@article {pmid41652334,
year = {2026},
author = {Allison, GO and McCage, S and Brandt, S and Presciutti, M and Walker, K and Cornelius, T and Parker, RA and Dams-O'Connor, K and Dickerson, B and Ritchie, C and Vranceanu, AM and Bannon, SM},
title = {"We can do this. That I learned.": A nonrandomized open pilot of Resilient Together for Dementia, a post-diagnosis dyadic intervention.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07059-9},
pmid = {41652334},
issn = {1471-2318},
support = {R01NR019982-01/NR/NINR NIH HHS/United States ; 1K24AT011760-01/AT/NCCIH NIH HHS/United States ; 1K23AG075188-01A1/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND AND OBJECTIVES: Alzheimer's disease and related dementias (ADRDs) are prevalent conditions that are stressful and elevate emotional distress in couples after diagnosis. Without treatment, emotional distress may become chronic and negatively affect couples' quality of life. We report results from an NIH Stage 1A open pilot of Resilient Together for Dementia (RT-ADRD), a novel, dyadic, skills-based intervention aimed at preventing chronic emotional distress in couples early after diagnosis. We describe results from our mixed-methods single arm feasibility study, including preliminary feasibility and acceptability of the intervention, and qualitative feedback from exit interviews. We also present exploratory analyses for change in outcomes and mechanisms of action.

METHODS: Six couples (N = 12 individuals) were recruited within six months of ADRD diagnosis by their diagnosing providers. Participants completed baseline assessments, participated in weekly RT-ADRD sessions together, then completed post-intervention assessments and one 60-min exit interview together.

RESULTS: RT-ADRD exceeded all a-priori feasibility and acceptability benchmarks (> 70%). Feedback from exit interviews suggested that participants had favorable impressions of the program and found the skills useful and relevant. Participants also offered perspectives on barriers and facilitators of engagement and program enhancement. In exploratory analyses, persons living with dementia exhibited significant reductions in perceived stress at post-intervention (p < .05; Cohens d > 0.8). Both persons living with dementia and their care partners exhibited statistically significant improvements in positive dyadic interactions measured by the Dyadic Relationship Scale (ps < .05); Cohens ds > 0.8).

CONCLUSIONS: RT-ADRD shows promise as a feasible and acceptable dyadic intervention delivered early after diagnosis. Results support a future NIH Stage 1B trial of RT-ADRD to establish definitive feasibility markers of both intervention and control before formal efficacy testing.

TRIAL REGISTRATION: This open pilot was registered on ClinicalTrials.gov (NCT06421545) on 05/20/2024.},
}

@article {pmid41652156,
year = {2026},
author = {Morgan, GC and Gregory, A and Tang, C and Hwang, SH and Border, JJ and Xu, J and Liu, Y and Bai, S and Lee, TJ and Cantwell, C and Bunn, D and Wagner, KM and Morisseau, C and Pittman, C and Ngo, A and Osayi, P and Pabbidi, A and O'Herron, P and Bagi, Z and Filosa, JA and Yu, H and McReynolds, C and Hammock, BD and Roman, RJ and Fan, F},
title = {PTUPB improves cognitive function in Alzheimer's disease associated with enhancing cerebral vascular myogenic response and attenuating vascular remodeling.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41652156},
issn = {2509-2723},
support = {AG079336//National Institute of Health/ ; AG079336//National Institute of Health/ ; P20GM104357//National Institute of Health/ ; R35ES030443//National Institute of Health/ ; U54NS127758//National Institute of Health/ ; NS126920//National Institute of Health/ ; AG057842//National Institute of Health/ ; P42ES004699//National Institute of Health/ ; AG057842//National Institute Health/ ; 25PRE1365157//American Heart Association/ ; TRIBA//Physiology Faculty Startup Fund from Augusta University/ ; A25-1690//Harrington Brain Health Medicine Scholar Award/ ; },
abstract = {Genetic studies have linked EPHX2 (encoding soluble epoxide hydrolase, sEH) and PTGS2 (encoding cyclooxygenase-2, COX-2) to Alzheimer's disease (AD). Elevated levels of sEH and COX-2 found in AD patients and animals suggest their involvement in neurodegeneration, glial activation, vascular dysfunction, and inflammation. This study evaluated the effects of a new dual sEH/COX-2 inhibitor, PTUPB, on cerebrovascular function and cognition in TgF344-AD rats. The rats received oral PTUPB (2 mg/kg/day) for 25 days. Body weight, plasma glucose, and HbA1c levels remained stable between PTUPB- and vehicle-treated AD rats. PTUPB significantly improved recognition memory in AD rats, as detected by the novel object recognition test. Pressure myography showed that PTUPB restored myogenic responses and increased the distensibility of the middle cerebral arteries (MCAs) in AD rats. Acute PTUPB (0.1 and 1 μM) enhanced myogenic contraction in response to elevated perfusion pressure in AD MCAs, with minimal effects in wild-type vessels. Transcriptomic analysis of cerebral vascular smooth muscle cells from AD rats revealed that PTUPB influences genes involved in contractility, extracellular matrix remodeling, inflammation, and oxidative stress. These results provide new evidence that dual inhibition of sEH and COX-2 improves cognition in AD and is associated with enhanced myogenic response via attenuation of vascular remodeling. Our findings highlight the potential of PTUPB as a therapeutic approach for cerebrovascular dysfunction in AD.},
}

@article {pmid41652154,
year = {2026},
author = {Wong, SQ and Ouellette, A and Harrison, L and McNamara, A and Tam, RA and Alexandrov, A and Nawrocik-Madrid, A and Sanchez, JJ and Ginsburg, BC and Andrade, AA and Lapierre, LR},
title = {Spatial memory in Alzheimer's disease 5XFAD mice is enhanced by XPO1 inhibitor KPT-330.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41652154},
issn = {2509-2723},
support = {R01 AG051810/AG/NIA NIH HHS/United States ; R21 AG068922/AG/NIA NIH HHS/United States ; P30 AG013319/AG/NIA NIH HHS/United States ; 519531//Institute of Aging/ ; },
abstract = {The proteostatic decline in Alzheimer's disease is well established, and improvement in proteostasis could potentially delay cognitive impairment. One emerging entry point to modulate proteostasis is the regulation of nucleo-cytoplasmic partitioning of proteins across the nuclear pore via karyopherins. The nuclear exportin XPO1 is a key regulator of proteostasis by driving the assembly of ribosomes and by modulating the process of autophagy. We recently found that the XPO1 inhibitor KPT-330 (Selinexor), an FDA-approved drug against multiple myelomas, enhances proteostasis, leading to benefits in models of neurodegenerative diseases in C. elegans and Drosophila. Here, we find that KPT-330 increases autophagy in murine neuronal cells. In a murine model of Alzheimer's disease (5XFAD), KPT-330 improved spatial memory performance. Unexpectedly, general amyloid deposition in several brain regions was significantly increased by KPT-330, but specific regions, especially the thalamus, displayed significantly lower deposition, suggesting that XPO1 inhibition has regional-specific effects on proteostasis and amyloid plaque formation. Altogether, we conclude that, despite overall increases in amyloid plaque burden, XPO1 inhibition can improve cognition via spatially-specific reductions in amyloid deposition.},
}

@article {pmid41651693,
year = {2026},
author = {Park, SE and Cha, YJ and Kim, YK and Kim, HK and Kwon, C and Oh, YR and Kim, G and Gah-Hyeon Kim, K and Lee, HG and Kang, YP and Shin, MK},
title = {Microglial GM3 accumulation impairs Aβ phagocytic activity and promotes neuroinflammation in Alzheimer's disease.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00851},
doi = {10.1016/j.neurot.2026.e00851},
pmid = {41651693},
issn = {1878-7479},
abstract = {Growing evidence underscores the critical role of lipid metabolism in the pathogenesis of Alzheimer's disease (AD). We previously demonstrated that 5xFAD mice exhibit a marked accumulation of ganglioside GM3 in the cerebral cortex and hippocampus as the disease progresses, with this increase being more pronounced in females than in males. However, the specific brain cell types exhibiting elevated GM3 accumulation, along with GM3's underlying molecular mechanisms and functional significance in AD pathogenesis, remain to be fully elucidated. Here, we report that elevated GM3 levels in 5xFAD are associated with increased expression of Hexa and Hexb-which encode the α- and β-subunits, respectively, of lysosomal β-hexosaminidase A (HexA), the enzyme that catalyzes the conversion of GM2 to GM3 within lysosomes-but not with St3gal5. Analysis of a publicly available single-nucleus RNA sequencing dataset from 5xFAD mice revealed that Hexa and Hexb are highly expressed in microglial cells, with their expression considerably upregulated in these cells compared to other brain cell types. Functional studies demonstrated that overexpression of Hexa and Hexb in microglial cells results in lysosomal GM3 accumulation, impaired Aβ phagocytosis, and increased production of proinflammatory cytokines. Conversely, microglia-specific knockdown of Hexa and Hexb using AA5-microRNA30-based shRNAs not only enhances cognitive function but also alleviates Aβ pathology and neuroinflammation in 5xFAD mice. Collectively, these findings implicate HexA-driven GM3 accumulation in microglia as a key contributor to impaired Aβ clearance and heightened neuroinflammation in AD, highlighting HexA as a potential therapeutic target for restoring microglial function and mitigating disease progression.},
}

@article {pmid41651661,
year = {2026},
author = {Meftah, S and Wilson, MA and Elliott, J and McLay, L and Dobrovolskis, V and Rosencrans, S and Taylor, LW and Mugnaini, C and Mostallino, R and Durrant, CS and Booker, SA},
title = {GABAB Receptor signaling in CA1 Pyramidal Cells is not Regulated by Aging in the APP/PS1 Mouse Model of Amyloid Pathology.},
journal = {eNeuro},
volume = {13},
number = {2},
pages = {},
doi = {10.1523/ENEURO.0099-23.2025},
pmid = {41651661},
issn = {2373-2822},
mesh = {Animals ; *Pyramidal Cells/metabolism/pathology/drug effects ; *Receptors, GABA-B/metabolism ; Male ; Amyloid beta-Protein Precursor/genetics/metabolism ; Female ; *CA1 Region, Hippocampal/metabolism/pathology ; *Aging/metabolism ; Disease Models, Animal ; Mice, Transgenic ; *Alzheimer Disease/metabolism/pathology ; Presenilin-1/genetics/metabolism ; Signal Transduction/physiology ; Mice ; Mice, Inbred C57BL ; },
abstract = {Dementia-causing diseases, including Alzheimer's disease (AD), are one of the greatest health concerns facing the aging world population. A key feature of AD is excessive accumulation of amyloid-beta, leading to synapse and cell loss in brain structures, such as the hippocampus. This neurodegeneration is preceded by impaired neuron function, notably reduced synaptic inhibition. Metabotropic GABAB receptors (GABABRs) may be modulated by amyloid precursor protein (APP) and are reported to be progressively lost from neuronal membranes of hippocampal pyramidal neurons. However, it remains unknown whether functional GABABR-mediated signaling changes over aging and whether or not pharmacological intervention can prevent receptor loss. In this study, we combine electrophysiological and biochemical analysis of hippocampal neurons in the Amyloid Precursor Protein/Presenilin-1 (APP/PS1) mouse model of AD from acute brain slices and organotypic slice cultures prepared from male and female mice to determine if functional GABABRs are lost and the effect of pharmacological modulation. Overall, we found that GABABR expression decreased with age, independent of genotype, with no evidence for postsynaptic GABABR loss in CA1 pyramidal cells at any age. We did observe a genotype-dependent reorganization of postsynaptic GABABR-mediated IPSCs, which was independent of age. Presynaptic GABABR-mediated inhibition was impaired in APP/PS1 mice, also independent of age. We observed that chronic GABABR modulation differentially regulated function but was independent of genotype. Overall, our data show that functional GABABR signaling is altered in APP/PS1 mice, independent of age, increasing our understanding of amyloidopathy-induced dysfunction.},
}

Animals
*Pyramidal Cells/metabolism/pathology/drug effects
*Receptors, GABA-B/metabolism
Male
Amyloid beta-Protein Precursor/genetics/metabolism
Female
*CA1 Region, Hippocampal/metabolism/pathology
*Aging/metabolism
Disease Models, Animal
Mice, Transgenic
*Alzheimer Disease/metabolism/pathology
Presenilin-1/genetics/metabolism
Signal Transduction/physiology
Mice
Mice, Inbred C57BL

@article {pmid41651444,
year = {2026},
author = {Dillon, E and Lee, CM and Gan, W and Charles, D and Soliman, G and Robison, J},
title = {Nursing Home Ratings and Characteristics Predict Hospice Use Among Decedents With Serious Illnesses.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {106109},
doi = {10.1016/j.jamda.2025.106109},
pmid = {41651444},
issn = {1538-9375},
abstract = {OBJECTIVES: Approximately one-third of older Americans experience a nursing home (NH) stay within 3 months of death, but it is unclear how NH characteristics influence end-of-life care. We investigated associations between NH characteristics and hospice use.

DESIGN: Retrospective cohort study analyzing Medicaid and Traditional Medicare claims, Minimum Data Set, Centers for Medicare and Medicaid Services (CMS) Care Compare ratings, and other NH characteristics.

SETTING AND PARTICIPANTS: Connecticut Medicaid-insured individuals with a serious illness and an NH stay within 6 months of death, deceased January 1, 2017-September 30, 2024.

METHODS: Multivariable logistic regression analyzing associations between NH characteristics and (1) hospice use within 6 months of death and (2) short hospice use (≤7 days). Covariates included sociodemographics and clinical characteristics.

RESULTS: Of 25,302 individuals, 51% were ≥85 years, 64.8% were women, and 79.3% were non-Hispanic White. Overall, 12,453 (49.2%) received hospice care, 4768 of 12,453 (38.3%) with short hospice use (≤7 days). Short-term (vs long-term) NH stays were associated with increased odds of hospice use and short hospice use. Many NH characteristics were associated with hospice use. Individuals with long-term stays had lower odds of hospice use with stays at NHs with the highest (vs lowest) CMS ratings for quality measures and staffing (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.44-0.68, OR, 0.78; 95% CI, 0.66-0.93, respectively). Those with short-term stays had lower odds of hospice use with stays at NHs with the highest CMS Health Inspection ratings. People with long-term stays at NHs that were part of a chain, had Alzheimer's care units, or had more beds had increased odds of hospice care.

CONCLUSIONS AND IMPLICATIONS: Among Connecticut Medicaid-insured decedents with NH stays, people with long-term stays and stays in NHs with better CMS ratings had lower odds of hospice use. The inverse relationship between hospice care and NH quality warrants further research and consideration of incorporating end-of-life quality measurement into CMS quality ratings.},
}

@article {pmid41651379,
year = {2026},
author = {Huang, X and Sun, YY and Qin, YR and Chen, H and Pan, TT and Zhao, SS and Cai, Q and Zhang, XS and Nie, XD and Feng, L and Hu, H and Tang, Y and Zhang, PZ and Zhong, ZY and Li, J and Lu, L and Meng, FH and Ma, QH},
title = {ApoE-directed CpG nano-immunoadjuvant ameliorates Alzheimer's-like pathology in mice.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114687},
doi = {10.1016/j.jconrel.2026.114687},
pmid = {41651379},
issn = {1873-4995},
abstract = {Toll-like receptor 9 (TLR9), expressed in both microglia and neurons of the CNS, represents a promising therapeutic target for Alzheimer's disease (AD). While either microglial or neuronal TLR9 activation exerts neuroprotective effects that ameliorate AD pathology and preserve cognitive function, CpG oligodeoxynucleotides (ODNs), the synthetic agonists, cannot cross the blood-brain barrier (BBB). To overcome this, we developed tNCpG, an apolipoprotein E (ApoE)-functionalized polymersome nanocarrier for brain-targeted delivery of CpG ODNs. APP/PS1 transgenic mice, which overexpress human mutant APP/PS1 and are widely used in AD mouse models for preclinical studies, were administered tNCpG intravenously biweekly for 3 months, starting at 4 months of age. tNCpG achieved efficient brain delivery while specifically targeting microglia and neurons. tNCpG treatment enhanced microglial recruitment to and phagocytosis of Aβ plaques, suppressed Aβ production while promoting its degradation, and improved BBB integrity and Aβ efflux. Collectively, these effects significantly reduced cerebral Aβ burden, neuroinflammation, and neurodegeneration, leading to the rescue of cognitive deficits. Our study establishes targeted TLR9 activation via tNCpG as a disease-modifying therapeutic strategy for AD.},
}

@article {pmid41651301,
year = {2026},
author = {Zeying, W and Houyu, L and Zhongbin, Y and Yu, T and Qi, H and Kun, H and Qihang, H and Yingnan, Z and Zhi, L and Xiaojing, L and Xueming, Z and Qiang, M and Jingye, Z and Caixia, S and Liran, H and Jing, J and Yan, S},
title = {D-Ribose-Induced Cytotoxicity in K562 Cells: RBKS-Dependent Disruption of Copper Homeostasis and Mitochondrial Function.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.01.062},
pmid = {41651301},
issn = {1873-4596},
abstract = {BACKGROUND: D-ribose, a highly reducing pentose sugar, can be phosphorylated by ribokinase (RBKS) to form ribose-5-phosphate (R-5-P). Elevated urinary D-ribose levels have been reported in patients with type 2 diabetes mellitus (T2DM) and Alzheimer's disease, implicating its potential role in disease pathogenesis. Previous investigations into D-ribose cytotoxicity have primarily focused on its non-enzymatic glycation activity, while alternative mechanisms remain underexplored. Since hemoglobin is a major in vivo target of glycation, this study utilized K562 cells-which retain inducible hemoglobin expression-to examine additional cytotoxic mechanisms of D-ribose.

METHODS AND RESULTS: CCK-8 assays demonstrated that D-ribose inhibited K562 cell proliferation in a concentration- and time-dependent manner, and this inhibitory effect was significantly enhanced in hemin-induced differentiated K562 cells. Conversely, RBKS overexpression promoted proliferation and alleviated oxidative stress in K562 cells. Transcriptomic analysis revealed that differentially expressed genes in D-ribose-treated cells were enriched in mineral absorption and oxidative phosphorylation pathways (KEGG), as well as in biological processes related to copper ion homeostasis (GO). RT-qPCR confirmed that both D-ribose treatment and RBKS knockout downregulated key copper homeostasis genes (e.g., SLC31A1, MT1F, ATOX1) and mitochondrial respiratory chain genes (e.g., COX17, COX11, MTATP8, MTND6), and were accompanied by a significant reduction in intracellular free copper levels.

CONCLUSIONS: These findings reveal a novel cytotoxic mechanism mediated by the RBKS-copper-oxidative phosphorylation axis in D-ribose-treated K562 cells, providing key insights into the intracellular role of D-ribose.},
}

@article {pmid41651180,
year = {2026},
author = {Yang, FG and Yang, H and Han, SW and Wang, JT and Gao, W and Ye, QY and Zhang, MM and Yang, Y and Li, HL},
title = {Microglial Metabolic Reprogramming in Alzheimer's Disease: Pathways, Mechanisms, and Therapeutic Implications.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103050},
doi = {10.1016/j.arr.2026.103050},
pmid = {41651180},
issn = {1872-9649},
abstract = {In recent years, the immune metabolism of central nervous system cells has gained increasing attention from researchers. Microglia (MG) are innate immune cells of the central nervous system. They can metabolize a wide range of energy substrates. The pathways and products generated through these processes play a critical role in the onset and progression of Alzheimer's disease (AD). This paper provides a comprehensive review of metabolic reprogramming in MG during AD. It focuses on the three primary energy substrates: glucose, fatty acids, and amino acids. It delves deeply into the molecular signaling pathways that regulate this reprogramming, including TREM2, PI3K-AKT-mTOR, HIF-1α, AMPK, PPARs, and LXRs. Additionally, the paper explores the potential of metabolomics as a tool for early diagnosis of AD, identifying biomarkers that could enhance detection in its early stages. Therapeutic strategies targeting the regulation of microglial phagocytic function, mitochondrial activity, and glycolysis are also examined, highlighting their potential to alleviate disease progression. This review article aims to uncover the dynamic network of microglial metabolic reprogramming. It also explores its causal relationship with the pathological cascade of AD. The findings provide theoretical support for developing innovative drugs that combine metabolic regulation and neuroprotective functions.},
}

@article {pmid41651103,
year = {2026},
author = {Górska, AM and Santos-García, I and Kvasnička, A and Dobešová, D and Friedecký, D and Gildenblat, J and Pahnke, J},
title = {ABCA7 deficiency exacerbates glutamate excitotoxicity in Alzheimer's disease mice - a new pharmacological target for Glu-related neurotoxicity.},
journal = {Progress in neurobiology},
volume = {},
number = {},
pages = {102891},
doi = {10.1016/j.pneurobio.2026.102891},
pmid = {41651103},
issn = {1873-5118},
abstract = {Increasing attention has been directed towards the perturbation of glutamate (Glu) and γ-aminobutyric acid (GABA) homeostasis during the pathogenesis of Alzheimer's disease (AD). The prevailing disequilibrium, stemming from hyperactivation of the glutamatergic system, culminates in progressive neuronal impairment and cognitive deterioration. This study aimed to elucidate the contributory role of the ATP-binding cassette transporter A7 (ABCA7), identified as the second most critical genetic determinant in AD, in glutamatergic-associated neurotoxicity. This endeavor sought to advance molecular comprehension of neurological disorders where Glu-GABA neurotransmission represents a pivotal pharmacotherapeutic target. Utilizing multi-omics approaches, we rigorously analyzed four distinct mouse models, both with and without APPtg and ABCA7 expression, to simulate varied pathological and ABCA7-deficient states. Our results revealed amyloid-beta (Aβ) deposition as a catalyst for surging glutamatergic transmission. Notably, ABCA7 ablation exacerbated glutamatergic-induced neurotoxicity, attributed to diminished enzymatic activity related to neurotransmitter degradation and amplified expression levels of specific neurotransmitter transport proteins and receptor subunits, notably NMDA, AMPA, and GABAA. These findings furnish the first comprehensive description elucidating ABCA7's amplification of neurotoxic effects through modulation of Glu-GABA neurotransmission systems in neurodegenerative contexts, primarily mediated by lipid interaction. The evidence underscores ABCA7's imperative role in shaping future pharmacological strategies aimed at counteracting neurodegeneration precipitated by Glu-mediated neurotoxicity. This research advances the frontier for therapeutic exploration to ameliorate the deleterious neural consequences characteristic of neurodegenerative pathologies.},
}

@article {pmid41650876,
year = {2026},
author = {Charlton, PE and Burke, K and Abdavinejad, S and Ashour, M and Zaharkin, Z and McLaughlin, R and Paul, S and Lauer, AM and Dent, ML},
title = {Differences in hearing across the lifespan in two strains of Alzheimer's mouse models as measured using behavioral and physiological techniques.},
journal = {Hearing research},
volume = {472},
number = {},
pages = {109550},
doi = {10.1016/j.heares.2026.109550},
pmid = {41650876},
issn = {1878-5891},
abstract = {Alzheimer's disease (AD) is a brain condition with heterogeneity in disease progression due to genetic and environmental variables. There is a critical need to better understand the relationship of AD pathologies and potential modifiable factors like hearing loss. Auditory processing measurements in AD mouse models have been reported, but the results are mixed. Most were conducted using evoked potential recordings measured under anesthesia, unlike typical hearing assessments on aging adult humans. Here, we used operant conditioning and signal detection theory to measure daily pure tone behavioral detection throughout the lifespan of trained mutant and wild-type (WT) control APP/PS1 (on a C57BL/6J background) and 5xFAD (on a C57/SJL background) mice. At the conclusion of operant testing, auditory brainstem response (ABR) measures were taken on the same subjects to determine if evoked potentials provided accurate estimates of perceptual abilities. Behavioral detection worsened significantly across the lifespan in APP/PS1 mice, but there were no differences between mutant and WT mice. For 5xFAD mice, behavioral thresholds generally worsened over the lifespan but with substantial variability, which may be explained by genetic heterogeneity among the background strain. There were no differences between 5xFAD mutant and WT mice. ABR hearing threshold estimates generally matched behavioral findings, with APP/PS1 having significantly worse thresholds than 5xFAD mice but no within-model differences between mutants and WTs. The within-subject differences between behavioral and ABR thresholds ranged from <1 dB to over 40 dB across subjects, suggesting physiological measurements of auditory function are not necessarily reflective of an animal's acoustic perception.},
}

@article {pmid41650822,
year = {2026},
author = {López-Sampere, Y and Mengod Soler, P and Roca-Pereira, S and Vinyals, A and Mato-Blanco, X and Vela-Martínez, M and Dakterzada, F and Romero, L and Santamaría, E and Fernández-Irigoyen, J and Ferrer, I and Povedano, M and Del Rio, JA and Santpere, G and Portero-Otín, M and Piñol-Ripoll, G and Andrés-Benito, P},
title = {NRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse model.},
journal = {Redox biology},
volume = {91},
number = {},
pages = {104068},
doi = {10.1016/j.redox.2026.104068},
pmid = {41650822},
issn = {2213-2317},
abstract = {BACKGROUND: Nuclear factor erythroid 2-related factor 2 (NRF2) regulates antioxidant defenses and protects against neurodegeneration, including Alzheimer's disease (AD). Its age-related decline disrupts redox balance and increases neuronal vulnerability, but the early hippocampal effects remain unclear. Here, we tested whether NRF2 loss affects tau seeding and spreading in a PHF-tau-inoculated mouse model, contributing to accelerated aging.

METHODOLOGY: Three-month-old NRF2-knockout (Nfe2l2[-/-]) and wild-type (WT) mice received hippocampal inoculations of human AD-derived PHF-tau, and tau propagation was analyzed after three months. To elucidate the molecular underpinnings of the observed changes, we performed integrative phosphoproteotranscriptomic analyses of hippocampal tissue, supported by RT-qPCR and Western blot validation.

RESULTS: PHF-tau inoculation at 3 months of age in Nfe2l2[-/-] mice, surprisingly, exhibited markedly reduced tau seeding and spreading compared to WT after 3 months of incubation. Molecular characterization of the Nfe2l2[-/-] hippocampus was carried out to unravel the molecular changes associated with impaired tau propagation. Transcriptomic profiling revealed 745 deregulated genes in Nfe2l2[-/-] mice, characterized by upregulation of immune and metabolic pathways but downregulation of oxidative stress and redox-related genes. RT-qPCR confirmed diminished expression of antioxidant enzymes and anti-inflammatory receptors, alongside altered astrocytic markers. Proteomic analysis identified 157 dysregulated proteins associated with mitochondrial, synaptic, and inflammatory processes, while phosphoproteomics detected 824 altered phosphosites enriched in cytoskeletal and synaptic networks. Western blot showed increased GFAP-C-term, AQP4, 8-OHdG, and MDAL, with reduced GSTM2 expression. Notably, total and 4R-tau levels were decreased, while 3R-tau was elevated in Nfe2l2[-/-] mice.

CONCLUSION: Our findings suggest that NRF2 loss induces a hippocampal state marked by impaired antioxidant defenses, astrocytic remodeling, and disrupted tau isoform balance. This environment, while metabolically altered, paradoxically hinders tau propagation, highlighting NRF2 as a key regulator of both redox and cellular maturity programs essential for tau spread and as a potential therapeutic target in tauopathies.},
}

@article {pmid41650809,
year = {2026},
author = {Anwar, M and Qadri, JA and Ashar, MS and Pradhan, R and Dey, AB and Dey, S},
title = {Circulating bio-elements and their association with cognitive impairment.},
journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)},
volume = {94},
number = {},
pages = {127835},
doi = {10.1016/j.jtemb.2026.127835},
pmid = {41650809},
issn = {1878-3252},
abstract = {BACKGROUND AND OBJECTIVE: Rapid industrialization and urbanization have caused a significant increase in environmental pollution of bio-elements in India. Changes in bio-element concentrations, particularly an imbalance in the normal homeostasis in the blood leads to severe neurodegenerative effect. There has been very limited data on the association of bio-elements and cognitive decline. Present study performed the quantitative profiling of circulatory bio-element in cognitively impaired (CI) patients.

METHODS: Elemental quantification of 19 elements were performed inductively coupled plasma mass spectrometry (Agilent Technologies, USA). A total of 65 participants were recruited for the study. All the participants underwent comprehensive clinical and functional assessments for cognitive abilities.

RESULTS: Quantitative profiling revealed a significant increase in eight elements (Li, Al, V, Mn, Co, Ni, Zn, and Ag) in CI patients compared to control. MMSE score analysis was found to be 13.77 ± 0.9921 in CI compared to control 27.78 ± 0.3575. The concentrations of Li (Control; 25.84 ± 3.051 µg /L; CI; 41.52 ± 5.312 µg /L), Al (Control; 2.582 ± 0.739 µg /L; CI; 21.17 ± 6.092 µg /L), V (Control; 2.583 ± 0.739 µg /L; CI; 13.59 ± 2.757 µg /L), Mn (Control; 20.56 ± 1.919 µg /L; CI; 36.06 ± 3.086 µg /L), Co (Control; 2.52 ± 0.220 µg /L; CI; 4.143 ± 0.287 µg /L), Ni (Control; 2.723 ± 0.752 µg /L; CI; 22.83 ± 4.456 µg /L) Zn (Control; 8040 ± 1199 µg /L; CI; 11121 ± 838.6 µg /L) and Ag (Control; 0.7454 ± 0.127 µg /L; CI; 3.302 ± 0.699 µg /L).

CONCLUSION: Present study suggest that bio-elements (Li, Al, V, Mn, Co, Ni, Zn, and Ag) may contribute to generate a distinctive signature in CI patients, and its detection in elderly might help in early management of element induced neurotoxicity.},
}

@article {pmid41650358,
year = {2026},
author = {Hall, BJ and Aumont, E and Hosseini, SA and Fernandez Arias, J and Boré, A and Bezgin, G and Trudel, L and Chan, T and Therriault, J and Macedo, AC and Woo, MS and Oliva-Lopez, D and Rahmouni, N and Zheng, Y and Servaes, S and Stevenson, J and Gauthier, S and Benedet, AL and Dumont, M and Houde, JC and Triana-Baltzer, G and Kolb, HC and Ashton, NJ and Zetterberg, H and Medina, YI and Vitali, P and Descoteaux, M and Klostranec, JM and Pascoal, T and Rosa-Neto, P},
title = {Association of Cortical Free Water With Brain Tau Tangle Load in the Alzheimer Disease Continuum.},
journal = {Neurology},
volume = {106},
number = {5},
pages = {e214606},
doi = {10.1212/WNL.0000000000214606},
pmid = {41650358},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; Female ; *tau Proteins/metabolism/blood ; Male ; Aged ; Cross-Sectional Studies ; Positron-Emission Tomography ; *Neurofibrillary Tangles/pathology/metabolism ; *Cerebral Cortex/diagnostic imaging/metabolism/pathology ; Aged, 80 and over ; Magnetic Resonance Imaging ; Water/metabolism ; *Brain/diagnostic imaging/metabolism ; Diffusion Magnetic Resonance Imaging ; },
abstract = {BACKGROUND AND OBJECTIVES: Neurofibrillary tangles (NFTs) progressively damage gray matter in Alzheimer disease (AD). Resulting cortical microstructural alterations might not be detectable using macrostructural metrics but may be studied using isotropic water diffusion, as it reflects extracellular free water content. The aim of this study was to examine the effect of NFTs on cortical microstructure by investigating whether cortical free water increases as a function of tau load. We also investigated whether phosphorylated tau in blood plasma also indicated cortical microstructural abnormalities.

METHODS: For this cross-sectional study, we sampled participants with T1 MRI, multishell diffusion-weighted MRI, amyloid PET ([[18]F]AZD4694), tau PET, and plasma phosphorylated tau 217+ (p-tau217) from the Translational biomarkers in Aging and Dementia cohort at McGill University; participants were recruited between 2017 and 2024. We used the Neurite Orientation Dispersion and Density Imaging algorithm to calculate isotropic free water images ("free water"). FreeSurfer was used to calculate cortical thickness in the entorhinal, fusiform, inferior temporal, and middle temporal gyri regions of interest ("meta-ROI"); Automatic Segmentation of Hippocampal Subfields was used to calculate hippocampal volumes. We grouped participants by amyloid PET positivity (A), plasma p-tau217 positivity (T1), and tau PET positivity (T2). We performed voxel-wise correlation analyses between free water and these proteinopathy markers, as well as ROI-based analyses in the meta-ROI.

RESULTS: A total of 303 participants (mean age 67 years, 58.7% female) were included in this study (168 cognitively normal individuals, 43 with mild cognitive impairment, 23 with AD dementia, 68 not diagnosed). Tau PET was positively correlated with free water in gray matter predominantly in the temporal lobe (partial R[2] = 0.39, p < 0.001), and the correlation of p-tau217 with the meta-ROI free water was entirely mediated by tau PET (p < 0.001). In addition, medial temporal and hippocampal free water was negatively correlated with Montreal Cognitive Assessment scores in the A-T1+ and A+T2+ groups. The strongest ROI-based multilinear models for predicting temporal gray matter and hippocampal tau PET burden used both cortical thickness and free water as predictors (temporal gray matter partial R[2] = 0.62; hippocampal partial R[2] = 0.64).

DISCUSSION: In AD-relevant regions, increased free water correlates with tau load independently of macrostructural metrics or amyloid load. Free water may serve as an imaging marker for microstructural changes in gray matter resulting from NFT accumulation, complementary to macrostructural metrics.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
Female
*tau Proteins/metabolism/blood
Male
Aged
Cross-Sectional Studies
Positron-Emission Tomography
*Neurofibrillary Tangles/pathology/metabolism
*Cerebral Cortex/diagnostic imaging/metabolism/pathology
Aged, 80 and over
Magnetic Resonance Imaging
Water/metabolism
*Brain/diagnostic imaging/metabolism
Diffusion Magnetic Resonance Imaging

@article {pmid41650298,
year = {2026},
author = {Eugene, DY and Kilmer, G and Ali, AR and Claxton, JS and Woodruff, R and Coronado, F and Strahan, AE},
title = {Subjective Cognitive Decline Among Adults Aged ≥45 Years-United States, 2023.},
journal = {Journal of public health management and practice : JPHMP},
volume = {},
number = {},
pages = {},
pmid = {41650298},
issn = {1550-5022},
abstract = {In 2025, an estimated 7.2 million Americans aged ≥65 years had Alzheimer's disease. Subjective cognitive decline (SCD) is an early indicator of possible future dementia. Using 2023 Behavioral Risk Factor Surveillance System data, this study described the SCD prevalence among US adults aged ≥45 years. Estimates were examined by selected characteristics, state, and SCD-related features, including worry, functional limitations, and discussions about SCD with a health care provider. Overall, SCD prevalence was 16.9% (95% confidence interval [CI] = 16.5-17.3). Among those reporting SCD, 59.3% (95% CI = 57.9-60.7) were worried about it and 42.8% (95% CI = 41.4-44.1) reported having discussed SCD with a health care provider. Engaging health care providers about concerns related to memory loss or increasing confusion is a key to early identification, diagnosis, and management. These findings emphasize the need for targeted public health efforts to support individuals with SCD-especially among high-risk populations.},
}

@article {pmid41650268,
year = {2026},
author = {Hayashi, H and Saito, R and Miyashita, A and Ikeuchi, T and Tada, M and Akazawa, K and Onodera, O and Tainaka, K and Kakita, A},
title = {Expansive spatial pattern of Aβ deposition in patients with cerebral amyloid angiopathy: A three-dimensional surface-to-depth analysis.},
journal = {Science advances},
volume = {12},
number = {6},
pages = {eaea7539},
doi = {10.1126/sciadv.aea7539},
pmid = {41650268},
issn = {2375-2548},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/metabolism/pathology/diagnostic imaging ; *Amyloid beta-Peptides/metabolism ; *Imaging, Three-Dimensional/methods ; Aged ; Male ; Female ; Aged, 80 and over ; Brain/metabolism/pathology/diagnostic imaging ; Actins/metabolism ; Plaque, Amyloid/metabolism/pathology ; Alzheimer Disease/metabolism/pathology ; Middle Aged ; },
abstract = {Cerebral amyloid angiopathy (CAA) is a neurodegenerative condition characterized by amyloid-β (Aβ) deposition in small vessel walls, often coexisting with Alzheimer's disease due to impaired Aβ clearance. However, the spatial distribution of Aβ within the human brain remains unclear as the vascular network's complexity and scale hinder visualization by conventional thin-slice analysis. To address this, we performed three-dimensional (3D) volumetric imaging of the cerebrovascular network and Aβ deposition in autopsied brains with CAA using advanced tissue clearing and light-sheet fluorescence microscopy, labeling for smooth muscle actin (SMA) and Aβ. We found prominent Aβ deposition and SMA loss in leptomeningeal and superficial cortical segments, which were anatomically contiguous with deeper Aβ-positive segments, indicating a surface-to-deep progression pattern of Aβ extension. The perivascular plaque density was significantly lower around Aβ-positive vessels. This technology may provide further insights into CAA pathology and is recommended for research on the 3D pathology of neurological disorders.},
}

Humans
*Cerebral Amyloid Angiopathy/metabolism/pathology/diagnostic imaging
*Amyloid beta-Peptides/metabolism
*Imaging, Three-Dimensional/methods
Aged
Male
Female
Aged, 80 and over
Brain/metabolism/pathology/diagnostic imaging
Actins/metabolism
Plaque, Amyloid/metabolism/pathology
Alzheimer Disease/metabolism/pathology
Middle Aged

@article {pmid41650217,
year = {2026},
author = {Olchanyi, MD and Schreier, DR and Li, J and Maffei, C and Sorby-Adams, A and Kinney, HC and Healy, BC and Freeman, HJ and Shless, J and Destrieux, C and Tregidgo, H and Iglesias, JE and Brown, EN and Edlow, BL},
title = {Probabilistic mapping and automated segmentation of human brainstem white matter bundles.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {6},
pages = {e2509321123},
doi = {10.1073/pnas.2509321123},
pmid = {41650217},
issn = {1091-6490},
support = {DP2hd101400//HHS | NIH | NIH Office of the Director (OD)/ ; R21NS109627//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 1R01AG070988//HHS | NIH | National Institute on Aging (NIA)/ ; 1RF1AG080371//HHS | NIH | National Institute on Aging (NIA)/ ; R01AG070988//HHS | NIH | National Institute on Aging (NIA)/ ; 1RF1MH123195//HHS | NIH | National Institute of Mental Health (NIMH)/ ; RF1MH123195//HHS | NIH | National Institute of Mental Health (NIMH)/ ; N/A//James S. McDonnell Foundation (JSMF)/ ; N/A//American Academy of Neurology (AAN)/ ; N/A//American Brain Foundation (ABF)/ ; N/A//Center for Integration of Medicine and Innovative Technology/ ; N/A//Rappaport Foundation (PJLRF)/ ; N/A//American SidS Institute/ ; N/A//Chen Institute MGH Research Scholar Award/ ; N/A//MIT/MGH Brain Arousal State Control Innovation Center (BAScic) project/ ; N/A//MIT-Takeda fellowship/ ; N/A//MIT IMES fellowship/ ; P500PM_210834//Swiss NSF (SNSF)/ ; 24POST1023166//American Heart Association (AHA)/ ; W81XWH2210999//U.S. Department of Defense (DOD)/ ; },
mesh = {Humans ; *White Matter/diagnostic imaging/pathology ; *Brain Stem/diagnostic imaging/pathology ; Diffusion Tensor Imaging/methods ; Male ; Multiple Sclerosis/diagnostic imaging/pathology ; Female ; Alzheimer Disease/diagnostic imaging/pathology ; Parkinson Disease/diagnostic imaging/pathology ; *Brain Mapping/methods ; Adult ; Brain Injuries, Traumatic/diagnostic imaging/pathology ; },
abstract = {Brainstem white matter (WM) bundles are essential conduits for neural signals that modulate homeostasis and consciousness. Their architecture forms the anatomic basis for brainstem connectomics, subcortical circuit models, and deep brain navigation tools. However, their small size and complex morphology, compared to cerebral WM, makes mapping and segmentation challenging in neuroimaging. As a result, fundamental questions about brainstem modulation of human homeostasis and consciousness remain unanswered. We leverage diffusion MRI tractography to create BrainStem Bundle Tool (BSBT), which automatically segments eight WM bundles in the rostral brainstem. BSBT performs segmentation on a custom probabilistic fiber map using a convolutional neural network architecture tailored to detect small anatomic structures. We demonstrate BSBT's robustness across diffusion MRI acquisition protocols with in vivo scans of healthy subjects and ex vivo scans of human brain specimens with corresponding histology. BSBT also detected distinct brainstem bundle alterations in patients with Alzheimer's disease, Parkinson's disease, multiple sclerosis, and traumatic brain injury through tract-based analysis and classification tasks. Finally, we provide proof-of-principle evidence for the prognostic utility of BSBT in a longitudinal analysis of traumatic coma recovery. BSBT creates opportunities for scalable mapping of brainstem WM bundles and investigation of their role in a broad spectrum of neurological disorders.},
}

Humans
*White Matter/diagnostic imaging/pathology
*Brain Stem/diagnostic imaging/pathology
Diffusion Tensor Imaging/methods
Male
Multiple Sclerosis/diagnostic imaging/pathology
Female
Alzheimer Disease/diagnostic imaging/pathology
Parkinson Disease/diagnostic imaging/pathology
*Brain Mapping/methods
Adult
Brain Injuries, Traumatic/diagnostic imaging/pathology

@article {pmid41650159,
year = {2026},
author = {Qi, H and Ban, J and Wang, N and Yao, T and Li, L and Tang, S},
title = {Factors influencing the caregiver burden for family caregivers of people with moderate-to-severe dementia: A structural equation modeling analysis.},
journal = {PloS one},
volume = {21},
number = {2},
pages = {e0341719},
doi = {10.1371/journal.pone.0341719},
pmid = {41650159},
issn = {1932-6203},
mesh = {Humans ; Male ; Female ; *Caregivers/psychology ; Quality of Life ; *Dementia/psychology ; Aged ; Activities of Daily Living ; Cross-Sectional Studies ; Middle Aged ; Depression/psychology ; China ; Aged, 80 and over ; *Caregiver Burden/psychology ; Latent Class Analysis ; Cost of Illness ; Surveys and Questionnaires ; },
abstract = {BACKGROUND: Dementia poses an increasingly serious public health challenge worldwide, particularly in China, where home-based care remains the primary form of management. Family caregivers of older adults with moderate-to-severe dementia often experience a substantial caregiving burden, which can adversely affect both their own well-being and that of the patients.

OBJECTIVE: This study aimed to examine the level of caregiver burden among family caregivers of older adults with moderate-to-severe dementia and to explore the relationships between patient activities of daily living (ADL), quality of life (QoL), depression severity, caregiver QoL, depression severity, and caregiver burden.

METHODS: A cross-sectional study in 22 tertiary general hospitals in Shanxi Province, China, involved 529 dyads of older adults with moderate-to-severe dementia and their family caregivers. Caregivers completed the Zarit Burden Interview, the Patient Health Questionnaire-9, and the World Health Organization Quality of Life-Brief Version. Older adults completed the Patient Health Questionnaire-9, the Activity of Daily Living Scale, and the Quality of Life in Alzheimer's Disease scale. Structural equation modeling evaluated relationships among patient ADL, QoL, depression severity, caregiver QoL, depression severity, and caregiver burden.

RESULTS: Patient QoL, ADL, and caregiver QoL had direct negative effects on caregiver burden, whereas patient and caregiver depression severity had direct positive effects on caregiver burden. Meanwhile, caregiver QoL partially mediated the relationships between patient QoL, depression severity, ADL, caregiver depression severity, and caregiver burden.

CONCLUSION: The results indicate that higher patient QoL, better patient ability in ADL, higher caregiver QoL, and lower levels of depressive severity in both patients and caregivers are associated with reduced caregiver burden. Healthcare professionals should implement family-centered, comprehensive interventions to alleviate caregiver burden.},
}

Humans
Male
Female
*Caregivers/psychology
Quality of Life
*Dementia/psychology
Aged
Activities of Daily Living
Cross-Sectional Studies
Middle Aged
Depression/psychology
China
Aged, 80 and over
*Caregiver Burden/psychology
Latent Class Analysis
Cost of Illness
Surveys and Questionnaires

@article {pmid41650091,
year = {2026},
author = {Chen, ZH and Wang, LX and Li, R and Jiang, YH and Zong, GH and Yi, ZX and Ren, XY and Jia, BH},
title = {Causality between noise pollution and Alzheimer disease: A Mendelian randomization analysis.},
journal = {Medicine},
volume = {105},
number = {6},
pages = {e47612},
doi = {10.1097/MD.0000000000047612},
pmid = {41650091},
issn = {1536-5964},
support = {2023YFC3503704//National Key R&D Program of China Modernization of Traditional Chinese Medicine/ ; BJZYYB-2023-10//Beijing Municipal Science and Technology Development Fund for Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Alzheimer Disease/etiology/genetics/epidemiology ; Mendelian Randomization Analysis ; *Noise/adverse effects ; Genome-Wide Association Study ; Risk Factors ; Causality ; },
abstract = {The role of noise pollution as a risk factor for Alzheimer disease (AD) is unclear, with observational studies yielding conflicting results susceptible to confounding and reverse causality. To clarify this relationship, we performed a 2-sample Mendelian randomization (MR) study using summary statistics from large-scale genome-wide association studies of European populations. Genetically predicted daytime and evening noise exposure was used as an instrumental variable to assess a causal effect on AD risk. The primary analysis was conducted using the inverse-variance weighted method, with weighted median and MR-Egger methods as key sensitivity analyses. We assessed instrument validity and pleiotropy using the Cochran Q test, the MR-Egger intercept, and leave-one-out analysis. Our MR analysis found no evidence of a causal association between genetically predicted daytime noise (odds ratio [95% confidence interval] = 0.999 [0.993-1.006], P = .819) or evening noise (odds ratio [95% confidence interval] = 0.999 [0.993-1.005], P = .643) and the risk of AD. Sensitivity analyses were consistent, with no evidence of heterogeneity or directional pleiotropy. In conclusion, this study does not support a direct causal link between noise and AD. While our findings mitigate common observational biases, they do not preclude indirect mechanisms whereby noise may influence AD pathogenesis via established risk pathways, such as chronic sleep disruption and cardiovascular stress. Studies are needed to focus on disentangling these potential indirect effects.},
}

Humans
*Alzheimer Disease/etiology/genetics/epidemiology
Mendelian Randomization Analysis
*Noise/adverse effects
Genome-Wide Association Study
Risk Factors
Causality

@article {pmid41650053,
year = {2026},
author = {Cui, X and Zhai, W and Wang, Z and Xu, Y and Fan, D and Zhang, Q and Sun, L},
title = {Genetic evidence on the association between pulmonary function and cognitive impairment: A 2-sample Mendelian randomization study.},
journal = {Medicine},
volume = {105},
number = {6},
pages = {e47457},
doi = {10.1097/MD.0000000000047457},
pmid = {41650053},
issn = {1536-5964},
support = {No. 82071442//General Program of the National Natural Science Foundation of China/ ; JLSWSRCZX2021-004//Jilin Provincial Department of Finance/ ; No. 2018YFC1312301//Major Chronic Disease Program of the Ministry of Science and Technology of China/ ; No. 2021ZD0201802//STI2030-Major Projects/ ; },
mesh = {Humans ; Mendelian Randomization Analysis ; *Cognitive Dysfunction/genetics/physiopathology ; Vital Capacity/genetics ; *Dementia/genetics ; Male ; },
abstract = {Some observational studies have suggested that lower pulmonary function increases the risk of cognitive decline or dementia; however, the evidence remains inconclusive. We performed 2-sample Mendelian randomization (MR) analyses to investigate the potential associations between forced vital capacity (FVC) and a range of dementia- and cognition-related outcomes. FVC was selected as the primary indicator of pulmonary function because it is less effort- and cognition-dependent and better reflects overall lung capacity. Outcomes included 6 dementia types: all-cause dementia, Alzheimer disease (AD), dementia with lewy bodies, Parkinson disease dementia, frontotemporal dementia, and vascular dementia, and 6 cognitive domains, including intelligence, fluid intelligence (reasoning and problem-solving ability independent of acquired knowledge), cognitive performance, numeric memory, executive function, and prospective memory. All genetic associations were reported per 1-standard-deviation increase in genetically predicted FVC - expressed as log-odds ratios (log-ORs) for dementia outcomes and standard-deviation changes for cognitive outcomes. The inverse-variance weighted method was used as the primary analysis, complemented by MR-Egger, weighted median, weighted mode, simple mode and MR-PRESSO for sensitivity analyses. False discovery rate (FDR) correction, colocalization, and reverse MR analyses were also performed. This study provides genetic evidence supporting an association between reduced pulmonary function and cognitive impairment. Further studies are needed to clarify the underlying mechanisms. Higher genetically predicted FVC was associated with a lower risk of AD (log-OR per 1-SD increase = -0.24; P = .002; FDR-adjusted P = .011). An inverse association was also observed with all-cause dementia (log-OR per 1-SD increase = -0.37; P = .031), but it did not remain significant after FDR correction (FDR-adjusted P = .094). No significant associations were observed for other dementia subtypes or cognitive outcomes. The results were robust in sensitivity analyses, with no significant findings in reverse MR. Colocalization analysis did not support shared causal variants between FVC and AD (PP.H4.abf <0.75).},
}

Humans
Mendelian Randomization Analysis
*Cognitive Dysfunction/genetics/physiopathology
Vital Capacity/genetics
*Dementia/genetics
Male

@article {pmid41650025,
year = {2026},
author = {Hou, XH and Zhang, W and Kang, K and Jin, Y and Ren, P and Wang, L and Li, Z and Li, Y and You, J and Zhang, B and Ma, Q and , and Xie, F and Yu, JT and Feng, JF and Cheng, W},
title = {Proteomics reveals three molecular subtypes of Alzheimer's disease with distinct progression patterns.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71106},
doi = {10.1002/alz.71106},
pmid = {41650025},
issn = {1552-5279},
support = {2023YFC3605400//National Key R&D Program of China/ ; 2018YFC1312904//National Key R&D Program of China/ ; 2019YFA0709502//National Key R&D Program of China/ ; 2025ZD0546300//Noncommunicable Chronic Diseases-National Science and Technology Major Project/ ; 82472055//National Natural Science Foundation of China/ ; 62433008//National Natural Science Foundation of China/ ; 82071201//National Natural Science Foundation of China/ ; 81971032//National Natural Science Foundation of China/ ; 92249305//National Natural Science Foundation of China/ ; 25TQ010//Shanghai Pilot Program for Basic Research-Fudan University 21TQ1400100/ ; 23JS1410100//Shanghai Science and Technology Commission Program/ ; 2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; 2022QD002//Research Start-Up Fund of Huashan Hospital/ ; 3030277001//Excellence 2025 Talent Cultivation Program at Fudan University/ ; 2019074//Shanghai Talent Development Funding for the Project/ ; 2018SHZDZX01//Shanghai Municipal Science and Technology Major Project/ ; B18015//111 Project/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/classification/pathology ; Disease Progression ; *Proteomics ; Male ; Female ; Aged ; tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Cognitive Dysfunction/cerebrospinal fluid/pathology ; Longitudinal Studies ; Atrophy/pathology ; Machine Learning ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) shows marked molecular heterogeneity. Defining biological subtypes may refine diagnosis and treatment.

METHODS: We analyzed cerebrospinal fluid (CSF) proteomics and longitudinal data from 550 participants in the Alzheimer's Disease Neuroimaging Initiative with up to 16.5 years of follow-up. We profiled 6361 proteins, applied machine learning to identify biological subtypes, and validated them in three independent cohorts.

RESULTS: Three AD subtypes were identified. Subtype 1, enriched in RNA metabolism pathways, showed the mildest atrophy and slowest cognitive decline. Subtype 2, characterized by axonogenesis-related pathways, exhibited the greatest CSF tau elevations, moderate atrophy, and intermediate decline. Subtype 3, associated with catabolic processes, showed the most severe atrophy and fastest progression. These patterns were consistently replicated across validation cohorts.

DISCUSSION: These findings demonstrate robust, biologically distinct AD subtypes linked to divergent molecular pathways, clinical features, and progression rates. Such refined stratification supports precision diagnostics and targeted therapeutic strategies.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/classification/pathology
Disease Progression
*Proteomics
Male
Female
Aged
tau Proteins/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Cognitive Dysfunction/cerebrospinal fluid/pathology
Longitudinal Studies
Atrophy/pathology
Machine Learning
Aged, 80 and over

@article {pmid41649237,
year = {2026},
author = {Pressman, PS and Schaffer, J and Finch, K and Dino, F and Filley, CM and Arciniegas, DB},
title = {A Single-Item Screening Tool for the Assessment of Hoarding: Preliminary Observations.},
journal = {The Journal of neuropsychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {appineuropsych20250152},
doi = {10.1176/appi.neuropsych.20250152},
pmid = {41649237},
issn = {1545-7222},
abstract = {OBJECTIVE: Hoarding disorder is defined as persistent difficulty discarding or parting with possessions, regardless of their actual value. Hoarding is associated with biopsychosocial distress and reduced quality of life, and although it is often associated with obsessive-compulsive spectrum disorders, hoarding is also encountered in cases of neurodegeneration. Assessments of hoarding behavior traditionally involve a comprehensive evaluation that may be challenging in clinical settings. The authors developed a simplified hoarding screen for patients with neurobehavioral disorders.

METHODS: The Single-Item Hoarding Screen (SIHS) is a single-item questionnaire. In total, 135 patients from the University of Colorado Behavioral Neurology Clinic were surveyed; caregivers filled out the SIHS. Patients' diagnoses included a range of neurobehavioral disorders, including Alzheimer's disease, behavioral variant frontotemporal dementia, Lewy body dementia, primary progressive aphasia, major neurocognitive disorder not otherwise specified, and minor neurocognitive disorder not otherwise specified.

RESULTS: The mean age of the patients was 70.9 years, and 39% were female. Among the patients surveyed, 10% and 13% of caregivers (23% total) answered yes and maybe, respectively, to the question on the SIHS. Yes responses on this screen were significantly associated with higher scores on the established Hoarding Rating Scale, compared with maybe responses. Statistical analyses revealed significant correlations between hoarding behaviors and neuropsychiatric symptom severity as well as caregiver well-being.

CONCLUSIONS: These results suggest the potential benefits of a tool containing only a single item to screen for hoarding behavior in neurobehavioral disorders. Future research may focus on refining and validating the SIHS.},
}

@article {pmid41649236,
year = {2026},
author = {Monção, J and Diniz, LT and Martins, AP and Guimarães, HC and Gambogi, LB and Saraiva, LA and Caramelli, P and de Souza, LC},
title = {Clinical Validation of the Behavioral Evaluation Scale of Frontotemporal Dementia: A Pilot Study.},
journal = {The Journal of neuropsychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {appineuropsych20250120},
doi = {10.1176/appi.neuropsych.20250120},
pmid = {41649236},
issn = {1545-7222},
abstract = {OBJECTIVE: Besides cognitive deficits, dementias are characterized by behavioral symptoms, hampering efforts to distinguish between different types of dementia, such as Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Moreover, instruments adapted to the local sociocultural context are lacking in non-English-speaking countries. The authors developed a scoring instrument (the Behavioral Evaluation Scale of Frontotemporal Dementia [BES-FTD]) for use in the Latin American context to assess behavioral changes among patients with bvFTD and to test its accuracy to differentiate bvFTD from AD.

METHODS: The BES-FTD and the Cambridge Behavioral Inventory-Revised (CBI-R) were administered to three groups of participants: patients with probable bvFTD, patients with probable AD, and cognitively healthy individuals (control). The authors investigated diagnostic accuracies with receiver operating characteristic (ROC) curve analysis.

RESULTS: The sample comprised 86 participants matched on sex, age, and education: bvFTD group, N=26; AD group, N=16; and healthy control group, N=44. The AD and bvFTD groups were also matched on the severity of disease. The individuals in the bvFTD group had significantly higher scores on the BES-FTD and on the CBI-R compared with the control and AD groups, indicating more severe behavioral disorders. ROC curve analysis indicated an area under the curve of 0.86 for the BES-FTD and 0.58 for the CBI-R. The BES-FTD had higher specificity (93.7%) than the CBI-R (81.2%).

CONCLUSIONS: The BES-FTD provided higher diagnostic accuracy than the CBI-R for distinguishing between bvFTD and AD, demonstrating the clinical usefulness of the BES-FTD. Future studies are needed to confirm these results.},
}

@article {pmid41649131,
year = {2026},
author = {Lee, S and Lee, J and Lee, K},
title = {Translational roadmap of BBB-targeted nanoparticle strategies for neuroregenerative therapy in neurodegenerative diseases.},
journal = {Biomaterials science},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5bm01582k},
pmid = {41649131},
issn = {2047-4849},
abstract = {Neuroregeneration has drawn scientific attention due to its therapeutic potential for neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and traumatic brain injury (TBI). A major obstacle in delivering neuroregenerative and neuroprotective drugs is crossing the blood-brain barrier (BBB)-a selective, physiological barrier that protects the central nervous system (CNS) from circulating toxins and pathogens. While this protective role is essential for maintaining CNS homeostasis, it also limits therapeutic efficacy and increases the risk of systemic side effects due to off-target accumulation. To overcome these challenges, recent advances in nanoparticle engineering have focused on enhancing BBB transcytosis by employing biologically inspired surface modifications. In this review, we highlight three mechanistically distinct approaches: (1) transporter-mediated transcytosis (TMT), which uses glucose or amino acid conjugation; (2) receptor-mediated transcytosis (RMT) via ligands such as transferrin or angiopep-2; and (3) adsorptive-mediated transcytosis (AMT), utilizing cationic polymer coatings or cell-penetrating peptides (CPPs).},
}

@article {pmid41648642,
year = {2026},
author = {Cortés, H and Lima, E and Duarte-Peña, L and Peña-Corona, SI and Almarhoon, ZM and Kaverikana, R and Mangalpady, SS and Shet, VB and Manjeshwar, N and Sharifi-Rad, J and Chen, JT and Leyva-Gómez, G and Setzer, WN and Calina, D},
title = {Ginsenoside Rg1 as a Multifunctional Therapeutic Agent: Pharmacological Properties, Molecular Mechanisms and Clinical Perspectives in Complementary Medicine.},
journal = {Food science & nutrition},
volume = {14},
number = {2},
pages = {e71486},
pmid = {41648642},
issn = {2048-7177},
abstract = {Ginsenoside Rg1 (GRg1), a major bioactive component of Panax ginseng, exhibits potent antioxidant, anti-inflammatory, and neuroprotective properties, positioning it as a promising therapeutic agent in neurodegenerative and metabolic disorders. This review critically examines the current literature on GRg1, emphasizing its molecular mechanisms, pharmacological pathways, and clinical translation in complementary medicine. GRg1 demonstrates protective effects in conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, cardiovascular dysfunction, diabetes, and aging, acting primarily through the nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and peroxisome proliferator-activated receptor gamma/heme oxygenase-1 (PPARγ/HO-1) signaling pathways. Evidence from in vitro, in vivo, and clinical studies indicates that GRg1 enhances cellular resilience, reduces oxidative damage, and regulates apoptosis. Despite its broad therapeutic potential, low bioavailability remains a major limitation, warranting the development of advanced delivery systems such as nanoparticles and liposomes. Overall, this review provides a comprehensive assessment of GRg1's pharmacological actions and highlights its growing relevance as a multifunctional therapeutic agent in complementary and integrative medicine.},
}

@article {pmid41648599,
year = {2026},
author = {Silva, JM and Lahiri, S and Monteiro-Fernandes, D and Soares-Cunha, C and Solis-Mezarino, V and Volker-Albert, M and Papadimitrou, G and Gomes, P and Marques, C and Coimbra, B and Campos, IC and Samiotaki, M and Panayotou, G and Kokras, N and Dalla, C and Wolozin, B and Oliveira, JF and Abisambra, JF and Ihnof, A and Rodrigues, AJ and Sousa, N and Sotiropoulos, I},
title = {The loss of Tau in the adult brain triggers neuroplastic, epigenetic and behavioral deficits.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.21.700784},
pmid = {41648599},
issn = {2692-8205},
abstract = {INTRODUCTION: Accumulation of pathological Tau precipitates neuronal malfunction in Alzheimer's disease (AD). However, the impact of loss of normal Tau function in the adult brain, independently of Tau aggregates, remains unclarified.

METHODS: We used a mouse model with conditional mapt knocking-down in forebrain of 5-7 months old animals (cTau-KO), a virus-driven selective Tau knockdown in wild-types (WT) and Tau re-expression approaches, accompanied by neurostructural, epigenetic, proteomic, electrophysiological, neurochemical and behavioral analyses.

RESULTS: Loss of Tau in the adult brain of cTau-KOs triggers neuronal atrophy and malfunction, epigenetic as well cognitive and mood deficits. Importantly, these perturbations were confirmed by selective Tau loss in WT adult brain and reverted by Tau re-expression or pharmacologically-induced epigenetic correction in cTau-KOs.

DISCUSSION: Our findings highlight the contribution of loss of normal Tau function in the adult brain malfunction that could be relevant in diverse brain pathologies beyond AD, associated to Tau and its dysfunction.},
}

@article {pmid41648589,
year = {2026},
author = {Bhatta, S and Grzybowski, A and Ortiz, G and DiStasio, M},
title = {Mechanobiological Specialization of Choroid Plexus Macrophages Defined by Titin Expression.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.20.700716},
pmid = {41648589},
issn = {2692-8205},
abstract = {Functioning both as the site of cerebrospinal fluid production and as an interface between the peripheral circulation and the central nervous system, the choroid plexus (ChP) modulates the gating of immune cells and signals from the periphery as they pass from the blood into cerebrospinal fluid. We generated a single-nucleus and spatial transcriptomic atlas of the adult human ChP, in donors with and without Alzheimer's disease (AD), revealing transcriptionally and spatially distinct macrophage states. We identified a previously unrecognized population of titin-expressing (TTN [+]) tissue-resident macrophages characterized by coordinated activation of cytoskeletal remodeling, phagocytosis, autophagy, and inflammatory programs. Isoform-specific qPCR, protein immunofluorescence, and single-molecule FISH validated TTN expression in situ. In AD, TTN [+] macrophages expand and undergo broad transcriptional rewiring, including activation of MEF2-linked mechanotransduction pathways, elevated senescence signatures, and a loss of ligand-receptor connectivity with epithelial, endothelial, and stromal partners. Collectively, our findings define a mechanosensitive macrophage program at the blood-CSF interface and uncover a TTN-associated shift in macrophage function and microenvironment integration in AD.},
}

@article {pmid41648534,
year = {2026},
author = {Biju, AP and Karim, F and Schafer, DM and Sison, SA and Liang, C and Head, E and Mukherjee, J},
title = {Measurement of tau protein and Aβ amyloid plaques in postmortem human brains of Down syndrome and Alzheimer's disease by using [ [125] I]IPPI and [ [125] I]IBETA autoradiography.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.17.700075},
pmid = {41648534},
issn = {2692-8205},
abstract = {The accumulation of tau tangles and Aβ plaques are prominent neuropathologies that characterize Alzheimer's disease (AD) and Down Syndrome (DS). Continuous developments of PET tracers as biomarkers can be supported by autoradiography to validate effectiveness and accuracy of binding properties that elucidate the pathophysiology of DSAD and AD. This in vitro comparative study evaluates [ [125] I]IPPI binding to tau and [ [125] I]IBETA binding to Aβ plaques in the frontal cortex (FCX) and temporal cortex (TCX) of postmortem human brain slices of AD (n=5), DSAD (n=5), and cognitively normal (CN) (n=5) cases. With anti-tau and anti-Aβ immunostains confirming the presence of tau and Aβ plaques, [ [125] I]IPPI and [ [125] I]IBETA binding in autoradiographic images were significantly higher in DSAD and AD gray matter (GM) compared to CN. When comparing DSAD with AD, FCX and TCX GM binding was similar throughout DSAD and AD except in FCX GM where there was 48% more [ [125] I]IPPI binding in DSAD than AD. In vitro drug inhibition studies revealed that [ [125] I]IPPI binding was significantly inhibited with increasing harmine concentrations (IC 50 =115±40 nM) in DSAD FCX and TCX but KuFal194 minimally inhibited [ [125] I]IPPI binding in the same cases. The GM/white matter ratios for DSAD ([ [125] I]IPPI=4.1, [ [125] I]IBETA=2.9) and AD ([ [125] I]IPPI=4.2, [ [125] I]IBETA=2.6) were significantly greater than CN ([ [125] I]IPPI=1.3, [ [125] I]IBETA=1.2). A positive correlation between [ [125] I]IPPI and [ [125] I]IBETA binding suggests a synergistic relationship between tau and Aβ plaque in DSAD and AD pathology. This study demonstrates that [ [125] I]IPPI and [ [125] I]IBETA may serve as novel radiotracers in both DSAD and AD to continue diagnostic investigations in vivo.},
}

@article {pmid41648480,
year = {2026},
author = {Bartholomew, SK and Turk, J and Winslow, W and Foley, C and Shaw, A and Rokey, S and Tallino, S and Judd, MJ and Beach, TG and Serrano, GE and Wilms, G and Kushwaha, R and McMahon, A and Ginn, S and Becker, W and Hulme, C and Dunckley, T and Velazquez, R},
title = {Dyrk1a inhibition with the Novel Compound DYR533: A Cross-Disease Therapeutic Strategy Targeting Amyloidosis, Tau Pathogenesis, and Neuroinflammation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.20.700091},
pmid = {41648480},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) and related dementias are rapidly increasing in prevalence, yet disease-modifying therapies remain largely focused on amyloid-β (Aβ) with limited efficacy against tau pathology and neuroinflammation-key drivers of neurodegeneration and clinical decline. Dual-specificity tyrosine-phosphorylation-regulated kinase 1a (Dyrk1a) phosphorylates tau and amyloid precursor protein and regulates inflammatory signaling, positioning it as a convergence point across pathogenic pathways. We show that brain Dyrk1a protein levels are consistently elevated across ADRDs, replicating findings in AD, confirming prior observations in Pick's disease, and demonstrating dysregulation in corticobasal degeneration and progressive supranuclear palsy. We developed DYR533, a selective, orally bioavailable, brain-penetrant Type 1 Dyrk1a kinase inhibitor that also inhibits autophosphorylation and reduces kinase abundance. Across three mouse models (3xTg-AD, PS19, Ts65Dn), DYR533 reduced pathological tau hyperphosphorylation, attenuated neuroinflammation, ameliorated amyloidosis, and improved anxiety-like behavior and spatial memory, collectively supporting Dyrk1a inhibition and DYR533 as a therapeutic strategy for ADRD.},
}

@article {pmid41648433,
year = {2026},
author = {Kaur, B and Nada, H and Zhang, L and Gabr, M},
title = {Targeting CHI3L1 in Alzheimer's Disease: Optimization of G721-0282 and Functional Evaluation in Astrocyte Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.13.699206},
pmid = {41648433},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) involves astrocytic dysfunction characterized by impaired lysosomal activity, defective amyloid clearance, and neuroinflammation, processes strongly regulated by the inflammatory effector CHI3L1. G721-0282 , a reported CHI3L1-binding small molecule with demonstrated modulation of downstream signaling pathways including MAPK and STAT3, provides a validated chemical starting point for targeting CHI3L1-driven astrocytic pathology in AD, but exhibits suboptimal potency and drug-like properties that limit its translational potential. We therefore performed a virtual screening of commercially available analogues of G721-0282 to enable structure-guided optimization, generating a detailed structure-activity map and prioritizing 24 derivatives. Biophysical analyses identified compound G721-0377 as the most promising candidate, with optimized substitutions improving CHI3L1 binding affinity. Compound G721-0377 also exhibited favorable pharmacokinetic properties, including improved solubility, balanced permeability, reduced microsomal clearance, and an enhanced cardiac safety margin. Functionally, G721-0377 uniquely reversed CHI3L1-induced astrocytic dysfunction, restoring amyloid uptake, lysosomal proteolysis and acidification, suppressing CHI3L1 and IL-6 secretion, and inhibiting NF-κB activation to levels comparable to a neutralizing anti-CHI3L1 antibody. In contrast, compounds G721-0179 and G857-1069 showed minimal activity. Collectively, these findings establish G721-0377 as a next-generation CHI3L1 inhibitor with improved affinity, safety, and robust functional efficacy, supporting its further development as a disease-modifying therapeutic for AD.},
}

@article {pmid41648425,
year = {2026},
author = {Nada, H and Yuan, S and Gaamouch, FE and Cho, S and Gabr, MT},
title = {Small Molecule Agonists of TREM2 Reprogram Microglia and Protect Synapses in Human Alzheimer's Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.19.700278},
pmid = {41648425},
issn = {2692-8205},
abstract = {Triggering receptor expressed on myeloid cells-2 (TREM2) is a key immune receptor in the central nervous system that regulates microglial phagocytosis, survival, and neuroinflammatory responses. TRME2 variants have been established as genetic risk factors for Alzheimer's disease (AD). However, the therapeutic development of TREM2 modulators has been limited to antibody-based approaches that face limitations in blood-brain barrier penetration and manufacturing scalability. Furthermore, there are no FDA approved TREM2 therapeutics available to date marking an unmet therapeutic gap. Herein, we report the identification of the first TREM2 small molecule submicromolar binders as a result of optimizing compound 4a to yield S9 with TREM2 binding affinity of 0.95 µM. S9 demonstrated robust TREM2 agonism in cellular assays where it induced proximal Syk phosphorylation, activated downstream NFAT transcriptional signaling, enhanced APOE internalization and microglial phagocytic capacity. Pharmacokinetic profiling of the optimized hits revealed S9 to exhibit improved drug-likeness compared to 4a with 7-fold enhanced aqueous solubility, superior metabolic stability, reduced intrinsic clearance and a 9-fold improved hERG safety margin. Functional validation in human iPSC-derived microglia confirmed that S9 suppresses amyloid-beta (Aβ)-induced IL-1β secretion through a TREM2-dependent mechanism. In human neuron-microglia co-culture models exposed to amyloid stress, S9 treatment preserved synaptic integrity as measured by PSD95 expression that indicates promising neuroprotective activity. Together, these findings establish S9 as a first-TREM2 submicromolar small molecule TREM2 agonist which is orally bioavailable with favorable pharmacokinetic properties and promising therapeutic potential for the treatment of Alzheimer's disease.},
}

@article {pmid41648397,
year = {2026},
author = {Riffo-Lepe, N and Gonzalez-Sanmiguel, J and Meza, I and Saavedra-Sieyes, P and Armijo-Weingart, L and Salinas, A and Martín, LS and Aguayo, LG},
title = {Selective impairment of long-term depression in accumbal D1-MSNs involves calcium-permeable AMPARs in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.19.700385},
pmid = {41648397},
issn = {2692-8205},
abstract = {Early neuropsychiatric symptoms in Alzheimer's disease emerge before cognitive decline, yet their synaptic basis remains poorly defined. Here we identify an early, cell-type-specific disruption of synaptic plasticity in the nucleus accumbens during pre-plaque stages of disease. In APP/PS1 mice, intracellular amyloid-beta accumulation is associated with a selective loss of mGluR1/5-dependent long-term depression in dopamine D1 receptor-expressing medium spiny neurons, despite comparable intracellular amyloid-beta levels across neuronal subtypes. This impairment is accompanied by aberrant postsynaptic remodeling characterized by functional accumulation of calcium-permeable AMPA receptors and increased excitatory drive. These synaptic alterations coincide with reduced dopamine-dependent signaling and selective changes in reward-related behavior, including altered hedonic consumption. Together, these findings identify an early vulnerability of the mesolimbic reward system and suggest that non-cognitive manifestations of Alzheimer's disease arise from circuit-level imbalance before plaque deposition.},
}

@article {pmid41648350,
year = {2026},
author = {Terry, GA and Aziz, S and Raihana, N and Xie, L and Rockwell, P and Serrano, P and Figueiredo-Pereira, ME},
title = {Agomelatine drives sex-specific neuroprotection and reduced pathology in rat and human Alzheimer's models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.17.700104},
pmid = {41648350},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) remains without effective disease-modifying therapies, underscoring the need for interventions that target interconnected molecular and cellular processes driving cognitive decline. Leveraging a cross-species translational framework integrating a progressive rat model of Alzheimer's disease with human iPSC-derived neurons carrying familial AD mutations, we identify agomelatine (AGO) as a disease-modifying candidate. A clinically used melatonergic agonist and 5-HT 2C serotonergic antagonist, we found that AGO acts as a sex-selective modulator of AD-related neuronal and microglial dysfunction with therapeutic relevance across species. TgF344-AD rats and their wildtype littermates received chronic dietary AGO (∼10 mg/kg/day) from 5 to 11 months of age and underwent hippocampal-dependent spatial learning assessment, quantitative hippocampal histopathology, and bulk RNA sequencing to evaluate the therapeutic effect on cognition, pathology, and molecular mechanisms. Human isogenic iPSC-derived cortical neurons carrying PSEN2 [N141I] or APPV [717I] mutations were treated with 20 µM AGO followed by bulk RNA sequencing, to define AGO-driven transcriptional pathway modulation in AD neurons In TgF344-AD rats, AGO produced robust female-specific benefits. AGO selectively restored hippocampal-dependant cognitive performance in female but not male transgenic rats. These improvements were independent of amyloid burden and instead aligned with reductions in microgliosis and pathogenic AT8-positive tau phosphorylation. Additionally, AGO normalized reactive and amoeboid microglial states exclusively in females and enhanced doublecortin-defined neurogenesis without altering mature NeuN[+] neuronal density. This coordinated hippocampal stabilization highlights AGO's capacity to restore plasticity rather than simply suppress pathology. Transcriptomic analyses revealed sex-divergent mechanisms underlying these effects. In females, AGO activated metabolic, oxygen-handling, lipid-processing, neuroimmune, and CREB/IGF-1 signaling pathways while suppressing ER-stress, epigenetic, and ion-channel transcripts, changes consistent with resilience-promoting cellular reprogramming. In males, AGO preferentially modulated mitochondrial redox biology, transcriptional regulators, and extracellular matrix components. Despite these differences, both sexes showed AGO-induced engagement of conserved AD-relevant pathways, including shared induction of synaptic plasticity and hemoglobin/oxygen-transport related genes, suggesting a convergent neuroprotective molecular signature. To translate these findings to a human system, we examined AGO's effects in PSEN2 [N141I] and APP [V717I] iPSC-derived cortical neurons. Both mutations produced convergent deficits in synaptic integrity, neuronal maturity, trophic signaling, proteostasis, metabolism, and excitability, alongside dysregulated developmental and ECM-remodeling programs. AGO partially reversed these pathogenic transcriptional changes, up-regulating synaptic, metabolic, vesicle-trafficking, and redox-stress resilience genes while suppressing pathological developmental and inflammatory pathways, demonstrating conserved engagement of neuronal recovery programs. Together, these results identify AGO as a promising non-amyloid therapeutic candidate capable of modulating AD-relevant pathways in rodents and human models. The sex-selective efficacy observed in vivo , combined with conserved transcriptional responses across species, underscores the translational relevance of AGO-driven molecular reprogramming in AD.},
}

@article {pmid41648322,
year = {2026},
author = {Balasubramanian, N and Gaudencio, G and Khan, KM and Biggerstaff, N and Marcinkiewcz, CA},
title = {Adolescent Social Isolation Facilitates Tau Spread in Raphe Nuclei, Linking Depression and Hyperalgesia in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.23.701108},
pmid = {41648322},
issn = {2692-8205},
abstract = {Tau pathology in brainstem serotonergic circuits drives early neuropsychiatric dysfunction in Alzheimer's disease (AD), yet mechanisms linking the exposome, particularly social stress exposures to depression and altered pain perception, remain unclear. Here, we demonstrate that adolescent social isolation, a critical psychosocial exposome factor and major trigger of depression, facilitates tau propagation in the dorsal raphe nucleus (DRN) and downstream raphe nuclei, producing both neuropsychiatric and pain-related sequelae. Tau[P301L] was transduced into the DRN of 30-day socially isolated or group housed C57BL/6J mice using AAV, with control mice receiving AAV-GFP. Four weeks post-transduction, anxiety, social behavior, and pain sensitivity were assessed, and phosphorylated tau (ptau) within the DRN and spread to the median raphe (MRN) and raphe magnus (RMg) serotonergic neurons were evaluated. Socially isolated tau[P301L] mice exhibited hyperlocomotion, anxiety-like behavior, social deficits and hyperalgesia. Histological analysis revealed elevated ptau within TPH2 neurons in the DRN and trans-synaptic tau spread to MRN and RMg, accompanied by reduced TPH2 and increased ptau at the downstream raphe nuclei. Fluorescence in situ hybridization confirmed altered expression of Slc6a4 and Tgm2 , a stress-responsive gene implicated in AD. These results indicate that DRN tau under social stress drives neuropsychiatric phenotypes, while tau spread to MRN and RMg disrupts serotonergic modulation of pain. This study provides the first evidence that adolescent stress promotes tau propagation within the raphe nuclei, linking early neuropsychiatric and pain-processing deficits to prodromal Alzheimer's disease and identifying a critical pathway through which psychosocial exposome risk converges with tau pathology to enable early intervention.},
}

@article {pmid41648321,
year = {2026},
author = {Cardenas-Rivera, A and Erdogmus, E and Birmingham, A and Yee, E and Anton, J and Lu, Z and Li, Y and Morais, M and Loghmani, N and Liu, C and Yaseen, MA},
title = {Aerobic Exercise Preserves Capillary Oxygen Homeostasis and Neurovascular Function in a Mouse Model of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.15.699787},
pmid = {41648321},
issn = {2692-8205},
abstract = {Age-related cerebrovascular dysfunction is increasingly recognized as a critical contributor to cognitive decline and Alzheimer's disease (AD) progression [1,2], yet the extent to which lifestyle interventions preserve microvascular oxygen delivery remains poorly defined. Physical activity (PA) improves vascular health and cognition in humans [3-7], but its impact on capillary-level oxygenation and functional hyperemia during aging and amyloid pathology is unknown. Here, we longitudinally quantified microvascular oxygen tension and stimulus-evoked oxygen dynamics in awake APP/PS1 mice and wild-type littermates using two-photon phosphorescence lifetime microscopy. Chronic aerobic PA initiated in early adulthood preserved basal arteriolar, capillary, and venular oxygenation, prevented age-dependent increases in microvascular heterogeneity, and mitigated excessive oxygen extraction in preclinical AD mice. While amyloid pathology impaired stimulus-evoked oxygen responses across vascular compartments, PA selectively enhanced capillary dilation and accelerated hyperemic kinetics without altering vascular density or architecture. Notably, sedentary AD mice developed widespread capillary hypoxia and bimodal oxygen distributions, hallmarks of malignant microvascular dysfunction, which were largely absent in physically active animals. These findings demonstrate that routine aerobic PA preserves microvascular oxygen homeostasis and functional responsiveness during aging and amyloid accumulation, supporting a capillary-centric mechanism through which exercise confers neurovascular resilience in preclinical AD.},
}

@article {pmid41648312,
year = {2026},
author = {Huang, Y and Xie, X and Huang, Z and Chen, R and Gangal, H and Wang, X and Souza, K and Hunter, J and Wu, X and Reddy, DS and Chin, J and Wang, J},
title = {Early-Stage Corticostriatal Circuit Hyperactivity Impairs Cholinergic Function and Cognitive Flexibility in an Alzheimer's Model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.13.699380},
pmid = {41648312},
issn = {2692-8205},
abstract = {UNLABELLED: Cognitive flexibility deficits are a hallmark of early-stage Alzheimer's disease (AD), but the underlying circuit mechanisms remain poorly understood. Here, we show that the 5xFAD mouse model of AD neuropathology exhibited early deficits in instrumental reversal learning, indicating cognitive inflexibility preceding spatial memory deficits. This impairment was associated with excessive neuronal reactivation in the medial prefrontal cortex (mPFC) and dorsomedial striatum (DMS), key regions for goal-directed behavior. Electrophysiological recordings revealed that mPFC neurons in young 5xFAD mice were hyperexcitable and received elevated excitatory input. Moreover, the mPFC-to-direct pathway medium spiny neuron (dMSN) circuit and the dMSNs themselves were selectively hyperactive. These hyperactive dMSNs exerted increased inhibitory control over cholinergic interneurons (CINs) in the DMS, coinciding with reduced CIN firing and diminished striatal acetylcholine (ACh) release. Critically, sustained chemogenetic inhibition of the mPFC-to-DMS circuit in 5xFAD mice reduced cortical Aβ accumulation, normalized glutamatergic transmission in both the mPFC and DMS, restored striatal ACh levels, and rescued reversal learning deficits. Together, these findings identify a hyperactive mPFC-to-DMS circuit that disrupts corticostriatal and cholinergic signaling, contributing to cognitive inflexibility in 5xFAD mice. Targeting this circuit may offer a therapeutic strategy to preserve cognitive function in the early stages of AD.

HIGHLIGHTS: 5xFAD mice exhibit early cognitive deficits in instrumental reversal learning.mPFC neurons and corticostriatal circuits are hyperactive, while cholinergic neurons are hypoactive in 5xFAD mice.Sustained inhibition of mPFC-to-DMS circuit hyperactivity normalizes glutamatergic transmission and slows Aβ accumulation in 5xFAD mice.Sustained inhibition of the mPFC-to-DMS circuit rescues reversal learning deficits in 5xFAD mice.},
}

@article {pmid41648304,
year = {2026},
author = {Chandio, BQ and Feng, Y and Gari, IB and Alibrando, JD and Thomopoulos, SI and Villalón-Reina, JE and Liou, K and Somu, S and Yoo, H and Nir, TM and Garyfallidis, E and Lüders, E and Yeh, FC and Jahanshad, N and Thompson, PM},
title = {Tractometry-Based Quantification of Along-Tract White-Matter Hemispheric Asymmetry in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.23.701434},
pmid = {41648304},
issn = {2692-8205},
abstract = {White-matter hemispheric asymmetry is a fundamental property of human brain organization and is known to change in aging, neurodevelopment, and neurodegenerative disorders. Tractometry analyzes diffusion-derived microstructural measures along the full length of tracts, localizing changes to specific tract-segments rather than collapsing tracts into a single value. Yet, existing frameworks lack a principled way to quantify left-right hemispheric asymmetries along homologous tracts. Here, we introduce an asymmetry-aware tractometry framework that integrates a symmetric white-matter atlas with BUAN (Bundle Analytics) to enable anatomically consistent, along-tract comparison of homologous pathways. By defining homologous bundles with a shared template and consistent orientation, each left-hemisphere segment is directly matched to its right-hemisphere counterpart, enabling principled, segmentwise comparison and revealing spatially localized asymmetries along-tract. Applying this framework to diffusion MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) comprising 1,215 subjects, we demonstrate how this approach reveals systematic left-right asymmetries across major white-matter pathways and show how these patterns differentiate cognitively normal (CN) individuals from those with mild cognitive impairment (MCI) and dementia. This method provides a sensitive and anatomically grounded tool for studying hemispheric specialization and its disruption in aging and disease, and establishes a general approach for asymmetry-aware tractometry in population neuroimaging studies.},
}

@article {pmid41648223,
year = {2026},
author = {Xu, L and Yang, H and Leon, J and Li, X and Oehler, A and Modavi, C and Abate, AR and Condello, C},
title = {Spatially resolved transcriptome-metabolome integration reveals region-specific glial lipid dysregulation associated with Alzheimer's pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.23.701345},
pmid = {41648223},
issn = {2692-8205},
abstract = {Glial cells maintain the brain's lipid and energy balance, and their breakdown is increasingly recognized as a causal contributor to Alzheimer's disease (AD). While this concept is established, no approach has directly shown how glial homeostatic failure manifests across brain regions and microenvironments or how it links local pathology, such as plaques, to global metabolic imbalance. To address this gap, we developed iMIST, an integrated platform that combines MALDI-based metabolite imaging, histology, and spatial transcriptomics within a single tissue section to align molecular and anatomical information. Using a mouse model of late-onset AD that recapitulates both amyloid deposition and metabolic vulnerability, iMIST revealed that glial lipid dysregulation is widespread but spatially specialized. In gray matter, plaque-associated microglia were associated with upregulated glycerophospholipid-remodeling in cortico-thalamic areas indicating metabolic stress around local pathology. In contrast, white matter tracts rich in lipid-producing oligodendrocytes show plaque-independent deficits in galactosylceramide metabolism reflecting their high myelin demand. Both processes intensify with age, transforming adaptive glial responses into persistent metabolic dysfunction. Together, these findings demonstrate the spatial interplay between global glial metabolic imbalance and local microenvironmental stressors associated with AD pathology. By integrating transcriptomic and metabolomic information in situ , iMIST provides a framework for uncovering how regional glial vulnerability shapes the pathogenesis of neurodegenerative diseases.},
}

@article {pmid41648205,
year = {2026},
author = {Rahman, S and Israel, AR and Ryan, A and Williams, R},
title = {Screening Molecular Recognition Element-Based SWCNT Optical Sensors for the Inflammatory Cytokine TNF-α.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.22.701124},
pmid = {41648205},
issn = {2692-8205},
abstract = {TNF-α (Tumor Necrosis Factor) is a proinflammatory cytokine that amplifies inflammatory response and promotes leukocyte recruitment. TNF-α is primarily produced by activated macrophages, among others, in response to infection, inflammation, or tissue damage. Given its central role in normal and abnormal immune responses, it is the target of several therapeutics, such as adalimumab and etanercept. TNF-α is also a prognostic and diagnostic biomarker associated with Rheumatoid Arthritis, Alzheimer's disease, Multiple Sclerosis, several kidney diseases, several cancers, Type 2 diabetes, sepsis, and others. Spatial quantification of TNF-α in disease models can also be a powerful tool to understand the contributions of inflammatory processes to disease progression. Single-walled carbon nanotubes (SWCNT) are cylindrical carbon lattices that emit distinct near-infrared bandgap photoluminescence. In this work, we evaluated three aptamer-based sensor constructs, plus an additional two iterations of one aptamer sequence, and two antibody-based sensor constructs for TNF-α that use SWCNT near-infrared photoluminescence signal transduction. Several, but not all, of these aptamer and antibody-based sensors sensitively and selectively detected TNF-α in serum in a physiologically relevant range, and we found that their sensing was improved by both passivation and incorporating an exogenous quencher onto the aptamer sequence. Specifically, we found that modification of one aptamer sequence with a Black Hole Quencher induced selective detection in serum when passivated with poly-L-Lysine. This study highlights the importance, and challenges, of translating previously-validated molecular recognition elements to new detection conditions, in this case on the surface of SWCNT and in challenging serum conditions. It also validated a lead sensor construct that builds upon constructs that failed in serum. We anticipate that the sensors evaluated here will have utility in both the diagnosis and study of inflammation-driven chronic disease, while the sensor assessment framework will help drive the broader field of molecularly specific diagnostics.},
}

@article {pmid41648171,
year = {2026},
author = {Kumar, V and Sanchez Franco, VM and Ferry, FS and Xie, Y and Hutson, AN and Zhang, YJ and Daniels, SD and Nguyen, DL and Spera, LK and Snyder, EM and Knauss, A and Sudhakar, SL and Duan, GY and Paul, EM and Tabuchi, M},
title = {Neuronal microscale biophysical instability mediates macroscale network dynamics shaping pathological manifestations.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.20.697254},
pmid = {41648171},
issn = {2692-8205},
abstract = {UNLABELLED: Microscale biophysical alterations in neuronal dynamics can have profound implications for macroscale pathological outcomes in the brain. Despite the critical need to link neuronal perturbations to large-scale disease manifestations, few studies successfully bridge these hierarchical scales. Here, we bridge microscale biophysical variability within neuronal dynamics to macroscale disease-related phenotypes. We find that Drosophila models expressing tauopathy- and epilepsy-associated molecular mutations exhibit increased dynamic instability in the timing of action potential initiation, and microscale biophysical changes are manifested at the level of the macroscale global brain state. We show that variability in voltage-gated sodium channel currents during non-stationary channel inactivation may act as a microscale biophysical contributor to the increased dynamic instability observed in action potential timing. We also find that treatment with antiepileptic drugs stabilizes neuronal dynamics by modulating this variability in voltage-gated sodium channel currents. Finally, we show that neurons derived from human induced pluripotent stem cells (iPSCs) from patients with Alzheimer's disease and epilepsy exhibit analogous dynamic instability, which is reversible by administration of antiepileptic medications. Our results highlight how subtle microscale neuronal instabilities propagate and are amplified to produce macroscopic pathological phenotypes, providing new biophysical insights into neurological disorders and potential strategies for therapeutic intervention.

SIGNIFICANCE STATEMENT: Linking microscale neuronal changes to macroscale disease phenotypes remains a key challenge in neuroscience biophysics. Here, we show that subtle biophysical instability, such as variability in action potential timing and increased noise in voltage-gated sodium channel activity, can destabilize neuronal network integrity and cause systemic pathology. Stabilizing neuronal dynamics with antiepileptic drugs reverses tau-induced instabilities in a Drosophila disease model. Similar neuronal instabilities occur in fly neurons expressing epilepsy-linked sodium channel mutations and in human iPSC-derived neurons from Alzheimer's and epilepsy patients, revealing a shared cellular mechanism. These findings highlight that targeting microscale instabilities may offer a unifying therapeutic approach for complex neurological disorders.},
}

@article {pmid41648144,
year = {2026},
author = {Shukla, K and Zhang, Z and Plafker, KS and Matsuzaki, S and Salinas-Salinas, C and Thomason, Y and Houmam, S and Barber, D and Fakye, A and Humphries, KM and Plafker, SM and Lin, J and Rice, HC},
title = {Amyloid precursor protein interacts with the mitochondrial phosphatase PGAM5 and regulates mitochondrial respiration.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.20.700642},
pmid = {41648144},
issn = {2692-8205},
abstract = {Amyloid Precursor Protein (APP) has been reported to partially localize to mitochondria, and mitochondrial dysfunction is a key feature of Alzheimer's disease; however, the mechanisms linking APP to mitochondrial functions remain incompletely defined. In this study, we found that mitochondria isolated from the brains of APP knockout (KO) mice have impaired substrate-specific respiration and electron transport chain function. We identified a novel interaction between APP and phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial phosphatase. We determined that APP and PGAM5 co-localize at mitochondria-ER contact sites (MERCS), and we confirm an endogenous interaction using proximity ligation assays in mouse brain slices. Using in vitro binding assays, we demonstrate a direct interaction between the linker region of APP and a region of PGAM5 that includes the Kelch-like ECH-associated protein 1 (Keap-1) binding domain. PGAM5 is known to anchor a portion of Nuclear respiratory factor 2 (Nrf2) through Keap1 at the outer mitochondrial membrane to regulate the expression of mitochondrial respiratory chain complexes and enzymes. Consistent with this, we found that the Nrf2-regulated genes Hmox1 (Heme oxygenase-1) and Nnqo1 (NADH:quinone oxidoreductase 1), which are involved in mitochondrial respiration, are downregulated in APP KO astrocytes. Together, these findings suggest that APP supports mitochondrial function by modulating PGAM5-Keap1-Nrf2 signaling, providing a mechanistic link between loss of APP function and impaired mitochondrial respiration.},
}

@article {pmid41648133,
year = {2026},
author = {Berdasco, C and Cho, WH and Lee, J and Annu, A and Ledo, JH and Jeong, YY and Kim, YS and An, SS and Tanaka, Y and Ahn, JH and Kim, Y},
title = {Wasf1 deletion attenuates tau hyperphosphorylation, microglial state transition, and cognitive deficits in P301S tau mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.14.699391},
pmid = {41648133},
issn = {2692-8205},
abstract = {We previously reported that WAVE1, a major activator of Arp2/3 complex-mediated actin polymerization, is downregulated in postmortem brains of Alzheimer's disease (AD) and that WAVE1 regulates amyloid precursor protein trafficking and amyloid-β production. However, its role in tau pathology remains unknown. Here, we demonstrate that WAVE1 activity is suppressed in P301S tau mice through elevated inhibitory phosphorylation. Strikingly, WAVE1 gene (Wasf1) knockout in P301S tau mice significantly reduces tau hyperphosphorylation and improves cognition, suggesting a compensatory role for WAVE1 suppression in tau pathogenesis. Single-nucleus RNA sequencing reveals that Wasf1 deletion in P301S tau mice reverses microglial state transitions, with minimal impact on other brain cell types. Wasf1 mRNA is highly translated in microglia in non-Tg mice, while its expression is downregulated in P301S tau mice. Wasf1 knockdown in BV2 microglia cells enhances the degradation of engulfed tau fibrils, indicating WAVE1 as an endogenous regulator of microglial function. Additionally, CellChat analysis indicates that Wasf1 deletion alters microglial autocrine signaling and their interactions with other cell types in P301S tau mice. These findings, taken together, suggest that Wasf1 deletion restores homeostatic microglial function, mitigates tau pathology, and alleviates cognitive deficits, highlighting WAVE1 as a potential therapeutic target for tauopathy-related dementias.},
}

@article {pmid41648112,
year = {2026},
author = {Fotio, Y and Al Masri, S and Shi, Z and Le, J and Das, S and Rubtsova, VI and Mabou Tagne, A and Jang, C and Swarup, V and Piomelli, D},
title = {Metabolic reallocation in spinal cord oligodendrocytes drives chronic pain via neuronal β-amyloid production.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.23.701389},
pmid = {41648112},
issn = {2692-8205},
abstract = {Peripheral injury reprograms metabolism in spinal cord oligodendrocytes, initiating a molecular cascade that drives chronic pain via neuronal β-amyloid (Aβ) release. After injury, mouse spinal oligodendrocytes downregulate myelin protein synthesis and upregulate lipid biosynthesis-but reroute lipids toward neuroplastic remodeling and away from myelin maintenance. This metabolic reallocation disrupts myelin integrity and axonal function, causing neuronal accumulation of amyloid precursor protein, enhanced expression of its processing β-secretase BACE1, and local release of Aβ peptides. Blocking Aβ production or clearing Aβ deposits stops the transition to pain chronicity. Deleting the lysosomal lipid hydrolase NAAA in oligodendrocytes prevents both injury-induced Aβ production and chronic pain development. The findings identify an unexpected mechanistic link between chronic pain and Alzheimer's-like neurodegeneration, positioning Aβ as a target for therapeutic intervention.},
}

@article {pmid41647242,
year = {2026},
author = {Corti, M and Ahern, A and Goriely, A and Kuhl, E and Antonietti, PF},
title = {A whole-brain model of amyloid beta accumulation and cerebral hypoperfusion in Alzheimer's disease.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41647242},
issn = {2331-8422},
abstract = {Accumulation of amyloid beta proteins is a defining feature of Alzheimer's disease, and is usually accompanied by cerebrovascular pathology. Evidence suggests that amyloid beta and cerebrovascular pathology are mutually reinforcing; in particular, amyloid beta suppresses perfusion by constricting capillaries, and hypoperfusion promotes the production of amyloid beta. Here, we propose a whole-brain model coupling amyloid beta and blood vessel through a hybrid model consisting of a reaction-diffusion system for the protein dynamics and porous-medium model of blood flow within and between vascular networks: arterial, capillary and venous. We discretize the resulting parabolic--elliptic system of PDEs by means of a high-order discontinuous Galerkin method in space and an implicit Euler scheme in time. Simulations in realistic brain geometries demonstrate the emergence of multistability, implying that a sufficiently large pathogenic protein seeds is necessary to trigger disease outbreak. Motivated by the "two-hit vascular hypothesis" of Alzheimer's disease that hypoperfusive vascular damage triggers amyloid beta pathology, we also demonstrate that localized hypoperfusion, in response to injury, can destabilize the healthy steady state and trigger brain-wide disease outbreak.},
}

@article {pmid41647233,
year = {2026},
author = {Silva, S and Reguig, G and Oxtoby, NP and Altmann, A and Lorenzi, M},
title = {Fed-ComBat: A Generalized Federated Framework for Batch Effect Harmonization in Collaborative Studies.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41647233},
issn = {2331-8422},
abstract = {The use of multi-centric analyses is crucial for obtaining sufficient sample sizes and representative clinical populations in experimental studies. In this setting, data harmonization techniques are typically employed to address systematic biases and ensure the interoperability of the data. State-of-the-art harmonisation approaches are based on the statistical theory of random effect modeling, allowing to account for either linear of non-linear biases and batch effects. However, optimizing these statistical methods generally requires data centralization at some point during the analysis pipeline, therefore introducing the risk of exposing individual patient information while posing significant data governance issues. To overcome this challenge, in this paper we present Fed-ComBat, a federated framework for batch effect harmonization on decentralized data. Fed-ComBat enables the preservation of nonlinear covariate effects without requiring centralization of data and without prior parametric hypothesis on the variables to account for. We demonstrate the effectiveness of Fed-ComBat against a comprehensive panel of existing approaches based on the state-of-the-art ComBat, along with distributed and nonlinear variants. Our experiments are based on extensive simulated data, and on the analysis of multiple cohorts based on 7 neuroimaging studies comprising healthy controls (CI) and subjects with various disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and autism spectrum disorder (ASD). Our results show that in a federated settings, Fed-ComBat harmonization exhibits comparable results to centralized methods for both linear and nonlinear cases. On real data, harmonized trajectories of the thickness ofthe right hippocampus across lifespan measured on a set of 7 public studies show comparable results between centralized and federated models and are consistent with the literature when using a nonlinear model. The code is publicly available at: https://gitlab.inria.fr/greguig/fedcombat.},
}

@article {pmid41647227,
year = {2026},
author = {Vázquez-García, C and Martínez-Murcia, FJ and Román, FS and Forte, A and Ramírez, J and Illán, I and Hernández-Segura, A and Jiménez-Mesa, C and Górriz, JM},
title = {An explainable framework for the relationship between dementia and glucose metabolism patterns.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41647227},
issn = {2331-8422},
abstract = {High-dimensional neuroimaging data presents challenges for assessing neurodegenerative diseases due to complex non-linear relationships. Variational Autoencoders (VAEs) can encode scans into lower-dimensional latent spaces capturing disease-relevant features. We propose a semi-supervised VAE framework with a flexible similarity regularization term that aligns selected latent variables with clinical or biomarker measures of dementia progression. This allows adapting the similarity metric and supervised variables to specific goals or available data. We demonstrate the approach using PET scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI), guiding the first latent dimension to align with a cognitive score. Using this supervised latent variable, we generate average reconstructions across levels of cognitive impairment. Voxel-wise GLM analysis reveals reduced metabolism in key regions, mainly the hippocampus, and within major Resting State Networks, particularly the Default Mode and Central Executive Networks. The remaining latent variables encode affine transformations and intensity variations, capturing confounds such as inter-subject variability and site effects. Our framework effectively extracts disease-related patterns aligned with established Alzheimer's biomarkers, offering an interpretable and adaptable tool for studying neurodegenerative progression.},
}

@article {pmid41647226,
year = {2026},
author = {Anderson, SD and Chaudhari, NN and Chowdhury, NF and Jomsky, J and Zheng, XR and Irimia, A and Initiative, ADN},
title = {Graph Neural Network Reveals the Local Cortical Morphology of Brain Aging in Normal Cognition and Alzheimers Disease.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41647226},
issn = {2331-8422},
abstract = {Estimating brain age (BA) from T1-weighted magnetic resonance images (MRIs) provides a useful approach to map the anatomic features of brain senescence. Whereas global BA (GBA) summarizes overall brain health, local BA (LBA) can reveal spatially localized patterns of aging. Although previous studies have examined anatomical contributors to GBA, no framework has been established to compute LBA using cortical morphology. To address this gap, we introduce a novel graph neural network (GNN) that uses morphometric features (cortical thickness, curvature, surface area, gray/white matter intensity ratio and sulcal depth) to estimate LBA across the cortical surface at high spatial resolution (mean inter-vertex distance = 1.37 mm). Trained on cortical surface meshes extracted from the MRIs of cognitively normal adults (N = 14,250), our GNN identifies prefrontal and parietal association cortices as early sites of morphometric aging, in concordance with biological theories of brain aging. Feature comparison using integrated gradients reveals that morphological aging is driven primarily by changes in surface area (gyral crowns and highly folded regions) and cortical thickness (occipital lobes), with additional contributions from gray/white matter intensity ratio (frontal lobes and sulcal troughs) and curvature (sulcal troughs). In Alzheimers disease (AD), as expected, the model identifies widespread, excessive morphological aging in parahippocampal gyri and related temporal structures. Significant associations are found between regional LBA gaps and neuropsychological measures descriptive of AD-related cognitive impairment, suggesting an intimate relationship between morphological cortical aging and cognitive decline. These results highlight the ability of GNN-derived gero-morphometry to provide insights into local brain aging.},
}

@article {pmid41647218,
year = {2026},
author = {Witherow, MA and Evans, ML and Temtam, A and Okhravi, HR and Iftekharuddin, KM},
title = {Machine learning-enhanced non-amnestic Alzheimer's disease diagnosis from MRI and clinical features.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41647218},
issn = {2331-8422},
abstract = {Alzheimer's disease (AD), defined as an abnormal buildup of amyloid plaques and tau tangles in the brain can be diagnosed with high accuracy based on protein biomarkers via PET or CSF analysis. However, due to the invasive nature of biomarker collection, most AD diagnoses are made in memory clinics using cognitive tests and evaluation of hippocampal atrophy based on MRI. While clinical assessment and hippocampal volume show high diagnostic accuracy for amnestic or typical AD (tAD), a substantial subgroup of AD patients with atypical presentation (atAD) are routinely misdiagnosed. To improve diagnosis of atAD patients, we propose a machine learning approach to distinguish between atAD and non-AD cognitive impairment using clinical testing battery and MRI data collected as standard-of-care. We develop and evaluate our approach using 1410 subjects across four groups (273 tAD, 184 atAD, 235 non-AD, and 685 cognitively normal) collected from one private data set and two public data sets from the National Alzheimer's Coordinating Center (NACC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). We perform multiple atAD vs. non-AD classification experiments using clinical features and hippocampal volume as well as a comprehensive set of MRI features from across the brain. The best performance is achieved by incorporating additional important MRI features, which outperforms using hippocampal volume alone. Furthermore, we use the Boruta statistical approach to identify and visualize significant brain regions distinguishing between diagnostic groups. Our ML approach improves the percentage of correctly diagnosed atAD cases (the recall) from 52% to 69% for NACC and from 34% to 77% for ADNI, while achieving high precision. The proposed approach has important implications for improving diagnostic accuracy for non-amnestic atAD in clinical settings using only clinical testing battery and MRI.},
}

@article {pmid41647067,
year = {2025},
author = {Totlani, J and Bashir, MA and Tay, L and Ngor, A and Steiner, AJ and Hirsch, D and Contreras, L and Renteria, S and Danovitch, I and Pechnick, RN and Ishak, WW and Kim, S},
title = {Neurocognitive Disorders: Systematic Review of Approved (2008-2024) and Pipeline Phase III Medications.},
journal = {Innovations in clinical neuroscience},
volume = {22},
number = {10-12},
pages = {57-71},
pmid = {41647067},
issn = {2158-8333},
abstract = {OBJECTIVE: Neurocognitive disorders (NCDs), which include delirium, major and mild NCDs such as Alzheimer's disease (AD), and other forms of dementia, constitute a significant and growing public health burden, affecting tens of millions of individuals worldwide. This systematic review aims to examine the medications approved by the United States Food and Drug Administration (FDA) for NCDs from 2008 to 2024, as well as those in the pipeline in Phase III, and to describe the mechanism of action, clinical indications, dosing, evidence for efficacy, and adverse effects.

METHODS: We searched the literature using the PubMed database for studies published from January 1, 2008, to December 31, 2024, focusing on FDA-approved psychiatric medications and Phase III pipeline medications, using the keywords "neurocognitive" OR "dementia" OR "Alzheimer*" AND "psychopharm*" OR "medic*" OR "pharm*." Two reviewers performed an independent assessment of the resulting publications and reached a consensus on the eligible studies to include in the systematic review.

RESULTS: From 2008 to 2024, the FDA approved eight medications for major and mild NCDs, including monoclonal antibodies, acetylcholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, and an atypical antipsychotic. Additionally, we identified 22 pipeline medications currently in Phase III clinical trials for NCDs as of December 31, 2024, including biologics and neuroprotective agents, among others. No medications for delirium were FDA-approved or in Phase III, although agents for a variety of encephalopathies have been developed.

CONCLUSION: Significant advancements in the pharmacological management of NCDs have been made during this period, including developing disease-modifying therapies for AD. However, available medications primarily provide symptomatic relief, and challenges persist in the implementation of disease-modifying treatments due to adverse effects and high costs of care. The pipeline of Phase III clinical trials includes many emerging agents with novel mechanisms of action, and ongoing trials will prove essential to confirm the efficacy and safety of these therapies.},
}

@article {pmid41647032,
year = {2025},
author = {Hou, X and Wei, Y and Wang, Y and Wang, L},
title = {Mendelian randomization studies on the causal relationship between insomnia and disease.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1709983},
pmid = {41647032},
issn = {2296-858X},
abstract = {Insomnia, a prevalent sleep disorder, poses significant threats to both physical and mental health. Traditional studies suggest multiple factors are associated with insomnia, yet the causal direction often remains unclear and susceptible to confounding biases. Mendelian randomization, a cutting-edge method leveraging genetic instrumental variables for causal inference, effectively overcomes these limitations by providing high-quality evidence to clarify causal relationships between insomnia and various diseases. This review systematically integrates 105 recent Mendelian randomization studies on insomnia. Evidence indicates that insomnia exerts clear causal effects on multiple diseases, though the strength of these associations and the robustness of evidence vary by disease type. Insomnia is a robust risk factor for coronary heart disease, anxiety-depressive disorders, type 2 diabetes, and chronic pain. Causal relationships with osteoarthritis and lung cancer are also supported, though effect sizes are relatively small. Conversely, associations with Alzheimer's disease and schizophrenia remain unconfirmed. The studies establish a dominant causal direction from "insomnia → disease," effectively correcting potential reverse causality bias in observational research. These findings reposition insomnia from a common symptom to a key modifiable cause of a range of psychosomatic disorders. Causal inferences grounded in genetic evidence provide a robust scientific foundation for early identification of high-risk populations, precision prevention targeting insomnia, and cross-system comorbid management.},
}

@article {pmid41646826,
year = {2026},
author = {Cholerton, B and Godrich, D and Pasteris, J and Rivero, J and Martin, ER and Kunkle, BW and Naj, AC and Hamilton-Nelson, KL and Wang, H and Lee, WP and Dumitrescu, L and Hohman, TJ and Mayeux, R and Larson, EB and Crane, PK and Keene, CD and Latimer, CS and Mukherjee, S and Kofler, JK and Kamboh, MI and Bennett, DA and Molina-Porcel, L and Cuccaro, M and Pericak-Vance, MA and Rundek, T and Scott, WK and Kukull, W and Schellenberg, G and , and Beecham, GW and Montine, TJ},
title = {Genome wide association study meta-analysis of neuropathologic lesions of Alzheimer's disease and related dementias in a multi-site autopsy cohort.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.22.26344634},
pmid = {41646826},
abstract = {UNLABELLED: Understanding the genetic foundations of dementia is critical to unraveling its complex molecular basis. Given that a clinical diagnosis of Alzheimer's disease (AD) dementia often results from interplay between multiple underlying neuropathologic co-morbidities, previous genome-wide association studies (GWAS) of clinically diagnosed AD are restricted in their ability to translate genetic associations to potential targeted therapeutics. The current study seeks to address these limitations by presenting the largest GWAS to date (n=12,509) of neuropathologic hallmarks of AD and AD related dementias (ADRDs). We further performed a candidate-variant analysis using loci previously identified in GWAS of clinically diagnosed AD dementia and Parkinson's disease (PD). Finally, we conducted heritability and genetic correlation analyses using linkage disequilibrium (LD) score regression. We found broad genome-wide significant associations with APOE across AD and ADRDs but not cerebrovascular disease and vascular brain injury. We further identified 12 significant loci across 10 neuropathologic phenotypes, including 5 loci previously implicated in GWAS of clinical AD and ADRDs (variants on BIN1, PICALM / EED, TMEM106B, GRN, and SNCA / SNCA-AS1) and 7 novel genome-wide associations (variants on EPHA5, PSMG1, LINC00276, VAPA, LINC00290, DOCK4 and SLAIN2 / SLC10A4). Our analysis of AD and PD clinical candidate variants demonstrated several that were associated with AD neuropathologic change and Lewy body disease, as well as substantial overlap with neuropathologic lesions other than the primary neuropathologic hallmarks of these diseases. Heritability analyses demonstrated heritability that was high for amyloid plaques (78%) relative to prior clinical AD heritability analyses, intermediate for TDP-43 inclusions (41%), and low for remaining AD and ADRD pathologic features. This study underscores the importance of investigating the underlying neuropathologic hallmarks of AD and ADRDs as a step toward refining the translation of genetic associations to biomarker interpretation and development of targeted therapeutics.

AUTHOR SUMMARY: Clinically diagnosed Alzheimer's disease (AD) dementia is commonly associated with its hallmark pathologic changes plus neuropathologic features of prevalent co-morbid diseases such as cerebrovascular disease, Lewy body disease, and more recently discovered abnormalities in protein called TDP-43 (collectively, AD related dementias; ADRD). As a result, previous studies that associated clinical diagnosis of AD with specific genes may not tell us the whole story. For this study, we gathered autopsy and genetic data to identify relationships between genes and dementia-associated brain changes. We found some relationships between these diseases and genes that had been previously identified as contributing to clinical dementia, as well as some new relationships that had been previously unknown. We also found that some genes that had previously been identified in relation to AD were associated with different dementia-associated brain lesions. Finally, we found that the various brain lesions differ in the proportion that can be attributed to genetic vs. environmental differences. These results support that the pathway to a diagnosis of dementia can be caused by multiple factors and are an important step in beginning to identify individually based dementia treatments.},
}

@article {pmid41646789,
year = {2026},
author = {Dadgostar, M and Hanford, LC and Tavakoli, M and Arnold, SE and Salat, DH and Sitnikova, T and Webb, PK and Green, JR and Liu, H and Richburg, BD and Tkeshelashvili, M and Eshghi, M},
title = {Detecting Preclinical Alzheimer's Disease Risk in Cognitively Normal Adults Using Speech Acoustics: Validation with Plasma p-Tau217 and APOE-ε4 Status.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.15.26344226},
pmid = {41646789},
abstract = {INTRODUCTION: We tested whether spontaneous speech acoustics provide a scalable digital marker of biologically defined Alzheimer's disease (AD) risk.

METHODS: Forty-nine cognitively unimpaired older adults were stratified within APOE genotype into Low-, Moderate-, and High-Risk groups based on log₁₀-transformed plasma p-tau217. Acoustic features were extracted from spontaneous speech and entered into multiclass SVM classifiers with leave-one-out cross-validation, with and without genetic-algorithm feature selection and age. Parallel models using neuropsychological measures were evaluated for comparison. Feature contributions were interpreted using SHAP.

RESULTS: Speech-based models substantially outperformed cognition-only models and exceeded chance performance for three-group classification (33.3%), achieving up to 77% accuracy compared with 47% for neuropsychological models. SHAP analyses identified a compact, stage-dependent acoustic signature dominated by voice-quality, spectral-envelope, and formant-bandwidth features, with age contributing secondary effects.

DISCUSSION: Spontaneous speech acoustics capture p-tau217/APOE-defined AD risk despite preserved cognition, supporting speech as a scalable, biologically grounded biomarker for preclinical AD risk stratification.},
}

@article {pmid41646778,
year = {2026},
author = {Walker, E and Rodríguez-Carmona, Y and Wang, X and Mukherjee, B and Arboleda-Merino, L and Hao, W and Dodge, H and Albin, RL and Paulson, HL and Park, SK and Bakulski, KM},
title = {Cadmium Exposure and Incidence of All-Cause Dementia and Alzheimer's Disease in US Adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.16.26344271},
pmid = {41646778},
abstract = {INTRODUCTION: While longitudinal studies aid in understanding and preventing long-latency disorders like dementia, evidence for cadmium's role in these conditions is still limited. We evaluated associations between cadmium exposure and incident Alzheimer's disease (AD) and all-cause dementia in US adults.

METHODS: National Health and Nutrition Examination Survey (NHANES) III (1988-1994) and continuous NHANES (1999-2016) data were linked with Medicare claims to identify incident AD and dementia cases through 2018. Urinary and/or blood cadmium were measured during NHANES. We used covariate-adjusted, survey-weighted Cox proportional hazard models to evaluate the associations between cadmium exposure biomarkers and AD/dementia over follow-up.

RESULTS: In NHANES III (N=6,122), baseline age was 53.9±0.5 years and urinary cadmium was 0.8±0.02 ug/L. Over a follow-up of 20.4±0.3 years, 743 AD and 1,508 all-cause dementia cases occurred. Urinary cadmium was not associated with AD (HR: 1.01, 95% CI: 0.9-1.0) nor all-cause dementia incidence (HR: 1.02, 95% CI: 0.96-1.08). In continuous NHANES (urinary cadmium N=2,833; blood cadmium N=8,038), baseline age was 64.1±0.2 years, urinary cadmium was 0.5±0.03 ug/L, and blood cadmium was 0.6±0.01 ug/L. Over 9.5±0.1 years, 587 AD and 1,260 all-cause dementia cases occurred. Urinary and blood cadmium showed no associations with AD (HR [95% CI]: 1.09 [0.9, 1.4]; 1.06 [0.9, 1.2]) nor all-cause dementia (HR [95% CI]: 1.07 [0.9, 1.3]; 1.06 [0.95, 1.2]).

CONCLUSION: No association between cadmium exposure and dementia incidence was observed. Our null findings should be interpreted while considering potential methodological issues and verified by subsequent studies.},
}

@article {pmid41646775,
year = {2026},
author = {Rose, CM and Liu, S and Bush, WS and Haines, JL and Williams, SM and Crawford, DC},
title = {Opposing effects of SARS-CoV-2/COVID-19 infection and recombinant zoster vaccination on the risk of late-onset Alzheimer disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.21.26344555},
pmid = {41646775},
abstract = {IMPORTANCE: More than half a decade since the emergence of SAR-CoV-2, its broader sequelae are still poorly understood. Initial data indicate viral infections such as SARS-CoV-2 and herpes zoster negatively impact cognition, but studies examining their independent or synergistic impact on late-onset Alzheimer disease (LOAD) risk among older adults are lacking.

OBJECTIVE: To test the hypothesis that SARS-CoV-2/COVID-19 infection and recombinant zoster vaccination are independently associated with higher and lower risk of LOAD, respectively, among older (≥65 years of age) individuals.

A retrospective cohort of 1,480,535 patients from the US National Clinical Cohort Collaborative (N3C) COVID-19 Enclave with no diagnosis of LOAD on January 20, 2020. The follow-up period ended May 16, 2025.

EXPOSURE: Recorded SARS-CoV-2 infection/COVID-19 and recombinant zoster (Shingrix) vaccination.

MAIN OUTCOMES AND MEASURES: Late-onset Alzheimer disease incidence within the five-year follow-up period.

RESULTS: Cox proportional hazard models adjusted for age at baseline, sex, and race found that COVID-19 infection was associated with a 12% increased hazard of LOAD (HR=1.12, 95% CI: 1.09-1.15, p<0.0001). Having a Shingrix vaccine did not significantly change the hazard estimate of LOAD (HR=1.13, 95% CI: 1.10-1.16, p<0.0001). Recombinant zoster vaccination was associated with reduced hazard of LOAD in both COVID-19-absent and COVID-19-positive individuals, though the protective effect was attenuated among those with COVID-19 infection. Specifically, among individuals without documented COVID-19 infection, adjusted for age at baseline, sex, and race, Shingrix vaccination was associated with a 37% reduced hazard of LOAD (HR=0.63, 95% CI: 0.60-0.65, p<0.0001), while among COVID-19 patients, the reduction was 23% (HR=0.77, 95% CI: 0.73-0.81, p<0.0001), suggesting a significant interaction between COVID-19 infection and vaccination status on LOAD risk.

CONCLUSIONS AND RELEVANCE: SARS-CoV-2/COVID-19 infection and recombinant zoster vaccination are modifiable risk factors for LOAD among older individuals, with a modestly significant interaction between the two. Recombinant zoster vaccination reduced LOAD risk regardless of sex and race, though the protection is greater in those without documented COVID-19 infection. Recombinant zoster vaccination and reduced exposure to COVID-19 infection in the later decades of life reduce the risk of developing Alzheimer disease over at least a five-year period.

QUESTION: Is SARS-CoV-2/COVID-19 infection among older individuals associated with late-onset Alzheimer disease (LOAD), and is this risk modified by recombinant zoster vaccination?

FINDINGS: Retrospective cohort analysis of older individuals (age ≥65 between January 20, 2020 and May 16, 2025; n∼1.5 million) indicates that those with ≥1 reported COVID-19 infection were at increased LOAD risk compared with those with no reported infection. Recombinant zoster vaccinated patients had decreased LOAD risk, and among those with a COVID-19 infection, the vaccination mitigated the elevated LOAD risk.

MEANING: Recombinant zoster vaccination reduces LOAD risk among older individuals and mitigates the COVID-19-associated LOAD risk.},
}

@article {pmid41646765,
year = {2026},
author = {Chiotis, K and Blazhenets, G and Soleimani-Meigooni, DN and Aisen, PS and Amuiri, A and Atri, A and Beckett, L and Brickhouse, M and Clark, DG and Dage, JL and Day, GS and Duara, R and Eloyan, A and Foroud, T and Graff-Radford, NR and Grant, IM and Hammers, DB and Honig, LS and Johnson, ECB and Jones, DT and Kirby, K and Koeppe, R and Kramer, JH and Kukull, WA and Lagarde, J and Leuzy, A and Maiti, P and Masdeu, JC and Mendez, MF and Musiek, E and Nudelman, KN and Onyike, CU and Riddle, M and Rocha, S and Rogalski, E and Salloway, S and Schonhaut, DR and Sha, S and Shankar, R and Taurone, A and Thangarajah, M and Toga, AW and Touroutoglou, A and Turner, RS and Vemuri, P and Wingo, TS and Wolk, DA and Womack, K and Zhang, J and Carrillo, MC and Dickerson, BC and Apostolova, LG and La Joie, R and Rabinovici, GD and , },
title = {Distinct Tau PET Dynamics in Early vs. Late Age-of-Onset Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.25.26344738},
pmid = {41646765},
abstract = {UNLABELLED: Early-onset Alzheimer's disease (EOAD) and Late-onset AD (LOAD) differ in clinical presentations and rates of progression. We aimed to compare baseline and longitudinal tau PET burden, and their relationship with clinical variables in amyloid-PET positive, cognitively impaired participants from the Longitudinal Early-Onset Alzheimer's Disease Study (EOAD; n=390) and Alzheimer's Disease Neuroimaging Initiative (LOAD; n=211). Patients with EOAD showed higher baseline tau PET retention, broader neuroanatomical involvement and faster accumulation rates over time compared to LOAD, after adjusting for amyloid load and clinical stage. Tau PET showed stronger correlations with baseline amyloid burden and clinical measures of global cognition and function in EOAD than LOAD. We conclude that earlier age of onset in AD is linked to a more aggressive tauopathy, which in turn is a primary driver of clinical decline. These findings suggest that optimal therapeutic targets and strategies may differ between EOAD and LOAD.

ONE SENTENCE SUMMARY: Younger patients with Alzheimer's disease show more aggressive tau spread, suggesting age of onset defines distinct disease pathways with key clinical implications.},
}

@article {pmid41646760,
year = {2026},
author = {Okorie, M and Jiang, X and Yaffe, K and Yokoyama, JS and Andrews, SJ and , },
title = {Associations of dementia polyexposure scores to Alzheimer's disease endophenotypes in diverse populations.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.10.26343864},
pmid = {41646760},
abstract = {INTRODUCTION: Dementia clinical risk scores (CRS) provide accessible tools for identifying individuals at risk for Alzheimer's disease (AD), yet their performance across diverse populations and relationships to AD endophenotypes remains unclear.

METHODS: We evaluated four CRS, mCAIDE, WHICAP, LIBRA, and CogDRisk, in relation to cognitive impairment diagnoses and endophenotypes for AD, including plasma biomarkers, neuroimaging measures, and cognitive composite scores. Logistic and linear regression models stratified by self-reported race/ethnicity were used to assess the associations of CRS with diagnosis and their predictive performance, and associations with endophenotypes.

RESULTS: Higher CRS were consistently associated with increased odds of dementia across all races/ethnicities. CogDRisk showed the strongest and most consistent performance across diagnostic and endophenotypic outcomes. The other three CRS performed similarly, with mCAIDE performing the worst and lacking associations with plasma biomarkers.

CONCLUSIONS: CRS capture AD-related risk across diverse populations and modestly reflect underlying biological endophenotypes, supporting their utility in community-based risk assessment.},
}

@article {pmid41646759,
year = {2026},
author = {Lang, YR and Vrillon, A and Pasternak, S and Blazhenets, G and Soleimani-Meigooni, D and Ravinovici, GD and Weiner, MW and Hantke, N and Silbert, L and Schwartz, DL and Ezer, AL and Segev, OL and Ganmore, I and Ravona-Springer, R and Yaffe, K and Landau, SM and Korecka, M and Shaw, LM and Joie, R and Gardner, RC},
title = {Effect of prior traumatic brain injury on Alzheimer's disease blood biomarkers in Vietnam Veterans.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.13.26344009},
pmid = {41646759},
abstract = {IMPORTANCE: Traumatic brain injury (TBI) is a risk factor for dementia and is known to impact levels of several Alzheimer's disease (AD) blood biomarkers. Plasma pTau217/ Aβ42 ratio has been reported to be 90% accurate for detection of brain amyloid in civilian cohorts.

OBJECTIVE: To evaluate the accuracy of emerging AD blood biomarkers in Veterans with and without TBI history.

DESIGN: We assessed the performance of the FDA-approved plasma pTau217/Aβ42 ratio and plasma levels of pTau217 and Aβ42/40 ratio for detecting brain amyloid-β positivity (e.g., amyloid-PET consensus visual read). We compared biomarkers' accuracy in Veterans with no TBI (N=93), TBI with loss of consciousness (LOC) 0-5 minutes (N=89), and TBI with LOC >5 minutes (N=90).

SETTING: Cross-sectional cohort study using existing data and banked plasma from the Alzheimer's Disease Neuroimaging Initiative Department of Defense (ADNI-DOD) study.

PARTICIPANTS: 272 older Vietnam Veterans without dementia (83% cognitively unimpaired, 17% mild cognitive impairment), median (IQR) age 69 (67,72) years, 270/272 male, who had amyloid-PET and concurrently collected banked plasma available for analysis.

RESULTS: Amyloid-PET positivity prevalence was 30.5%. Plasma pTau217/Aβ42 ratio was highly accurate (90%) in Veterans with no TBI, but not in Veterans with TBI with LOC 0-5 minutes (78% accuracy, P =0.027 vs no TBI) nor in Veterans with TBI with LOC>5 minutes (63% accuracy, P <0.001 vs no TBI). Results were similar for plasma pTau217 alone and plasma Aβ42/40 ratio. Results were also similar after excluding Veterans with TBI within the past 10 years, or when amyloid-PET positivity was defined using a quantitative threshold rather than consensus visual read.

DISCUSSION: Prior TBI is a modifier of AD biomarkers accuracy in prediction of brain amyloid-PET positivity. Caution is advised in interpreting AD blood test results in this context. Further research is warranted to refine precision AD diagnosis in Veterans and civilians with TBI history.

QUESTION: What is the accuracy of the plasma pTau217/Aβ42 ratio test for detecting amyloid-PET positivity for Alzheimer's disease (AD) diagnosis in older Veterans with and without a history of traumatic brain injury (TBI)?

FINDINGS: In this cross-sectional study (n=272), plasma pTau217/Aβ42 ratio test accuracy was 90% in Veterans without TBI history, but was significantly lower (63-78% accuracy) in Veterans with TBI history, with lowest accuracy in those with greater TBI severity.

MEANING: TBI history and severity is a modifier of AD blood test accuracy in prediction of brain amyloid-PET positivity.AD blood tests should be interpreted with caution in Veterans and civilians with TBI history.},
}

@article {pmid41646752,
year = {2026},
author = {Kuhn, E and Kleinedam, L and Stark, M and Peters, O and Hellmann-Regen, J and Preis, L and Gref, D and Priller, J and Jakob Spruth, E and Gemenetzi, M and Schneider, A and Fliessbach, K and Wiltfang, J and Bartels, C and Hansen, N and Rostamzadeh, A and Düzel, E and Glanz, W and Incesoy, E and Buerger, K and Janowitz, D and Stöcklein, S and Perneczky, R and Rauchmann, BS and Teipel, SJ and Kilimann, I and Laske, C and Sodenkamp, S and Spottke, A and Kronmüller, M and Roeske, S and Brosseron, F and Ramirez, A and Synofzik, M and Schmid, MC and Jessen, F and Wagner, M and , and , },
title = {Subjective cognition trajectories, Alzheimer biomarkers, and incident mild cognitive impairment.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.27.26344715},
pmid = {41646752},
abstract = {BACKGROUND: Subjective cognitive decline (SCD) is common in older adults and may precede mild cognitive impairment (MCI). Whether longitudinal changes in self- or study partner (SP)-reported SCD improve early identification of individuals at risk for clinical progression, particularly along the Alzheimer's disease (AD) biological continuum, remains unclear.

METHODS: We pooled data from two longitudinal observational cohorts (DELCODE and ADNI). Cognitively unimpaired (CU) participants were recruited through public advertisement or memory clinics and included if baseline amyloid status, ≥2 SCD assessments, and clinical follow-up were available. SCD was assessed using the Everyday Cognition questionnaire (self- and SP-report). Linear mixed-effects models examined longitudinal associations between SCD trajectories, baseline AD biomarkers, and progression to incident MCI. Multivariable Cox proportional hazards models tested whether one-year changes in SCD predicted subsequent progression.

FINDINGS: Among 770 participants (median age 69·9years [IQR 66·0-74·6]; 52·6% women; median follow-up 5·0years [4·0-7·0]), amyloid-positive individuals and those who progressed to MCI showed steeper longitudinal increases in both SCD reports. In amyloid-positive participants, only increases in SP-reported SCD differentiated progressors from non-progressors. One-year increases in SP-reported SCD predicted a higher risk of subsequent MCI compared with unchanged scores (hazard ratio 3·24 [95%CI 1·73-6·07]), with effects confined to amyloid-positive participants.

INTERPRETATION: Longitudinal increases in SP-reported cognitive difficulties, particularly over short intervals, are associated with near-term progression to MCI in amyloid-positive CU older adults. SP-based longitudinal monitoring may represent a low-burden approach to support earlier clinical surveillance in aging populations.

FUNDING: German Center for Neurodegenerative Diseases, US National Institutes of Health.},
}

@article {pmid41646748,
year = {2026},
author = {Luo, J and Wu, H and Du, W and , and Liu, G},
title = {Nonlinear dynamic genetic regulation identifies peripheral drivers of neurodegenerative disease progression.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.29.26345161},
pmid = {41646748},
abstract = {The dynamic genetic regulation of gene expression during the progression of common neurodegenerative diseases (NDDs) remains poorly characterized, obscuring the genetic architecture of longitudinal clinical traits. Here, we present 2sGen-GPS, a two-stage genetic Granger temporal causality framework designed to integrate genetic variants, intermediate longitudinal molecular traits, and disease progression phenotypes. In the discovery stage, we utilized multivariate polynomial temporal genetic association (MPTGA) analysis of peripheral blood to identify 774,533 time-dependent cis-eQTLs (11,936 eGenes), enabling the imputation of individual-level longitudinal expression trajectories. In the second stage, these imputed profiles were linked to NDD phenotypes to infer temporal causal relationships. Applying 2sGen-GPS to Parkinson's disease multi-omics cohorts, we identified a peripheral-to-central regulatory axis; specifically, the rs11241912-driven temporal expression of C5orf63 exhibits a lagged causal association with cerebrospinal fluid LRP1 levels and motor symptom progression. Cross-regional single-cell analysis further revealed that rs11241912 carriers harbor a localized compensatory signature in excitatory neurons of the globus pallidus interna, characterized by the up-regulation of dopamine receptor signaling pathways. Extending 2sGen-GPS to Alzheimer's disease, we identified 328 genes linked to cognitive decline and prioritized drug compounds capable of reversing these expression signatures. Our study elucidates how dynamic genetic effects shape the trajectories of NDD-related traits and nominates peripherally accessible, causal genes as promising therapeutic targets for modulating disease progression.},
}

@article {pmid41646738,
year = {2026},
author = {Khani, M and Yeboah, SN and Cerquera-Cleves, C and Kedmi, A and Bustos, BI and Grant, SM and Akerman, SC and Akçimen, F and Lee, PS and Reyes-Pérez, P and Lange, LM and Leonard, H and Koretsky, MJ and Makarious, MB and Schneider, Z and Jonson, C and Chen, PS and Tay, YW and Rothstein, JD and Lin, CH and Lim, SY and Klein, C and Merchant, K and Mencacci, NE and Krainc, D and Cookson, MR and , and Singleton, A and Bandres-Ciga, S},
title = {Is SORL1 a common genetic target across neurodegenerative diseases?: A multi-ancestry biobank scale assessment.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.24.26344530},
pmid = {41646738},
abstract = {SORL1, the gene encoding the SORLA protein, has arisen as a potential therapeutic target for Alzheimer's disease (AD). Studies suggest that restoring SORLA function or its trafficking pathways, particularly the SORLA-retromer recycling system, may offer a promising strategy to slow or halt AD progression. While both rare and common SORL1 variants have been associated with increased AD risk, recent evidence suggests a potential involvement of SORL1 in other neurodegenerative conditions. This study assessed the contribution of SORL1 genetic variation to the risk of AD, related dementias (RD), and Parkinson's disease (PD) using data from six large-scale biobanks, comprising 15,043 AD, 9,943 RD, and 42,763 PD cases, along with 111,969 controls across 11 ancestries. We identified 53 potentially disease-related SORL1 variants (CADD score > 20, MAC ≥ 2, annotated as protein-altering or splicing, and with the mutated allele present only in cases), including 41 novel and 12 previously reported variants. Three were found across multiple ancestries. Overall, 13 variants were found in AD-related cohorts, 5 in RD cohorts, and 35 in PD cohorts. Association analysis identified 10 nominally significant variants associated with AD and 5 with PD. The replication of multiple SORL1 variants across neurodegenerative diseases and ancestrally diverse populations underscores its potential broad genetic contribution to neurodegeneration and reinforces its relevance across distinct clinical phenotypes. Gene-based burden analysis did not reveal any significant cumulative effect of SORL1 variants in the populations tested. A family-based analysis identified a rare predicted-damaging variant in two East Asian families (11:121478242:G:A, p.R176Q) and two variants in two families of European ancestry (11:121514222:A:C, p.N371T; 11:121545392:G:A, p.V672M) that show some evidence of segregation in PD families. Although these variants were slightly more frequent in unrelated PD cases vs. controls, none of them showed statistically significant enrichment in PD, likely due to their very low frequency. Overall, our results extend the understanding of SORL1 beyond AD, suggesting a broader role in neurodegeneration and emphasizing the need for diverse population studies when evaluating genetic risk.},
}

@article {pmid41646721,
year = {2026},
author = {Cruz, LA and Liu, S and Miskimen, KL and Cooke Bailey, JN and Kinzy, T and Song, YE and Laux, RA and Miron, P and Ogrocki, PK and Lerner, AJ and Lynn, A and Fuzzell, SL and Hochstetler, SD and Konidari, I and McCauley, JL and Scott, WK and Pericak-Vance, MA and Haines, JL and Crawford, DC},
title = {Evidence for reduced somatic T-cell receptor sequence diversity profiles among Midwestern Amish in an aging cohort study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.25.26344754},
pmid = {41646721},
abstract = {Late-onset Alzheimer disease (LOAD), the most common form of dementia among older adults, is a neurodegenerative disease characterized by brain amyloid-β (Aβ) plaque deposition and neurofibrillary tangles. The causes of LOAD are not known but several recent lines of evidence implicate the adaptive immune system. Here, we sought to characterize somatic T-cell receptor (TCR) sequence diversity profiles and class I and II human leukocyte antigen (HLA) alleles from DNA extracted from peripheral tissues from Midwestern Amish participating in longitudinal studies of aging. We immunosequenced the TCR beta chain from genomic DNA of 72 Midwestern Amish, including participants with clinically diagnosed LOAD (n=6), mild cognitive impairment (MCI; n=16), cognitive impairment but not AD (CINAD; n=3), and 35 cognitively unaffected. TCR sequence diversity by cognitive status was examined using a variety of metrics, and tests of association were performed between cognitive status and HLA alleles. For a subset of participants, plasma biomarkers for LOAD pathogenesis were available to evaluate TCR sequence diversity by cognitive status. TCR sequence diversity measured as Simpson's clonality was lower among LOAD+MCI compared with non-LOAD, but these differences were not independent of age. Relatively few clonotypes (exact nucleotide sequences) were shared across participants; of those few shared include the Epstein Barr virus associated clonotype. HLA-A*03:01 and several HLA-DRB1 alleles were under-represented among LOAD+MCI participants compared with cognitively unaffected participants, but these associations were no longer significant in adjusted analyses. Among LOAD+MCI participants with plasma biomarkers, increased p-tau181 was associated decreased TCR sequence diversity, and the association was independent of age. In this limited Midwestern Amish sample, the observed TCR diversity associations are consistent with the involvement of the adaptive immune system in LOAD.},
}

@article {pmid41646720,
year = {2026},
author = {Mukesha, D and Firat, H and Sacco, G},
title = {Integrating large-scale serum metabolomics and APOE ε4 genotype status for the non-invasive detection of Alzheimer's disease in the ADNI cohort.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.29.25343146},
pmid = {41646720},
abstract = {INTRODUCTION: Accurate Alzheimer's disease (AD) detection remains challenging and often requires invasive or costly procedures. Blood-based metabolomic signatures offer a promising non-invasive approach. This study aimed to identify a serum metabolite panel and evaluate its performance alone and in combination with apolipoprotein E (APOE) ε4 genotype status for distinguishing AD from cognitively normal (CN) individuals.

METHODS: Baseline data from 594 participants in the Alzheimer's Disease Neuroimaging Initiative (237 AD, 357 CN) were analyzed. High-resolution serum metabolomics (Biocrates MxP® Quant 500) and APOE genotype data were used for LASSO-based feature selection, followed by machine learning model training and evaluation on a held-out test set.

RESULTS: A panel of 151 metabolites distinguished AD from CN with high accuracy (test-set AUC=0.90). Adding APOE to the panel further improved model performance (AUC=0.91 versus AUC=0.75 for APOE alone; p <0.001), achieving strong sensitivity (0.92), specificity (0.84), and negative predictive value (0.94). Key predictive metabolites included bile acids, ether-linked phosphatidylcholines, and acylcarnitines, which are associated with pathways related to lipid metabolism, mitochondrial function, and the gut-liver-brain axis.

CONCLUSION: Integrating serum metabolomics with APOE enables accurate, non-invasive AD detection and offers a scalable screening approach with strong potential to rule out AD in primary care.

CLINICALTRIALSGOV IDENTIFIER: NCT00106899 and related ADNI phases.},
}

@article {pmid41646718,
year = {2026},
author = {Weckstein, AR and Carr, S and Wang, P and Krüger, N and Danaei, G and Schneeweiss, S and Desai, RJ},
title = {Lithium therapy and delayed progression of Alzheimer's disease and related dementias in patients with bipolar disorder and mild neurocognitive disorders.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.12.26343472},
pmid = {41646718},
abstract = {Recent mechanistic evidence identifies lithium deficiency as a driver of Alzheimer's disease and related dementias (ADRD) pathogenesis. To evaluate this hypothesis in a population-based setting, we emulated a target trial comparing ADRD progression after initiation of lithium versus antiepileptic mood stabilizers among adults ≥55 years with bipolar disorder and mild neurocognitive disorder, using US Medicare claims with replication in two commercial databases. Lithium initiation was associated with a lower 5-year risk of progression to advanced ADRD (risk ratio 0.87; 95% CI 0.78-0.99) and long-term care stay with ADRD (0.75; 0.56-0.97). Lower risks were most pronounced in patients with later stages of mild cognitive impairment. Results were consistent across sensitivity analyses and replications. Validations using linked cognitive assessments from standardized instruments strengthened confidence in findings. While results may be susceptible to residual bias, this study supports investigating lithium's potential to delay ADRD progression with randomized trials of optimized lithium formulations.},
}

@article {pmid41646703,
year = {2026},
author = {Walker, CS and Barnoin, G and Bennett, M and Tremblay-Mercier, J and Villeneuve, S and Nathan Spreng, R and Poirier, J and Morris, LS and , and Geddes, MR},
title = {The neural basis of prosocial effort-based decision making in older adults at risk for Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.10.26343857},
pmid = {41646703},
abstract = {BACKGROUND: Alzheimer's disease is associated with impairments in decision making that undermine autonomy, health behaviors, and quality of life. Effort-based decision making, the process of weighing reward value against effort costs, is particularly disrupted in aging and Alzheimer's disease. However, aging is also characterized by a shift toward socioemotional and prosocial goals, which may preserve motivation and effortful behavior. Understanding prosocial effort-based decision making and its neural substrates in individuals at risk for AD may reveal early alterations in decision making and neural circuits that support healthy aging.

METHODS: Fifty-two older adults from the PREVENT-AD cohort (mean age = 68.48, 38 females, 18 APOE4 carriers) completed an effort-based decision-making task comparing monetary rewards obtained for oneself or for charity. Decision response (accept/reject), response time, and vigor were analyzed using mixed-effects models controlling for demographic and clinical covariates. Reward-effort relationships were modeled using various functions and compared using Bayesian model comparison. Seed-to-voxel resting-state functional connectivity from the ventromedial prefrontal cortex and anterior cingulate gyrus examined neural substrates of prosocial effort-based decision making, and ROI-to-ROI connectivity within the frontostriatal reward network was compared between APOE4 carriers and non-carriers.

RESULTS: Participants were more likely to accept effort for prosocial compared to self-oriented rewards. The relationship between reward and effort in both conditions was best captured by a sigmoid function, with higher bias away from effort expenditure for self-oriented compared to prosocial rewards. Across all participants, lower bias away from effort expenditure for prosocial compared to self-oriented rewards was associated with vmPFC and ACCg resting-state functional connectivity to frontal, temporal, and parietal regions. APOE4 carriers showed greater overall bias away from effort expenditure but higher vigor for prosocial than self-oriented rewards, along with reduced nucleus accumbens-dorsal anterior cingulate connectivity that was associated with bias away from effort.

CONCLUSIONS: Prosocial incentives may be an effective strategy for motivating effortful behavior in older adults at risk for Alzheimer's disease. Although APOE4 carriers show greater aversion to initiating effort, they exhibit heightened vigor when working for prosocial compared to self-oriented rewards. Leveraging prosocial motivation and its underlying neural circuitry may therefore represent a promising strategy to sustain goal-directed behavior and decision making, promote physical and cognitive activity, and support emotional and brain health in aging.},
}

@article {pmid41646682,
year = {2026},
author = {McEvoy, LK and Zhang, B and Nguyen, S and Maihofer, AX and Nievergelt, CM and Ramon, C and Horvath, S and Lu, AT and Davatzikos, C and Erus, G and Resnick, SM and Espeland, MA and Rapp, SR and Beckman, K and Ferrucci, L and LaCroix, AZ and Shadyab, AH},
title = {Association of epigenetic age acceleration with MRI biomarkers of aging and Alzheimer's disease neurodegeneration.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.23.26344650},
pmid = {41646682},
abstract = {Epigenetic clocks of biological aging have been associated with cognitive impairment and dementia. Less is known about whether they are associated with an older-appearing brain or with an atrophy pattern associated with dementia. We examined associations of five epigenetic clocks measured at baseline with the Spatial Pattern of Atrophy for Recognition of Brain Aging (SPARE-BA) and the Alzheimer's Disease Pattern Similarity Score (AD-PS) derived from structural MRIs obtained an average of 8 years later among 1,196 older women. Using linear regression models adjusting for relevant covariates, we observed no associations between any epigenetic clock and accelerated brain aging based on SPARE-BA. We observed a significant association between AgeAccelGrim2 and AD-PS (β = 0.015; 95% CI 0.004 to 0.027; p = 0.01). This association appeared to be primarily driven by the association of a DNA methylation marker of smoking pack years with frontal and temporal lobe volumes. AgeAccelGrim2 was not associated with volumes in regions implicated in early AD (hippocampus and entorhinal cortex). Taken together with prior findings, these results suggest that measures of epigenetic and brain age acceleration capture different aspects of biological aging, and that AgeAccelGrim2 is predictive of neurodegenerative changes associated with smoking that increase risk of dementia.},
}

@article {pmid41646663,
year = {2026},
author = {Miller, MI and Xie, Y and Stouffer, KM and Ceritoglu, C and Li, J and Ratnanather, JT and Younes, L and Bakker, A and Rani, N and Albert, MS and Troncoso, JC and Morris, M and , },
title = {Rostral Associations of MRI Atrophy of the Amygdala and Entorhinal Cortex Across the AD Spectrum.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.27.26344987},
pmid = {41646663},
abstract = {UNLABELLED: This paper examines associations of atrophy in the amygdala, entorhinal cortex and hippocampus based on magnetic resonance imaging (MRI) and Positron Emission Tomography (PET) scans from two independent cohorts: Alzheimer's Disease Neuroimaging Initiative (ADNI) and Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD) study. The amygdala and entorhinal cortex (ERC) are shown to change earlier in the disease than the hippocampus based on atrophy of laminar thickness of the ERC and amygdala volumes. Over four hundred laminar reconstructions showed that ERC volume loss is linked to cortical thinning, as a more specific measure historically linked to the layer specific pattern of tau pathology deposition. Additionally, high field atlasing with delineations of amygdala subregions shows predominant volume loss in medial subregions including basomedial, basolateral, and corticocentromedial compared with the lateral subregion. In the context of earlier work linking MRI-based atrophy with hyperphospho-rylated tau deposition in the ERC and amygdala, the atrophy rate marker is shown to be strongly associated with tau deposition as measured by tau positron emission tomography imaging and co-localization of the atrophy marker to the spatial distribution of tau deposition.

HIGHLIGHTS: Structural MRI analyses across ADNI and BIOCARD cohorts reveal significantly greater early atrophy in amygdala and entorhinal cortex (ERC), marking them as sensitive indicators of preclinical Alzheimer's disease.ERC volume loss is shown to correspond to cortical laminar thinning by surface-based diffeomorphic reconstructions, confirming MRI volume atrophy as a biologically valid marker of early neuronal degeneration.Predominant atrophy in medial amygdala subregions (basomedial, basolateral, corticocentromedial) are identified compared to the lateral amygdala using high-field (11T) atlases, mirroring known histopathological tau distribution.MRI volume atrophy correlates with tau burden measured by tau PET imaging, demonstrating region-specific correspondence between structural atrophy and molecular pathology.},
}

@article {pmid41646662,
year = {2026},
author = {Lee, Y and Kim, S and Kim, S and Kang, Y and , },
title = {Feature Integration of [ [18] F]FDG PET Brain Imaging Using Deep Learning for Sensitive Cognitive Decline Detection.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.22.26344669},
pmid = {41646662},
abstract = {BACKGROUND: Distinguishing individuals with cognitive decline (CD), including early Alzheimer's disease, from cognitively normal (CN) individuals is essential for improving diagnostic accuracy and enabling timely intervention. Positron emission tomography (PET) captures functional brain alterations associated with CD, but its broader application is often limited by cost and radiation exposure. To enhance the clinical utility of PET while addressing data limitations, we propose a multi-representational learning framework that leverages both imaging data and region-level quantification in a data-efficient manner.

METHODS: Voxel-level features were extracted using convolutional neural networks (CNN) or principal component analysis networks (PCANet) from [¹⁸F]FDG PET imaging. Region-level features were derived from standardized uptake value ratio measurements across predefined brain regions and processed using a deep neural network (DNN). These voxel- and region-level information are integrated through direct concatenation. For final prediction, different machine learning models and ensemble technique were applied. The models were trained and validated using 5-fold cross-validation on PET scans from 252 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), comprising 118 CN and 134 CD subjects. Additional correlation analysis and disease classification comparison with the Mini-Mental State Examination (MMSE) were also performed.

RESULTS: In 5-fold cross-validation, CNN, PCANet, and DNN models achieved classification accuracies of 0.69 ± 0.04, 0.69 ± 0.06, and 0.82 ± 0.06, respectively. The integrated DNN-CNN model using direct concatenation yielded the highest accuracy (0.87 ± 0.05), with a 6.10% improvement in accuracy and reduced standard deviation relative to the DNN-only model. Moreover, there were an increase of 14.29% in Recall (0.77 to 0.88) and an increase of 7.32% in F1-Score (0.82 to 0.88). Moreover, the model output showed a significant level of relation with MMSE, and it outperformed the MMSE-based classification in accuracy, recall, and f1, except precision.

CONCLUSION: Combining PET imaging with region-level quantification and deep learning improves diagnostic performance over single-feature based models. Notably, fusion-based approaches enhanced sensitivity to cognitive decline. This multimodal strategy offers a more data-efficient and accurate approach for classifying cognitive decline and supports broader PET application in clinical settings.},
}

@article {pmid41646661,
year = {2026},
author = {Korthauer, LE and De la Roca, A and Rosen, RK and Arias, I and Tremont, G and Davis, JD},
title = {Experiences of Personalized Dementia Risk Education: A Qualitative Study to Refine the TEACH (Tailored Education for Aging and Cognitive Health) Behavioral Intervention.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.27.26344961},
pmid = {41646661},
abstract = {BACKGROUND: This study used qualitative methods to test and refine a framework for educating cognitively unimpaired individuals about their individual risk for Alzheimer's disease and related dementias (ADRD) and intrapersonal health belief factors as part of the TEACH (Tailored Education for Aging and Cognitive Health) intervention.

METHOD: We assessed individuals' ADRD risk factors and health belief concepts. Personalized data were presented individually, followed by a semi-structured phenomenographic interview. Applied thematic analysis was used to identify representative statements, trends, and differences.

RESULTS: In N=11 individual interviews with middle-aged and older participants (ages 49-69; 45% women), participants had generally positive experiences of learning their personal dementia risk; the information was perceived to be unsurprising and occasionally consoling. They demonstrated a good understanding of the health belief concepts, including identifying relationships between intrapersonal health beliefs and health behaviors. Participants provided feedback on the visual aids and methods of conveying health belief information.

CONCLUSIONS: We used qualitative data from individual interviews to refine an explanatory framework for educating individuals about their personalized risk for ADRD and intrapersonal health beliefs that may be barriers or facilitators of health behavior change. The refined TEACH intervention is designed to promote long-term maintenance of target health behaviors in middle-aged adults to mitigate ADRD risk.},
}

@article {pmid41646660,
year = {2026},
author = {Perales-Puchalt, J and Aschenbrenner, AJ and Marquine, M and Rascovsky, K and Parks, A},
title = {Optimal cutoffs for the Montreal Cognitive Assessment among English and Spanish speaking Latinos.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.26.26344881},
pmid = {41646660},
abstract = {The Montreal Cognitive Assessment (MoCA) is widely used to screen for cognitive impairment, yet commonly applied cutoff scores have been found to perform poorly among US Latinos. Prior studies relied on small samples, combining persons with mild cognitive impairment (MCI) and dementia into a single group, or failing to account for multiple intersecting demographic factors. We identified optimal MoCA cutoffs for MCI and dementia among US Latinos while addressing these limitations. We analyzed cross-sectional data from the National Alzheimer's Coordinating Center Unified Data Set. Participants included English- and Spanish-speaking Latinos who completed testing in their primary language. Research diagnostic groups consisted of cognitively unimpaired (CU), MCI, and dementia. Groups were further stratified by testing language, age, and level of education. Diagnostic accuracy and receiver operating characteristic (ROC) analyses were performed. The Youden Index was used to determine the optimal cutoff score. Of the 1,673 participants in the total sample, 46% completed the MoCA in Spanish and 54% in English, 54% were CU, and 28% had MCI and 19% had dementia. Area under the curve (AUC) values for CU vs. MCI were 0.70 for Spanish-tested participants and 0.79 for English-tested participants, while values for MCI vs. dementia were 0.85 and 0.89 for the Spanish and English tested participants, respectively. Overall AUC values were 0.76 for CU vs. MCI and 0.86 for mild cognitive impairment vs. dementia. Optimal cutoffs were consistently found to be lower among participants tested in Spanish, those older than age 75, and participants with the fewest years of education, with some optimal cutoffs shown to be substantially lower than the traditionally used standard cutoff. These findings provide cutoffs that better reflect differences amongst language and demographic groups. We also provide a scoring calculator for clinical and research use.},
}

@article {pmid41646372,
year = {2026},
author = {Bao, R and Shi, W and Bao, H and Zhang, T and Li, X and Ding, W},
title = {Plasma p-tau217, p-tau181, and Aβ42 Predicts Amyloid PET Positivity in Cognitively Unimpaired Adults.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8587114/v1},
pmid = {41646372},
issn = {2693-5015},
abstract = {Background Early detection of Alzheimer's disease (AD) pathology in cognitively unimpaired individuals is critical for preclinical intervention. Plasma biomarkers, especially phosphorylated tau217 (p-tau217), are promising predictors of amyloid-β (Aβ) accumulation. Methods In this cohort study, we analyzed data from cognitively unimpaired older adults in the A4 and LEARN studies (n=1,407), comprising 452 participants with Aβ positron emission tomography (PET)-negative status and 955 participants with Aβ PET-positive status. We evaluated the accuracy of plasma biomarkers (p-tau217, p-tau181, Aβ42/40 ratio, and others) in predicting Aβ PET positivity using receiver operating characteristic analysis, comparing models with biomarkers alone versus those combined with covariates (age, sex, apolipoprotein E [APOE] ε4 genotype). Results Plasma p-tau217 showed the strongest individual association with Aβ PET status (area under the curve [AUC] 0.85). A combined model integrating p-tau217, p-tau181, Aβ42, age, sex, and APOE ε4 achieved the highest diagnostic accuracy (AUC 0.87), significantly outperforming individual biomarkers. Conclusions Plasma p-tau217, particularly when combined with other biomarkers and clinical covariates, provides a robust method for predicting Aβ PET positivity in cognitively unimpaired older adults. This biomarker profile could enhance preclinical trial screening by identifying individuals likely to harbor Aβ pathology, potentially reducing the need for confirmatory PET scans.},
}

@article {pmid41646364,
year = {2026},
author = {Verma, K and Kumar, S},
title = {Amyloid Probability in Alzheimer Disease From Plasma, Cerebrospinal Fluid, and Amyloid Imaging.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8492792/v1},
pmid = {41646364},
issn = {2693-5015},
abstract = {Blood-based biomarkers are increasingly used to triage patients for amyloid confirmation, yet performance is often reported versus a single comparator despite discordance between amyloid PET and CSF. In a cross-sectional secondary analysis of the Alzheimer's Disease Neuroimaging Initiative (ADNI), we assembled one PET-anchored PET-CSF-plasma triad per participant (n = 320). Bayesian latent class models integrating PET, CSF and plasma (Aβ42/40 or %p-tau217) estimated pattern-level posterior probabilities of latent amyloid positivity, with prespecified sensitivity analyses for PET-CSF conditional dependence, timing gaps (≤ 7, 8-30, > 30 days) and CSF cutpoints. Concordant PET+/CSF + and PET-/CSF - patterns mapped to probabilities near 1 and 0, whereas discordant patterns yielded intermediate probabilities refined by plasma strata and most sensitive to dependence assumptions. PET-CSF discordance occurred even within ≤ 7 days (12/98; 12%). A CSF Aβ42 coverage analysis showed similar gradients. Pattern-to-probability reporting may aid interpretation without privileging a reference test.},
}

@article {pmid41646354,
year = {2026},
author = {Jiakponnah, N and Curran, J and Watermeyer, T and Shah, J and Musili, L and Onyango, S and Aliwa, B and Mackelfresh, A and Bubu, OM and Onyike, C and Okonkwo, O and Merali, Z and Akinyemi, R and Hughes, T and Saleh, M and Petersen, M and Blackmon, K and Ogunniyi, A and Hendrie, H and Udeh-Momoh, C},
title = {Contextual variability in under-diagnosed cardiometabolic disease and cognitive vulnerability among populations at high risk for Alzheimer's disease and related dementias.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8570591/v1},
pmid = {41646354},
issn = {2693-5015},
abstract = {Underdiagnosis of cardiometabolic risk factors (CMRFs) may represent an unrecognised biological pathway contributing to dementia risk; yet remains poorly characterised in African and African diaspora populations. We quantified the prevalence and determinants of underdiagnosed hypertension and abnormal glycaemia across four cohorts comprising up to 7,000 adults aged ≥ 40 years from Nigeria, Kenya, and The United States: Indianapolis, and North Texas. Underdiagnosis was defined as absence of self-reported diagnosis despite elevated systolic blood pressure (≥ 130 mmHg) or fasting blood glucose (≥ 100 mg/dL). Cohort-stratified analyses examined demographic, socioeconomic, cognitive, Alzheimer's genetic, and blood-based biomarker correlates. Underdiagnosis was pervasive in African cohorts. Elevated fasting glucose was associated with cognitive impairment in Kenya and North Texas, while severe hypertension and diabetes were linked to Alzheimer's disease-related biomarkers [pTau217/181, NFL and Aβ42/40] in North Texas (all p ≤ 0.05). These findings identify context-specific diagnostic gaps in populations at high dementia risk and highlight cardiometabolic detection as a mechanistic target for prevention.},
}

@article {pmid41646317,
year = {2026},
author = {Comolli, D and Murari, E and Cerovic, M and Soltuzu, L and Liao, W and Bianchi, A and Seminara, S and Craparotta, I and Fumagalli, S and Balducci, C and Forloni, G and De Paola, M},
title = {Glial and Neuronal Alzheimer's Disease-Related Alterations Reproduced in Human Induced Pluripotent Stem Cells With Presenilin-1 Mutation.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8549806/v1},
pmid = {41646317},
issn = {2693-5015},
abstract = {Background A pathogenetic role of glial cells has been established virtually in all neurodegenerative disorders. In Alzheimer's disease (AD), together with β-amyloid deposition and the formation of fibrillary tangles, neuroinflammation contributes to neuronal dysfunction associated with the disease. Thus, selective control of glial cell activation becomes part of the multifactorial therapeutic strategies in AD. Astrocytes and microglia are highly heterogeneous in their morphology and physiology, and this diversity underlies their distinct functional states in the central nervous system. In AD, they exhibit dynamic and stage-dependent pathological phenotypes during disease onset and progression. In this context, investigating the disease-associated glia signature would provide significant progress in understanding pathological mechanisms and in the development of beneficial treatments. The use of human induced pluripotent stem cells (iPSCs) to study CNS cell alterations during brain pathologies greatly improves the possibility of identifying human- and cell-specific changes likely contributing to AD progression. Methods Here we used isolated glia cultures and neuron/glia cocultures derived from iPSC carrying a mutation in the presenilin-1 (PSEN1) gene to investigate AD-related microglia and astrocyte impairments and their contribution to neuronal degeneration. Results Microglia from AD iPSCs showed compromised functional properties while astrocytes exhibited a predominant fibroblast-like phenotype and increased expression of inflammatory markers. Consistently, transcriptomic derangement for reactive phenotype-related genes, correlating with cell morphology, allowed to well distinguish AD astrocytes from control cells. We finally observed that glia-specific AD-related changes affected some neuronal properties in mixed neuron/glia cocultures, while the presence of the mutation in both cell population triggered a dramatic neuronal damage, involving neuronal network degradation, synaptic alterations and impaired electrophysiological properties. On the other hand, the replacement of AD with healthy glia was not sufficient to protect from neurodegeneration, suggesting the pivotal role of mutated PSEN1 in neurons. Conclusions We herein succeeded in reproducing crucial AD-related changes in iPSC-derived in vitro models providing new insights in the neuropathological communication amongst brain cells, thus representing a promising tool to deepen disease mechanisms and develop neuroprotective treatments.},
}

@article {pmid41646315,
year = {2026},
author = {Thierry, M and Kavanagh, T and Balcomb, K and Tang, L and Leitner, D and Kanshin, E and William, C and Oakley, D and Hyman, B and Ueberheide, B and Drummond, E and Wisniewski, T},
title = {Proteomic remodelling of the neurofibrillary tangle from "PART" to advanced Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8703254/v1},
pmid = {41646315},
issn = {2693-5015},
abstract = {Alzheimer's disease (AD) is characterised by the intraneuronal aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles and by the extracellular deposition of β-amyloid (Aβ). Tau pathology restricted to the medio-temporal lobe is frequently observed in the elderly brain in the absence of any Aβ deposition and considered as "primary age-related tauopathy" (PART). Here, we applied an unbiased proteomic approach to determine if and how concomitant Aβ pathology modifies the neurofibrillary tangle proteome. Neurofibrillary tangles were isolated by laser capture microdissection from hippocampal sections of 17 post-mortem brains spanning three groups: PART (n = 5; A0, B1-2, C0 scores), intermediate AD (n = 6; A1-2, B2-3, C1-2 scores) and advanced AD (n = 6; A3, B3, C3 scores). Mass spectrometry identified a conserved core of 63 proteins enriched in tangles across all groups, associated with RNA binding. Group-specific signatures were also observed: 33 proteins were significantly enriched only in tangles collected from PART cases and were predominantly linked to structural activity, whereas Aβ-positive cases showed specific enrichment of RNA binding and translation pathways - with intermediate AD cases displaying a transitional profile. Our findings are consistent with PART having distinct tangle proteomic features that could precede Aβ-driven changes; however, the majority of its proteomic signature is in common with tangles within the AD continuum. By addressing how Aβ accumulation alters the tangle proteome, this study provides mechanistic insights into the expansion of Tau pathology, paving the way towards the identification of biomarkers and therapeutic strategies that would allow for stabilisation of Tau pathology in the elderly.},
}

@article {pmid41646305,
year = {2026},
author = {Nelson, DA and Swaminathan, SK and Seo, HS and Azarin, SM and Kalari, KR and Kandimalla, KK},
title = {Acute amyloid-β exposure disrupts insulin signaling in blood-brain barrier endothelial cell culture models.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8436616/v1},
pmid = {41646305},
issn = {2693-5015},
abstract = {Background Brain insulin resistance and cerebrovascular dysfunction emerge early in late-onset Alzheimer's disease, but how amyloid-β (Aβ) disrupts insulin signaling at the cerebrovascular blood-brain barrier-a major site of insulin receptor signaling and transport into the brain-remains unclear. Methods We exposed two distinct human blood-brain-barrier endothelial cell models to soluble Aβ40 or Aβ42 for 1 h, followed by 100 nM insulin for 10 min. Protein and phosphoprotein responses were quantified by reverse-phase protein array, and differential expression was evaluated using linear models. Results Aβ40 reduced insulin-stimulated Akt activation and converted insulin's normal inhibition of AMPK into modest stimulation. Aβ42 did not alter insulin-stimulated Akt signaling but moderately suppressed basal Akt activation. Conclusions These findings suggest that Aβ40 acutely impairs insulin signal transduction in BBB endothelial cells, supporting a model in which vascular Aβ exposure contributes directly to the early development of brain insulin resistance in AD.},
}

@article {pmid41646303,
year = {2026},
author = {Lee, S and English, AC and Peloso, GM and Bis, JC and Boerwinkle, E and Choi, SH and Heard-Costa, NL and Lin, H and Xia, R and Seshadri, S and Destefano, AL and Fornage, M and Sedlazeck, FJ},
title = {The Impact of Structural Variation on Alzheimer's Disease in the Alzheimer's Disease Sequencing Project.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8562759/v1},
pmid = {41646303},
issn = {2693-5015},
abstract = {Introduction : Structural variants (SV), genomic alterations spanning more than 50 base pairs, can significantly impact gene expression and protein function. However, their contribution to Alzheimer's Disease (AD) remains poorly understood. Leveraging a novel SV calling pipeline, we identified SVs with high accuracy in a diverse sample of the Alzheimer's Disease Sequencing Project (ADSP) and investigated the role of SVs in AD. Results : We analyzed SVs in 16,841 individuals from ADSP whole genome sequencing data using BioGraph, a semi-assembly-based method that employs graph-based representation for accurate SV detection. We identified 456,644 high-quality SVs, 65% of which were novel. Of these, 272,728 SVs directly impact genes, including 86 AD-related genes. Association analyses were performed within three ancestry groups, including 3,371 African (AFR), 6,327 European (EUR), and 2,126 Latin (LAT). Multiple deletions and insertions were observed in moderate to high linkage disequilibrium with known AD loci, including TPCN1 and TMEM106B . In EUR, genome-wide association analysis identified two significant low-frequency deletions associated with AD, located in introns of CCDC12 and CCDC88B , both encoding coiled-coil domain-containing proteins. Gene-based analyses further identified rare pathogenic SVs in several known AD genes, including PSEN1 in LAT and ABCA7 in AFR. Conclusions : Using a novel graph-based SV calling pipeline, we identified high-quality SVs across a large and ancestrally diverse cohort. Our analyses revealed both common and rare SVs associated with AD. These findings provide valuable insights into the genetic architecture of AD, emphasizing the value of including diverse populations in AD genomic studies.},
}

@article {pmid41646292,
year = {2026},
author = {Weber, MA and Hunter, CM and Narayanan, NS},
title = {Parkinson's and Alzheimer's disease impairs temporal precision.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8628264/v1},
pmid = {41646292},
issn = {2693-5015},
abstract = {Several studies have reported temporal processing deficits in neurodegenerative diseases such as Parkinson's and Alzheimer's disease. These deficits can be quantified by interval timing paradigms that require participants to estimate or produce an interval of several seconds and require working memory for temporal rules as well as attention to time. Timing performance can be quantified by a variety of measures; however, two relatively universal metrics include: 1) temporal accuracy, defined as the mean temporal estimate and 2) temporal precision, reflected by the variability of temporal estimates. We examined temporal accuracy and precision in a meta-analysis of 14 studies in patients with Parkinson's disease and 10 studies in patients with Alzheimer's disease. Strikingly, in both diseases, temporal precision was reliably impaired across studies, while temporal accuracy was not. Our meta-analysis suggests that despite the diversity of interval timing paradigms and the complexity of Parkinson's and Alzheimer's disease, temporal precision is consistently impaired in these diseases. These results advance interval timing as a reliable assay to study cognitive dysfunction in Parkinson's and Alzheimer's disease and may extend to other neurological and psychiatric disorders.},
}

@article {pmid41646005,
year = {2026},
author = {Peng, J and Fan, T and Wang, J and Deng, Y and Xu, R},
title = {Current potential biomarkers for Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis: review of literature.},
journal = {Dialogues in clinical neuroscience},
volume = {28},
number = {1},
pages = {17-39},
doi = {10.1080/19585969.2026.2622722},
pmid = {41646005},
issn = {1958-5969},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/blood/metabolism ; *Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/diagnosis/blood/metabolism/cerebrospinal fluid ; *Parkinson Disease/diagnosis/blood/metabolism/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are several common neurodegenerative diseases (NDs). At present, is the lack of effective diagnosis, progression, prognosis and therapeutic biomarkers. it is a urgent demand to search the relevant confident biomarkers.

AREA COVERED: This review systematically analysed the potential biomarkers of blood, cerebrospinal fluid, neuroimaing and emerging non-invasive indicators, and synthesises current evidences on the biomarkers of AD, PD and ALS about diagnosis, progression, prognosis and therapeutic, especially diagnosis biomarkers.

EXPERT COMMENTARY: In this review, we focus on discussing relevant diagnosis, progression, prognosis and therapeutic biomarkers for AD, PD and ALS in recent years, and prospecting the possible future directions of relevant biomarkers.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/blood/metabolism
*Biomarkers/cerebrospinal fluid/blood
*Alzheimer Disease/diagnosis/blood/metabolism/cerebrospinal fluid
*Parkinson Disease/diagnosis/blood/metabolism/cerebrospinal fluid

@article {pmid41645892,
year = {2026},
author = {Kushwaha, S and Roy Choudhury, R and Bhat, P and Kumaran, SS and Karunakaran, S},
title = {Female-biased astrocytic priming shapes early locus coeruleus vulnerability in an Aβ oligomer milieu.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71168},
doi = {10.1002/alz.71168},
pmid = {41645892},
issn = {1552-5279},
support = {//Centre for Brain Research (CBR)/ ; },
mesh = {Animals ; *Locus Coeruleus/metabolism/pathology/diagnostic imaging ; *Astrocytes/metabolism/pathology ; Female ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Mice ; Glial Fibrillary Acidic Protein/metabolism ; Disease Models, Animal ; *Alzheimer Disease/pathology/metabolism ; Male ; *Peptide Fragments/metabolism ; Amyloid beta-Protein Precursor/genetics ; *Sex Characteristics ; },
abstract = {INTRODUCTION: The locus coeruleus (LC) is an early site of Alzheimer's disease (AD) pathology, yet the role of brainstem astrocytes in early, sex-dependent vulnerability remains unclear.

METHODS: In 2- to 3-month-old APP/PS1 mice, we combined in vivo proton magnetic resonance spectroscopy (MRS) of the brainstem with region-resolved molecular analyses, including quantitative real-time polymerase chain reaction, amyloid beta 42 (Aβ42) oligomers enzyme-linked immunosorbent assay, lactate assay, immunohistochemistry, immunoblotting, astrocyte isolation, and 3D structural assessment. Environmental enrichment (EE) served as a non-pharmacologic intervention.

RESULTS: Females exhibited higher brainstem Aβ42 oligomers and an astrocyte-weighted MRS profile. Pontine glial fibrillary acidic protein (GFAP), complement component 3, and nuclear factor kappa-light-chain-enhancer of activated B cells were selectively upregulated without pan-reactive astrocytic and microglial markers. LC-restricted GFAP elevation occurred without changes in astrocyte counts or morphology, indicating a "primed" state. Females also showed higher lactate levels, increased monocarboxylate transporter 2 expression, and elevations in selected oxidative phosphorylation-associated transcripts, and reduced astrocytic alpha 2A-adrenergic receptor expression. EE normalized noradrenergic and pontine astrocytic changes.

DISCUSSION: Female-biased, LC-centric astrocytic priming emerges early in this amyloid-driven model and is modifiable.},
}

Animals
*Locus Coeruleus/metabolism/pathology/diagnostic imaging
*Astrocytes/metabolism/pathology
Female
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
Mice
Glial Fibrillary Acidic Protein/metabolism
Disease Models, Animal
*Alzheimer Disease/pathology/metabolism
Male
*Peptide Fragments/metabolism
Amyloid beta-Protein Precursor/genetics
*Sex Characteristics

@article {pmid41645874,
year = {2026},
author = {Pugh, DA and Cary, GA and Greathouse, KM and Nassour-Caswell, LC and Hobby, EL and Seyfried, NT and Herskowitz, JH},
title = {NRN1 as a therapeutic target for Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71149},
doi = {10.1002/alz.71149},
pmid = {41645874},
issn = {1552-5279},
support = {T32 NS061788 (D.A.P.)/NH/NIH HHS/United States ; F31 AG084195 (D.A.P.)/NH/NIH HHS/United States ; R01 AG061800 (J.H.H. and N.T.S.)/NH/NIH HHS/United States ; R21AG085379 (J.H.H.)/NH/NIH HHS/United States ; P30AG086401/NH/NIH HHS/United States ; R01NS128031/NH/NIH HHS/United States ; U54AG065187/NH/NIH HHS/United States ; NS061788/NS/NINDS NIH HHS/United States ; AG084195/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/genetics ; Humans ; Animals ; Mice ; Mice, Transgenic ; tau Proteins/genetics/metabolism ; Brain/metabolism ; Disease Models, Animal ; Neurons/metabolism ; Neuropeptides ; GPI-Linked Proteins ; },
abstract = {INTRODUCTION: Neuritin-1 (NRN1) was identified as a synaptic protein associated with cognitive resilience to Alzheimer's disease (AD).

METHODS: Target risk score and cell type expression profiles were generated for NRN1 using methods developed by the Emory-Sage-SGC-JAX Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) Center and Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD). Antibody characterization was conducted using Western blots and densitometry to assess the relative protein abundances of NRN1 in rodents, humans, and cell models.

RESULTS: NRN1 has a TREAT-AD target risk score of 3.29 out of 5. Based on single-nucleus RNA sequencing from SEA-AD, NRN1 expression in excitatory neurons tends to decrease with increasing donor pseudo-progression. Abcam ab64186 polyclonal NRN1 antibody detects NRN1 protein in vitro and in vivo at molecular weights that suggest NRN1 forms a homodimer. NRN1 protein abundance is comparable among controls and primary tauopathy cases, as well as Tau P301S mice and non-transgenic littermates at 3 and 9 months.

DISCUSSION: These findings advance the investigation of NRN1 as a therapeutic candidate for AD.},
}

*Alzheimer Disease/metabolism/genetics
Humans
Animals
Mice
Mice, Transgenic
tau Proteins/genetics/metabolism
Brain/metabolism
Disease Models, Animal
Neurons/metabolism
Neuropeptides
GPI-Linked Proteins

@article {pmid41645833,
year = {2026},
author = {},
title = {Correction to "The microbiota-gut-brain axis in mild cognitive impairment and Alzheimer's disease: A scoping review of human studies".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71221},
doi = {10.1002/alz.71221},
pmid = {41645833},
issn = {1552-5279},
}

@article {pmid41645816,
year = {2026},
author = {Liu, W and Rao, X and Sun, W and Chen, X and Yu, L and Zhang, J},
title = {Radiofrequency electromagnetic fields in Alzheimer's therapy: emerging evidence and future prospects.},
journal = {Electromagnetic biology and medicine},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/15368378.2026.2627962},
pmid = {41645816},
issn = {1536-8386},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia in humans. The accumulation of abnormal protein aggregates, including extracellular amyloid plaques and intracellular neurofibrillary tangles, is considered a key pathological hallmark of AD. Currently, the primary approach for treating AD is pharmacological treatment, which is only symptomatic and unable to cure or reverse the progression of AD. Increasing evidence suggests that radiofrequency electromagnetic fields (RF-EMFs) may attenuate the progression of AD and improve memory function. This article reviews the studies related to the application of RF-EMFs in the field of AD, including investigations at the cellular and molecular levels, in animal models, and in clinical applications. The therapeutic potential of RF-EMFs as an intervention for AD is discussed in the present review, along with current challenges and future research directions.},
}

@article {pmid41645773,
year = {2026},
author = {Tjin, A and Thang, LL and Stewart, R},
title = {Primary care service utilisation pattern in dementia: a 10-year longitudinal population-based study.},
journal = {Age and ageing},
volume = {55},
number = {2},
pages = {},
doi = {10.1093/ageing/afag016},
pmid = {41645773},
issn = {1468-2834},
support = {//King's College London/ ; //The Clinical Records Interactive Search (CRIS)/ ; //National Institute for Health Research/ ; //Mental Health Biomedical Research Centre at South London/ ; //Maudsley NHS Foundation Trust/ ; //NIHR Maudsley Biomedical Research Centre at the South London/ ; //NIHR Health Tech Research Centre in Brain Health/ ; //NIHR Applied Research Collaboration South London/ ; //UKRI-Medical Research Council/ ; MR/W014386/1//DATA-MIND HDR UK Mental Health Data Hub/ ; MR/Z504816/1//DATA-MIND HDR UK Mental Health Data Hub/ ; Violence, Health and Society; MR-VO49879/1//UK Prevention Research Partnership/ ; //NIHR/ ; //Department of Health and Social Care/ ; },
mesh = {Humans ; Male ; Female ; *Primary Health Care/trends/statistics & numerical data ; Retrospective Studies ; Aged ; Longitudinal Studies ; *Dementia/therapy/diagnosis/epidemiology/psychology ; Aged, 80 and over ; Time Factors ; London/epidemiology ; Cognition ; Lewy Body Disease/therapy/diagnosis/epidemiology ; Dementia, Vascular/therapy/diagnosis/psychology/epidemiology ; *Patient Acceptance of Health Care/statistics & numerical data ; },
abstract = {BACKGROUND: Primary care services play a key role in dementia care, yet activity may vary between subtypes.

OBJECTIVE: To investigate longitudinal determinants of primary care contact across Alzheimer's disease (ad), vascular dementia (VD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia (PDD) 5 years pre-and-post-diagnosis, encompassing clinical, cognitive, functional, and sociodemographic factors.

DESIGN: Retrospective cohort study.

METHODS: Data on 4384 individuals with first dementia diagnoses (2008-2023) were obtained from a South London catchment linking dementia services with primary care records. Linear mixed-effects models were run on 3-month interval counts (up to 40 intervals per individual, 20 pre-and-post-diagnosis). Separate pre-and-post-diagnosis models assessed longitudinal trends, adjusted for age, sex, and antidepressant use, with subgroup analyses by dementia subtype and cognitive status.

RESULT: Service utilisation increased over time, with VD showing a steeper pre-diagnosis rise and PDD moderate post-diagnosis increases compared to ad. Across both periods, worse cognitive impairment and antipsychotic receipt were associated with lower contacts, while older age and Black/British Black ethnicity were associated with higher contact. Pre-diagnosis, agitation, depressed mood, relationship and living conditions problems were linked to lower contact, whereas hallucinations were associated with higher use. Post-diagnosis, hypnotic/anxiolytic use predicted lower contact, while acetylcholinesterase inhibitor receipt, comorbidities, daily living difficulties, and mixed ethnicity were associated with increased utilisation.

CONCLUSION: Person-centred care pathways should anticipate subtype-specific and individual patterns, providing targeted support for those with reduced pre-diagnosis contact who may have unmet needs, while considering early intervention for groups anticipated to require increased service use after diagnosis.},
}

Humans
Male
Female
*Primary Health Care/trends/statistics & numerical data
Retrospective Studies
Aged
Longitudinal Studies
*Dementia/therapy/diagnosis/epidemiology/psychology
Aged, 80 and over
Time Factors
London/epidemiology
Cognition
Lewy Body Disease/therapy/diagnosis/epidemiology
Dementia, Vascular/therapy/diagnosis/psychology/epidemiology
*Patient Acceptance of Health Care/statistics & numerical data

@article {pmid41645766,
year = {2026},
author = {Li, W and Guo, Y and Wang, X and Yang, C and Zhu, J and Cao, Z},
title = {Design, synthesis and biological evaluation of donepezil-safinamide hybrids as dual AChE and MAO-B inhibitor for Alzheimer's disease treatment.},
journal = {Journal of enzyme inhibition and medicinal chemistry},
volume = {41},
number = {1},
pages = {2622769},
doi = {10.1080/14756366.2026.2622769},
pmid = {41645766},
issn = {1475-6374},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Donepezil/pharmacology/chemistry/chemical synthesis ; *Monoamine Oxidase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Drug Design ; *Acetylcholinesterase/metabolism ; Animals ; Structure-Activity Relationship ; Mice ; *Monoamine Oxidase/metabolism ; Molecular Structure ; Dose-Response Relationship, Drug ; *Alanine/analogs & derivatives/chemistry/pharmacology/chemical synthesis ; Molecular Docking Simulation ; Humans ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Male ; Blood-Brain Barrier/metabolism ; Benzylamines ; },
abstract = {Alzheimer's disease (AD) still lacks therapies that definitively halt its progression. Dual AChE/MAO-B inhibitors offer a promising strategy to address both symptoms and pathology. Here, we designed and synthesised a series of donepezil-safinamide hybrids. The optimised compound 28c was identified as a potent inhibitor of AChE (IC50 = 1.70 μM) and MAO-B (IC50 = 0.18 μM). Mechanistic studies indicated that 28c acts as a reversible mixed-type inhibitor of AChE and a competitive reversible inhibitor of MAO-B. Molecular docking and molecular dynamic simulations revealed that 28c could strongly and stably bind to MAO-B and AChE mainly through van der Waals interactions. Moreover, compound 28c demonstrated effective blood-brain barrier penetration, exhibited suitable stability in mouse plasma and brain homogenate, and showed a favourable safety profile both in vitro and in vivo. Furthermore, 28c could attenuate AD-related symptoms and exert hippocampal neuroprotection effect in vivo, highlighting its promise as an anti-AD candidate.},
}

*Alzheimer Disease/drug therapy/metabolism
*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
*Donepezil/pharmacology/chemistry/chemical synthesis
*Monoamine Oxidase Inhibitors/pharmacology/chemistry/chemical synthesis
*Drug Design
*Acetylcholinesterase/metabolism
Animals
Structure-Activity Relationship
Mice
*Monoamine Oxidase/metabolism
Molecular Structure
Dose-Response Relationship, Drug
*Alanine/analogs & derivatives/chemistry/pharmacology/chemical synthesis
Molecular Docking Simulation
Humans
*Neuroprotective Agents/pharmacology/chemical synthesis/chemistry
Male
Blood-Brain Barrier/metabolism
Benzylamines

@article {pmid41645754,
year = {2026},
author = {Li, W and Wang, WH and Song, Y and Li, XJ and Li, Y and Wang, X and Tian, TT and Huang, X and Zhao, L},
title = {Mechanistic advances in exercise‑mediated regulation of autophagy dysfunction in Alzheimer's disease (Review).},
journal = {International journal of molecular medicine},
volume = {57},
number = {4},
pages = {},
doi = {10.3892/ijmm.2026.5755},
pmid = {41645754},
issn = {1791-244X},
mesh = {Humans ; *Alzheimer Disease/metabolism/therapy/pathology/physiopathology ; *Autophagy ; *Exercise/physiology ; Animals ; Signal Transduction ; MicroRNAs/genetics/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive cognitive decline and whose pathology is closely linked to cellular autophagy dysfunction. Autophagy is a key process involved in cell clearance. Impaired autophagy can drive neuronal damage and death related to AD pathology. Therefore, targeting autophagy dysfunction has emerged as a promising therapeutic strategy. Exercise, as a non‑pharmaceutical and low‑cost intervention method, can enhance autophagy activity and alleviate AD symptoms. However, the mechanism by which it regulates autophagy in AD remains unclear. The present review summarizes evidence that exercise acts as an effective early intervention. Exercise activates key cellular signaling pathways (mammalian target of rapamycin, sirtuin 1 and adiponectin receptor 1) and regulates microRNAs (small non‑coding RNAs) and irisin (a muscle hormone) to restore normal autophagy. The present review also explores the use of exercise combined with natural products for potential synergistic therapeutic effects. This review provides insights into developing new AD prevention and management strategies by detailing how exercise corrects AD‑related autophagy dysfunction.},
}

Humans
*Alzheimer Disease/metabolism/therapy/pathology/physiopathology
*Autophagy
*Exercise/physiology
Animals
Signal Transduction
MicroRNAs/genetics/metabolism

@article {pmid41645747,
year = {2026},
author = {Wu, C and Ding, Y and Liu, X and Gao, S and Wang, X and Tang, W},
title = {Thymol carbamates bearing cyclic amines as potent and selective BuChE inhibitors alleviate memory impairments for Alzheimer's disease therapy.},
journal = {Journal of enzyme inhibition and medicinal chemistry},
volume = {41},
number = {1},
pages = {2623314},
doi = {10.1080/14756366.2026.2623314},
pmid = {41645747},
issn = {1475-6374},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Carbamates/chemistry/pharmacology/chemical synthesis ; *Thymol/chemistry/pharmacology/chemical synthesis ; Mice ; *Butyrylcholinesterase/metabolism ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug ; *Amines/chemistry/pharmacology ; *Memory Disorders/drug therapy/metabolism ; Amyloid beta-Peptides/antagonists & inhibitors ; Male ; Humans ; Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Acetylcholinesterase/metabolism ; },
abstract = {Thymol, an isomer of carvacrol, exhibits anti-Aβ activity. Thymol carbamates were designed, and their inhibition on cholinesterase (ChE) activity was assessed and analysed, among them, TC-4, TC-6, H4 and H5 bearing cyclic amines exhibited nanomolar inhibitory activity with IC50 values of 13, 3.6, 47, and 12 nM. TC-6 bearing a piperidinyl moiety demonstrated nanomolar hBuChE inhibition (IC50 = 3.6 nM), >2,500-fold selectivity over hAChE, and pseudo-irreversible kinetics (Kd = 0.25 μM, k2 = 0.98 min[-1]). TC-6 exhibited low cytotoxicity, crossed the blood-brain barrier, and protected neurons against H2O2-induced damage. In Aβ1-42-induced AD mice, TC-6 (10 mg/kg) greatly enhanced cognitive abilities in MWM tests, reduced brain Aβ levels, and restored hippocampal neuron density. These results highlight TC-6 as a potent, brain-penetrant BuChE inhibitor with therapeutic potential for AD.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
Animals
*Alzheimer Disease/drug therapy/metabolism
*Carbamates/chemistry/pharmacology/chemical synthesis
*Thymol/chemistry/pharmacology/chemical synthesis
Mice
*Butyrylcholinesterase/metabolism
Structure-Activity Relationship
Molecular Structure
Dose-Response Relationship, Drug
*Amines/chemistry/pharmacology
*Memory Disorders/drug therapy/metabolism
Amyloid beta-Peptides/antagonists & inhibitors
Male
Humans
Neuroprotective Agents/pharmacology/chemistry/chemical synthesis
Acetylcholinesterase/metabolism

@article {pmid41645728,
year = {2026},
author = {Lodhi, MS and Maisam, M and Khan, MT and Bibi, A and Wei, D and Mou, K},
title = {Targeted Nanodelivery of WGX50 and Curcumin via Gold Nanoparticles for Alzheimer's Therapy.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {3},
pages = {e71045},
doi = {10.1111/jcmm.71045},
pmid = {41645728},
issn = {1582-4934},
mesh = {*Curcumin/chemistry/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Gold/chemistry ; Animals ; *Metal Nanoparticles/chemistry ; Rats ; Male ; Disease Models, Animal ; Drug Delivery Systems ; Humans ; Blood-Brain Barrier/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Rats, Sprague-Dawley ; Nanoconjugates/chemistry ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, posing a global health challenge. It affects millions of people, causing cognitive decline and a heavy burden on healthcare systems. Neuroinflammation is a key pathological feature of AD, often associated with the dysregulation of microRNAs such as hsa-miR-146a-5p. WGX50 (N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-phenyl-acrylamide), a small molecule derived from Zanthoxylum bungeanum Maxim, has antioxidant and anti-inflammatory activities. While WGX50 demonstrates potent inhibition of neuroinflammation, its poor blood-brain barrier permeability may be improved using targeted delivery strategies. The current study aimed to design a novel nanoconjugate of WGX50 and curcumin with gold nanoparticles (AuNPs) to observe its therapeutic effects in a rat model. All nanoconjugates were synthesised as targeted (Cys-capped AuNPs with WGX50-insulin and curcumin-insulin) and non-targeted (without insulin). Immunohistochemical analysis revealed that both non-targeted (WGX50-NT) and targeted (WGX50-T) therapies have a significant effect in the rat model, with WGX50-T showing a more pronounced effect. The histopathology results of WGX50 and WGX50-T showed an approximate 80%-90% reduction in Aβ plaque deposition. The treatment with both curcumins targeted (C-T) and non-targeted (C-NT) formulations led to a significant reduction in Aβ levels in AD rats. Fluorescence microscopy confirmed that targeted delivery was more effective, potentially leading to better therapeutic outcomes. The expression levels of hsa-miR-146a-5p showed differential expression levels with targeted treatments correlating with lower expression levels, suggesting a role in modulating neuroinflammation and immune responses. Overall, these findings highlight the potential of targeted drug delivery systems in enhancing the efficacy of AD treatments.},
}

*Curcumin/chemistry/pharmacology/administration & dosage
*Alzheimer Disease/drug therapy/pathology/metabolism
*Gold/chemistry
Animals
*Metal Nanoparticles/chemistry
Rats
Male
Disease Models, Animal
Drug Delivery Systems
Humans
Blood-Brain Barrier/drug effects/metabolism
Amyloid beta-Peptides/metabolism
Rats, Sprague-Dawley
Nanoconjugates/chemistry

@article {pmid41645578,
year = {2026},
author = {İlhan, A and Güneş, F and Ertürk, A and Anıl, B and Gülçin, İ and Koca, M},
title = {Acetylcholinesterase and Carbonic Anhydrase Inhibition Profiles of New 5-HMF Chalcones and Their Ester Derivatives.},
journal = {Archiv der Pharmazie},
volume = {359},
number = {2},
pages = {e70198},
doi = {10.1002/ardp.70198},
pmid = {41645578},
issn = {1521-4184},
support = {TBTK-0097-8209//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; },
mesh = {*Carbonic Anhydrase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Molecular Docking Simulation ; *Chalcones/pharmacology/chemistry/chemical synthesis ; *Acetylcholinesterase/metabolism ; Structure-Activity Relationship ; Esters/pharmacology/chemistry/chemical synthesis ; Molecular Structure ; Dose-Response Relationship, Drug ; Carbonic Anhydrase I/antagonists & inhibitors/metabolism ; Carbonic Anhydrase II/antagonists & inhibitors/metabolism ; Humans ; Animals ; },
abstract = {Acetylcholinesterase (AChE) is one of the most important therapeutic targets in the treatment of neurological disorders such as Alzheimer's disease. In recent years, studies on the use of carbonic anhydrase (CA) inhibitors in the treatment of Alzheimer's disease have attracted considerable attention. In this study, novel benzene/5-HMF-chalcone hybrids and their benzoate esters were synthesized. Furthermore, the AChE, carbonic anhydrases I and II (CA I and II) inhibition potentials of the compounds were evaluated through in vitro enzyme inhibition assays and molecular docking studies to identify new potential drug candidate molecules. According to the inhibition results, the Ki values of the synthesized compounds were found to be in the range of 1.51-2.91 nM against AChE, 26.15-68.66 nM against CA I, and 27.91-107.04 nM against CA II. Molecular docking studies revealed that the compounds bind to both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, with Glide scores ranging from -5.76 to -8.50 kcal/mol. In contrast, the molecules interacted with the active site of CA I/II by coordinating with the catalytic Zn[2+] ion. All compounds complied with Lipinski's Rule of Five, indicating favorable drug-like properties. These results suggest that 5-HMF-chalcone hybrids and their benzoate derivatives could serve as promising scaffolds for the development of new anti-Alzheimer's agents. These findings suggest that 5-HMF-chalcone hybrids and their benzoate derivatives may be useful in establishing the structural basis of new anti-Alzheimer's agents.},
}

*Carbonic Anhydrase Inhibitors/pharmacology/chemical synthesis/chemistry
*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry
Molecular Docking Simulation
*Chalcones/pharmacology/chemistry/chemical synthesis
*Acetylcholinesterase/metabolism
Structure-Activity Relationship
Esters/pharmacology/chemistry/chemical synthesis
Molecular Structure
Dose-Response Relationship, Drug
Carbonic Anhydrase I/antagonists & inhibitors/metabolism
Carbonic Anhydrase II/antagonists & inhibitors/metabolism
Humans
Animals

@article {pmid41645538,
year = {2026},
author = {Yun, T and Xiao, Y and Gong, Y and Lai, Y and Huang, S and Ma, Y and Zeng, Y and Zhang, L and Deng, C},
title = {Maackiain Reduces Neuroinflammation by Modulating Inflammatory Signals in LPS-Induced In Vitro and In Vivo Models.},
journal = {Journal of microbiology and biotechnology},
volume = {36},
number = {},
pages = {e2508046},
doi = {10.4014/jmb.2508.08046},
pmid = {41645538},
issn = {1738-8872},
mesh = {Animals ; *Lipopolysaccharides ; Mice ; *Neuroinflammatory Diseases/drug therapy/chemically induced ; *Anti-Inflammatory Agents/pharmacology ; Reactive Oxygen Species/metabolism ; Disease Models, Animal ; Nitric Oxide/metabolism ; Cell Survival/drug effects ; Male ; Hippocampus/drug effects ; Cell Line ; Microglia/drug effects ; Cyclooxygenase 2/metabolism ; Mice, Inbred C57BL ; *Inflammation/drug therapy ; Mitochondria/drug effects ; Interleukin-6/metabolism ; Neurons/drug effects ; },
abstract = {Neuroinflammation, an immune process in the central nervous system (CNS), is a key contributor to a range of neurological diseases, including neurodegenerative disorders (e.g., Alzheimer's and Parkinson's disease), stroke, and depression, underscoring its significant pathological relevance. While maackiain (MAA) exhibits potent anti-inflammatory activity, its potential to mitigate neuroinflammation remains poorly understood. This study investigated the therapeutic effects of MAA on lipopolysaccharide (LPS)-induced neuroinflammation and its underlying mechanisms. In vitro, MAA significantly improved BV2 cell viability and reduced nitric oxide (NO) expression in LPS-treated cells, decreased the expression of reactive oxygen species (ROS), and it also inhibited the accumulation of Ferrous ion (Fe[2+]) and lipid peroxides as well as the damage to mitochondria. Higher concentrations of MAA were more effective, consistent with subsequent animal experiments. In vivo, mice treated with MAA showed improved memory in the Morris water maze compared to the LPS group. Nissl staining revealed fewer IBA-1 positive cells and a decrease in COX-2 and IL-6 levels in the hippocampus and cortex. This compound also increased the number of normal neurons in the cortex and CA3 region. The results of this study highlight the inhibitory effects of MAA on neuroinflammation, suggesting its potential as an effective therapeutic agent for treating neuroinflammation.},
}

Animals
*Lipopolysaccharides
Mice
*Neuroinflammatory Diseases/drug therapy/chemically induced
*Anti-Inflammatory Agents/pharmacology
Reactive Oxygen Species/metabolism
Disease Models, Animal
Nitric Oxide/metabolism
Cell Survival/drug effects
Male
Hippocampus/drug effects
Cell Line
Microglia/drug effects
Cyclooxygenase 2/metabolism
Mice, Inbred C57BL
*Inflammation/drug therapy
Mitochondria/drug effects
Interleukin-6/metabolism
Neurons/drug effects

@article {pmid41645510,
year = {2026},
author = {Weaver, MG and Abbott, JA and Popescu, GK},
title = {Distinct allosteric paths mediate Ca[2+]-dependent increase in the NMDA receptor sensitivity to open-channel blockers.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2026.02.002},
pmid = {41645510},
issn = {1542-0086},
abstract = {When active, NMDA receptors pass Ca[2+]-rich excitatory currents that are essential for the normal development and function of the central nervous system. In turn, fluctuations in extracellular Ca[2+] levels, as observed during synaptic activity and pathological states, affect the NMDA receptor gating kinetics and conductance. Here, we used patch-clamp electrophysiology, kinetic analyses, and mutagenesis to evaluate how changes in the ambient Ca[2+] concentration affect the sensitivity of recombinant NMDA receptors to open-channel blockers. NMDA receptor currents are characteristically sensitive to voltage-dependent block by Mg[2+], which endows them physiologically, with coincidence detection. This regulatory mechanism is shared with ketamine and memantine, two synthetic compounds that are clinically effective for treating depression and Alzheimer's disease, respectively. We found that extracellular Ca[2+] increased the sensitivity of NMDA receptors to block by Mg[2+] and memantine, but not by ketamine. Further, the effect of Ca[2+] on block by memantine required intracellular Ca[2+] and functional calmodulin, whereas the effect of Ca[2+] on block by Mg[2+] required the extracellular residue GluN1-D658. We conclude that extracellular Ca[2+] fluctuations modulate the sensitivity of NMDA receptors to open-channel blockers by discrete mechanisms, which may explain the distinct clinical profiles of NMDA receptor blockers.},
}

@article {pmid41645328,
year = {2026},
author = {Xiao, J and Liu, Y and Peng, M and Ma, J and Lei, S and Chen, Y and Liu, S and Zhao, X and Lu, D and Sun, Q},
title = {ISX9 activates the Wnt/β-catenin signaling pathway and exerts neuroprotective effects in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01961-5},
pmid = {41645328},
issn = {1758-9193},
support = {82470591//National Natural Science Foundation of China/ ; 82273485//National Natural Science Foundation of China/ ; JCYJ20240813142838050//Shenzhen Basic Research Program/ ; 2022A1515010598 and 2024A1515012466//Natural Science Foundation of Guangdong Province/ ; },
abstract = {BACKGROUND: Defective Wnt/β-catenin signaling is closely associated with the pathogenesis of Alzheimer's disease (AD), thus validating this pathway as a therapeutic target for AD. ISX9 is a potent agonist of the Wnt/β-catenin pathway. However, it remains unknown whether ISX9 exerts anti-AD effects by enhancing the Wnt/β-catenin signaling pathway. We therefore explored the neuroprotective potential of ISX9 using both hippocampal neuron-derived HT22 cells and 5×FAD transgenic mouse model of AD.

METHODS: In HT22 cells, we employed the SuperTOPFlash reporter gene, Co-IP and Western blot assays to investigate the mechanism by which ISX9 activates the Wnt signaling pathway. The effects of ISX9 on the biological behavior of HT22 cells were further evaluated through MTT, BrdU and IF staining. To study the therapeutic effect of ISX9 on AD, six-month-old 5×FAD transgenic mice were randomly divided into four groups: WT, WT/ISX9, AD and AD/ISX9. The mice were intraperitoneally injected with ISX9 or vehicle at an interval of one day for 2 months. Behavioral tests were conducted to evaluate the cognitive and learning abilities of mice, while the expression levels of Aβ peptides, Tau-related proteins, neuroinflammatory factors, blood-brain barrier (BBB)-related proteins and the components of Wnt/β-catenin signaling were investigated.

RESULTS: Our results demonstrated that ISX9 potently activated Wnt/β-catenin signaling by promoting the association of LRP6 with AXIN1, and increased the viability and proliferation of hippocampal cells. At the behavioral level, ISX9 improved learning and memory abilities in 5×FAD mice, and ameliorated hippocampal neuronal damage. Furthermore, ISX9 treatment effectively reduced the expression of Aβ peptides, total Tau, and phosphorylated Tau (S404) proteins in the AD mice. Mechanistically, ISX9 exhibited its neuroprotective effects, activating the Wnt/β-catenin signaling pathway via potentiating the interaction of LRP6 with AXIN1, upregulating the expression of BBB-related proteins and downregulating neuroinflammatory factors in AD mice.

CONCLUSION: Our findings indicate that ISX9 potently activates the Wnt/β-catenin signaling pathway and confers cognitive protection in hippocampal cells and AD mice. This compound may serve as a promising therapeutic agent for the treatment of AD.},
}

@article {pmid41645313,
year = {2026},
author = {Aslanyan, A and Foiani, MS and Giovannucci, TA and McDade, E and Duff, KE and Mummery, CJ and Schöll, M and Wildsmith, KR and Paterson, RW},
title = {Targeting tau in Alzheimer's Disease: rationale, approach and challenges.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00925-5},
pmid = {41645313},
issn = {1750-1326},
support = {PTC-22-982162//Alzheimer's Association Part the Cloud/ ; ARUK-RF2023B-015//Alzheimer's Research UK Research Fellowship/ ; 23AARFD-1029918/ALZ/Alzheimer's Association/United States ; K23AG046363; U01AG059798/AG/NIA NIH HHS/United States ; KAW2014.0363 and KAW2023.0371//Knut and Alice Wallenberg Foundation (Wallenberg Centre for Molecular and Translational Medicine/ ; 2017-02869, 2021-02678, 2021-06545 and 2023-06188//Swedish Research Council/ ; 101132933 (AD-RIDDLE) and 101112145 (PROMINENT)//the European Union's Horizon Europe research and innovation program/ ; R01 AG081394-01//National Institute of Health/ ; ALFGBG-813971 and ALFGBG-965326//the ALF-agreement/ ; FO2021-0311 and FO2024-0372//Swedish Brain Foundation/ ; AF-1011738//the Swedish Alzheimer Foundation/ ; VGFOUREG-995510//the Västra Götaland Region R&D/ ; RS-2023-00263612//the National Research Foundation of Korea/ ; AACSF-20-685780//Alzheimer's Association Clinician Scientist Fellowship/ ; },
}

@article {pmid41645227,
year = {2026},
author = {Vigneswaran, S and Verberk, IMW and Rousset, RZ and Gouda, M and Trieu, C and Claessen, T and de Giessen, EV and Lemstra, AW and Wilson, D and Pijnenburg, YAL and Flier, WMV and Teunissen, CE and Harten, ACV},
title = {Real-world diagnostic performance of blood-based biomarkers for Alzheimer's disease: robust performance except after stroke and high charlson comorbidity index.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01979-9},
pmid = {41645227},
issn = {1758-9193},
abstract = {BACKGROUND: Accurate plasma biomarker interpretation is essential for diagnosing Alzheimer's disease (AD). This study evaluated how patient factors influence the association between plasma biomarkers and amyloid status in a memory clinic population.

METHODS: A cross-sectional study of 1199 participants from the Amsterdam Dementia Cohort analysed plasma biomarkers (pTau217, pTau181, Aβ42/40, GFAP, NfL, and a combined panel) and patient factors (comorbidities, medication use, vital signs, body mass index, and kidney function). Amyloid status was determined via amyloid PET (n = 309) or CSF pTau181/Aβ1-42 (n = 890).

RESULTS: Stroke, hypercholesterolemia, antidepressant use and Charlson Comorbidity Index (CCI) influenced biomarker performance. Stroke reduced the diagnostic value of pTau217, Aβ42/40 and the biomarker panel, while hypercholesterolemia and antidepressant use enhanced pTau217 and Aβ42/40, respectively. A CCI ≥ 2 reduced the biomarker panel's performance.

CONCLUSIONS: Overall, patient factors had limited impact on biomarkers, but caution is needed for patients with stroke or high CCI.},
}

@article {pmid41645184,
year = {2026},
author = {Liu, D and Baranova, A and Sun, W and Cao, H and Zhang, B and Zhang, F and , and , },
title = {A phenome-wide hunt for risk factors of Alzheimer's disease: from metabolic clues to neuroimaging evidence.},
journal = {Journal of translational medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12967-026-07756-4},
pmid = {41645184},
issn = {1479-5876},
abstract = {BACKGROUND: This study systematically investigated phenotypes causally associated with Alzheimer's disease (AD) across the phenome and validated the findings at cognitive and neuroimaging levels using real-world clinical data.

METHODS: We performed phenome-wide Mendelian Randomization (MR) analyses on genetic proxies for over 860 disease phenotypes to identify traits causally associated with AD. Lipid metabolism-related phenotypes identified through MR were further examined in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset to assess associations with AD risk, brain structure, and cognition.

RESULTS: MR analyses revealed a significant causal association between lipid metabolism, particularly low-density lipoprotein cholesterol (LDL-C), and the risk of AD (OR: 1.05, 95% CI: 1.03-1.07). In ADNI, higher LDL-C indicators correlated with increased AD risk, reduced hippocampal and entorhinal volumes, and poorer cognitive performance. Notably, elevated cholesterol-to-total lipid ratios in small LDL particles were negatively associated with the entorhinal-hippocampal complex. Among cognitively normal individuals, higher LDL-C indicators were associated with smaller hippocampus-amygdala transition area (HATA) and CA3 head volumes. In those with mild cognitive impairment, higher LDL-C was associated with reduced entorhinal surface area.

CONCLUSIONS: Our findings suggest that disrupted LDL-C metabolism may play a causal role in the development and progression of AD.},
}

@article {pmid41644863,
year = {2026},
author = {Ma, Z and Xiao, Z and Yang, Z and Huang, B and Wang, X},
title = {Trends and Research Frontiers in Mammalian Target of Rapamycin and Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {421},
pmid = {41644863},
issn = {1559-1182},
support = {2023YFS0212//Sichuan Provincial Department of Science and Technology Foundation (Key research and development projects)/ ; 2022NSFSC0677//Natural Science Foundation of Sichuan Province/ ; },
mesh = {*Alzheimer Disease/metabolism/drug therapy ; *TOR Serine-Threonine Kinases/metabolism ; Humans ; Animals ; Bibliometrics ; *Biomedical Research/trends ; },
abstract = {BACKGROUND: The mammalian target of rapamycin (mTOR) plays a pivotal role in regulating neuronal survival and synaptic plasticity, both of which are crucial for the progression of Alzheimer's disease (AD). This study aims to delineate the research trends concerning mTOR and AD through bibliometric analysis.

METHODS: A systematic search was conducted in the Web of Science Core Collection database to retrieve publications relevant to mTOR and AD from 2003 to 2025. Subsequently, bibliometric analysis and visualization were performed utilizing VOSviewer, CiteSpace, and the R package "Bibliometrix."

RESULTS: A total of 1,025 articles were included in the analysis. The annual publication growth rate reached 21.22%, peaking in 2022. The three most cited articles addressed topics such as autophagy induction and clearance in neurons related to AD pathology, mTOR in microglial metabolic fitness, and mTOR inhibition against cognitive deficits. China led in publication volume, followed by the USA. The University of Texas System, Egyptian Knowledge Bank, and University of Texas Health Science Center at San Antonio emerged as the top 3 institutions. Oddo Salvatore ranked as the top author by H-index. Keyword analysis revealed four prominent clusters: cellular signaling and neuroplasticity, molecular mechanisms, neuroprotective effects of mTOR inhibition, and roles of mTOR in AD pathogenesis. Burst analysis identified "target," "neuroinflammation," "stress," "kinase," and "clearance" as the latest hotspots in the field.

CONCLUSION: This bibliometric analysis provides a comprehensive overview of publication trends related to mTOR and AD. Future research is anticipated to focus on refining mTOR inhibitors as a therapeutic strategy and further exploring the underlying mechanisms of AD.},
}

*Alzheimer Disease/metabolism/drug therapy
*TOR Serine-Threonine Kinases/metabolism
Humans
Animals
Bibliometrics
*Biomedical Research/trends

@article {pmid41644802,
year = {2026},
author = {Healey, N},
title = {Blood tests for Alzheimer's disease could reshape research and care.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {41644802},
issn = {1546-170X},
}

@article {pmid41644506,
year = {2026},
author = {Zhou, X},
title = {Natural Anti-NMDAR1 autoantibodies associate with slowed decline of cognitive functions in Alzheimer's diseases.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-03878-x},
pmid = {41644506},
issn = {2158-3188},
support = {NIH R01NS135620//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
abstract = {Low titers of blood circulating natural anti-NMDAR1 autoantibodies were reported in ~10% of the general human population. Their potential effects on NMDAR functions in the brain, however, remain unknown. We developed a new method to more accurately quantify these low titers of natural anti-NMDAR1 autoantibodies. After quantifying natural anti-NMDAR1 autoantibodies in the plasma of 324 subjects (163 healthy controls; 161 Alzheimer's disease (AD) patients), I found that AD patients carrying higher levels of natural anti-NMDAR1 autoantibodies have significantly (p value: 0.0015) higher scores of Mini-Mental State Examination (MMSE score: 23.5) than AD patients carrying lower levels of natural anti-NMDAR1 autoantibodies (MMSE score: 21.4). No significant differences in MMSE scores were, however, found between healthy controls with either higher or lower levels of natural anti-NMDAR1 autoantibodies, indicating little harmful effect of the autoantibodies. Consistently, superior cognitive performances were found in AD patients carrying higher levels of natural anti-NMDAR1 autoantibodies in comparison with AD patients carrying lower levels of the autoantibodies. Although this association is intriguing, a causal relationship between natural anti-NMDAR1 autoantibodies and neuroprotection has not yet been established. Since anti-NMDAR1 autoantibodies can bind NMDA receptors to suppress glutamate excitotoxicity in the brain, natural anti-NMDAR1 autoantibodies may have neuroprotective effects against cognitive decline in AD patients.},
}

@article {pmid41644472,
year = {2026},
author = {O'Shea, DM and Dhanekula, D and Kumar, S and Wang, L and Wiese, L and Rundek, T and Galvin, JE},
title = {Community perspectives on epigenetic dementia risk testing: Willingness, implementation preferences, and reasons for not testing in midlife and older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71094},
doi = {10.1002/alz.71094},
pmid = {41644472},
issn = {1552-5279},
support = {//National Centers for Advancing Translational Sciences (NCATS)/ ; //National Institutes of Health (NIH)/ ; 1K12TR004555//Clinical and Translational Science Award (CTSA) Program/ ; //Miami Clinical and Translational Science Institute (CTSI)/ ; },
mesh = {Humans ; Male ; Female ; Middle Aged ; *Dementia/genetics/diagnosis ; Aged ; Surveys and Questionnaires ; Health Literacy ; Risk Assessment ; *Genetic Testing ; },
abstract = {INTRODUCTION: Epigenetic assays may support non-invasive dementia risk stratification; community views on willingness and implementation remain under-characterized.

METHODS: In a survey of 425 adults ≥50 years old, we assessed the willingness for a hypothetical epigenetic test, implementation preferences, reactions to a high-risk result, behavior-change intentions, and reasons for not testing using multivariable models.

RESULTS: Overall, 82.1% showed a willingness. Health literacy (odds ratio [OR] = 2.61) and Alzheimer's disease (AD) concern (OR = 2.06) increased that willingness; doctor dependence decreased it (OR = 0.62). The top drivers were perceived to be accuracy and speed. The preferred modality was a combination of biomarker and cognitive over biomarker-only. Intended changes prioritized alcohol reduction, then diet, exercise, cognitive activity. Risk worry and insurance concerns exceeded stigma; higher literacy related to lower stigma, and epigenetics familiarity and AD worry related to higher insurance concern. The reasons for not testing were data privacy/accuracy concerns, logistics/costs, and needles.

DISCUSSION: Findings support emphasizing test accuracy, turnaround, and governance/legal information when implementing DNAm testing for dementia risk.},
}

Humans
Male
Female
Middle Aged
*Dementia/genetics/diagnosis
Aged
Surveys and Questionnaires
Health Literacy
Risk Assessment
*Genetic Testing

@article {pmid41644076,
year = {2026},
author = {Boyle, TA and Dixit, S},
title = {Oral Anticoagulation Use and Dementia Risk in Patients with Atrial Fibrillation.},
journal = {Trends in cardiovascular medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tcm.2026.02.001},
pmid = {41644076},
issn = {1873-2615},
}

@article {pmid41644019,
year = {2026},
author = {Yao, LL and Ma, XT and Li, FB and Zheng, LY and Zeng, Q and Zhu, JW and Liu, SW and Du, YT and Chen, H and Sun, YY and Wang, EL and Liu, CF and Ma, QH and Hu, H},
title = {Correlation between sarcopenia and changes in oligodendrocyte lineage cells in the brains of Alzheimer's disease model mice.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {113057},
doi = {10.1016/j.exger.2026.113057},
pmid = {41644019},
issn = {1873-6815},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive dysfunction. The discovery and identification of non-cognitive symptoms in the preclinical stage hold promise for early diagnosis and intervention. Previous studies have shown that diagnosed AD patients commonly exhibit alterations in sarcopenia-related indicators, which might represent early symptoms of progression from mild cognitive impairment (MCI) to AD.

METHODS: This study used 3-month-old APP/PS1 transgenic (AD) mice and C57BL/6J wild-type (WT) mice. Hindlimbs were immobilized with plaster casts for 2 weeks. After immobilization, body, brain, and muscle weights were measured. Behavioral tests were conducted. Immunofluorescence staining was used to assess muscle morphology and analyze oligodendrocyte precursor cells (OPCs) lineage-related indicators.

RESULTS: Hindlimb immobilization induced sarcopenia in both AD and WT mice, manifested as decreased body, brain, gastrocnemius (Gas), and soleus (Sol) muscle weights. Immobilized mice showed decreased motor ability and impaired exploration behavior. Long-term spatial learning and memory were also affected. Muscle histological analysis revealed that AD mice exhibited baseline muscle fiber type switching. After immobilization, AD mice showed increased proportions of MyHC IIa fast-twitch fibers in the Sol and MyHC IIb fast-twitch fibers in the tibialis anterior (TA). At the central nervous system level, immobilization inhibited the OPCs proliferation and significantly increased activation of microglia and astrocytes of immobilized mice.

CONCLUSION: Hindlimb immobilization-induced sarcopenia correlated with slow-to-fast fiber transformation, reduced OPCs proliferation, and enhanced neuroinflammation. This study highlights the importance of sarcopenia in the progression of AD-related white matter pathology.},
}