@article {pmid41935184,
year = {2026},
author = {Lei, Y and Chen, Y and Guo, M and Patel, F and Bai, Y and Goo, B and Du, Q and Weintraub, NL and Lu, XY},
title = {Neuronal HDAC9: A key regulator of cognitive and synaptic aging, rescuing Alzheimer's disease-related phenotypes.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41935184},
issn = {1476-5578},
support = {AG076235//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG064895//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG083841//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG062166//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG076235//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG064895//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Epigenetic regulation is a key determinant of the aging process, and its dysregulation contributes to cognitive aging and increased vulnerability to Alzheimer's disease (AD). As major regulators of epigenetic processes, histone deacetylases (HDACs) have emerged as potential therapeutic targets for cognitive enhancement in neurodegenerative diseases. However, the distinct roles of individual HDAC isoforms remain to be defined. Here, we report that HDAC9 is specifically expressed in neurons of human and mouse brains, and its expression declines with age. HDAC9 deficiency impairs cognitive function and synaptic plasticity in young mice. Selective deletion of HDAC9 in hippocampal CA1 neurons also induces cognitive impairment. In contrast, overexpression of HDAC9 in forebrain glutamatergic neurons preserves cognitive function in aged mice. Moreover, HDAC9 is also downregulated in the brain of AD mouse models, whereas neuronal overexpression of HDAC9 alleviates AD-related cognitive and synaptic deficits and reduces Aβ deposition. Together, these findings suggest neuronal HDAC9 is necessary and sufficient for maintaining cognitive and synaptic functions in the context of aging and AD.},
}

@article {pmid41935248,
year = {2026},
author = {Basak, A and Erol, FMB and De Rosa, MC and Dong, Z and Ogbolu, V and Glover, HJ and Rausch, R and Hargus, G and Creus-Muncunill, J and Buchanan, H and Bai, Y and Su, Q and Chang, B and Adler, C and Flaherty, D and Ciener, B and Xiao, H and Reddy, H and Aime-Wilson, P and Reitz, C and Sleeman, MW and Altarejos, JY and Leibel, RL and Qiang, LO and Teich, AF and Doege, CA},
title = {Cellular signatures of melanocortin pathway genes across the locus coeruleus.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02287-x},
pmid = {41935248},
issn = {2051-5960},
}

@article {pmid41935326,
year = {2026},
author = {Jati, S and Taheri, S and Kal, S and Sinha, SC and Head, BP and Mahata, SK and Sahoo, D},
title = {AI guided discovery of a murine model of asymptomatic Alzheimer's disease.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02286-y},
pmid = {41935326},
issn = {2051-5960},
}

@article {pmid41935371,
year = {2026},
author = {Moftakhar-Bazkiaei, A and Farzaneh, M},
title = {Network-based Transcriptomic Profiling of Fetal Astrocyte Differentiation Reveals Therapeutic Targets for Neurodegenerative Disease.},
journal = {Current molecular medicine},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115665240412373260224061022},
pmid = {41935371},
issn = {1875-5666},
abstract = {INTRODUCTION: Neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD), and Age-related Macular Degeneration (AMD), are marked by the progressive loss of specific neuronal populations. Astrocytes, the glial cells surrounding neurons, play a critical role in maintaining neuronal health by providing neurotrophic support, producing antioxidants, and clearing waste. Dysfunctional astrocytes contribute to disease progression, yet their developmental trajectory and molecular regulation remain incompletely understood.

METHOD: This study aims to computationally characterize transcriptional differences between fetal astrocytes and neural stem cell lines to identify key regulatory genes, pathways, and therapeutic targets relevant to astrocyte-linked neurodegeneration. Using microarray data and bioinformatics pipelines, 359 Differentially Expressed Genes (DEGs) were identified, including 249 upregulated and 110 downregulated transcripts.

RESULTS: Protein-Protein Interaction (PPI) network analysis revealed ten hub genes- COL1A1, TIMP1, LOX, COL6A1, COL6A3, COL5A1, CD44, LTBP2, ACTA2, and PLAU-central to extracellular matrix remodeling and cell adhesion. Drug-gene interaction analysis linked these genes to compounds such as Estradiol valerate, Retinoic acid, and Calcitriol, suggesting therapeutic relevance.

DISCUSSION: Enrichment analysis highlighted transcriptional regulation, apoptosis, and ECM-receptor interaction as dominant biological themes. Key miRNA-mRNA interactions, including hsa-miR-877-5p and hsa-miR-767-5p targeting LOX and COL6A3 were also identified.

CONCLUSION: Overall, this study integrates transcriptomic profiling, network modeling, and drug-gene interaction analysis to uncover astrocyte-specific molecular targets, offering a computational framework for therapeutic exploration in neurodegenerative disease.},
}

@article {pmid41935386,
year = {2026},
author = {Dhanawat, M and Malik, G and Wilson, K and Bhushan, B},
title = {Anti-alzheimer Drugs Development and Small Molecules: Mechanistic Understanding of the 5HT4 and 5-HT6 Receptor.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X428162260224193303},
pmid = {41935386},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) affects millions worldwide, yet currently approved therapies provide only symptomatic relief without altering disease progression. Increasing evidence shows that serotonergic dysfunction contributes to cognitive decline in AD, particularly through altera-tions in the 5-HT4 and 5-HT6 receptor pathways. Modulation of these receptors influences acetyl-choline release, APP processing, amyloid burden, and synaptic plasticity. This review summarizes the mechanistic roles of 5-HT4 and 5-HT6 receptors in AD pathology, highlights key structure-activity relationship (SAR) trends in ligand development, and evaluates clinical outcomes of recep-tor-targeted therapies. Recent work supports 5-HT4 agonists and 5-HT6 antagonists as promising candidates for cognitive enhancement and disease modification. However, challenges in target en-gagement, receptor selectivity, and clinical translation underscore the need for more refined drug-design strategies.},
}

@article {pmid41935406,
year = {2026},
author = {Sannemann, L and Gerards, M and Bohr, L and Brosseron, F and Escher, C and Kalthegener, F and Müller, T and Ramírez, A and Zeyen, P and Jessen, F and Rostamzadeh, A},
title = {Dementia risk factor assessment in a local Alzheimer's prevention population: a German cross-sectional, observational study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100556},
doi = {10.1016/j.tjpad.2026.100556},
pmid = {41935406},
issn = {2426-0266},
abstract = {BACKGROUND: The risk for dementia is to a significant extent driven by potentially modifiable factors. Prevention strategies are increasingly aiming at individually tailored risk reduction approaches, particularly in light of emerging Brain Health Services for dementia prevention (dBHS).

METHODS: The cross-sectional observational study "Individual Risk Profiling for Alzheimer's and Dementia Prevention" (INSPIRATION) assessed the individual risk factors of 162 participants of the local Cologne Alzheimer Prevention Registry and provided individual feedback on risk profiles during a single visit. We analysed the frequency and patterns of risk factors and explored their association with cognition and Alzheimer's disease (AD) plasma biomarkers.

FINDINGS: The most common risk factors in this population were obesity, non-adherence to a Mediterranean diet, low subjective sleep quality, subjective experience of stress, and hearing impairment. A principal component analysis (PCA) revealed six principal components (PC), which we labeled as (1) psychosocial factors, (2) blood pressure, (3) physical condition, (4) hearing impairment, (5) lifestyle, and (6) substance use. We found isolated associations between PCs, cognition, and AD plasma biomarkers.

INTERPRETATION: These findings provide initial insights into which risk factors may be most relevant and actionable for highly-educated and prevention-motivated populations likely to seek dBHS. Interventions addressing the domains of psychosocial factors, physical condition, and lifestyle may be particularly relevant to consider for a personally tailored risk reduction approach in comparable populations.

FUNDING: The study was funded by research funds of the Medical Faculty and the University Hospital Cologne, University of Cologne and the non-profit association Kölner Verein für seelische Gesundheit e.V.},
}

@article {pmid41935407,
year = {2026},
author = {Wu, J and Zhou, J and Shan, S and Tang, K and Zhu, L and Ying, J and Liu, X and Song, P},
title = {Global, regional, and national burden of dementia attributable to mood disorders: a comparative risk assessment study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100559},
doi = {10.1016/j.tjpad.2026.100559},
pmid = {41935407},
issn = {2426-0266},
abstract = {BACKGROUND: Mood disorders, particularly depressive and bipolar disorders, have emerged as potentially modifiable risk factors for dementia. However, the burden of dementia attributable to mood disorders remains unquantified. We aimed to quantify that burden among adults aged 45 years and older using a comparative risk assessment approach.

METHODS: A literature search was performed in PubMed, Embase, and MEDLINE to identify cohort studies that assessed the association between mood disorders and subsequent dementia from database inception to 9th April 2025. Random-effects models were used to derive pooled risk ratios (RRs). Assuming a 5-year lag between mood disorders and dementia onset, we calculated population attributable fractions (PAFs) and age-standardized disability-adjusted life year (DALY) rates (ASDRs) at global, regional, and national levels. Temporal trends in ASDR were analyzed using joinpoint regression to estimate average annual percentage change.

RESULTS: 77 articles were included. The pooled RR for all-cause dementia was 1.90 (95% confidence interval [CI]: 1.70, 2.12) for depressive disorders, and 3.10 (95% CI: 2.21, 4.35) for bipolar disorder. For dementia subtypes, depressive disorders showed an association with Alzheimer's disease (RR: 2.57, 95% CI: 2.05, 3.23), and bipolar disorder was associated with vascular dementia (RR: 3.67, 95% CI: 2.42, 5.57). In 2016, the global PAFs of dementia attributable to depressive disorders were 4.79% (95% CI: 3.19%, 6.58%) in males and 5.56% (95% CI: 3.56%, 7.84%) in females. PAFs for bipolar disorder were 1.22% (95% CI: 0.65%, 2.01%) in males and 1.34% (95% CI: 0.71%, 2.18%) in females. In 2021, the global ASDR of dementia attributable to depressive disorders was 89.61 (95% CI: 34.80, 192.24) per 100,000 population, while the global ASDR for bipolar disorder was 15.91 (95% CI: 5.56, 37.87) per 100,000 population.

CONCLUSION: Since mood disorders are a substantial contributor to dementia burden, integrating mental health management into public health policies is essential.},
}

@article {pmid41935590,
year = {2026},
author = {Wang, J and Mao, X and Zheng, R and Gao, H and Chen, G and Zhang, Y and Xu, M and Lin, Q and Nivar, J and Tao, YX and Sun, M and Cao, H and Zhang, J and Li, J},
title = {Chloride intracellular channel 4 contributes to Aβ-induced cognitive impairment in mice through the regulation of mitochondrial fission. CLIC4 promotes mitochondrial fission.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112499},
doi = {10.1016/j.cellsig.2026.112499},
pmid = {41935590},
issn = {1873-3913},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by impaired memory and cognitive decline. The early stages of AD in mice present with neuropathy in the hippocampus. Excessive mitochondrial fragmentation and dysfunction are critical pathological features of AD. Chloride intracellular channel 4 (CLIC4) is involved in neuronal apoptosis and regulates mitochondrial functions. Glial maturation factor β (GMFβ) inhibits mitochondrial DNA replication and energy metabolism, causes mitochondrial dysfunction, and regulates apoptosis. Dynamic related protein 1 (DRP1), a key protein in mitochondrial division, exhibits increased activity when its Ser616 site is phosphorylated. However, the role of CLIC4 in Aβ-induced cognitive impairment through the modulation of GMFβ and p-DRP1 (Ser616) to induce mitochondrial dysfunction remains unclear. This study examined the role of CLIC4 in Aβ-induced cognitive impairment in AD mice, focusing on its regulation of GMFβ and p-DRP1 (Ser616) and the subsequent effects on mitochondrial hyperfission and dysfunction. Our findings demonstrate that overexpression of CLIC4 in the mouse hippocampus or in HT22 cells resulted in pathological changes analogous to those observed following Aβ exposure. These changes include elevated levels of GMFβ and p-DRP1 (Ser616) proteins, mitochondrial fission, and increased intracellular ROS production. Conversely, CLIC4 knockdown mitigated Aβ-induced neuronal damage. These findings indicate that CLIC4 may be crucial in Aβ-induced hippocampal neurological damage in mice by regulating GMFβ and DRP1 phosphorylation.},
}

@article {pmid41935644,
year = {2026},
author = {Aumont-Rodrigue, G and Poirier, A and Picard, C and Poirier, J and , },
title = {Human APOB mice translates molecular phenotypes across the Alzheimer's disease spectrum.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106575},
doi = {10.1016/j.bbi.2026.106575},
pmid = {41935644},
issn = {1090-2139},
abstract = {BACKGROUND: Apolipoprotein B (APOB), a structural component of low-density lipoproteins (LDL), has historically been associated with peripheral lipid transport and cardiovascular disease. Recent studies have revealed a link between APOB and Alzheimer's disease (AD), with increased cerebrospinal fluid (CSF) APOB levels correlating with tau pathology. Although APOB is known to be locally expressed in the brain, albeit at very low levels, its function in the central nervous system and contribution to neurodegenerative processes remains poorly understood. To investigate the effects of chronic APOB overexpression on brain molecular homeostasis, we used a transgenic mouse model expressing human APOB-100 and integrated findings with human cohort data to assess its functional relevance to AD pathology.

METHODS: Human APOB transgenic (hAPOB) and wild-type mice were aged to 6 and 12 months. Frontal cortices were analyzed using RNA sequencing and mass spectrometry-based proteomics. Differentially expressed genes and proteins were analyzed via pathway enrichment and cell type deconvolution. Findings were contrasted to post-mortem proteomic alterations observed in brain tissue (ROSMAP) and in the CSF (ADNI).

RESULTS: hAPOB overexpression in mice induced a robust and persistent upregulation of innate immune genes, particularly those associated with type I interferon responses (Irf7, Ifit1, Oas2), in both young and old transgenic mice. Reduced microglial and endothelial cell signatures were observed through cell type deconvolution, which suggests immune activation without proliferation and possible blood-brain barrier damage. Proteomic analyses showed differentially expressed proteins associated with oxidative stress and dendritic remodeling. Proteins dysregulated in mice-such as CTSD, CRK, and SULT4A1-also showed altered expression in AD human brain and CSF. Remarkably, these proteins are dysregulated in the opposite direction in humans than in mice, unveiling a complex downstream regulation of APOB overexpression.

CONCLUSION: Chronic hAPOB overexpression drives sustained neuroinflammatory and oxidative responses, potentially mimicking viral-like immune activation in the brain. The proteins dysregulated in hAPOB transgenic mice brains were also dysregulated in humans on opposite side of the APOB level spectrum. Nevertheless, this result shows a consistency across species on hAPOB-driven downstream effects. Some of these proteins were also shown to associate with key features of AD pathology, namely Aβ, Tau and pTau. Our findings support a novel role for APOB in modulating brain immune homeostasis and neurodegenerative processes, offering a mechanistic link between vascular risk and Alzheimer's disease.},
}

@article {pmid41935672,
year = {2026},
author = {Hao, X and Wang, X and Liu, R and Li, Y and Dong, C and Liu, J},
title = {Amyloid pathology drives cognitive decline in Alzheimer's Disease through impairing neurovascular coupling: An [[18]F]-Florbetapir PET/MRI Study.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111863},
doi = {10.1016/j.brainresbull.2026.111863},
pmid = {41935672},
issn = {1873-2747},
abstract = {BACKGROUND: Neurovascular coupling (NVC) impairment is implicated in Alzheimer's disease (AD), but its relationship with amyloid-β (Aβ) pathology and diagnostic value remain unclear. We examined Aβ-related NVC changes and their mediating role in cognitive decline.

METHODS: Using [¹⁸F]-florbetapir PET/MRI, we assessed Aβ deposition, neural activity, and cerebral blood flow (CBF) in 96 participants (24 Aβ-negative mild cognitive impairment [MCI⁻], 30 Aβ-positive MCI [MCI⁺], and 42 Aβ-positive AD [AD⁺]). Neural activity was quantified using amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and degree centrality (DC). Multidimensional NVC was derived from spatial correlations between CBF and these neural activity metrics.

RESULTS: Global NVC progressively decreased (MCI⁻ > MCI⁺ > AD⁺). Compared to MCI⁻, the MCI⁺ group exhibited reduced NVC in default mode network hubs, including posterior cingulate gyrus, angular gyrus, and precuneus. These regional metrics demonstrated good diagnostic performance in distinguishing MCI⁺ from MCI⁻, with the combined model achieving an AUC of 0.935 and robust internal validation. The AD⁺ group showed extended impairment to frontal, visual, limbic, and subcortical areas compared to MCI⁺. Mediation analysis identified CBF-DC coupling in left posterior cingulate gyrus as a key mediator between Aβ burden and cognitive impairment for MMSE (β = -1.893, 95% CI: [-4.237, -0.253]) and MoCA (β = -2.614, 95% CI: [-5.472, -0.472]).

CONCLUSION: NVC impairment links Aβ pathology to cognitive decline, with the left posterior cingulate gyrus as a key region. This supports AD's neurovascular hypothesis in vivo and highlights NVC as a potential biomarker and target for early diagnosis and intervention.},
}

@article {pmid41935791,
year = {2026},
author = {Juanlu, C and Chen, PS},
title = {Transcriptomic Dissociation Between Synaptic Plasticity Suppression and Structure-Related Maintenance Signaling in the Alzheimer's Frontal Cortex: A Molecular Analysis.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116202},
doi = {10.1016/j.bbr.2026.116202},
pmid = {41935791},
issn = {1872-7549},
abstract = {BACKGROUND: Early Alzheimer's disease (AD) frequently presents with frontal lobe-related behavioral abnormalities, such as executive dysfunction and confabulation, despite minimal frontal cortical atrophy on neuroimaging. The molecular basis of this dissociation between behavioral dysfunction and preserved structure remains poorly understood.

METHODS: To address this paradox, we performed a transcriptomic re-analysis of postmortem frontal cortex samples from individuals with AD, vascular dementia (VaD), and cognitively normal controls (GSE122063). Gene set enrichment analysis was applied to interrogate functional pathways related to synaptic plasticity and structure-related maintenance pathways represented by the KEGG focal adhesion gene set.

RESULTS: In Alzheimer's disease, synaptic plasticity pathways were strongly negatively enriched in the frontal cortex (normalized enrichment score = -1.86, false discovery rate q < 0.001), whereas the KEGG focal adhesion pathway showed significant positive enrichment within the original GSEA framework (normalized enrichment score = 1.20, false discovery rate q = 0.17). This pattern indicates profound suppression of synaptic functional programs alongside relative preservation of structure-related maintenance signaling. In vascular dementia, frontal synaptic suppression was also observed but was less pronounced (normalized enrichment score = -1.48, false discovery rate q = 0.07).

CONCLUSIONS: These findings support a transcriptomic dissociation in the Alzheimer's frontal cortex in which synaptic dysfunction may emerge in the context of relative preservation of structure-related maintenance signaling. This framework may help explain early frontal behavioral impairment despite limited or delayed frontal cortical atrophy on neuroimaging. However, the focal adhesion pathway is biologically broad, and this significant enrichment signal related to structure-associated processes should therefore not be interpreted as a pure or exclusive measure of preserved cortical structural integrity.},
}

@article {pmid41935801,
year = {2026},
author = {Kong, L and Wu, Y and Zeng, H and Wu, R and Xu, X and Lu, Z and Zhang, W and Ma, C},
title = {The preclinical evidence and clinical translational prospects of medicarpin.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108183},
doi = {10.1016/j.phrs.2026.108183},
pmid = {41935801},
issn = {1096-1186},
abstract = {Medicarpin (MED) is an isoflavonoid compound derived from traditional Chinese medicine (TCM). Numerous preliminary experimental studies have shown that MED has significant pharmacological effects in the treatment of cancer, osteoporosis, osteoarthritis, Alzheimer's disease (AD), arthritis, and other diseases. However, the clinical application of MED has not yet been reported. Summarizing the preclinical drug research of MED is helpful for clarifying its pharmacological activities and evaluating its research prospects. In this review, we search for the preliminary experimental research of MED, encompassing pharmaceutics, pharmacodynamics, pharmacology, pharmacokinetics, clinical studies, and toxicology. A comprehensive review of the chemical synthesis and biosynthesis, biological activities, mechanisms, bioavailability, and clinical research of MED is conducted to systematically evaluate its safety, efficacy, and druggability. Ultimately, our work promotes the understanding of MED and facilitates its clinical translation and application.},
}

@article {pmid41936289,
year = {2026},
author = {Ullah, U and Habib, S and Islam, M},
title = {LADNET: An MRI-based deep learning approach for Alzheimer's disease detection.},
journal = {Computers in biology and medicine},
volume = {208},
number = {},
pages = {111647},
doi = {10.1016/j.compbiomed.2026.111647},
pmid = {41936289},
issn = {1879-0534},
abstract = {Alzheimer's disease (AD) is considered a leading form of dementia, found in the majority of individuals, and it accounts for the highest prevalence of all the types of dementia. It is a gradually progressing condition which can begin with mild memory impairment and may lead to the inability to engage in meaningful conversations in the future. In addition to that, it is also capable of reacting appropriately to the environment around it. According to official data, there has been an increase in reported cases of AD-related mortality in recent years, along with rising rates of the disease itself. Therefore, it is beneficial for patients to be diagnosed with AD as early as possible in order to maximize their chance of survival. In medical field, deep learning (DL) is employed in many applications, especially the identification of Alzheimer's disease, has shown considerable success. Based on the fact that these methods are capable of acquiring and extracting features from extensive datasets autonomously, they are highly suitable for analyzing intricate medical images with the aid of these methods. Design the Lightweight Alzheimer's Disease Net (LADNET) model for the current task. Accurate detection of AD using magnetic resonance imaging (MRI)-based scans is presented in this work. The model classifies the three dementia types, namely Mild Dementia (MD), Moderate Dementia (MDD), and Very Mild Dementia (VMD), while also accurately categorizing the non-demented (ND) category based on the severity of the condition. We measure the performance of the model we recommend against a publicly available Kaggle dataset that contains over six thousand images from four different types of images. LADNET model achieves 99.4% accuracy and 99% AUC, outperforming existing methods. With a lightweight design of approximately 1.2 million parameters and fast inference (4.2 ms per image), LADNET demonstrates strong potential for practical clinical deployment, where it could help extract biomarker information from conventional MRIs, potentially reducing patient burden and diagnostic costs.},
}

@article {pmid41936347,
year = {2026},
author = {Rirash, AF and Franzen, S and Bourdage, R and Kreuk, E and Visser, NC and Babulal, GM and van den Berg, E and Papma, JM},
title = {Barriers and facilitators to recruitment, engagement, and retention of underrepresented populations in dementia prevention research: a scoping review.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100557},
doi = {10.1016/j.tjpad.2026.100557},
pmid = {41936347},
issn = {2426-0266},
abstract = {Underrepresented populations in dementia prevention research, including minoritized racial/ethnic groups, individuals with lower socioeconomic status, and others facing social and structural disadvantages, are disproportionately affected by dementia risk. This scoping review examined barriers and facilitators to recruitment, engagement, and retention of these populations in Alzheimer's disease and related dementias (ADRD) prevention studies, synthesizing evidence from both empirical studies and review articles. Guided by PRISMA-ScR and the conceptual structure described by Gilmore-Bykovskyi et al., findings were synthesized from 19 reviews and 53 empirical studies. Findings were interpreted with attention to how overlapping factors-such as ethnicity, age, gender, and structural inequities-may influence study participation. Studies originated primarily from the United States (U.S.). Five key themes were identified: 1) mistrust, 2) stigma and limited research literacy, 3) logistical and financial constraints, 4) communication gaps and lack of team diversity, and 5) systemic-level barriers. Facilitators included culturally tailored outreach, long-term community partnerships, and inclusive study design. Retention strategies remain underreported, and little is known about the non-U.S. context. These findings highlight the need for context-specific, multi-level strategies that address the intersecting barriers faced by underrepresented groups to support equitable participation in dementia prevention research, and ultimately, dementia prevention.},
}

@article {pmid41936348,
year = {2026},
author = {Shimasaki, R and Kurihara, M and Bannai, T and Hatano, K and Suzuki, F and Tokumaru, AM and Ishii, K and Ihara, R and Iwata, A},
title = {Amyloid-related imaging abnormalities in Japanese patients with Alzheimer's disease treated with Lecanemab: A real-world study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100562},
doi = {10.1016/j.tjpad.2026.100562},
pmid = {41936348},
issn = {2426-0266},
abstract = {BACKGROUND: Although clinical trials have suggested a lower incidence of adverse events associated with Lecanemab in Asian populations compared to global cohorts, longitudinal real-world data across broader clinical indications are necessary to confirm these findings in routine practice.

OBJECTIVES: This study aimed to provide real-world evidence regarding the safety profile of Lecanemab in Japanese patients in a clinical setting.

DESIGN: A real-world observational study with a follow-up period of up to 18 months.

SETTING: A single center in Japan.

PARTICIPANTS: We included 120 Japanese patients who received Lecanemab between December 2023 and November 2025 and underwent at least one brain MRI before the fifth infusion.

MEASUREMENTS: Safety outcomes included amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation.

RESULTS: The mean age was 74.2 ± 7.9 years, and 89 (74%) were female. The majority of patients (88%) had a baseline CDR global score of 0.5. During follow-up, 81 patients completed the 12-month assessment. ARIA occurred in 24 patients (20%); ARIA-E with or without ARIA-H occurred in 5 patients (4%), and isolated ARIA-H occurred in 19 patients (16%). Crucially, no patients experienced symptomatic ARIA. All patients with ARIA-E who had available APOE data were ε4 carriers. Patients with ARIA had significantly lower baseline MMSE scores (p = 0.04), alongside non-significant trends toward higher plasma GFAP levels (p = 0.11) and higher deep white matter Fazekas scores (p = 0.05). IRRs occurred in 34 patients (28%), all of which were mild. Treatment was discontinued in 19 patients (16%), mainly due to disease progression (n = 8).

CONCLUSION: In this Japanese AD cohort, Lecanemab demonstrated a manageable safety profile in a real-world setting. In exploratory analyses, potential trends toward a higher frequency of ARIA were observed in patients with lower MMSE scores, higher plasma GFAP levels, and higher Fazekas scores, underscoring the importance of individualized risk assessment prior to therapy.},
}

@article {pmid41936465,
year = {2026},
author = {Zhang, H and Liu, X and Lyu, D and Hou, T and Xue, F and Du, Y},
title = {Association of Cardiovascular-Kidney-Metabolic Health With Structural Brain Imaging and the Risk of Specific-Cause Dementia: A Cohort Study.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.03.205},
pmid = {41936465},
issn = {1545-7214},
abstract = {OBJECTIVES: CKM syndrome may represent the coexistence of multiple risk factors for dementia; however, its large sample-based effects on the risk of specific-cause dementia and the alterations revealed by brain imaging remain unclear.

MEASUREMENTS: The 239,617 dementia-free participants from the UK Biobank were included in this study. Multivariate Cox regression analyses and stratifications were used to assess longitudinal associations. Linear regression analyses were employed to evaluate CKM-brain structure links. Sensitivity and Mendelian randomization (MR) analyses were performed to confirm the robustness of the results.

RESULTS: Over a 13.6-year median follow-up duration, 3,503 participants developed dementia that included 1,526 Alzheimer's disease (AD) and 770 vascular dementia (VaD) cases. Advanced CKM syndrome stages showed a dose-dependent risk of dementia: stage 3 (Hazard Ratio [HR] = 1.74 versus stage 0, χ² = 19.92, df = 1, p <0.001) and stage 4 (HR = 1.92, χ² = 38.52, df = 1, p <0.001). This pattern held for VaD but not AD, although CKM syndrome stage progression elevated the risk of AD by 130%. MR analysis confirmed significant associations. As a component of the CKM syndrome, metabolic disorders (MD) (abdominal obesity and metabolic syndrome) significantly elevated the risk of VaD but not that of AD. Notably, midlife adults, women, non-APOEε4 carriers, and those displaying low physical activity and education exhibited heightened susceptibility to dementia. Further, there was a spatial correlation pattern between CKM syndrome and brain atrophy (imaging biomarker of dementia): early sensorimotor-limbic shrinkage expanded to prefrontal-parietal and posterior cingulate regions, culminating in hippocampal degeneration.

CONCLUSIONS AND IMPLICATIONS: CKM syndrome stages may serve as a comprehensive predictor of dementia. Individualized monitoring of CKM factors across the lifespan of a person may mitigate progressive neurodegeneration and the risk of dementia.},
}

@article {pmid41936484,
year = {2026},
author = {Ho, A and Ngala, B and Yamada, C and Garcia, C and Duarte, C and Akkaoui, J and Ciolac, D and Nusbaum, A and Kochen, W and Efremova, D and Groppa, S and Nathanson, L and Bissel, S and Oblak, A and Kacena, MA and Movila, A},
title = {Corrigendum to "IL-34 exacerbates pathogenic features of Alzheimers disease and calvaria osteolysis in triple transgenic (3x-Tg) female mice" [Biomed. Pharmacother. 166 (2023) 115435].},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {},
number = {},
pages = {119293},
doi = {10.1016/j.biopha.2026.119293},
pmid = {41936484},
issn = {1950-6007},
}

@article {pmid41936849,
year = {2026},
author = {Pavanello, C and Ossoli, A and Comi, C and Turri, M and Tremolizzo, L and Conti, E and D'Incecco, P and Barbiroli, A and Parini, P and Mitro, N and Caruso, D and Sierri, G and Re, F and Chinello, C and Fumagalli, C and Magni, F and Fernandes, K and Calabresi, L},
title = {Cerebrospinal fluid CEFA composition is enriched in saturated fatty acids and it is altered in Alzheimer's Disease.},
journal = {Journal of lipid research},
volume = {},
number = {},
pages = {101034},
doi = {10.1016/j.jlr.2026.101034},
pmid = {41936849},
issn = {1539-7262},
abstract = {Cholesterol esterification is a fundamental step in cholesterol metabolism and transport, and in humans it is operated by three enzymes. Lecithin:cholesterol acyltransferase (LCAT) is responsible of cholesterol esterification in plasma and other biological fluids including cerebrospinal fluid (CSF), where it is mainly activated by apolipoprotein E. Esterification of cholesterol within cells is instead operated by sterol O-1 and O-2 acyltransferases (SOAT1 and SOAT2). SOAT1 is expressed in all cell types, while SOAT2 is expressed in hepatocytes and enterocytes, where it produces cholesteryl esters (CEs) to be assembled within VLDL and chylomicrons. LCAT and SOAT1/2 have different substrate specificity; LCAT has a preference for the unsaturated fatty acids, while the SOAT enzymes prefer the saturated and monounsaturated fatty acids. Here we show that CSF CEs have a different composition compared to plasma CEs and specifically are more enriched in saturated and monounsaturated fatty acids, typical substrates of the SOAT2 enzyme, and less frequently used by LCAT. Protein and RNA analysis in astrocytes, the main lipoprotein-producing cells in the central nervous system, excluded the presence of SOAT2, thus suggesting that CSF CEs are product of the LCAT enzyme. In line with this hypothesis, CSF phosphatidylcholine, the substate of LCAT, is enriched in saturated and monounsaturated fatty acids and depleted in polyunsaturated fatty acids. Moreover, we show that in AD patients, CSF CEs are enriched in saturated fatty acids, thus adding new insights into our recent observation that LCAT-mediated cholesterol esterification is hampered in AD. In conclusion, the present findings not only clarify the enzymatic origin of CSF CEs but also open avenues for developing enzyme-specific biomarkers and therapeutic strategies aimed at restoring lipid homeostasis in the brain.},
}

@article {pmid41936874,
year = {2026},
author = {Wang, YX and Zhou, XW and Du, WR and Qin, SH and Zhang, CY and Ma, ZY},
title = {Novel 2-aminopyrimidine carboxamide derivatives as potential anti-Alzheimer's disease agents: Design, synthesis, biological activity and computational simulation evaluation.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {130650},
doi = {10.1016/j.bmcl.2026.130650},
pmid = {41936874},
issn = {1464-3405},
abstract = {In this study, a series of 2-amino-5-formamidopyrimidine derivatives were designed and synthesized. Their potential as cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer's disease (AD) were evaluated by the Ellman method. Meanwhile, the antioxidant activity of these compounds were assessed by the DPPH (2,2-diphen-yl-1-picrylhydrazyl) free radical scavenging assay. The cholinesterase (ChE) inhibition test showed that most compounds exhibited excellent to moderate inhibitory effects on acetylcholinesterase (AChE), while most of them did not show significant inhibitory effects on butyrylcholinesterase (BuChE), demonstrating significant selectivity. Among them, compound 9 s (AChE: IC50 = 1.60 μM) whose AChE inhibitory activity is superior to the positive control galantamine (AChE: IC50 = 5.10 μM) is the most promising representative compound. Meanwhile, compound 9 s has high selectivity with a SI (IC50 ratio of BuChE to AChE) value of 29.85. The results of enzyme kinetics study determined that compound 9 s was a mixed-type inhibitor. Additionally, the molecular docking studies results indicated that compound 9 s could simultaneously interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, which was consistent with the results of the enzyme kinetics experiments. Molecular dynamics (MD) simulation study further verified the stability of the 9 s-AChE complex. In addition, the DPPH radical scavenging assay indicated that these compounds also possessed relatively weak antioxidant activities. Among them, compound 9p exhibited the best antioxidant activity with an IC50 value of 113.93 μM, which was lower than that of the positive control ascorbic acid (IC50 = 41.17 μM). Overall, these experimental results suggested that compound 9 s as AChE inhibitor had potential value for further research.},
}

@article {pmid41936902,
year = {2026},
author = {Li, X and Feng, X and Cai, A and Guo, X and Li, J and Liao, W and Long, H and Luan, P},
title = {Research Progress on Carotid Artery Changes and Cognitive Impairment in Alzheimer's Disease Patients.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103127},
doi = {10.1016/j.arr.2026.103127},
pmid = {41936902},
issn = {1872-9649},
abstract = {This article aims to comprehensively analyze the vascular factors in Alzheimer's Disease (AD), particularly the changes in the carotid arteries, and their complex correlations with hippocampal atrophy and cognitive function. Besides the traditional β-amyloid protein (Aβ) and Tau protein hypotheses, vascular factors are increasingly regarded as crucial factors in the development of AD. This article systematically reviews the roles of cerebral blood flow perfusion changes and micro-infarctions in the vascular pathophysiological processes during the progression of AD, and focuses on how thickening of the carotid intima-media thickness (IMT) and plaque formation in large vessels affect cerebral perfusion, thereby accelerating the deterioration of cognitive function (measured by the Montreal Cognitive Assessment (MoCA) score and the Mini-Mental State Examination (MMSE) score). Through the integration and analysis of existing literature and research data up to 2025, it is found that a large number of basic and clinical studies have confirmed the close connection between carotid artery changes and AD, but there is still a significant evidence gap regarding the association between carotid artery changes and the hippocampal region related to cognition.},
}

@article {pmid41933197,
year = {2026},
author = {Tabuena, DR and Jang, SS and Grone, B and Yip, O and Aery Jones, EA and Blumenfeld, J and Liang, Z and Mann, RS and Li, Y and Necula, D and Koutsodendris, N and Rao, A and Ding, L and Zhang, AR and Hao, Y and Xu, Q and Yoon, SY and De Leon, S and Huang, Y and Zilberter, M},
title = {Neuronal APOE4-induced early hippocampal network hyperexcitability in Alzheimer's disease pathogenesis.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {41933197},
issn = {2662-8465},
support = {R01AG061150//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG087323//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG092390//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; F32AG085961//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG055682//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG071697//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P01AG073082//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {The full impact of APOE4 (apolipoprotein E4), the strongest genetic risk factor for Alzheimer's disease (AD), on neuronal and network function remains unclear, particularly during early preclinical stages of disease. Here we show that young APOE4 knockin (E4-KI) mice exhibit hippocampal region-specific network hyperexcitability that predicts later cognitive deficits. This early phenotype arises from cell-type-specific subpopulations of smaller, hyperexcitable neurons and is eliminated by selective removal of neuronal APOE4. With aging, E4-KI mice develop granule cell hyperexcitability, progressive inhibitory dysfunction and excitation-inhibition imbalance in the dentate gyrus. Single-nucleus RNA sequencing with multilevel gene filtering reveals age-dependent and cell-type-specific transcriptional changes and identifies candidate mediators of early neuronal hyperexcitability, including Nell2. Targeted CRISPR interference knockdown of Nell2 rescues abnormal excitability, implicating Nell2 as a contributor to APOE4-driven dysfunction. Together, these findings define molecular and circuit mechanisms linking neuronal APOE4-induced early network impairment to AD pathogenesis with aging.},
}

@article {pmid41933339,
year = {2026},
author = {Huang, N and Hong, R and Cui, X and Cao, L and Shi, L and Chen, B and Su, Y and Xu, X and Hua, C and Ying, T},
title = {Targeting the HDAC4-NHE6-endosomal pH axis restores amyloid-β clearance and cognitive function in Alzheimer's disease mice.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04297-2},
pmid = {41933339},
issn = {1477-3155},
support = {82272018//the National Natural Science Foundation of China/ ; ynnkxzd202404//Shanghai Sixth People's Hospital Institutional Brain Science and Brain-Inspired Research Project/ ; },
abstract = {BACKGROUND: Impaired clearance of amyloid-β (Aβ) is a major pathological hallmark of Alzheimer's disease (AD). Although histone deacetylase (HDAC) inhibitors show therapeutic potential, their clinical translation for AD is hampered by poor blood brain barrier (BBB) penetration and an incomplete understanding of their mechanism in Aβ clearance. Here, angiopep2-conjugated nanoparticles (SAHA@LIPO-ANG2) for efficient BBB translocation and delivery of the HDAC inhibitor vorinostat (SAHA) was developed and its underlying mechanisms were validated.

RESULTS: Our result demonstrates that SAHA@LIPO-ANG2 potently inhibits HDAC4 nuclear translocation, which was identified as a key upstream event responsible for the transcriptional repression of sodium-hydrogen exchanger 6 (NHE6). Restoration of NHE6 expression rectifies endosomal hyperacidification, thereby rescuing the trafficking and plasma membrane expression of the Aβ clearance receptor, low-density lipoprotein receptor-related protein 1 (LRP1). Furthermore, this HDAC4-NHE6-pH axis modulates the neuroimmune microenvironment to enhance Aβ clearance through multiple synergistic mechanisms: it upregulates phagocytic receptors and recruit microglial to phagocytize Aβ plaques, while concurrently reactivating autophagy-lysosomal function in astrocytes by increasing LAMP2 expression. Consequently, treatment with SAHA@LIPO-ANG2 in 5xFAD mice significantly reduced Aβ burden, suppressed neuroinflammation, rescued synaptic loss, and ultimately reversed cognitive deficits.

CONCLUSIONS: Our study not only elucidates a HDAC4-NHE6-pH regulatory axis in AD pathogenesis but also establishes a multifaceted nanotherapeutic strategy for restoring Aβ homeostasis. Our findings may provide therapeutic strategies for treating amyloid-related diseases.},
}

@article {pmid41933395,
year = {2026},
author = {Bayram, E and Carter, DJ and Aslam, S and Forbes, E and Holden, SK},
title = {Sex differences for clinical presentations and co-pathologies in four-repeat tauopathies.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-026-00899-5},
pmid = {41933395},
issn = {2042-6410},
support = {R00AG073453/AG/NIA NIH HHS/United States ; Private donation//University of Colorado/ ; },
abstract = {BACKGROUND: Four-repeat (4R)-tauopathies cause variable clinical profiles leading to clinical misdiagnosis. While sex differences are reported in Alzheimer's disease (AD), Lewy body disease (LBD), and clinically-defined frontotemporal dementia (FTD), little is known in 4R-tauopathies.

METHODS: National Alzheimer's Coordinating Center data were used for pathologically-defined 4R-tauopathies: progressive supranuclear palsy (PSP, n = 175), corticobasal degeneration (CBD, n = 114), argyrophilic grain disease (AGD, n = 230), Other-4R (n = 67). Sex differences for clinical presentation and co-pathologies were assessed adjusting for age and multiple comparisons.

RESULTS: Most common clinical diagnosis was PSP (41%) for PSP; unspecified FTD (36%) for CBD; AD for AGD (57%) and Other-4R groups (48%), without sex differences. Females had less cognitive decline, apathy, motor symptoms; were older at cognitive, behavioral change onset. Males were more likely to demonstrate LBD co-pathology and clinical profile.

CONCLUSION: Both females and males have low clinical diagnostic accuracy for 4R-tauopathies. Females with 4R-tauopathies may experience less severe clinical presentations and less co-pathology.},
}

@article {pmid41933660,
year = {2026},
author = {Wang, Y and Bao, G and Li, H and Li, X and Lv, L},
title = {The Role of Non-Coding RNA-Mediated Autophagy in Alzheimer's Disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111860},
doi = {10.1016/j.brainresbull.2026.111860},
pmid = {41933660},
issn = {1873-2747},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and one of the leading causes of dementia, imposing a profound burden on patients, families, and healthcare systems worldwide. Autophagy, an evolutionarily conserved lysosomal degradation pathway critical for maintaining cellular homeostasis, removes damaged organelles and misfolded proteins, thereby preserving metabolic balance and enabling intracellular biomolecule recycling. Growing evidence indicates that dysfunctional autophagy contributes to AD pathogenesis. Concurrently, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as pivotal regulators of AD pathology, particularly through mechanisms involving autophagy. These ncRNAs not only play a role in disease progression but also represent promising molecular targets for therapeutic intervention via autophagy modulation. This review systematically explores the regulatory networks through which ncRNAs influence autophagy in AD, with the goal of identifying potential therapeutic targets and offering a conceptual framework to guide clinical translation.},
}

@article {pmid41933683,
year = {2026},
author = {Chen, W and Su, F and Kong, H and Wang, Y and Yi, C and Zheng, Y and Fang, Y and Shi, X and Lin, Y and Zhou, J and Zhang, X and Pei, Z},
title = {APOE genotype and astrocyte activity collectively influence AD biomarkers and Aβ burden.},
journal = {Brain research},
volume = {1883},
number = {},
pages = {150283},
doi = {10.1016/j.brainres.2026.150283},
pmid = {41933683},
issn = {1872-6240},
abstract = {BACKGROUND: The apolipoprotein E ε4 (APOE ε4), a well-established genetic risk factor for Alzheimer's disease (AD), is deeply involved in amyloid-β (Aβ) and tau pathology. Blood-based biomarkers (BBMs), including Aβ42/40, phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL), offer accessible proxies of AD pathology. Reactive astrocytes, indicated by elevated GFAP, are increasingly recognized as key players in AD progression. However, how astrocyte reactivity interacts with APOE genotype to shape BBMs and Aβ deposition remains unclear.

METHODS: We included 283 participants across the cognitive spectrum including cognitively unimpaired (CU), mild cognitive impairment (MCI), and all-cause dementia (ACD) from Guangzhou health aging and dementia cohort. Primary outcome measures were plasma biomarkers (Aβ42/40 ratio, p-tau181, GFAP, and NfL) and amyloid PET standardized uptake value ratio (SUVR). Participants were stratified by APOE ε4 carrier status and astrocyte activation. Group comparisons, correlation analyses, and sensitivity analyses were performed.

RESULTS: Stage-dependent APOE effects were observed: while modulating Aβ42/40 ratios in both CU and MCI, APOE influenced p-Tau181 only in MCI, exclusively under Ast-. SUVR was significantly higher in APOE ε4 + group at MCI stage, particularly in Ast- cases. Intriguingly, p-Tau/Aβ42 showed strong SUVR correlations across all subgroups except APOE ε4- Ast- group.

DISCUSSION: Our findings indicate that astrocyte reactivity is associated with differences in how APOE ε4 relates to both peripheral BBMs and central Aβ deposition, supporting an interplay between genetic risk and neuroinflammatory states in AD pathogenesis.},
}

@article {pmid41933684,
year = {2026},
author = {Younis, M and Vints, WAJ and Kušleikienė, S and Helsper, S and Himmelreich, U and Česnaitienė, VJ and Masiulis, N and Levin, O and Bautmans, I},
title = {Neural correlates of handgrip strength asymmetry in normal aging and older adults with mild cognitive impairment.},
journal = {Brain research},
volume = {},
number = {},
pages = {150299},
doi = {10.1016/j.brainres.2026.150299},
pmid = {41933684},
issn = {1872-6240},
abstract = {BACKGROUND: Handgrip strength asymmetry (HGS-A) has emerged as a potential non-invasive biomarker reflecting cognitive and neural vulnerability in older adults, yet the neural mechanisms linking asymmetry with cognitive decline remain incompletely characterized. This study aimed to determine the relationships between HGS-A, cognitive function, and regional cortical thickness in healthy older adults and individuals with mild cognitive impairment (MCI).

METHODS: Sixty-eight community-dwelling adults aged 60-85 (42 cognitively healthy, 26 MCI) underwent bilateral handgrip strength assessment using Jamar dynamometry. Cognitive evaluations included global cognition (MoCA) and domain-specific functions (ANAM4 battery). Structural MRI was performed, and cortical thickness was quantified from T1-weighted images within regions affected in MCI and Alzheimer's disease. Associations between HGS-A, cognitive performance, and cortical thickness were examined using partial correlation analyses adjusted for age and sex.

RESULTS: In cognitively healthy participants, greater handgrip strength asymmetry within normal limits (<15%) significantly correlated with higher global cognitive scores (MoCA; r = 0.32, p = 0.043) and increased cortical thickness in the left postcentral gyrus (r = 0.52, p < 0.001; FDR-corrected). Conversely, these relationships were absent in participants with MCI and in those exhibiting high asymmetry levels (≥15%). Domain-specific cognitive tasks showed no significant associations with HGS-A in either group. Exploratory analyses suggested an inverted U-shaped relationship, where both minimal and excessive asymmetry reflect worse cognitive function.

CONCLUSIONS: Handgrip strength asymmetry within normal limits (<15%) is linked to better cognition and cortical integrity, whereas both minimal and excessive asymmetry may reflect reduced cognitive function in older adults.},
}

@article {pmid41933799,
year = {2026},
author = {Huang, Q and Lv, Y and Ye, X and Xia, X and Chen, Y and Wang, X and Tong, F and Yang, W and Bozorov, K and Shevtsov, M and Li, H and Gao, H and Ye, B},
title = {Engineered microglial membrane-coated polydopamine-based nanomedicine for precise treatment of Alzheimer's disease.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114896},
doi = {10.1016/j.jconrel.2026.114896},
pmid = {41933799},
issn = {1873-4995},
abstract = {Multimodal treatment for Alzheimer's disease (AD) is a pivotal option because of its complex pathogenesis. The major challenge of pharmacotherapies is effective drug delivery to the diseased brain and reduction of associated toxicity. Here, we propose a dual-target nanomedicine (PDA@R@M/K) for the management of AD by coating engineered microglial cell membrane (M/K) onto polydopamine (PDA) cores encapsulated with rivastigmine. M/K conferred nanoparticles (NPs) with reduced circulation clearance, pathological blood-brain barrier recognition, and enhanced brain inflammation chemotaxis. PDA cores not only acted as potent ROS scavengers to alleviate neuroinflammation but also piggybacked rivastigmine and implemented responsive release. After applying PDA@R@M/K in preclinical transgenic mouse models, amyloid plaque deposition, neurologic changes, and cognitive decline were largely rescued. These results provide the possibility of directly using NPs as therapeutics rather than merely as nanocarriers, and demonstrate the feasibility of engineered microglia membrane-coated NPs to improve the pharmacokinetics and efficacy of anti-AD drugs.},
}

@article {pmid41933838,
year = {2026},
author = {Zhang, N and Andresen, J and Janzi, S and Glans, I and Samuelsson, J and Nägga, K and Borné, Y and Palmqvist, S and Hansson, O and Sonestedt, E},
title = {Free sugar intake and dementia risk: a Swedish cohort study on dietary sources and dementia subtypes.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {101518},
doi = {10.1016/j.tjnut.2026.101518},
pmid = {41933838},
issn = {1541-6100},
abstract = {BACKGROUND: Dementia is a growing public health concern, and while diet is a modifiable potential risk factor, the role of free sugar intake remains unclear. Excess sugar has been linked to metabolic and cardiovascular dysfunction, both associated with cognitive decline, but evidence regarding specific sugar sources is limited.

OBJECTIVE: We aimed to investigate the associations between free sugar intake, its dietary sources, and the risk of all-cause dementia, Alzheimer's disease, and vascular dementia, and to assess potential modification by APOE ε4 status.

METHODS: We included 27,786 participants without dementia at baseline (mean age: 58 years; 61% women) from the Malmö Diet and Cancer Study, a population-based prospective cohort. Dietary intake was assessed using a validated diet history method. Dementia diagnoses were obtained from national registers through and validated by memory clinic physicians. During a median follow-up of 25 years, 3,224 participants (11.6%) were diagnosed with dementia.

RESULTS: Free sugar intake was not significantly associated with all-cause dementia or Alzheimer's disease. However, a U-shaped association was observed for vascular dementia, with moderate intake (10-12.5% of energy) associated with lower risk (HR: 0.70, 95% CI: 0.52-0.95). Sugar-sweetened beverage intake showed no association with dementia risk. High chocolate intake was associated with lower risks of all-cause (HR for Q5 vs Q1: 0.81, 95% CI: 0.72-0.91) and vascular dementia (HR for Q5 vs Q1: 0.68, 95% CI: 0.50-0.92), while high jam/marmalade intake was linked to a lower risk of all-cause dementia (HR: 0.86, 95% CI: 0.77-0.97 for >10 servings/week vs <0.5 servings/week). No significant interactions with APOE ε4 status were observed.

CONCLUSIONS: Free sugar intake was not associated with overall dementia risk, but moderate intake may reduce the risk of vascular dementia. These findings suggest that future dietary guidelines for cognitive health should consider not only sugar quantity but also its food source.},
}

@article {pmid41933844,
year = {2026},
author = {Wang, L and Gao, Y and Lu, J and Jiang, Q and Wang, H and Dong, F and Zhao, Q and Guan, Y and Qi, X and Zuo, C and Yu, J and Jiang, J},
title = {Individual gray-white matter functional connection predicts tau spread and cognitive decline in Alzheimer's disease.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121904},
doi = {10.1016/j.neuroimage.2026.121904},
pmid = {41933844},
issn = {1095-9572},
abstract = {PURPOSE: Alzheimer's disease is characterized by progressive accumulation of hyperphosphorylated tau protein, which propagates in a prion-like manner along connected neuronal pathways. However, it remains unclear whether functional connectivity between gray and white matter (FCGW) can predict tau spread. This study aimed to determine the association between FCGW and tau deposition and to evaluate its value in predicting longitudinal tau spread.

METHODS: We integrated resting-state fMRI with cross-sectional and longitudinal tau-PET data from two independent cohorts. We assessed baseline associations between FCGW and tau deposition and then constructed an individual-level spreading model to predict longitudinal tau accumulation.

RESULTS: In both cohorts, FCGW showed a positive correlation with tau deposition. Model-simulated white-matter tau deposition was associated with clinical scales and predicted cognitive decline. The spreading model, which incorporated baseline tau-PET and the top 10% of gray and white matter, yielded the highest predictive performance for future tau accumulation.

CONCLUSION: FCGW captures key network pathways underlying tau spread in AD and improves prediction of future tau accumulation. These findings highlight the importance of FCGW in understanding tau propagation and support development of network-targeted therapeutic strategies.},
}

@article {pmid41933850,
year = {2026},
author = {Li, D and He, J and Liu, B and Zhu, L and Yang, Y and Peng, Y and Nie, L and Wang, R},
title = {Multimodal Radiomics of Precisely Segmented Hippocampal Subfields: Iron Deposition and Structural Biomarkers for Early Diagnosis of Alzheimer's Disease.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121900},
doi = {10.1016/j.neuroimage.2026.121900},
pmid = {41933850},
issn = {1095-9572},
abstract = {Profiling imaging biomarkers of prodromal Alzheimer's disease (AD) against AD dementia may aid earlier diagnosis, yet approaches jointly capturing iron-related pathology and hippocampal subfield heterogeneity remain scarce. We developed a hippocampal-subfield multimodal radiomics framework integrating quantitative susceptibility mapping (QSM) and 3D T1-weighted MRI. A primary cohort of 92 participants (50 prodromal AD, 42 AD dementia) and an independent external cohort of 30 (15/15) were included. Twenty-four hippocampal subfields were segmented on super-resolution T1 images and propagated to co-registered QSM for feature extraction. Radiomic features were condensed into a radiomics score (Rad-score) via a training-only selection pipeline. Using the Rad-score as the sole predictor, a support vector machine (SVM) classifier was trained. On the external cohort, the SVM achieved an area under the receiver operating characteristic curve of 0.85 and an accuracy of 0.83. The predictive signature was dominated by QSM texture features in Cornu Ammonis 1 and the granule cell layer of the dentate gyrus, complemented by T1 first-order heterogeneity. Modality ablation suggested potential-but not definitive-complementarity of multimodal integration. This framework shows promise for AD stage classification and warrants further validation in larger independent cohorts.},
}

@article {pmid41933902,
year = {2026},
author = {Pinkwart, K and Lang, T},
title = {Clustering hinders APP α-secretase processing in the plasma membrane.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2026.03.061},
pmid = {41933902},
issn = {1542-0086},
abstract = {Alzheimer's disease (AD) is associated with the extracellular accumulation of neurotoxic Aβ-peptides in the brain. Aβ-peptides are produced via an amyloid precursor protein (APP) cleavage pathway that is initiated by the β-secretase. The majority of APP circumvents the amyloidogenic pathway due to α-secretase cleavage at the plasma membrane. In this study, we set out to identify potential mechanisms limiting α-cleavage. We employed isolated cell membranes to study α-secretase cleavage in the absence of APP delivery to the plasma membrane and internalization. We distinguish a readily cleavable and a cleavage-resistant APP pool. The cleavage-resistant and most likely immobile APP pool is organized in clusters and by this could escape the amyloidogenic pathway. In sum, our results identify that α-secretase cleavage at the plasma membrane occurs rapidly though in an incomplete manner due to the presence of cleavage-resistant APP clusters.},
}

@article {pmid41933986,
year = {2026},
author = {Patel, S and Reisch, A and Narapareddy, BR},
title = {Frontal variant Alzheimer's disease presenting as late-onset psychiatric illness: A case series highlighting diagnostic challenges on inpatient psychiatric units.},
journal = {Journal of the National Medical Association},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jnma.2026.03.005},
pmid = {41933986},
issn = {1943-4693},
abstract = {BACKGROUND: Neurocognitive disorders are classified within psychiatric nosology and may present with prominent behavioral, mood, or psychotic symptoms that resemble other psychiatric illnesses. This overlap can lead to diagnostic ambiguity, delayed recognition of neurodegeneration, and unnecessary or harmful treatments. Frontal variant Alzheimer's disease (fvAD) is particularly prone to misdiagnosis because behavioral symptoms may precede memory impairment.

OBJECTIVE: To describe three cases of fvAD initially diagnosed as other psychiatric illnesses and to highlight strategies for improving diagnostic accuracy on inpatient psychiatric units.

METHODS: Three adults hospitalized for late-onset psychiatric syndromes refractory to standard treatment underwent systematic cognitive assessment, neuropsychological evaluation, and neuroimaging. Diagnoses were subsequently clarified as fvAD.

RESULTS: All patients initially received antipsychotic medications; two developed extrapyramidal symptoms. Cognitive assessment, collateral history, neuropsychological testing, and FDG-PET/MRI demonstrated patterns consistent with fvAD, enabling diagnostic clarification, discontinuation of ineffective treatments, and engagement of appropriate dementia care.

CONCLUSION: Late-onset psychiatric syndromes resistant to treatment may represent early manifestations of neurocognitive disorders rather than other psychiatric conditions. Systematic assessment facilitates accurate diagnosis, reduces unnecessary interventions, and supports timely referral to multidisciplinary dementia care.},
}

@article {pmid41934033,
year = {2026},
author = {Cohen, G and Mati, MB and Woodward, OJ and Hepburn, K and Perkins, MM},
title = {Undiagnosed dementia in underserved African American populations: Missed opportunities for care.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100208},
doi = {10.1016/j.inpsyc.2026.100208},
pmid = {41934033},
issn = {1741-203X},
abstract = {BACKGROUND: Missed and late diagnoses of dementia are frequent in underserved populations and impact the implementation of dementia interventions.

METHODS: Twenty dyads of persons living with dementia and comorbidity, new to the principal investigator's panel at a Geriatrics Clinic, and their caregivers. Quantitative Assessment: geriatric assessment, cognitive and staging scales, review of all medical records. Qualitative analysis: interviews with the dyad, coding for factors for late diagnosis and impact of the non-diagnosis.

RESULTS: Ninety percent women, mean age: 78 years (range 65-96), all African- American. Diagnosis distribution: Alzheimer's disease (11), mixed dementia (7), vascular dementia (1), Lewy Body Disease (1). Calculated mean time from the first symptom of dementia to diagnosis: 3.3 years (range: 1-10). Of the 20 cases, 15 did not have a prior formal diagnosis of dementia; their staging at diagnosis was: severe dementia: 5, moderate dementia: 4, mild dementia: 6. Eight cases had a delay in diagnosis of at least 4 years. We estimated the impact on health outcomes of years of living with undiagnosed dementia and found a high frequency of non-compliance with medications, uncontrolled comorbid conditions, weight loss, and multiple health transitions.

CONCLUSIONS: We observed a significant time delay in the diagnosis of dementia, while many participants had moderate to severe dementia when diagnosed. Strategies to improve screening and dementia diagnosis in primary care settings are needed to increase access to dementia-specific services and improve care and well-being in this vulnerable African American population and their caregivers.},
}

@article {pmid41934111,
year = {2026},
author = {Rutter, LA and Hamilton, LJ},
title = {Cognitive dispersion and depressive symptoms in aging: Distinct contributions to longitudinal decline.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbag055},
pmid = {41934111},
issn = {1758-5368},
abstract = {OBJECTIVES: Depression is a noted risk factor for general cognitive decline and Alzheimer's disease and related dementias. Evidence suggests that this may be due to its association with greater variability in performance across cognitive tasks, known as cognitive dispersion. The current study examines how depression and dispersion uniquely predict cognitive decline in a longitudinal study of cognitively normal older adults.

METHODS: Data were drawn from the Harvard Aging Brain Study. Participants were 287 individuals who were cognitively normal at baseline, contributing 1,547 observations across six longitudinal waves over 8.68 years. Depression was assessed using the Geriatric Depression Scale. Cognitive status was assessed via the Preclinical Alzheimer's Cognitive Composite. Cognitive dispersion was defined as the intraindividual standard deviation of scores across five cognitive tasks that represent complementary dimensions of executive functioning and cognitive control.

RESULTS: Cross-sectional mixed-effects models revealed that higher depression was associated with lower baseline cognitive performance (β=-0.02, SE = 0.01, t(1482) = -4.01, p<.001), but depression was not related to dispersion. In combined longitudinal models including both depression and dispersion, higher average dispersion (between-persons) predicted lower cognitive performance (β=-0.38, SE = 0.11, t(272)=-3.45, p<.001) and faster decline (β=-0.07, SE = 0.03, t(258)=-2.34, p = .02). Depression was not a significant predictor of cognitive decline when modeled with dispersion.

DISCUSSION: Our findings highlight the importance of monitoring depression during clinic visits, as it is significantly related to concurrent cognitive performance in aging populations. Since dispersion and not depression predicted decline over time, cognitive dispersion may serve as a specific marker of future impairment risk.},
}

@article {pmid41934300,
year = {2026},
author = {Li, Y and Lai, Q and Li, Q and Fan, Y},
title = {Effect of edaravone on synaptic damage in Alzheimer's disease via Rho/ROCK signaling.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {6},
pages = {1625-1630},
doi = {10.36721/PJPS.2026.39.6.154.1},
pmid = {41934300},
issn = {1011-601X},
mesh = {*rho-Associated Kinases/metabolism/genetics ; Animals ; *Edaravone/pharmacology ; *Alzheimer Disease/drug therapy/pathology/genetics/metabolism ; *Signal Transduction/drug effects ; Rats ; PC12 Cells ; *Synapses/drug effects/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; Synapsins/metabolism/genetics ; *Neuroprotective Agents/pharmacology ; Peptide Fragments ; Promoter Regions, Genetic ; },
abstract = {BACKGROUND: Edaravone can reduce damage to brain cells in a variety of ways. Rho/ROCK signaling is involved in Alzheimer's disease.

OBJECTIVES: This study uses AD cell models to explore edaravone's effect on AD nerve synapse damage.

METHODS: The ROCK2 promoter luciferase reporter gene was constructed, Aβ25-35 was used as a processing factor and transfected into PC12 cells to construct an AD cell model which was then treated with edaravone, followed by analysis of 95 antibody (PSD95), synapse-related mRNA synapsin 1 (SYN1) level to observe its effect on Rho/ROCK signaling.

RESULTS: Edaravone can effectively inhibit the transcriptional activity of ROCK2 promoter in AD cell model, upregulate SYN1 and GAP43 protein and downregulate ROCK2. After ROCK2 overexpression, edaravone can affect SYN1 expression in AD cell model, while SYN1 expression did not change significantly after ROCK2 was silenced.

CONCLUSION: Edaravone has a protective effect on AD nerve synapse damage and plays a role in repairing nerve synapse damage through ROCK2 signaling pathway.},
}

*rho-Associated Kinases/metabolism/genetics
Animals
*Edaravone/pharmacology
*Alzheimer Disease/drug therapy/pathology/genetics/metabolism
*Signal Transduction/drug effects
Rats
PC12 Cells
*Synapses/drug effects/pathology/metabolism
Amyloid beta-Peptides/metabolism
Synapsins/metabolism/genetics
*Neuroprotective Agents/pharmacology
Peptide Fragments
Promoter Regions, Genetic

@article {pmid41934491,
year = {2026},
author = {Alameen, AAM and Al-Kuraishy, HM and Al-Gareeb, AI and Alexiou, A and Papadakis, M and Faheem, SA and El-Saber Batiha, G},
title = {SIRT1 Activators as Geroprotective Agents in Brain Aging: Mechanisms and Therapeutic Potential.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {},
pmid = {41934491},
issn = {1559-1174},
mesh = {Humans ; *Sirtuin 1/physiology ; *Aging/drug effects/physiology ; *Brain/drug effects/physiology ; Animals ; Neurodegenerative Diseases/drug therapy/prevention & control ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Cellular Senescence/drug effects ; Signal Transduction/drug effects ; Autophagy/drug effects ; *Senotherapeutics/therapeutic use/pharmacology ; *Enzyme Activators/therapeutic use/pharmacology ; },
abstract = {The brain undergoes profound molecular and structural changes during the aging process, resulting in the development of neurodegeneration, cognitive impairment, and increased vulnerability to chronic diseases. At the cellular level, brain aging is characterized by oxidative damage, genomic instability, and chronic low-grade inflammation known as inflammaging. Central to this process is Sirtuin 1 (SIRT1), a NAD[+]-dependent class III histone deacetylase, known for its regulatory role in chromatin remodeling, oxidative stress responses, mitochondrial biogenesis, and neuroplasticity. Recent research has identified SIRT1 as a molecular target capable of reversing or attenuating several hallmarks of aging, particularly within the central nervous system (CNS). This narrative review critically evaluates the emerging evidence surrounding the geroprotective effects of SIRT1 activators, which exert dual actions, senomorphic and senolytic, via modulation of signaling pathways, thereby reducing neuronal senescence, enhancing autophagy, and mitigating inflammatory responses. The discussion also addresses the region-specific role of SIRT1 across the brain, particularly in the hippocampus and hypothalamus, which are essential for memory, energy homeostasis, and resilience to stress. Additionally, this review explores how SIRT1 depletion during aging contributes to the development of synaptic dysfunction, impaired cognitive function, and susceptibility to neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The therapeutic potential of SIRT1 activators is supported by preclinical and early clinical studies, suggesting their value in preventing or delaying brain aging. Thus, SIRT1 could be a promising pharmacological target for age-associated brain disorders, warranting more robust translational studies to validate these findings in humans.},
}

Humans
*Sirtuin 1/physiology
*Aging/drug effects/physiology
*Brain/drug effects/physiology
Animals
Neurodegenerative Diseases/drug therapy/prevention & control
*Neuroprotective Agents/therapeutic use/pharmacology
Oxidative Stress/drug effects
Cellular Senescence/drug effects
Signal Transduction/drug effects
Autophagy/drug effects
*Senotherapeutics/therapeutic use/pharmacology
*Enzyme Activators/therapeutic use/pharmacology

@article {pmid41934639,
year = {2026},
author = {Liang, H and Yu, W and Han, Z and Xu, B and Zhuang, Z and Liu, J},
title = {The role of olfactory and salivary gland pathways in periodontal disease-mediated Alzheimer's disease progression: mechanistic insights and early diagnostic implications.},
journal = {Acta clinica Belgica},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/17843286.2026.2652268},
pmid = {41934639},
issn = {2295-3337},
abstract = {OBJECTIVES: Periodontal disease, characterized by subgingival biofilm dysbiosis and Porphyromonas gingivalis (P. gingivalis) colonization, has been increasingly implicated in Alzheimer's disease (AD) pathogenesis. This review systematically delineates the pathophysiological mechanisms underlying the periodontal-AD nexus, highlighting olfactory dysfunction (OD) and salivary gland hypofunction as putative prodromal biomarkers for periodontal disease-associated AD progression.

METHODS: PubMed/MEDLINE database was systematically searched for English-language articles published between January 1994 and March 2025. Search terms encompassed periodontal disease, Porphyromonas gingivalis, Alzheimer's disease, neuroinflammation, olfactory dysfunction, salivary gland hypofunction, blood-brain barrier, microglial activation, and cognitive decline.

RESULTS: Periodontal disease compromises blood-brain barrier integrity via bacterial translocation, systemic pro-inflammatory mediator dissemination, and peripheral immune cell activation, thereby potentiating microglial polarization and neuroinflammatory cascades integral to early AD neuropathology. Both OD and salivary gland hypofunction demonstrate robust associations with periodontal disease severity and constitute sensitive biomarkers for prodromal AD.

CONCLUSIONS: Periodontal disease-mediated neuroinflammation constitutes a pivotal mechanistic pathway linking oral dysbiosis to AD onset. OD and salivary gland hypofunction emerge as promising early diagnostic indicators for periodontal disease-associated AD susceptibility, warranting prospective clinical validation.},
}

@article {pmid41934727,
year = {2026},
author = {Li, D and Zhang, Y and Wang, R and Jin, L and Cui, X and Hong, JS and Li, S and Zhao, J and Guo, Y},
title = {Chicoric acid enhanced brain cholesterol efflux and reduced Aβ pathology via LXR-ABCA1 signaling in Alzheimer's models.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {3},
pages = {e00899},
doi = {10.1016/j.neurot.2026.e00899},
pmid = {41934727},
issn = {1878-7479},
abstract = {Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key driver of AD. Given the established link between dysregulated lipid metabolism and amyloid-beta (Aβ) aggregation, we investigated whether chicoric acid (CA), a dietary polyphenol with reported lipid-modulating properties, could mitigate Aβ pathology by modulating lipid metabolism in 5xFAD transgenic mice. In the brain, we found that CA upregulated the expression of liver X receptor Beta (LXR-β) and ATP-binding cassette transporter A1 (ABCA1) in 5xFAD mice. Through this pathway, it promoted apolipoprotein E (ApoE) lipidation and enhanced the expression of Aβ-clearance proteins (IDE and LRP1). Notably, in the periphery, CA reshaped the gut microbiota in 5xFAD mice, which reduced serum neurotoxic bile acid levels and preserved the integrity of the peripheral Aβ clearance system. Together, our study first demonstrated that CA globally regulated lipid homeostasis to alleviate Aβ pathology by coordinating cerebral cholesterol efflux with peripheral bile acid metabolism. The findings facilitated exploring active compounds from traditional Chinese medicine that may reduce Aβ deposition by targeting lipid metabolism pathways.},
}

@article {pmid41934898,
year = {2026},
author = {Zhong, J and He, X and Yang, H and Zhang, J and Liu, J and Yang, J and Dong, X},
title = {Icariin, astragaloside IV and puerarin mixture salvages synaptic loss by enhancing mitochondrial biogenesis: A multi-target strategy for Alzheimer's disease therapy.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {198},
number = {},
pages = {119320},
doi = {10.1016/j.biopha.2026.119320},
pmid = {41934898},
issn = {1950-6007},
abstract = {OBJECTIVE: This study aimed to elucidate the potential mechanism by which the Icariin, astragaloside IV and puerarin (Ying-Huang-Ge, YHG) mixture regulates mitochondrial-synaptic homeostasis in Alzheimer's disease (AD) MOD mice through the Glycogen Synthase Kinase-3β (GSK-3β)/Peroxisome Proliferator-Activated Receptor γ Coactivator-1α (PGC-1α) signaling axis.

METHODS: Thirty 5-month-old male APP/PS1 mice were randomly divided into the MOD group, the YHG treatment group (YHG), and the Donepezil treatment group (DNP) (n = 10 per group). Ten age-matched male C57BL/6 J mice served as the CON group. Following two months of continuous administration, cognitive function was assessed using the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests. Dendritic spine density in the hippocampal CA1 region was evaluated via Golgi staining, and ultrastructural changes were examined using transmission electron microscopy (TEM). Hippocampal levels of adenosine triphosphate (ATP), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured using biochemical assay kits. Protein expression levels of GSK-3β, p-GSK-3β (Ser9), PGC-1α, mitochondrial functional proteins (NRF-1, TFAM), and synaptic plasticity-related proteins (PSD95, SYN) were determined by Western blot.

RESULTS: Compared with the CON group, the MOD group exhibited significantly impaired learning and memory capabilities, reduced dendritic spine density in the hippocampal CA1 region, and disrupted synaptic ultrastructure. Mitochondria displayed pathological changes, including swelling and vacuolization. Furthermore, ATP and SOD levels were significantly decreased, while MDA content was elevated. Western blot analysis revealed increased total GSK-3β expression and significantly decreased expression of p-GSK-3β (Ser9), PGC-1α, downstream mitochondrial biogenesis proteins (NRF-1, TFAM), and synaptic proteins (PSD95, SYN). Intervention with YHG significantly ameliorated these cognitive deficits, mitigated pathological damage to mitochondria and synapses, and reversed the abnormal molecular expression profiles.

CONCLUSION: The YHG ameliorates cognitive dysfunction and attenuates synaptic impairment in APP/PS1 mice. The underlying mechanism may involve the inhibition of GSK-3β activity, which subsequently activates PGC-1α-mediated mitochondrial biogenesis, enhances mitochondrial quality, and mitigates oxidative stress, ultimately leading to the restoration of synaptic structural integrity.},
}

@article {pmid41934906,
year = {2026},
author = {Yuan, L and Chen, QL and Yang, Q and Zheng, P and Liu, Y and Lin, R and Zou, QC and Fan, H and Tao, XY and Xu, SC},
title = {Deciphering the galantamine biosynthetic pathway in Lycoris species lays the foundation for plant chassis-based production.},
journal = {Plant physiology and biochemistry : PPB},
volume = {233},
number = {},
pages = {111252},
doi = {10.1016/j.plaphy.2026.111252},
pmid = {41934906},
issn = {1873-2690},
abstract = {Galantamine, a clinically essential Amaryllidaceae alkaloid widely used to treat Alzheimer's disease, faces a constrained and unsustainable plant-derived supply, yet our understanding of its biosynthesis in Lycoris is relatively limited. Here, we provide the first comprehensive elucidation of galantamine biosynthesis in Lycoris longituba, a species with exceptionally high galantamine content. Comparative alkaloid metabolomics between L. longituba and the low-galantamine species L. insularis revealed ∼10-fold higher galantamine accumulation in L. longituba, particularly at the S1 developmental stage (November), when all precursor metabolites were markedly enriched. Using PacBio full-length and Illumina short-read transcriptomes, we identified 83 differentially expressed isoquinoline alkaloid genes, 53 of which were upregulated in L. longituba. Furthermore, integrative correlation of DEGs-metabolite networks analysis combined with Nicotiana benthamiana transient assays functionally identified LlNMT1, an N-methyltransferase, co-expressed with NtCYP96T6, converting 4'-O-methylnorbelladine to narwedine, and LlAKR4, an aldo-keto reductase mediating narwedine conversion to galantamine. In addition, we cloned cytochrome P450 candidates for the oxidative coupling of 4'-O-methylnorbelladine, obtaining 21 and 18 CYP96T-like sequences from L. longituba and L. insularis, respectively. Phylogenetic screening yielded 10 candidates, of which only LlCYP96T_clone20 and LiCYP96T_clone1 produced a galantamine-matching peak in 35S::LlAKR4-p2A-LlNMT1 tobacco, with LlCYP96T_clone20 showing ∼2.89-fold higher response. Moreover, structural modelling of the ten CYP96T-like proteins further suggested that a conserved residue, Ile386 adjacent to the heme cofactor, plays an important role in catalytic efficiency. Collectively, our work not only elucidates the downstream biosynthetic pathway from 4'-O-methylnorbelladine to galantamine in Lycoris, but also lays a robust molecular foundation for heterologous production in engineered plant chassis and the subsequent development of its clinical and industrial applications.},
}

@article {pmid41934929,
year = {2026},
author = {Yao, M and Guo, H and Fang, Y and Chen, Y and Liu, Y and Liu, S and Guo, J and Guo, Z and Qian, J and Ma, Q},
title = {Microplastics released from dental materials induce oral inflammatory bone resorption and apoptosis via mitochondrial dysfunction.},
journal = {Environment international},
volume = {210},
number = {},
pages = {110226},
doi = {10.1016/j.envint.2026.110226},
pmid = {41934929},
issn = {1873-6750},
abstract = {Microplastics (MPs) are emerging pollutants that are associated with many diseases including atherosclerosis, inflammatory bowel disease (IBD), and Alzheimer's. The oral cavity is the primary point for the uptake of MPs by human, where MPs could pose risks to oral and even system health. Various polymer-based materials have been used as dental materials in oral treatment, however, the assessment of MPs in dental treatments remains limited and the processes and mechanisms by which MPs affect human health through the oral route are elusive. Here, we report the assessment of the risks and sources of MPs in dental clinics, the establishment of the relationship between MPs and oral inflammatory disorders, and also the elucidation of underlying mechanisms. Our results showed that commonly used therapeutic dental materials could generate MPs in dental clinics with proportions significantly higher than those in office areas and outdoors. As a representative, polymethyl methacrylate (PMMA) MPs showed significant toxicity to human oral keratinocytes (HOK), human periodontal ligament stem cells (hPDLCs), and THP-1-derived macrophages. Mechanistic investigations of apoptosis and inflammation processes revealed that MPs could lead to mitochondrial stress and autophagy and trigger the Notch signaling pathway and the JAK-STAT signaling pathway. Mice experiments showed that prolonged high-dose MPs exposure induced periodontal inflammatory reactions and even led to inflammatory bone resorption. This study provides a scientific basis for the oral health risks by MPs in dental practice and addresses the need for the development of dental materials with higher biocompatibility and environmentally sustainability.},
}

@article {pmid41934938,
year = {2026},
author = {Parameswari, M and Deepa, N and Sathya Priya, J and Muthulakshmi, K},
title = {A computational framework for Alzheimer's disease detection using SwinRes Transformer.},
journal = {Computers in biology and medicine},
volume = {208},
number = {},
pages = {111663},
doi = {10.1016/j.compbiomed.2026.111663},
pmid = {41934938},
issn = {1879-0534},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder that severely impacts cognitive functions. Early and accurate detection of Alzheimer's disease is significant to improve patient outcomes. However, the conventional model is difficult to capture the structural abnormalities and long-range inter-regional dependencies from the medical images, while maintaining computational efficiency. To address these challenges, this research implements a novel SwinRes Transformer model to detect Alzheimer's disease accurately. The Dilated InceptionV3 framework is employed to extract the features from the image that utilized a Fused MBConv and Group Convolution to mitigate the training time and parameters. The SwinRes Transformer is designed to detect Alzheimer's disease, which is designed by integrating a Modified Residual Network, Convolutional Shifted-Window Spatial-Channel Swin Transformer, and Feature Fusion Module. The Convolutional Shifted-Window Spatial-Channel Swin Transformer is employed to capture the global information and enhance the model's computational efficiency. The Modified Residual Network is employed to extract the local features and contextual information, solve the degradation trouble, and reduce the training time. Moreover, the Feature Fusion Module is designed to refine the features from the Modified Residual Network and Convolutional Shifted-Window Spatial-Channel Swin Transformer, thereby improving the relevant information and suppressing redundancy. Experiments are conducted on four Magnetic Resonance Imaging-based datasets, and the proposed SwinRes Transformer model achieves a superior accuracy of 98.93% and a lower execution time of 1.1 s when compared to existing Alzheimer's disease detection methodologies, providing a computationally efficient solution for accurate and scalable Alzheimer's disease detection.},
}

@article {pmid41935066,
year = {2026},
author = {Shou, R and Wang, Z and Han, Z and Li, A and Shang, J and Lou, H and Zhang, F and Zhan, Y and Shen, G and Lu, X and Jiang, H and Fan, X},
title = {Dietary silver nanoparticle supplementation induces Alzheimer-like lesions through Bifidobacterium deficiency-dominated gut microbiota dysbiosis and neuroinflammation.},
journal = {NPJ science of food},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41538-026-00820-9},
pmid = {41935066},
issn = {2396-8370},
support = {No. LY23B070004//Zhejiang Provincial Natural Science Foundation of China/ ; No. 82374136//National Natural Science Foundation of China/ ; No.2024SDXT001-7//Key R&D Program of Zhejiang/ ; },
abstract = {Dietary supplement silver nanoparticles have recently drawn attention following reports of hazards associated with long-term use. However, their biosafety, especially their effects on the gut-brain axis, remains largely unexplored. This study demonstrated that dietary supplement silver nanoparticles can accumulate in the intestines, brain, and liver of mice. Chronic exposure to these nanoparticles leads to Alzheimer-like lesions, primarily by disrupting gut microbiota balance. Specifically, this exposure depletes Bifidobacterium and Ruminococcaceae, resulting in reduced intestinal metabolites such as sphingomyelin (d18:1/20:0), tryptophan, and indole. Consequently, this disruption causes neuroinflammation, cognitive impairment, and amyloid-β deposition in mice. Moreover, Bifidobacterium was identified as a key microbial group contributing to Alzheimer-like lesions after exposure, whereas supplementation with Bifidobacterium breve MCC1274 effectively alleviated these lesions. Therefore, the potential risks of silver nanoparticles in dietary supplements should be carefully evaluated. This study provides a promising new direction for the prevention and treatment of Alzheimer-like lesions through microbial interventions.},
}

@article {pmid41935181,
year = {2026},
author = {Cheng, W and Yang, S and Lu, Y and Wang, Y and Tan, AH},
title = {Baicalein alleviates Alzheimer's disease pathology in AD models by activating the PI3K/AKT/GSK3β pathway to inhibit neuronal apoptosis.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-47003-w},
pmid = {41935181},
issn = {2045-2322},
support = {202520204//the Open Fund of Hubei Key Laboratory of Germplasm Improvement and Utilization of Dabie Shan Dao-di Herbs/ ; 82405523//National Natural Science Foundation of China/ ; 2025DJA044//Hubei Provincial Youth Science and Technology Innovation Talent Project/ ; 2025AFD318//Hubei Provincial Natural Science Foundation Huanggang Joint Fund Key Project/ ; },
}

@article {pmid41927845,
year = {2026},
author = {Sande, NV and Ahmed, S and Deurse, WV and Jansen, WJ and Braber, AD and Visser, PJ and Verhey, FRJ and Thach, M and Verbraak, FD and Bouwman, FH and Nuijts, RMMA and Ramakers, IHGB and Webers, CAB and Sharma, A and Gijs, M},
title = {Association of tear fluid glutathione synthetase and glutathione levels with amyloid positivity.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-46738-w},
pmid = {41927845},
issn = {2045-2322},
support = {09150161810102//NWO (Dutch Research Council) Veni Fellowship/ ; },
}

@article {pmid41927877,
year = {2026},
author = {Miao, J and Wang, J and Zhou, W and Guo, J},
title = {Small-molecule PCSK9 inhibition enhances BBB amyloid-β clearance and suppresses microglial inflammation in Alzheimer's disease models.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-46671-y},
pmid = {41927877},
issn = {2045-2322},
support = {No. 202303021222348//Fundamental Research Program of Shanxi Province/ ; No. 202303021221212//Fundamental Research Program of Shanxi Province/ ; No. 32571692//National Natural Science Foundation of China/ ; 2021ZD 0201801//STI2030-Major Projects/ ; 2023YFC3605400//National Key Research and Development Program of China/ ; },
abstract = {Impaired amyloid-β (Aβ) clearance and chronic neuroinflammation are central drivers of Alzheimer's disease (AD) progression, yet therapeutic strategies targeting these processes remain limited. Proprotein convertase subtilisin/kexin type 9 (PCSK9) negatively regulates low-density lipoprotein receptor family members, including low-density lipoprotein receptor -related protein 1 (LRP1), a key mediator of blood-brain barrier (BBB) Aβ efflux, and has emerging roles in inflammatory signaling. In this study, to define the therapeutic relevance of PCSK9 inhibition in AD-like pathology, we examined SBC-115,076 in AlCl3-challenged zebrafish larvae and mechanistically validated its effects using complementary endothelial-microglial in vitro models. SBC-115,076 significantly improved locomotor behavior and sensorimotor responsiveness, reduced Aβ deposition and neuronal apoptosis, and normalized oxidative stress, cholinergic dysfunction, and neuroinflammatory markers in vivo. Mechanistically, SBC-115,076 downregulated endothelial PCSK9 and upregulated LRP1, thereby enhancing Aβ endocytosis, lysosomal trafficking, and selective brain-to-blood efflux across an in vitro BBB model. In parallel, SBC-115,076 suppressed Aβ-induced CD36/TLR4 signaling in microglia, attenuated M1-like activation, promoted M2-like polarization, and reduced pro-inflammatory cytokine release. Collectively, these findings demonstrate that small-molecule PCSK9 inhibition ameliorates AD-like pathology through coordinated enhancement of BBB-mediated Aβ clearance and suppression of microglial inflammatory amplification, highlighting PCSK9 as a multifaceted therapeutic target and supporting a BBB-oriented strategy for AD intervention.},
}

@article {pmid41927939,
year = {2026},
author = {Sakakibara, R and Yamamoto, T and Uchiyama, T},
title = {Urogenital dysfunction in neurological diseases.},
journal = {Nature reviews. Neurology},
volume = {22},
number = {4},
pages = {226-238},
pmid = {41927939},
issn = {1759-4766},
mesh = {Humans ; *Nervous System Diseases/complications/physiopathology ; *Sexual Dysfunction, Physiological/etiology/physiopathology ; Male ; *Female Urogenital Diseases/etiology ; },
abstract = {Neural damage at any level of the neuraxis can lead to urogenital dysfunction, involving the lower urinary tract (LUT) and/or the sexual organs. The LUT consists of the bladder and the urethra (plus the prostate in males); LUT dysfunction can manifest as an underactive bladder, leading to urinary retention, or as an overactive bladder, leading to urinary incontinence. Manifestations of sexual dysfunction include loss of libido and dysfunction of erection, ejaculation and orgasm. In this Review, we address the physiology and innervation of the LUT and the sexual organs and discuss various aspects of urogenital dysfunction in CNS (brain and spinal cord) disorders including stroke, Alzheimer disease, white matter disease, normal-pressure hydrocephalus, Parkinson disease, dementia with Lewy bodies, multiple system atrophy, spinal cord injury, multiple sclerosis and spina bifida. We also review advances in the management of urogenital dysfunction in patients with neurological disorders.},
}

Humans
*Nervous System Diseases/complications/physiopathology
*Sexual Dysfunction, Physiological/etiology/physiopathology
Male
*Female Urogenital Diseases/etiology

@article {pmid41928108,
year = {2026},
author = {Hamaguchi, T and Hamano, T and Senoh, T and Kawasaki, Y and Uehara, T and Satoh, K and Hara, N and Miyashita, A and Ikeuchi, T and Kitamoto, T and Asahina, M},
title = {Early onset Alzheimer's disease with V180I variant of prion protein gene and a family history of dementia: a case report.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-04865-x},
pmid = {41928108},
issn = {1471-2377},
support = {23FC1007//Ministry of Health, Labour and Welfare/ ; 23FC1007//Ministry of Health, Labour and Welfare/ ; 23FC1007//Ministry of Health, Labour and Welfare/ ; JP25dk0207060//Japan Agency for Medical Research and Development/ ; },
}

@article {pmid41928135,
year = {2026},
author = {Hayat, SZ and Saad, M and Bukhari, SR and Nazi, N},
title = {A Buffering Role of Perceived Social Support and Resilience between Caregiver Burden and Perceived Stress among Informal Caregivers of Dementia Elderly Patients.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07351-8},
pmid = {41928135},
issn = {1471-2318},
}

@article {pmid41928210,
year = {2026},
author = {Leelahavarong, P and Prawjaeng, J and Angkab, P and Wongkom, N and Scheltens, P and Srinonprasert, V and Senanarong, V},
title = {Cost-utility analysis of cerebrospinal fluid versus blood biomarkers for early detection of Alzheimer's disease and mild cognitive impairment in Thailand: a modeling study.},
journal = {BMC health services research},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12913-026-14405-5},
pmid = {41928210},
issn = {1472-6963},
}

@article {pmid41928223,
year = {2026},
author = {Chen, L and Chen, H and Wang, G and Zhang, Y and Li, C and He, G and Shi, W and Fan, J and Wang, Y and Guo, X and Peng, L and Zhao, M and Li, M and Ma, X},
title = {Family caregivers' perceptions of postoperative recovery experience following deep cervical lymphovenous anastomosis in patients with Alzheimer's disease: a qualitative study.},
journal = {BMC nursing},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12912-026-04573-4},
pmid = {41928223},
issn = {1472-6955},
support = {2024YLZDJH261//Zhengzhou Science and Technology Bureau/ ; 252102311063//Zhengzhou Science and Technology Bureau/ ; },
}

@article {pmid41928225,
year = {2026},
author = {Kato, M and Isazawa, A and Ohki, A and Fujita, A and Araki, M and Yanaizu, M and Kino, Y},
title = {Functional sQTLs regulating PTK2B exon 31 splicing uncover an RNA-dependent modulation of its kinase activity and cellular phenotype.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-02835-x},
pmid = {41928225},
issn = {1478-811X},
support = {19J15024//Ministry of Education, Culture, Sports, Science and Technology/ ; 19K07982//Ministry of Education, Culture, Sports, Science and Technology/ ; },
}

@article {pmid41928377,
year = {2026},
author = {Minta, K and Söderberg, L and Gkanatsiou, E and Johannesson, M and Möller, C and Björklund, M and Osswald, G and Lannfelt, L and Fabre, S and Michno, W},
title = {MALDI mass spectrometry imaging (MSI) reveals molecular and structural heterogeneity of amyloid-β in sporadic Alzheimer's disease and Down syndrome.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02280-4},
pmid = {41928377},
issn = {2051-5960},
}

@article {pmid41928507,
year = {2026},
author = {Kim, B and Tate, MD and Karahan, H and Wijeratne, HRS and Sharify, AD and Wang, SS and Kim, JR and Al-Amin, MM and Hartigan, K and Chung, S and Dabin, LC and Acri, DJ and Doud, EH and John, SK and Mosley, AL and Kim, J},
title = {Deletion of SPI1 in microglia exacerbates amyloid pathology by impairing microglial response in Alzheimer's disease models.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.03.011},
pmid = {41928507},
issn = {1097-4199},
abstract = {Recent human genetic studies have highlighted the potential role of microglial genes and their regulatory functions in the pathogenesis of Alzheimer's disease (AD). The transcription factor PU.1 (encoded by SPI1) is expressed mainly in microglia in the central nervous system and has been reported to be a genetic risk factor for AD. However, the role of microglial SPI1 in AD etiology is still poorly understood. Here, we demonstrate that the selective deletion of Spi1 in microglia exacerbates AD-related pathologies in an amyloid mouse model. Specifically, microglial Spi1 deletion increases amyloid deposition, gliosis, and dystrophic neurites while decreasing the microglial response to plaques. By combining proteomics and functional analyses, we reveal that the loss of microglial Spi1 impairs phagocytosis through Syk, Lyn, and Fcgr1. Furthermore, directly activating these genes rescues the impaired amyloid-beta (Aβ) uptake caused by Spi1 knockdown, unveiling the potential mechanism of SPI1 in amyloid pathology.},
}

@article {pmid41928515,
year = {2026},
author = {Dubnov, S and Piran, Z and Alper, A and Yefroimsky, A and Soreq, H and Nitzan, M},
title = {Identifying maximally informative signal-aware representations of single-cell data using the information bottleneck.},
journal = {Cell systems},
volume = {},
number = {},
pages = {101571},
doi = {10.1016/j.cels.2026.101571},
pmid = {41928515},
issn = {2405-4720},
abstract = {Rapid advancements in single-cell RNA sequencing (scRNA-seq) technologies revealed the richness of myriad attributes encompassing cell identity. However, the complexity of the data hinders tasks focusing on a specific biological signal. To address this challenge, we introduce bioIB, a framework based on the information bottleneck method, designed to extract an interpretable compressed representation of scRNA-seq data, optimally informative with respect to a specific biological signal, such as disease state. Provided with cellular labels representing the signal of interest, bioIB generates weighted gene clusters, termed metagenes, that compress the data while maximizing signal-specific information. Further, bioIB provides the hierarchical structure of the metagenes, revealing the interconnections between the corresponding biological processes and cellular populations, such as the developmental hierarchy of hematopoietic cell types. We showcase bioIB's applicability to diverse biological contexts, including Alzheimer's disease, epithelial-to-mesenchymal transition, immune development, and hematopoiesis, demonstrating diverse applications of optimally compressed multicellular representations.},
}

@article {pmid41928630,
year = {2026},
author = {Chen, X and Chen, J and Mu, Y and Pan, X and Feng, S},
title = {Application of Chinese Pre-trained Language Models in Early Detection of Cognitive Impairment: A Comparative Study Based on Spoken Text.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050434686260214223520},
pmid = {41928630},
issn = {1875-5828},
abstract = {INTRODUCTION: Degenerative cognitive disorders, such as Alzheimer's Disease (AD), impose a substantial burden on societies and families worldwide. Currently, no definitive treatments or curative medications exist, and the academic consensus emphasizes the critical importance of early detection and intervention to mitigate disease progression. With advancements in artificial intelligence, particularly the rapid evolution of Natural Language Processing (NLP) technologies, novel approaches for the early identification of cognitive impairments have emerged. Text embeddings derived from Pre-Trained Language Models (PLMs) offer a promising means to classify spoken language samples, enabling objective assessment of cognitive status. However, research on the application of Chinese PLMs in this domain remains relatively scarce.

MATERIALS AND METHODS: Six representative Chinese Pre-Trained Language Models (PLMs) were used as feature extractors to generate text embeddings from transcribed spoken texts. The corpus included 45 healthy young adults, 46 elderly individuals with Mild Cognitive Impairment (MCI), and 48 patients diagnosed with Alzheimer's Disease (AD). These embeddings were combined with four classic machine learning algorithms, Support Vector Machines (SVM), Random Forests (RF), K-Nearest Neighbors (KNN), and Logistic Regression (LR), to conduct classification experiments.

RESULTS: Results showed RoBERTa performed best, achieving 95.71% accuracy with SVM, followed by BERT. MacBERT, SimCSE, ERNIE, and BGE had decreasing performance. Among classifiers, SVM and LR outperformed RF and KNN.

DISCUSSION: The results of this study not only verify the strong ability of Chinese pre-trained language models in mining semantic degradation features but also indicate that traditional machine learning algorithms still have competitiveness in scenarios with small samples and high-dimensional data. Compared with traditional methods that rely on manually designed language features, the text embedding-based classification strategy in this study undoubtedly shows higher performance.

CONCLUSION: These findings highlight the potential of Chinese PLMs in facilitating early detection of cognitive impairment, providing a technical foundation for developing accessible screening tools for Chinese-speaking populations.},
}

@article {pmid41928631,
year = {2026},
author = {Huang, Y and Zhu, X and Yang, S and Zhang, Y and Tan, Z and Han, S},
title = {Digital Technology in Cognitive Decline: Bibliometric and Visualization Study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050420571260126043841},
pmid = {41928631},
issn = {1875-5828},
abstract = {With an increasing prevalence of cognitive decline diseases around the world, digital technologies are becoming an important tool for their prevention, diagnosis, and treatment. In this study, we present a comprehensive bibliometric study on the application of these digital technologies in the field of cognitive decline. This study intends to examine the trends of development and research hotspots of digital technology in cognitive decline field by bibliometric analysis. The literature has been analyzed in a systematic way. Bibliometrix R-package and VOSviewer were used to investigate publication tendency, country contribution, scholar influence, and research hotspots. A total of 1661 articles from 2006 to 2023 were analyzed. Results show an exponential increase in the number of annual publications on digital technologies applications and cognitive decline. The top journals, by volume of publication, are Alzheimer's & Dementia, the Journal of Alzheimer's Disease, and Neurology. The US is the dominant contributor of literature to this field, and the key countries for author impact include Greece, the USA, and Italy. Current research hotspots include virtual reality, machine learning, and artificial intelligence, based on analysis of keywords. This study characterizes the overall research progress and reveals research hotspots, trends, and the collaboration status among countries, on the utilization of digital technologies for cognitive decline. Moving forward, we call on researchers to increase developed/developing countries collaboration, to further implement digital technologies to counteract the public health burden of cognitive decline.},
}

@article {pmid41928632,
year = {2026},
author = {Mehrabadi, S and Samarghandian, S},
title = {Glymphatic System Dysfunction in Alzheimer's Disease: Insights into its Mechanisms, Diagnostic Imaging, and Therapeutic Perspectives: A Systematic Review.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050428286260225033532},
pmid = {41928632},
issn = {1875-5828},
abstract = {INTRODUCTION: The glymphatic system, a perivascular network that facilitates cerebrospinal fluid (CSF)-mediated clearance of metabolic waste, including amyloid-β (Aβ) and tau, has emerged as a critical player in the pathophysiology of Alzheimer's disease (AD). Growing evidence suggests that an impaired glymphatic function may contribute to the onset and progression of AD by disrupting brain homeostasis and facilitating neurotoxic protein accumulation. This systematic review aims to synthesize current evidence from preclinical and clinical studies investigating the role of glymphatic system dysfunction in Alzheimer's disease, with a focus on its imaging biomarkers, clearance mechanisms, cognitive implications, and therapeutic interventions.

METHODS: A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science to identify studies published up to June 2025. Thirteen eligible studies were included: five preclinical experiments, eight human imaging or biomarker studies, and one clinical trial protocol. All studies examined glymphatic system function in relation to Aβ or tau clearance, neuroimaging markers (e.g., DTI-ALPS, PVS, PET), cognitive outcomes, or therapeutic modulation (e.g., exercise, sensory stimulation).

RESULTS: Preclinical models demonstrate that impaired aquaporin-4 (AQP4) polarization and reduced CSF-interstitial fluid exchange promote Aβ accumulation and plaque formation. Human imaging studies consistently report reduced glymphatic activity in AD and mild cognitive impairment (MCI), often measured via diffusion MRI (ALPS index) and associated with increased amyloid burden, reduced cognitive performance, and altered sleep. Emerging interventions, such as aerobic exercise and 40 Hz gamma sensory stimulation, appear to enhance glymphatic clearance and reduce Aβ levels in experimental settings. A recently published trial protocol is currently evaluating the effects of exercise on glymphatic function in MCI/AD.

DISCUSSION: The current body of evidence supports a probable association between glymphatic dysfunction and Alzheimer's disease pathology. Disruption of perivascular clearance pathways may serve as an early biomarker of AD and a novel therapeutic target. Future longitudinal and interventional studies are needed to establish causal relationships and evaluate clinical applications.

CONCLUSION: Glymphatic system impairment plays a significant role in AD pathogenesis, contributing to the accumulation of neurotoxic proteins and cognitive decline. Therapeutic strategies targeting glymphatic function enhancement, such as lifestyle interventions and neuromodulation, hold promise for early prevention and disease modification.},
}

@article {pmid41928782,
year = {2026},
author = {Tzeng, HM and Kuo, YF and Pappadis, MR and Hennessy, EA and Marquez-Bhojani, MM and David, SV and Passy, E and Raji, MA},
title = {A Qualitative Study of a Pilot of Clinician Perspectives on the Delivery of Medicare Annual Wellness Visits for Patients with Dementia in an Academic Health Science Center in Texas.},
journal = {Health services insights},
volume = {19},
number = {},
pages = {11786329261432894},
pmid = {41928782},
issn = {1178-6329},
abstract = {BACKGROUND: Little is known about clinicians' perspectives on the process and outcomes of Medicare Annual Wellness Visits (AWVs) in Medicare beneficiaries with mild cognitive impairment (MCI) or Alzheimer's Disease and Related Dementias (ADRD).

OBJECTIVES: We sought clinicians' opinions on the impact of AWVs on health outcomes and disparity reduction for beneficiaries with MCI/ADRD.

DESIGN: Institute for Healthcare Improvement's 4Ms framework of an age-friendly health system informed the design of this qualitative study of a pilot.

METHODS: We used convenience sampling and recruited clinicians from a single academic-health-science center's catchment area in Texas, who billed for at least 1 AWV to participate in a one-time, one-on-one, semi-structured interview conducted via phone/Zoom. Participants verbally agreed to participate. This study met the federal regulations for a Quality Assessment project.

RESULTS: We interviewed 26 clinicians (17 female; 26 non-Hispanic, 12 White, 10 Asian, 4 Black; 16 in family medicine and 5 in internal medicine). Most agreed AWVs improve health outcomes (n = 23, 88.5%) and reduce health disparities for Medicare beneficiaries with MCI/ADRD (n = 20, 76.9%). The top three "what works" themes were: (1) non-primary care providers (eg, wellness nurses) streamline AWV delivery by screening patients, providing resources/support, and sharing abnormal findings with primary care providers (PCPs); (2) PCPs do AWVs themselves to be in alignment with issues identified; and (3) sufficient time allotted to learn what matters most to patients and caregivers. The top three "what does not work" themes were: (1) clinicians desire having a family caregiver present; (2) clinicians need the full hour for in-depth screenings and holistic care; and (3) clinics need on-site social workers to address nonmedical issues.

CONCLUSIONS: Clinicians agreed that AWVs helped improve health outcomes and reduce health disparities. Tailoring AWV components by MCI/ADRD stage will optimize the visit, maximize health outcomes, and decrease disparities in access to care.},
}

@article {pmid41928804,
year = {2026},
author = {Xiao, Y and Spotorno, N and An, L and Bazinet, V and Hansen, J and Strandberg, O and Shafiei, G and Behjat, H and Funck, T and Salvadó, G and Stomrud, E and Smith, R and Palmqvist, S and Ossenkoppele, R and Mattsson-Carlgren, N and Palomero-Gallagher, N and Dagher, A and Misic, B and Hansson, O and Vogel, J},
title = {Brain network dynamics determine tau presence while regional vulnerability governs tau load in Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8687892/v1},
pmid = {41928804},
issn = {2693-5015},
abstract = {In Alzheimer's disease (AD), tau pathology accumulates gradually throughout the brain, with clinical decline reflecting tau progression. A comprehensive understanding of, first, whether tau propagation is predominantly governed by connectome-based diffusion, regional vulnerability, or an interplay of both, and second, which types of brain connectivity or regional factors best explain tau propagation, remains crucial for advancing our understanding of AD progression. Here, we apply multi-scale, biologically informed disease progression simulations to human data, to disentangle the influence of local mechanisms on global tau progression patterns in AD. We find that whether tau reaches a brain region (presence) and how much tau accumulates there (load) are governed by different mechanisms. Tau presence patterns are highly consistent across the population, and can be largely explained through synaptic spread through white-matter networks and excitatory-inhibitory dynamics. Meanwhile tau load differs across people, and is driven by a combination of synaptic spread and intrinsic or extrinsic regional properties, including regional β-amyloid load, MAPT gene expression and regional blood flow. Finally, while distinct tau patterns in the population could each be explained by established AD mechanisms, our models highlight a role of distinct brain networks (parietal networks in MTL-sparing AD tau subtype) and neurotransmitter systems (cholinergic system in posterior subtype). Together, this work suggests that network dynamics likely determine the sequence of regional tau progression, while individual-specific tissue-vulnerability factors influence regional tau load.},
}

@article {pmid41928917,
year = {2026},
author = {Stites, SD and Lee, DS and Kuz, C and Humphreys, V and Streitz, ML and Xie, SX and Flatt, J and Glover, CM and Mechanic-Hamilton, D},
title = {Repeated Administration of Social and Structural Determinants of Health (SSDOH) Questions in an Alzheimer's Disease Research Center: The Aging Brain Study (ABC) Life Experience Survey.},
journal = {Sage open aging},
volume = {12},
number = {},
pages = {30495334261430788},
pmid = {41928917},
issn = {3049-5334},
abstract = {Social and structural determinants of health (SSDOH) must be measured longitudinally to understand how lived experiences shape trajectories of Alzheimer's disease and related dementias (ADRD). This study evaluated the feasibility of administering an SSDOH survey to cognitively unimpaired older adults, examining response consistency, changes over time, and missing data patterns. A follow-up survey was conducted with participants in the UPenn Alzheimer's Disease Research Center clinical cohort an average of 1.7 years after the initial survey. The 225-item questionnaire covered domains including education, social networks, and stressors. At follow-up, markers of feasibility included a 60% completion rate (81 of 135 participants), high item completion (>93%), and minimal missing data (<3% missed more than 10% of data). Logistic regression identified gender, social network size, and social readjustment experiences as predictors of nonrandom missingness. Response changes between administrations were likely due to ambiguity in item phrasing, instructions, or changes in participants' experiences. Overall, repeated administration of the SSDOH survey was feasible. The response rate was reasonable but lower than expected for a volunteer research sample, suggesting multiple modes of completion may increase engagement. Repeated administration also helped identify ambiguous items and methods for improving the validity and reliability of SSDOH measures.},
}

@article {pmid41928929,
year = {2026},
author = {Coulon, A and Rabiller, F and Takalo, M and Roy, A and Pelletier, A and Martiskainen, H and Siedlecki-Wullich, D and Lannette-Weimann, N and Majerníková, N and Grenon, A and Gao, V and Erhardt, A and Pernodet, A and Lemaire, M and Limoge, F and Walle, P and Mendes, T and Guyot, K and Lemeu, C and Carvalho, LI and Melo de Farias, AR and Hulsman, M and Najdek, C and Freire-Regatillo, A and Saha, O and Amouyel, P and Charbonnier, C and Deleuze, JF and Dols-Icardo, O and Jeskanen, H and Willman, RM and Kuulasmaa, T and Kurki, M and Hardy, J and Heikkinen, S and Holstege, H and Mäkinen, P and Nicolas, G and Mead, S and Wagner, M and Ramirez, A and Rauramaa, T and Palotie, A and Sims, R and Soininen, H and van Swieten, J and Williams, J and Bellenguez, C and Gelle, C and Lambert, E and Costa, MR and Tcw, J and Glaab, E and Ayral, AM and Demiautte, F and Grenier-Boley, B and Muntaner, M and Eberlé, D and Deforges, S and Haas, J and Kilinc, D and Mulle, C and Chapuis, J and Hiltunen, M and Dumont, J and Lambert, JC},
title = {Non-microglial downregulation of PLCG2 impairs synaptic function and elicits Alzheimer disease-related hallmarks.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.29.591575},
pmid = {41928929},
issn = {2692-8205},
abstract = {We developed a high content screening to investigate how Alzheimer disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Out of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased Aβ levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a 10-fold increased AD risk. PLCG2 LoF carriers exhibit low mRNA/protein PLCG2/ PLCγ2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single nuclei RNAseq analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexin in neurons. In conclusion, PLCγ2 downregulation could increase AD risk by impairing synaptic functions and increasing the Aβ levels and Tau phosphorylation in neurons.},
}

@article {pmid41928945,
year = {2026},
author = {Duncan, WE and Fenik, P and Strus, E and Veasey, S and Naidoo, N},
title = {Hippocampal BiP Overexpression Rescues Cognitive Performance and Increases REM theta in 3xTg Mouse Model of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.23.713240},
pmid = {41928945},
issn = {2692-8205},
abstract = {The accumulation of Aβ plaques and hyperphosphorylation of Tau neuropathologically characterize Alzheimer's disease (AD). Synaptic dysfunction and endoplasmic reticulum (ER) stress precede overt neuropathology. ER stress is characterized by the accumulation of unfolded/misfolded proteins, which leads to activation of the adaptive signaling pathway, the unfolded protein response (UPR). Chronic or unresolved ER stress, as in disease, is maladaptive and triggers the integrated stress response (ISR). We hypothesize that targeted attenuation of ISR activation would mitigate the early cognitive deficits and molecular pathology in the triple transgenic (3xTg) mouse model of AD. To test this hypothesis, we used an adeno-associated viral (AAV) vector to overexpress BiP, the key ER chaperone and UPR regulator, in the hippocampi of young 3xTg mice. BiP overexpression reduced phosphorylated PERK (pPERK), a marker of ISR activation, and increased synaptic proteins BDNF, PSD95, and choline acetyltransferase marker (ChAT). Hippocampal-dependent working memory, social memory, long-term spatial memory, and REM theta power were improved without changes in locomotion. BiP overexpression reduced neuroinflammation, as evidenced by a decrease in the astrocyte marker GFAP. Additionally, Aβ and Aβ42 levels were reduced in the hippocampus and cortex. Collectively, these findings indicate that modulation of ER stress via BiP overexpression ameliorates early cognitive and molecular alterations associated with AD.},
}

@article {pmid41928975,
year = {2026},
author = {Ma, X and Koppelmans, V and Akcicek, H and Akcicek, EY and Shen, J and Chen, L and Balu, N and Yuan, C and King, JB},
title = {SNAP MRI Reveals Association Between Distal Cerebral Arterial Flow and Cognitive Function in an Aging Population.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.21.713392},
pmid = {41928975},
issn = {2692-8205},
abstract = {OBJECTIVE: Impaired blood flow has recently been recognized as a critical contributor to cognitive impairment and dementia. It was reported that cerebral distal arterial flow measured from Simultaneous Non-contrast Angiography and Intraplaque Hemorrhage (SNAP) MRI is associated with post-treatment cognitive function improvement in carotid atherosclerosis patients. In this study, we aim to evaluate the value of SNAP-based measurements in assessing cerebrovascular function in an aging population.

MATERIALS AND METHODS: Neurovascular MRI data were collected on 36 aging participants (22 cognitively unimpaired and 14 impaired; 9 mild cognitive impairment (MCI) and 5 Alzheimer's Disease (AD)). Neurovascular MRI measurements, including white matter hyperintensities (WMH) volumes, cerebral blood flow (CBF), and SNAP-based distal cerebral arterial flow (dCAF) index, were quantified. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

RESULTS: Significant differences in the dCAF index were observed between cognitively unimpaired and impaired groups, and the dCAF index was significantly correlated with the RBANS total score. While CBF was significantly associated with dCAF index, there is no significant correlation of CBF or WMH with the RBANS score in this population.

CONCLUSION: Our findings suggest that the dCAF measured with SNAP MRI is valuable for evaluating the cognition-related cerebrovascular condition in an aging population.},
}

@article {pmid41928996,
year = {2026},
author = {Wang, Z and Hu, Z and Jiang, D and Song, J and Gou, Y and Shi, W and Wu, J and Xu, C and Akinwale, O and Hazel, K and Pottanat, G and Ge, Y and Wisniewski, T and Yedavalli, V and Sair, HI and Burhanullah, MH and Rosenberg, P and Lu, H},
title = {Non-invasive MRI mapping of tissue-CSF water exchange reveals glymphatic fluid movement in live human cortex.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.26.714533},
pmid = {41928996},
issn = {2692-8205},
abstract = {Efficient metabolic waste clearance, via the postulated glymphatic system, is essential for neural homeostasis. However, direct visualization of tissue-cerebrospinal fluid (CSF) exchange remains limited, leading to ongoing debate in the neuroscientific field. The present work revealed evidence of tissue-CSF water exchange in the live human cortex, by employing a novel MRI technique demonstrating the flux of water molecules across the perivascular interface. We observed robust water exchange inside the cortical ribbon, which was more prominent than white matter and deep brain tissue. We validated that the signal originates from CSF and is independent of cerebral perfusion. Water exchange between tissue and CSF declined with age. Furthermore, we demonstrated for the first time that tissue-CSF exchange was impaired in Alzheimer's disease (AD), in particular in regions where the perivascular space is clogged by anti-amyloid immunotherapy.},
}

@article {pmid41929014,
year = {2026},
author = {Yang, J and Nomura, M and Meng, JX and Garcia, TY and Matsuura, TR and Kelly, DP and Nakamura, K and Newman, JC},
title = {Requirement for oxidation of neuronal ketone bodies in aging and neurodegeneration.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.24.712448},
pmid = {41929014},
issn = {2692-8205},
abstract = {Glucose is the brain's primary fuel, but the brain can also use alternative energy substrates, especially during development or starvation. Emerging evidence suggests ketone metabolism may help the brain adapt to energy stress in neurodegenerative diseases such as Alzheimer's disease, although its role in constitutive brain function in normal aging is poorly understood. Using iPSC-derived human neurons and adult-inducible, neuron-specific Bdh1 knockout mice, we show that ketone body metabolism is essential for maximum energy production, neuronal function, and mouse survival-even under normal nutritional conditions. Mechanistically, phenotypes of Bdh1 knockout neurons are mitigated by provision of acetoacetate, a downstream energy metabolite. Moreover, loss of neuronal ketone oxidation markedly increases mortality and memory deficits in Alzheimer's disease model mice. These findings identify ketones as critical neuronal fuels, with particular importance during neurodegeneration. While non-energetic activities of ketone bodies are increasingly appreciated, oxidation for energy provision is an essential mechanism for normal function in neurons and mice. Targeting the energetic function of ketones may thus offer new therapeutic strategies for both aging and neurodegenerative diseases such as Alzheimer's.},
}

@article {pmid41929021,
year = {2026},
author = {Zeng, Y and Xiong, J and Lovchykova, A and Nguyen, TP and Song, A and Gitler, SW and Abu-Remaileh, M and Gitler, AD},
title = {Granulin loss and TMEM106B risk converge on lysosomal C-terminal fragment pathology in frontotemporal dementia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.25.713523},
pmid = {41929021},
issn = {2692-8205},
abstract = {UNLABELLED: Frontotemporal dementia (FTD) is the second most common cause of dementia after Alzheimer disease. Mutations in GRN , which encodes progranulin, are a major cause of FTD. Common genetic variants in the TMEM106B gene modify risk of FTD and the effect is especially strong in GRN mutation carriers. Intriguingly, in GRN mutation carriers, being homozygous for the protective TMEM106B haplotype seems to confer near lifetime protection against FTD. Despite the strong genetic link between GRN and TMEM106B , how these two genes interact mechanistically has remained unresolved. Recent studies have revealed that a C-terminal fragment of TMEM106B forms amyloid fibrils and accumulates in the brains of older individuals and patients with neurodegenerative disorders, including FTD. How the production of this fragment connects to granulin deficiency is also unknown. Using lysosome immunoprecipitation, we show that granulin deficiency drives the accumulation of the TMEM106B C-terminal fragment within lysosomes in Grn -knockout mice and GRN -null human iPSC-derived neurons. Recombinant progranulin supplementation reduced TMEM106B C-terminal fragment accumulation. Isogenic neurons carrying the TMEM106B risk allele displayed allele-dose-dependent fragment accumulation that was reversible by progranulin. Structural and genetic analyses demonstrated that TMEM106B dimerization stabilizes the protein and limits C-terminal fragment formation. These findings define a lysosomal pathway linking granulin deficiency to TMEM106B C-terminal fragment accumulation and explain how protective TMEM106B alleles can confer resistance to FTD, even for GRN mutation carriers.

ONE SENTENCE SUMMARY: Granulin deficiency drives lysosomal accumulation of an amyloidogenic TMEM106B C-terminal fragment, revealing a molecular mechanism that explains how TMEM106B alleles can confer risk or protection from frontotemporal dementia.},
}

@article {pmid41929023,
year = {2026},
author = {Romero-Molina, C and Gomez-Gutierrez, R and See, WY and Patel, T and Davtyan, H and Ma, J and Xu, Q and Sewell, M and Allton, K and McReynolds, M and Calderon, O and Lightfoot, YL and Bommer, G and Cruchaga, C and Blurton-Jones, M and Ray, WJ and Marcora, E and Goate, AM},
title = {Reduced LACTB expression in myeloid cells is associated with elevated succinylcarnitine levels and reduced Alzheimers disease risk.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.24.711053},
pmid = {41929023},
issn = {2692-8205},
abstract = {BACKGROUND: Lactamase B (LACTB) is a mitochondrial protease associated with cancer progression and lipid metabolism. LACTB is located in an AD locus and has been associated with Alzheimers Disease (AD) in a proteomic study.

METHODS: We performed Mendelian randomization (MR) to evaluate the relationship between LACTB expression, succinyl-carnitine, and AD risk. We generated LACTB knock-down (KD) THP1 macrophages, LACTB knock-out (KO) iPSC-derived microglia and LACTB enzymatically-dead (ED) mice. The impact of LACTB downregulation in myeloid cells was characterized via transcriptomics, metabolomics, lipidomics, and functional assays. Finally, human LACTB KO microglia precursors were xenotransplanted into the brains of amyloid-pathology mice to assess in vivo interactions with amyloid plaques.

RESULTS: MR analyses revealed that lower LACTB expression in myeloid cells reduces AD risk and is genetically associated with increased levels of succinylcarnitine, a metabolite that independently correlates with reduced AD risk. We identified LACTB as a primary enzyme responsible for succinylcarnitine hydrolysis. Transcriptional and functional studies showed that loss of LACTB enhances OXPHOS, reduces protein synthesis, and alters lipid profiles. LACTB expression was upregulated following IFN/TNF stimulation, and its loss modified efferocytosis-related functions under inflammatory conditions. In vivo, xenotransplanted human LACTB-KO microglia exhibited enhanced association with amyloid plaques compared to controls.

CONCLUSIONS: Our findings define a previously unrecognized axis linking LACTB and succinylcarnitine to myeloid cell function and AD susceptibility. Given the druggability of LACTB and the potential for succinylcarnitine to serve as a translational biomarker, this pathway represents a promising therapeutic target for modulating neuroinflammation in AD.},
}

@article {pmid41929024,
year = {2026},
author = {Hebbar, P and Potapova, T and Loucks, H and Ray, K and Rodrigues, MF and Ryabov, F and Malukiewicz, J and Yoo, D and de Lima, L and Haber, A and Kumar, S and Banerjee, S and Borchers, M and Garcia, GH and Gardner, J and Hachem, S and Heath, H and Ha, SK and Mastoras, M and McNulty, B and Menendez, J and Munson, KM and Pal, K and Park, J and Ploesch, S and Roos, C and Seligmann, WE and Shepelev, V and Spruce, C and Violich, I and Walter, L and Makova, KD and Thathiah, A and Rizzo, SJS and Silva, AC and Carter, GW and Miga, KH and Eichler, EE and Conrad, DF and Gerton, JL and Alexandrov, I and Paten, B},
title = {A Complete Genome for the Common Marmoset.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.25.713844},
pmid = {41929024},
issn = {2692-8205},
abstract = {The common marmoset is a New World monkey (NWM) commonly used as a model organism to investigate questions in primate evolution and human disease, including Alzheimer's and other neurodegenerative diseases, as well as neuropsychiatric disorders. Here we present the first telomere-to-telomere (T2T) reference genome for the common marmoset, adding over 88 Mb of sequence and resolving challenging genomic regions. An additional near-T2T assembly from a second unrelated individual yields a total of four high-quality haplotypes for analysis. The improved contiguity and accuracy of these assemblies enable unprecedented insights into complex and rapidly evolving genomic regions such as centromeres, sex chromosomes, ribosomal DNA (rDNA) structure, and the major histocompatibility complex (MHC). We fully resolved all marmoset centromeres, uncovering dimeric alpha satellites with chromosomal specificity and stratified inactive layers documenting ancestral centromere turnover. We assembled six acrocentric autosomes with gene-poor, satellite-rich short arms and provide evidence that most of them can harbor rDNA and all of them share large pseudo-homologous regions (PHRs). The Y chromosome, but not the X chromosome, carries active rDNA and PHRs, and the rDNA copy number is sexually dimorphic. Chromosomes that share PHRs also share closely related centromeric satellite DNA, supporting a model of ongoing recombinational exchange between heterologous chromosomes facilitated by rDNA. We discovered multiple novel, marmoset-specific MHC genes that are predicted to protect against pathogens encountered in its environment. Leveraging this complete reference, we further identified over 500 transcribed genes with transcript models or expansions specific to the marmoset lineage. Together with additional long-read marmoset assemblies, these genomes were used to construct a marmoset pangenome, providing a robust reference framework for short-read mapping across diverse individuals. This resource will improve the utility of the common marmoset as a biomedical model organism and fill key gaps in our understanding of primate evolution.},
}

@article {pmid41929034,
year = {2026},
author = {Durell, SR and Shafrir, Y and Robert Guy, H},
title = {The concentric β-barrel hypothesis for amyloids: Models of soluble and transmembrane amyloid-β42 oligomers and channels composed of identical subunits and GM1 gangliosides.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.19.711324},
pmid = {41929034},
issn = {2692-8205},
abstract = {Soluble oligomers and transmembrane channels formed by the 42-residue variant of amyloid beta (Aβ42) play key roles in Alzheimer's disease. Unfortunately, detailed structures of these assemblies have not been determined. Our group addresses this problem by developing atomic scale models. Previously we proposed that both soluble Aβ42 oligomers and transmembrane channels have symmetric concentric β-barrel structures. Here we expand this hypothesis to include GM1 gangliosides and sometimes cholesterol and lattice models of channel assemblies. The presence of GM1 gangliosides increases the toxicity of Aβ42, enhances its ability to penetrate liposome membranes, and facilitates interactions between adjacent liposomes. Although the conformations of numerous model assemblies vary, in these models the carboxyl group of GM1 always binds to side-chains of histidine 13 and/or histidine 14. Our soluble oligomer models are consistent with electron microscopy images of beaded annular protofibrils. Our models of membrane-bound assemblies are consistent with the following: freeze-fracture and atomic force microscopy images of Aβ42 in lipid bilayers, secondary structure results, the calcium hypothesis of Alzheimer's Disease, effects of lithium depletion on AD, established β-barrel theory, and energetic criteria.},
}

@article {pmid41929047,
year = {2026},
author = {Stahr, N and Moriarty, AK and Ma, SD and Keeter, WC and Kim, WK and Sanford, LD and Galkina, EV},
title = {STAT4-dependent regulation of neuroinflammation in atherosclerosis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.20.713185},
pmid = {41929047},
issn = {2692-8205},
abstract = {Atherosclerosis is linked to an increased risk of cognitive decline, with chronic inflammation being a common feature of both pathologies. IL-12 activates STAT4 to regulate myeloid cell functions, and blockade of this pathway alleviates cognitive impairment in Alzheimer's models. However, the mechanisms connecting vascular pathology to neuroinflammation remain unclear. Here, we examine whether STAT4 functions as a common mediator of neuroinflammation in atherosclerosis. We demonstrate that LysM [Cre] -specific STAT4 deficiency ameliorates deficits in long-term memory in low-density lipoprotein-deficient (Ldlr [-/-]) mice fed a high-fat diet (HFD-C). STAT4 deficiency moderately reduces Ser199-phosphorylated Tau burden. Atherosclerosis alters brain immune composition, characterized by increased numbers of CD45 [+] leukocytes, activated microglia, and activated T and B cells, whereas STAT4 deficiency attenuates these effects. Nanostring gene-expression pathway analysis further highlights the importance of STAT4 in regulating multiple neuroinflammatory pathways and the Rhodopsin-like receptor signaling, which is associated with synaptic plasticity. LysM [Cre] -specific STAT4 deficiency supports microglial efferocytosis in atherosclerotic Ldlr [-/-] mice and increases the number of efferocytotic macrophages. Accordingly, STAT4 deficiency also reduced neuronal death. Overall, our data reveal an important role for myeloid-driven STAT4 expression in the pathogenesis of cognitive decline associated with atherosclerosis, mediated through impaired efferocytosis and enhanced leukocyte activation, leading to increased brain neuroinflammation.},
}

@article {pmid41929081,
year = {2026},
author = {Fodder, K and Murthy, M and de Silva, R and Raj, T and Farrell, K and Humphrey, J and Bettencourt, C},
title = {Cross-disease genetic and epigenetic architecture of the MOBP locus shows convergence in ALS-PSP.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.25.714147},
pmid = {41929081},
issn = {2692-8205},
abstract = {Myelin oligodendrocyte basic protein (MOBP) is an abundant oligodendrocyte gene implicated in multiple neurodegenerative diseases. Genetic variation at the MOBP locus has been associated with risk for progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTD), corticobasal degeneration (CBD), Alzheimer's disease (AD), Lewy body dementia (LBD), and Creutzfeldt-Jakob disease (CJD). Epigenetically, MOBP promoter hypermethylation and reduced expression have been reported in multiple system atrophy (MSA). Although MOBP is thought to play a role in oligodendrocyte morphology and myelin structure, how genetic and epigenetic variation at this locus influences gene regulation and contributes to disease risk remains poorly understood across neurodegenerative disorders. Here, we investigated whether shared or disease-specific genetic mechanisms at MOBP converge on altered DNA methylation and expression across neurodegenerative disorders. We analysed MOBP variants using summary statistics from recent GWAS for ALS, PSP, FTD, LBD, PD, MSA, AD, and CJD. Colocalisation (COLOC and SuSiE-coloc) was used to test whether disease-associated variants overlapped between diseases, and with oligodendrocyte expression quantitative trait loci (eQTLs) and bulk brain methylation quantitative trait loci (mQTLs). To further investigate mQTL effects at this locus, rs1768208, a variant previously associated with PSP, was genotyped in an overlapping brain methylation cohort, allowing direct testing of genotype-methylation associations in frontal white matter tissue. ALS and PSP GWAS demonstrated strong association at MOBP , with most strongly associated SNPs (e.g. rs631312, rs616147, rs1768208) shared between both disorders. Colocalisation analyses indicated high posterior probability that ALS and PSP share the same causal variant, with weaker overlap with FTD. mQTL colocalisation highlighted cg15069948, located near an exon junction within MOBP , as strongly colocalising with the ALS/PSP risk variants. In complementary tissue analyses, rs1768208-T carriers showed hypomethylation at cg15069948 in PSP brains. No genotype-methylation effects were detected in MSA or Parkinson's disease. Together with prior evidence of promoter hypermethylation and reduced expression in MSA, our findings identify cg15069948 as a regulatory methylation site linking ALS/PSP risk variants to altered MOBP methylation, and support MOBP dysregulation as a shared feature of neurodegeneration. However, the underlying mechanisms appear disease-specific, highlighting the complexity of involvement of this gene across neurodegenerative disorders.},
}

@article {pmid41929143,
year = {2026},
author = {Peng, W and Chung, KB and Al-Qazzaz, A and Straut, A and O'Banion, MK and Lawrence, BP and Dirksen, RT and Onukwufor, JO},
title = {Iron toxicity potentiates cell-type specific amyloid beta proteotoxicity in C. elegans via altered energy homeostasis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.25.714217},
pmid = {41929143},
issn = {2692-8205},
abstract = {UNLABELLED: Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by memory loss and a decline in cognitive function. Hallmarks of AD include an age-dependent accumulation of toxic amyloid beta (Aβ) 42 in the brain, energy dyshomeostasis caused by mitochondrial dysfunction, and iron overload. However, the role of iron overload and mitochondrial dysfunction in AD pathology is unknown and their precise relationship with Aβ 42 toxicity in AD pathology is unclear. C. elegans provide a powerful model system to untangle and clarify these relationships. In this study, we quantify the temperature-dependence of iron toxicity (16, 20 and 25[0]C) in neurons and muscle of C. elegans that overexpress Aβ 42. We found that Aβ 42, regardless of the cell-type expression, caused accelerated paralysis compared to age-matched WT worms with the greatest degree of paralysis observed at an elevated temperature (25[0]C). Moreover, the combination of iron toxicity and Aβ 42 results in an enhanced paralytic phenotype at 16[0]C. Thus, iron exposure potentiates Aβ toxicity observed at low temperatures. Iron toxicity stimulated both maximum (State 3) and leak (State 4) respiration in WT and Aβ 42 worms. Aβ 42 worms also exhibited increased leak respiration at baseline that was further exacerbated by iron toxicity. Iron burden and sensitivity increased Aβ 42 peptide toxicity. Aβ 42 worms exhibited reduced levels of Ca, Zn, Mn, and K. Overall, our results suggest that iron potentiates Aβ toxicity at low temperature and enhances Aβ peptide mediated mitochondrial bioenergetic dysfunction in C. elegans .

HIGHLIGHTS: Temperature stress modulates the synergetic interactions of iron toxicity and Aβ 42 pathologyIron sensitivity drives increased cell-type specific Aβ 42 pathologyEnergy dyshomeostasis via impaired mitochondrial function and increased proton leak contributes to iron- and Aβ-induced pathology.},
}

@article {pmid41929211,
year = {2026},
author = {Bieberich, E},
title = {RIFT: A Fractal-Holographic Theory of Consciousness and Autopoietic Control.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.23.713535},
pmid = {41929211},
issn = {2692-8205},
abstract = {Consciousness remains poorly understood as a causative force: existing theories treat it as an epiphenomenal correlate of neural activity rather than explaining how inner experience controls its substrate. I present Recurrent Integration Fractal Theory (RIFT), proposing that consciousness arises when fractal compression of sensory information generates a holographic endospace: the spatiotemporal dimension in which the Self perceives the outer world (exospace) and, through autopoietic feedback, controls the molecular substrate from which it emerged, making consciousness causally efficacious rather than epiphenomenal. In RIFT networks, core neurons form recurrent loops through fractal dendritic trees, generating dynamic information integration through coincidence-based synaptic selection. Coincident EPSPs program somatic multifractals, Ising lattices of ion channels and membrane lipids, encoding a fractal Self-attractor: a geometric field whose coherent point sources generate the holographic endospace through which the Self arises. The Self modulates multifractal growth through lipid domains, controlling ion channel opening probability and action potential generation. Through Generational Fractal Mapping, compressed seeds of prior conscious moments integrate with new EPSPs, replacing infinite downscaling as in classical fractals with sequential self-referential mapping that sustains incremental updating of inner experience, temporal continuity of the Self and Self-attractor transfer across brain regions for global conscious access, establishing irreducibility and unity: the whole is in each part. This architecture was validated computationally against three core properties of consciousness: irreducibility, information integration, and holographic encoding. RIFT generates testable predictions for lipid substrate disruption in Alzheimer's disease, fractal signatures of conscious states, and criteria for consciousness in artificial systems with autopoietic feedback.},
}

@article {pmid41929229,
year = {2026},
author = {Hollis, HC and Veltri, A and Korac, K and Menon, V and Bennett, DA and Ronnekleiv-Kelly, SM and Kim, J and Anafi, RC},
title = {Single-cell Transcriptomic Variance Analysis Reveals Intercellular Circadian Desynchrony in the Alzheimer's Affected Human Brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.23.713759},
pmid = {41929229},
issn = {2692-8205},
abstract = {Bulk tissue rhythms arise from the coordination of thousands of individual cellular oscillations. Bulk rhythm amplitude differences may reflect changes in the amplitude of the underlying cellular oscillators or changes in their temporal coherence. To resolve this fundamental ambiguity, we developed ORPHEUS (O scillatory R hythm P hase H eterogeneity E stimated U sing S tatistical-moments), an analytical method that quantifies cellular desynchrony by leveraging the unique 12hr rhythmic signature it imparts on intercellular expression variance. After validating ORPHEUS in silico and on data from the mouse suprachiasmatic nucleus (SCN), we applied it to data from the mouse liver and human brain to uncover disease- and pathway-related differences in intercellular synchrony. In both tissues, we found that circadian synchrony is higher in cells and samples with higher MTORC activity. Most critically, we observed a dramatic loss of cellular synchrony in excitatory neurons from subjects with Alzheimer's Disease (AD) dementia. By decoupling the influence of cellular amplitude and synchrony, ORPHEUS introduces a new, interpretable tool for analyzing circadian coordination in time-course single-cell data.},
}

@article {pmid41929284,
year = {2026},
author = {Boeriu, AI and Gu, T and Fullton-Howard, B and Lucero, EM and Shortt, J and Gignoux, C and Rajabli, F and Griswold, AJ and Yaffe, K and Andrews, SJ},
title = {Ancestry-specific effects of APOE on Alzheimer Disease Endophenotypes.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.23.26349095},
pmid = {41929284},
abstract = {IMPORTANCE: APOE *ε4 is the strongest genetic risk factor for Alzheimer's disease (AD), yet its effect varies across ancestral populations. As blood-based biomarkers increasingly inform AD diagnosis, failure to account for both APOE genotype and ancestry could lead to misinterpretation of biomarker profiles and inaccurate diagnostic classification. Understanding how ancestry modulates APOE effects is crucial for ensuring accurate biomarker-based assessments and AD diagnosis.

OBJECTIVE: To determine whether genetic ancestry modulates APOE association with cognitive function, brain morphometry, and plasma biomarkers.

DESIGN SETTING PARTICIPANTS: Cross-sectional analysis of community-dwelling older adults from the Health and Aging Brain Study-Health Disparities (HABS-HD) cohort (N = 2733). Participants spanning the cognitive spectrum underwent cognitive assessment, neuroimaging, plasma biomarker collection, and genome-wide genotyping from 2018 to 2023.

MAIN OUTCOMES AND MEASURES: Cognitive performance (global cognition, memory, executive function, verbal ability), brain morphometry (cortical thickness, hippocampal volume), and plasma biomarkers (Aβ 42 /Aβ 40 , pTau 181 , pTau 217 , total tau, NfL).

RESULTS: In the full cohort, APOE ε4+ was associated with worse cognitive performance across all domains, reduced cortical thickness and hippocampal volume, lower Aβ 42 /Aβ 40 , and elevated pTau 181 and pTau 217 . APOE ε2+ was associated with lower pTau 217 . Ancestry-stratified analyses revealed attenuated ε4+ effects on pTau 217 and pTau 181 in African compared with European participants (∼2.5-fold for both), with the pTau 217 difference surviving FDR correction. Compositional analysis confirmed that ε4+ effects on pTau 181 and pTau 217 strengthened with increasing European ancestry proportion. Local ancestry analysis showed ε4+ effects on pTau 217 were significantly attenuated in individuals with African local ancestry at the APOE locus. In contrast, ε4+ effects on Aβ 42 /Aβ 40 , cognition, and neuroimaging were largely consistent across ancestry groups. Meta-analysis with an independent multi-ancestry cohort replicated the attenuated pTau 181 findings.

CONCLUSIONS AND RELEVANCE: Genetic ancestry modifies the effect of APOE on AD endophenotypes. In particular, African ancestry attenuates the association between APOE ε4+ and pTau 181 and pTau 217. Accurate AD diagnosis requires consideration of both APOE genotype and ancestry to avoid misclassification in biomarker-based evaluations.},
}

@article {pmid41929290,
year = {2026},
author = {Wu, LY and du Toit, T and Georgiades, T and Stafford, EJ and Levine, K and Fang, ZH and Jasaityte, S and Martinez, AG and Cullinane, P and De Pablo Fernandez, E and Blauwendraat, C and Singleton, AB and Scholz, SW and Traynor, BJ and Wood, N and Hardy, J and Chinnery, P and Houlden, H and Cain, R and Troakes, C and Chelban, V and Serrano, GE and Gveric, D and McLean, C and Love, S and King, A and Robinson, AC and Roncaroli, F and Shepherd, C and Halliday, G and Parkkinen, L and Morris, CM and Smith, C and Beach, TG and Gentleman, S and Warner, TT and Lashley, T and Jaunmuktane, Z and Real, R and Morris, HR and , },
title = {Pathology and genetics in a global cohort of Parkinsonian Disorders.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.23.26348322},
pmid = {41929290},
abstract = {IMPORTANCE: Accurate diagnosis of neurodegenerative movement disorders is challenging because of a lack of in vivo biomarkers, overlapping clinical features and a delay in the emergence of pathognomonic features.

OBJECTIVE: To evaluate clinicopathological correlation, diagnostic accuracy, genetic association with pathology, and ancestry-related differences in a multi-ancestry brain bank cohort.

DESIGN: Multicentre retrospective autopsy cohort study on donors enrolled between 1985 - 2024.

SETTING: 11 academic brain banks in the UK, US and Australia.

PARTICIPANTS: Brain donors identified from participating brain banks with available brain tissue and a clinical diagnosis of Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, or neurologically normal controls.

EXPOSURE: Genetic variant carrier status and clinical diagnostic category.

MAIN OUTCOME: Clinical diagnostic accuracy; Lewy body and Alzheimer's disease pathology burden; survival; association with genetic variants and genetically inferred ancestry.

RESULTS: We studied 3,353 brain donors (1281 [38.2%] female, mean [SD] age at death, 76.8 [10.6] years). Misdiagnosis rates for movement disorders ranged approximately from 10% - 20%. Clinical diagnoses of dementia with parkinsonism (PDD/DLB) were more strongly associated with Lewy body pathology than Parkinson's disease without dementia (OR = 1·96, 95% CI = 1·30 - 3·04, p = 7·2e-04). Lewy pathology was identified in 4% of neurologically normal controls. Alzheimer's disease co-pathology was present in 40% of cases with Lewy body disease. GBA1 variant carriers exhibited greater Lewy body burden compared with noncarriers (OR = 1·94, 95% CI = 1·24 - 3·03, p = 0·01) or LRRK2 carriers (OR = 7·44, 95% CI = 2·16 - 25·64, p = 0·01). Pathological diagnoses differed by ancestry, with South Asian donors more likely to have progressive supranuclear palsy pathology and Ashkenazi Jewish donors more likely to have Lewy body disease (p < 0.0001), independent of GBA1 and LRRK2 mutation status.

CONCLUSION AND RELEVANCE: Our findings highlight the value of integrating genetic and pathological data to improve diagnostic accuracy. The high prevalence of Alzheimer's disease co-pathology and ancestry-related differences in pathology point to the need for biologically informed diagnostic tools. These results support the integration of genetically and pathologically stratified approaches, correlating pathology with in vivo biomarkers, for future therapeutic trials.

FUNDING: Medical Research Council, Global Parkinson's Genetic Program/Aligning Science Across Parkinson's.

KEY POINTS: Question: How do genetic variants and neuropathology influence clinical features and diagnostic accuracy in movement disorders?Findings: In this multi-ancestry brain bank series including over 3000 individuals, clinical misdiagnosis was common. Dementia with parkinsonism was more strongly associated with Lewy body (LB) pathology than Parkinson's disease without dementia, and Alzheimer's disease co-pathology was frequent. Genetic variation was associated with pathological differences. GBA1 carriers had greater LB burden, while LRRK2 pathogenic variant carriers had a lower LB burden and longer survival. Pathological diagnosis differed by ancestry. Meaning: Integrating genetics and neuropathology may improve diagnosis and support pathology-informed therapeutic trials.},
}

@article {pmid41929317,
year = {2026},
author = {Kowshik, SS and Jasodanand, VH and Bellitti, M and Puducheri, S and Xu, L and Liu, Y and Saichandran, KS and Dwyer, BC and Gabelle, A and Hao, H and Kedar, S and Murman, DL and O'Shea, SA and Saint-Hilaire, MH and Samudra, NP and Sartor, EA and Swaminathan, A and Taraschenko, O and Yuan, J and Au, R and Kolachalama, VB},
title = {Domain-adapted language model using reinforcement learning for various dementias.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.17.26348154},
pmid = {41929317},
abstract = {Large language models excel at processing complex clinical data and advanced reasoning, yet domain-specific adaptation is essential to realize their full potential in fields such as Alzheimer's disease and related dementias (ADRD). Here, we present a generative language model for ADRD fine-tuned via reinforcement learning with verifiable rewards using a self-certainty-aware advantage. Model development and validation leveraged data from five ADRD cohorts, totaling 54, 535 participants. Our framework integrates demographics, personal and family medical histories, medication use, neuropsychological test results, functional assessments, physical and neurological examination findings, laboratory data and multimodal neuroimaging to construct comprehensive clinical profiles. On held-out testing data involving 36, 688 participants, our model achieved robust performance on syndromic classification, primary etiological diagnosis and biomarker prediction. Model predictions were validated against postmortem-confirmed diagnoses, and clinical utility was demonstrated in a controlled within-subjects crossover study where board-certified neurologists reviewed cases with and with-out model assistance, showing that exposure to model responses improved diagnostic performance. These results demonstrate that targeted domain adaptation with reinforcement learning can enable language models to deliver accurate, reasoning-driven support in ADRD evaluation. Prospective validation will be essential to translate these advances into improved patient outcomes.},
}

@article {pmid41929322,
year = {2026},
author = {Lorkiewicz, SA and Abdelnour, C and Bolen, M and Smith, AM and Shahid-Besanti, M and Hemachandra, D and Müller-Oehring, EM and Siddiqui, N and Montoliu-Gaya, L and Arslan, B and Ashton, NJ and Wilson, EN and Tian, L and Andreasson, KI and Mormino, EC and Henderson, VW and Zetterberg, H and Poston, KL},
title = {Plasma pTau217 as a Prognostic, Monitoring, and Risk-Stratification Biomarker of Clinical Progression in Lewy Body Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.26.26349399},
pmid = {41929322},
abstract = {BACKGROUND AND OBJECTIVES: In Lewy body disease (LBD), co-occurring Alzheimer's disease (AD) neuropathologic change (ADNC) is associated with worse clinical outcomes. While plasma pTau217 detects ADNC in LBD, its prognostic, monitoring, and risk-stratification utility remains unclear. We evaluated whether plasma pTau217 predicted cognitive and functional decline and risk for progression to MCI or dementia in LBD.

METHODS: We included 501 participants enrolled in the Stanford Alzheimer's Disease Research Center with plasma pTau217 data who were clinically diagnosed as LBD spectrum (n = 131), AD spectrum (n = 133), or healthy controls (HC; n = 237). To assess prognostic and monitoring utility in LBD, linear mixed-effect models tested continuous baseline and longitudinal (2-5 years) plasma pTau217 as predictors of change in 2-8-year clinical outcome trajectories including: daily functioning (CDR-SB), global cognition (MoCA), and five domain-specific cognitive indices. For risk-stratification in LBD, baseline plasma pTau217 was dichotomized using an amyloid PET-derived, LBD-specific cut-point to examine effects of abnormal versus normal levels on clinical outcomes in separate mixed-effects and survival models.

RESULTS: In LBD, higher continuous baseline plasma pTau217 predicted accelerated CDR-SB increase (β = 0.29, p < 0.001), MoCA decline (β =-0.37, p = 0.014), and cognitive index decline (memory, executive function, visuospatial function, processing speed; βs =-2.24 to-0.06, ps ≤ 0.01). Faster longitudinal pTau217 increase predicted accelerated CDR-SB increase (β = 0.24, p = 0.001). In AD, higher continuous baseline pTau217 predicted accelerated CDR-SB increase and MoCA decline, whereas faster longitudinal increase predicted accelerated cognitive index decline (ps ≤ 0.04). In HC, higher continuous baseline pTau217 predicted accelerated memory index decline (p = 0.008). In LBD, abnormal baseline pTau217 predicted a 0.87 points/year (95% CI:-1.62,-0.58) faster MoCA decline, 0.85 points/year (95% CI: 0.56, 1.14) faster CDR-SB increase, accelerated decline on cognitive indices, and a three-fold higher risk of progressing to MCI or dementia (HR = 3.41, 95% CI 1.60, 7.28, p = 0.002) compared to normal pTau217.

DISCUSSION: Plasma pTau217 is a promising prognostic, monitoring, and risk stratification biomarker of clinical progression in LBD, underscoring its utility in mixed pathology groups for clinical practice and trials.},
}

@article {pmid41929343,
year = {2026},
author = {Kriwokon, SL and Flores-Alonso, SI and Kent, BA and Wilson, TW and Spooner, RK and Wiesman, AI},
title = {Peripheral Mitochondrial Energetics are Associated with Cortical Neurophysiological Alterations in Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.25.26349329},
pmid = {41929343},
abstract = {Alzheimer's disease is associated with both mitochondrial dysfunction and altered neurophysiological signalling. Peripheral measures of mitochondrial respiration have been established as effective predictors of mitochondrial function in the healthy brain, and more recently, of altered brain signalling in clinical groups. Here, we sought to assess whether peripheral mitochondrial energetics are associated with altered neural signalling in Alzheimer's disease. We collected task-free magnetoencephalography (MEG) from individuals on the Alzheimer's disease continuum (69.21 [6.91] years; n = 38) and cognitively normal older adults (72.20 [4.73] years; n = 20). Each participant also provided a blood sample for analysis of mitochondrial respiration using the Seahorse XF96 Analyzer. We used region-wise linear models to test the relationship between ATP-linked mitochondrial respiration and Alzheimer's disease-associated neurophysiological changes. We found that mitochondrial respiration linked to ATP production is associated with altered alpha and theta band cortical rhythms in Alzheimer's disease (α: p FDR < 0.05, r = -0.7; θ: p FDR < 0.05, r = -0.6). We then tested colocalization of mitochondria-neurophysiological relationships with a human brain atlas of respiratory capacity and found that brain regions with lower mitochondrial respiratory capacity exhibit a stronger relationship between aperiodic signalling and peripheral ATP-linked respiration (p FDR = 0.003, r = 0.35). Our findings suggest that peripheral blood measures of mitochondrial function can offer insight into the neurophysiological alterations associated with energetic changes in Alzheimer's disease and warrant further investigation into the translational potential of joint neuronal-mitochondrial markers of neurological diseases of aging.},
}

@article {pmid41929577,
year = {2026},
author = {Kandasamy, K and Narasimhamoorthi, SP and Arulselvan, P and Jaganathan, D},
title = {Protective effects of the natural polyphenol garcinol from Garcinia indica mitigates aluminium chloride-induced Alzheimer's-like neurodegeneration in Drosophila melanogaster.},
journal = {3 Biotech},
volume = {16},
number = {4},
pages = {154},
pmid = {41929577},
issn = {2190-572X},
abstract = {UNLABELLED: Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects millions of people affected in worldwide. Natural resources such as medicinal plants have been utilized for the treatment of various memory disorders like amnesia, dementia, Alzheimer's, and Parkinson's for a long time. This study aimed to investigate plants with therapeutic bioactivities for a range of scientific investigations focused on the neuroprotective effects of garcinol from Garcinia indica against the Aluminium chloride (AlCl3)-induced AD in the Drosophila melanogaster model. Polar and non-polar solvents were active on the G. indica fruit rind and subjected to phytochemical investigation. Garcinol was extracted from the EtOH extract of G. indica fruit rind using TLC, column chromatography, GC-MS, UV-visible, and FT-IR. In vitro free radical scavenging effect of the EtOH extract of G. indica fruit rind was studied to determine its antioxidant properties. The effect of garcinol on the interaction and predicted binding interaction of the AD-associated enzymes Amyloid-β, Acetylcholinesterase (AChE), and β-secretase was studied by the in-silico analysis. AD condition was initiated in D. melanogaster by challenging them with AlCl3, and they were pre-treated with garcinol, which is isolated from the EtOH extract of G. indica fruit rind. The effect of garcinol on the AChE activity, oxidative stress markers, and pro-inflammatory cytokines was studied using the respective assay kits. The apoptotic proteins were studied using the RT-PCR analysis. The findings of the phytochemical analysis. In silico garcinol effectively interacts with and inhibits the intermolecular Amyloid-β, AChE, and β-secretase enzymes. AD, garcinol treatment successfully moderated the amendments in behavioural and cognitive impairments, regulated the oxidative stress markers, decreased AChE activity, and reduced the pro-inflammatory cytokine levels. The RT-PCR method proved that garcinol regulated the pro- and anti-apoptotic protein expressions in the AD-induced D. melanogaster. The findings suggested that garcinol from EEGIFR acts against AlCl3-induced AD in D. melanogaster because of its anti-inflammatory, antioxidant, and apoptosis-modulating capabilities, and it may develop as a capable therapeutic agent in treating AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-026-04763-6.},
}

@article {pmid41929599,
year = {2026},
author = {Liu, Y and Li, Y and Zheng, P and Zhang, B},
title = {Associations between systemic inflammatory markers and cognitive decline in patients with early-stage Alzheimer's disease: a retrospective clinical study.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1765287},
pmid = {41929599},
issn = {1664-2295},
abstract = {BACKGROUND: Emerging evidence implicates systemic inflammation in Alzheimer's disease (AD)'s development and progression, yet comprehensive clinical data linking specific systemic inflammatory biomarkers to cognitive decline in early-stage AD remain limited.

OBJECTIVE: To evaluate the correlation between key systemic inflammatory biomarkers and cognitive decline in early-stage AD, to identify potential inflammatory indicators for risk screening and disease monitoring.

METHODS: In this retrospective study, 155 patients with early-stage AD and 100 matched healthy controls were enrolled between March 2020 and March 2025. Peripheral blood levels of inflammatory biomarkers, including IL-1β, IL-6, IL-8, IL-10, TNF-α, MCP-1, and CRP, were measured. Cognitive function was assessed using the MMSE and MoCA. Group comparisons, Spearman correlation analyses, and ROC curves with DeLong tests were performed.

RESULTS: The groups were comparable in baseline demographics (p > 0.05). The AD group exhibited significantly lower MMSE and MoCA scores (p < 0.001). AD patients had significantly elevated plasma levels of IL-1β, IL-6, TNF-α, and MCP-1 (p < 0.001), and decreased levels of IL-8 and IL-10 (p < 0.001). Correlation analyses revealed significant negative correlations between MMSE/MoCA scores and IL-1β, IL-6, TNF-α, and MCP-1 (p < 0.05), and positive correlations with IL-8 and IL-10 (p < 0.05). IL-6, IL-1β, and TNF-α showed the strongest associations. ROC analysis indicated AUCs of 0.766 for IL-1β, 0.716 for TNF-α, and 0.768 for IL-6. A panel combining IL-1β, TNF-α, and IL-6 achieved a significantly higher AUC of 0.894, with 77.42% sensitivity and 86.00% specificity.

CONCLUSION: Elevated levels of IL-6, IL-1β, and TNF-α are strongly associated with cognitive decline in early-stage AD, suggesting their utility as potential biomarkers for disease progression. A multi-marker inflammatory panel significantly enhances diagnostic accuracy, supporting the exploration of anti-inflammatory strategies for early intervention.},
}

@article {pmid41929929,
year = {2025},
author = {Tang, Y and Zhuo, E and Li, P and Wang, C and Hu, X and Liu, X and Xu, G and Shen, Q},
title = {MANF improves cognitive function and attenuates neuroinflammation in APP/PS1 transgenic mice through the TLR4/MYD88/NF-κB signaling pathway.},
journal = {Journal of anesthesia and translational medicine},
volume = {4},
number = {4},
pages = {241-254},
pmid = {41929929},
issn = {2957-3912},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by progressive cognitive decline, as well as pathological features such as β-amyloid (Aβ) plaque deposition, tau hyperphosphorylation, synaptic dysfunction, and neuronal loss. Growing evidence suggests that neuroinflammation, oxidative stress, and apoptosis play critical roles in the pathogenesis of AD, thereby contributing to neuronal damage and cognitive decline. Mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum stress-inducible protein, has been shown to exert neuroprotective effects by modulating immune responses, alleviating oxidative stress, and suppressing apoptosis in various neurological disease models. These properties suggest that MANF could serve as a promising therapeutic candidate treating AD. This study investigated the therapeutic potential of MANF in improving cognitive function and ameliorating pathological changes in APP/PS1 transgenic (Tg) mice by modulating neuroinflammation and enhancing neural plasticity.

METHODS: Beginning at 10 months of age, male APP/PS1 transgenic mice received daily intraperitoneal injections of recombinant human MANF (rhMANF) at a dose of 1 μg/g for a duration of one month. Behavioral assessments, including the Morris water maze, open field, and fear conditioning tests, were conducted to evaluate cognitive function. Brain tissue was analyzed for β-amyloid (Aβ) deposition, neuroinflammation, oxidative stress, and neuronal apoptosis using immunofluorescence, immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. RNA sequencing (RNA-seq) and a BV2 microglial/HT22 neuronal co-culture system were used to further elucidate the mechanisms underlying MANF's effects.

RESULTS: rhMANF treatment significantly improved cognitive function in APP/PS1 Tg mice by reducing Aβ deposition, inhibiting microglial activation, and suppressing inflammatory cytokines (TNF-α, IL-1β, and IL-6). MANF also mitigated oxidative stress, reduced neuronal apoptosis, and restored synaptic protein levels, including those of Postsynaptic density protein-95(PSD95) and synaptophysin (SYN). In vitro studies confirmed that MANF effectively counteracts Aβ1-42-induced toxicity in the BV2/HT22 co-culture system. Transcriptomic analysis identified that MANF exerts its protective effects by regulating the TLR4/MYD88/NF-κB signaling pathway, thereby reducing inflammation and promoting synaptic plasticity.

CONCLUSIONS: This study demonstrates the protective role of MANF in AD and establishes MANF as a promising therapeutic candidate for AD and aging-related neurodegenerative disorders.},
}

@article {pmid41929942,
year = {2026},
author = {Yan, K and Li, H and He, S and Jia, X and Liu, D and Chen, J},
title = {The diagnostic value of plasma phosphorylated tau 181 in Alzheimer's disease within the Chinese population: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261432112},
pmid = {41929942},
issn = {2542-4823},
abstract = {BACKGROUND: Among all related biomarkers, plasma phosphorylated tau (p-tau181) has demonstrated strong diagnostic performance in the very early stages of Alzheimer's disease (AD), showing significant differences between AD patients and healthy controls.

OBJECTIVE: The aim of our present systematic review and meta-analysis was to roundly evaluate the clinical diagnostic value of plasma p-tau181 based on the Simoa platform in Chinese populations.

METHODS: We systematically searched five databases (Embase, PubMed, Cochrane Library, MEDLINE, and Web of Science) from inception to May 11, 2024, as well as the references of retrieved relevant articles. We included prospective cohort studies and retrospective case-control studies in our analysis.

RESULTS: Out of 1165 identified articles, 10 met the inclusion criteria for meta-analysis. Our quantitative analysis showed that plasma p-tau181 levels were significantly increased in patients with AD and mild cognitive impairment (MCI) compared to healthy controls (standard mean difference SMD: 1.45 1.25-1.65, p < 0.00001; SMD: 0.55 0.31-0.78, p < 0.00001) and were lower in MCI patients compared to AD patients (SMD: -0.88 -0.93--0.82, p < 0.00001). The reference values for plasma p-tau181 were 4.48 95% confidence interval (CI): 4.01-5.00 for AD patients, 2.86 95% CI: 2.45-3.34 for MCI patients, and 2.09 95% CI: 1.90-2.30 for healthy controls.

CONCLUSION: The meta-analysis confirmed that plasma p-tau181 significantly increases from healthy controls to MCI and then to AD in the Chinese population. We also provide reliable reference values for plasma p-tau181, which contribute to the early diagnosis of AD in Chinese clinical settings.},
}

@article {pmid41929943,
year = {2026},
author = {Rubio, CM and Fernández-Romero, L and Balugo, P and Fraile-Pereda, A and Suárez-Coalla, P and Cabrera-Martin, MN and Yus-Fuertes, M and Matias-Guiu, JA and Ayala, JL},
title = {Prediction of clinical and language changes after a single session of repetitive transcranial magnetic stimulation in primary progressive aphasia: A machine learning approach.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261420785},
pmid = {41929943},
issn = {2542-4823},
abstract = {BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) offers a non-invasive therapeutic option for primary progressive aphasia (PPA) and Alzheimer's disease among other neurological conditions.

OBJECTIVE: This study aims to enhance the personalization of rTMS therapy by predicting patient-specific changes after one session of rTMS across multiple clinical assessments, based on the targeted stimulation area.

METHODS: We studied 20 PPA patients, each receiving rTMS targeting in three distinct brain regions. Using machine learning, we developed predictive models for eight clinical outcome measures, incorporating features extracted from structural MRI, resting-state EEG, and individualized electric field modeling via SimNIBS. These features were used to estimate each patient's likely response to rTMS in terms of cognitive and language function.

RESULTS: Of the outcome measures, 'Clinical impression of change' emerged as the most reliable indicator of perceived improvement, achieving a top F1-score of 0.80 using a Decision Tree model based solely on sociodemographic features. Meanwhile, 'Words per minute' reached an F1-score of 0.77 with a Random Forest model utilizing EEG-derived features.

CONCLUSIONS: The predictive models developed in this study underscore the feasibility of using EEG and SimNIBS data to anticipate patient outcomes from rTMS therapy. This data-driven framework can aid in customizing rTMS protocols, paving the way for more targeted and effective interventions for PPA and related neurodegenerative conditions.},
}

@article {pmid41929944,
year = {2026},
author = {Baghcheghi, Y and Razazpour, F and Mohammadi, M and Mashayekhi, H and Hedayati-Moghadam, M},
title = {Unraveling the molecular links: Alzheimer's disease-induced mechanisms of memory impairment: A narrative review.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823251412327},
pmid = {41929944},
issn = {2542-4823},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive memory impairment and cognitive decline, significantly impacting the quality of life for millions worldwide. Understanding the intricate molecular pathways linking AD pathology to memory dysfunction is crucial for developing effective therapies. This narrative review aims to elucidate the key molecular mechanisms underlying memory impairment in AD. We conducted a comprehensive literature search across major scientific databases (e.g., PubMed, Scopus, Web of Science) focusing on peer-reviewed studies (original research, reviews) exploring the molecular links between AD pathology and memory deficits. The review identifies and details several interconnected molecular pathways driving memory impairment in AD: (1) Synaptic dysfunction and neuronal loss triggered by amyloid-β (Aβ) peptide accumulation and aggregation; (2) Intracellular transport disruption and neurodegeneration caused by tau protein hyperphosphorylation and aggregation; (3) Exacerbation of cognitive deficits by neuroinflammation, mediated through activated microglia and pro-inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6); (4) Impairment of synaptic plasticity and cognitive function due to dysregulation of neurotrophic factors, particularly brain-derived neurotrophic factor; (5) Contributory roles of oxidative stress, mitochondrial dysfunction, disrupted neurotransmission (e.g., acetylcholine, GABA), and apoptotic pathways. This review comprehensively unravels the critical molecular links between AD pathology and memory impairment, emphasizing the interplay of Aβ, tau, neuroinflammation, neurotrophic factor dysregulation, and other mechanisms. Targeting these interconnected pathways represents a promising strategic approach for developing therapies to mitigate cognitive decline and improve outcomes in AD patients.},
}

@article {pmid41929945,
year = {2026},
author = {Yang, Y and Meng, Y and Li, M and Xu, Z and Wu, H and Zhang, Q and Zhang, S and Kong, F and Wang, Z and Li, X and Zhu, Y},
title = {Identification of potential short-chain fatty acid biomarkers in Alzheimer's disease through bioinformatics analysis.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261424808},
pmid = {41929945},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder. Accumulating evidence suggests that short-chain fatty acids (SCFAs) can regulate the central nervous system, thereby affecting cognitive and behavior function.

OBJECTIVE: This study aimed to investigate the association between the AD development and SCFA metabolism via bioinformatic analysis.

METHODS: Gene expression profiles were obtained from the GEO database. 1243 genes related to SCFA were screened from Genecards database. Through weighted gene co-expression network analysis (WGCNA) and differential analysis, 10 SCFA hub genes were screened. Machine learning algorithms, including support vector machine recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) regression models, were used to identify candidate biomarkers. The CIBERSORT algorithm was utilized to evaluate the infiltration of immune cells and its relationship with the potential biomarkers. The candidate biomarker chemicals were identified in the Comparative Toxicogenomics Database as underlying targeted drugs for treating AD.

RESULTS: Five genes-EZR, SNCA, GFAP, NFKBIA, and SST-were identified as potential biomarkers for AD through LASSO and SVM-RFE analyses. These genes can also be used to predict the risk of AD and have good diagnostic effects. The candidate biomarkers are associated with plasma cells, activated dendritic cells, M1 macrophages and resting natural killer cells. Notably, valproic acid and tretinoin were found to target these candidate genes, suggesting a new treatment approach for AD.

CONCLUSIONS: This study identified EZR, SNCA, GFAP, NFKBIA, and SST as potential key SCFA-related genes associated with the progression of AD, providing new insights into the prevention and treatment of AD.},
}

@article {pmid41929946,
year = {2026},
author = {Behroozi, Z and Askarpour, H and Baghcheghi, Y},
title = {Molecular sabotage of hippocampal synaptic plasticity by amyloid-β in Alzheimer's disease: A narrative review.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261415807},
pmid = {41929946},
issn = {2542-4823},
abstract = {This narrative review aims to synthesize and critically evaluate the complex molecular mechanisms by which amyloid-β (Aβ) accumulation disrupts hippocampal synaptic plasticity, the cellular cornerstone of learning and memory in Alzheimer's disease (AD). AD is characterized by progressive hippocampus-dependent cognitive decline, strongly linked to impaired synaptic plasticity, the cellular basis of learning and memory. This review deciphers how Aβ accumulation orchestrates synaptic sabotage in the hippocampus. We detail the core molecular machinery of hippocampal synaptic plasticity, emphasizing glutamate receptor trafficking (NMDAR/AMPAR), Ca[2+] signaling, and neurotrophin pathways (BDNF/TrkB). Central to AD pathogenesis, soluble Aβ oligomers initiate synaptic dysfunction by targeting receptors like PrPᶜ/mGluR5, triggering NMDAR overactivation (via Fyn/NR2B) and AMPAR endocytosis. Aβ further drives tau hyperphosphorylation (via GSK-3β/CDK5), leading to dendritic p-tau accumulation and destabilization of the postsynaptic density (PSD). Concurrently, Aβ activates microglia (via TLR4/TREM2) and astrocytes, promoting neuroinflammation (IL-1β, TNF-α, C1q) and complement-mediated synaptic phagocytosis. Aβ-induced oxidative stress (ROS/RNS, lipid peroxidation) and mitochondrial failure (mPTP opening, energy depletion) exacerbate Ca[2+] dyshomeostasis and plasticity impairment. Critically, Aβ disrupts BDNF/TrkB signaling, promoting proBDNF/p75ᴺᵀᴿ-mediated spine loss and inhibiting CREB-dependent plasticity gene expression. These converging pathways-glutamate receptor dysregulation, p-tau toxicity, neuroinflammation, oxidative stress, mitochondrial dysfunction, and neurotrophic collapse-culminate in synaptic apoptosis, profound structural damage (spine loss, PSD dissolution), and functional deficits (long-term potentiation (LTP) blockade, enhanced long-term depression (LTD)). This molecular cascade directly underlies hippocampal circuit failure and cognitive decline in AD. Future research must address Aβ strain specificity, regional vulnerability, glial metabolic coupling, resilience mechanisms, and novel therapeutic strategies targeting these pathways.},
}

@article {pmid41929947,
year = {2026},
author = {Shimohama, S and Azami, S and Oyama, M and Takizawa, T and Kubota, M and Suzuki, H and Yamada, M and Nakahara, J and Ito, D},
title = {Large-scale APP duplication in early-onset Alzheimer's disease without cerebral amyloid angiopathy: A case report.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823251412896},
pmid = {41929947},
issn = {2542-4823},
abstract = {We present the case of a patient who began experiencing cognitive decline in her 30 s and was diagnosed with duplication of the amyloid precursor protein (Dup-APP) associated early-onset Alzheimer's disease (EOAD). The diagnosis was supported by the presence of amyloid and tau biomarkers. The clinical course, neuroimaging findings, and genetic testing excluded other diseases known to cause early-onset cognitive impairment. Our case exhibited a markedly large duplication of 19 Mb and did not present with cerebral amyloid angiopathy. Our findings suggest a potential association between the size of the duplication and the clinical phenotype.},
}

@article {pmid41929948,
year = {2026},
author = {Watanabe, M and Bun, S and Shimizu, A and Iwabuchi, Y and Mori, S and Jinzaki, M and Mimura, M and Ito, D},
title = {Distinct brain volume changes associated with the head-turning sign and Neucop-Q response patterns in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261437682},
pmid = {41929948},
issn = {2542-4823},
abstract = {BACKGROUND: The "head-turning sign" (HTS) and Neurocognitive Questionnaire (Neucop-Q) capture toritsukuroi (saving appearance) behaviors commonly observed in Alzheimer's disease (AD). Neucop-Q is a brief screening questionnaire assessing current event memory (News; N), self-awareness/concern (Consciousness; C), and engagement in pleasurable activities (Pleasure; P). Previously, HTS-positivity and impaired N/impaired C/normal P (NimpCimpPnor) combination show high specificity for amyloid PET positivity.

OBJECTIVE: To investigate the neuroanatomical correlates of HTS and specific Neucop-Q response patterns across the AD continuum.

METHODS: One hundred thirty-seven individuals (54 cognitively normal controls, 9 preclinical AD, 36 mild cognitive impairment, and 38 AD dementia patients) underwent clinical evaluation and structural MRI. Gray matter volumes were analyzed using voxel-based morphometry with MVision software based on a Multi-Atlas Likelihood Fusion approach. Regional volumes were normalized to intracranial volume and adjusted for age and sex. Group differences were tested with false discovery rate (FDR) correction, and logistic regression assessed associations between regional volume and Neucop-Q responses.

RESULTS: HTS was significantly associated with right hippocampal atrophy (FDR-corrected p = 0.024). In the logistic regression analyses, none of the associations survived correction for multiple comparisons. The NimpCimpPnor combination was correlated with medial and inferior temporal lobe atrophy (FDR < 0.01) and larger globus pallidus (FDR = 0.034), with logistic regression surviving correction.

CONCLUSIONS: HTS reflected reduced right hippocampal volume, whereas NimpCimpPnor involved broader temporal atrophy with relatively larger pallidal volumes, suggesting distinct regional gray matter patterns across behavioral response profiles.},
}

@article {pmid41929949,
year = {2026},
author = {Zhang, Q and Almanie, L and Ouyang, Y and Cheng, Z and Zhang, H},
title = {From routine periodontal therapy to Alzheimer's disease early detection: A scoping review.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261421629},
pmid = {41929949},
issn = {2542-4823},
abstract = {An epidemiological association has been observed between periodontitis and Alzheimer's disease (AD); however, salivary and blood assays often show low specificity. Periodontal tissues and fluids, which are routinely removed and discarded during periodontal treatment, may be collected to offer matrices useful for the early detection of AD. This study aimed to map current preclinical and clinical evidence on biomarkers measured in periodontal tissues and fluids for the early detection of AD and organize them within an AD-specificity pyramid anchored to brain-relevant endpoints. Following PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Extension for Scoping Reviews) guidance, we searched PubMed, Scopus, and Web of Science (January 1, 2015-August 31, 2025) for preclinical and clinical studies measuring AD-relevant biomarkers in periodontal matrices. The protocol was pre-registered (OSF DOI: 10.17605/OSF.IO/EDVU9; August 20, 2025). Two reviewers extracted the data, and other two independently verified them. The findings were organized using a four-tier AD-specificity pyramid. Results: Fourteen studies met the inclusion criteria. The biomarkers from the included studies were clustered into microbiome features, molecular signals, and genetic/transcriptomic findings. Evidence ranged from Tier-1 contextual inflammation/pathogens to Tier-4 core-pathology adjacency; five studies incorporated clinical/biological anchoring, with cerebrospinal fluid amyloid-β positivity providing the most brain-relevant anchor. Periodontal matrices are practicable, high-signal sources for AD-relevant biomarkers. However, translational validation linking periodontal biomarkers to brain endpoints is needed to assess the feasibility of multi-tier and chairside panels for early AD detection as part of routine periodontal care.},
}

@article {pmid41929950,
year = {2026},
author = {Lin, F and Yang, X and Xie, X and Qiu, L and Zheng, C and Zheng, X and Li, Z and Nie, B},
title = {The causal association between the new gut microbiota and Alzheimer's disease: A Mendelian randomization study.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261422629},
pmid = {41929950},
issn = {2542-4823},
abstract = {BACKGROUND: There is a need for more studies to validate the role of gut microbiota in Alzheimer's disease (AD).

OBJECTIVE: This study aims to explore the causal association between new gut microbiota and AD using Mendelian randomization.

METHODS: Using genome-wide association study (GWAS) of 473 gut microbiota species and AD in IEU Open GWAS database, independent genetic loci related to gut microbiota were extracted as instrumental variables. The inverse variance weighting method was employed as the main indicator for evaluation. The stability and reliability of the results were further verified by heterogeneity test, outlier detection, horizontal pleiotropy test and leave-one-out analysis.

RESULTS: Following a thorough screening process, a total of 14 intestinal microbiota were included in the final analyses. The elevated abundance of Agathobacter, Citrobacter A, Clostridium E sporosphaeroides, Eubacterium R, Megamonas funiformis, and Pseudomonas aeruginosa can reduce the risk of AD. Higher abundance of Bifidobacterium, Holdemania massiliensis, Hydrogenophaga, Intestinimonas massiliensis, Megasphaera, Paenibacillus J, Prevotella, and Raoultella could increase the risk of AD. The MR-Egger analyses at 14 "genus" levels showed no horizontal pleiotropy and the p values were all more than 0.05. The leave-one-out analysis showed that results were relatively stable.

CONCLUSIONS: This study revealed a causal relationship between 14 specific gut microbiota and the risk of AD occurrence. Some bacteria are protective, while others increase the risk of AD. These findings are of clinical significance for the treatment and prevention strategies in clinical practice, and it also provides new perspectives for related research on the "gut-brain axis".},
}

@article {pmid41929951,
year = {2026},
author = {An, X and Wang, Y and Cao, M and Yi, Z and Zeng, X and Yu, W and Ren, Z},
title = {Exploring BSCL2 and associated genes in Alzheimer's disease by integrative analysis of bioinformatics, sn-RNAseq and machine learning approach.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261423079},
pmid = {41929951},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by significant cognitive decline and memory impairment. This condition imposes a considerable economic burden on healthcare systems worldwide.

OBJECTIVE: Current diagnostic approaches often lack specificity and sensitivity, necessitating innovative methods to identify potential biomarkers that could facilitate earlier intervention and improved patient outcomes.

METHODS: In this study, we aimed to elucidate the role of the BSCL2 gene in the pathogenesis of AD by employing various bioinformatics techniques, including transcriptomic analysis and single-nucleus RNA sequencing (sn-RNAseq). We also integrated machine learning algorithms to identify potential biomarkers associated with AD. A weighted gene co-expression network was constructed to uncover co-expression modules linked to BSCL2, alongside AGPAT1 and EHD2, which demonstrated promising diagnostic potential with area under the curve (AUC) values exceeding 0.7.

RESULTS: Our analyses revealed significant alterations in immune cell profiles across different AD subtypes, providing insights into personalized immunotherapy approaches. Furthermore, pathway enrichment analyses highlighted key biological processes involved in AD, including oxidative phosphorylation, neuroactive ligand-receptor interactions, and Notch signaling pathways. Notably, sn-RNAseq data indicated that BSCL2-related gene activity exhibited significant changes in neural lineages, suggesting its influence on neurodegenerative mechanisms.

CONCLUSIONS: This study underscores the potential of BSCL2, AGPAT1, and EHD2 as novel biomarkers for early detection of Alzheimer's disease. The insights gained from the co-expression analyses and immune profiling pave the way for personalized therapeutic strategies aimed at modulating the immune response in AD. Future research should focus on the clinical validation of these biomarkers and their role in the development of targeted interventions, ultimately enhancing our understanding of AD pathophysiology and improving patient management.},
}

@article {pmid41929952,
year = {2026},
author = {Huang, S and Guo, Y},
title = {Network meta-analysis of the efficacy of nine drugs for cognitive function in patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261422205},
pmid = {41929952},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) remains a global challenge, and the comparative cognitive efficacy of emerging pharmacotherapies is still unclear.

OBJECTIVE: To compare and rank nine pharmacological agents against placebo in AD with respect to key cognitive outcomes using a network meta-analysis.

METHODS: We systematically searched randomized controlled trials published up to May 2025 that evaluated aducanumab, lecanemab, donanemab, gosuranemab, semorinemab, tilavonemab, zagotenemab, masupirdine, or sodium oligomannate in AD. The primary outcomes were Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog); Mini-Mental State Examination (MMSE) was a secondary outcome. Treatments were ranked using the Surface Under the Cumulative Ranking curve (SUCRA).

RESULTS: Fifteen randomized trials encompassing 33 treatment arms were included. No drug demonstrated statistically robust superiority over placebo in primary outcomes. Semorinemab and tilavonemab achieved highest SUCRA rankings, but without significant pairwise advantage. For MMSE, aducanumab showed a modest mean difference versus placebo (1.98, 95% CI 0.03-3.93), though evidence of publication bias reduced confidence.

CONCLUSIONS: Current pharmacological treatments do not consistently outperform placebo in AD. Tau-targeted antibodies (semorinemab, tilavonemab) display modest but non-significant promise, whereas aducanumab's apparent benefit is likely confounded by publication bias. Further large, rigorous randomized controlled trials and improved preclinical models are essential.},
}

@article {pmid41929953,
year = {2026},
author = {Oso, TA and Okesanya, OJ and Adebayo, UO and Obadeyi, KB and Ayelaagbe, OB and Talabi, OA and Adewole, PD and Anorue, CO and Ahmed, MM and Talabi, OT and Ogaya, JB and Lucero-Prisno, DE},
title = {Microbiome alterations in Alzheimer's disease: A systematic review of current evidence and global perspectives.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261436287},
pmid = {41929953},
issn = {2542-4823},
abstract = {BACKGROUND: Growing evidence implicates the gut-brain axis in Alzheimer's disease (AD), with gut microbiome dysbiosis proposed to modulate neuroinflammation, amyloid pathology, and cognitive decline.

OBJECTIVE: To systematically synthesize human studies (2021-2025) profiling gut microbiomes in AD; identify consistent taxonomic and functional signatures; map geographic study distribution; and highlight translational gaps.

METHODS: A PRISMA-compliant systematic review of human studies using 16S rRNA, metagenomics, metatranscriptomics, or fecal microbiota transplantation (FMT)/probiotic designs was conducted. Two reviewers screened studies and assessed quality using Joanna Briggs Institute tools. Owing to heterogeneity, findings were narratively synthesized across microbiome diversity, taxonomy, function, metabolism, oral-brain links, causality, interventions, and predictive analyses.

RESULTS: Thirty-seven studies, mainly from Asia with some from Europe, North America, and Africa, revealed consistent gut dysbiosis in AD. Findings show reduced alpha-diversity, loss of short-chain fatty acid-producing bacteria (e.g., Faecalibacterium prausnitzii, Bifidobacterium), and enrichment of pro-inflammatory taxa (Escherichia/Shigella, Proteobacteria). Functional analyses indicate reduced butyrate synthesis, disrupted lipid and tryptophan-kynurenine metabolism, and links with apolipoprotein epsilon (ε4) gene and cognition. Limited causal evidence arises from Mendelian randomization and small FMT trials, with randomized, longitudinal confirmation still needed.

CONCLUSIONS: Current evidence suggests a biologically plausible association between gut microbiota and AD pathogenesis, positioning microbiome-derived biomarkers and interventions as promising but still exploratory avenues. Harmonized, longitudinal, multi-omic, and geographically inclusive studies are urgently needed to clarify causal mechanisms and translate these correlational findings into validated diagnostics and therapeutics.},
}

@article {pmid41929954,
year = {2026},
author = {Emani, LS and Rao, JK and Dasappa, JK and Narayan, P and Mullur, G and Avula, P and Kosagisharaf, JR},
title = {Studies on copper (II) interaction with the (CCG)12 repeats sequence: An insight into genomic instability in neurodegeneration.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261429082},
pmid = {41929954},
issn = {2542-4823},
abstract = {BACKGROUND: Studies indicate that a comprehensive understanding of the mechanisms underlying neurodegeneration in Alzheimer's disease, Parkinson's disease, and related disorders is still not clearly understood. Fragile X-associated tremor/ataxia syndrome (FXTAS) is one such late-onset neurodegenerative disorder characterized by premutation alleles (55-200 CGG repeats) in the genome. In parallel, dysregulation of trace metal homeostasis, particularly copper (Cu) imbalance, has been documented in Alzheimer's disease, Parkinson's disease, and FXTAS. However, the precise role of trace metal dyshomeostasis as a disease modifier in neurodegeneration, and its contribution to disease onset and progression, remains poorly understood.

OBJECTIVE: To understand the interaction of Copper (II) with the (CCG)12 repeats sequence using spectroscopic and computational modeling studies.

METHODS: (CCG)12 repeats were done by the phosphonamidite technique with a 380B ABI automated synthesizer. The binding of Cu to (CCG)12 was studied using Circular Dichroism, Fluorescence, UV spectroscopy, and a molecular docking model.

RESULTS: The current study shows conformational changes to the (CCG)12 repeat sequence by abnormal interactions of Cu using CD and other spectroscopic methods. Circular dichroism results confirm binding of Cu to the base pairs of DNAs and alter the structure from B-DNA to an altered B-DNA conformation. Further, molecular docking studies reveal the Cu binding to DNA directly through the hydrogen bond formation between G-C base pairs.

CONCLUSIONS: The altered form of B-DNA will affect the integrity of DNA, which in turn modulates the replication and transcription processes, leading to genomic instability and cell dysfunction in neurodegenerative disorders.},
}

@article {pmid41929955,
year = {2026},
author = {Qiu, Q and Qian, W and Zhao, W and Xie, H and Cao, L and Ye, L and , },
title = {P-tau217 and %p-tau217 exhibited superior diagnostic accuracy over other blood biomarkers in the initial assessment of individuals being diagnosed with mild cognitive impairment and Alzheimer's disease dementia.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261439687},
pmid = {41929955},
issn = {2542-4823},
abstract = {BACKGROUND: High-performance blood tests may improve diagnostic accuracy and support personalized treatment for Alzheimer's disease (AD), but validation at the time of initial clinical diagnosis remains limited.

OBJECTIVE: To assess whether plasma biomarkers can aid diagnostic decision-making at first clinical assessment, particularly as tools to triage patients for confirmatory testing in routine practice.

METHODS: We analyzed 241 cognitively normal (CN) controls, 211 patients with mild cognitive impairment (MCI), and 59 patients with AD dementia from the Alzheimer's Disease Neuroimaging Initiative. Plasma aliquots underwent analysis with the C2N Diagnostics PrecivityAD2[®] and Roche Diagnostics Elecsys[®] assays.

RESULTS: The AD group showed a lower Aβ42/Aβ40 ratio than the CN group (p < 0.01) and a mild decrease compared to the MCI group (p < 0.05). The AD group had significant increases in p-tau181, p-tau217, and %p-tau217 (p < 0.001) versus both MCI and CN groups. Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were also significantly elevated in AD. The MCI and CN groups only differed in p-tau217 and %p-tau217 (p < 0.05). The AD versus CN AUCs for p-tau181, p-tau217, and %p-tau217 were 0.84, 0.87, and 0.87; for AD versus MCI, they were 0.79, 0.80, and 0.81. The p-tau181, p-tau217, and %p-tau217 showed a moderate correlation with the Alzheimer's Disease Assessment Scale-cognitive subscale. %p-tau217 demonstrated a strong correlation with the p-tau181/Aβ42 ratio in CSF (R = 0.72, p < 0.001).

CONCLUSIONS: In the setting of first-presentation diagnosis of clinically defined MCI and AD, p-tau217, and %p-tau217 outperformed other plasma biomarkers and may help triage patients for further confirmatory evaluation.},
}

@article {pmid41929956,
year = {2026},
author = {Rahman-Filipiak, A and Lesniak, M and Burgei, A and Sadaghiyani, S and Roberts, JS and Lichtenberg, PA and Iordan, A and Mozersky, J and Hampstead, BM},
title = {Qualitative insights into participant and care partner perspectives on research-based Alzheimer's disease biomarker testing and disclosure.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261429997},
pmid = {41929956},
issn = {2542-4823},
abstract = {BACKGROUND: There is strong desire for the return of individual results, including biomarker testing, among participants in Alzheimer's disease and related dementias (ADRD) studies. However, it is not known whether participants accurately understand the utility, limitations, benefits and risks of biomarker disclosure, nor how they weigh these factors to inform their decision to undergo testing and learn results. Furthermore, little is known about how factors like participant race or diagnosis influence a desire to learn biomarker results.

OBJECTIVE: This mixed-methods study explored how clinically and racially diverse participant-care partner dyads perceive and plan to use AD biomarker testing in the context of research studies.

METHODS: 57 participants (Age: M = 74.28 ± 5.98; Race: n = 22 Black, n = 35 White; Diagnosis: n = 23 with mild cognitive impairment; n = 34 cognitively healthy) and care partners were recruited from AD studies wherein the participant completed amyloid-β and tau positron emission tomography without receiving results. Each completed an independent interview about their perspectives on learning the participant's results.

RESULTS: Responses suggested strong interest in learning results, driven by perceived benefits (e.g., informing treatment, lifestyle changes, and social support). Risks were rarely discussed, though some respondents cited concerns about psychological burdens of a positive result. Few nuanced differences in perceived risks or benefits were observed across race and diagnosis.

CONCLUSIONS: The decision to learn the results of biomarker testing is motivated by highly varied perceived benefits and minimal consideration of risks. Testing should be preceded by individualized counseling that carefully reviews potential benefits and risks.},
}

@article {pmid41929957,
year = {2026},
author = {Zakharov, S and Schröter, A and Teichmann, B},
title = {Validation of Russian versions of the DKAS, DAS, and CODE scales: Measuring dementia knowledge, attitudes, and care confidence.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823251409406},
pmid = {41929957},
issn = {2542-4823},
abstract = {BACKGROUND: Dementia is one of the main public health challenges worldwide. To evaluate awareness programs, it is necessary to use validated scales, such as the Dementia Knowledge Assessment Scale (DKAS), the Dementia Attitude Scale (DAS), and the Confidence in Dementia Care Scale (CODE), none of which exist in Russian.

OBJECTIVE: The present study aims to translate and evaluate the psychometric properties of the DKAS-R, DAS-R, and CODE-R within the Russian-speaking population.

METHODS: A cross-sectional online study was conducted using convenience sampling (N = 533). Validation included assessing reliability (internal consistency and four-week test-retest reliability of a subgroup of 130 participants), analyzing structural validity through confirmatory factor analysis, and assessing construct validity through the known-groups method. Additionally, an item analysis was conducted. The STROBE checklist was used to report this study.

RESULTS: Acceptable to excellent internal reliability was found for DKAS-R (α/ω = 0.81), DKAS-R20 (α/ω = 0.81), DAS-R (α = 0.81, ω = 0.84), DAS-R14 (α/ω = 0.84), and CODE-R (α = 0.89, ω = 0.88). The proposed factor structures were confirmed after minor modifications (item reductions and correlated residuals). The known-groups analysis revealed that all scales could distinguish between individuals with or without experience with people with dementia and with or without participation in a dementia course. Retest-reliability was moderate for DAS-R/DAS-R14, good for the DKAS-R/DKAS-R20 and CODE-R.

CONCLUSIONS: This study provides the first psychometric validation of the DKAS-R, DAS-R, and CODE-R for the Russian-speaking populations. After minor adaptations, all three scales demonstrated robust structure and reliability, supporting their use in research.},
}

@article {pmid41929958,
year = {2026},
author = {Kant, WM and de Swart, WK and Smit, JM and Loog, M and Krijthe, JH},
title = {Applications and implicit assumptions in dementia risk scores: A scoping review of the LIBRA score.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261416457},
pmid = {41929958},
issn = {2542-4823},
abstract = {Dementia risk scores are commonly used tools to estimate the risk of developing Alzheimer's disease and dementia. We lack an overview of what risk scores are used for, what is claimed they ought to be used for, and whether they are suitable for these applications. To address this, we use the 'Lifestyle for Brain Health' (LIBRA) score as a representative example risk score and conduct a literature review to study its applications. The goals of this study are (1) to create an overview of how the LIBRA score has been utilized in scientific articles, (2) to record other applications that these same articles mention, and (3) to critically assess whether LIBRA is suitable for these applications. Of the 66 articles included in our review, 36 involved analyzing associations of LIBRA with dementia, cognition, or other outcomes. We also identified several other applications, with 32 articles mentioning LIBRA as an estimate of 'dementia prevention potential', 6 articles used LIBRA as a surrogate outcome for their trial or intervention, and 7 articles mentioned that it could help support clinician decisions in practice. Although there is a clear need for tools that can be used for these applications, the amount of evidence supporting the suitability of dementia risk scores for many of these applications is limited. We recommend that researchers transparently report the purposes of these dementia risk scores, which may include causal tasks, and that research is done to evaluate whether it is valid to use these scores in this way.},
}