}

@article {pmid42926376,
year = {2026},
author = {Hillman, N and Chen, AA and Hu, F and Vandekar, SN and Melhem, R and Beason-Held, LL and Satterthwaite, TD and Davatzikos, C and Shou, H and Shinohara, RT and , },
title = {Imputation-Based Harmonization Mitigates Site Effects Without Data Leakage in Machine Learning Studies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.28.755204},
pmid = {42926376},
issn = {2692-8205},
abstract = {Neuroimaging studies that pool data across clinical sites often suffer from site effects - variability in imaging measures that arises from technical heterogeneity across sites as opposed to true biological signal. While numerous harmonization methods have been proposed to remove site effects from imaging features, less attention has been placed on how to incorporate harmonization models into common machine-learning pipelines. We demonstrate that current approaches for integration either suffer from data leakage, fail to fully remove site effects from the target data, or attenuate true biological associations during the harmonization process. To address these issues, we propose Multiple Imputation for Removing Technical Heterogeneity (MIRTH), which uses imputed outcomes to harmonize the test data. We benchmark MIRTH's performance using both simulated and real-world volumetric data from the Alzheimer's Disease Neuroimaging Initiative and the Baltimore Longitudinal Study of Aging, demonstrating that MIRTH can achieve high predictive accuracy while avoiding inflated performance when the outcome is imbalanced across clinical sites.},
}

@article {pmid42926382,
year = {2026},
author = {Moallem, EZ and Bruntz, RC and Cox, MF and Bytyqi, L and Roberts, TK and Patel, SP and Macheda, T and Roberts, KN and Higgins, EK and Sun, RC and Gentry, MS and Sullivan, PG and Johnson, LA and Bachstetter, AD},
title = {Closed-head injury produces a delayed, region-specific defect in glucose-carbon routing at the pyruvate branchpoint in APP/PS1 KI mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.29.755475},
pmid = {42926382},
issn = {2692-8205},
abstract = {Traumatic brain injury (TBI) is a risk factor for Alzheimer's disease (AD), and both conditions are associated with impaired glucose metabolism and mitochondrial dysfunction. We previously reported time-dependent mitochondrial dysfunction following closed-head injury (CHI) in amyloid precursor protein/presenilin 1 (APP/PS1) knock-in (KI) mice, but whether glucose-derived carbon labeling showed a corresponding temporal pattern remained unknown. We hypothesized that early deficits would involve tricarboxylic acid (TCA)-cycle metabolites, whereas chronic changes persisted upstream at the pyruvate-lactate branchpoint. Here, oral uniformly [13] C-labeled glucose ([U- [13] C]-glucose) tracing and gas chromatography-mass spectrometry (GC-MS)-based isotopologue analysis were used to quantify first-turn glucose-derived carbon fate in cortex and hippocampus. To distinguish the effects of age at injury from those of post-injury interval, mice were analyzed 1 month after injury either at 7 or 12 months of age or 8 months after injury at 12 months of age. The most pronounced alterations occurred 8 months after CHI, when KI mice exhibited increased pyruvate and lactate labeling in the cortex and broader increases in glycolytic labeling in the hippocampus. These findings suggest that in APP/PS1 KI mice, chronic closed-head injury produced a delayed shift in glucose-derived carbon labeling centered on glycolytic and pyruvate/lactate nodes, with loss of hippocampal precursor-product coupling but without broad reduction of first-turn TCA-linked labeling.},
}

@article {pmid42926390,
year = {2026},
author = {Deng, Q and Chen, C and Zikopoulos, B and Yazdanbakhsh, A},
title = {Biophysical modeling of excitation/inhibition imbalance in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.30.755800},
pmid = {42926390},
issn = {2692-8205},
abstract = {INTRODUCTION: Alzheimer's disease (AD) involves early sensory and perceptual changes that can precede memory decline. We developed a two-layer rate-based neural model of early and higher visual areas with feedforward, feedback, and recurrent connections to examine how excitatory/inhibitory (E/I) balance shapes visual motion perception in AD.

METHODS: Using Motion-Induced Position Shift and Altered Motion Repulsion stimuli, we factorially manipulated excitatory (E) and inhibitory (I) subfield power and connectivity to examine their effects on illusion representation across visual layers.

RESULTS: Increased E, decreased I, and increased E/I reduced illusion representation, consistent with reduced illusion susceptibility in AD, whereas the converse increased illusion representation, reflecting neurotypical processing. Higher-level layer 2 representations were more resistant to E/I perturbations than lower-level layer 1. Illusion representation was less affected by E/I increases in intra-areal (recurrent) connectivity than in inter-areal (feedforward/feedback) connectivity.

DISCUSSION: This mechanistic framework links E/I balance and connectivity to altered visual motion illusion representations in AD and suggests that E/I and connectivity measures may provide probes of early AD neurobiology. The framework may also generalize beyond vision.},
}

@article {pmid42926395,
year = {2026},
author = {Huang, M and Lövestam, S and Cheam, KAX and Ghetti, B and McEwan, WA and Scheres, SHW and Goedert, M},
title = {Templated paired helical filament formation and tau fold-dependent inclusion morphologies in primary neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.30.755038},
pmid = {42926395},
issn = {2692-8205},
abstract = {UNLABELLED: Neurodegenerative tauopathies are characterized by the abnormal assembly of tau into amyloid filaments with distinct, disease-specific folds. These filaments are proposed to spread in a prion-like manner, thus underlying the progression of pathology in diseased brains. A prediction of this hypothesis is that tau filaments will induce progeny filaments identical to the input seed material, yet cellular models of templated tau assembly have failed to fully recapitulate brain-derived filament structures. Here, we show that mixed primary mouse cortical neurons overexpressing full-length human tau via adeno-associated virus transduction propagate Alzheimer's disease paired helical filaments upon exposure to human brain-derived seeds. Using minimal tags and core mutations, we were able to unambiguously differentiate induced aggregates from the original seeds. Super-resolution microscopy and live-cell imaging revealed progressive inclusion formation in neurons. Moreover, seeding primary neurons with brain extracts from individuals with Pick's disease, corticobasal degeneration and progressive supranuclear palsy induced the formation of morphologically distinct inclusions. Together, these findings establish that primary neurons provide an environment for the faithful propagation of paired helical filaments and show that tau filament folds dictate higher-order inclusion morphologies within neurons.

SIGNIFICANCE STATEMENT: Neurodegenerative tauopathies are characterized by the assembly of tau protein into disease-specific amyloid folds. While prion-like propagation is hypothesized to drive disease progression, cell models have previously failed to fully replicate human-brain derived filament structures. Here we show that primary mouse neurons support the templated propagation of human Alzheimer's disease paired helical filaments. By incorporating a disease-causing mutation (V337M) into the amyloid core, we unambiguously resolved cryo-EM structures of the induced assemblies. Moreover, by using super-resolution light microscopy, we show that seeds from tauopathies induced the formation of morphologically distinct intraneuronal inclusions. These findings describe a system for dissecting the cellular factors that govern tau fold propagation and for understanding how distinct filament structures dictate phenotypic differences across tauopathies.},
}

@article {pmid42926415,
year = {2026},
author = {Farina, R and Wang, Y and Gabitto, MI and Agrawal, A and Mena, GE},
title = {Multi-Trajectory Pseudotime Inference via Permutation Factorizations.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.27.728207},
pmid = {42926415},
issn = {2692-8205},
abstract = {Inferring disease progression from cross-sectional data typically relies on placing individuals along a single latent pseudotemporal axis. However, diseases often exhibit different biomarkers that evolve with different dynamics, making a single shared trajectory insufficient and often leading to biased or inconsistent orderings. We propose a probabilistic framework that maintains a shared global ordering of individuals while allowing clusters of features to follow distinct monotone trajectories along this ordering. Rather than assigning individuals to separate progressions, our approach captures heterogeneity through cluster-specific temporal responses defined with respect to a common latent sequence of individuals. Our key observation is that monotone transformations of a common progression preserve the ordering of individuals, so multiple pseudotimes factorize into a single latent permutation over individuals and cluster-specific monotonic functions, enabling flexible yet comparable representations of biomarker dynamics. We jointly infer donor ordering, biomarker clusters, and trajectories within a unified Bayesian framework, using stochastic variational inference over permutations. Across two major neuropathological datasets in Alzheimer's disease, our method recovers biologically meaningful feature clusters and improves overall alignment with established staging measures compared to single-trajectory baselines. These results show that modeling heterogeneous dynamics relative to a shared progression yields more accurate and interpretable reconstructions of disease progression from cross-sectional data.},
}

@article {pmid42926432,
year = {2026},
author = {Liu, H and Tong, M and Fang, S and Mormino, EC and Sperling, RA and Aisen, P and Buckley, RF and Crane, PK and Hohman, TJ and Saykin, AJ and Yan, J and , },
title = {Continuous amyloid staging complements global amyloid burden in early Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.03.756367},
pmid = {42926432},
issn = {2692-8205},
abstract = {INTRODUCTION: Early Alzheimer's disease (AD) staging remains challenging because clinical categories and global amyloid PET measures provide only coarse characterization of disease progression. We developed a continuous amyloid staging score from regional amyloid PET to complement global amyloid burden.

METHODS: Using longitudinal florbetapir PET from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we trained an end-to-end deep learning model to directly estimate a continuous amyloid staging score. We evaluated longitudinal consistency, its relationship with global amyloid burden, regional contributors to early-stage variation, and whether the staging score stratified subsequent memory decline among participants matched for baseline global amyloid burden. Cognitive analyses were replicated in A4+LEARN.

RESULTS: The staging score better preserved longitudinal visit order than existing amyloid staging approaches. During early disease stages, it captured regional amyloid variation despite relatively stable global amyloid burden. Among participants with similar baseline global amyloid burden, higher staging scores were associated with faster subsequent memory decline in both ADNI and A4+LEARN.

DISCUSSION: A continuous amyloid staging score complements global amyloid burden for early AD staging and cognitive risk stratification.},
}

@article {pmid42926465,
year = {2026},
author = {Ji, C and Zhu, Y and Erdjument-Bromage, H and Song, SC and Chang, N and Liu, AR and Lee, AR and DeGulis, O and Schoppik, D and Neubert, TA and Ryoo, HD and Sigurdsson, EM},
title = {Pathological tau leads to network hyperexcitability through neuronal-subtype-specific functional impairment.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.05.756807},
pmid = {42926465},
issn = {2692-8205},
abstract = {UNLABELLED: Pathological tau disrupts neuronal activity and brain function in Alzheimer's disease and other tauopathies. However, the underlying mechanisms for neuronal network dysfunction remain largely unknown. Using human inducible pluripotent stem cell (iPSC) - derived neurons, we show that the familial MAPT P301L mutation leads to neuronal network hyperexcitability. Imbalanced excitation and inhibition were attributable to neuronal subtype-specific tau pathology that was associated with different alterations of tau interactomes in excitatory versus inhibitory neurons. Suppressing enhanced excitatory synaptic transmission or blocking Ca [2+] influx resulting from enhanced P301L tau/AHNAK interaction in inhibitory neurons rescued the neuronal network hyperexcitability. This study expands our understanding on how disease-causing tau mutations alter the excitatory/inhibitory balance, leading to network dysfunction in human neurons.

HIGHLIGHTS: The FTD-causing P301L tau mutation leads to neuronal network hyperexcitability.P301L tau causes hyperactivity of excitatory neurons while hypoactivity of inhibitory neurons.Tau and P301L tau interactomes differ in excitatory vs. inhibitory neurons.Enhanced excitatory synaptic transmission and P301L tau/AHNAK interaction in inhibitory neurons contribute to neuronal network hyperexcitability.},
}

@article {pmid42926485,
year = {2026},
author = {Suh, Y and Wang, H and Li, L and Gu, H and Johnson-Martinez, J and Magis, AT and Gibbons, SM and Cui, JY},
title = {The microbial soy metabolite S-equol mitigates cadmium neurotoxicity in mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.01.756095},
pmid = {42926485},
issn = {2692-8205},
abstract = {Environmental exposures are major but understudied determinants of chronic disease. Cadmium is a pervasive toxic metal encountered through diet and tobacco smoke that has been associated with cognitive impairment and Alzheimer's disease mortality, yet strategies to mitigate its neurotoxicity remain limited. S-equol is a gut microbial metabolite of soy daidzein that crosses the blood brain barrier and preferentially activates estrogen receptor beta. Here, we show that cadmium disrupts an axis linking the equol producing gut bacterium Adlercreutzia equolifaciens to circulating S-equol and hippocampal estrogen receptor expression in mice, that S-equol attenuates cadmium-induced cytotoxicity and restores neuronal, glutamatergic and synaptic transcriptional programs in mouse neural progenitor cells, and that circulating S-equol in older humans is lower in apolipoprotein E4 carriers and covaries with body mass index, identifying S-equol as a microbiome-derived, host-modulated candidate countermeasure against cadmium neurotoxicity.},
}

@article {pmid42926510,
year = {2026},
author = {Huang, LY and Zeng, V and Raymond, N and Stiltner, B and Molho, W and Cao, Y and Bannai, D and Ying, D and Oss, E and Dhunna, DP and Patel, P and Adesokan, A and Hricay, M and Lyons, V and Tolentino, N and Keshavan, MS and Fried, P and Jammoul, M and Kuegler, D and Estrada, S and Reuter, M and Lizano, P},
title = {A large, comprehensive labeled MRI dataset of the human lateral ventricle choroid plexus.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.08.757728},
pmid = {42926510},
issn = {2692-8205},
abstract = {The choroid plexus (ChP) is a highly vascularized structure located in the brain ventricles that plays important roles in multiple central nervous system functions. ChP enlargement has been implicated in many neuropsychiatric conditions such as multiple sclerosis, depression, schizophrenia, and Alzheimer's disease. However, limitation in the accuracy of the current segmentation tools highlight the need for more reliable methods to quantify ChP volume in healthy and clinical human populations. The shape and size of the ChP vary drastically from person to person, and currently there are no large ChP datasets which allow comprehensive training of segmentation models. Here we introduce DataPlex, a collection of 700 structural MRI brain images where the lateral ventricle ChP has been manually labeled and checked by expert human raters. DataPlex is balanced and representative across a wide range of scanning parameters, demographics, and clinical profiles, and subject-level information will be available for each labeled image. DataPlex will be open source to support the creation of reliable segmentation tools for the human lateral ventricle ChP.},
}

@article {pmid42926600,
year = {2026},
author = {Landon, B and Abraham Daniel, A and Fischer, T and Phillips, NR and Barber, RC and Reynolds, AW and , },
title = {A Multiethnic Analysis of DNA Methylation Reveals Links Between Alzheimer's Disease and Metabolic Comorbidities.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.05.26364777},
pmid = {42926600},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading contributor to dementia burden, and the risk of developing it is impacted by a multitude of factors. Among these factors are metabolic conditions like type-2 diabetes (T2D) and metabolic syndrome (MetS), along with ethnicity, which interacts both with AD and the metabolic comorbidities. Previous studies have established associations between methylation patterns at specific CpG sites and risk for AD, T2D and MetS individually, but the underlying etiology that is responsible for interactions between metabolic conditions and AD risk remains unresolved.

OBJECTIVE: We aimed to examine methylation patterns among Mexican American (MA) and Non-Hispanic White (NHW) individuals in the context of AD, alongside T2D and MetS, to identify CpG sites associated with disease-specific and interaction-dependent methylation effects related to those comorbidities.

METHODS: DNA methylation data from 551 patients of MA or NHW ancestry who were enrolled in the Texas Alzheimer's Research and Care Consortium (TARCC) were available for analysis. Participants were stratified into groups by AD/T2D status or AD/MetS score and Beta-values from the Illumina MethylationEPIC chip array were obtained for each patient. Differential methylation status was analyzed using the lumi and cate packages in R.

RESULTS: Five CpG sites had statistically significant differential methylation patterns, including two (cg06322660 and cg25514677) which exhibited significant interactions between AD and T2D status or AD and MetS score respectively, with cg06322660 being significant in the NHW cohort and cg25514677 being significant in the MA cohort. The association at cg25514677 was replicated in an independent MA cohort.

CONCLUSIONS: The two sites associated with interactions between AD and a metabolic condition could explain the influence that those conditions have on the risk for AD and are prime candidates for future study.},
}

@article {pmid42926604,
year = {2026},
author = {Chen, Y and Boon, BDC and Engelberg-Cook, E and Zhu, L and Rothberg, D and Rozemuller, A and Grinberg, LT and Ushizima, D},
title = {Generalizing Amyloid β Pathology from Postmortem Human Brains with Vision Foundation Models for Lesion Quantification.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.05.26364184},
pmid = {42926604},
abstract = {BACKGROUND: Traditional neuropathological assessment of Alzheimer's disease (AD) relies on manual, semi-quantitative scoring of amyloid-beta (Aβ) burden. This approach is limited by high inter-rater variability and often qualitative, failing to capture subtle, continuous pathology changes. While 11C-PiB PET neuroimaging provides non-invasive longitudinal monitoring, it has a limited dynamic range and lacks the sub-millimeter spatial resolution necessary to track localized microvascular and parenchymal Aβ trajectories.

METHODS: We introduce ViTamyloid, a generalizable modular computational pathology pipeline for high-throughput Aβ segmentation and classification in postmortem tissue. In Stage 1, a pathologist-supervised hybrid framework combining an EfficientNet-B4 encoder with a Residual U-Net decoder, complement with a localization-aware Faster R-CNN detector, to generate binary segmentation masks and isolated lesion candidates. In Stage 2, classification model powered by a frozen, high-resolution UNI2-h computational pathology foundation backbone and a ViT-Adapter, classifies candidates into a fine-grained four-class taxonomy: classic cored plaques (CCP), coarse-grained plaques (CGP), capillary cerebral amyloid angiopathy (CAA Type 1), and parenchymal/leptomeningeal CAA (CAA Type 2). We bench-marked out-of-distribution (OOD) robustness on external datasets from different brain banks, and validated clinical scalability across 1,646 whole-slide images from three brain banks.

RESULTS: The ViTamyloid classifier achieved strong feature-separation metrics, yielding area under the receiver operating characteristic curve (AUROC) and precision-recall curve (AUPRC) values of 0.994/0.958 for CCP, 0.989/0.945 for CGP, 0.992/0.977 for CAA Type 1, and 0.997/0.978 for CAA Type 2. More importantly, ViTamyloid consistently outperforms other pipelines' models and frozen features in all external datasets with different antibodies, and scanner settings, and image quality.

CONCLUSION: By replacing empirical, from-scratch architectures with a generalizable foundation model adapter framework, ViTamyloid provides a highly sensitive scalable digital pathomics toolkit. This pipeline expose continuous microscopic neuropathological dynamics beyond the spatial and sensitivity plateaus of in vivo neuroimaging, offering objective, quantitative endpoints for Alzheimer's disease clinical trials and disease subtyping.},
}

@article {pmid42926614,
year = {2026},
author = {Sharma, RU and Tolosa-Tort, P and Okorie, M and Chatterjee, A and Jonson, C and Yaffe, K and Belloy, ME and Andrews, SJ and , },
title = {Sex differences in genetic liability to modifiable Alzheimer's disease risk factors.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.01.26364536},
pmid = {42926614},
abstract = {INTRODUCTION: Alzheimer's disease (AD) shows sex differences in risk, clinical progression, and biomarker profiles, but whether inherited genetic liability to modifiable risk factors contributes differently to AD susceptibility in females and males remains unclear. We evaluated whether genetic relationships between several modifiable dementia risk factors and AD differ between females and males.

METHODS: We integrated polygenic risk scores (PRSs) for modifiable risk factors, genome-wide genetic correlation, and two-sample Mendelian randomization (MR) analyses. PRS associations with AD diagnosis were evaluated in the Alzheimer's Disease Genetics Consortium (n=27,751) and with AD plasma biomarkers in the Health and Aging Brain Study-Health Disparities (n=2,307-2,737, depending on the biomarker). Primary analyses evaluated female- and male-specific associations and compared sex-specific estimates.

RESULTS: Educational attainment and physical activity PRSs were associated with AD in both sexes. PRS sex differences were nominal for educational attainment, total cholesterol, and LDL cholesterol, but none remained significant after FDR correction. Genetic correlation showed FDR-significant sex differences for social isolation, physical activity, LDL cholesterol, and pulse pressure. MR identified FDR-significant associations within sex strata; higher HDL cholesterol was associated with lower AD risk in females, whereas higher total cholesterol and type 2 diabetes were associated with lower and higher AD risk, respectively, in males. Sensitivity analyses provided inconsistent support, and no sex difference in MR estimates remained significant after FDR correction. In HABS-HD, type 2 diabetes PRS was associated with higher NfL, BMI PRS with higher pTau 181 , and the composite PRS with higher NfL among males after FDR correction.

DISCUSSION: Evidence that modifiable dementia risk factors relate differently to AD by sex was limited and depended on the genetic measure examined. Sex differences in genome-wide genetic overlap were not consistently reflected in PRS or MR, indicating that shared genetic architecture does not necessarily translate into sex-specific inherited liability or causal effects.

RESEARCH IN CONTEXT: Systematic review: We reviewed the published literature on modifiable dementia risk factors, Alzheimer's disease (AD) genetics, and sex differences using PubMed and relevant reference lists. Previous studies support genetic relationships between several modifiable risk factors and AD, but systematic comparisons of female- and male-specific relationships across complementary genetic approaches remain limited.Interpretatio: The strongest evidence of sex heterogeneity for modifiable risk factors and AD was observed in their shared genetic architectures, with FDR-significant female-male differences for social isolation, physical activity, LDL cholesterol, and pulse pressure. PRS and Mendelian randomization analyses provided less evidence of formal sex heterogeneity, suggesting that sex differences in shared genetic architecture do not necessarily imply sex-specific causal effects.Future directions: Larger sex-stratified and ancestry-diverse GWAS integrated with longitudinal exposure and biomarker data are needed to determine whether these signals reflect sex-dependent biological mechanisms and whether they have implications for dementia prevention.Highlights: - Sex differences in AD-related genetic architecture were concentrated in behavioral, lipid, and vascular traits.- Genetic correlations with AD differed between females and males for social isolation, physical activity, LDL cholesterol, and pulse pressure.- PRS analyses implicated educational attainment and physical activity in AD in both sexes, but no PRS sex difference survived FDR correction.- MR identified associations within sex strata but provided little robust evidence of sex-specific causal effects.},
}

@article {pmid42926616,
year = {2026},
author = {Dai, Q and Murphy, M and Lyu, J and Tang, S and Hu, J and Tasaki, S and Wang, Y and Bennett, DA and Menon, V and De Jager, PL and Buchman, AS and Epstein, MP and Yang, J},
title = {Cell-Cell Communication Patterns in Alzheimer's Disease Differ by Cortical Layer.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.05.26364776},
pmid = {42926616},
abstract = {INTRODUCTION: Existing cell-cell communication (CCC) studies of Alzheimer's disease dementia (ADD) using cortical snRNAseq data do not account for the distinct cell-type and gene-expression profiles within cortical layers. Cortical-layer-aware CCC analysis may clarify biological mechanisms associated with ADD and mild cognitive impairment (MCI).

METHODS: We applied our recent analytical tool STACCato to identify CCC events associated with ADD and MCI within cortical layers, using a large-scale prefrontal cortex snRNAseq dataset (∼1.4M nuclei, n=395) with cortical layers annotated from reference spatial transcriptomics data.

RESULTS: We identified ADD/MCI-related CCC events with distinct patterns within cortical layers, including ADD-related interactions involving the known AD risk genes APOE and APP that were detected only in microglia in layer 5, and those with opposite effects of ADD and MCI in layers 5 and 6.

DISCUSSION: Our findings on cortical-layer-aware ADD/MCI-related CCC events underscore the importance of spatially-aware genomics studies of AD.},
}

@article {pmid42926649,
year = {2026},
author = {Matthey, N and Palani, RS and Liu, J and Bahri, S and Silvers, R and Michael, B and Gershenfeld, N and Linse, S and Griffin, RG},
title = {1H, 13C, and 15N chemical shift assignments of monomorphic Aβ1-40 at 100 kHz MAS in a diamond rotor.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-11089530/v1},
pmid = {42926649},
issn = {2693-5015},
abstract = {Amyloid-β (Aβ) fibrils are the principal component of the senile plaques that characterize Alzheimer's disease, and fibrils formed from the Aβ 1-40 alloform are strongly polymorphic, which has long complicated their structural characterization. We recently reported a reproducible, unseeded, monomorphic Aβ 1-40 fibril grown at neutral pH from supersaturated monomer, together with its atomic-resolution structure and its [13] C and [15] N chemical shift assignments (PDB 12GB; BMRB 31300). Here we extend that reference to [1] H. From a 3D [1] H-detected hCCH (RFDR) experiment and a 2D hNH experiment recorded at 18.8 T and ω r /2π = 100 kHz on approximately 0.5 mg of hydrated fibrils packed in a home-built 0.7 mm single-crystal diamond rotor, we assign 123 [1] H resonances, corresponding close to 90% of the distinct [1] H sites of the rigid core (residues Q15→V40), together with sixteen [1] H of the dynamic N-terminal segment. The [1] H-detected data additionally yield six previously unassigned [13] C and three previously unassigned [15] N resonances, predominantly in aromatic side chains and in the mobile N-terminus, and nine [1] H- [13] C and twenty [1] H- [15] N inter-residue contacts that are consistent with the published structure. These assignments provide a residue-level reference for fingerprinting Aβ 1-40 polymorphs and for mapping the binding of antibodies, chaperones and small molecules to this fibril.},
}

@article {pmid42926663,
year = {2026},
author = {Kotredes, KP and Pandey, RS and Reagan, AM and Sarica, Z and O'Rourke, R and Herrick, S and Davis, A and Garceau, D and Sasner, M and Carter, GW and Howell, GR},
title = {MTHFR*677C>T produces distinct prodromal disease signatures in a mouse model of late-onset Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-11166891/v1},
pmid = {42926663},
issn = {2693-5015},
abstract = {Background Late-onset Alzheimer's disease (LOAD) comprises more than 95% of all AD cases. Transgenic, overexpression animal models have off-target side effects, do not effectively produce the heterogeneity observed clinically in LOAD patients, and are therefore not best suited for preclinical therapeutic development. The Model Organism Development and Evaluation for Late-onset Alzheimer's Disease (MODEL-AD) Consortium was established to develop novel mouse strains to model human-relevant genetic and environmental risk factors for LOAD. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme in the folate/methionine pathway. Variants in the MTHFR gene, notably 677C > T , are associated with ADRD, and we have previously shown the Mthfr [677C>T] mouse model phenocopies humans carrying the variant and develops cerebrovascular deficits. Methods To examine the contributions of Mthfr [677C>T] in the context of late-onset Alzheimer's disease (LOAD), MODEL-AD created a novel mouse strain on the C57BL/6J (B6) background that was homozygous for Mthfr [677C>T] , in combination with humanized Aβ , APOEe4 , and Trem2*R47H (referred to as LOAD2.Mthfr [677C>T]) . Mice were assessed over multiple ages for disease-relevant phenotypes. Regular behavior measurements and biometric samples were collected longitudinally to 24 months of age. Blood and brain tissue were collected for transcriptomics, proteomics, human disease correlation, and neuropathology. Results Despite lacking hallmark pathologies such as amyloid deposition and significant neuroinflammation, compared to LOAD2 controls, LOAD2.Mthfr [677C>T] mice showed transcriptional and proteomic signatures in the brain that relate to the cerebrovasculature, myelination, and synaptic biology, similar to those seen in human LOAD patients. Conclusions These data further support the use of the LOAD2.Mthfr [677C>T] mouse model to study aspects of ADRD such as cerebrovascular compromise.},
}

@article {pmid42926671,
year = {2026},
author = {Rutherford, S and Zahid, Z and Welsh, RC and Avena-Koenigsberger, A and Hammers, DB and Koppelmans, V and Mejia, AF and Initiative, ADN},
title = {A Pipeline for ADNI Resting-State Functional MRI Processing and Quality Control.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-11132707/v1},
pmid = {42926671},
issn = {2693-5015},
abstract = {The Alzheimer's Disease Neuroimaging Initiative (ADNI) provides a comprehensive multimodal neuroimaging resource for studying aging and Alzheimer's disease (AD). However, its resting-state functional MRI (rs-fMRI) data remain underutilized, in part due to challenges with data processing driven by considerable variability in acquisition protocols, inconsistent organization, missing or incomplete imaging sessions, and frequency of data quality issues due to participant motion and aging-related factors. To facilitate widespread use of ADNI rs-fMRI data, we developed an open-source pipeline encompassing the download and organization of imaging and clinical data, conversion to Brain Imaging Data Structure (BIDS), preprocessing with fMRIPrep, and automated quality control (QC). Our QC considers acquisition parameters and 16 structural and functional MRIQC image-quality metrics, flagging scans that fall outside acceptable ranges based on expert input and robust outlier detection techniques. Processed imaging sessions are matched to temporally aligned clinical assessments to produce an analysis-ready dataset. Applying the pipeline to more than 2,800 sessions from ADNI GO, ADNI 2, and ADNI 3 yielded 2,086 quality-checked functional and structural MRI sessions from 935 unique participants. Exclusions occurred at every processing stage and were driven primarily by BIDS conversion errors, image quality flags, and preprocessing- or motion-related failures. The open-source pipeline described in this work produces one of the largest pre-processed, quality controlled, and analysis-ready functional and structural MRI datasets yet available for studying aging and AD. It lowers barriers to large-cohort and longitudinal neuroimaging research and supports large-scale neuroimaging biomarker discovery in AD.},
}

@article {pmid42926678,
year = {2026},
author = {Elia, A and Vazquez-Torres, R and Carey, A and Wolf, M and Gade, VR and Alves, M and Fossati, S},
title = {Carbonic anhydrase inhibition rescues heart function in the Tg2576 Alzheimer's mouse model by ameliorating cardiac amyloid-β pathology and neurotrophic-signaling impairment.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.08.757731},
pmid = {42926678},
issn = {2692-8205},
abstract = {FDA-approved carbonic anhydrase inhibitors (CAIs) have shown robust efficacy in reducing amyloid-β (Aβ) pathology, neurodegeneration, and cerebrovascular dysfunction in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) models, highlighting carbonic anhydrase (CAs) as a promising, previously untapped therapeutic target for AD and vascular contribution to dementia. We have recently shown that Aβ aggregates disrupt neuro-signaling and deplete neurotrophic factors (particularly BDNF) in the heart of AD mouse models and human subjects. In this study, we present the first in-depth examination of CAI therapy (acetazolamide-ATZ) in Tg2576 mice, a well-established model of AD and CAA. We confirm that progressive cardiac fibrosis and Aβ deposition in 13-month-old mice severely impair the cardiac neuro-signaling system, marked by a drastic decrease in BDNF and reductions in adrenergic fibers and regenerating nerve endings (TH and GAP-43 markers), leading to significant declines in ejection fraction and fractional shortening compared to age-matched WT littermates. Critically, this study demonstrates that long-term ATZ treatment in Tg2576 mice significantly reduces cardiac Aβ burden, prevents adverse neuro-signaling remodeling, and restores heart physiological function, as assessed via speckle tracking strain echocardiography. These in vivo findings were corroborated in human cardiomyocytes, in which CA inhibition reduced human Aβ40 oligomer-dependent disruption of CREB signaling, thus preserving BDNF expression. Together, these results reveal a previously unrecognized cardio-neuroprotective role for CAIs in preventing Aβ-induced cardiovascular remodeling and neuro-signaling disruption in the Tg2576-AD model. Given the established benefits of CAIs on cerebrovascular function and cognition, our findings further support advancing repurposing efforts into clinical trials. CAIs such as ATZ could offer a dual-action therapy approach, addressing both the central nervous system and cardiac pathologies associated with AD and, potentially, the systemic effects of amyloidosis.},
}

@article {pmid42926699,
year = {2026},
author = {Shi, R and Choity, LT and Farinas, MF and Zeng, X and Emanuel, JE and Saeed, A and Reis, SE and Lopez, OL and Kamboh, IM and Cohen, AD and Gildengers, AG and Wilckens, KA and Karikari, TK},
title = {Clinical utility of plasma APOE proteotyping for Alzheimer's disease risk and prognosis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.08.26364972},
pmid = {42926699},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder strongly influenced by genetic factors, with apolipoprotein E (APOE) ε4 allele being the most established risk variant. Although DNA-based genotyping remains standard, plasma proteotyping may provide scalable, isoform-specific alternatives. Here, we aimed to investigate the clinical utility of APOE proteotyping as a surrogate for genotyping in different clinical and research cohorts.

METHODS: Plasma APOE4 protein were quantified using the NULISAseq CNS panel across four cohorts (ADRC, HeartSCORE, LATTICE, and ALPS). DNA-based APOE genotyping was the reference standard. Proteotyping thresholds for APOE ε4 carrier status and copy number were derived in ADRC and externally validated in the other cohorts. Logistic, proportional-odds, and Cox proportional-hazards models compared genotype- and proteotype-defined groups in relation to amyloid positivity, cross-sectional CDR global scores, and time to CDR-SB worsening, respectively.

RESULTS: Plasma APOE4 accurately classified APOE ε4 carrier status in ADRC (AUC=0.977, 95%CI 0.967-0.985; threshold 5.78 NULISA protein quantification [NPQ] value) and achieved near-perfect external validation in HeartSCORE, LATTICE, and ALPS (all AUCs=1.000, 95%CI 1.000-1.000). Plasma APOE4 also well-differentiated heterozygous from homozygous ε4 carriers (ADRC AUC=0.879, 95%CI 0.834-0.921; threshold 12.23 NPQ value). Genotype- and proteotype-defined ε4 carrier status showed similar associations with amyloid positivity (OR=4.40 vs 4.45), higher CDR global scores (OR=1.50 for both), and CDR-SB worsening (HR=1.22 for both).

DISCUSSION: Plasma APOE4 proteotyping accurately distinguished genotype-defined APOE ε4 carrier status and copy number while demonstrating AD-related associations comparable to DNA genotyping.},
}

@article {pmid42926738,
year = {2026},
author = {Dashnaw, CM and Rastogi, S and Morgan, N and Memon, I and Jaczynska, K and Nguyen, BA and Saelices, L and White, CL and Shahmoradian, S and Joachimiak, LA},
title = {Large-Scale Mutagenesis Identifies Sequence Changes That Bias Tau Toward CTE-like Aggregation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.08.757173},
pmid = {42926738},
issn = {2692-8205},
abstract = {Tau amyloid fibrils adopt disease-specific structures across tauopathies, yet the sequence determinants that favor one pathological fold over another remain poorly defined. Here we combine computational saturation mutagenesis and energetic profiling, in vitro aggregation, cryo-EM and cellular seeding assays to identify sequence changes that alter tau fold compatibility. Across six tauopathy fibril structures, approximately 12,000 substitutions revealed that mutational sensitivity is concentrated within interaction networks formed by amyloidogenic motifs rather than uniformly distributed across the fibril core. Comparison of Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) folds identified residues within the 335-363 region that differentially influence fold compatibility. The S341L/S352I double mutant accelerated aggregation and remodeled packing within the PAM4-containing amyloidogenic region, producing an alternative amyloid architecture in a minimal tau fragment. S341L/S352I biosensors preferentially responded to CTE-derived over Alzheimer's disease-derived seeds, while aggregates generated from recombinant S341L/S352I tau exhibited CTE-like cellular templating behavior. Although these assemblies are not established to reproduce the atomic CTE fold, the results demonstrate that targeted sequence changes can bias tau aggregation and propagation toward a CTE-compatible state. This framework provides a strategy for defining sequence-structure relationships in polymorphic amyloids and developing conformation-selective models and biosensors.},
}

@article {pmid42926775,
year = {2026},
author = {Tan, G and Demarest, P and Kardashina, T and Adams, J and Willie, JT and Roland, J and Gorlewicz, JL and Brunner, P and Leuthardt, EC},
title = {Vibrotactile transcutaneous auricular vagus nerve stimulation (taVNS) during working memory: convergent electrophysiological evidence for cortical efficiency.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.07.756069},
pmid = {42926775},
issn = {2692-8205},
abstract = {BACKGROUND: Working memory, the cognitive ability to maintain and manipulate a finite amount of information, is fundamental in reasoning, learning, and decision-making. Working memory erodes in conditions from Alzheimer's disease to stroke to healthy aging. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising neuromodulation method for improving working memory. By stimulating the auricular branch of the vagus nerve, taVNS is thought to engage ascending arousal systems such as the locus coeruleus-norepinephrine (LC-NE) system. However, the physiological link between LC-NE system modulation via taVNS and improved working memory remains largely unknown. This mechanistic gap limits the rational optimization of the stimulation protocol and the identification of the cognitive functions and patient populations that are likely to benefit.

OBJECTIVE: We test two competing hypotheses for how taVNS may improve working memory: sensory amplification or enhancement of cortical efficiency. The sensory-amplification hypothesis predicts increased cortical responses to stimuli, whereas the cortical-efficiency hypothesis predicts reduced cortical responses.

METHODS: Twenty healthy adults completed N-back working memory tasks during three counterbalanced sessions: baseline, active vibrotactile taVNS (vtaVNS), and sham stimulation, while we simultaneously recorded electroencephalography, electrocardiography, eye-tracking, and behavioral responses. To study the effect of vtaVNS on neuronal activity, we also recruited 20 patients with epilepsy undergoing invasive monitoring. Of these, 19 fully completed the spatial working-memory task. We quantified cortical responses to visual stimuli using event-related potentials (ERPs) in scalp EEG and high-gamma activity in intracranial local field potentials. To examine prediction of the cortical-efficiency hypothesis, we further explored the effect of vtaVNS on distance to criticality and heartbeat-evoked potentials.

RESULTS: Active vtaVNS reduced both scalp-recorded visual ERP and high-gamma response in temporal cortices, relative to sham stimulation. Moreover, smaller visual event-related potentials were associated with successful encoding during the most demanding working-memory condition (i.e., 4-back task). Exploratory analyses showed that vtaVNS shifted cortical dynamics closer to criticality.

CONCLUSION: Our results converge on the conclusion that vtaVNS does not uniformly amplify cortical responses to external stimuli. Instead, vtaVNS enhances cortical efficiency, supporting more effective allocation of cognitive resources between exteroceptive and mnemonic processes. These findings provide a framework for predicting when taVNS will be most beneficial and for optimizing stimulation protocols across cognitive and clinical applications.

HIGHLIGHTS: Consistent visual event-related potential in human subjects during an N-back working memory taskVibrotactile taVNS reduced stimulus-evoked cortical responses in both scalp EEG and intracranial high-gamma activity (70-150 Hz).Reduced visual event-related potentials are associated with successful encoding in the 4-back task.Vibrotactile taVNS shifted cortical dynamics toward a near-critical regime.},
}

@article {pmid42926800,
year = {2026},
author = {Zhang, A and Shen, W and Yan, S and Chen, J and Liu, X and Zou, J and Li, S and Hu, S and Liu, Y and Pan, C and Lan, Z and Peng, G and Zhang, Q and Peng, W and Ahmadizar, F and Zhang, J and , },
title = {Cross-Tissue Inflammatory Convergence Supports a Putative Muscle-Brain Axis in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.07.751107},
pmid = {42926800},
issn = {2692-8205},
abstract = {BACKGROUND: Reduced muscle strength is associated with cognitive decline and Alzheimer's disease (AD), suggesting that skeletal-muscle aging and AD-related neurodegeneration may share biological mechanisms. Vascular dysfunction, immune activation, and extracellular-matrix remodeling have been implicated in both tissues, but the extent of shared cellular and molecular programs remains unclear. We investigated cross-tissue transcriptional programs in aging skeletal muscle and AD-related brain tissue and evaluated whether related signals are detectable in peripheral blood.

METHODS: We analyzed independent, unpaired human transcriptomic datasets from skeletal muscle (23 donors), the SEA-AD middle temporal gyrus atlas (84 donors), and peripheral blood. Donor-aware models identified age-associated changes in muscle and transcriptomic changes across continuous pseudoprogression score (CPS) in brain. Cross-tissue comparisons focused on 30 brain donors within an early CPS window. Shared tissue-derived programs were assessed in peripheral blood mononuclear cells and independently tested in frailty bulk-blood and Alzheimer's Disease Neuroimaging Initiative (ADNI) whole-blood datasets. CellOracle simulations were used to prioritize candidate transcriptional regulators.

RESULTS: Aging muscle showed increased inflammatory, extracellular-matrix, and stromal communication programs. During early AD-related brain progression, vascular and immune populations showed increasing inflammatory and matrix-associated activity together with shifts in intercellular communication. Cross-tissue analysis identified six concordantly enriched pathways comprising 109 leading-edge genes in endothelial populations and four pathways comprising 51 genes in myeloid populations. Related peripheral-blood signatures varied across cohorts and cell types. However, in independent frailty and ADNI mild cognitive impairment and AD datasets, 23 of 30 predefined tissue-derived pathway-subset tests showed significant positive enrichment after false-discovery-rate correction, whereas individual gene-level bulk-blood associations did not survive correction. CellOracle analyses prioritized ETS2 and BHLHE40 as exploratory endothelial regulators whose simulated perturbation consistently reduced selected shared program scores across tissues.

CONCLUSIONS: Aging skeletal muscle and AD-related brain tissue exhibit convergent endothelial and myeloid inflammatory programs, with related pathway-level signals detectable in peripheral blood. These cross-tissue programs and candidate endothelial regulators provide testable hypotheses for mechanisms linking systemic aging, muscle dysfunction, and AD-related neurodegeneration.},
}

@article {pmid42926809,
year = {2026},
author = {Shi, R and Zeng, X and Farinas, MF and Nafash, MN and Smirnov, DS and Kamboh, MI and Snitz, BE and Kofler, JK and Cohen, AD and Pascoal, TA and Ikonomovic, MD and Zetterberg, H and Lopez, OL and Karikari, TK},
title = {Plasma eMTBR-tau as a robust biomarker for Alzheimer's disease tangle pathology up to 10 years before death.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.29.26363951},
pmid = {42926809},
abstract = {Scalable and accessible biomarkers of neurofibrillary tangle pathology are needed for Alzheimer's disease prognosis, diagnosis and monitoring. Here, we show that a blood-based immunoassay for an endogenously-cleaved "eMTBR-tau" fragment of tau protein is strongly associated with autopsy-diagnosed Alzheimer neuropathologic change (ADNC) and predominantly reflects the burden and anatomical progression of tangle pathology but not amyloid plaque load despite being most elevated in amyloid-positive symptomatic individuals. Plasma eMTBR-tau was significantly more accurate than plasma p-tau217 in classifying Braak staging and ADNC statuses at autopsy. Importantly, neuropathologic classification by plasma eMTBR-tau remained high (AUC=0.91-0.95) even when increasing intervals between blood collection and death up to a decade, while maintaining superior sensitivity and specificity over p-tau217. Higher baseline plasma eMTBR-tau was associated with worse cognition cross-sectionally and longitudinally predicted faster worsening. These results were replicated in a living cohort with in vivo tangle and plaque neuroimaging. Plasma eMTBR-tau concordance with tau neuroimaging was up to 94%, suggesting surrogacy. Together, plasma eMTBR-tau captures biological signatures of Braak staging and ADNC over a prolonged pre-mortem window, highlighting potential for early disease detection, biological staging, prognosis and therapeutic development.},
}

@article {pmid42926826,
year = {2026},
author = {Costa, AP and Karim, HT and Farinas, MF and Nicholson, N and Geissinger, MM and Zeng, X and Tudorascu, DL and Butters, MA and Karikari, TK and Andreescu, C},
title = {Association between plasma brain-derived p-tau variants and anxiety phenotypes in older adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.02.26364610},
pmid = {42926826},
abstract = {OBJECTIVES: To determine whether distinct anxiety phenotypes (rumination, global anxiety and worry; RAW) are associated with plasma brain-derived (BD) phosphorylated-tau (p-tau) biomarkers of Alzheimer's disease (AD) in older adults.

DESIGN: Cross-sectional observational study.

METHODS: Participants were 89 older adults aged ≥50 years (mean age 64.3±8.8 years) enrolled in the RAW Brain study (R01 MH108509) in Pittsburgh, Pennsylvania. Anxiety phenotypes were assessed using the Penn State Worry Questionnaire (PWSQ≥50), Rumination Subscale from the Response Style Questionnaire (RSQ>50), and Hamilton Anxiety Rating Scale (HARS>17). Participants were classified as High-RAW if they exceeded established severity thresholds on ≥1 domain; continuous anxiety scores were used for primary analyses. Plasma BD-tau, BD-p-tau181, BD-p-tau217, and BD-p-tau231, and matched non-BD versions were quantified using the NULISAseq™ CNS Panel. Associations between anxiety phenotypes and tau biomarkers were examined using multivariable linear regression adjusted for age, sex, and APOE4 status, with Benjamini-Hochberg false discovery rate correction.

RESULTS: Greater global anxiety was associated with higher plasma BD-p-tau181 (β=0.308, 95% CI [0.003,0.048], p=0.047). This association was also observed categorically (adjusted Cohen's d=0.462, p=0.049). Worry and rumination were not associated with BD-p-tau181, and no anxiety phenotypes were associated with BD-tau, BD-p-tau217, BD-p-tau231, or corresponding non-BD alternatives.

CONCLUSIONS: Greater late-life global anxiety, but not worry or rumination, was selectively associated with higher plasma BD-p-tau181. These findings extend epidemiologic evidence linking anxiety to AD risk by identifying a biologically specific blood-based correlate linking anxiety with AD-related p-tau biology. Longitudinal studies incorporating amyloid and tau biomarker confirmation are needed to determine whether anxiety precedes, accompanies, or results from early AD pathophysiology.

HIGHLIGHTS: 1) What is the primary question addressed by this study? -The question addressed by the study must limited to only one sentence. Is late-life anxiety, including rumination, global anxiety, and worry, associated with plasma brain-derived (BD) phosphorylated-tau (p-tau) biomarkers of Alzheimer's disease in older adults? 2) What is the main finding of this study? -The finding must be limited to two sentences. Greater global anxiety, but not worry or rumination, was associated with higher plasma BD-p-tau181 after adjustment for age, sex, and APOE4 status. No associations were observed with other BD-tau variants or with non-BD-tau versions. 3) What is the meaning of the finding? -The meaning of the finding must be limited to one sentence. These findings suggest that global anxiety may be linked to early Alzheimer's disease-related tau biology and support further longitudinal investigation of anxiety as a potential marker of preclinical disease.},
}

@article {pmid42926842,
year = {2026},
author = {Lee, YR and Zeng, X and Farinas, MF and Lopresti, BJ and Habte, RF and Wilckens, KA and Karikari, TK},
title = {Analytical performance of a delayed-centrifugation blood collection tube for remote blood biomarker assessment.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.05.26364780},
pmid = {42926842},
abstract = {Current biobanking guidelines require in-person blood collection and immediate processing for Alzheimer's disease (AD) biomarker assessment. We recently reported that the P100 blood collection tubes containing protease inhibitors improve protein biomarker stability over delayed centrifugation periods. However, whether this comparability extends beyond a small set of biomarkers to the broad panels enabled by high-plex platforms has not been established. Here, we performed a head-to-head comparison of 127 neurodegeneration-related biomarkers in paired P100 vs. standard ethylenediaminetetraacetic acid (EDTA) plasma samples from n = 43 community-dwelling older adult participants using the NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) proteomic technology. The NULISA assay demonstrated excellent technical reproducibility (intra- and inter-plate coefficients of variation [CVs] <10%). Biomarker levels in P100 and EDTA tubes were strongly correlated, with mean and median Spearman coefficients exceeding ρ = 0.8. Six conventional AD biomarkers showed strong P100-EDTA correlations (ρ > 0.8) with minimal mean differences and no significant proportional bias in Bland-Altman analysis, including plasma Aβ42, GFAP, MAPT, NEFL, p-tau181, and p-tau231, while p-tau217 showed a P100-EDTA correlation of ρ = 0.57. Two biomarker ratios (Aβ42/Aβ40 and p-tau217/Aβ42) also showed minimal bias with no proportional bias detected. Receiver operating characteristic analysis using amyloid status, assessed with positron emission tomography in a subset of participants, showed comparable classification performance between the two tube types, with classification concordance up to 92% and no significant DeLong differences for most (80%) biomarkers. These findings indicate that, on the NULISA platform, P100 tubes yield analytical and classification performance comparable to conventional EDTA tubes, supporting their use for blood-based neurodegeneration biomarker research where immediate sample processing is not feasible.},
}

@article {pmid42926851,
year = {2026},
author = {Koenders, CL and Chiu, R and Medeiros-Furquim, T and Bergink, S},
title = {Astrocytic timekeepers and their influence on brain waste clearance in Alzheimer's disease.},
journal = {Neurobiology of sleep and circadian rhythms},
volume = {21},
number = {},
pages = {100155},
doi = {10.1016/j.nbscr.2026.100155},
pmid = {42926851},
issn = {2451-9944},
abstract = {Alzheimer's disease is associated with disruptions in circadian rhythmicity, yet the underlying mechanisms remain only partially understood. Developing insights suggest that astrocytes possess their own intrinsic circadian clocks, influencing multiple functions in brain homeostasis. Given the central role of astrocytes in brain waste clearance, this review investigates how the astrocytic clock mediates brain waste clearance and contributes to Alzheimer's disease pathology. By reviewing recent findings on extracellular clearance, cellular protein homeostasis, cellular detoxification/redox defence and neurotransmitter homeostasis, this review bridges research on astrocytic clock disruption with altered brain waste clearance dynamics. It further highlights the relevance of these alterations to Alzheimer's disease pathology. Interestingly, some clock-gene disruptions are associated with markers suggestive of increased autophagic activity and glymphatic-related gene expression, which may represent a compensatory response to circadian clock alteration. However, whether these changes translate into improved functional clearance in vivo, and whether they meaningfully affect Alzheimer's disease progression, remains uncertain. In contrast, similar clock-gene alterations generally impair blood-brain barrier integrity, glutamate clearance and antioxidant response, decreasing waste clearance capacity. These findings suggest a possible bidirectional relationship, in which some pathways may partially compensate for impairments in others. However, it remains unclear to what extent an imbalance in these pathways contributes to the development and/or progression of Alzheimer's disease. Altogether, the astrocytic circadian clock is positioned as an important regulator of brain waste clearance and warrants future mechanistic and therapeutic investigation.},
}

@article {pmid42926864,
year = {2026},
author = {Gautier, A and Zheng, L and Schreurs, BG},
title = {Forecasting Alzheimer's disease progression using non-imaging clinical features and XGBoost.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.05.26364229},
pmid = {42926864},
abstract = {UNLABELLED: Identifying progressive dementia during its prodromal stage is a challenging yet critical task for healthcare providers. Traditional clinical assessments are often not sensitive enough to detect warning signs of cognitive decline. Machine learning (ML) methods have shown promise in modeling clinical trajectories associated with neurodegenerative disorders such as Alzheimer's disease (AD). Validation of these models' forecasting abilities, however, is widely lacking in the literature. To address this gap, we established a longitudinal cohort from the National Alzheimer's Coordinating Center (n = 15,727) comprising individuals who were cognitively normal (CN) or had mild cognitive impairment (MCI) at baseline. Cognitive status and clinical observations collected over up to 10 visits were used to train several ML classifiers. We employed the gradient-boosted tree ensemble method XGBoost with a custom feature-engineering pipeline. On non-imputed data, our models achieved an AUC-ROC of 0.9447 [0.9417-0.9476] and PR-AUC of 0.8554 [0.8497-0.8611] for the CN→MCI task, and an AUC-ROC of 0.9059 [0.8983-0.9134] and PR-AUC of 0.9214 [0.9156-0.9272] for the MCI→AD task. In a lead-time forecasting analysis spanning mean follow-up periods of 56.1 months (range, 9.1-214.1) for CN→MCI and 42.7 months (range, 9.1-126.1) for MCI→AD, the non-imputed models detected future progression before diagnosis in 29.58% [28.29%-30.87%] of CN→MCI progressors and 22.41% [21.36%-23.46%] of MCI→AD progressors. Among these individuals, the mean lead time was 33.04 months [32.52-33.56] and 17.95 months [17.71-18.19], respectively. False alarm rates among non-progressors were 12.6% [11.5%-13.7%] and 20.0% [18.4%-21.6%], respectively. These findings suggest that longitudinal machine learning models can identify future cognitive decline before diagnosis, indicating clinical utility for early dementia risk stratification.

AUTHOR SUMMARY: Alzheimer's disease (AD) is a progressive and currently incurable neurodegenerative disorder that remains highly difficult to diagnose during its early stages. While modern early-stage dementia research relies on advanced neuroimaging, the high cost of these tests excludes many vulnerable communities. We designed our study to advance scalable, low-cost diagnostic alternatives that can identify individuals at significant risk of cognitive decline, ensuring faster access to emerging therapies.We examined trajectories of cognitive decline in 15,727 adults (mean age = 71.45 years, SD = 9.06) who had between 2 and 10 follow-up visits. Using 37 demographic, behavioral, clinical, and genetic variables, we modeled cognitively stable and declining trajectories using the XGBoost algorithm. Additionally, we evaluated the models' ability to forecast future diagnoses and the impact of longitudinal imputation.Our models performed well in both classification tasks (AUC-ROC ≥ 0.90).Imputation did not substantively alter the classifiers' performance. In forecasting diagnosis conversion, the models raised alarms before the recorded conversion visit in a subset of progressors, with non-imputed models yielding longer net lead times than imputed models in AD forecasting. This work describes a strategy for handling mixed-length temporal dimensions in longitudinal cohorts and evaluates its prognostic ability.},
}

@article {pmid42926876,
year = {2026},
author = {Zeng, X and Abrahamson, EE and Balogun, WG and Kofler, J and Paljug, WR and Pivtoraiko, VN and Ikonomovic, MD and Karikari, TK},
title = {Brain region- and solubility-dependent proteomic signatures of neurofibrillary tangle pathology in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.04.26361149},
pmid = {42926876},
abstract = {Neurofibrillary tangles (NFTs) containing hyperphosphorylated tau proteins are a hallmark neuropathology of Alzheimer's disease. However, the molecular basis underlying their spatial heterogeneity and biochemical complexity remain unclear. To address this, we performed mass spectrometry-based proteomic profiling of two neocortical regions with different susceptibilities to NFT pathology-the inferior temporal (IT) and middle frontal (MF) cortices-from 27 autopsy cases stratified by Braak NFT stage (Low 0-II, n=8; Mid III-IV, n=11; High V-VI, n=8). Brain homogenates were sequentially fractionated using buffers of increasing solubility (TBS, Na2CO3, and Urea), followed by trypsin digestion and analysis by nanoLC-MS/MS with data-independent acquisition. Proteins were identified using PEAKS Studio 12 and linear mixed-effects models were applied to assess Braak stage-associated and region-specific changes in protein abundance and solubility. A total of 5,573 protein groups were identified, including 452 differentially expressed proteins (DEPs), 183 bidirectional expression proteins (BEPs), and 693 differentially soluble proteins (DSPs) associated with NFT pathology. These proteins were enriched in pathways related to cytoskeletal organization, synaptic transmission, metabolism, vesicular trafficking, and proteostasis. Marked regional differences were observed, with limited overlap between IT and MF across DEPs, BEPs, and DSPs. Protein change in MF was dynamic with a higher number of BEPs and suggested active cytoskeletal remodeling, whereas IT showed fewer BEPs and evidence of structural disruption, including alterations in intermediate filament components, consistent with vulnerability of IT and possible compensatory/plasticity changes in MF cortex. MF cortex had the greatest downregulation of DEPs between Low and Mid Braak stages, while the transition from Mid to High Braak stage showed upregulation of most of DEPs in both regions. In addition, widespread changes in protein solubility were observed, particularly decreased solubility at later Braak stages, implicating disruption of proteostasis. Together, these findings highlight region- and stage-dependent proteomic alterations associated with tau pathology and underscore their relevance for understanding disease mechanisms and informing biomarker development.},
}

@article {pmid42926894,
year = {2026},
author = {Roussos, P and Choi, Y and Bendl, J and Hoffman, G and Vicari, J and M, PN and Kosoy, R and Wang, X and Kinrot, S and Yang, H and Girdhar, K and Lee, D and Fullard, J and Dong, P},
title = {Cell-type-resolved mRNA 3'-end remodeling in Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-11143166/v1},
pmid = {42926894},
issn = {2693-5015},
abstract = {Alternative polyadenylation diversifies messenger RNAs by altering coding sequences and 3' untranslated regions, but its organization across human brain cell types and disruption in neurodegeneration remain poorly understood. By analyzing 3'-capture single-nucleus RNA sequencing data of 6.3 million nuclei from the prefrontal cortex of 1,494 human donors, we defined 108,768 polyadenylation sites across 25,274 genes, most of which were absent from the GENCODE polyadenylation-site annotation. Polyadenylation-site usage was strongly cell-type-specific and revealed regulatory differences not captured by gene expression. With increasing Alzheimer's disease clinicopathological severity, excitatory neurons, oligodendrocytes and immune cells showed increased distal-site preference, including reduced relative usage of intronic sites and increased distal 3' untranslated region usage in synaptic and RNA-processing genes. External single-nucleus data supported neuronal and oligodendrocyte patterns, while complementary analyses of purified microglia supported selected immune-cell findings. Integrative analyses of cleavage and polyadenylation factor expression, co-regulated usage networks, sequence motifs and published perturbations prioritized the cleavage factor Im complex as a candidate regulator. These findings identify cell-type-specific messenger RNA 3'-end remodeling as a reproducible dimension of Alzheimer's disease molecular pathology that is only partly captured by gene-level analyses.},
}

@article {pmid42926906,
year = {2026},
author = {Campbell, A and Becker, L and Kreimer, S and Gonzales, M and Raedschelders, K and Eyk, JV},
title = {Scalable Hydrogel Nanoparticle Enrichment for Enhanced Mass Spectrometry-based Proteomic Analysis of Plasma or Volumetric Dried Blood Samples.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-11053241/v1},
pmid = {42926906},
issn = {2693-5015},
abstract = {Discovery-based proteomics for translational research requires workflows that reveal deep proteomes with a high degree of analytical precision, are scalable across large sample cohorts, and that can be adapted to different sample matrices. In our work, these sample matrices often extend beyond plasma to include volumetric dried blood samples (VDBS) that offer a minimally invasive alternative to standard venipuncture and enable remote, self-directed sampling. We describe the development and validation of a one-day, 96-well plate-based workflow built on the Ceres Nanotrap Protein Enrichment Affinity (PEAK) nanoparticle platform, optimized independently for both plasma and VDBS ahead of liquid chromatography-tandem mass spectrometry (LC-MS/MS). We benchmarked a tube-based Ceres workflow against both a Seer-encrichment and an unenriched SP3 workflow, assessed its suitability for VDBS, and translated this workflow to a plate-based protocol with a 2-hour digestion. The adapted workflow demonstrated robust reproducibility for both matrices: plasma yielded 4,937 unique proteins with a median inter-day CV of 11% whereas VDBS yielded 3,613 proteins with a median inter-day CV of 19%. Plasma and VDBS proteomes were highly concordant, with 75% of shared proteins quantified within one order of magnitude between matrices. We preliminarily evaluated the biological utility of this platform against a curated panel of 20 Alzheimer's Disease-associated proteins. Our results reveal the Ceres PEAK platform as a flexible, laboratory-adaptable workflow capable of deep and reproducible proteomic profiling of both plasma and VDBS.},
}

@article {pmid42926943,
year = {2026},
author = {Srikanth, M and Jiang, S and Wellman, SM and Sarkar, S and Lorman, DE and Lantin, T and Runyan, AM and Kumar, M and Sydney, E and Figueroa, HY and Yang, M and Wang, Q and Myeku, N},
title = {Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-11129729/v1},
pmid = {42926943},
issn = {2693-5015},
abstract = {Background Immunoproteasome induction is prominent in Alzheimer's disease (AD), but whether this response protects proteostasis or amplifies neuroinflammation remains unresolved. Microglia must engage, internalize and degrade pathological protein cargo, yet uptake alone may not indicate successful clearance. We investigated how loss of inducible immunoproteasome function affects AD-related protein pathology and microglial processing of pathological cargo. Methods We crossed L7M1 mice, which lack the immunoproteasome catalytic subunits β2i/MECL-1/PSMB10 and β5i/LMP7/PSMB8, with PS19 tauopathy mice and APP/human tau double-knock-in mice. Tau and amyloid pathology, glial reactivity, constitutive proteasome activity and behavior were evaluated in vivo. Microglial uptake and processing of tau aggregate-bearing material were examined using primary microglial cultures, live-cell imaging and longitudinal in vivo two-photon microscopy. Mouse single-nucleus RNA sequencing and reanalysis of two human single-nucleus transcriptomic datasets were used to define associated cellular programs. Isolated brain mitochondrial respiration was also assessed. Results Immunoproteasome deficiency increased phospho-tau burden and microglial reactivity in PS19 mice and exacerbated tau and amyloid-β pathology in APP/human tau double-knock-in mice. These pathological changes occurred without detectable suppression of constitutive 26S proteasome activity. Although immunoproteasome-deficient microglia engaged and engulfed tau aggregate-bearing material, live-cell imaging showed inefficient resolution of internalized cargo. Longitudinal two-photon imaging similarly demonstrated retention or accumulation of microglia-associated tau in immunoproteasome-deficient mice, identifying a post-engulfment degradative defect in vivo. Single-nucleus transcriptomics revealed a remodeled P2ry12low/Trem2high microglial state accompanied by altered phagolysosomal cargo-processing and mitochondrial programs. In two human datasets, lower microglial immunoproteasome expression was associated with cargo-processing gene-program changes that overlapped with those observed in immunoproteasome-deficient mouse microglia. Despite transcriptional suppression of mitochondrial programs, no detectable impairment of isolated brain mitochondrial respiration was observed. Conclusions These findings support immunoproteasome biogenesis as a protective glial stress response that facilitates post-engulfment processing of pathological cargo and restrains tau and amyloid accumulation in AD-relevant brain environments. They further distinguish microglial engagement and uptake from successful intracellular resolution, identifying immunoproteasome function as an important component of aggregate clearance in AD.},
}

@article {pmid42926960,
year = {2026},
author = {Quiring, M and Shuai, Y and Zhao, W and Alitin, JPM and Kapoor, A and Engstrom, AC and Joyce, JL and Iyengar, P and Lohman, T and Lashin, B and Gaubert, A and Shenasa, F and Contreras, L and Law, KW and Ferrer, F and Wang, DJJ and Head, E and Malhas, R and Rodgers, K and Han, SD and Thayer, JF and Bondi, MW and Mather, M and Nation, DA},
title = {Locus coeruleus intensity as a marker of early-stage Alzheimer's disease: associations with plasma pTau 217 and memory.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.07.26364896},
pmid = {42926960},
abstract = {INTRODUCTION: The locus coeruleus (LC) is one of the earliest sites of Alzheimer's disease (AD) pathophysiological changes. LC magnetic resonance imaging (MRI) intensity may reflect effects of AD pathophysiology on the LC, providing a biomarker of early-stage AD. This study examined relationships among MRI-derived LC intensity, plasma phosphorylated tau 217 (pTau 217), and memory in older adults without dementia.

METHODS: Independently living adults aged 59-89 years (N = 163) underwent neuropsychological assessment and T1-weighted fast spin-echo MRI. We quantified a bilateral LC contrast ratio relative to a pontine reference region, averaged across axial slices. Plasma pTau 217 was measured using the Quanterix ALZpath p-Tau217 Advantage PLUS assay. For a subset (n = 127), a memory composite score was calculated.

RESULTS: After adjustment for age, sex, and APOE ɛ4 status, lower LC intensity was associated with higher plasma pTau 217 concentrations (β = -0.17, P = .02). Each 1- SD decrease in LC intensity was associated with 53% higher odds of pTau 217 positivity (P = .03). In models additionally adjusted for education, a significant LC × pTau 217 interaction for memory (β = -0.18, P = .009) indicated that lower LC intensity was associated with worse memory at low (P = .01), but not high (P = .64) pTau 217 levels.

DISCUSSION: These findings support MRI-derived LC intensity as a marker of early AD-related processes and suggest that LC intensity may provide complementary information not captured by plasma pTau 217 alone. Longitudinal studies are warranted to determine how these relationships change across the early stages of AD.},
}

@article {pmid42926980,
year = {2026},
author = {Britt, KC and Harb, A and Bailey, B and Saffold, B and Luo, X and Brown, RT and Huang, B},
title = {Navigating Life After Dementia Diagnosis: Questions, Challenges, and Support Needs Among Dementia Dyads.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.07.26364992},
pmid = {42926980},
abstract = {BACKGROUND: Older adults living with mild cognitive impairment (MCI) or Alzheimer's disease and related dementias (AD/ADRD) and their care partners face substantial daily challenges that evolve with disease progression and extend far beyond the clinical setting, including symptom management, care coordination, healthcare navigation, and planning for future care needs. Understanding these challenges is essential for developing innovative solutions to provide ongoing and targeted support. In this study, we explored questions, challenges, and support needs dementia dyads experienced following diagnosis to inform the development of an artificial intelligence (AI)-based chatbot designed to provide ongoing support for dementia dyads.

METHODS: We recruited 11 community-dwelling dyads comprising persons living with MCI or mild AD/ADRD and their care partners, one additional care partner, and 12 dementia care experts from academic medical centers, clinics, and aging organizations in the U.S. We conducted semi-structured interviews and analyzed them using conventional content analysis.

RESULTS: Participants described interconnected questions, challenges, and support needs that evolved while navigating life with MCI or AD/ADRD. Questions centered around day-to-day care management, medical concerns, behavioral symptom management, diagnosis and prognosis, safety, and resources and services. Challenges included care partner overwhelm, limited dementia knowledge, condition-related uncertainty, healthcare system navigation difficulties, financial constraints, and technology-related barriers. Participants identified needs for ongoing education, personalized care planning, resource navigation, logistical support and follow-up, culturally responsive care, and social and emotional support.

CONCLUSIONS: Dementia dyads experience substantial informational, emotional, and practical support needs in the early stages of MCI and AD/ADRD. Findings suggest that post-diagnostic support should extend beyond information provision alone to provide ongoing, personalized, and practical guidance that helps dyads navigate changing needs, resources, and everyday dementia care. These findings are informing the development of an AI-based chatbot intended to complement existing dementia care by extending access to education, practical guidance, and resource navigation between clinical encounters.},
}

@article {pmid42927022,
year = {2026},
author = {Jin, Z and Xu, K and Qi, M and Zhu, Q and Yang, B and Ferrada, GA and Fu, JS and Scovronick, N and Chang, HH and Alonso, A and Steenland, K and Liu, Y},
title = {Carbonaceous Components Underlying Wildfire Smoke PM 2.5 -Associated Alzheimer's Disease and Related Dementias in Older US Adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.08.26364863},
pmid = {42927022},
abstract = {Wildfire smoke exposure is increasing across the U.S., but the long-term neurological effects of smoke-specific fine particulate matter (PM 2.5) and its carbonaceous components remain uncertain. Using Medicare data from 2002 through 2019, we examined incident Alzheimer's disease (AD) and Alzheimer's disease and related dementias (ADRD) among 39,678,630 fee-for-service Medicare beneficiaries followed from 2005 through 2019. We identified 3,501,414 incident AD cases over 258.5 million person-years and 8,377,416 incident ADRD cases over 248.6 million person-years. We linked the cohort with annual, high-resolution estimates of smoke and non-smoke PM 2.5 mass and carbonaceous components (elemental and organic carbon) and fitted stratified Cox proportional hazards models. Per 1 µg/m [3] increase, smoke PM 2.5 was associated with incident AD (hazard ratio [HR], 1.015, 95% confidence interval [CI], 1.005-1.026) and ADRD (1.029 [1.024-1.035]). Smoke carbonaceous fraction was also associated with AD (1.063 [1.042-1.085]) and ADRD (1.090 [1.077-1.103]). Within the ADRD endpoint, smoke-related associations exceeded their corresponding non-smoke associations on a per-unit-mass basis. Per interquartile range, associations were smaller for smoke PM 2.5 (AD, 1.005 [1.002-1.008]; ADRD, 1.009 [1.008-1.011]) than for non-smoke PM 2.5 (AD, 1.086 [1.079-1.094]; ADRD, 1.048 [1.043-1.053]). Associations varied across geographic, racial, socioeconomic, and clinical subgroups. Long-term wildfire smoke exposure, particularly its carbonaceous fraction, was associated with higher incidence of AD and ADRD among older U.S. adults. The associations correspond to 2,284 and 11,142 incident cases per year of AD and ADRD attributable to smoke PM 2.5 among older Medicare beneficiaries, with the carbonaceous fraction accounting for most of this burden. These findings support the use of source-resolved and composition-specific smoke metrics in dementia research and wildfire-smoke health-impact assessments.},
}

@article {pmid42927039,
year = {2026},
author = {Mouton, CP and Pappadis, M and Schlag, K and Westra, J and Kuo, YF and Raji, M and Wood, L and Temple, J},
title = {ELDER MISTREATMENT: A ROAD TO A NEW RISK ALGORITHM USING ICD-10 DATA.},
journal = {Transactions of the American Clinical and Climatological Association},
volume = {136},
number = {},
pages = {98-116},
pmid = {42927039},
issn = {0065-7778},
abstract = {Elder mistreatment (EM)-a growing public health problem in the United States-is associated with poor quality of life, accelerated disability, and premature death. EM remains underrecognized and underreported, with the diagnosis frequently being made at a late stage when the afflicted older adults have experienced prolonged suffering including emotional, physical, and financial abuse. One way to increase early EM recognition and timely management is through the development and implementation of predictive algorithms that can help alert clinicians to the need for additional screening. In earlier work, using International Classification of Diseases, Tenth Revision (ICD-10) diagnostics codes, we were able to develop a logistic regression approach to determine an EM predictive algorithm with an area under the curve (AUC) of 0.73, a sensitivity of 80%, and specificity of 47%. Subsequently, this model was applied to a vulnerable group of older adults-those with Alzheimer's disease and related dementias (ADRD). In this cohort, we found illiteracy to be the strongest predictor associated with EM. These EM predictive algorithms can be useful in the creation of electronic health record (EHR) reminders to prompt clinicians to suspect EM and implement appropriate follow-up care plans.},
}

@article {pmid42927045,
year = {2026},
author = {Wang, Y and Zhan, W and Wu, Z and Zhang, Y and Ma, Z and Ding, X},
title = {Updating deficits in subjective cognitive decline: A differential pattern of executive dysfunction across clinical stages.},
journal = {International journal of clinical and health psychology : IJCHP},
volume = {26},
number = {3},
pages = {100728},
doi = {10.1016/j.ijchp.2026.100728},
pmid = {42927045},
issn = {2174-0852},
abstract = {Identifying objective cognitive markers in the preclinical stage of Alzheimer's disease (AD), particularly in Subjective Cognitive Decline (SCD), is critical for early intervention. While executive function comprises three core components (inhibition, updating/switching), their impairment trajectory during the SCD-to-Mild Cognitive Impairment (MCI) progression remains unclear. This study aims to systematically compare these components among Cognitively Normal (NC), SCD, and MCI individuals to determine the earliest sensitive cognitive indicators of AD pathology. Community-dwelling adults aged ≥50 years were classified into NC, SCD, and MCI groups based on comprehensive screening (MoCA, SCD-Q, CDR, ADL). All participants completed standardized computerized tasks assessing inhibition (Oddball, Stop Signal Task), updating (spatial 1-back, VWM task), and switching (task-cue paradigm). One-way ANOVA with post-hoc tests compared group differences in accuracy and reaction time. SCD showed no difference from NC in inhibition but intermediate switch costs; crucially, SCD's spatial 1-back performance was significantly worse than NC and comparable to MCI, indicating early MCI-level updating deficits. Visuospatial storage capacity showed gradual impairment. Updating ability (visuospatial working memory) is the earliest and stably impaired indicator in SCD, serving as a sensitive marker for ultra-early AD screening. These findings suggest that updating ability, particularly visuospatial working memory, is the earliest and most stable impaired executive component, making it a sensitive behavioral marker for identifying high-risk SCD and enabling ultra-early AD screening. In contrast, significant impairments in inhibition and switching are delayed or progressive. This provides new scientific evidence for early assessment and targeted cognitive intervention.},
}

@article {pmid42927060,
year = {2026},
author = {Tanwar, S and Bhatt, LK},
title = {Flavokawain A: a multi-targeted kava chalcone with diverse therapeutic potential.},
journal = {3 Biotech},
volume = {16},
number = {11},
pages = {476},
doi = {10.1007/s13205-026-05100-7},
pmid = {42927060},
issn = {2190-572X},
abstract = {Piper methysticum G. Forst., commonly known as Kava, is a culturally significant shrub native to the Pacific islands, including Fiji, Vanuatu, and Tonga. Flavokawain A is one of the primary non-kavalactone constituents found within its rhizomes. This review aims to provide a comprehensive and critical evaluation of the current state of research on Flavokawain A. Specifically, it aims to elucidate the diverse molecular mechanisms and signaling networks that drive its pharmacological effects, while assessing its viability as a multi-targeted therapeutic candidate for diverse diseases. Flavokawain A exhibits profound therapeutic potential across a spectrum of pathological conditions, including malignancy, chronic inflammation, myocardial infarction, and neurodegenerative disorders such as Alzheimer's disease. Evidence from in silico, in vitro and in vivo models suggests that Flavokawain A's efficacy is rooted in its ability to modulate key signaling hubs, notably the TGF-β1, NF-κB, PI3K/AKT, and Nrf2 pathways, as well as regulatory proteins like PRMT5, CDK2, and SKP2. These multi-target interactions underpin Flavokawain A's potent antioxidant, anti-apoptotic, and anti-inflammatory properties, positioning it as a promising candidate for multifactorial disease management. FKA represents a versatile, multi-targeted potential therapeutic scaffold with a robust pharmacological profile. Its demonstrated anti-fibrotic, anti-inflammatory, and anti-proliferative activities across diverse disease models underscore its clinical potential. However, bridging the gap from bench to bedside requires rigorous translational studies and clinical trials to validate its safety, bioavailability, and therapeutic efficacy in human populations.},
}

@article {pmid42919989,
year = {2026},
author = {Rossini, E and Garibaldi, M and Hanna, MG and Pitceathly, RDS and Pizzamiglio, C},
title = {Mitochondrial dysfunction in neurology: biomarkers and clinical implications.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42919989},
issn = {1759-4766},
abstract = {Mitochondrial dysfunction is increasingly recognized as a shared downstream pathogenic mechanism across a wide spectrum of neurological disorders, ranging from primary mitochondrial diseases to conditions including amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, multiple sclerosis, hereditary ataxias and idiopathic inflammatory myopathies. This Review examines the role of mitochondrial biomarkers in improving diagnostic accuracy, patient stratification and monitoring of disease progression and therapeutic response. Primary mitochondrial diseases are presented as proof-of-concept models of impaired oxidative phosphorylation, providing a framework for biomarker identification and validation with translational relevance to other neurological diseases. Mitochondrial biomarkers can be broadly categorized into four domains: fluid biomarkers, reflecting metabolic alterations and stress signalling; genetic biomarkers, capturing mitochondrial DNA integrity and dynamics; multi-omics approaches, integrating transcriptomic, proteomic and metabolomic signatures; and imaging biomarkers, enabling in vivo assessment of structural and functional consequences of mitochondrial dysfunction. Across disorders, these biomarkers reveal shared disturbances in bioenergetics, redox homeostasis, mitochondrial genome maintenance and inflammatory signalling. However, clinical implementation remains limited by methodological heterogeneity, biological variability and reduced disease specificity. Integrated, multimodal biomarker strategies, combined with longitudinal validation, will be essential for supporting precision medicine and guiding the development of therapies to target mitochondrial pathways in neurology.},
}

@article {pmid42920192,
year = {2026},
author = {Ralph, LT and Salter, EW and Tidball, P and Park, B and Choi, SL and Zhang, L and Tian, M and Kadia, A and Jin, F and Bradley, CA and Fraser, PE and Schmitt-Ulms, G and Gertsenstein, M and Nutter, LMJ and Georgiou, J and Collingridge, GL},
title = {Antithetical roles of tau in hippocampal long-term synaptic depression in rats versus mice.},
journal = {Molecular brain},
volume = {19},
number = {1},
pages = {},
pmid = {42920192},
issn = {1756-6606},
support = {PJT 173497//CIHR Project Grant/ ; #154276//CIHR (Canadian Institutes of Health Research) Foundation Grant/ ; },
mesh = {Animals ; *tau Proteins/metabolism/deficiency ; *Hippocampus/metabolism/physiology ; *Long-Term Synaptic Depression/physiology ; Mice, Knockout ; Schaffer Collaterals ; Male ; Mice, Inbred C57BL ; Rats ; Synapses/metabolism ; Mice ; },
abstract = {Synaptic dysfunction is a primary feature of tauopathies, a group of major neurodegenerative diseases that includes Alzheimer's disease. However, the normal synaptic functions of tau are poorly understood. Since rats provide advantages over mice for understanding human tau, such as expressing six tau isoforms and showing more robust signs of tau pathology, as well as offering a richer behavioural repertoire, we developed a tau knockout (Mapt KO) rat line. We primarily investigated the impact of tau elimination on long-term synaptic depression (LTD)-a form of synaptic weakening that tau mediates in mice. Low-frequency stimulation of hippocampal Schaffer collateral-CA1 synapses revealed a robust enhancement of LTD in Mapt KO rats relative to WT littermates. In contrast, in interleaved experiments, Mapt KO mice exhibited reduced LTD compared to WT littermates, in line with previous reports. Together, our findings demonstrate a species-dependent role for endogenous tau in regulating hippocampal LTD, promoting it in mice yet constraining it in rats. Therefore, the functions of tau are not necessarily conserved in rodents, underscoring the importance of animal model choice.},
}

Animals
*tau Proteins/metabolism/deficiency
*Hippocampus/metabolism/physiology
*Long-Term Synaptic Depression/physiology
Mice, Knockout
Schaffer Collaterals
Male
Mice, Inbred C57BL
Rats
Synapses/metabolism
Mice

@article {pmid42920245,
year = {2026},
author = {Ekanayake, A and Hwang, S and Peiris, S and Elyan, R and Mustafa, G and Tulchinsky, M and Wang, J and Eslinger, P and Yang, Q and Karunanayaka, P},
title = {An exploratory synthetic MRI-derived FLAIR-DIR contrast in olfactory-limbic regions in mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498397},
doi = {10.1177/13872877261498397},
pmid = {42920245},
issn = {1875-8908},
abstract = {BackgroundOdor identification impairment is an early feature of Alzheimer's disease and predicts memory decline, but its microstructural basis remains unclear.ObjectiveTo evaluate FD, a semi-quantitative synthetic magnetic resonance imaging (MRI)-derived Fluid-Attenuated Inversion Recovery (FLAIR)-Double Inversion Recovery (DIR) contrast, against myelin volume fraction (MVF) in olfactory-limbic brain regions of patients diagnosed with mild cognitive impairment (MCI).MethodsSixteen healthy controls (HC) and 17 individuals diagnosed with MCI completed olfactory and cognitive testing and underwent 3T MRI using a QALAS sequence. MVF maps were generated and FD was computed as (FLAIR - DIR)/FLAIR. Group differences were examined in olfactory-limbic gray matter and associated white-matter tracts, and voxel-wise regression assessed FD-odor identification associations, including models adjusted for voxel-wise MVF. Region of interest and voxel-wise analyses were exploratory and largely uncorrected for multiple comparisons.ResultsCompared with HC, MCI showed lower FD across olfactory-limbic gray matter and white-matter pathways, including hippocampus, amygdala, orbitofrontal cortex, thalamus and corpus callosum, whereas MVF differences were more limited. Better odor identification was associated with higher FD in hippocampal/parahippocampal regions and insula, persisting after MVF adjustment. MVF showed positive associations in the right parahippocampal gyrus, left thalamus and genu of the corpus callosum. In an exploratory secondary analysis reported in the Supplemental Material, FD-based classification exceeded chance but was not separable from age alone.ConclusionsFD is a semi-quantitative relaxation-contrast metric showing regional patterns partially distinct from MVF. These exploratory findings require replication in larger, demographically matched, biomarker-confirmed cohorts before FD can be regarded as a marker of early olfactory-limbic microstructural change in MCI.},
}

@article {pmid42920246,
year = {2026},
author = {Duboisdindien, G and Durieux, N and Kieu, M and Cattini, J},
title = {Discourse-based assessment in clinical context for persons with Alzheimer's disease: A scoping review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497928},
doi = {10.1177/13872877261497928},
pmid = {42920246},
issn = {1875-8908},
abstract = {BackgroundDiscourse assessment captures communicative abilities integrating linguistic, cognitive, and pragmatic processes and is widely used to characterize communication changes in Alzheimer's disease (AD).ObjectiveTo identify and map clinically applicable methods and linguistic measures for assessing discourse changes in persons with AD.MethodsThis scoping review followed JBI methodology and PRISMA-ScR guidelines. Observational studies assessing spoken discourse in persons with AD compared with normocognitive controls were identified through systematic searches of MEDLINE, PsycINFO, Linguistics and Language Behavior Abstracts, and Scopus. Studies based exclusively on automated language-processing approaches were excluded to maintain a focus on clinically applicable assessment. English or French-language studies were included. To assess inter-rater reliability, data from 17/76 studies (22.4%) in the broader review were independently extracted by two reviewers, with high agreement; remaining studies were extracted by one reviewer, with uncertainties resolved collectively. Extracted data included elicitation tasks, coding procedures, linguistic domains, and outcome measures and were summarized descriptively.ResultsFifty-nine papers were included. Picture description predominated, followed by conversational and narrative formats. Across papers, 291 distinct linguistic measures were identified. Discourse/pragmatic measures constituted the largest domain and had the greatest number of reported statistically significant findings. Fluency measures were also frequently associated with statistically significant differences, whereas morphosyntactic measures showed fewer such findings.ConclusionsSubstantial variability in elicitation procedures, operational definitions, and linguistic measures limits cross-study comparability. Methodological harmonization and further evaluation of the psychometric and clinical properties of discourse measures are needed to support evidence-based clinical assessment.},
}

@article {pmid42920248,
year = {2026},
author = {Duboisdindien, G and Durieux, N and Kieu, M and Cattini, J},
title = {Discourse-based assessment in clinical context for persons with mild cognitive impairment: A scoping review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261499243},
doi = {10.1177/13872877261499243},
pmid = {42920248},
issn = {1875-8908},
abstract = {BackgroundDiscourse assessment may capture subtle communication changes in persons with mild cognitive impairment (MCI) that are not readily detected by standardized test batteries.ObjectiveTo identify and map clinically applicable methods and linguistic measures for assessing discourse changes in persons with MCI.MethodsThis scoping review followed JBI methodology and PRISMA-ScR reporting guidance. Observational studies assessed spoken discourse in persons with MCI, including comparisons with normocognitive controls or persons with Alzheimer's disease (AD). Studies published in English or French were identified through systematic searches of MEDLINE, PsycINFO, Linguistics and Language Behavior Abstracts, and Scopus, updated in January 2025. Studies based exclusively on automated language-processing approaches were excluded. Data from 17 of the 76 studies in the broader review program (22.4%) underwent independent double extraction, with high inter-rater agreement. Data from the remaining studies were extracted by one reviewer, with uncertainties resolved collectively. Findings were summarized descriptively.ResultsSeventeen studies were included. Narrative and descriptive tasks predominated. Across studies, 119 distinct linguistic measures were identified across six domains. Only implausible or irrelevant details showed statistically significant MCI-control differences consistently across independent studies. No measure showed this pattern for MCI-AD comparisons. Most other measures were reported in single studies or yielded inconsistent findings across tasks and samples.ConclusionsHeterogeneity in elicitation procedures, operational definitions, and linguistic measures limits comparability across studies. Methodological harmonization and further evaluation of psychometric properties and clinical feasibility are needed to support evidence-based discourse assessment by speech-language pathologists.},
}

@article {pmid42920249,
year = {2026},
author = {Elmaleh, D and Gupta, A and Brazier, D and Garofano, W and Conti, PS},
title = {A phase III trial of ALZT-OP1 (cromolyn + ibuprofen) in early Alzheimer's disease: Primary results and exploratory analyses by APOE4 genotype.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498247},
doi = {10.1177/13872877261498247},
pmid = {42920249},
issn = {1875-8908},
abstract = {BackgroundThis study tested ALZT-OP1 (inhaled cromolyn 17.1 mg and oral ibuprofen 10 mg) in early Alzheimer's disease (AD).ObjectiveTo evaluate the efficacy and safety of ALZT-OP1 in early AD.MethodsCognite was a Phase III, double-blind, placebo-controlled, four-arm factorial trial in 619 participants with early AD (cerebrospinal fluid [CSF] amyloid-β42 (Aβ42) 180-690 pg/mL; Clinical Dementia Rating-Global 0.5). Randomization was 1:1:1:1 to cromolyn, ibuprofen, combination therapy, or placebo for 72 weeks. The primary endpoint was change from baseline to Week 72 in Clinical Dementia Rating-Sum of Boxes (CDR-SB), comparing combination versus each monotherapy. Secondary and exploratory endpoints included comparisons with placebo, subgroup analyses by apolipoprotein E4 (APOE4) status, Mini-Mental State Examination scores, CSF biomarkers, and safety.ResultsIn the modified intent-to-treat population (n = 594), the primary endpoint was not met. No statistically significant difference was found between combination and cromolyn (difference 0.16, 95% CI -0.58 to 0.90; p = 0.675) or ibuprofen (0.40, 95% CI -0.32 to 1.13; p = 0.276). APOE4 non-carriers receiving combination therapy showed a numerical benefit versus placebo (least-squares mean difference -0.96; 95% CI -2.00 to 0.08; p = 0.069), although this was not statistically significant. ALZT-OP1 was safe and well tolerated.ConclusionsALZT-OP1 did not demonstrate efficacy in an unselected early AD population. The numerical benefit observed in APOE4 non-carriers warrants prospective evaluation in a genotype-stratified trial. ALZT-OP1 was safe and well tolerated over 72 weeks, and the study provides insights for future AD trial design.The study is registered at ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT02547818; NCT02547818).},
}

@article {pmid42920252,
year = {2026},
author = {Tian, D and Shi, T and Xu, S and Lan, J and Zhao, M and Wu, H and Yang, J and Wang, Z and Wang, J},
title = {A putative iron-related evolving framework in Alzheimer's disease: From iron dyshomeostasis and ferro-aging to ferroptosis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261501439},
doi = {10.1177/13872877261501439},
pmid = {42920252},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) ranks as a prototypical age-related neurodegenerative disorder. Emerging evidence indicates that disrupted brain iron metabolism and ferroptosis act as critical upstream drivers of AD pathological progression. AD exhibits core hallmarks of ferroptosis, including iron overload, lipid peroxidation, elevated reactive oxygen species, and impaired antioxidant enzyme activity. These abnormalities interact synergistically with amyloid-β plaques and tau pathology. Iron accumulation during aging and damage-associated molecular patterns released concomitantly with ferroptosis drive susceptible microglia toward M1-like polarization, propagate chronic neuroinflammation, and fuel the vicious cycle of AD pathology. Targeting ferroptotic pathways represents a promising strategy to alleviate cognitive impairment in AD. Ferro-aging ranks as a recently identified form of programmed cellular senescence marked by iron dependency, ACSL4 regulation, and lipid peroxidation-driven damage. Although ferro-aging has only been preliminarily validated in aging models, its molecular signatures, regulatory axes, and phenotypic outcomes align remarkably well with the progression of brain aging and AD. It thus emerges as a potentially pivotal hub linking physiological aging to iron-associated pathology in AD. We systematically summarize the physiological regulation of brain iron homeostasis and core ferroptotic pathways disrupted in AD. We further integrate current evidence to explore how ferro-aging may contribute to AD pathogenesis, proposing a mechanistic framework in which: iron dyshomeostasis initiates damage, ferro-aging drives chronic progression, and ferroptosis mediates acute injury. Finally, we review intervention strategies targeting iron-related pathology, providing theoretical insights for understanding the aging-dependent nature of AD and developing novel therapeutic approaches.},
}

@article {pmid42920257,
year = {2026},
author = {Chuang, TC and Liang, CK and Chou, MY and Chan, YH and Wang, HP and Wang, YC and Hsu, YH and Lin, YT},
title = {Changes in gray matter volume associated with gait speed and muscle mass in older adults with mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500490},
doi = {10.1177/13872877261500490},
pmid = {42920257},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI) is an early stage of cognitive decline between normal aging and dementia. Gait speed, a key marker of physical function, has been associated with both cognitive decline and brain atrophy. Sarcopenia, characterized by age-related loss of muscle mass and function, has also been linked to structural brain changes.ObjectiveTo investigate the associations between sarcopenia, its individual components and regional gray matter volume (GMV) in older adults with MCI.MethodsThis cross-sectional study included 234 older adults with MCI. Sarcopenia, gait speed, handgrip strength, and appendicular skeletal muscle mass index (ASMI) were assessed according to the 2019 Asian Working Group for Sarcopenia criteria. Brain T1-weighted magnetic resonance imaging was analyzed using voxel-based morphometry. Voxel-wise group comparisons were performed to identify GMV differences after adjustment age, sex, comorbidity, depressive symptoms, nutritional status, and total intracranial volume.ResultsSlower gait speed was significantly associated with lower GMV in the bilateral putamen and left superior frontal cortex. Lower ASMI was associated with higher GMV in the left inferior temporal cortex. No significant GMV differences were found by sarcopenia status or handgrip strength.ConclusionsSlower gait speed is associated with reduced GMV in motor-related brain regions, indicating early brain structural changes in older adults with MCI. Although lower ASMI was associated with higher GMV, this finding should be interpreted cautiously. These findings highlight the complex interactions between physical function and brain structure, emphasizing gait speed as a potential indicator of brain health in older adults with MCI.},
}

@article {pmid42920259,
year = {2026},
author = {Tian, H and Zhang, J and Zuo, H and Liu, Y and Kim, ID and Gui, Y},
title = {Cerebrospinal fluid cell-free DNA methylation captures disease-specific biology in tauopathies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500498},
doi = {10.1177/13872877261500498},
pmid = {42920259},
issn = {1875-8908},
abstract = {BackgroundDifferentiating tau-related dementias remains challenging, particularly during early disease stages when clinical symptoms overlap. Existing biomarkers mainly reflect downstream pathology and provide limited insight into disease-specific molecular processes.ObjectiveWe examined whether cerebrospinal fluid (CSF)-derived cell-free DNA (cfDNA) methylation could distinguish Alzheimer's disease (AD), behavioral variant frontotemporal dementia (bvFTD), and progressive supranuclear palsy (PSP).MethodsPromoter methylation of 20 genes associated with AD risk, neuroinflammation, cellular senescence, and glymphatic or lymphatic regulation was analyzed in CSF and matched plasma cfDNA from controls (n = 15), AD (n = 21), bvFTD (n = 14), and PSP (n = 17). cfDNA concentration and fragmentomic profiles were assessed. Diagnostic performance was evaluated using logistic regression and receiver operating characteristic (ROC) analysis. Findings were validated in an independent cohort.ResultsCSF cfDNA concentrations were increased in AD, whereas fragment size distributions were similar across diagnostic groups. Disease-associated methylation signatures were prominent in CSF but weak or absent in plasma. AD demonstrated widespread hypomethylation of inflammatory and senescence-associated genes together with hypermethylation of glymphatic and lymphatic regulators. bvFTD showed intermediate glial- and stress-related methylation changes, while PSP retained relatively preserved inflammatory and clearance-associated profiles. CSF methylation panels consistently outperformed plasma-derived markers for disease classification. ROC analyses demonstrated strong discrimination for AD, with AUC values reaching 0.84-0.85, while plasma-based markers showed limited diagnostic utility.ConclusionsCSF cfDNA methylation captures disease-specific epigenetic states linked to core pathogenic pathways in tau-related dementias. This approach may provide a biologically informative and clinically useful platform for molecular classification and diagnostic stratification.},
}

@article {pmid42920264,
year = {2026},
author = {Passmore, SR and Gooding, DC and Medina, MN and Ocoko, F and Bouges, S and Randolph, M and Smith, T and Carter, FP and Zuelsdorff, M and Nirschl, J and Gleason, CE},
title = {Decision-making in biospecimen and biomarker research among African American participants: Procedure-specific perspectives including on the uniqueness of brain donation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500123},
doi = {10.1177/13872877261500123},
pmid = {42920264},
issn = {1875-8908},
abstract = {BackgroundAfrican Americans are disproportionately affected by Alzheimer's disease (AD) but remain significantly underrepresented in research. While previous studies often assess these barriers to such research engagement using hypothetical scenarios, there is a need to focus on in vivo decision-making processesObjectiveTo identify the specific facilitators and barriers influencing African American participants' decisions to engage in or decline four types of biospecimen data collection: biomarker collection via MRI, PET, or lumbar puncture (LP), and brain donation.MethodsSemi-structured interviews were conducted with 41 participants (68.2% female; age range 58-84; average 68) recruited from the African Americans Fighting Alzheimer's in Midlife Study who had made the decision for or against these four types of research. A descriptive content analysis identified specific factors that influenced decision-making.ResultsAcceptability levels varied by procedure: MRI (80.5%) and PET scans (63.4%) were the most accepted, whereas LP (36.6%) and brain donation (34.1%) were the least. Common motivations included personal family experience with AD and a desire to benefit the African American community. Barriers for LP and MRI included perceived physical risk and claustrophobia, respectively. Brain donation emerged as a unique, family-centered decision rather than an individual one. A high percentage of participants (34%) remained undecided about brain donation due to concerns about family burden during end-of-life transitions and a lack of procedural information.ConclusionsThis examination of real-life research decisions confirmed prior findings and highlighted opportunities to improve outreach to African American community members, particularly regarding brain donation, which may require unique approaches.},
}

@article {pmid42920267,
year = {2026},
author = {Case, K and Halliwell, C and Clay, T and Ding, Y and Colon, K and Callen, E},
title = {A scoping literature review: Identifying the comorbidities of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500119},
doi = {10.1177/13872877261500119},
pmid = {42920267},
issn = {1875-8908},
abstract = {BackgroundThere are many co-occurring conditions of Alzheimer's disease (AD).ObjectiveThis scoping literature review aims to identify the comorbidities of AD found in the literature.MethodsWe conducted an extensive scoping search using PubMed for January 1, 2015 to June 10, 2025, yielding 461 articles. 39 articles met inclusion criteria. Descriptive statistics were completed on the extracted information.ResultsThe conditions identified encompass the body's major organ systems, with diabetes and hypertension appearing the most.ConclusionsThis scoping review highlights the large number of comorbidities associated with AD.},
}

@article {pmid42920272,
year = {2026},
author = {Minucchi, E and Di Gerlando, R and Dragoni, F and Imbimbo, C and Zardini, E and Cotta Ramusino, M and Costa, A and Gagliardi, S},
title = {pTau217 immunoassays in Alzheimer's disease continuum: A comparative study of Ella and Lumipulse.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500491},
doi = {10.1177/13872877261500491},
pmid = {42920272},
issn = {1875-8908},
abstract = {BackgroundPlasma phosphorylated tau 217 (pTau217) has emerged as one of the most accurate biomarkers for Alzheimer's disease (AD). However, direct comparisons of pTau217 levels between different automated immunoassays remain limited.ObjectiveIn this context, our work aimed to compare Lumipulse and Ella platforms for the measurement of plasma pTau217 across the AD continuum.MethodsBlood samples were collected from 32 subjective cognitive decline (SCD), 25 mild cognitive impairment (MCI), and 10 Alzheimer's disease (AD) patients. Plasma pTau217 levels were assessed using Lumipulse G600II automated system and Ella immunoassay SR-X platform. Associations with clinical variables and agreement between platforms were assessed.ResultsPlasma pTau217 levels increased from SCD to AD with both assays. Lumipulse showed a significant difference between SCD and AD (p = 0.0011), while Ella detected differences between SCD and MCI (p = 0.0198) and SCD and AD (p = 0.0001). Both assays showed a significant inverse correlation with Mini-Mental State Examination (Lumipulse: r = -0.4913; p = 0.0001. Ella: Pearson r = -0.5139; p = 0.0001). A moderate correlation between platforms was observed. Bland-Altman analysis revealed a negative bias, with Lumipulse yielding lower values than Ella and increasing variability at higher concentrations.ConclusionsLumipulse and Ella provided consistent qualitative information on plasma pTau217 across the AD continuum and show similar associations with cognitive performance, meaning that they are both comparable techniques. However, systematic bias and proportional variability limit their quantitative interchangeability, highlighting the need for cross-platform standardization.},
}

@article {pmid42920275,
year = {2026},
author = {Liu, B and Wu, J and Liu, J and Mo, Y and Lin, G and Zhang, Y and Wei, C and Tao, R},
title = {A five-gene mitochondrial-lipid metabolism signature for Alzheimer's disease diagnosis identified by machine learning and validated in independent cohorts.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500762},
doi = {10.1177/13872877261500762},
pmid = {42920275},
issn = {1875-8908},
abstract = {BackgroundMitochondrial dysfunction and lipid metabolism dysregulation represent early key events in Alzheimer's disease (AD), yet integrated transcriptomic signatures combining these two biological processes for AD diagnosis remain poorly defined.ObjectiveThis study aimed to construct and validate a mitochondrial-lipid metabolism (MLM) gene-based diagnostic classifier for AD using machine-learning approaches and explore its underlying biological mechanisms.MethodsTwo public GEO datasets GSE5281 (training) and GSE28146 (independent validation) were included. Candidate MLM genes were retrieved from MSigDB. Differentially expressed MLM genes were screened by limma, followed by two-step feature selection with LASSO regression and random forest. Four machine-learning algorithms were compared. Model performance was evaluated by AUC, calibration, decision-curve analysis and subgroup analysis across AD severity. GSVA and hypergeometric test were applied for mechanistic exploration.ResultsA five-gene signature (SDR16C5, EGR1, ASAH2B, HIP1R, CKMT1B) was finally identified. Logistic regression model achieved 5-fold cross-validated AUC of 0.953 in training cohort and AUC = 0.892 (95%CI:0.768-1.000) in validation cohort. The signature maintained high diagnostic accuracy across incipient, moderate and severe AD stages. Hypergeometric test demonstrated significant MLM-set enrichment (p = 3.85 × 10[-5]). GSVA revealed close correlations between this signature with oxidative stress, synaptic dysfunction and apoptosis pathways.ConclusionsThis validated five-gene MLM signature exhibits favorable diagnostic performance for AD and reflects disturbed mitochondrial-lipid metabolic network. It provides a promising transcriptomic biomarker for AD diagnosis.},
}

@article {pmid42920282,
year = {2026},
author = {Mowafi, S and Nassar, L and Ezzeldin, S and Salama, M and Chun, S},
title = {The uncinate fasciculus in frontotemporal dementia subtypes: A systematic review and meta-analysis of diffusion-tensor imaging studies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500138},
doi = {10.1177/13872877261500138},
pmid = {42920282},
issn = {1875-8908},
abstract = {BackgroundFrontotemporal dementia (FTD) is a leading cause of early-onset neurodegeneration with selective frontal and temporal lobe degeneration. Despite well-characterized gray and white matter atrophy patterns across FTD subtypes, the extent of degeneration of the uncinate fasciculus (UF) tract has not been systematically quantified across FTD subtypes.ObjectiveTo compare uncinate fasciculus fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity between frontotemporal dementia subtypes and healthy controls.MethodsWe systematically searched PubMed, Scopus, and Web of Science and performed a random-effects meta-analysis of diffusion tensor imaging studies published between 2011 and October 2025 according to PRISMA 2020 guidelines.ResultsWe systematically reviewed 11 studies and performed a meta-analysis of 540 participants across 10 studies. We found that all FTD subtypes demonstrated significant degeneration of the UF compared to controls. The greatest effect sizes were observed when comparing the left UF between the semantic variant primary progressive aphasia (svPPA) and controls (FA: SMD = -2.5396, 95% CI: -3.7914, -1.2878, p < 0.0001; RD: SMD = 2.2414, 95% CI:1.7972, 2.6855, p < 0.0001; AD: SMD = 1.9831, 95% CI: 1.1434, 2.8227, p < 0.0001; MD: SMD = 2.5268, 95% CI: 1.9993, 3.0542, p < 0.0001), while the behavioral variant (bvFTD) showed the largest reduction in right UF fractional anisotropy. Within-group analyses revealed significant left-right asymmetry in svPPA and non-fluent aphasia (nfvPPA), with greater left UF involvement, while bvFTD and controls showed no hemispheric differences.ConclusionsWe highlight the UF as a promising tract for understanding disease mechanisms and developing imaging biomarkers in FTD.},
}

@article {pmid42920665,
year = {2026},
author = {Liu, Z and Yu, Y and Wang, Y and Ning, S and Huang, T and Li, J and Fan, S and Lu, C},
title = {TSC1-mTORC1 signaling in Alzheimer's disease: an integrated bioinformatic analysis linking gene expression to neuropathology.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1920487},
pmid = {42920665},
issn = {1663-4365},
abstract = {BACKGROUND AND OBJECTIVE: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques and tau pathology, with mTORC1 hyperactivation implicated in disease pathogenesis via suppression of autophagy. However, systematic evidence regarding its key upstream repressor, TSC1, in human AD brains remains limited.

METHODS: Using an integrated, multi-level bioinformatic approach combining RNA-seq, neuropathological, and clinical data from the ROSMAP cohort, we comprehensively investigated the TSC1-mTORC1 axis in AD. Gene co-expression network analysis and gene set enrichment analysis were applied to contextualize TSC1 within disease-associated molecular networks.

RESULTS: Our analysis revealed significant TSC1 downregulation and concomitant mTOR and RPTOR upregulation in AD brains. Critically, lower TSC1 expression was strongly correlated with higher Aβ plaque density, greater tau tangle burden, worse global cognitive performance, and an exacerbated neuroinflammatory microenvironment characterized by increased microglial and astrocytic activation. Gene co-expression network analysis positioned TSC1 within a disease-associated module showing the strongest association with AD pathology. Gene set enrichment analyses further demonstrated that the TSC1 low-expression phenotype was associated not only with suppression of autophagy-related pathways but also with significant enrichment of broad pro-inflammatory and immune response pathways.

CONCLUSION AND DISCUSSION: These integrated human data provide compelling evidence that TSC1 deficiency is a hallmark of AD and is associated with mTORC1 hyperactivation, aggravated amyloid-tau pathologies, cognitive impairment, and neuroinflammation. These findings are consistent with a model in which TSC1 deficiency and mTORC1 hyperactivation may contribute to AD pathophysiology, thereby nominating the TSC1-mTORC1 axis and its associated inflammatory networks as promising multi-faceted therapeutic targets. Future replication in independent cohorts is warranted to assess the generalizability of these findings.},
}

@article {pmid42920686,
year = {2026},
author = {Gupta, S and Gupta, R},
title = {A SynNotch-PiggyBac gene circuit for inflammation-responsive IL-10 delivery in Alzheimer's disease: a hypothesis and design framework.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1866161},
pmid = {42920686},
issn = {1663-4365},
abstract = {Chronic neuroinflammation driven by sustained microglial and astrocyte activation contributes to Alzheimer's disease progression, yet no therapeutic strategy addresses it with precision or durability in the brain. Interleukin-10 occupies an unresolved position in this problem. Constitutive interleukin-10 overexpression in amyloid precursor protein transgenic mice increased plaque burden by suppressing microglial phagocytic activity, while interleukin-10 deletion has been reported to restrict amyloidosis in one setting and to worsen tau hyperphosphorylation in another. We interpret this pattern as evidence that interleukin-10 carries opposite signs on the two principal pathologies of Alzheimer's disease, so that any therapy holding it at a fixed concentration is committed in advance to being wrong about one of them. We therefore propose a falsifiable hypothesis: conditional, inflammation-gated interleukin-10 expression may suppress damaging inflammatory signaling while limiting the impairment of microglial phagocytosis associated with continuous exposure. We present a design framework for a synthetic gene circuit combining an adeno-associated viral vector for delivery to the central nervous system, a synthetic Notch receptor that detects membrane-bound tumor necrosis factor alpha on activated microglia through juxtacrine contact, and a PiggyBac transposon intended to integrate the circuit into the astrocyte genome. Receptor engagement is expected to release a transcription factor that drives interleukin-10 from a synthetic promoter, with transcription ceasing as the stimulus is withdrawn. We provide a quantitative packaging analysis showing that the circuit requires a compacted vector design to fit within viral capacity, and we identify three unvalidated assumptions: the recognition domain does not yet exist, ligand surface density on activated microglia is unmeasured, and shed soluble tumor necrosis factor alpha is predicted to act as a competitive inhibitor of receptor activation. A computational analysis of simulated resting-state electroencephalography, in which 45 of 171 electrode pairs differed after false discovery rate correction, is presented as a fully specified analysis workflow for delta-band connectivity as a secondary outcome measure rather than as evidence of effect, and yields effect sizes indicating that a rodent study would need roughly 11 animals per group. A four-arm validation plan is specified that separates the contribution of conditional regulation from that of genomic integration.},
}

@article {pmid42920727,
year = {2026},
author = {Tabi, YA and Meyer, EC and Tabi, A and Rave, J and Philippen, S and Bartsch, T},
title = {Financial counselling gaps in Alzheimer's care: Patient out-of-pocket expenses and physician barriers in a regional German cross-sectional pilot study.},
journal = {Dialogues in health},
volume = {9},
number = {},
pages = {100364},
pmid = {42920727},
issn = {2772-6533},
abstract = {Alzheimer's disease (AD) is associated with substantial societal and household costs, but patient-level direct out-of-pocket expenses and perceived financial counselling needs in routine memory-clinic care remain insufficiently characterised. We conducted a regional exploratory mixed-methods cross-sectional pilot survey in Schleswig-Holstein, Germany, including 38 patients recruited from a single university memory clinic and 136 responding outpatient physicians (general practitioners and neurologists; 8.8% response rate). Patients reported direct out-of-pocket expenses, perceived financial impact, and information/counselling needs. Physicians reported counselling practices, perceived burden, and barriers, complemented by brief free-text responses analysed using inductive qualitative content analysis informed by Grounded Theory coding principles. In this patient sample, 34% reported increased out-of-pocket expenses, most commonly medication co-payments and transportation costs. Nearly 40% reported insufficient information about financial implications and 32% expressed a strong desire for more financial counselling. Bayesian Kendall analyses indicated that higher household income was associated with better perceived health (τ = 0.39, 95% CrI [0.13, 0.58], BF10 = 28.68) and perceived health with quality of life (τ = 0.80, 95% CrI [0.51, 0.90], BF10 = 5.62 × 10[8]). Longer time since symptom onset was associated with lower perceived health (τ = -0.33, 95% CrI [-0.52, -0.08], BF10 = 8.40) and quality of life (τ = -0.38, 95% CrI [-0.56, -0.13], BF10 = 25.64), whereas evidence for an association with total out-of-pocket expense category was inconclusive (τ = 0.20, 95% CrI [-0.04, 0.40], BF10 = 0.86). Among responding physicians, 64% reported rarely or never discussing financial aspects of AD care. Free-text responses described time constraints, limited training/resources, and uncertainty about professional role boundaries. Thus, modest direct out-of-pocket expenses in this local sample coexisted with substantial perceived information and counselling needs. Because of the single-clinic patient sample and low physician response rate, these findings are exploratory and should not be interpreted as representative of German AD care.},
}

@article {pmid42920885,
year = {2026},
author = {Romano, RR and Roby, D and Bhattacharyya, K and Joshi, A and Kaur, B and Wick, K and Gifford, A and Eaton, J and Ibarra-Scurr, D and Gifford, K},
title = {Implementation and outcomes of a statewide ECHO tele-mentoring program to enhance dementia care in primary care settings: The Tennessee Dementia ECHO Program.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70339},
pmid = {42920885},
issn = {2352-8737},
abstract = {BACKGROUND: Primary care clinicians play a leading role in dementia care but often report limited training and confidence, particularly in rural settings. Scalable strategies are needed to strengthen workforce capacity.

METHODS: We conducted a pre/post mixed-methods evaluation of the Tennessee Dementia Extension for Community Healthcare Outcomes (ECHO) program, a statewide tele-mentoring initiative. Implementation outcomes included reach, adoption, and satisfaction. Effectiveness outcomes included changes in clinician confidence, knowledge, and self-reported skills assessed via session-specific surveys. Analyses included descriptive changes and effect sizes.

RESULTS: A total of 641 learners registered, with 173 attending at least one session and 97 attending more than one session. Satisfaction was high (median 96/100). Matched session-specific confidence scores increased after participation. Knowledge outcomes varied across sessions and content domains, with selected item-level improvements observed.

DISCUSSION: A statewide ECHO model was feasible and well accepted and was associated with meaningful short-term improvements in clinician confidence. Knowledge findings were mixed and suggested possible learning in selected domains. These findings support tele-mentoring as a scalable approach to strengthening dementia care capacity.},
}

@article {pmid42921107,
year = {2026},
author = {Zhang, VZ and Ferreira, PCL and Dong, Y and Minhas, D and Povala, G and Bellaver, B and , and Pascoal, TA and Zeng, X and Karikari, TK and Cohen, AD and Deek, RA and Wu, Q and Tudorascu, DL},
title = {Evaluation of harmonization methods to mitigate assay and cohort effects in plasma p-tau217.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70518},
pmid = {42921107},
issn = {2352-8729},
abstract = {INTRODUCTION: The growing number of assay platforms measuring blood-based biomarkers (BBMs) for Alzheimer's disease (AD) has introduced challenges in interpretability and comparability across assays. Differences across studies also limit comparability of data. To address these challenges, a systematic evaluation of harmonization methods is needed to support BBM data integration within or across studies.

METHODS: Two multisite studies, Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 219) and Human Connectome Project (HCP, n = 111), were used to evaluate harmonization methods for mitigating assay and cohort effects in plasma phosphorylated tau 217 (p-tau217) measurements. Methods included various normalization, regression, and standardization approaches, including the recently developed CentiMarker. Assay effects were evaluated using repeated-measures data across assay platforms within each cohort, whereas cohort effects were assessed using pooled ADNI and HCP data. Harmonization performance was evaluated using distributional statistics and downstream modeling of p-tau217.

RESULTS: Quantile normalization and quantile mapping methods were most effective for mitigating assay effects, whereas conditional quantile mapping performed best for pooled multi-cohort data. These methods also preserved biological variability. In contrast, simple means adjustment and reference-based Z-score standardization were least effective for mitigating assay effects, whereas simple means adjustment, Z-score standardization, and quantile normalization were least effective for mitigating cohort effects. CentiMarker had minimal impact on assay or cohort effects.

DISCUSSION: Based on our evaluation, we recommend (conditional) quantile mapping for p-tau217 studies integrating data across multiple assays or cohorts. In contrast, we caution against using CentiMarker and Z-score-based methods, as they limit comparability and do not effectively mitigate technical variability.},
}

@article {pmid42921194,
year = {2026},
author = {Li, J and Wang, WJ and Chen, H and Sun, JQ and Zhong, WJ and Guan, CX and Zhou, Y},
title = {B-Cell-Related Neuroinflammation Across Central Nervous System Diseases: A Bibliometric and Science-Mapping Analysis, 2006-2026.},
journal = {Journal of inflammation research},
volume = {19},
number = {},
pages = {635719},
doi = {10.2147/JIR.S635719},
pmid = {42921194},
issn = {1178-7031},
abstract = {PURPOSE: Research on B cells in central nervous system (CNS) diseases rests on a mature multiple sclerosis (MS) literature, whereas evidence in CNS injury and neurodegeneration is still emerging. We mapped publications from 2006 to 2026 and separated bibliometric visibility from mechanistic maturity.

METHODS: We searched the Web of Science Core Collection (WoSCC) on August 17, 2026, for English-language records carrying the Article document-type tag and published from January 1, 2006, through August 17, 2026. Two reviewers independently screened all records, with unresolved disagreements adjudicated by a third reviewer. Publication trends, collaboration, co-citation, journal flows, citation bursts, and keyword evolution were analyzed using VOSviewer, CiteSpace, bibliometrix, R, and SCImago Graphica. Search materials, parameters, and source tables were archived.

RESULTS: After database-level limits, 2,701 records were screened; 467 (17.3%) were excluded and 2,234 (82.7%) included. The corpus had accrued 91,218 WoSCC citations. Annual output rose from 91 articles in 2016 to 231 in 2025; 173 articles from 2026 represent a partial year. The United States contributed the most articles, and the University of California, San Francisco ranked first after affiliation normalization. Co-citation and keyword analyses showed an MS/experimental autoimmune encephalomyelitis (EAE)-centered foundation built around B-cell depletion trials, meningeal pathology, diagnostic criteria, and regulatory B-cell biology. Recent bursts included anti-CD20 therapy, single-cell RNA sequencing, autoimmune encephalitis, ischemic stroke, Mendelian randomization, B-cell depletion, and Alzheimer disease.

CONCLUSION: B-cell-related CNS research has expanded, but evidence maturity remains disease-specific. MS/EAE provides the clearest foundation. Findings in CNS injury, neurodegeneration, and candidate peripheral-CNS routes remain context-dependent and require validation by disease, anatomical compartment, B-cell state, and stage. Bibliometric prominence reveals attention, not shared causality or therapeutic efficacy.},
}

@article {pmid42921247,
year = {2026},
author = {Chen, A and Bhuvaneshwaran, S and Akkara, Y and Burke, T and Perneczky, R and Sastre, M},
title = {Molecular mechanisms underpinning cognitive reserve and resilience.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1957901},
doi = {10.3389/fnagi.2026.1957901},
pmid = {42921247},
issn = {1663-4365},
abstract = {The concept of cognitive reserve (CR) and resilience originates from clinicopathological observations that amyloid-β deposition, tau pathology and neurodegeneration do not uniformly translate into clinical dementia, highlighting inter-individual differences in the brain's capacity to tolerate pathology. Although CR and resilience lack a single accepted definition, they broadly describe the ability to maintain cognition in the presence of age-related or pathological brain changes. This review synthesises current molecular, cellular, and brain network mechanisms of cognitive reserve and critically examines key controversies. We also identify convergent biological pathways across multiple levels of organisation. Available evidence implicates that CR is not attributable to a single factor but reflects interactions among environmental exposures, genetic background, epigenetic regulation, cellular homeostasis, glial function, and large-scale brain network organisation. Lifestyle factors are associated with reduced pathology accumulation, preserved brain structure, and maintenance of cognition despite pathology, depending on the mechanism and outcome considered and are understood to exert their effects through epigenetic modulation of neuroplasticity, neurotrophic signalling, metabolic regulation, and inflammatory pathways. At the cellular level, preservation of dendritic spine integrity, synaptic signalling balance, mitochondrial energetic flexibility, and adult hippocampal neurogenesis supports efficient circuit function under pathological stress. Glial cells play central roles in mediating adaptive plasticity, neuroinflammatory control, and metabolic support, with dysregulation accelerating cognitive decline. Collectively, these findings frame CR as an emergent property of coordinated biological processes operating across molecular, cellular, and network scales, with important implications for developing reserve-enhancing therapeutic and lifestyle-based interventions that complement traditional pathology-focused approaches.},
}

@article {pmid42921272,
year = {2026},
author = {He, Z and Zeng, J and Wang, G and Li, Y and Zhang, F},
title = {Neurodegenerative Diseases: Epidemiology, Risk Factors, Classification, Pathophysiology, Clinical Features, Diagnosis, and Therapeutic Strategies.},
journal = {MedComm},
volume = {7},
number = {11},
pages = {e71090},
doi = {10.1002/mco2.71090},
pmid = {42921272},
issn = {2688-2663},
abstract = {Neurodegenerative diseases are a growing cause of disability worldwide, particularly as populations age. Although these disorders differ in etiology and clinical presentation, advances in genetics, neuropathology, and biomarker research have identified shared disturbances in protein homeostasis, mitochondrial function, and immune regulation. These processes may contribute to selective neuronal vulnerability and neural circuit dysfunction. These findings are refining disease classification and diagnosis, yet effective disease-modifying therapies remain limited. Disease-specific abnormalities remain essential to clinical interpretation and treatment selection. Existing reviews often focus on individual disorders or isolated mechanisms, leaving the links between shared biology and disease-specific phenotypes insufficiently clear. We synthesize evidence on the epidemiology, risk factors, classification, and pathophysiology of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, frontotemporal dementia, Friedreich's ataxia, and multiple sclerosis. We compare their clinical manifestations and diagnostic approaches, including the evolving role of biomarkers, and critically assess established and emerging therapies. By distinguishing shared mechanisms from disease-specific abnormalities, we identify key translational gaps and explore how common biological disturbances may lead to distinct clinical trajectories. This cross-disease perspective may inform diagnostic reasoning, treatment development, and future comparative research.},
}

@article {pmid42921321,
year = {2026},
author = {Esakova, OE and Palmer, CD and Warui, DM and McCarthy, EL and Booker, SJ},
title = {Lipoyl Synthase in Focus: Radical SAM Chemistry and the Biosynthesis of Lipoic Acid.},
journal = {ACS bio & med chem Au},
volume = {6},
number = {5},
pages = {495-507},
doi = {10.1021/acsbiomedchemau.6c00104},
pmid = {42921321},
issn = {2694-2437},
abstract = {Lipoic acid (1,2-dithiolane-3-pentanoic acid or 6,8-thioctic acid) is a sulfur-containing cofactor essential for central metabolism, where it functions in oxidative decarboxylation reactions catalyzed by the 2-oxoacid dehydrogenase complexes and glycine degradation catalyzed by the glycine cleavage system. Beyond its canonical metabolic roles, the redox-active disulfide/dithiol pair of lipoic acid has attracted considerable interest because of its proposed therapeutic relevance in ailments associated with oxidative stress and inflammation, such as Alzheimer's and Parkinson's disease. Despite the broad biological importance of this cofactor, the molecular details of its biosynthesis remained elusive for many years because of the unusual chemistry required for sulfur insertion into unactivated carbon centers. Recent advances have subsequently expanded the understanding of this pathway, particularly through mechanistic and structural studies of lipoyl synthase, a radical S-adenosylmethionine enzyme that catalyzes sulfur incorporation during cofactor assembly. This perspective highlights current insights into lipoic acid biosynthesis and lipoyl synthase, with an emphasis on emerging mechanistic paradigms, lipoyl synthase auxiliary cluster function and regeneration, and the broader biochemical context of radical-mediated sulfur insertion.},
}

@article {pmid42921516,
year = {2026},
author = {Zhang, P and Chen, D and Luo, J and Chen, S and Lin, Z and Gu, S and Chang, T and Tang, Z and Zhang, C},
title = {Age- and Site-Specific Ecological Concordance Between Bone Fractures and Alzheimer's Disease and Other Dementias: A Global Burden Analysis with Hospital-Based Contextualization.},
journal = {Risk management and healthcare policy},
volume = {19},
number = {},
pages = {636188},
doi = {10.2147/RMHP.S636188},
pmid = {42921516},
issn = {1179-1594},
abstract = {BACKGROUND: Bone fractures and Alzheimer's disease and other dementias (ADD) are major ageing-related conditions, but their population-level co-burden and ecological concordance remain incompletely characterized.

METHODS: We analyzed Global Burden of Disease estimates from 1990 to 2023 to characterize global, age-specific, country-level, and site-specific patterns of bone fractures and ADD. Pearson and Spearman ecological correlations and lagged analyses were performed across age groups, countries, and Socio-demographic Index strata. Separately, a hospital-based descriptive analysis of patients with recorded ADD diagnoses from 2015 to 2025 was conducted to provide clinical context and was not designed to validate the ecological findings.

RESULTS: Fracture and ADD incidence showed stronger ecological concordance in older age groups. The strongest unadjusted lagged ecological association was observed at approximately 3 years (r=0.930 (95% CI, 0.927-0.933; unadjusted P<2.2×10[-16])). Hip, sternum/rib, and pelvic fractures showed positive site-specific correlations with lagged ADD incidence (r=0.62,0.59, and 0.58, respectively; all P<0.001). In the hospital-based cohort, 896 patients with recorded ADD diagnoses were included, of whom 342 (38.2%) had documented fracture records. Among these patients, fracture records preceded the first recorded ADD diagnosis in 195 cases (57.1%). Because no non-ADD comparison group was included, these findings were descriptive only.

CONCLUSION: Fracture burden and ADD burden show age-dependent, site-specific, and lagged ecological concordance. In the hospital-based descriptive cohort, fracture records were frequently documented before the recorded dementia diagnosis date. These findings should be interpreted as hypothesis-generating and support future individual-level longitudinal studies to determine whether fragility fractures can serve as markers for subsequent cognitive decline.},
}

@article {pmid42921589,
year = {2025},
author = {Zhang, Y and Bobryk, P and Morrow, SA and Wilken, J and Marrie, RA and Bainbridge, J and Stewart, R and Stacom, R and Bostick, MD and Choman, MT and Foley, FW and Corboy, JR and Newsome, SD and Hua, LH and Graves, JS},
title = {Age-Related Changes in Multiple Sclerosis Pathophysiology and Clinical Function.},
journal = {International journal of MS care},
volume = {27},
number = {Suppl 2},
pages = {T53-T58},
doi = {10.7224/1537-2073.2025-089},
pmid = {42921589},
issn = {1537-2073},
abstract = {Older adults with multiple sclerosis (MS) face unique issues related to the combined effects of MS and age-related changes, which often present with overlapping symptoms that complicate assessment and treatment decisions. In this review, based on the Consortium of MS Centers' Aging and MS Consensus Statement committee meeting in 2024, we address the contributions of aging in MS by focusing on direct, biological aging effects on MS pathology and comorbid age-related changes in physical and cognitive function. Features of biological aging include cellular senescence and immune dysregulation, which may drive disease progression in MS through a variety of proinflammatory mediators that may maintain low levels of chronic inflammation in the immune and central nervous system compartments and offset regulatory processes, ultimately impairing remyelination and increasing neurodegeneration. Measuring biological aging in MS may help identify individuals at risk of worse MS outcomes and support gerotherapeutic treatments that target aging mechanisms. Compounding any direct effects of aging on MS pathology, aging-related impairments in neuromuscular function and cognition can worsen functional outcomes in people with MS. Characteristics of cognitive impairments in MS affecting attention and processing speed occur early in the disease course and are distinct from other age-associated neurodegenerative disorders, such as Alzheimer disease, that commonly affect language and executive function domains. As MS clinicians care for growing numbers of older adults with MS, a more comprehensive understanding of the interplay between aging and MS-related changes can improve the timing and modality of treatments to optimize MS neurogeriatric care.},
}

@article {pmid42921695,
year = {2026},
author = {Cheng, H and Xia, H and Wang, Y and Cao, L and Hu, S and Wang, H and Kwapong, WR and Wang, Z and Wen, C},
title = {Multimodal Characterization of APOE ε4-Associated Neurovascular Heterogeneity Using Retinal, Plasma, and Neuroimaging Biomarkers in Alzheimer's Disease.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {10},
pages = {},
doi = {10.1002/cns.71220},
pmid = {42921695},
issn = {1755-5949},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging/blood ; *Apolipoprotein E4/genetics ; Female ; Male ; Biomarkers/blood ; Aged ; *Retinal Vessels/diagnostic imaging ; *Retina/diagnostic imaging/metabolism ; Neuroimaging/methods ; Positron-Emission Tomography ; Multimodal Imaging/methods ; Magnetic Resonance Imaging ; Tomography, Optical Coherence ; Aged, 80 and over ; },
abstract = {BACKGROUND: Biological heterogeneity remains a major challenge in Alzheimer's disease (AD), even among individuals with biomarker-confirmed disease. The apolipoprotein E (APOE) ε4 allele is associated with greater amyloid burden, neurodegeneration, and vascular dysfunction. We investigated whether retinal microvascular imaging provides complementary information beyond plasma and neuroimaging biomarkers for characterizing APOE ε4-associated neurovascular heterogeneity in biologically defined AD.

METHODS: Eighty-four amyloid-positive patients with AD underwent color fundus photography, swept-source optical coherence tomography angiography (OCTA), plasma biomarker assessment, amyloid positron emission tomography, and magnetic resonance imaging. Retinal vascular parameters were compared between APOE ε4 carriers and non-carriers using generalized estimating equations. Candidate multimodal biomarkers were identified using least absolute shrinkage and selection operator (LASSO) regression, followed by multivariable logistic regression to evaluate the incremental contribution of retinal biomarkers within a multimodal phenotyping model.

RESULTS: Compared with non-carriers, APOE ε4 carriers demonstrated significantly lower retinal superficial vascular complex (SVC) and deep vascular complex densities, reduced retinal vascular fractal dimension, higher amyloid PET standardized uptake value ratios, increased peak width of skeletonized mean diffusivity, and smaller hippocampal volumes (all p < 0.05). Following penalized feature selection, retinal SVC density remained independently associated with APOE ε4 status alongside amyloid burden, hippocampal volume, and white matter microstructural injury. Incorporation of SVC modestly improved discrimination and calibration of the multimodal model compared with neuroimaging biomarkers alone.

CONCLUSIONS: Retinal microvascular alterations are associated with APOE ε4-related biological heterogeneity in biomarker-confirmed AD. Retinal vascular imaging provides complementary information beyond established plasma and neuroimaging biomarkers and may enhance multimodal characterization of neurovascular phenotypes rather than serve as a surrogate for genetic testing.},
}

Humans
*Alzheimer Disease/genetics/diagnostic imaging/blood
*Apolipoprotein E4/genetics
Female
Male
Biomarkers/blood
Aged
*Retinal Vessels/diagnostic imaging
*Retina/diagnostic imaging/metabolism
Neuroimaging/methods
Positron-Emission Tomography
Multimodal Imaging/methods
Magnetic Resonance Imaging
Tomography, Optical Coherence
Aged, 80 and over

@article {pmid42921714,
year = {2026},
author = {Renwick, R and Rossmann, C and Patterson, S and Gabbert, J},
title = {Pharmacist role in transforming Alzheimer's care: Anti-amyloid therapy experience at Vanderbilt University Medical Center.},
journal = {American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists},
volume = {},
number = {},
pages = {},
doi = {10.1093/ajhp/zxag359},
pmid = {42921714},
issn = {1535-2900},
abstract = {PURPOSE: Anti-amyloid infusion therapies are a new and complex treatment option for patients with Alzheimer's disease. Use of lecanemab or donanemab requires specific diagnostic criteria and frequent ongoing monitoring that requires in-depth coordination of care. We describe how neurology clinical pharmacists were an integral part of adoption of anti-amyloid therapy at our institution. With implementation of this service by pharmacists, we describe the impact on patient outcomes for those receiving anti-amyloid infusions and several aspects of impact on the health system as a whole that pharmacists should anticipate with these complex infusions.

SUMMARY: Neurology clinical pharmacists dedicated to infusions therapies are responsible for many aspects of use of anti-amyloid therapies, including order entry, patient counseling, Centers for Medicare and Medicaid Services (CMS) registry submission, infusion scheduling, and coordination of magnetic resonance imaging. At our institution, the first year of anti-amyloid infusions included 58 patients starting infusions. Safety and adverse effects, including amyloid-related imaging abnormalities, were similar to those previously reported in the primary literature. The majority of patients utilized Medicare as their primary coverage for infusions, and we describe successful navigation of the unique CMS registry requirement for billing.

CONCLUSION: Adoption of anti-amyloid therapies by a health system requires unique aspects of coordination not previously encountered. Clinical pharmacists are positioned to successfully coordinate care for patients receiving anti-amyloid infusions.},
}

@article {pmid42921916,
year = {2026},
author = {Hamzeh, O and Halaji, M and Rostami, A and Md Ashraf, G},
title = {Targeting the gut-brain axis with Bifidobacterium breve in neurodegeneration: A comprehensive narrative review of current evidence in Alzheimer's disease and cognitive aging.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261496277},
doi = {10.1177/13872877261496277},
pmid = {42921916},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder arising from the interplay of amyloid, tau, neuroimmune, oxidative stress, metabolic, vascular, and synaptic processes, ultimately resulting in neurodegeneration across multiple brain regions and progressive memory and cognitive impairment. Gut dysfunction may contribute to the initiation and progression of AD-related processes through the gut-brain axis, whereby alterations in the gut microbiota can influence brain function through chemical, neuronal, immune, and metabolic pathways. Growing interest in the microbiota-gut-brain axis has consequently prompted investigation of strain-specific probiotics as potential adjunctive approaches to restoring gut microbial homeostasis. This comprehensive narrative review critically integrates preclinical and human evidence on Bifidobacterium breve in AD-related pathology and age-associated cognitive impairment. Targeted searches of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar were conducted through April 2026 and supplemented by reference-list searching. The evidence base comprised 13 preclinical publications and five human publications representing four independent clinical cohorts. Preclinical studies, predominantly conducted in rodent models, reported strain-dependent effects on cognition, amyloid- and tau-related measures, synaptic proteins, neuroinflammation, oxidative stress, microbial composition, and metabolite profiles. Human evidence was limited to B. breve MCC1274 (A1) and primarily involved Japanese adults with memory complaints or suspected mild cognitive impairment. Overall, current evidence supports a mechanistic rationale for the potential role of B. breve as a gut-brain modulator; however, the heterogeneity of preclinical findings and the small, geographically concentrated clinical evidence base highlight the need for further well-designed studies to more clearly define clinical efficacy and long-term safety.},
}

@article {pmid42921942,
year = {2026},
author = {Zi, M and Ye, Q and Yao, M and Feng, J and Meng, S and Wu, X and Jiang, H and Yang, F and Huang, Y and Hu, X and Ma, C and Zheng, J and Zeng, S and Li, H},
title = {Pathogenesis and therapeutic targets of neuroinflammation in Alzheimer's disease mediated by microglia lysosomal dysfunction.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500025},
doi = {10.1177/13872877261500025},
pmid = {42921942},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by two core pathological features: senile plaques formed by amyloid-β protein (Aβ) deposits and neurofibrillary tangles formed by hyperphosphorylated tau protein. In recent years, neuroinflammation has been recognized as a key driver in the pathogenesis of AD, and microglia, as innate immune cells of the central nervous system, play a central role in regulating the onset and progression of neuroinflammation. Lysosomes are key organelles within microglia responsible for degrading pathological proteins and regulating inflammatory signaling; dysfunction of lysosomes in microglia severely impairs their ability to clear Aβ, damaged proteins, and cellular debris, thereby promoting inflammatory responses. This manuscript summarizes upstream mechanisms that may influence microglial lysosomal dysfunction from four perspectives: pathological proteins, genetic factors, lipid metabolism disorders, and proinflammatory cytokines. Pathological proteins can impair lysosomal acidification and biogenesis by interfering with key pathways such as the TFEB-v-ATPase axis; various genetic factors exacerbate functional dysregulation by influencing the expression of lysosome-related genes and lipid metabolism; lipid metabolism disorders promote lysosomal membrane permeabilization, block the autophagy cascade and activate the inflammasome; proinflammatory cytokines can exert varying effects on the clearance of pathological substrates and by regulating lysosomal function. The aforementioned factors can influence microglial lysosomal function through various mechanisms, thereby contributing to impaired clearance of pathological substrates and the onset and progression of neuroinflammation. Intervention strategies targeting microglial lysosomal dysfunction, including enhancing lysosomal degradation capacity, regulating autophagy related pathways, correcting cellular metabolic dysregulation and suppressing excessive neuroinflammation, may offer new avenues for AD treatment.},
}

@article {pmid42922070,
year = {2026},
author = {Wang, X and Wang, P and Song, X},
title = {Marginal Analysis of Clustered Interval-Censored Competing Risks Data With Informative Cluster Size.},
journal = {Statistics in medicine},
volume = {45},
number = {25-27},
pages = {},
doi = {10.1002/sim.70792},
pmid = {42922070},
issn = {1097-0258},
support = {JJKH20261316KJ//Scientific Research Project Funding from the Education Department of Jilin Province/ ; 14303622//Research Grant Council of the Hong Kong Special Administration Region/ ; 14300425//Research Grant Council of the Hong Kong Special Administration Region/ ; },
mesh = {Humans ; Cluster Analysis ; Computer Simulation ; Likelihood Functions ; *Models, Statistical ; Risk Factors ; Alzheimer Disease/epidemiology ; Incidence ; },
abstract = {Motivated by the National Alzheimer's Coordinating Center (NACC) study, this paper addresses the marginal analysis of clustered data under a complex setting involving interval censoring, competing risks, and informative cluster size, for which existing methods are not readily applicable. We consider a class of marginal generalized odds-rate transformation models for the cumulative incidence function in the presence of interval-censored competing risks, with the Fine-Gray model and the sub-distribution proportional odds model included as special cases. For statistical inference, a cluster-weighted sieve maximum pseudo-likelihood estimation procedure is developed, in which B-splines are used to approximate the nonparametric components of the semiparametric models. This method effectively reduces the original infinite-dimensional estimation problem to a finite-dimensional one. We establish the asymptotic properties of the resulting parameter estimators and conduct extensive simulation studies to evaluate their finite-sample performance. The proposed methodology is applied to the motivating NACC data to investigate potential risk factors for the cumulative incidence of Lewy body dementia.},
}

Humans
Cluster Analysis
Computer Simulation
Likelihood Functions
*Models, Statistical
Risk Factors
Alzheimer Disease/epidemiology
Incidence

@article {pmid42922076,
year = {2026},
author = {Lee, L and Hantke, N and Hanna, EJ and Mattek, N and DeCapo, M and Ferguson, H and Pierce, A and Kaye, JA and Duff, K},
title = {Normative data and change scores on the CERAD Word List in a robustly intact sample of older adults and preliminary validation in an impaired sample.},
journal = {Journal of the International Neuropsychological Society : JINS},
volume = {},
number = {},
pages = {1-10},
doi = {10.1017/S1355617726102409},
pmid = {42922076},
issn = {1469-7661},
abstract = {OBJECTIVES: The Word List subtest of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery has been widely used in clinical research to identify and track cognitive disorders. However, normative data and change scores are lacking. The current study aimed to create normative data for the Word List subtest.

METHODS: CERAD Word List data from 1,530 older adults diagnosed as cognitively intact, Mild Cognitive Impairment (MCI), or dementia were seen for two annual visits in a longitudinal observational study from the Uniform Data Set of the National Alzheimer's Coordinating Center. Multiple linear regression predicted Time 2 scores from Time 1 scores, demographic variables (age, education, sex, and race), and retest interval. Validation included comparing predicted scores to observed scores in the original sample, and additional validation across five comparison groups (cognitively intact, MCI, dementia, worsening cognition, or improving cognition) and one-sample chi-square test of probabilities to compare group classification to predicted categorization based on chance alone.

RESULTS: The four demographic variables significantly predicted test scores for the six primary scores from the Word List subtest. For change data, when predicted Time 2 scores were compared to observed Time 2 scores, there were significant differences for 4 of the 6 scores, but the effect sizes were small. Significant differences were found across the five comparison groups for Total Recall and Delayed Recall (p-values < .001).

CONCLUSIONS: The current study provides normative data and regression-based change scores for the CERAD Word List subtest for older adults.},
}

@article {pmid42922158,
year = {2026},
author = {Shateri, A},
title = {Chromosome 21 gene dosage and Alzheimer's disease in Down syndrome: DYRK1A mechanism and its translation to blood-based biomarkers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261499713},
doi = {10.1177/13872877261499713},
pmid = {42922158},
issn = {1875-8908},
abstract = {Down syndrome (DS), caused by trisomy 21, is the most common genetic cause of early-onset Alzheimer's disease (AD). Virtually all individuals with DS develop AD neuropathology by the fourth decade of life, and the majority develop clinical dementia by the seventh decade. Triplication of the APP gene on chromosome 21 (HSA21) is the established central driver of the substantial amyloid burden in this population. However, HSA21 contains hundreds of genes, and additional triplicated genes may compound DS-associated AD (DSAD) risk. This narrative review examines DYRK1A (dual-specificity tyrosine-phosphorylation-regulated kinase 1A), a triplicated HSA21 kinase overexpressed approximately 1.5-fold in DS brains, as a potential complementary contributor to DSAD. Evidence from cell and animal models proposes three mechanistic axes: (1) phosphorylation of amyloid-β protein precursor at Thr668, promoting amyloidogenic processing; (2) phosphorylation of tau at Thr212, the site corresponding to the p-tau212 epitope, priming downstream GSK3β-mediated hyperphosphorylation; and (3) transcriptional suppression of neprilysin, impairing amyloid-β clearance. Direct human mechanistic evidence for these pathways remains limited. Because DYRK1A has been implicated in broader tau-regulatory pathways, individuals with DS may exhibit distinct plasma p-tau profiles compared with euploid AD populations. Recent cohort studies have reported DS-specific plasma p-tau217 and p-tau212 thresholds substantially higher than euploid references. Dedicated quantitative syntheses of plasma p-tau217 and p-tau212 diagnostic accuracy specifically in DS remain limited, representing a key translational gap.},
}

@article {pmid42922315,
year = {2026},
author = {Dreznal, YP and Kmet, TI and Davydenko, IS and Slobodian, KV and Kushnir, OV and Pudiak, KI},
title = {Systemic disorders of the oxidant-antioxidant system of the brain and kidney in scopolamine-induced Alzheimer's disease and their correction with carbacetam.},
journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)},
volume = {79},
number = {8},
pages = {1850-1858},
doi = {10.36740/WLek/222257},
pmid = {42922315},
issn = {0043-5147},
mesh = {Animals ; *Alzheimer Disease/chemically induced/drug therapy/metabolism ; Male ; Scopolamine ; Rats ; *Kidney/metabolism/drug effects ; *Antioxidants/metabolism/pharmacology ; *Hippocampus/metabolism/drug effects ; Oxidative Stress/drug effects ; *Brain/metabolism/drug effects ; Lipid Peroxidation/drug effects ; Rats, Wistar ; Disease Models, Animal ; },
abstract = {OBJECTIVE: Aim: To assess the state of the oxidant-antioxidant system of the hippocampus and kidneys of rats with scopolamine-induced Alzheimer's disease and with the administration of carbacetam, as a GABA receptor modulator, and to clarify the possible systemic oxidative process.

PATIENTS AND METHODS: Materials and Methods: The experiments were carried out on mature and old male rats. Alzheimer's disease was simulated by scopolamine hydrochloride (Sigma, USA). It was introduced into the peritoneum in a dose of 1 mg/kg of the body weight once a day during 27 days. On the 28th day, carbacetam was administered in a dose of 5 mg/kg once a day during 14 days. Intensity of lipid peroxide oxidation (LPO) was evaluated by the content of products reacting with 2-thiobarbituric acid reactive substances (TBARS). The content of protein oxidation modification (POM), also known as protein oxidation, in homogenates was determined by the amount of their oxidative modification products with the help of spectrophotometric method. The state of antioxidant protection was assessed by catalase and SOD activity.

RESULTS: Results: Simulated Alzheimer's disease was found to cause affliction of the protein amino groups in the hippocampal neurons and endotheliocytes, and in the mesangial matrix of non-collapsed renal glomeruli of rats of different ages with more pronounced changes in brain cells. At the same time, there is a clear existing relationship between affliction of the nerve cells and kidneys, which makes a foundation for further study of pathogenic processes and interrelations in neurodegenerative processes.

CONCLUSION: Conclusions: Thus, the group of rats of different ages with experimental Alzheimer's disease presented increase of the lipid and protein peroxidation products with more pronounced lesion in the hippocampal cells than those of the kidneys. Moreover, decrease of the lipid and protein peroxidation products in the examined organs of rats with scopolamine-induced Alzheimer's disease after administration of carbacetam indicates the involvement of the GABA-ergic system in the pathogenesis of damage to hippocampal neurons and kidney cells.},
}

Animals
*Alzheimer Disease/chemically induced/drug therapy/metabolism
Male
Scopolamine
Rats
*Kidney/metabolism/drug effects
*Antioxidants/metabolism/pharmacology
*Hippocampus/metabolism/drug effects
Oxidative Stress/drug effects
*Brain/metabolism/drug effects
Lipid Peroxidation/drug effects
Rats, Wistar
Disease Models, Animal

@article {pmid42922329,
year = {2026},
author = {Izhytska, NV and Sobczyk, KA and Ogrodnik, KW and Mazurkiewicz, M and Malentowicz, D and Szafraniec, NJ},
title = {Effects of hyperbaric oxygen therapy in the treatment of selected diseases of the nervous system.},
journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)},
volume = {79},
number = {8},
pages = {1982-1988},
doi = {10.36740/WLek/226613},
pmid = {42922329},
issn = {0043-5147},
mesh = {Humans ; *Hyperbaric Oxygenation ; *Nervous System Diseases/therapy ; Parkinson Disease/therapy ; Animals ; Diving and Hyperbaric Medicine ; Alzheimer Disease/therapy ; },
abstract = {Hyperbaric Oxygen Therapy (HBOT) has attracted increasing interest as a potential supportive intervention in neurological disorders. By increasing the amount of oxygen dissolved in blood plasma, HBOT enhances oxygen delivery to hypoxic tissues and may influence mechanisms involved in neuroplasticity, inflammation, and tissue repair. Experimental and clinical studies suggest that HBOT may support neurological recovery in selected conditions, particularly following ischemic or traumatic brain injury. However, the effectiveness of HBOT varies depending on the underlying disease, and further high-quality clinical studies are needed to establish its role in neurological rehabilitation.The article was based on an analysis of data from Google Scholar and PubMed regarding the effects of hyperbaric therapy.},
}

Humans
*Hyperbaric Oxygenation
*Nervous System Diseases/therapy
Parkinson Disease/therapy
Animals
Diving and Hyperbaric Medicine
Alzheimer Disease/therapy

@article {pmid42922412,
year = {2026},
author = {Keler Soares, L and Srivastava, G and Dwelle, C and Waggoner, B and Tedone, V and Hickman, JJ and Guo, X},
title = {Deanna Protocol Ameliorates the Deficits in Human iPSC-Cortical Neurons Carrying Familial Alzheimer's Mutation.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {10},
pages = {},
pmid = {42922412},
issn = {1755-5949},
support = {AWD4941//Winning the Fight Against Neurodegenerative Diseases (WFND)/ ; 1R03AG070514-01//National Institutes of Health, National Institute on Aging/ ; 1R01AG077651//National Institutes of Health, National Institute on Aging/ ; 1R43 AG060886-01//National Institutes of Health, National Institute on Aging/ ; R44AG071386-01A1//National Institutes of Health, National Institute on Aging/ ; },
mesh = {Humans ; *Induced Pluripotent Stem Cells/physiology ; *Alzheimer Disease/genetics/pathology/therapy ; *Presenilin-1/genetics ; *Neurons/drug effects/pathology/physiology ; *Mutation/genetics ; *Cerebral Cortex/pathology/cytology ; Cells, Cultured ; Long-Term Potentiation/drug effects/physiology ; Patch-Clamp Techniques ; Mitochondria/drug effects/metabolism ; },
abstract = {AIMS: Deanna Protocol (DP) is an anaplerotic, mechanism-based therapy designed to address impaired cellular energy flux. The present study aims to investigate the effects of DP in treating Alzheimer's disease (AD) by using cortical neurons derived from AD patient iPSCs carrying a PSEN1 mutation, while cortical neurons differentiated from iPSCs of a healthy subject serve as control.

METHODS: PSEN1 cortical neurons were treated with DP acutely (24 h) and chronically (1-3 weeks). The effect of DP was assessed by utilizing TMRE assay for mitochondrial function, immunofluorescent staining for AD neuron morphological pathology, whole cell patch clamp for neuron electrophysiological property, and microelectrode array (MEA) analysis of long-term potentiation (LTP) for neurocircuit function.

RESULTS: PSEN1 cortical neurons demonstrated impaired mitochondrial function, elevated pathological biomarkers, reduced neurite complexity, altered electrophysiology, and decreased LTP. DP treatment significantly ameliorated all these phenotypes.

CONCLUSION: This study, while confirming iPSC-PSEN1 cortical neurons as a valid AD model, demonstrated the efficacy of DP on ameliorating structural and functional pathologies in AD neurons. It highlights that targeting energy production could be an effective approach in treating neurodegeneration in AD and suggests its potential efficacy in other neurodegenerative diseases.},
}

Humans
*Induced Pluripotent Stem Cells/physiology
*Alzheimer Disease/genetics/pathology/therapy
*Presenilin-1/genetics
*Neurons/drug effects/pathology/physiology
*Mutation/genetics
*Cerebral Cortex/pathology/cytology
Cells, Cultured
Long-Term Potentiation/drug effects/physiology
Patch-Clamp Techniques
Mitochondria/drug effects/metabolism

@article {pmid42922476,
year = {2026},
author = {Stangis, KA and Pandey, RS and Wang, A and Beck, JS and Counts, SE and Carter, GW and Park, KHJ},
title = {Aberrant neuronal cell cycle re-entry induces late-onset Alzheimer's disease relevant neuropathological and gene expression changes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.28.747879},
pmid = {42922476},
issn = {2692-8205},
abstract = {Aberrant neuronal cell cycle re-entry (NCCR) is an alternative pathogenic mechanism in Alzheimer's disease (AD) that has gained substantial support in the literature. The pathogenic role of ectopic NCCR is supported by our past work demonstrating that SV40T-mediated NCCR in adult mice can induce numerous pathologies associated with AD. Since NCCR is chronically induced for an extended period in the mouse model which gives rise to numerous pathologies including neuroinflammation, many of these neuropathological changes could simultaneously participate in driving disease progression. We hypothesized that the NCCR is a primary pathogenic driver and that halting this disease process at a later age could be sufficient for preventing the progression of AD-related pathologies. Here we show that modulation of NCCR at a later age prevents the progression of AD pathologies, including Aβ and tau pathologies. Furthermore, functional genomics analysis demonstrates the late-onset AD (LOAD)-relevance of NCCR. Our findings suggest that our NCCR mouse model could help identify novel therapeutic targets that could aid in preventing AD progression.},
}

@article {pmid42922477,
year = {2026},
author = {Or, PSK and Yon, M and Narvaez, O and Sitnikova, V and Malm, T and Bouhrara, M and Sierra, A and Topgaard, D and Benjamini, D},
title = {Multidimensional diffusion MRI reveals heterogeneous microstructural remodeling associated with amyloid pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.26.747377},
pmid = {42922477},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) pathology involves amyloid deposition, reactive gliosis, and localized tissue alterations that coexist within the same brain regions, creating heterogeneous microstructural environments within individual imaging voxels. Conventional diffusion MRI averages these environments into aggregate measures, potentially obscuring their distinct contributions. Frequency-dependent multidimensional MRI (ωMD-MRI) resolves distributions of water components with different diffusion length scales, anisotropies, and relaxation properties, providing sensitivity to microstructural restriction, heterogeneity, and shape-size correlations within a voxel. Whether these measurements reveal microstructural complexity associated with AD pathology remains unclear. Here, we performed ωMD-MRI on ex vivo brain specimens from approximately 8-month-old 5xFAD and wild-type mice and interpreted the imaging findings alongside complementary histology. ωMD-MRI revealed widespread but spatially nonuniform differences between 5xFAD and wild-type brains. Measurements sensitive to microstructural restriction, heterogeneity, and shape-size correlations consistently indicated greater microstructural heterogeneity in 5xFAD brains, with the most prominent differences in the hippocampal formation and major cerebral white matter tracts. Complementary qualitative histology demonstrated extensive amyloid deposition and glial activation in affected regions, while overall cytoarchitecture and myelin organization remained largely preserved. Thus, the ωMD-MRI abnormalities occurred in tissue characterized by multiple coexisting pathological and relatively preserved microstructural environments rather than widespread structural degeneration. These findings demonstrate that ωMD-MRI can reveal the spatial and microstructural heterogeneity associated with amyloid pathology and provide a more comprehensive characterization of AD-related tissue alterations.},
}

@article {pmid42922531,
year = {2026},
author = {Ding, S and Nazarenkov, N and Kim, J and Dore, K and Choi, SH and Miller, YI},
title = {Excessive cholesterol accumulation in microglia increases neuronal synaptic vulnerability to amyloid-beta.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.27.747668},
pmid = {42922531},
issn = {2692-8205},
abstract = {Cholesterol efflux is an important determinant of cellular lipid homeostasis. However, how microglial excessive cholesterol accumulation affects neuronal synaptic integrity remains poorly understood, particularly in the context of Alzheimer's disease. Here, we utilized a conditional knockout mouse model targeting the cholesterol transporters ABCA1 and ABCG1 in microglia. The microglia-specific ABCA1/ABCG1 deficiency triggered marked cholesterol accumulation, microglial hypertrophy, downregulation of the homeostatic marker P2ry12 , and upregulation of the reactivity-associated marker CD11b, indicating shift toward a reactive phenotype. This phenotype was accompanied by increased reactive oxygen species, consistent with enhanced oxidative stress in ABCA1/ABCG1-deficient microglia compared with control. Using organotypic hippocampal slice cultures, we investigated the downstream neuronal outcomes of microglial ABCA1/ABCG1 deficiency. Under basal conditions, microglial ABCA1/ABCG1 knockdown did not significantly alter dendritic spine density in CA1 pyramidal neurons. However, upon exposure to amyloid-beta (Aβ) stress, microglial ABCA1/ABCG1 deficiency markedly exacerbated dendritic spine loss in CA1 pyramidal neurons. Taken together, our findings highlight an important role for ABCA1/ABCG1-dependent cholesterol efflux in maintaining microglial homeostasis and limiting neuronal synaptic vulnerability to Aβ-associated stress. These results support further investigation of microglial cholesterol transport as a potential target for preserving synaptic resilience in Alzheimer's disease.},
}

@article {pmid42922534,
year = {2026},
author = {Voth, JP and Ramos Benitez, JA and Wilson, AM and Kennedy, SR and Damodarasamy, M and Kirkland, A and Miller, JA and Latimer, CS and Ragaglia, E and Nolan, A and Child, DD and Keene, LM and Reichel, CL and Kohrn, BF and Sherman, LS and Back, SA and Keene, CD},
title = {Single nucleus RNA sequencing and spatial transcriptomics reveal unique functionalities of gray matter versus white matter oligodendrocytes in aging and Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.29.747923},
pmid = {42922534},
issn = {2692-8205},
abstract = {Oligodendrocyte (OL) dysfunction and white-matter (WM) vulnerability are increasingly recognized as important aspects of aging and Alzheimer's Disease (AD), yet human WM-focused, cellular-resolution transcriptomic data remain limited. Here, we profiled prefrontal WM from 48 brain donors spanning young adulthood and late-life with low versus high AD Neuropathologic Change (ADNC) using single-nucleus RNA sequencing followed by spatial transcriptomics (CosMx) in a subset of matched donors. We integrated aged WM OLs with a reference dorsolateral prefrontal cortex grey-matter (GM) OL dataset (SEA-AD) to define region- and pathology-associated OL programs. Across modalities, GM OLs exhibited a robust synapse/neurotransmitter-associated transcriptional signature relative to WM OLs, whereas this program was reduced with aging and attenuated in high ADNC GM. In contrast, WM OLs showed stronger immune-associated programs with aging and further enhancement in high ADNC, including cytokine/chemokine signaling and antigen presentation-related pathways. High ADNC WM OLs also displayed amplified proteostasis and stress-adaptation signatures, including selective upregulation of chaperone/heat shock genes and ferritin subunits, consistent with increased protein-folding demand and altered iron handling. To resolve OL state organization beyond static differential expression, we annotated OL sub-states using marker panels and inferred pseudotime-guided directional state-to-state flows within each tissue/condition stratum. This analysis identified a conserved newly formed differentiating (NFOL)/differentiating → lipid remodeling (APOE/ABCA1/LPL+) → Stress/ISR-reactive architecture, with a pronounced expansion of the Stress/ISR-reactive compartment and altered transition-associated pathway enrichment in high ADNC WM. Together, these data define WM-specific OL programs linked to aging and ADNC and nominate a stress/immune-enriched OL state landscape consistent with a putative senescence-like phenotype in diseased WM.},
}

@article {pmid42922648,
year = {2026},
author = {Xu, Y and Zou, B and Xie, G and Chen, T and Jia, W and Zhang, L and , and , },
title = {Decoding heterogeneous aging clocks and disease risk stratification using MetAgeFormer.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.18.725977},
pmid = {42922648},
issn = {2692-8205},
abstract = {Metabolomic aging clocks estimate biological age by modeling metabolite concentrations, thereby capturing aging signals from healthspan and adverse outcomes. However, existing clocks generally assume homogeneous aging trajectories and yield only a single age acceleration metric, limiting their capacity to capture inter-individual metabolic heterogeneity and characterize nuanced individual-level representations. To address these limitations, we proposed MetAgeFormer, a transformer-based metabolomic model pre-trained on nuclear magnetic resonance (NMR) metabolomic profiles from over 430,000 participants in UK Biobank via self-supervised learning. This large-scale pre-training enables MetAgeFormer to learn a metabolomic representation space that captures the complex, nonlinear structure of systemic metabolism as reflected in NMR data. Building on MetAge-Former, we developed a mortality-informed metabolomic aging clock by fine-tuning an attached survival module, deriving age acceleration that demonstrates significant associations with multiple age-related diseases and factors. We further validated zero-shot transfer in the independent Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. More importantly, we utilized embeddings generated by MetAgeFormer to identify 13 distinct metabolic subtypes and consolidated them into four meta-subtypes with markedly divergent susceptibility profiles for major age-related diseases, particularly type 2 diabetes and neurodegenerative disorders. This finding empirically demonstrated substantial metabolic heterogeneity across populations, persisting even at comparable levels of age acceleration. To enhance clinical applicability, we further employed contrastive learning to distill a lightweight model that approximates the learned metabolomic representation space using only 14 routine clinical blood test measurements as inputs. Both hold-out testing within UK Biobank and external validation in the China Health and Retirement Longitudinal Study replicated similar disease onset patterns across the identified subtypes, underscoring the robust generalizability of MetAgeFormer and supporting its translational potential as a scalable framework for metabolomic aging assessment and early disease risk stratification.},
}

@article {pmid42922684,
year = {2026},
author = {Soto, C and Gorski, D and Evans, H and Pinho, M and Rehan, Z and Perkins, M and Pinarbasi, E and Reader, J and Barmada, S and Paulson, H and Pritzkow, S},
title = {Tandem Tau and α-Synuclein Seed Amplification Assays Reveal α-Synuclein Copathology Potentiates Tau Seeding in Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10845149/v1},
pmid = {42922684},
issn = {2693-5015},
abstract = {Accumulating evidence highlights the frequent co-occurrence of tau and α-synuclein (αSyn) pathology across neurodegenerative diseases, including Alzheimer's disease (AD) and synucleinopathies. Whether the co-deposition of these proteinopathic aggregates influences their respective seeding capacities remains unknown. Seed amplification assays (SAAs) enable sensitive and specific detection of pathological seeding activity in brain tissue and cerebrospinal fluid (CSF) and have been widely used to assess tau or αSyn seeding independently; however, their tandem application in the same individuals has not been thoroughly investigated. Here we apply Tau- and αSyn-SAA in parallel on a well-characterized postmortem cohort of matched brain tissue and CSF spanning AD, synucleinopathies, other neurological diseases, and neuropathologically defined controls. We demonstrate that tau seeding activity in both brain and CSF closely reflects underlying neuropathological burden, increasing stepwise with the grade of AD neuropathological change (ADNC) and neurofibrillary tangle (NFT) stage, with strong within-donor concordance between matrices (r = 0.79, p < 0.001). Tau-SAA measured in postmortem CSF robustly discriminated AD-related neuropathology from other groups, supporting its potential as a neuropathologically informed biomarker. αSyn-SAA identified all synucleinopathy donors as positive and revealed that 44% of AD donors harbor concomitant αSyn seeding activity. Leveraging this tandem dataset, we find that αSyn-SAA positive AD donors exhibit significantly enhanced tau seeding activity in both brain and CSF, independent of NFT stage, age, and sex (p = 0.014). In synucleinopathy donors, tau seeding did not alter αSyn seeding capacity (p = 0.606). Together, these results suggest a potentially unidirectional relationship between tau and αSyn seeding in human disease, wherein αSyn copathology acts as a catalyst of tau seeding in AD. Our findings carry implications for understanding how mixed proteinopathies shape disease burden and trajectory and may represent the beginning of a new direction in the field moving towards precision medicine to identify all types of pathology concomitantly affecting the brain, which will have a profound impact on patient prognosis and treatment.},
}

@article {pmid42922715,
year = {2026},
author = {Wang, E and Xie, B and Wang, M and Fu, Y and Wang, X and Li, Y and Xu, P and Liu, H and Ho, L and Tu, Z and Mobbs, C and Gaiteri, C and Ehrlich, ME and Bennett, DA and Haroutunian, V and Peng, J and Zhang, B},
title = {A Multi-Omics Study of Cognitive Resilience to Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.02.746746},
pmid = {42922715},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is the most severe form of dementia. While significant efforts have been made to identify AD risk factors and develop therapeutics, much less attention has been given to neurobiological factors and molecular signatures associated with cognitive resilience. Substantial evidence suggests that modifiable factors, such as physical and mental activity, may contribute to cognitive reserve and resilience. To this end, we developed a resilient cohort of paired genetics, transcriptomics and proteomics data from the prefrontal cortex of 282 cognitively normal older adults. We conducted extensive preprocessing and rigorous quality control (QC), including QC on sequence metrics and sample matching across multiomics. This cohort can be leveraged for identification of molecular signatures of cognitive resilience to AD and is freely shared with the research community.},
}

@article {pmid42922720,
year = {2026},
author = {Chandrashekar, DV and Roules, GC and Panchal, U and Jagadeesan, N and Newhart, C and Chu, J and Carson, B and Win, S and Than, TA and Kaplowitz, N and Garcia, J and Han, D and Sumbria, RK},
title = {Chronic Liver-Specific LRP1 Silencing Drives Progressive Brain Amyloidosis, Neuroinflammation, and Behavioral Deficits in APP/PS1 Mice.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10843451/v1},
pmid = {42922720},
issn = {2693-5015},
abstract = {Liver dysfunction is increasingly implicated in Alzheimer's disease (AD) pathogenesis, yet the underlying mechanisms remain poorly understood. Hepatic low-density lipoprotein receptor-related protein 1 (LRP1), the principal receptor mediating peripheral amyloid-beta (Aβ) clearance, is downregulated in chronic liver diseases. Using an AAV8-TBG hepato-specific silencing strategy in APP/PS1 mice, we previously demonstrated that 12 weeks of hepatic LRP1 silencing elevated soluble brain Aβ and locomotor hyperactivity without affecting insoluble Aβ, neuroinflammation, or cognition. Here, we extended silencing to 28 weeks to model hepatic LRP1 reduction with chronic liver dysfunction and assessed whether sustained hepatic LRP1 loss drives a more severe AD phenotype. Hepatic LRP1 was reduced by 70% with no off-target effects on brain or kidney LRP1, liver histology, or systemic inflammation, confirming liver specificity and safety. Prolonged silencing produced a time-dependent progression of brain Aβ accumulation, shifting from soluble to insoluble Aβ species from 12 to 28 weeks of hepatic LRP1 silencing. Elevated plasma Aβ42 was strongly and positively correlated with insoluble brain Aβ42 (r = 0.65, p < 0.05), supporting a liver-plasma-brain axis in modulating brain Aβ. Sustained hepatic LRP1 silencing was accompanied by reactive astrogliosis (p < 0.01), microglial transition to a disease-associated state (p < 0.05), increased brain ApoE (p < 0.05), and worsened locomotor hyperactivity (p < 0.05) and spatial memory impairment (p = 0.056). Mechanistically, hepatic LRP1 silencing transiently increased hepatic APP expression (p < 0.01) and elevated plasma ApoB48 (p < 0.05), suggesting dual contributions of reduced Aβ clearance and increased peripheral Aβ production. Absence of compensatory changes in other hepatic Aβ transporters confirms that the observed AD phenotypes are driven by alterations in hepatic LRP1. These findings underscore hepatic LRP1 as a critical regulator of Aβ pathology. Future work will further highlight the potential of hepatic LRP1 as a therapeutic target and perhaps as a biomarker for AD risk associated with liver disease.},
}

@article {pmid42922738,
year = {2026},
author = {Ismail, O and Woodruff, SS and Zimmerman, B and Zhang, W and Stackhouse, TL and Pike, MM and Woltjer, RL and Mishra, A},
title = {Stroke and Alzheimer's disease have distinct consequences on neurovascular function but synergize to increase amyloid deposition.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.29.746901},
pmid = {42922738},
issn = {2692-8205},
abstract = {INTRODUCTION: We examined whether stroke induces chronic cerebrovascular dysfunction and thereby exacerbates Aβ pathology.

METHODS: We exposed Tg2576 mice to a transient mild subcortical ischemia and examined cerebrovascular function at chronic timepoints as well as reactive astrocytes and Aβ deposition post-mortem.

RESULTS: Baseline cerebral blood flow and cerebrovascular reactivity (CVR) are both influenced by anesthesia regimen. Aβ strongly impairs CVR at earlier ages, while mild ischemia impairs CVR at later ages. Mild ischemia reduces neurovascular coupling more strongly than Aβ and synergistically increases Aβ deposition in Tg2576 mice.

DISCUSSION: Stroke-induced cerebrovascular dysfunction and astrocyte reactivity persist for long periods after the injury. Although there is variability in the spatiotemporal progression of ischemia-and Aβ-induced vascular impairments, they generally follow the pattern of Thal staging. Surprisingly, the ischemia+Aβ group showed the least cerebrovascular dysfunction yet an exacerbation of Aβ deposition, suggesting that these pathologies are connected but not tightly coupled.},
}

@article {pmid42922770,
year = {2026},
author = {Hirose, T and Akamatsu, W and Kato, T and , },
title = {A data-driven regional amyloid PET score predicts cognitive decline beyond Centiloid.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.26.26360248},
pmid = {42922770},
abstract = {BACKGROUND: The Centiloid (CL) scale standardizes global amyloid PET quantification and is widely used to define amyloid positivity. As a global summary measure, however, CL may not fully reflect the regional distribution of amyloid deposition, which can carry additional prognostic information about the rate of cognitive decline.

OBJECTIVE: To develop and externally validate a fixed, regional amyloid PET composite score that complements CL for predicting cognitive decline in Alzheimer's disease.

METHODS: The Regional Amyloid PET Score (RAPS) was derived from 82 FreeSurfer regions using machine learning with bootstrap stability selection to predict the rate of change in CDR-Sum of Boxes (CDR-SB) in 433 amyloid-positive ADNI [ [18] F]florbetapir participants. The fixed nine-region weights were applied without retraining in a cross-tracer ADNI [ [18] F]florbetaben subset (N = 71; largely overlapping the discovery participants) and two external validation cohorts, NACC SCAN (N = 1531; four tracers) and OASIS-3 (N = 428).

RESULTS: RAPS comprised nine regions. In ADNI, RAPS correlated more strongly with CDR-SB slope than CL and showed higher discrimination of rapid decliners (AUC 0.813 vs 0.713). Performance was directionally consistent across validation cohorts; in NACC SCAN, RAPS and CL independently predicted clinical progression. Cross-cohort meta-analysis of the three independent cohorts supported incremental discrimination beyond CL (pooled ΔAUC +0.066; I [2] = 0%).

CONCLUSIONS: RAPS, a fixed regional amyloid PET-derived score, may complement CL for prognostic stratification in Alzheimer's disease research.},
}

@article {pmid42922812,
year = {2026},
author = {Langbaum, JB and Erickson, CM and Langlois, C and Wood, EM and Egleston, BL and Harkins, K and Mim, R and John, S and Brown, C and Brown, S and Howe, S and Cacioppo, C and Eppelmann, L and Enos, J and Salata, H and DeSantiago, D and Largent, EA and Reiman, EM and Denkinger, MN and Ashton, NJ and Roberts, JS and Karlawish, J and Bradbury, AR},
title = {Returning APOE and pTau-217 Results: the eSMARTER Randomized Noninferiority Clinical Trial.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.27.26361535},
pmid = {42922812},
abstract = {IMPORTANCE: Patients are increasingly learning Alzheimer's disease (AD) genetic and biomarker results through electronic health portals. Evaluation of alternative scalable delivery models for return of AD risk information is needed to best support patient understanding and psychological well-being.

OBJECTIVE: To determine whether a patient-centered digital platform is comparable to clinician-mediated telehealth sessions for returning APOE and plasma pTau-217 results on outcomes of knowledge and psychological well-being.

DESIGN: The Evaluation of Self-Mediated Alternatives for Risk Testing Education and Return of Results (eSMARTER) study was a noninferiority trial of a patient-centered digital platform compared to clinician-mediated disclosure of APOE genotype and optional pTau-217 disclosure.

SETTING: Decentralized, fully remote trial enrolled participants in the contiguous United States (U.S.) between October 2024 and February 2025, with follow-up completed in November 2025.

PARTICIPANTS: Eligible participants were aged 60-80 and had previously undergone APOE genotyping (without disclosure) via the GeneMatch program, passed psychological screening, had internet access, and were English-speaking.

INTERVENTIONS: Participants were randomized, 2:1, to the eSMARTER digital platform or clinician-mediated disclosure of APOE genotype. Following the 6-month post- APOE assessment, participants were offered optional pTau-217 disclosure via the same randomized modality.

MAIN OUTCOMES AND MEASURES: Primary outcomes at 1-7 days following APOE disclosure included changes in anxiety, disease-specific distress, and AD-related knowledge within a priori non-inferiority margins.

RESULTS: 674 persons (mean [SD] age 68 [4.7] years; 451 [67%] female; mean [SD] telephone MoCA=19 [2]) were eligible and provided demographic information. 651 participants were randomized to clinician-mediated (n=216) or digital disclosure (n=435) and completed APOE disclosure (66 [10%] APOE4 homozygotes, 377 [58%] heterozygotes, 208 [32%] non-carriers). 604 participants completed the study; 500 completed optional pTau-217 disclosure. Baseline characteristics were balanced across groups. At 1-7 days following APOE disclosure, scores on AD-related knowledge, PROMIS Anxiety, and disease-specific distress measures met non-inferiority.

CONCLUSIONS AND RELEVANCE: Disclosure of APOE genotype by the eSMARTER digital platform is non-inferior to clinician-mediated telehealth disclosure. No significant between group differences were found following disclosure of pTau-217 results. Together, these results suggest that this digital platform may provide an evidence-based scalable approach for returning AD genetic and biomarker results.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT06459583.},
}

@article {pmid42922830,
year = {2026},
author = {Choe, S},
title = {Systematic Modality Ablation of Multimodal Machine Learning for Predicting 24-Month Progression from Mild Cognitive Impairment to Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.01.26360413},
pmid = {42922830},
abstract = {INTRODUCTION: Multimodal biomarkers have transformed Alzheimer's disease research, but the incremental contribution of each modality to predicting progression from mild cognitive impairment (MCI) remains unclear. We systematically evaluated individual biomarker modalities using a comprehensive ablation framework.

METHODS: We analyzed 2,430 participants with MCI from the Alzheimer's Disease Neuroimaging Initiative with known 24-month progression status. XGBoost models were trained using combinations of demographic variables, cognitive assessments, apolipoprotein E (APOE) genotype, structural MRI, cerebrospinal fluid (CSF) biomarkers, and PET biomarkers. Performance was evaluated using repeated stratified 5×10 cross-validation; discrimination was assessed using the area under the receiver operating characteristic curve (AUC), with pairwise comparisons via DeLong's test on single-pass out-of-fold predictions, Holm-Bonferroni corrected. Complete-case analyses evaluated the impact of missing data and median imputation.

RESULTS: The full multimodal model achieved the highest discrimination (AUC=0.934). Excluding cognitive assessments produced the largest reduction (AUC=0.883, P<0.001 vs. multimodal), the only comparison to remain significant after correction. Removing APOE, CSF, or MRI produced only modest, statistically indistinguishable reductions (AUC=0.933, 0.931, 0.932). Removing PET produced a similarly small reduction in the primary analysis (AUC=0.932), but complete-case sensitivity analysis showed imputation significantly inflated this estimate (P=0.005); PET's true contribution may exceed the other three. The baseline clinical model performed near chance (AUC=0.556).

DISCUSSION: Cognitive assessment contributes substantially more predictive information for 24-month progression than structural imaging, molecular biomarkers, or genetic risk, whose removal produces only modest, largely statistically indistinguishable performance loss - with the exception of PET, whose apparent equivalence may be an imputation artifact. These findings establish an evidence-based hierarchy of biomarker utility and provide a quantitative framework for designing cost-effective prediction models and prioritizing biomarker acquisition in clinical research and multimodal AI systems.},
}

@article {pmid42922833,
year = {2026},
author = {Sadia, H and Doyon, N and Duchesne, S and , },
title = {External Validation of a Mathematical Model of Brain Health.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.01.26361929},
pmid = {42922833},
abstract = {BACKGROUND: Understanding the mechanisms underlying brain aging and age-related pathological changes is essential for advancing brain health research. Our group previously developed a mechanistic mathematical model of healthy brain Chamberland et al. (2024) that integrates key biological processes involved in normal aging, from which Alzheimer's disease (AD)-related changes may emerge naturally.

OBJECTIVES: To characterize and validate this brain model by evaluating its sensitivity, calibrating its parameters, and assessing generalizability in independent populations.

METHODS: The model represents the evolution of key biological processes associated with brain aging, including amyloid beta (A β), tau pathologies, neuroinflammation, and neuronal death. After identifying the 30 most influential parameters, we calibrated the model using cognitively normal (CN) participants from the AD Neuroimaging Initiative (ADNI) database (n = 211) by minimizing a loss function composed of three outcomes (A β plaques, tau tangles, and neuronal density). The calibrated model was then applied to the UK Biobank cohort (n = 35, 899) of normal controls (aged 44-82 years). The effects of sex and APOE were evaluated using stratified simulations.

RESULTS: Parameter calibration significantly reduced the prediction errors for A β and tau. Neuronal density predictions showed strong agreement in the UK Biobank cohort. The variance decomposition identified APOE status as a major contributor to variability in A β .

CONCLUSION: Our validated brain health model links mechanistic pathways with population data and reproduces neuronal density patterns in an independent cohort. These findings support its use as a framework for studying brain aging and investigating how Alzheimer's disease-related pathological changes may emerge with aging.},
}

@article {pmid42922840,
year = {2026},
author = {Choe, S},
title = {Comparative Value of Cognitive and Functional Assessments for Predicting 24-Month Progression from Mild Cognitive Impairment to Alzheimer's Disease: An ADNI Cohort Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.01.26360561},
pmid = {42922840},
abstract = {BACKGROUND: Accurate prediction of progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is important for prognosis, patient management, and clinical trial enrollment.

OBJECTIVE: Cognitive and functional assessments are routinely used in memory clinics, but their relative predictive value remains unclear. We sought to identify which assessments are most predictive of 24-month progression from MCI to AD.

METHODS: We analyzed 2,430 participants with baseline MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who were classified by 24-month progression to AD. Extreme Gradient Boosting (XGBoost) models were trained using repeated stratified 5-fold cross-validation with 10 repetitions. We compared demographic and genetic variables, global cognitive measures (MMSE, ADAS-Cog13, CDR-SB, MoCA), episodic memory, executive function, functional status, and Everyday Cognition (ECog) questionnaires.

RESULTS: The baseline clinical model (age, sex, education, APOE ε4 status) achieved an area under the receiver operating characteristic curve (AUC) of 0.692. Episodic memory showed the highest predictive performance (AUC = 0.915), followed by the Functional Activities Questionnaire (AUC = 0.913).Combining episodic memory, functional assessment, and executive function achieved the best performance (AUC = 0.943, sensitivity = 0.857, specificity = 0.889). Among individual memory measures, Logical Memory Delayed Recall achieved the highest standalone performance (AUC = 0.896), whereas RAVLT Learning provided minimal incremental value.

CONCLUSIONS: Episodic memory is the strongest predictor of 24-month progression from MCI to AD, with functional assessment providing substantial complementary value. Streamlined assessment batteries emphasizing episodic memory and functional status may improve efficient risk stratification in memory clinics and AD clinical trials.},
}

@article {pmid42922844,
year = {2026},
author = {Onoria, JLG and Mukasa, MK and Lwere, K and Buwembo, D and Nassanga, R and Nakasujja, N},
title = {The Complex Dynamics of Caregiving for ADRD Patients in Uganda: Selection Factors, Challenges, and Benefits.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10625978/v1},
pmid = {42922844},
issn = {2693-5015},
abstract = {Background: Family caregivers provide most of the care for people living with Alzheimer's disease and related dementias (ADRD), often without preparation or formal support. While caregiver burden is well documented, little is known about how caregivers are selected within families, the challenges they face, and the personal meaning they derive from caregiving in Uganda. This study explored caregiver selection, caregiving challenges, and perceived benefits in a low‑resource setting. Methods: This qualitative study was conducted in Wakiso District, Uganda, using in-depth interviews with 14 family caregivers purposively selected from a previous caregiver cohort. Interviews were conducted in Luganda, transcribed verbatim, translated into English, and analysed using thematic analysis. The Mental Models Framework guided the interpretation of caregivers' experiences. Results: Three interrelated themes emerged: relational foundations of caregiving, multidimensional struggles of caregiving, and benefits of caregiving. Caregiver selection was shaped by longstanding family relationships, emotional closeness, a sense of responsibility, and, in some cases, the preferences of the person living with ADRD. Caregivers described overlapping emotional, physical, financial, and social challenges that frequently required substantial personal sacrifices, including leaving employment or education to provide care. At the same time, many reported positive experiences, including increased knowledge of dementia, greater empathy, stronger relationships with healthcare providers and community members, and a sense of fulfilment through giving back to relatives who had previously cared for them. Conclusion: Caregiving for people living with ADRD in Uganda is both demanding and deeply rooted in family relationships and cultural expectations. While caregivers face considerable pressures, they also find meaning and personal growth through caregiving. These findings underscore the urgent need for culturally tailored interventions that combine education, psychosocial support, practical skills training, and community‑based resources to strengthen caregiver wellbeing and improve dementia care in sub‑Saharan Africa.},
}

@article {pmid42922881,
year = {2026},
author = {de Bruin, H and Przygodda, X and Wisse, LEM and Ravikumar, S and Duezel, E and Pijnenburg, YAL and Yushkevich, PA and Groot, C and Berron, D and Franzmeier, N and Ossenkoppele, R},
title = {Tau deposition patterns within the medial temporal lobe follow the connectivity of the entorhinal and perirhinal cortex - a combined post-mortem and 7T fMRI study.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10581799/v1},
pmid = {42922881},
issn = {2693-5015},
abstract = {In aging, tau pathology can develop in the medial temporal lobe (MTL), but generally only progresses to the cortex in the context of amyloidosis, driving neurodegeneration and Alzheimer's disease (AD) dementia. Functional connectivity shapes this cortical tau expansion, supporting trans-neuronal tau spreading. However, it is unclear whether MTL tau accumulation itself follows within-MTL connections - particularly those of the transentorhinal (Brodmann area 35 [A35]) and entorhinal cortex (ErC), the earliest cortical sites of tau accumulation in AD and variably affected in aging. To address this, we assessed three-dimensional neurofibrillary tangle (NFT) burden across 14 MTL subregions using post-mortem quantitative histopathology in 25 individuals (n = 4 amyloid-β negative; n = 21 amyloid-β positive) on the AD continuum. These data were combined with high-resolution 7T resting-state functional MRI-based functional connectivity among the same 14 subregions obtained from 30 young healthy controls. We examined covariance in NFT burden across MTL subregions and tested associations with functional connectivity strength. We then applied seed-based connectivity analyses to identify which MTL subregion's connectivity profile best predicted MTL NFT patterns. NFT levels were highest and comparable across A35 (0.62 ± 0.40), posterior cornu ammonis 1 (CA1; 0.61 ± 0.46), anterolateral ErC (alErC; 0.60 ± 0.39), and anterior CA1 (0.57 ± 0.43). We found a significant positive association between MTL connectivity and covariance in MTL NFTs (β = 0.49, p < 0.001), with closely connected MTL regions showing similar NFT levels. When assessing seed-based connectivity as a predictor of NFT patterns, alErC (ρ = 0.66, p < 0.001), A36 (ρ = 0.64, p < 0.001), and posteromedial ErC (pmErC; ρ = 0.59, p < 0.001) connectivity showed the strongest, comparable correspondence with MTL NFT deposition. This pattern was consistent within low (Braak 0-II) and high (Braak III-VI) NFT burden groups. These results suggest that within-MTL tau propagation is shaped by intrinsic network organization, highlighting entorhinal and perirhinal connectivity profiles as potential drivers of MTL tau progression and as candidate targets for therapeutic interventions.},
}

@article {pmid42922884,
year = {2026},
author = {Chen, L and Jin, W and Zhao, F and Ma, X and Lu, Q and Esser, K and Sun, R},
title = {DeepCNet: A multimodal deep learning model for predicting cell type-specific gene expression and promoter-enhancer interactions from single-cell multiome data.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8716015/v1},
pmid = {42922884},
issn = {2693-5015},
abstract = {Understanding promoter-enhancer (PE) interactions is essential for elucidating gene regulation mechanisms. Although existing computational methods leverage DNA sequence to predict gene expression, many were developed primarily for bulk-level genomic data and emphasize predictive accuracy rather than regulatory inference. Here, we propose DeepCNet, a multimodal deep learning framework that predicts cell type-specific gene expression and infers cell type-specific PE interactions, enabling the construction of transcription factor gene regulatory networks (TF-GRNs) from single-cell multiome data. Evaluated on two single-cell multiome datasets from blood and brain tissues, DeepCNet consistently outperforms state-of-the-art methods in predicting cell type-specific gene expression. Importantly, PE interactions inferred by DeepCNet showed greater concordance with orthogonal chromatin interaction and CRISPR perturbation data than competing approaches. Analysis of cell type-specific GRNs identified TF hubs and highlighted both cell type-specific and shared regulatory programs. DeepCNet further extends to two-condition single-cell multiome studies, enabling the identification of differential PE interactions and characterization of TF-GRN alterations across conditions. As an illustrative application, we applied DeepCNet to single-cell multiome data from one Alzheimer's disease (AD) and one healthy control sample, identifying candidate differential PE interactions at AD risk loci and candidate TF hubs associated with AD-related pathways. Together, these results demonstrate the potential of DeepCNet to characterize transcriptional regulatory programs and cooperative TF interactions underlying cell type- and condition-specific gene expression.},
}

@article {pmid42922898,
year = {2026},
author = {Salman, Y and Tomé, SO and Joudiou, N and Annettesdotter, A and Khandelwal, P and Lawson, TM and Behets, C and Lengelé, B and Thal, DR and Yushkevich, PA and Gallez, B and Wisse, LE and Hanseeuw, BJ},
title = {50µm ex vivo MRI reveals distant layer-specific hippocampal atrophy in early Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10800434/v1},
pmid = {42922898},
issn = {2693-5015},
abstract = {Tau pathology is a major driver of neurodegeneration in Alzheimer's disease, yet its earliest structural correlates remain poorly understood because of the limited resolution of in vivo magnetic resonance imaging (MRI). We studied 19 postmortem brains spanning Braak neurofibillary tangle (NFT) stages I (N = 9) and II (N = 10) using ultra-high-resolution ex vivo MRI of the medial temporal lobe (MTL) at 50 × 50 µm[2] in-plane resolution and 100 µm slice thickness. MTL subregions and layers were delineated across the anterior and posterior MTL, including layers of cornu ammonis (CA)1 and CA3, subiculum, dentate gyrus, transentorhinal cortex (Brodmann area 35 [BA35]), and entorhinal cortex (ERC). Associations between AT8-positive NFT density and regional thickness were assessed using nonparametric models controlling for demographic factors and co-pathologies. Ultra-high-resolution MRI enabled visualization of previously inaccessible mesoscopic features, including dentate gyrus lamination, subicular boundaries, and the internal organization of the stratum radiatum/lacunosum-moleculare. Compared with Braak stage I, Braak stage II cases showed significantly lower thickness of the anterior CA1 pyramidal cell layer and anterior subicular stratum lacunosum-moleculare, with findings remaining robust across sensitivity analyses. Anterior CA1 and subicular thinning were strongly associated with NFT burden in early Braak-affected regions (ERC/BA35), rather than with local tau pathology, supporting a distant effect of tau on neurodegeneration. Interaction analyses further suggested that the association between tau pathology and CA1 atrophy differed according to TDP-43 status. These findings demonstrate that tau-related atrophy is detectable as early as Braak stage II and preferentially affects anterior CA1 and subiculum at the laminar level, supporting a network-level mechanism of early neurodegeneration.},
}

@article {pmid42922925,
year = {2026},
author = {Rakovskaya, A and Lozhkov, A and Tverdokhlebova, V and Zabrodskaya, Y and Vinokurov, E and Kirenskaya, V and Erofeev, A and Garshinina, A and Zryacheva, V and Shtro, A and Pchitskaya, E and Vlasova, O and Elpaeva, E and Dav, P and Bezprozvanny, I and Vasin, A},
title = {Influenza A (H1N1)pdm infection exacerbates behavioral, cognitive, and synaptic impairments in 5xFAD mice.},
journal = {Frontiers in behavioral neuroscience},
volume = {20},
number = {},
pages = {1955816},
pmid = {42922925},
issn = {1662-5153},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline, synaptic dysfunction, and neuroinflammation, which may be influenced by systemic factors such as infection. The present study aimed to investigate the effects of prior influenza A (H1N1)pdm infection on behavioral, synaptic, and neuroinflammatory alterations in the 5xFAD mouse model of AD. Mice were intranasally infected at 2 months of age and underwent behavioral assessment from 7 months of age using tests of social, affective, exploratory, and cognitive function. Hippocampal synaptic function and structure were assessed by CA1 long-term potentiation (LTP) recordings and dendritic spine analysis, while neuroinflammation and amyloid pathology were evaluated by Western blot and immunohistochemistry. 5xFAD mice exhibited impairments in hippocampus-dependent memory, social behavior, and affective responses. Prior H1N1pdm infection modulated these phenotypes, resulting in increased depressive-like behavior in the tail suspension test and alterations in exploratory and social activity. At the synaptic level, reduced LTP and decreased dendritic spine density were observed in 5xFAD mice, along with a shift toward immature spine morphology. Viral infection induced similar synaptic alterations in wild-type mice but did not further exacerbate synaptic deficits in 5xFAD animals. Both amyloid pathology and infection were associated with increased astrocytic and microglial activation, with the strongest neuroinflammatory response detected in infected 5xFAD mice. Overall, prior H1N1pdm infection altered behavioral and neuroinflammatory phenotypes but did not further aggravate the already established synaptic deficits in 5xFAD mice. These findings support a non-additive interaction between systemic inflammation and neurodegenerative pathology and may help explain the heterogeneous consequences of viral infection in older individuals with cognitive impairment.},
}

@article {pmid42922938,
year = {2026},
author = {Farzana, S and Arian, A and Rundek, T and Desvarieux, M and Ahsan, H},
title = {Evaluating Clinical Foundation Models for Early Alzheimer's Disease and Related Dementia Prediction from Longitudinal EHRs.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.01.26361933},
pmid = {42922938},
abstract = {Early identification of Alzheimer's disease and related dementias (ADRD) remains challenging despite its importance for timely intervention, management of modifiable risk factors, and care planning. We developed and evaluated ADRD onset prediction models using longitudinal electronic health records (EHRs) from the All of Us Research Program at clinically meaningful lead times of 6, 12, 24, and 36 months before diagnosis, benchmarking interpretable count-based representations against four publicly available pretrained clinical foundation models (CLMBR-T, GPT-style, LLaMA-style, and Mamba) across multiple ADRD phenotype definitions. Count-based models consistently achieved the highest discrimination and calibration across all cohorts and prediction horizons. Predictive performance declined with increasing lead time for all approaches; however, the performance gap between count-based and pretrained representations progressively narrowed, with foundation models achieving comparable AUROC of 0.719 (compared to the AUROC of 0.738 of count-based model) at the 36-month horizon while providing higher sensitivity and F1 scores under a fixed operating threshold. External validation with zero-shot evaluation on UChicago EHRs exhibited limited generalizability for count-based and pretrained clinical foundation model based representations. These findings demonstrate that transparent count-based EHR representations remain the strongest overall approach for ADRD onset prediction, while pretrained clinical foundation models provide complementary advantages for long-term risk identification and establish a benchmark for evaluating transferable clinical representations in temporal ADRD risk prediction.},
}

@article {pmid42923152,
year = {2026},
author = {Zhao, J and Zhao, Z and Jiang, T and Guo, J and Yang, S and Fan, L and Zhu, L},
title = {Biological functions of progranulin and research progress in neurodegenerative diseases.},
journal = {American journal of translational research},
volume = {18},
number = {9},
pages = {7521-7538},
pmid = {42923152},
issn = {1943-8141},
abstract = {Progranulin (PGRN), a multifunctional glycoprotein, is widely expressed in the central nervous system, particularly in microglia. Dysregulation of PGRN is strongly linked to the pathogenesis of frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD), highlighting its essential role in brain homeostasis. While there are several mechanisms through which PGRN regulates lysosomal function, lipid metabolism, neuroinflammation, and microglial activation have been elucidated, its precise pathological network in neurodegenerative diseases remains incompletely understood. This review summarizes the biological functions of PGRN and recent research progress in neurodegenerative diseases, and discusses its potential as a biomarker and therapeutic target. In addition, we propose an integrative "cascade-amplifying pathological network" hypothesis - a self-reinforcing positive feedback loop involving lysosomal dysfunction, lipid accumulation, and microglial activation, with the strongest evidence in GRN-mutation FTD and emerging relevance to AD and PD. Moreover, we incorporate recent advances from 2024-2026, including updated clinical trial outcomes, novel insights into PGRN-mediated lipid metabolism regulation, and emerging evidence on cell-type-specific mechanisms of PGRN function.},
}

@article {pmid42923225,
year = {2026},
author = {Zhao, J and Nie, C and Gao, R and Hu, Z and Lin, Y},
title = {Noninvasive diagnosis of Alzheimer's disease: a review of emerging biomarkers and multimodal approaches.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1964029},
pmid = {42923225},
issn = {2296-634X},
abstract = {Noninvasive biomarkers are expanding access to biological assessment of Alzheimer's disease (AD). This review evaluates blood-based, neuroimaging, retinal, electrophysiological, digital, and behavioral measures alongside structured cognitive and functional assessment, and examines multimodal and machine-learning approaches for detection, differential diagnosis, prognosis, and treatment monitoring. Plasma phosphorylated tau, particularly p-tau217, currently offers the strongest scalable evidence for identifying amyloid and advanced tau pathology, whereas PET and MRI retain complementary roles in pathological confirmation, regional staging, exclusion of alternative causes, and characterization of atypical phenotypes. Retinal, electrophysiological, speech, sleep, and eye-tracking measures remain promising but require greater standardization and external validation. Across modalities, biomarker trajectories are temporally staggered, assay and platform differences affect interpretation, and pathology-phenotype mapping is modified by disease stage, cognitive reserve, copathology, vascular factors, and population characteristics. We therefore propose a phenotype-anchored, stepped pathway that begins with patient and informant history, objective cognitive and functional assessment, structural imaging, and routine laboratory evaluation; adds validated blood biomarkers when they resolve a defined uncertainty; and reserves CSF or PET for unresolved, atypical, or treatment-relevant cases. Discordant findings should prompt reassessment rather than automatic reclassification. We describe the literature-search and descriptive evidence-categorization approach used to select and categorize the evidence reviewed, and we place the findings within the emerging regulatory context of blood-based testing. Clinical translation will depend on harmonized thresholds, representative prospective cohorts, calibration, independent validation, and evidence that multimodal systems improve decisions and patient outcomes rather than benchmark accuracy alone.},
}

@article {pmid42923404,
year = {2026},
author = {Simić, S and Leuci, R and Pirker, M and Kalaba, P and Wackerlig-Damle, J and Piemontese, L and Langer, T},
title = {Rapid HPLC-Based ADME Profiling of Novel Donepezil and Rivastigmine Analogues for Potential Application in Alzheimer's Disease.},
journal = {ACS omega},
volume = {11},
number = {41},
pages = {63529-63553},
pmid = {42923404},
issn = {2470-1343},
abstract = {Multitarget ligands derived from established cholinesterase inhibitors offer a strategy for addressing the multifactorial pathology of Alzheimer's disease, but biological potency must be considered together with developability. In this study, a rapid biomimetic high-performance liquid chromatography-based workflow was used to characterize key absorption, distribution, metabolism and excretion-related properties of 26 donepezil- and rivastigmine-derived hybrid compounds, including plasma stability, plasma protein binding, membrane affinity, biomimetic distribution parameters, blood-brain barrier permeability, intestinal absorption, experimental log P and aqueous solubility. Plasma stability was reassessed using first-order regression across seven time points with 95% confidence intervals. Most profiles showed limited degradation during the 24 h experiment; accordingly, many apparent half-lives required extrapolation and are interpreted as comparative stability parameters rather than estimates of in vivo persistence. Human serum albumin and α1-acid glycoprotein binding was generally high, emphasizing the need to balance protein binding with the unbound fraction, while immobilized artificial membrane-based models predicted central nervous system-positive classification and high intestinal absorption across the series. Importantly, the blood brain barrier permeability and CNS-distribution estimates are derived from biomimetic models and should be regarded as predictive descriptors that require confirmation in dedicated in vivo pharmacokinetic studies. Solubility was more variable and emerged as an important differentiating property, with compound (26) showing the most favorable profile. An exploratory desirability-based ADME score placed compounds (15), (8), (26), (4), (10) and (24) in the highest tier. Integration with previously reported cholinesterase, fatty acid amide hydrolase and monoamine oxidase activities, which were not remeasured in the present study, further refined lead selection: (24) provided the clearest potency-developability compromise and was prioritized as the principal lead, whereas (26) emerged as a developability-oriented colead. (3) and (18) remained potency-driven secondary candidates. Overall, combining biomimetic ADME profiling with existing pharmacological evidence provides a transparent framework for early lead prioritization and supports confirmatory pharmacokinetic, exposure and in vivo efficacy studies.},
}

@article {pmid42923435,
year = {2026},
author = {Zhang, G and Li, H and Zhen, X and Liu, Y and Huang, L},
title = {Machine Learning in Amyloidogenic Polypeptide Research: From Sequence Prediction to Drug Discovery.},
journal = {ACS omega},
volume = {11},
number = {41},
pages = {62296-62309},
pmid = {42923435},
issn = {2470-1343},
abstract = {Over the past decade, machine learning (ML) has established a transformative paradigm for investigating amyloidogenic polypeptides. Characterized by their propensity to form ordered, β-sheet-rich fibrillar aggregates, these polypeptides are centrally implicated in the pathogenesis of numerous neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). This review systematically evaluates the application of ML across critical domains of amyloid investigation: sequence-based amyloidogenicity prediction, structural biology, inhibitor design, and amyloid-related clinical objectives. We further summarize the diverse array of ML architectures currently employed in amyloid research, spanning classical algorithms (e.g., support vector machines and random forests) to advanced deep learning frameworks, such as the transformer framework, protein language models (PLMs), etc. Additionally, we spotlight emerging frontiers, namely, the integration of ML with molecular dynamics (MD) simulations, the use of generative AI for de novo inhibitor design, etc., while addressing persistent bottlenecks in the field, including data standardization, model interpretability, and rigorous experimental validation for in silico predictions. Ultimately, this review serves as a foundational roadmap for emerging researchers and a definitive reference for established investigators operating at the intersection of artificial intelligence and amyloid biology.},
}

@article {pmid42923488,
year = {2026},
author = {Luo, Y and Gu, J},
title = {Protein glycosylation and glycation in Alzheimer's disease: mechanisms, crosstalk, and therapeutic perspectives.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1925934},
pmid = {42923488},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, pathologically characterized by extracellular senile plaques composed of amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau. Despite decades of research, the molecular mechanisms underlying AD pathogenesis remain incompletely understood, and effective disease-modifying therapies are still lacking. Protein glycosylation and glycation, two distinct post-translational modifications, have emerged as critical contributors to AD pathophysiology. Glycosylation, an enzymatically regulated process including N-linked glycosylation, O-GlcNAcylation, and O-GalNAc glycosylation, modulates the processing of amyloid precursor protein (APP), the aggregation propensity and hyperphosphorylation of tau, the function of apolipoprotein E (ApoE), and neuroinflammatory signaling. Aberrant glycosylation patterns have been consistently detected in the brain, cerebrospinal fluid (CSF), and plasma of AD patients, highlighting their potential as diagnostic biomarkers. In contrast, glycation is a non-enzymatic reaction between reducing sugars and proteins that generates advanced glycation end products (AGEs), which promote oxidative stress, neuroinflammation, blood-brain barrier (BBB) dysfunction, and Aβ and tau aggregation through interaction with the receptor for AGEs (RAGE). This review systematically summarizes recent advances in understanding the roles of glycosylation and glycation in AD pathogenesis, their crosstalk with classical hallmarks, and their translational value as biomarkers and therapeutic targets, providing novel perspectives for early diagnosis and multi-target intervention strategies for AD.},
}

@article {pmid42923504,
year = {2026},
author = {Hossan, R and Selim, S and Rakib, IH and Sayeed, MA and Chakrabarty, A and Hossain, MA and Mia, E and Debnath, D and Bristy, AH and Al Hasan, MS},
title = {Neuroprotective Effects of Carica papaya in Experimental Models of Neurodegeneration: A Comprehensive Review.},
journal = {Food science & nutrition},
volume = {14},
number = {10},
pages = {e72507},
pmid = {42923504},
issn = {2048-7177},
abstract = {Carica papaya (C. papaya) has long been used in traditional medicine, and experimental studies have reported neuroprotective effects across several models; however, the available evidence is distributed across different plant parts, preparations, and experimental systems. This review synthesizes existing evidence from in vitro and in vivo studies assessing the neuroprotective, antioxidant, anti-inflammatory, and neuromodulatory effects of C. papaya extracts derived from seeds, leaves, pulp, fruit, and fermented preparations. A comprehensive literature search of PubMed, Scopus, Web of Science, Google Scholar, and ScienceDirect identified relevant studies across multiple experimental models through 22 September 2026. Findings show that in Alzheimer's disease (AD) models, aluminum-induced neurotoxicity, D-galactose-induced brain aging, 6-hydroxydopamine (6-OHDA)-mediated oxidative damage, and chemically induced neurotoxicity (cyclophosphamide, acrylamide, and fluoride), C. papaya preparations were associated with improvements in selected cognitive, behavioral, biochemical, and oxidative-stress-related outcomes across the included experimental models. Toxicity studies generally reported no mortality within the tested dose ranges; however, behavioral, biochemical, and mild histopathological alterations were observed in some studies, particularly at higher doses, indicating that safety may vary according to extract type, dose, and duration of exposure. Overall, the available preclinical evidence suggests that C. papaya preparations may affect multiple pathways relevant to oxidative-stress-associated neurodegeneration. However, further mechanistic studies, bioactive compound isolation, pharmacokinetic assessments, and well-designed clinical trials are essential to support its future therapeutic development.},
}