@article {pmid41555522,
year = {2026},
author = {Lahiri, D and Cooper, J and Seixas-Lima, B and Roncero, C and Wellington, C and Cherktow, H},
title = {CAPS Plus: A Clinical Biomarker Scoring System to Predict Aβ Positivity and Facilitate Enrollment in Anti-Amyloid Clinical Trials.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-8},
doi = {10.1017/cjn.2026.10530},
pmid = {41555522},
issn = {0317-1671},
abstract = {BACKGROUND: A critical step toward determining eligibility for experimental and clinical treatment with anti-amyloid therapies in Alzheimer's disease (AD) is to select appropriate subjects having a high likelihood of being Aβ+. We propose a clinical biomarker composite score, named Clinical β-Amyloid Positivity Prediction Score Plus (CAPS Plus), for Aβ+ prediction in people presenting with clinical Alzheimer's syndrome including both prodromal and mild AD.

METHODS: The original CAPS incorporated scores from the neuropsychiatry inventory questionnaire, mini-mental state examination score loss per year and Fazekas score. Plasma p-tau-217, a novel addition to CAPS, was measured using the Simoa HD-X with the AlzPATH p-tau217 Advantage Plus assay. To incorporate p-tau-217 into CAPS Plus, an intra-cohort cut-off (>0.698 pg/ml) for p-tau217 was generated using logistic regression and Yoden's index. CAPS Plus had a maximum score of 5, with those ≥4 indicating a high probability of being Aβ+. The accuracy of CAPS Plus was computed through logistic regression and area under the receiver operating characteristic curve (AUROC) analysis.

RESULTS: Of n = 44 patients, n = 25 (57%) were Aβ+. Plasma p-tau-217 was significantly higher in the Aβ+ subgroup (1.36 vs 0.46 pg/mL, p < 0.0001). The AUROC was 0.89 for a CAPS Plus score of 4 or more, suggesting excellent discrimination and improving the accuracy of the original CAPS (0.86). CAPS Plus has a notably better specificity (89%) than the original CAPS (80%) and p-tau-217 alone (74%).

CONCLUSION: CAPS Plus is potentially a useful screening tool for enrollment in anti-Aβ therapy and clinical trials for AD, specifically addressing people with prodromal and mild AD.},
}

@article {pmid41881284,
year = {2026},
author = {Labib, MS and Abd-Allah, H and Bazan, LS and Ibrahim, HM and Abdel-Mottaleb, MMA},
title = {Nose-to-Brain delivery of genistein-loaded peppermint lipid nanocapsules for neuroprotection against Alzheimer's Disease: Formulation, Characterization, pharmacokinetic and Pharmacodynamic studies.},
journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V},
volume = {},
number = {},
pages = {115066},
doi = {10.1016/j.ejpb.2026.115066},
pmid = {41881284},
issn = {1873-3441},
abstract = {Lipid nanocapsules (LNC) are promising nanocarriers that have known mucus permeation enhancement properties, this makes them suitable for intranasal administration. They could act as potential nose-to-brain carriers for drugs like genistein with poor aqueous solubility and extensive metabolism, making them reach the brain in effective concentrations. This study was conducted to observe the effects of different essential oils (peppermint, lavender, and eucalyptus essential oils) on LNC characteristics including particle size, polydispersity index, and zeta potential. The optimized genistein-loaded peppermint LNC experienced a nearly full in-vitro release in 10 h. Transmission electron microscope, differential scanning calorimetry, and Fourier-transform infrared spectroscopy ensured the successful preparation of this formulation. In-vivo pharmacokinetic study revealed that the optimized LNC had better relative bioavailability than drug suspension by 60% with earlier T max at 30 min and C max of 23.17 ± 1.5 µg/g brain tissue. Pharmacodynamic assessment in AlCl3-induced Alzheimer's disease in rats showed that the optimized LNC preserved the spatial and reference memory in Morris water maze test. Biochemical analyses confirmed the enhanced oxidative defense (increased superoxide dismutase, reduced glutathione, and decreased malondialdehyde) and the inhibition of acetylcholinesterase enzyme. Histopathological examination showed preserved neuronal structure in the hippocampal brain region. Genistein-loaded peppermint LNC were able to have neuroprotective effects, making the intranasal LNC formulation a promising candidate for the neuroprotection against Alzheimer's disease.},
}

@article {pmid41881316,
year = {2026},
author = {Huang, Y and Wang, Y and Wang, Y and Cheng, H and Yang, H and Wang, C and Xu, Y},
title = {The design, synthesis and evaluation of [[18]F]ASK1-IN-6 as the first Fuorine-18 positron emission tomography radiotracer for ASK1 neuroimaging.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {130628},
doi = {10.1016/j.bmcl.2026.130628},
pmid = {41881316},
issn = {1464-3405},
abstract = {ASK1 is a key regulator in the molecular mechanisms underlying multiple neurological diseases, where it drives oxidative stress, inflammation, and apoptotic pathways. ASK1 has emerged as a potential therapeutic target in a range of neurodegenerative and neuroinflammatory diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. In the study, we designed and synthesized [[18]F]ASK1-IN-6 as the first fluorine-18 ASK1 radioligand with high purity (>95%). In in vitro autoradiography studies, [[18]F]ASK1-IN-6 showed good binding specificity to ASK1 protein and exhibited high binding in various brain regions of mice. Furthermore, the binding specificity of the [[18]F]ASK1-IN-6 in brain slice of wild-type mice and AD model (5 × FAD) mice were explored, the results showed [[18]F]ASK1-IN-6 have higher binding in AD model mice, indicating that the compound has great potential for brain imaging in AD patients. Further study will focus on improving the synthesis yield of the compound and investigate its in vivo imaging in mice.},
}

@article {pmid41881887,
year = {2026},
author = {Long, S and Wang, J and Li, Y and Zhang, L and Cui, W and Zhang, Y and Li, B},
title = {Multimodal profiling of gray matter differences in alcohol use disorder: An integrated SDM-PSI meta-analysis with neuroimaging fusion study.},
journal = {Drug and alcohol dependence},
volume = {283},
number = {},
pages = {113119},
doi = {10.1016/j.drugalcdep.2026.113119},
pmid = {41881887},
issn = {1879-0046},
abstract = {BACKGROUND: Alcohol use disorder (AUD) represents a major global health and economic challenge. While neuroimaging consistently reports widespread gray matter (GM) differences in AUD, the underlying molecular mechanisms, neurotransmitter associations, and genetic architecture remain insufficiently characterized.

METHODS: A coordinate-based meta-analysis was performed using Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) on 29 voxel-based morphometry studies (1112 individuals with AUD; 1136 controls). The resulting GM difference map was integrated with multimodal data to examine spatial associations with neurotransmitter systems (JuSpace), gene expression profiles (Allen Human Brain Atlas, noting its sample limitation of six donors), and behavioral and disease domains (BrainMap). Meta-regressions assessed associations with clinical variables.

RESULTS: Compared to controls, individuals with AUD showed lower GM volume in the left anterior cingulate/paracingulate gyri, left postcentral gyrus, and right Rolandic operculum. Behavioral decoding linked these regions to executive function, attention, reward-related emotion, and somatosensory processing. The spatial pattern showed overlap with schizophrenia, major depressive disorder, and Alzheimer's disease. Meta-regression associated GM volume with AUD duration, age of onset, anxiety, and depression severity. GM differences were spatially associated with serotonergic, dopaminergic, noradrenergic, and opioidergic receptor and transporter distributions. Transcriptomic analysis revealed enrichment in genes related to synaptic signaling, glutamatergic function, and myelination.

CONCLUSION: This multimodal meta-analysis identifies a consistent pattern of GM differences in AUD associated with behavioral domains, shared neuroanatomy across psychiatric conditions, and convergent neurotransmitter and genetic profiles, supporting a multi-system pathophysiological framework while highlighting the need for future causal investigations.},
}

@article {pmid41881962,
year = {2026},
author = {Baek, S and Jang, J and Yeo, S and Jung, HJ and Choe, Y},
title = {Oligodendrocyte precursor cells-microglia crosstalk via BMP4 drives microglial neuroprotective response and mitigates Alzheimer's disease.},
journal = {Signal transduction and targeted therapy},
volume = {11},
number = {1},
pages = {},
pmid = {41881962},
issn = {2059-3635},
mesh = {Animals ; *Bone Morphogenetic Protein 4/genetics ; *Alzheimer Disease/genetics/pathology/metabolism/immunology ; *Microglia/metabolism/pathology/immunology ; Mice ; Humans ; *Oligodendrocyte Precursor Cells/metabolism/pathology/immunology ; Signal Transduction/genetics ; Membrane Glycoproteins/genetics ; Receptors, Immunologic/genetics ; Neuroprotection/genetics ; Mice, Transgenic ; },
abstract = {Oligodendrocyte precursor cells (OPCs) rapidly respond to neural injury, becoming activated to preserve myelin homeostasis and interacting with diverse cell types in the central nervous system (CNS). However, the molecular basis of OPC communication with the CNS immune system remains poorly understood. In Alzheimer's disease (AD), microglia respond to amyloid pathology in a neuroprotective manner. Here, we found that Bmp4 produced by late-stage OPCs, termed committed oligodendrocyte precursors (COPs), acts as a critical signal shaping microglial neuroprotective programs in the context of amyloid pathology. OPC-specific genetic ablation of Bmp4 in 5xFAD mice suppressed microglial immune responses and exacerbated amyloid deposition. Single-cell RNA sequencing revealed that Bmp4 deficiency in COPs led to downregulation of disease-associated microglia (DAM) genes in the microglial cluster. Mechanistically, Bmp4-dependent Smad1/5/8 signaling directly regulated Trem2 expression in microglia. Replenishment of Bmp4-expressing COPs in 5xFAD mice enhanced Trem2[+] DAM acquisition, promoting beneficial barrier formation around Aβ plaques. Similarly, intracerebroventricular (ICV) administration of Sox10 promoter-driven AAV-Bmp4 efficiently ameliorated AD progression. Collectively, these findings uncover an OPC-microglia crosstalk that governs immune surveillance in AD, highlighting COP-targeted enhancement of Bmp4 as a promising avenue for interventions aimed at reinforcing early neuroprotective responses.},
}

Animals
*Bone Morphogenetic Protein 4/genetics
*Alzheimer Disease/genetics/pathology/metabolism/immunology
*Microglia/metabolism/pathology/immunology
Mice
Humans
*Oligodendrocyte Precursor Cells/metabolism/pathology/immunology
Signal Transduction/genetics
Membrane Glycoproteins/genetics
Receptors, Immunologic/genetics
Neuroprotection/genetics
Mice, Transgenic

@article {pmid41882255,
year = {2026},
author = {Yan, Y and Song, D and Li, G and Li, J and Tang, Y and Li, D and Mao, J and Li, H and Liu, X and Yu, D and Ma, F and Pang, Y and Jin, Y and Deng, Y and Qiu, Y and Quan, Z and Ni, J and Cheng, Y and Wang, Z and Dong, Z and Hong, Q},
title = {The dynamic impairment of synaptic transmission in the PCx-IL engram circuit contributes to early olfactory memory decline in Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41882255},
issn = {1476-5578},
support = {82371446//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Olfactory dysfunction has emerged as a promising target for the early diagnosis and treatment of Alzheimer's disease (AD). However, the mechanisms underlying neural circuit disruption associated with olfactory dysfunction in AD remain poorly understood. We conducted single-cell RNA sequencing (RNA-seq) and ex vivo electrophysiological studies to determine the link between olfactory memory in AD and dynamic synaptic transmission disorders in PCx-IL engram cell circuits. Clinical functional magnetic resonance imaging (fMRI) data revealed that connectivity between the piriform cortex (PCx) and the infralimbic cortex (IL) was impaired during the early mild cognitive impairment (MCI) stage of AD. Optogenetic stimulation of IL-projecting PCx engram neurons successfully improved olfactory memory retrieval in 5xFAD mice. In addition, single-cell RNA sequencing was employed to investigate the mechanisms of damage in IL engram cells, which revealed increased glutamate expression and impaired synaptic function as key alterations. Guided by single-cell sequencing data, we analyzed glutamatergic synaptic transmission in the PCx-IL engram cell circuit in 5xFAD mice. These results indicated dynamic impairments in AMPA receptor-associated synaptic transmission within this circuit. Optical long-term potentiation (LTP) of synaptic transmission restored directional engram synaptic transmission and prevented olfactory memory decline. Therefore, dynamic impairment of synaptic transmission in the PCx-IL engram cell circuit underlies the early decline in olfactory memory in AD. Impairment of PCx-IL functional connectivity may represent a new target for the diagnosis and treatment of early-stage AD.},
}

@article {pmid41882372,
year = {2026},
author = {Hajjar, IM and Neal, R and Singh, N and Yang, Z and Obideen, M and Shah, AM and Dammer, EB},
title = {Adhesion molecules provide an endothelial protein signature in preclinical and clinical Alzheimer's disease and predict clinical progression.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01519-4},
pmid = {41882372},
issn = {2730-664X},
abstract = {BACKGROUND: Cardiometabolic and inflammatory pathways may play important roles in Alzheimer's disease (AD) pathogenesis contributing to neuronal dysfunction even in the absence of cognitive symptoms. Our objective is to characterize proteomic signatures of these pathways in AD.

METHODS: We perform CSF and plasma-targeted proteomics using Olink's highly sensitive proximity extension assay from 354 participants, of which 4.2% had preclinical AD, and 19.5% had prodromal AD. Using data-driven bioinformatic pipeline, we describe proteomic signatures based on various AD traits.

RESULTS: The 276 measured proteins cluster into five modules that are associated with AD biomarkers and disease traits. We identify an AD signature in the CSF characterized by elevated levels of Hepatocyte Growth Factor (HGF), Intercellular and Vascular Cell Adhesion Molecules 1 (ICAM-1, VCAM-1), Neuropilin 1 and 2 (NRP-1, NRP-2), Scavenger Receptor Class B Member 2 (SCARB2), and Plasminogen Activator Urokinase (PLAU) that was detectable even in preclinical AD. This signature also predicts clinical disease progression. Independent validation (n = 75) suggests that CSF adhesion molecules showed significant positive correlation with CSF Aβ-42: (R[2] ranged: 0.05-0.44) and pTau (R[2] ranged: 0.15-0.70).

CONCLUSIONS: Our results identify a signature centered around CSF vascular adhesion proteins that associates with AD pathology and disease progression, with elevation detectable even in the preclinical stage, warranting further mechanistic investigation.},
}

@article {pmid41882455,
year = {2026},
author = {Guo, J and Liu, J and Zhang, Y and Liu, J and Zhai, H and Li, L and Han, H},
title = {Ultrastructural Evidence of Altered Dendritic Morphology in the Prefrontal Cortex of Alzheimer's Model Rats.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41882455},
issn = {1995-8218},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with synaptic pathology as a core theme in aging-related research. Conventional imaging and limited tools fail to resolve AD-relevant nanoscale structures. Here, we present an automated pipeline integrating volume electron microscopy (vEM) with deep learning to analyze synapses and subcellular components, enabling 3D reconstruction of neuronal architecture in ~130,000 μm[3] of rat prefrontal cortex (PFC). Preliminary results from small animal samples show that, vs. controls, AD rats have fewer mushroom spines but more thin/stubby spines. Synaptic and mitochondrial surface area/volume are reduced, with increased multi-contact synapses. These findings suggest mature spine loss with compensatory morphological changes, potentially impairing dendritic integration. Our method highlights the potential of vEM-deep learning integration for detailed ultrastructural quantification in neurodegenerative models, laying a foundation for future large-sample pathological studies.},
}

@article {pmid41882463,
year = {2026},
author = {Farouk, YK and Nagy, NE and El Amir, AM and Madbouly, NA and El-Khazragy, N},
title = {Investigating the Impact of ABCB1 3435C>T (rs1045642) Variant on Severity and Cognitive Decline in Egyptian Alzheimer's Disease Patients.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41882463},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/genetics ; Male ; Female ; Egypt/epidemiology ; *Cognitive Dysfunction/genetics ; ATP Binding Cassette Transporter, Subfamily B/genetics ; *Polymorphism, Single Nucleotide/genetics ; Aged ; *Genetic Predisposition to Disease ; Case-Control Studies ; *Severity of Illness Index ; Middle Aged ; Gene Frequency/genetics ; Genotype ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a complex genetic risk. The ABCB1 gene encodes P-glycoprotein, a blood-brain barrier efflux transporter involved in amyloid-β (Aβ) clearance. Variants in ABCB1 3435C>T (rs1045642) may influence AD susceptibility and severity, but data from Middle Eastern populations remain limited. The objective of the study is to investigate the ABCB1 3435C>T (rs1045642) polymorphism with AD susceptibility, dementia severity, and cognitive impairment in an Egyptian cohort. A case-control study was conducted on 300 subjects, including 150 cognitively healthy controls and 150 clinically diagnosed AD patients. Genotyping for ABCB1 3435C>T (rs1045642) was performed by polymerase chain reaction (PCR). Associations between genotype distribution and AD risk, Clinical Dementia Rating (CDR) scores, and Mini-Mental State Examination (MMSE) categories were analyzed. Logistic regression and Fisher's exact tests were applied to calculate odds ratios (OR) and 95% confidence intervals (CI). The CC genotype was significantly more frequent among controls (64.8%) compared with AD patients (35.2%), whereas the TT genotype predominated in AD (70.5% vs 29.5%). CC carriers were enriched in mild dementia and higher MMSE categories, while TT carriers dominated in severe dementia and lower MMSE groups. Logistic regression confirmed that TT carriers had a 4.4-fold increased risk of AD compared with CC (p < 0.001) and a 13.3-fold higher likelihood of scoring < 20 on MMSE (p < 0.001). The ABCB1 3435C>T (rs1045642) variant significantly influences AD susceptibility and cognitive decline in Egyptians, with TT conferring risk and CC exerting a protective effect. Genotyping may aid risk stratification and monitoring of disease progression.},
}

Humans
*Alzheimer Disease/genetics
Male
Female
Egypt/epidemiology
*Cognitive Dysfunction/genetics
ATP Binding Cassette Transporter, Subfamily B/genetics
*Polymorphism, Single Nucleotide/genetics
Aged
*Genetic Predisposition to Disease
Case-Control Studies
*Severity of Illness Index
Middle Aged
Gene Frequency/genetics
Genotype

@article {pmid41882476,
year = {2026},
author = {Ham, L and Villers, O and Lobo, JD and Bell, TR and Cookson, D and Galasko, D and Letendre, SL and Bondi, MW and Moore, DJ and Sundermann, EE},
title = {A cross-cohort comparison of the prevalence and clinical significance of Alzheimer's disease biomarkers in people with versus without HIV.},
journal = {Journal of neurovirology},
volume = {32},
number = {2},
pages = {},
pmid = {41882476},
issn = {1538-2443},
}

@article {pmid41882703,
year = {2026},
author = {Cao, F and Liu, J and Zuo, H and Lin, X and Su, Y and Wang, C and Cui, H and Du, J and Zhang, Y},
title = {Estradiol ameliorates AD pathology and cognitive deficits by SORLA-mediated APP endosomal trafficking.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02027-2},
pmid = {41882703},
issn = {1758-9193},
support = {82201731//the National natural Science Foundation of China/ ; HJYB202511//the Hebei Province Yanzhao Golden Platform Project/ ; H2024206135//the Natural Science Foundation of Hebei Province/ ; },
}

@article {pmid41882986,
year = {2026},
author = {Hoque, A and Cuthel, A and Grudzen, CR and Shah, MN and Brody, AA and Fleisher, JE and DiMascio-Donohue, J and McLain, K and Tun, LT and Levine, J and Goldfeld, KS and Chodosh, J and , },
title = {Emergency Departments Leading the Transformation of Alzheimer's and Dementia Care: Emergency Care Redesign.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70394},
pmid = {41882986},
issn = {1532-5415},
support = {U19 AG078105-01A1/AG/NIA NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; },
abstract = {Over 50% of persons living with dementia (PLWD) and their care partners (dyads) visit the emergency department (ED) every year. In the ED, healthcare professionals face complex challenges managing acute issues and symptoms of Alzheimer's disease and Alzheimer's disease-related dementias without provider training or in-ED structures to ensure a successful discharge. While many of these visits are for conditions more suitable for ambulatory care, as many as 50% of PLWD discharged from the ED return within 30 days, suggesting opportunities to improve ED care, and discharge processes. Emergency Care Redesign (ECR) includes intentional workflows where physicians, nurses, and social workers engage in a team-based approach with structured assessments to manage a myriad of potential psychosocial and behavioral issues contributing to the need for ED care. Three core components comprise this evidence-based, efficient pragmatic intervention for PLWD and their care partners: (1) problem identification, (2) problem prioritization, and (3) provision of non-pharmacologic solutions supported by community resources. Although these components are essential to provide optimal ED care and reduce revisits and other adverse outcomes, they require an embedded clinical decision support structure, focused training, and clear workflows. In this paper, we describe the ECR intervention as one of three being implemented in the cluster-randomized multifactorial pragmatic trial, Emergency Departments LEading Transformation of Alzheimer's and Dementia Care (ED-LEAD), designed to improve care for PLWD and their outcomes after discharge home within 15 health systems and 79 EDs across the United States.},
}

@article {pmid41883006,
year = {2026},
author = {García de la Garza, Á and Wang, C and Derby, CA and Gao, Q and Ye, KQ and Zetterberg, H and Engeland, CG and Lipton, RB and Katz, MJ},
title = {Generalizability of blood-based biomarkers of Alzheimer's disease and related dementias in a multicultural cohort of older adults: The effect of adjustment for kidney function.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261426582},
doi = {10.1177/13872877261426582},
pmid = {41883006},
issn = {1875-8908},
abstract = {BackgroundInterpreting blood-based biomarkers of Alzheimer's disease and related dementias (ADRD) in a multicultural cohort is complicated by inconsistent evidence on racial differences. Kidney function, which varies by race and influences biomarker levels, is often overlooked, potentially contributing to these inconsistencies.ObjectiveTo characterize racial differences in plasma levels of ADRD biomarkers after adjusting for comorbidities and assessed the impact of estimated glomerular filtration rate (eGFR) adjustment using either race-specific or race-neutral equations.MethodsData from the Einstein Aging Study, a multicultural cohort of older adults, included plasma biomarkers (Aβ40, Aβ42, pTau181, NfL, GFAP). Linear regression models evaluated racial differences in AD plasma biomarkers, adjusting for age, sex, body mass index, kidney function assessed via race-adjusted (eGFR-ASR) and race-neutral (eGFR-AS) equations, comorbidities (e.g., diabetes, hypertension, cardiovascular disease), and APOE ε4 carrier status.ResultsAmong 269 participants, Black participants had lower plasma levels of Aβ40 (p = 0.004), Aβ42 (p = 0.002), and NfL (p = 0.022) compared to White participants. We observed modest variation in the magnitude of racial differences depending on the method used to adjust for kidney function. However, race differences remained after adjusting for comorbidities or APOE ε4 carrier status.ConclusionsObserved racial differences in ADRD biomarkers remain unexplained by kidney function, comorbidities or APOE ε4 carrier status. Future research focusing on associations between blood-based biomarkers and gold standards of brain pathology in multicultural cohorts are essential to advance the usability of blood biomarkers.},
}

@article {pmid41883102,
year = {2026},
author = {Cheng, B and Chen, Y and Cai, F and Wen, X},
title = {Therapeutic Potential of Salvia miltiorrhiza Active Components in Various Diseases Based on the PI3K/Akt Signaling Pathway.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {3},
pages = {e03444},
doi = {10.1002/cbdv.202503444},
pmid = {41883102},
issn = {1612-1880},
support = {No.GJJ2400803//Science and Technology Research Project of the Jiangxi Provincial Department of Education/ ; No.2024B0016//the Science and Technology Project of the Jiangxi Provincial Administration of Traditional Chinese Medicine/ ; No.202410412151//the Student Innovation and Entrepreneurship Project of Jiangxi University of Chinese Medicine/ ; No.2025WBZR006//the Doctoral Research Startup Foundation Project of Jiangxi University of Chinese Medicine/ ; },
mesh = {Humans ; *Salvia miltiorrhiza/chemistry/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism/antagonists & inhibitors ; *Signal Transduction/drug effects ; Animals ; *Phosphatidylinositol 3-Kinases/metabolism ; Neoplasms/drug therapy/metabolism ; *Drugs, Chinese Herbal/chemistry/pharmacology ; *Phosphatidylinositol 3-Kinase/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Atherosclerosis/drug therapy/metabolism ; Diabetic Nephropathies/drug therapy/metabolism ; },
abstract = {Salvia miltiorrhiza Bunge, known as danshen in China, is a key medicinal herb in traditional Chinese medicine that has long been used for the treatment of cardiovascular and cerebrovascular disorders. Its principal bioactive constituents fall into two broad categories: water-soluble phenolic acids (primarily including danshensu, salvianic acid A, salvianolic acid B, and rosmarinic acid) and lipid-soluble diterpenoids (primarily including tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone). Accumulating evidence shows that these active components exert diverse pharmacological effects, including anti-tumor, anti-inflammatory, antioxidant, and anti-neurodegenerative activities, via modulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Consistently, these components hold promising therapeutic potential against various diseases, including cancer, atherosclerosis, Alzheimer's disease, and diabetic nephropathy. Nevertheless, there is still a lack of a comprehensive and systematic summary of the precise mechanisms by which the active ingredients of danshen exert their therapeutic actions against the aforementioned diseases via the PI3K/Akt signaling pathway. To address this gap, this review systematically summarizes the regulatory effects of danshen's active components on the PI3K/Akt signaling pathway, aiming to clarify their therapeutic potential in various pathological conditions and thereby provide novel insights for the basic research and clinical application of danshen.},
}

Humans
*Salvia miltiorrhiza/chemistry/metabolism
*Proto-Oncogene Proteins c-akt/metabolism/antagonists & inhibitors
*Signal Transduction/drug effects
Animals
*Phosphatidylinositol 3-Kinases/metabolism
Neoplasms/drug therapy/metabolism
*Drugs, Chinese Herbal/chemistry/pharmacology
*Phosphatidylinositol 3-Kinase/metabolism
Alzheimer Disease/drug therapy/metabolism
Atherosclerosis/drug therapy/metabolism
Diabetic Nephropathies/drug therapy/metabolism

@article {pmid41883140,
year = {2026},
author = {Yu, Z and Mulholland, A and Huang, T and Liu, Q},
title = {Multimodal AI for Alzheimer Disease Diagnosis: Systematic Review of Datasets, Models, and Modalities.},
journal = {Journal of medical Internet research},
volume = {28},
number = {},
pages = {e85414},
doi = {10.2196/85414},
pmid = {41883140},
issn = {1438-8871},
mesh = {*Alzheimer Disease/diagnosis ; Humans ; *Artificial Intelligence ; Machine Learning ; },
abstract = {BACKGROUND: Early detection of Alzheimer disease (AD) is essential for timely intervention; yet, diagnostic performance varies widely across modalities and datasets. Recent multimodal artificial intelligence (AI) models have made significant progress, but the evidence base remains fragmented due to heterogeneous datasets, modeling frameworks, and reporting quality.

OBJECTIVE: This systematic review aimed to analyze studies on multimodal AI models for AD diagnosis, prognosis, and risk prediction over 5 years. We evaluated dataset characteristics, modality combinations, modeling strategies, performance metrics, and methodological limitations. We further discuss real-world implications and translational pathways.

METHODS: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines, we systematically searched PubMed, IEEE Xplore, Scopus, ACM Digital Library, Cochrane, and arXiv, with the final datasets last searched on November 15, 2025. Studies applying multimodal machine learning or deep learning to AD, mild cognitive impairment, and dementia outcomes were included, whereas studies using a single modality or lacking sufficient methodological detail were excluded. QUADAS-2 (Revised Quality Assessment of Diagnostic Accuracy Studies tool) assessed risk of bias. Extracted performance results were synthesized across 4 major multimodal dataset families.

RESULTS: A total of 66 studies met the inclusion criteria. Across datasets, multimodal models consistently outperformed single-modal baselines. Alzheimer's Disease Neuroimaging Initiative-based diagnosis achieved an average accuracy of 92.5% (SD 3.8%), while mild cognitive impairment-conversion models achieved an average area under the curve (AUC) of 0.922 (SD 0.045), and several fusion architectures reported AUCs above 0.95. In contrast, UK Biobank risk-prediction studies reported an average AUC of 0.84 (SD 0.056), and this reflects performance in large, population-based datasets. DementiaBank speech-language studies achieved an average AUC of 0.813 (SD 0.042), and cross-lingual AD detection achieved an accuracy of 77% (SD 6.5%). Self-collected multimodal datasets demonstrated average accuracies around 96% (SD 2.4%), but their generalizability is limited due to small sample sizes and single-center designs.

CONCLUSIONS: This systematic review demonstrates that multimodal AI models consistently outperform single-modal models for AD diagnosis, prognosis, and risk prediction by integrating complementary biological, clinical, and behavioral information. Unlike prior reviews, this review provides a unified synthesis across heterogeneous clinical, imaging, genetic, and linguistic datasets, enabling cross-domain comparison of modeling strategies and performance. However, the generalizability of reported performance was limited due to substantial heterogeneity in dataset composition, outcome definitions, and validation, and prevalent risks of bias. By evaluating these factors, this review clarifies where current evidence is robust and where caution is warranted. The findings highlight the need for standardized multimodal benchmarks, transparent evaluation protocols, and clinically grounded model design to enable reliable real-world deployment. Overall, this work advances the field by framing multimodal AI not only as a performance-driven tool but also as a translational framework for equitable, interpretable, and scalable AD diagnosis.},
}

*Alzheimer Disease/diagnosis
Humans
*Artificial Intelligence
Machine Learning

@article {pmid41883201,
year = {2026},
author = {Saenz-Antoñanzas, A and Moreno-Valladares, M and Muñoz-Culla, M and Cruces-Salguero, S and Landa, J and Alberro, A and Vergara-Arce, J and Arroyo-Izaga, M and Otaegui, D and Matheu, A},
title = {Differential Gene Expression in Human Hippocampus With Aging.},
journal = {Aging cell},
volume = {25},
number = {4},
pages = {e70459},
doi = {10.1111/acel.70459},
pmid = {41883201},
issn = {1474-9726},
support = {PI22/01905//Instituto de Salud Carlos III/ ; FORT23-00026//Instituto de Salud Carlos III/ ; PI19/01355//Instituto de Salud Carlos III/ ; 2022111069//Eusko Jaurlaritza/ ; },
mesh = {Humans ; *Hippocampus/metabolism ; *Aging/genetics/metabolism ; Aged ; Male ; Adult ; Female ; Middle Aged ; Aged, 80 and over ; Young Adult ; },
abstract = {Brain aging consists of a progressive loss of functional capacities, which is associated with a progressive cognitive decline and can lead to neurodegenerative diseases. Studies comparing the underlying molecular mechanisms of the human hippocampus between young and older adults remain scarce. In our study, we completed a transcriptomic analysis from hippocampal samples of different ages and performed 2 complementary analyses. A comparison between young and old groups revealed a set of genes differentially expressed in aged individuals linked to inflammation and immune system pathways, DNA repair, metabolism, or neural activity. Correlation analysis showed that the expression of an additional subset of 6 genes was associated with chronological aging. Among them, further analysis identified RAD23B as the most significant gene with a negative correlation of its mRNA and protein expression with age in the human hippocampus. Its expression was even lower in patients with Alzheimer's disease. RAD23B was mostly expressed in neurons and astrocytes, where studies in human primary cultures uncovered that it is required for cell survival and function. In summary, these results unravel dynamic gene expression changes that distinguish young from older adults and identify RAD23B as a putative biomarker and regulator of cell aging in the brain.},
}

Humans
*Hippocampus/metabolism
*Aging/genetics/metabolism
Aged
Male
Adult
Female
Middle Aged
Aged, 80 and over
Young Adult

@article {pmid41883280,
year = {2026},
author = {Bugnon, A and Temperli, P and Abbes, H and Doser, N},
title = {[Cerebral amyloid angiopathy-related inflammation and anti-amyloid immunotherapies].},
journal = {Revue medicale suisse},
volume = {22},
number = {955},
pages = {1-7},
doi = {10.53738/REVMED.2026.22.955.e47917},
pmid = {41883280},
issn = {1660-9379},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/therapy/complications/diagnosis/immunology ; Alzheimer Disease/therapy ; *Immunotherapy/methods ; *Inflammation/therapy/etiology ; Prognosis ; },
abstract = {Cerebral amyloid angiopathy can be complicated by an inflammatory form known as CAA-ri (cerebral amyloid angiopathy-related inflammation), a rare but sometimes severe condition whose prognosis is improved by early diagnosis and treatment. CAA-ri shares physiopathological, clinical and radiological features with amyloid-related imaging abnormalities (ARIA), a complication observed during the development of novel anti-amyloid immunotherapies for Alzheimer's disease (AD). These ARIA are more frequent and severe in patients with CAA, requiring particular attention given the significant overlap between AD and this pathology. This article aims to raise awareness and improve recognition of these entities associated with amyloid deposition.},
}

Humans
*Cerebral Amyloid Angiopathy/therapy/complications/diagnosis/immunology
Alzheimer Disease/therapy
*Immunotherapy/methods
*Inflammation/therapy/etiology
Prognosis

@article {pmid41883283,
year = {2026},
author = {Koric, L and Mourre, H and Trompette, C and Brillant, L and Favre, M and Trinquet, L and Ceccaldi, M and Felician, O},
title = {Enhancing atypical Alzheimer's disease phenotyping through the oculomotor window in posterior cortical atrophy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261435137},
doi = {10.1177/13872877261435137},
pmid = {41883283},
issn = {1875-8908},
abstract = {BackgroundAlthough Alzheimer's disease (AD) is biologically well characterized, early and precise phenotypic diagnosis remains challenging, especially for atypical variants. Posterior cortical atrophy (PCA) is a rare form of AD with progressive neurovisual impairment related to degeneration in visual processing areas.ObjectiveTo investigate how alterations in eye movement metrics, measured through video-oculography (VOG), reflect dysfunction across distinct brain networks in various AD phenotypes, with particular emphasis on PCA.MethodsThis study compared oculomotor parameters derived from VOG saccade analysis in early AD patients exhibiting two clinical phenotypes, PCA-AD (n = 21) and amnestic mild cognitive impairment (aMCI-AD, n = 11), along with 27 age-matched controls. Parameters analyzed included saccade latency, gain, velocity, intrusions and antisaccade error rates. All patients exhibited cerebrospinal fluid biomarkers consistent with AD pathology.ResultsAs expected, neuropsychological testing revealed more severe neurovisual and executive deficits in PCA-AD versus aMCI-AD, and greater memory storage impairment in aMCI. Oculomotor data showed that PCA-AD patients exhibited prolonged saccade latencies, reduced gain, slower vertical saccades, and increased antisaccade errors compared to controls and aMCI-AD. Receiver operating characteristic analysis combining key saccadic metrics demonstrated up to 90% sensitivity and specificity in distinguishing PCA from controls and aMCI.ConclusionsThese findings support the use of VOG oculomotor metrics as phenotypic biomarkers in differentiating AD clinical forms. In PCA, they reflect the dysfunction of visuo-spatial attentional networks and their interaction with subcortical eye movement control circuits.},
}

@article {pmid41883286,
year = {2026},
author = {Park, J and Kwon, HJ and Joo, J and Jang, H and Seo, SW and Na, DL and Jung, NY and , },
title = {Sex-specific accelerated epigenetic aging in the Alzheimer's disease spectrum.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431795},
doi = {10.1177/13872877261431795},
pmid = {41883286},
issn = {1875-8908},
abstract = {BackgroundEpigenetic age acceleration (EAA) refers to the extent to which an individual's biological age, estimated from DNA methylation patterns, exceeds their chronological age, indicating accelerated cellular and tissue aging.ObjectiveWe investigated the association between EAA and Alzheimer's disease (AD), with a focus on sex-based differences.MethodsEAA was estimated from blood samples in 127 participants with Alzheimer's disease-related cognitive impairment (ADCI) and 143 cognitively unimpaired (CU) participants, recruited from a nationwide multicenter study under the Precision Medicine Platform for Mild Cognitive Impairment (PREMIER) consortium in Korea.ResultsEAA measures indicated higher acceleration in the ADCI group compared to the CU group, particularly for extrinsic epigenetic age acceleration (EEAA), AgeAccelResidualHannum, and AgeAccelPheno. Sex-specific analyses revealed that EEAA significantly differed between the ADCI and CU groups in both men and women, with a greater EEAA in men. Logistic regression analysis demonstrated that increased EEAA, the presence of APOE ɛ4 allele, and poorer nutritional status were significantly associated with a higher likelihood of ADCI. EEAA increased ADCI risk more strongly in men than in women, whereas chronological age showed a protective effect only in women.ConclusionsAs a marker of immune system aging, EEAA may be associated with ADCI. These findings suggest that EEAA serves as a complementary indicator of systemic biological aging within the AD spectrum. The greater EAA observed in men was consistently present in ADCI, highlighting the importance of considering sex differences in EAA-related AD research.},
}

@article {pmid41883393,
year = {2025},
author = {Wu, TC and Zhao, F and Liang, Y and Wu, ZZ and Chen, JB and Zhang, ZN and Yang, H},
title = {Creutzfeldt-Jakob disease mimicking Hashimoto's encephalopathy: steroid response followed by decline.},
journal = {Open life sciences},
volume = {20},
number = {1},
pages = {20251245},
pmid = {41883393},
issn = {2391-5412},
abstract = {The diagnosis of Creutzfeldt-Jakob disease (CJD) is particularly challenging because its heterogeneous clinical presentations mimic other rapidly progressive dementias and neurodegenerative disorders (e.g., Hashimoto's encephalopathy, autoimmune encephalitis, atypical Alzheimer's disease). Diffusion-weighted imaging (DWI) is the most sensitive neuroimaging sequence for diagnosing CJD. However, early magnetic resonance imaging (MRI) findings may be subtle or evolving, and autoimmune etiologies often remain in the differential. Therefore, empiric corticosteroids are reserved for cases in which an autoimmune etiology is under consideration while definitive tests are pending. A 67-year-old woman presented with rapidly progressive cognitive decline, ataxia, and visual symptoms. Short-course glucocorticoids produced transient improvement for three days, followed by rapid deterioration within a week. Serial MRI evolved from cortical ribboning to basal ganglia involvement. Electroencephalogram (EEG) showed non-convulsive status epilepticus that responded to diazepam and valproate. Cerebrospinal fluid (CSF) 14-3-3 protein (14-3-3) and RT-QuIC were positive, confirming prion disease. CJD can present with features resembling HE, and brief improvement after a short course of glucocorticoids, even in the presence of markedly elevated thyroid antibodies, does not exclude CJD. To avoid diagnostic delay, obtain CSF RT-QuIC and 14-3-3 at presentation before or in parallel with glucocorticoids, and use serial MRI and EEG to arbitrate.},
}

@article {pmid41883400,
year = {2025},
author = {He, F and Sha, FF and Hu, HY and Zhang, HZ and Zhang, R},
title = {Integrated bioinformatic analysis and machine learning strategies to identify new potential immune biomarkers for Alzheimer's disease and their targeting prediction with geniposide.},
journal = {Open life sciences},
volume = {20},
number = {1},
pages = {20251215},
pmid = {41883400},
issn = {2391-5412},
abstract = {To analyze the immune biomarkers, pathogenesis, level of immune infiltration, and anti-Alzheimer's disease (AD) potential of geniposide in immune-related AD. The expression profiles of the GSE132903 dataset were downloaded from the gene expression omnibus (GEO) database to obtain differentially expressed genes (DEGs) in AD, while immune-related genes (IRGs) were obtained from the ImmPortal database, and these genes were intersected to obtain immune differential genes. These genes were intersected to obtain immune differential genes, which were subsequently enriched for further analysis. With the help of protein-protein interaction (PPI) network and cytoHubba analysis, the key immune differential genes were screened out, and the characteristic biomarkers were further identified and screened by the least absolute shrinkage and selection operator (LASSO) regression model and SVM-RFE algorithm. The (receiver operating characteristic) ROC curve was validated in the validation group of GSE5281 microarray and the area under the ROC curve value was used to evaluate the diagnostic and therapeutic values. The CIBERSORT algorithm was used to analyze the pattern of immune cell infiltration and the association between immune cells and characteristic biomarkers. Finally, geniposide was subjected to molecular docking and molecular dynamic simulations with core characterized genes to predict its anti-AD potential. In total, 345 DEGs were identified and 18 AD immune-related differential genes were identified by intersecting immune-related genes, which were involved in multiple signaling pathways, cellular components, molecular functions, and pathways. Five characterized genes were identified using integrated machine learning, including glial fibrillary acidic protein (GFAP), VGF Nerve Growth Factor Inducible (VGF), Neuropeptide Y (NPY), Cholecystokinin (CCK), and NFKB Inhibitor Alpha (NFKBIA). The ROC curve validation results were as expected. Immune cell infiltration analysis revealed that multiple immune cells were associated with the characterized genes. Molecular docking and molecular dynamic simulations showed good binding activity and stability between geniposide and the key characterized targets. Characteristic biomarkers of AD were screened using various methods, and the biological processes and signaling pathways related to AD were identified by enrichment analysis, which elucidated immune-related mechanisms. In addition, geniposide may have binding affinity for key target proteins involved in the pathogenesis of AD, suggesting its potential as a candidate worthy of further investigation. And this study provides a new approach to the pathogenesis and targeted therapy for AD.},
}

@article {pmid41883434,
year = {2026},
author = {Choudhary, N and Zahid, M and Ahmad, M and Shaukat, M and Tariq, M and Rajeshwara, S and Usman, S and Wajid, T and Awosika, A},
title = {Neurobiological mechanisms linking vitamin d signaling to cognitive decline and neurodegeneration: Untangling epidemiology, pathophysiology, and evidence.},
journal = {World journal of experimental medicine},
volume = {16},
number = {1},
pages = {118761},
pmid = {41883434},
issn = {2220-315X},
abstract = {Dementia is a leading cause of disability and dependence among older adults, and its prevalence is projected to increase sharply with age. While age and genetics remain the dominant risk factors, modifiable contributors are gaining attention, including vitamin D deficiency, which is highly prevalent worldwide. This integrated review synthesizes current evidence on the association between vitamin D status and dementia, spanning the epidemiological, mechanistic, and interventional domains. Epidemiological studies have consistently linked low serum 25-hydroxyvitamin D levels with poorer cognition, faster decline, and higher risk of Alzheimer's disease and vascular dementia, although causality cannot be inferred. Mechanistic data suggest that vitamin D regulates amyloid and tau pathology, reduces neuroinflammation and oxidative stress, supports cerebrovascular integrity, and preserves mitochondrial function. Translation into clinical benefit has proven difficult; large randomized trials in generally healthy older adults, including VITAL and D-Health, report null effects, whereas smaller studies in vitamin D-deficient or cognitively impaired populations suggest potential improvements. Meta-analyses confirm mixed findings, typically indicating small or non-significant effects, with possible benefit restricted to vulnerable groups. The limitations across the literature include residual confounding in observational studies, assay variability, seasonal influences, heterogeneous cognitive measures, and publication bias. Future priorities include adequately powered randomized trials with standardized vitamin D assessments and harmonized cognitive endpoints as well as investigations into genetic moderators and multi-domain interventions. In conclusion, although vitamin D deficiency is consistently associated with cognitive decline and dementia, definitive evidence of causality remains lacking. Clarifying whether supplementation can alter dementia trajectory is a pressing public health priority.},
}

@article {pmid41883437,
year = {2026},
author = {García Menéndez, S and Inserra, F and de Cavanagh, EM and Ferder, L and Manucha, W},
title = {Renin-angiotensin system blockade attenuates brain mitochondrial dysfunction, oxidative stress, and neuroinflammation associated with hypertension, metabolic disorders, and aging.},
journal = {World journal of experimental medicine},
volume = {16},
number = {1},
pages = {113259},
pmid = {41883437},
issn = {2220-315X},
abstract = {Although aging is an inherent part of life, it represents a process of progressive dysfunction rather than a fixed biological outcome. Consequently, highly prevalent conditions such as cardiorenal-metabolic syndrome-which encompasses obesity, hypertension (HTN), and metabolic disorders-can accelerate age-related changes. The renin-angiotensin system (RAS) plays a critical role in pathophysiology and affects multiple organs, including the brain. The central nervous system contains both RAS branches: The ACE/Ang II/AT1 and AT2 receptor axis, as well as the ACE2/Ang-(1-7)/Mas receptor axis. Neuroinflammation is a chronic process characterized by glial cell activation triggered by increased production of reactive oxygen and nitrogen species, resulting in oxidative stress. Mitochondria are the primary cellular sites where these processes occur. Under conditions such as metabolic disorders, obesity, HTN, and aging, these reactions are markedly accelerated. Associated mechanisms include insulin resistance, elevated levels of advanced glycation end-products, and disruption of the blood-brain barrier. The consequences of these alterations may include brain dysfunction, cognitive decline, Parkinson's disease, and neurodegenerative conditions such as Alzheimer's disease. This review focuses on the primary effects of therapeutic interventions on mitochondrial function, with particular attention to the modulation of oxidative stress, chronic neuroinflammation, and glial dysregulation. We highlight the strategic use of angiotensin receptor blockers and ACE2 activators as promising tools that may redefine the prevention and treatment of vascular dementia and other neurodegenerative diseases of inflammatory origin.},
}

@article {pmid41883454,
year = {2026},
author = {Liu, YM and Liu, M and Yuan, H and Li, B},
title = {Double-edged role of N6-methyladenosine reader YTH structural domain family protein 2 in neurological disorders: Molecular mechanisms and translational prospects.},
journal = {World journal of experimental medicine},
volume = {16},
number = {1},
pages = {116383},
pmid = {41883454},
issn = {2220-315X},
abstract = {N6-methyladenosine (m6A) is the most prevalent internal RNA modification in eukaryotic transcripts, and YTH structural domain family (YTHDF) 2 is a principal m6A reader that governs RNA stability and turnover. Accumulating evidence indicates that YTHDF2 exerts context-dependent and sometimes opposing functions across major neurological disorders, including Alzheimer's disease, Parkinson's disease, glioblastoma, epilepsy, and experimentally induced cognitive and neuropsychiatric conditions. By selectively promoting decay of m6A-marked transcripts - such as leucine rich repeat and immunoglobulin domain containing 2, axis inhibition protein 1, breast cancer type 1 susceptibility protein associated protein 1, mitogen-activated protein kinase kinase 4, family with sequence similarity 134 member B, and NOD-like receptor family pyrin domain-containing 3 - YTHDF2 modulates diverse processes including amyloid processing, Wnt signaling, ferroptosis, neuroinflammation, metabolic homeostasis, and autophagy. Its activity is further shaped by upstream regulatory pathways (e.g., epidermal growth factor receptor-SRC proto-oncogene, non-receptor tyrosine kinase-extracellular signal-regulated kinase and protein arginine methyltransferase 6-cyclin-dependent kinase 9) and by dynamic interplay with m6A writers and erasers, including methyltransferase like 14 and fat mass and obesity-associated protein. This mini-review synthesizes recent mechanistic advances, emphasizes regional and cell-type heterogeneity of YTHDF2 function, and proposes a "dose-target dependency" framework to reconcile its bidirectional effects. We also outline emerging translational strategies aimed at evaluating YTHDF2 as a mechanistic biomarker and a selectively tractable therapeutic target in neurological disease.},
}

@article {pmid41883492,
year = {2026},
author = {Zhou, J and Zhang, Z and Li, X and Wan, J and Zhang, C and Chen, M and Liu, C},
title = {Bmssnet: a multi-scale feature and efficient spatial attention fusion model for early recognition of Alzheimer's disease.},
journal = {Cognitive neurodynamics},
volume = {20},
number = {1},
pages = {69},
pmid = {41883492},
issn = {1871-4080},
abstract = {Integrating structural magnetic resonance imaging (sMRI) with deep learning techniques is one of the important research directions for automated diagnosis of Alzheimer's disease (AD). Among these, Convolutional Neural Networks (CNNs) have been widely adopted as a mainstream approach due to their powerful feature extraction capabilities. However, existing convolutional neural network (CNN)-based voxel models with excellent performance are typically constrained to a single spatial scale. This limitation hinders the effective capture of complex, distributed brain atrophy features of AD and often results in insufficient model interpretability. To address these limitations, we propose BMSSnet, an interpretable AD recognition model based on a multi-scale multi-block attention mechanism. This model adopts a CNN-Transformer hybrid architecture. Specifically, it first captures local anatomical details using a 3D feature extraction network. Subsequently, it utilizes a dual-branch multi-scale attention mechanism to model patches of different sizes, enabling the Transformer to extract global long-range dependencies. Additionally, we devise a lightweight spatial gating unit to facilitate feature spatial interaction while maintaining computational efficiency. For interpretability, the model localizes decision-critical three-dimensional regions of interest (3D ROIs) using attention weights and aligns them with anatomical atlases to verify their pathological relevance. Finally, extensive experiments on the ADNI dataset demonstrate that BMSSnet not only achieves superior diagnostic performance but also accurately localizes AD-associated salient brain regions, offering reliable clinical interpretability.},
}

@article {pmid41883519,
year = {2026},
author = {Kim, H and Shim, S and Lee, S and Kim, J and Park, S and Kim, H and Lee, JY and Youn, JH},
title = {Preliminary normative study of Cognosis: A digital cognitive assessment battery for Korean elders.},
journal = {Digital health},
volume = {12},
number = {},
pages = {20552076261435931},
pmid = {41883519},
issn = {2055-2076},
abstract = {OBJECTIVES: Early detection of cognitive decline is critical for timely intervention, yet traditional neuropsychological assessments are time-intensive, require trained examiners, and may introduce administration bias. Digital platforms can offer scalable and accessible alternatives by enabling automated scoring and self-administration. To address this gap, we developed Cognosis, a tablet-based cognitive battery tailored for older adults, and aimed to (1) provide preliminary demographically stratified reference data and (2) examine the effects of age, education, and gender on cognitive performance in cognitively healthy Korean older adults.

METHODS: We conducted a community-based normative study using a cross-sectional design. A total of 381 cognitively healthy adults aged 55 to 84 years were recruited from community centers, hospitals, and other local settings across Seoul, Gyeonggi, and Jeolla provinces in South Korea. Cognosis assesses four cognitive domains: attention/executive function, language, memory, and social cognition. To evaluate demographic influences, we applied penalized regression models (Least Absolute Shrinkage and Selection Operator) and stratified the preliminary normative data by age (55-64, 65-74, and 75-84), education (0-6, 7-12, 13-16, and ≥17 years), and gender.

RESULTS: Age and education significantly influenced cognitive performance, with younger age and higher education associated with better scores. However, memory performance was not associated with these demographic variables. While gender did not have a main or interaction effect in regression analysis, subgroup analyses revealed that highly educated women outperformed men in several cognitive domains, including attention/executive function, fluency, and verbal/visual memory.

CONCLUSIONS: This study provides preliminary, demographically stratified reference data for Cognosis, improving its clinical utility for cognitive assessment in Korean older adults. Future research should validate its applicability in clinical and cross-cultural populations.},
}

@article {pmid41883550,
year = {2026},
author = {Okpete, UE and Byeon, H},
title = {Digital health and metaverse for Alzheimer's disease and related dementia: A scoping review.},
journal = {Digital health},
volume = {12},
number = {},
pages = {20552076251365002},
pmid = {41883550},
issn = {2055-2076},
abstract = {BACKGROUND: The metaverse, an emerging digital ecosystem that integrates virtual reality (VR) and augmented reality (AR), is gaining increasing attention in the healthcare industry. In Alzheimer's disease and related dementias (AD/ADRD) care, the metaverse offers transformative solutions for cognitive assessment, remote monitoring, caregiver education, and patient engagement.

OBJECTIVE: A comprehensive scoping review was conducted following the PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines to systematically identify, select, and synthesize relevant literature exploring how emerging digital solutions, including digital health and metaverse applications, are addressing clinical challenges associated with AD/ADRD.

METHODS: Searches were conducted across online databases including PubMed, IEEE Xplore, ACM Digital Library, and Google Scholar (with a restricted search strategy due to the high volume of available literature), yielding a total of 160 hit results. Of these, 18 relevant articles were selected for in-depth analysis.

RESULTS: Findings highlight that immersive virtual environments enable individuals with AD/ADRD to engage in cognitive training programs and simulations, aiding memory and cognitive function. Additionally, VR-based telemedicine enables patients to consult with healthcare professionals from the comfort of their homes, reducing travel burdens and ensuring continued medical care despite geographical constraints. Beyond direct patient benefits, the metaverse supports caregivers through virtual training, educational resources, and peer networks that help them navigate the complexities of dementia care. Virtual spaces promote social interaction, reducing isolation and enhancing well-being. However, adoption barriers include technological unfamiliarity, cognitive and physical limitations, caregiver concerns, privacy and cost-related challenges.

CONCLUSION: Personalized technology design, structured learning environments, and caregiver training can enhance adoption and effectiveness. To maximize impact, addressing barriers through education, improved accessibility, and tailored interventions is essential. Future research should explore scalable implementation strategies, assess long-term patient outcomes, and evaluate cost-effectiveness to support widespread adoption.},
}

@article {pmid41883682,
year = {2026},
author = {Just, MK and Christensen, KB and Wirenfeldt, M and Steiniche, T and Parkkinen, L and Myllykangas, L and Borghammer, P},
title = {Robust immunohistochemical detection of α-synuclein, tau and amyloid-β in human brain tissue archived for up to 78 years.},
journal = {Free neuropathology},
volume = {7},
number = {},
pages = {6},
pmid = {41883682},
issn = {2699-4445},
abstract = {Objective: Brain branks preserve extensive material relevant to neurodegenerative disease research. As these collections age, tissue becomes archival, raising the question of whether long-term fixed and stored human brain tissue remains suitable for contemporary immunohistochemical analyses. Materials and Methods: Forty-one autopsy brains collected between 1946 to 1980 were examined. For each case, midbrain and hippocampus were available both as original paraffin-embedded blocks and as tissue stored long term in fixative. New paraffin blocks were prepared from the long-term fixated tissue. Sections from original and newly prepared blocks were immunohistochemically stained for α-synuclein, hyperphosphorylated tau and amyloid-β. Immunoreactivity was assessed using semi-quantitative scoring. Results: Original blocks consistently showed good staining intensity and morphological preservation for each protein pathology. Newly prepared blocks showed slightly lower semi-quantitative scores for Lewy-related pathology, without statistically significant differences, except for astrocytic α-synuclein in the substantia nigra in cases from the 1960s. Tau pathology displayed modestly reduced labelling, particularly of the neuropil threads and neurofibrillary tangles, most evident in cases from the 1950s. Amyloid-β-positive senile plaques showed similar or slightly higher scores in newly prepared blocks, with no significant differences across regions. Conclusion: Human brain tissue preserved as paraffin-embedded blocks or stored in fixative for up to 78 years remains suitable for immunohistochemical analyses. Adequate-to-good detection of aggregated α-synuclein, hyperphosphorylated tau and amyloid-β is achievable, indicating preserved pathological hallmarks of Lewy Body Disease and Alzheimer's Disease in archival tissue.},
}

@article {pmid41883743,
year = {2025},
author = {Greenwell, SA and Curran, LS and Poe, CE and Klein, M and Yao, X and Ortyl, BK and Shih, PC and Nelson, EJ and Boustani, M and Dexter, P and Miled, ZB and Schootman, M and Dickinson, S and Unverzagt, FW and Jordan, EJ},
title = {Protocol for assessing urban-rural environmental stress disparities in ADRD through ecological momentary assessment (AURESIA).},
journal = {Alzheimer's & dementia. Behavior & socioeconomics of aging},
volume = {1},
number = {4},
pages = {},
pmid = {41883743},
issn = {2997-3805},
abstract = {INTRODUCTION: Consistent exposure to environmental stressors increases the risk of Alzheimer's disease and related dementias (ADRD). Little is known about the timing, location, and nature of these stressors. We outline the protocol for an ongoing study using a novel ecological momentary assessment app to evaluate environmental stressors in urban and rural adults with mild cognitive impairment (MCI).

METHODS: We assess cognitive status at baseline and follow-up appointments for 2 years. During a 2-week stress-reporting period, participants self-report environmental stressors. We monitor physiological data via Smartwatch. The app collects geospatial data, which we analyze via spatiotemporal regression models.

RESULTS: The study will take 3 years to complete.

DISCUSSION: This study will advance knowledge of when, where, and what stressors occur among older adults and will underscore targets for intervention at individual and neighborhood levels to prevent progression from MCI to ADRD and reduce urban-rural disparities in older adults.},
}

@article {pmid41884150,
year = {2026},
author = {Dang, M and Liu, B and Chen, Y and Zhang, Z},
title = {Multimodal neuroimaging and AI integration in cognitive disorders: advances, challenges, and future directions for precision medicine.},
journal = {Psychoradiology},
volume = {6},
number = {},
pages = {kkag007},
pmid = {41884150},
issn = {2634-4416},
abstract = {Cognitive disorders, with dementia as a primary exemplar, present profound diagnostic and therapeutic challenges due to their complex pathologies and heterogeneous presentations. Artificial intelligence (AI), particularly when applied to multimodal neuroimaging and clinical data, offers a powerful approach to advancing precision medicine in this domain. This comprehensive review first examines foundational AI algorithms, including artificial neural networks for feature extraction, multimodal fusion strategies (e.g. early, intermediate, and late fusion) for data integration, and explainable AI (XAI) techniques to enhance clinical transparency. The core focus is on the application of these multimodal AI frameworks across the dementia care continuum, encompassing improved differential diagnosis, early detection through presymptomatic biomarkers, development of predictive models for disease progression, and optimization of patient stratification for clinical trials. Despite significant advances, persistent challenges remain, including limited generalizability across populations and protocols, data scarcity for non-Alzheimer's dementias and prodromal stages-exacerbated by demographic biases-and barriers to interpretability. We discuss solutions such as federated learning for privacy-preserving data sharing and advanced XAI techniques. Finally, we outline pivotal future directions, including intelligent sensor fusion for discovering novel early biomarkers, hybrid AI architectures combining generative and discriminative models, innovations for handling missing modalities, and robust multicenter data integration frameworks. By synthesizing these advances, this review highlights the role of multimodal AI in advancing precise diagnosis, early prediction, and therapeutic development for neurodegenerative and vascular cognitive disorders, while identifying key translational challenges for precision medicine.},
}

@article {pmid41884282,
year = {2026},
author = {Chu, H and Sun, Y and Huang, C and Wang, L and Guo, Q and Jiang, L},
title = {Polydopamine Modified with Brain Targeting Peptide Rabies Virus Glycoprotein for Treatment of Alzheimer's Disease by Inhibiting Oxidative Stress and Inflammatory Response.},
journal = {International journal of nanomedicine},
volume = {21},
number = {},
pages = {564013},
pmid = {41884282},
issn = {1178-2013},
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology ; Oxidative Stress/drug effects ; *Indoles/chemistry/pharmacology/administration & dosage ; Mice ; *Polymers/chemistry/pharmacology/administration & dosage ; *Glycoproteins/chemistry/pharmacology/administration & dosage ; Nanoparticles/chemistry ; Brain/drug effects/metabolism ; *Viral Proteins/chemistry/pharmacology/administration & dosage ; Blood-Brain Barrier/metabolism/drug effects ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/administration & dosage/chemistry ; Reactive Oxygen Species/metabolism ; Mice, Transgenic ; Humans ; Inflammation/drug therapy ; Male ; Ferroptosis/drug effects ; Peptide Fragments ; },
abstract = {PURPOSE: Polydopamine (PDA) has been recognized as an antioxidant and anti-inflammatory agent. However, the difficulty to cross blood-brain barrier (BBB) limits PDA's neuroprotective effects in the brain. Here, we aimed to construct PDA-rabies virus glycoprotein (RVG) by modifying the RVG29 polypeptide on PDA nanoparticles (NPs) and investigate whether PDA-RVG improved the cognitive function and pathology of Alzheimer's Disease (AD) by inhibiting oxidative stress and inflammatory response.

METHODS: We prepared and characterized PDA NPs and tested whether PDA improved AD pathology in APP/PS1 mice. To facilitate PDA's penetration across BBB, we modified RVG29 on PDA and examined its brain-specific targeting ability and biocompatibility. We further tested the effects of PDA-RVG on oxidative stress, inflammatory response and ferroptosis in both in vitro and in vivo AD models.

RESULTS: PDA demonstrated robust reactive oxygen species (ROS)-scavenging activity and effectively reduced Aβ deposition and the expression of APP and PS1 in APP/PS1 mice. PDA-RVG successfully crossed BBB in an in vitro BBB model. Meanwhile, compared with PDA, PDA-RVG intravenous injection exhibited good brain-specific targeting ability. Moreover, the hematological analysis revealed no significant differences between the PDA-RVG and control groups. In the in vitro AD experiment, PDA-RVG reduced ROS, inducible nitric oxide synthase, and pro-inflammatory cytokines levels in BV2 cells. Besides, PDA-RVG decreased ROS and apoptosis, while increased glutathione peroxidase4 (GPX4) and the viability of PC12 cells. More importantly, intravenous delivery of PDA-RVG improved cognitive function assessed by Morris water maze, and upregulated the ferroptosis-protective proteins Ferritin Heavy Chain 1 and GPX4 expression, while PDA alone did not lead to cognitive improvement.

CONCLUSION: PDA reduces AD pathology, which is possibly attributed to its ability to scavenge ROS, ameliorate the inflammatory microenvironment and inhibit ferroptosis. Intravenous delivery of PDA-RVG has good brain-specific targeting ability and biocompatibility, and improves cognitive function in AD mice. This study provides a safe, effective, and promising therapeutic strategy for AD via oxidative stress-associated target.},
}

Animals
*Alzheimer Disease/drug therapy/pathology
Oxidative Stress/drug effects
*Indoles/chemistry/pharmacology/administration & dosage
Mice
*Polymers/chemistry/pharmacology/administration & dosage
*Glycoproteins/chemistry/pharmacology/administration & dosage
Nanoparticles/chemistry
Brain/drug effects/metabolism
*Viral Proteins/chemistry/pharmacology/administration & dosage
Blood-Brain Barrier/metabolism/drug effects
Disease Models, Animal
Neuroprotective Agents/pharmacology/administration & dosage/chemistry
Reactive Oxygen Species/metabolism
Mice, Transgenic
Humans
Inflammation/drug therapy
Male
Ferroptosis/drug effects
Peptide Fragments

@article {pmid41884339,
year = {2026},
author = {Maia da Silva, MN and James-Galton, M and Green, C and Plant, GT},
title = {Homonymous hemianopia in posterior cortical atrophy: right-left asymmetry, progression over time and relationship to the classical neuropsychological deficits.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1759440},
pmid = {41884339},
issn = {1664-2295},
abstract = {Following Benson's seminal paper published in 1988 visual field loss in Posterior Cortical Atrophy (PCA) has been largely denied or ignored. This is despite an earlier description by Cogan of a similar case of pathologically verified Alzheimer disease featuring homonymous hemianopia (HH). Although HH is now recognised as a core feature of PCA its characteristics and relationship to other PCA features are unexplored. This study aimed to characterise the perimetric abnormalities in PCA patients presenting with HH, focusing on the response to static and kinetic stimuli; progression of the deficit over time; and the relationship to co-existing cognitive deficits. 24 patients were recruited for the cross-sectional study, of whom 19 participated in the longitudinal study. Each assessment consisted of kinetic and static perimetry and a comprehensive neuropsychological evaluation. The latter included tests to all basic cognitive domains plus tests of posterior cortical function. Thirteen patients underwent additional kinetic perimetry using three target velocities. Left HH was predominant and a deficit in object perception universal. Neglect was uncommon and did not correlate with the laterality of the HH. Stato-kinetic dissociation (SKD) was observed in all patients, greater in the more affected hemifield. Longitudinally, static perimetric deficits declined at a greater rate in the initially more affected hemifield. The rate of decline to kinetic testing was lower and varied with target size and velocity. Deterioration to the smallest and lowest velocity target mirrored that of static loss. A longitudinal mixed-model analysis showed that right HH was associated with greater deficits in predominantly left hemisphere cognitive functions and bilateral HH with greater bilateral occipital deficits. However, no association was found between the laterality of the HH and right hemisphere cognitive deficits. The characteristic SKD (also known as the Riddoch phenomenon) does not represent a complete dissociation as kinetic detection deteriorates over time in all cases. The correlation of the HH with lateralised parietal deficits challenges the concept that HH is restricted to an extreme posterior variant of PCA and highlights the need for routine (static and kinetic) perimetry in the diagnosis, characterisation and monitoring of PCA.},
}

@article {pmid41884591,
year = {2026},
author = {Lu, L and Wang, P and Wu, X and Xiong, W and Sander, JW and Chen, J and Zhou, D},
title = {EEG features in late-onset epilepsy: possible correlation with cognitive impairment.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag067},
pmid = {41884591},
issn = {2632-1297},
abstract = {Late-onset epilepsy (LOE) increases the risk of cognitive impairment and is associated with dementia in a bidirectional manner. Scalp EEG is a potential tool for assessing this relationship, but this has not been fully explored. This cross-sectional study reviewed people who had undergone 24-h EEG monitoring at West China Hospital. Individuals with epilepsy whose seizure onset ≥55 years and older healthy controls were included. Diagnosis of cognitive impairment was established at the time of EEG using standardized neuropsychological metrics. EEGs were reviewed and annotated independently by two neurophysiologists. EEG features were extracted according to the standardized computer-based organized reporting of EEG. Potential clinical, MRI, and EEG risk factors of cognitive impairment were analysed in ordinal and binomial regression models. Least absolute shrinkage and selection operator model was used to select the variables most discriminative of cognitive impairment. Among the screened individuals (n = 8318), eligible participants with LOE (n = 287) and healthy controls (n = 132) were included; median age 65 (55-85) years; female 38%. Epilepsy aetiology was unknown in 177 (62%) participants. Structural aetiology was the most common in epilepsies (93%) with a definite aetiology (n = 110). Interictal epileptiform discharges were detected in 56% of participants with LOE and were primarily left temporal. Bitemporal interictal epileptiform discharges were found predominantly (38%) in those of an unknown aetiology. Focal slowing was found in 56%, and generalized slowing in 13% of participants with LOE. EEG markers of temporal neural hyperexcitability, including temporal intermittent rhythmic delta activity (TIRDA) and anterior temporal epileptiform discharges, were associated with cognitive impairment. In LOE of unknown aetiology, bilateral anterior temporal epileptiform discharges were the most discriminative indicator of cognitive impairment [odds ratio 53.280, 95% confidence interval (CI) 11.359-249.917]. The least absolute shrinkage and selection operator model achieved an area under the receiver operating characteristic curve of 0.869 (95% CI 0.813-0.925). In LOE with a definite aetiology, TIRDA was associated with cognitive impairment. In this study, LOE was associated with specific EEG patterns. Signatures of temporal hyperexcitability on EEG might be related to cognitive impairment in LOE, especially when presented in both hemispheres. These results also suggested that LOE of an unknown aetiology might have a neurodegenerative origin, similar to Alzheimer's disease. Future longitudinal studies should explore the role of temporal hyperexcitability and other EEG features in the bidirectional link between LOE and dementia.},
}

@article {pmid41884592,
year = {2026},
author = {Chai, YL and Hilal, S and Cai, VY and Mok, VCT and Chong, JR and Liao, Y and Tan, BY and Venketasubramanian, N and Arumugam, TV and Chen, CL and Lai, MKP},
title = {Elevated serum inflammasome adaptor protein ASC is associated with white matter hyperintensities in vascular cognitive impairment.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag068},
pmid = {41884592},
issn = {2632-1297},
abstract = {Alzheimer's disease (AD) and vascular dementia (VaD) exhibit distinct neuropathological hallmarks, with AD defined by cortical amyloid plaques and neurofibrillary tangles, while VaD arises primarily from cerebrovascular disease (CeVD). However, CeVD frequently coexists with AD, and both conditions fall within the spectrum of vascular cognitive impairment (VCI). Notably, chronic neuroinflammation is a shared mechanistic link between AD and VaD. Inflammasomes, multi-protein complexes that sense cellular damage and orchestrate inflammatory responses, have been implicated in preclinical models of both diseases. However, their translational potential in the clinical setting remains underexplored. Here, we investigate the inflammasome adaptor protein, apoptosis associated speck-like protein containing a CARD (ASC), as a novel serum biomarker for CeVD, cognitive decline and VCI progression. A total of 531 participants (123 non-cognitively impaired, 208 cognitive impaired, no dementia and 200 with dementia) were included from a Singapore-based clinical cohort. All subjects underwent comprehensive clinical, neuropsychological and neuroimaging assessments. Serum samples were collected, and ASC was measured using a microfluidics immunoassay platform. Compared to controls, serum ASC levels were increased in the VCI clinical subgroups, namely, cognitive impaired, no dementia with CeVD, AD with CeVD and VaD. Multivariate analyses using CeVD neuroimaging markers showed associations between serum ASC and white matter hyperintensities, but not with lacunes or cerebral microbleeds. Mediation analyses similarly showed that the association between ASC and VCI subgroups may be largely explainable by severity of concomitant CeVD, specifically white matter hyperintensities volume. Our findings indicate that elevated serum ASC levels may reflect a state of inflammasome activation in VCI, particularly in individuals with extensive white matter hyperintensities. These results underscore the potential role of dysregulated inflammasome activation not only as a pathogenic factor but also as a potential therapeutic target for VCI.},
}

@article {pmid41884593,
year = {2026},
author = {Gojani, EG and Sutherland, RJ and Mohajerani, MH},
title = {Pyruvate kinase M2 in Alzheimer's disease: from dysregulation to therapeutic inhibition.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag054},
pmid = {41884593},
issn = {2632-1297},
abstract = {Pyruvate kinase M2 (PKM2) has emerged as a critical regulator of Alzheimer's disease pathophysiology. This review synthesizes current evidence demonstrating how PKM2 dysregulation contributes to cognitive decline by driving Warburg-like metabolic reprogramming, altering post-translational modifications and modulating protein-protein interactions. These processes collectively impair cell-cycle control, transcriptional regulation and cytoskeletal stability in neuronal cells. We further examine the impact of PKM2 on neuroinflammation, highlighting its context-dependent roles in microglia and astrocytes. In addition, we provide a comprehensive evaluation of natural and synthetic PKM2 modulators with therapeutic potential in Alzheimer's disease, summarizing their mechanisms and reported outcomes. Clarifying the molecular basis of PKM2-mediated neurodegeneration and rigorously testing these modulators in preclinical models will be essential steps towards developing PKM2-targeted strategies for Alzheimer's disease intervention.},
}

@article {pmid41884594,
year = {2026},
author = {Kassinopoulos, M and Montesinos, P and Falcon, C and Huguet, J and Minguillon, C and Fauria, K and Kollmorgen, G and Quijano-Rubio, C and Molinuevo, JL and Grau-Rivera, O and Zetterberg, H and Blennow, K and Suárez-Calvet, M and Sanchez-Gonzalez, J and Gispert, JD and , },
title = {Intracellular fluid accumulation underlies brain volume increases in early Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag075},
pmid = {41884594},
issn = {2632-1297},
abstract = {In the preclinical stages of Alzheimer's disease, increased brain volume has been associated with amyloid-beta pathology, particularly in regions that undergo volume reductions as the disease progresses. Glial reactivity and water diffusion alterations have been linked to such macroscopic volumetric changes. Brain volume reductions have also been reported following amyloid-beta removal with anti-amyloid therapies with beneficial clinical effects, but it remains unclear whether these changes result from resolving amyloid-triggered neuroinflammation or neurodegeneration. Intravoxel incoherent motion modelling based on multi-shell diffusion-weighted imaging may provide a better understanding of the processes underlying these paradoxical changes. This study used intravoxel incoherent motion diffusion MRI to examine how alterations in cerebral water pools contribute to increased brain volume linked to amyloid-beta deposition and neuroinflammation in cognitively unimpaired individuals. We developed a three-compartment diffusion MRI model with four parameters of cerebral water diffusion: slow diffusion coefficient, fast diffusion coefficient, slow signal portion, and perfusion fraction. We computed these diffusion parameters in 297 cognitively unimpaired late middle-aged adults, 35% of whom showed evidence of amyloid deposition. We examined their correlation with demographic factors (age, sex, apolipoprotein E status), markers of Alzheimer's disease pathology, neurodegeneration, neuroinflammation, and mean diffusivity. Then, we identified regions showing grey matter volume increases related to amyloid burden and examined the association between grey matter volume and diffusion parameters within these regions. We did not find evidence of associations between diffusion parameters and amyloid-related biomarkers, whether assessed by PET or cerebrospinal fluid measures. In contrast, the four diffusion parameters showed strong and widespread associations with biomarkers of neuroinflammation and neurodegeneration, particularly in frontoparietal and cingulate regions. Additionally, in grey matter regions where volume increases were related to amyloid levels, volumes were negatively correlated with the slow diffusion coefficient (P = 0.001), perfusion fraction (P = 0.036) and mean diffusivity (P = 0.047). These findings indicate that diffusion-derived measures are more sensitive to neuroinflammatory and neurodegenerative processes than to amyloid pathology in cognitively unimpaired individuals. Furthermore, the observed negative association between grey matter volume and slow diffusion coefficient in amyloid-related regions may reflect increased cellular complexity rather than intracellular water accumulation. This interpretation suggests that glial remodelling or microstructural changes could underlie brain volume increases in amyloid-positive individuals without overt neurodegeneration. These results underscore the value of intravoxel incoherent motion-derived metrics for gaining deeper insights into the pathophysiological mechanisms of Alzheimer's disease, influencing brain volume changes as well as those resulting from the response to anti-amyloid therapies.},
}

@article {pmid41884596,
year = {2026},
author = {Giudicessi, A and Koops, E and Baena, A and Alvarez, S and Vidal, M and Martinez, L and Bonillas Félix, NA and Gonzalez, I and Medrano, R and Tristão-Pereira, C and Malotaux, V and He, B and Vila-Castelar, C and Jacobs, HIL and Aguillon, D and Cronin-Golomb, A and Quiroz, YT},
title = {Sex differences in diffusion-weighted imaging outcomes in autosomal dominant Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag081},
pmid = {41884596},
issn = {2632-1297},
abstract = {Alzheimer's disease is characterized by amyloid-β and tau protein accumulation. Growing evidence suggests that white matter degeneration contributes to disease progression. Despite Alzheimer's disease being more prevalent in women, understanding of sex differences in white matter microstructure across the Alzheimer's disease continuum remains limited. This study investigated sex-specific patterns of white matter integrity in individuals genetically predisposed to autosomal dominant Alzheimer's disease. We analysed data from 63 individuals (30 presenilin-1 glutamic acid to Alanine at codon 280 (PSEN1 E280A) mutation carriers, 33 non-carriers) from a Colombian kindred with early-onset autosomal dominant Alzheimer's disease. Participants underwent diffusion-weighted imaging, amyloid and tau positron emission tomography and cognitive assessment. Using fixel-based analysis, we examined fibre density, fibre-bundle cross-section and combined fibre density and cross-section across major white matter tracts. Linear regression models assessed sex differences in white matter microstructure and examined how sex moderated relations between pathological burden, white matter integrity and cognitive performance. Females showed trends towards higher fibre cross-section than males in the anterior thalamic radiation (β = 0.057, P = 0.004), forceps minor of the corpus callosum (β = 0.047, P = 0.012) and inferior fronto-occipital fasciculus (β = 0.030, P = 0.015), but lower values in the cingulum (cingulate gyrus portion) (β = -0.07, P = 0.031). Sex appeared to moderate the association between pathology and white matter in multiple tracts. However, these findings did not survive correction for multiple comparisons and should be interpreted as exploratory. In the right temporal superior longitudinal fasciculus, females showed relatively preserved integrity compared to males as tau burden increased (β = 0.23, P = 0.016), while males exhibited greater amyloid-β-associated disruption than females in the uncinate fasciculus (β = -0.14, P = 0.05). Sex also moderated relations between white matter integrity and cognition, with males showing stronger structure-function coupling than females in tracts such as the cingulum (hippocampus portion), forceps major and corticospinal tract. Our findings revealed significant sex-specific patterns of white matter microstructural alterations in autosomal dominant Alzheimer's disease, with females showing preserved fibre cross-section in key tracts and slower rates of white matter deterioration with increasing tau pathology in memory-related circuits, whereas males demonstrated advantages in structure-function coupling. These data highlight the importance of considering sex differences in understanding white matter alterations in Alzheimer's disease and suggest the potential utility of considering sex differences in the development of personalized interventions and clinical trials for persons with Alzheimer's disease.},
}

@article {pmid41884619,
year = {2026},
author = {Bruno, F and Spadafora, P and Abondio, P and Qualtieri, A and Paparazzo, E and Aceto, MA and Veltri, I and De Benedittis, S and Greco, BM and Cerantonio, A and Citrigno, L and Di Palma, G and Gallo, O and Passarino, G and Montesanto, A and Cavalcanti, F},
title = {Age at natural menopause, reproductive lifespan and Alzheimer's disease in females: is APOE ε4 the missing link?.},
journal = {Frontiers in genetics},
volume = {17},
number = {},
pages = {1733593},
pmid = {41884619},
issn = {1664-8021},
abstract = {BACKGROUND: The apolipoprotein E (APOE) gene represents the strongest genetic determinant of sporadic Alzheimer's disease (AD), yet its interaction with sex-specific endocrine factors remains poorly understood. Lifetime estrogen exposure, estimated through reproductive lifespan, may modulate neurodegenerative risk, but findings are inconsistent. Previous studies have examined reproductive factors and APOE interactions in relation to cognitive outcomes, but dose-dependent effects across all APOE alleles (ε2, ε3, ε4) in clinically diagnosed AD patients remain underexplored. This study investigates the joint effects of reproductive lifespan, age at natural menopause (ANM), and APOE genotype on AD risk in females.

METHODS: A total of 396 female participants (103 with AD, 293 cognitively healthy controls) were retrospectively analyzed. Demographic, clinical, and reproductive data were extracted from medical records. APOE genotyping was performed by sequencing rs429358 and rs7412 polymorphisms. Logistic regression models tested associations between ANM, reproductive lifespan, and AD diagnosis, adjusting for education, body mass index (BMI), smoking, diabetes, hypertension, and number of children. Moderation analyses assessed the interaction between reproductive variables and APOE ε2, ε3, and ε4 alleles, and were followed by simple slope analyses to clarify the direction of significant effects.

RESULTS: AD females exhibited later ANM (50.3 ± 4.4 vs. 48.3 ± 6.2 years; p = 0.004) and longer reproductive lifespan (37.4 ± 4.4 vs. 35.4 ± 6.0 years; p = 0.005) than controls. Both ANM and reproductive lifespan independently predicted higher AD risk (adjusted OR = 1.07, 95% CI = 1.02-1.12, p < 0.01). These effects were amplified by APOE ε4 and attenuated by ε3, while ε2 showed no influence. Simple slope analyses confirmed an allele-specific gradient, with the association between later menopause and AD risk steepest in ε4 carriers and absent in high ε3 carriers.

CONCLUSION: This work provides novel evidence that extended ovarian function is associated with increased AD vulnerability in females, particularly among APOE ε4 carriers. These findings highlight a dose-dependent, genotype-specific interaction between reproductive aging and neurodegeneration, suggesting APOE as a molecular bridge linking estrogenic exposure and AD risk.},
}

@article {pmid41884646,
year = {2026},
author = {Sudwarts, A and Thinakaran, G},
title = {Female-specific Cx3cr1-driven regulation of ALS and Alzheimer's risk genes in tauopathy.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {16},
pmid = {41884646},
issn = {3059-4944},
abstract = {UNLABELLED: By introducing haploinsufficiency of Cx3cr1 in the P301S (PS19) transgenic model of tau pathology, we report remarkable transcriptional changes, including crucial amyotrophic lateral sclerosis and Alzheimer's disease risk genes, several of which showed co-expression, suggesting gene-gene interactions among these genetic risk factors.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44477-026-00022-3.},
}

@article {pmid41884668,
year = {2026},
author = {Xia, L and Liu, T and Li, Z and Ao, X and Chen, Q and Zhou, X and Jiang, Q and Huang, N and Luo, Y},
title = {Icaritin ameliorates mitochondrial dysfunction and autophagy impairment in cellular models of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1741339},
pmid = {41884668},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive memory decline, with neuropathological hallmarks including amyloid plaques and neurofibrillary tangles. Current treatments only alleviate symptoms and cannot halt disease progression. Icaritin (ICT), a natural compound, has shown neuroprotective potential. Transactive response DNA-binding protein 43 (TDP-43) is widely recognized as a key neuropathological hallmark of AD and related dementias. This study investigated the protective effects of ICT against TDP-43-induced damage in N2a/APP695swe (APP) cells and explored the underlying mechanisms.

METHODS: N2a/APP695swe/TARDBP cells overexpressing APP and TDP-43 were constructed via lentiviral transfection, and the optimal ICT dosage was determined using the CCK-8 assay. The effects of ICT on TDP-43 cell phenotypes were then assessed using CCK-8, ELISA, and Western blot. Finally, transmission electron microscopy, flow cytometry, assay kits, and Western blot were used to investigate the protective mechanisms of ICT.

RESULTS: ICT treatment significantly increased cell viability, reduced Aβ42 levels, and alleviated phospho-Tau and phospho-TDP-43 accumulation. Mechanistically, ICT improved mitochondrial morphology, decreased ROS levels, enhanced ATP production, and modulated the AMPK/mTOR and PINK1/Parkin autophagy signaling pathways to mitigate TDP-43-mediated cellular stress.

CONCLUSION: ICT protects cells from TDP-43-induced mitochondrial dysfunction and autophagy impairment, providing mechanistic insight into its potential as a therapeutic agent for AD.},
}

@article {pmid41884955,
year = {2026},
author = {Hussain, M and Ikram, M and Vohora, D},
title = {Targeting Neuroinflammation in Alzheimer's Disease: Repurposed Nucleoside Reverse Transcriptase Inhibitors and the Therapeutic Potential of Kamuvudine-9.},
journal = {Fundamental & clinical pharmacology},
volume = {40},
number = {3},
pages = {e70079},
doi = {10.1111/fcp.70079},
pmid = {41884955},
issn = {1472-8206},
mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology ; Animals ; *Reverse Transcriptase Inhibitors/pharmacology/therapeutic use ; *Neuroinflammatory Diseases/drug therapy ; Drug Repositioning ; Neuroprotective Agents/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurological illness that causes cognitive deterioration. Current medications only help with the symptoms to a limited extent. Over the past decade, nucleoside reverse transcriptase inhibitors (NRTIs), historically used as antiretrovirals, have appeared as surprising contenders for modifying AD. Aside from their antiviral activity, NRTIs have immunomodulatory actions, such as inhibiting the NLRP3 inflammasome, lowering amyloid and tau pathology and modulating neuroinflammation. A second-generation analogue, Kamuvudine-9, has been designed to balance these neuroprotective advantages with reduced mitochondrial toxicity and off-target antiviral effects, offering a safer long-term solution for chronic neurodegenerative disorders. This review synthesises mechanistic data, preclinical data, observational studies and new clinical findings to make a unified case for NRTIs and K-9 as multitarget therapeutic compounds in AD. By emphasising their dual mechanism, retroelement inhibition and inflammasome blockade coupled with innovation in drug delivery and pharmacogenomics, we highlight how repurposing this class would remake the therapeutic landscape. In contrast to amyloid-directed interventions, NRTIs and K-9 act on converging inflammatory and genetic mechanisms that mediate both amyloid and tau pathology, making them universal modulators of disease course. Prospects for future advances in precision medicine, nanocarrier delivery and large-scale validation of interventions may reveal a new generation of accessible, disease-modifying treatments for AD.},
}

Humans
*Alzheimer Disease/drug therapy/physiopathology
Animals
*Reverse Transcriptase Inhibitors/pharmacology/therapeutic use
*Neuroinflammatory Diseases/drug therapy
Drug Repositioning
Neuroprotective Agents/pharmacology

@article {pmid41884999,
year = {2026},
author = {Bekena, S and Singh, RK and Zhu, Y and Harrison, K and Williams, JP and Laurido-Soto, OJ and Al-Hammadi, N and Dickerson, A and Carr, DB and Babulal, GM},
title = {Naturalistic Driving Outcomes and Sensorimotor Function in Cognitively Normal Older Adults.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70400},
pmid = {41884999},
issn = {1532-5415},
support = {R01 AG067428/NH/NIH HHS/United States ; R01 AG068183/NH/NIH HHS/United States ; R01 AG074302/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Driving supports independence and quality of life in later life but is vulnerable to age-related and/or disease-related decline. While cognitive impairment is a well-recognized risk for unsafe mobility, the contribution of sensorimotor function is less understood.

METHODS: We studied 374 cognitively normal older adults (Clinical Dementia Rating = 0 at baseline) enrolled in the DRIVES Project. A SensoryMotor Impairment Index (SMI) was constructed from six domains (grip strength, gait speed, reaction time, hearing, vision, olfaction) and categorized as 0, 1, 2, or ≥ 3 impairments. Naturalistic driving was continuously monitored using in-vehicle GPS dataloggers between 2019 and 2025. Linear mixed-effects models tested whether longitudinal driving trajectories differed by baseline SMI, adjusting for age, sex, race, education, body mass index, and cognition (Preclinical Alzheimer's Cognitive Composite).

RESULTS: At baseline, participants with higher SMI burden were older and had lower cognitive scores (both p < 0.01). Over time, greater sensorymotor impairment was associated with faster declines in driving exposure and spatial range. Compared with SMI = 0, participants with SMI ≥ 3 showed steeper reductions in nighttime trips (-0.050 vs. -0.037 trips/month), long-distance trips (> 20 miles; p < 0.001), and maximum trip distance (p = 0.009), and greater contraction of driving space (entropy and radius of gyration; p < 0.001). Self-reported driving behaviors showed that participants with higher SMI drove fewer days per-week and were more likely to avoid night driving (p < 0.01). Rates of self-reported adverse driving events (e.g., crashes or citations) did not differ significantly across SMI groups, consistent with compensatory self-regulatory behaviors.

CONCLUSION: Greater sensorymotor impairment predicts accelerated decline in naturalistic driving among cognitively normal older adults, independent of cognition. A composite SMI may provide a feasible, low-cost approach to identify older drivers at risk for declining mobility and support timely interventions to prolong safe driving.},
}

@article {pmid41885129,
year = {2026},
author = {Shah, M and Sinha, S and Bhasme, M and Yadav, MR and Nagani, A},
title = {Benzothiazole-Based Anti-Alzheimer's Agents: A Comprehensive Review of Developments from 2015 to 2025.},
journal = {Chemical record (New York, N.Y.)},
volume = {},
number = {},
pages = {e70137},
doi = {10.1002/tcr.70137},
pmid = {41885129},
issn = {1528-0691},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, remains one of the greatest medical challenges because of its multifactorial nature. In recent years (2015-2025), benzothiazole-based compounds have gained increasing attention as promising scaffolds for the development of anti-Alzheimer agents. This comprehensive review focuses on the biological evaluation and structure-activity relationship (SAR) trends of benzothiazole derivatives targeting key enzymes and pathways implicated in AD. These include acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase (BACE1), monoamine oxidase A and B (MAO-A, MAO-B), receptor-interacting protein kinase 1 (RIPK1), human DYRK1A (hDYRK1A), and human CLK1 (hCLK1). Benzothiazole hybrids with diverse heterocyclic frameworks have been explored, and SAR analysis suggests that the presence of electron-withdrawing substituents in the molecules significantly enhances their potency against Alzheimer's targets. Many of these compounds demonstrate strong in vitro activity, multitarget inhibition potential, and favorable interaction profiles in docking studies, highlighting their relevance as multitarget-directed ligands. This review consolidates data from the last decade to provide insights into the structural features contributing to anti-Alzheimer's activity and offers directions for the rational design of more selective, efficacious, and brain-penetrant benzothiazole derivatives. Future research should focus on optimizing pharmacokinetic properties, improving blood-brain barrier permeability, and validating in vivo efficacy of the designed molecules. Overall, benzothiazole remains a valuable and versatile scaffold in the ongoing search for effective therapeutics for AD.},
}

@article {pmid41885166,
year = {2026},
author = {Gibson, LL and Suemoto, CK and Attems, J and Abner, EL and Corrada, MM and Gomez-Isaza, L and Grinberg, LT and Kapasi, A and Jicha, GA and Kawas, C and Keene, CD and Kovacs, GG and Latimer, CS and Leite, REP and Montine, T and Myllykangas, L and Neltner, AM and Troncoso, J and Walker, KA and Walker, R and Wang, SJ and Aarsland, D and Nelson, PT},
title = {The prevalence of Lewy body pathology across nine international community-based cohorts.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag112},
pmid = {41885166},
issn = {1460-2156},
abstract = {Reported prevalence estimates of Lewy body pathology (LBP) vary widely, often without considering brain regional distributions or demographic influences. Large, population-representative autopsy cohorts are needed to provide estimates and clarify the distribution and clinical implications of LBP. Neuropathological, genetic, and clinical data were pooled from nine community- or population-based brain autopsy cohorts in the USA (n=6), Brazil, Austria, and Finland (n=7309 total; 59% women; mean age of death 84.2 years). Cognitive status was available for 6166 participants: dementia (38.5%), mild cognitive impairment (14.8%), and cognitively unimpaired (47.0%). Frequency of LBP was examined by anatomical distribution (neocortical, limbic, brainstem, amygdala, olfactory) and stratified by covariates. Prevalence was calculated in meta-analysis, and mixed-effect logistic regression examined associations with sex, cognitive status, Alzheimer's disease neuropathological change (ADNC), and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) co-pathology. Overall, 27.3% of participants had LBP: neocortical 8.4%, limbic 6.8%, brainstem 4.8%, amygdala 3.7%, and olfactory 3.6%. Neocortical LBP was associated with dementia (present in 15%; OR=4.06 [95%CI 3.24-5.10]) and with increased odds of ADNC (OR=2.30 [95%CI 1.88-2.81]) and LATE-NC (OR=2.03 [95%CI 1.69-2.44]). Sex differences were not observed in the frequencies of neocortical or limbic LBP. However, amygdala-predominant LBP was more frequent in women (OR=1.53 [95%CI 1.06-2.21]) whereas brainstem-predominant LBP was more common in men (OR=0.64 [95%CI 0.49-0.84]). Additionally, amygdala-predominant LBP was associated with increased odds of comorbid ADNC (OR=12.7 [95%CI 5.30-30.6]) while brainstem-predominant LBP was not associated with greater odds of ADNC co-pathology (OR=0.88 [95%CI 0.67-1.16]). Pooling data from large, international community-based autopsy cohorts allows for more robust estimates of region-specific LBP prevalence and their associations with cognitive status. The observed sex- and co-pathology-specific differences in brainstem and amygdala-predominant LBP highlight potential biological heterogeneity and suggest that distinct disease pathways may underlie these patterns.},
}

@article {pmid41885175,
year = {2026},
author = {Young, CB and Sheng, J and Winer, JR and Cody, K and Sai, I and Carlson, ML and Younes, K and Insel, PS and Schultz, AP and Mormino, EC},
title = {Longitudinal trajectories of divergent cortical tau patterns in preclinical Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag113},
pmid = {41885175},
issn = {1460-2156},
abstract = {Approximately 10% of clinically unimpaired individuals with abnormal amyloid (A+; preclinical Alzheimer's disease) have "divergent" cortical tau pathology (A+TCortical+), defined as greater than expected tau in cortical regions relative to medial temporal lobe and/or cortical asymmetry on tau PET in addition to or instead of traditional medial temporal lobe tau burden. Although these A+TCortical+ individuals have subtle cognitive deficits at baseline, the longitudinal imaging and clinical outcomes are unknown. We aimed to characterize longitudinal trajectories of A+TCortical+ individuals compared to other biomarker-defined clinically unimpaired groups given that identifying those at highest risk for decline is critical for informing prevention trials and understanding early disease mechanisms. In this longitudinal study, we examined tau PET, MRI, cognitive, and functional data from 395 clinically unimpaired participants, ages 65 to 85 years, enrolled in the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study. Participants had 2-5 flortaucipir scans over a mean (standard deviation) follow-up period of 4.7 (1.6) years. Change in regional and voxelwise tau patterns, atrophy, cognition, and functioning were examined. Longitudinal trajectories from A+TCortical+ (n=34) were compared to preclinical Alzheimer's disease with elevated tau PET signal in medial temporal lobe only (A+TMTL+, n=102), preclinical Alzheimer's disease without significant tau (A+TMTL-, n=210), and those without amyloid or tau (A-TMTL-, n=49). Cortical tau accumulation was fastest in A+TCortical+ (0.018-0.034 standardized uptake value ratios per year), whereas medial temporal lobe tau accumulation was comparable across A+TCortical+, A+TMTL+, and A+TMTL- groups (0.010-0.013 standardized uptake value ratios per year). Tau continued to accumulate in affected regions and contralateral homotopic regions in A+TCortical+ participants with asymmetrical tau at baseline such that asymmetrical patterns were maintained over time. Younger A+TCortical+ participants had an especially fast cortical accumulation rate. The A+TCortical+ group showed significantly greater neurodegeneration and faster clinical decline (Clinical Dementia Rating Scale Sum of Boxes = 0.610 points per year; Mini-Mental State Examination = -0.780 points per year) than all other biomarker-defined subgroups (Clinical Dementia Rating Scale Sum of Boxes = 0.048-0.182 points per year; Mini-Mental State Examination = -0.189-0.006 points per year). In summary, individuals with divergent cortical tau patterns continue to accumulate cortical tau at a faster rate, show greater neurodegeneration, and have faster cognitive and functional decline than other preclinical Alzheimer's disease subgroups. Clinical trials and research examining tau progression and clinical decline in preclinical Alzheimer's disease without subtyping may be disproportionately influenced by this small, high-risk subgroup.},
}

@article {pmid41885189,
year = {2026},
author = {Panza, E and Meyyazhagan, A and Picchi, E and Ribas, G and Faber, I and Miyamoto, R and Basavaraju, P and Eusebi, P and Kuchi Bhotla, H and Stasi, M and Gaudiello, F and Patti, F and Santorelli, FM and França, MC and Pedroso, JL and Barsottini, OGP and Teive, HAG and St George-Hyslop, PH and Kawarai, T and Orlacchio, A},
title = {SPG4 and Dementia: Expanding the Clinical Spectrum.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70371},
pmid = {41885189},
issn = {2328-9503},
support = {CN00000041//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; RC2025//Ministero della Salute/ ; RC5x1000//Ministero della Salute/ ; RF19.12//Ministero della Salute/ ; DSCH_BASE19_ORLACCHIO//Università degli Studi di Perugia/ ; RICERCABASE_2020_ORLACCHIO//Università degli Studi di Perugia/ ; },
abstract = {OBJECTIVE: Hereditary spastic paraplegia (HSP) is a group of disorders characterized by progressive spasticity and lower limb weakness, with mutations in SPG4/SPAST being the most common cause. Detailed studies and clinical and molecular comparisons across different populations are missing. We examined the clinical, pathological, and genetic spectrum of the SPG4/SPAST gene in patients with HSP.

METHODS: The study involved 726 HSP patients recruited from Italy, Brazil, and Japan between 2001 and 2025, with analysis conducted in collaborative centers. SPG4/SPAST variants were identified using direct and next-generation sequencing. The pathogenicity of novel variants was confirmed through familial segregation and in silico analysis.

RESULTS: Clinical and epidemiological differences were observed across populations, particularly in phenotype, age at onset, and disability, expanding the SPG4 clinical spectrum. Genetic analysis identified 52 pathogenic SPG4/SPAST mutations in 284 patients, including four novel variants. Several mutations were population-specific, and a possible founder effect was suggested for a recurrent variant in Italy. Dementia occurred in 44 HSP-SPG4 patients and was neuropathologically confirmed in four unrelated autopsied cases from four families comprising 28 individuals; atypical pathological features were observed in all four autopsied cases. Additionally, 18 patients with SPG4/SPAST mutations presented with thin corpus callosum and intellectual disability.

INTERPRETATION: In this study, we investigated pathogenic SPG4/SPAST variants in an international cohort of HSP patients from three continents. Our findings expand the clinical spectrum of HSP-SPG4, identifying a new type complicated by an atypical pathological form of dementia. Careful assessment of genotype-phenotype relationships offers insights into patient counseling and future research planning.},
}

@article {pmid41885326,
year = {2026},
author = {Dangpiaei, S and Kamal, KM and Shoair, OA and Al-Mamun, MA},
title = {Incidence of amyloid-related imaging abnormalities and health resource utilization in patients with Alzheimer disease receiving monoclonal antibody treatments: A real-world evidence study.},
journal = {Journal of managed care & specialty pharmacy},
volume = {32},
number = {4},
pages = {470-484},
doi = {10.18553/jmcp.2026.32.4.470},
pmid = {41885326},
issn = {2376-1032},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Female ; Aged ; Male ; Retrospective Studies ; Aged, 80 and over ; Incidence ; *Antibodies, Monoclonal/adverse effects/therapeutic use ; Middle Aged ; *Health Resources/statistics & numerical data ; Patient Acceptance of Health Care/statistics & numerical data ; },
abstract = {BACKGROUND: All recently approved monoclonal antibodies (eg, aducanumab, lecanemab, and donanemab) for Alzheimer disease (AD) were shown to increase the risks of amyloid-related imaging abnormalities (ARIA) in randomized clinical trials, which can include brain swelling or hemorrhage. Real-world evidence (RWE) studies are critically warranted to evaluate the associated risks of ARIA and health care resource utilization (HRU) with monoclonal treatments compared with existing nonmonoclonal (eg, donepezil, memantine and rivastigmine) treatments.

OBJECTIVE: To evaluate the risk of ARIA in patients receiving monoclonal vs nonmonoclonal treatments. The secondary aim was to investigate the HRUs including emergency department (ED) and inpatient visits between the 2 groups.

METHODS: We conducted a retrospective study using a large electronic health record dataset. Individuals (aged ≥18 years) diagnosed with AD and receiving monoclonal treatment were matched with a nonmonoclonal treatment group using propensity score matching. An Andersen-Gill survival model was used to estimate the cumulative hazard of ARIA after adjusting for baseline comorbidities. Negative binomial regression was applied to assess the HRUs between the 2 groups.

RESULTS: The monoclonal group included 240 patients. Most patients in both groups were aged 70-80 years (47.08% vs 47.29%), female (55.42% vs 56.25%), and White (85.42% vs 85.83%) in the monoclonal and the nonmonoclonal groups, respectively. The monoclonal group had significantly higher cumulative hazard of ARIA (hazard ratio = 4.65, 95% CI = 3.77-5.73; P < 0.001) compared with the nonmonoclonal group. Concurrent antithrombotic use (1.87, 1.48-2.37; P < 0.001), a history of stroke (1.59, 1.21-2.10; P < 0.001), and hyperlipidemia (1.41, 1.09-1.84; P = 0.008) were also associated with increased hazard of ARIA. Among those patients who had at least 180 days of follow-up, the monoclonal group had significantly fewer inpatient visits (β = -2.71, -3.84 to -1.58; P < 0.001) compared with the nonmonoclonal group.

CONCLUSIONS: Monoclonal treatment was associated with higher cumulative hazard of ARIA but fewer inpatient visits. This study indicated the potential of RWE, despite its distinct observational design and differences from randomized clinical trials, to serve as a credible proof-of-concept in postapproval assessment and to inform personalized treatment guidelines based on patients' risk factors.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging
Female
Aged
Male
Retrospective Studies
Aged, 80 and over
Incidence
*Antibodies, Monoclonal/adverse effects/therapeutic use
Middle Aged
*Health Resources/statistics & numerical data
Patient Acceptance of Health Care/statistics & numerical data

@article {pmid41885336,
year = {2026},
author = {Likitjaroen, Y and Chang, YT and Lim, L and Chiu, PY and Hsu, JL and Kim, S and Narita, W and Ryoo, NY and Suzuki, K and Kandiah, N and Crutch, S and Pai, MC},
title = {Posterior Cortical Atrophy in the Asia-Pacific: A Report From the PCA Asian Workgroup.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70347},
pmid = {41885336},
issn = {2328-9503},
abstract = {OBJECTIVE: Posterior Cortical Atrophy (PCA) is a distinct dementia syndrome primarily affecting spatial abilities and visual processing. It is associated with degeneration in the posterior part of the brain. PCA is subclassified into PCA-pure and PCA-plus syndromes based on consensus criteria. To address this, the PCA Asia Workgroup was established to study PCA in Asian countries.

METHODS: The Asia PCA Workgroup collected demographic and clinical data, including symptoms and signs, from PCA patients. Patients were classified into PCA-pure (solely meeting PCA criteria) and PCA-plus (additional features of other neurodegenerative syndromes). The frequency of clinical presentations, symptoms, and signs was compared to the consensus classification estimation and the meta-analysis of published data.

RESULTS: PCA-pure (76.2%) was the most common subtype, with earlier onset (80.95%) and distinct early prominent deficit of executive/memory > visual disturbances which is different from the consensus study has estimated and the meta-analysis of published data. PCA-Lewy body disease (PCA-DLB) exhibited higher frequencies of attention deficits, visual hallucinations, cognitive fluctuations, and rigidity compared to PCA-pure.

INTERPRETATION: This study reveals the real-world clinical presentation of PCA syndrome in an Asian population, emphasizing the differences from consensus estimations and the meta-analysis of published data. Further research is needed to validate these findings and compare them with real clinical data from PCA patients of other ethnicities, in order to gain a comprehensive understanding of PCA worldwide.},
}

@article {pmid41885638,
year = {2026},
author = {Sadhukhan, A and Chauhan, A and Kumar, M and Singh, TG and Mujwar, S and Awasthi, A},
title = {Cryptoxanthin as a multitarget neuroprotective agent: mechanistic and in silico perspectives.},
journal = {The Journal of pharmacy and pharmacology},
volume = {78},
number = {3},
pages = {},
doi = {10.1093/jpp/rgag029},
pmid = {41885638},
issn = {2042-7158},
mesh = {*Neuroprotective Agents/pharmacology/therapeutic use ; Humans ; Molecular Docking Simulation ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Xanthophylls/pharmacology/therapeutic use ; Animals ; Oxidative Stress/drug effects ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Computer Simulation ; },
abstract = {OBJECTIVES: Neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease (AD), and Amyotrophic lateral sclerosis (ALS) are complex disorders driven by multiple pathological processes, including oxidative stress, mitochondrial dysfunction, protein misfolding, and neuroinflammation. Due to this multifactorial nature, there is a growing interest in identifying natural compounds with multi-targeted neuroprotective properties. This review aims to evaluate the therapeutic potential of β-cryptoxanthin, a naturally occurring xanthophyll carotenoid, as a candidate molecule for mitigating neurodegenerative diseases.

METHODS: A comprehensive literature review was conducted to examine the neuroprotective mechanisms of β-cryptoxanthin, focusing on its antioxidant, anti-inflammatory, and immunomodulatory properties. In addition, in silico molecular docking studies were performed using AutoDock Vina to investigate the binding interactions of β-cryptoxanthin with key molecular targets associated with inflammation and neurodegenerative pathways.

KEY FINDINGS: β-Cryptoxanthin demonstrated strong neuroprotective potential due to its ability to scavenge reactive oxygen species (ROS) and modulate key molecular pathways involved in neuroinflammation and oxidative damage. Structurally characterized by a hydroxylated β-carotene backbone with 11 conjugated double bonds, β-cryptoxanthin showed favorable binding affinities with several inflammation- and neurodegeneration-related targets, including COX-2 (-11.6 kcal/mol), PI3K (-9.6 kcal/mol), mTOR1 (-9.2 kcal/mol), and GSK-3β (-8.7 kcal/mol). Additionally, interactions with JAK2, MAPK1, NF-κB, NRF2, and TLR4 suggest its involvement in regulating neuroimmune signalling pathways and inflammatory mediators.

CONCLUSIONS: The findings of this review highlight β-cryptoxanthin as a promising candidate for future neurotherapeutic investigation due to its multi-targeted mechanisms of action against key pathways implicated in neurodegeneration. Molecular docking results support its potential mechanistic role in modulating inflammation- and oxidative stress-related targets. However, these findings represent mechanistic plausibility rather than confirmed clinical efficacy, and further validation through preclinical and clinical studies is required.},
}

*Neuroprotective Agents/pharmacology/therapeutic use
Humans
Molecular Docking Simulation
*Neurodegenerative Diseases/drug therapy/metabolism
*Xanthophylls/pharmacology/therapeutic use
Animals
Oxidative Stress/drug effects
Anti-Inflammatory Agents/pharmacology
Antioxidants/pharmacology
Computer Simulation

@article {pmid41885695,
year = {2026},
author = {Zhao, H and Sun, Y and Hussain, SA and Gao, H},
title = {H3 relaxin mediated neuroprotection in Alzheimer's disease pathology induced by streptozotocin in mouse models: Impact on memory improvement, autophagy and PI3K/Akt-mTOR signalling pathway.},
journal = {Acta pharmaceutica (Zagreb, Croatia)},
volume = {76},
number = {1},
pages = {1-18},
doi = {10.2478/acph-2026-0009},
pmid = {41885695},
issn = {1846-9558},
mesh = {Animals ; TOR Serine-Threonine Kinases/metabolism ; *Alzheimer Disease/drug therapy/pathology/chemically induced/metabolism ; Streptozocin ; *Neuroprotective Agents/pharmacology/administration & dosage ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects ; Mice ; Autophagy/drug effects ; *Relaxin/pharmacology/administration & dosage ; Male ; Disease Models, Animal ; *Memory/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Oxidative Stress/drug effects ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Maze Learning/drug effects ; Hippocampus/drug effects/metabolism ; Donepezil/pharmacology ; },
abstract = {Alzheimer's disease (AD) is characterised by β-amyloid (Aβ) plaque accumulation and tau hyperphosphorylation. H3 relaxin, a neuro-peptide, is known to exert neuroprotective effects. In this study, we investigated how H3 relaxin confers neuroprotection in a streptozotocin (STZ)-induced mouse model and modulates PI3K/Akt-mTOR signalling. Mice were divided into four groups (n = 6 per group): control (saline), STZ, STZ + H3 relaxin, and STZ + donepezil. Following STZ induction, H3 relaxin (1 µg per day) was administered intracerebro ventricularly (ICV) for 14 consecutive days, whereas donepezil (2.5 mg kg[-1] per day) was administered orally for the same duration. Cognitive performance was assessed using the Morris water maze (MWM) test. Aβ deposition in the cortex was evaluated through immunohistochemistry. Western blotting was conducted for tau phospho rylation, PI3K/Akt/mTOR signalling, and autophagy markers in the hippocampus. Oxidative stress and inflammation markers were measured using ELISA. H3 relaxin markedly improved memory by decreasing escape latency and duration while spending more time in the target quadrant in the MWM test. Additionally, H3 relaxin reduced Aβ plaque burden and tau phosphorylation (Ser396/404) while enhancing PI3K/Akt-mTOR signalling. Oxidative stress was attenuated, as evidenced by increased GSH and HO-1 levels and reduced MDA and H2O2 concentrations. Moreover, markers of inflammation, NF-κB and TNF-α were suppressed. Overall, H3 relaxin ameliorated cognitive deficits in STZ-induced AD mice through modulation of impaired PI3K/Akt-mTOR signalling, reduction of Aβ and tau pathology, and promotion of autophagy.},
}

Animals
TOR Serine-Threonine Kinases/metabolism
*Alzheimer Disease/drug therapy/pathology/chemically induced/metabolism
Streptozocin
*Neuroprotective Agents/pharmacology/administration & dosage
Proto-Oncogene Proteins c-akt/metabolism
Signal Transduction/drug effects
Mice
Autophagy/drug effects
*Relaxin/pharmacology/administration & dosage
Male
Disease Models, Animal
*Memory/drug effects
Phosphatidylinositol 3-Kinases/metabolism
Oxidative Stress/drug effects
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Maze Learning/drug effects
Hippocampus/drug effects/metabolism
Donepezil/pharmacology

@article {pmid41885701,
year = {2026},
author = {Labernède, F and Lausecker, A and Sanna, L and Philippi, N and Demuynck, C and Cretin, B and Muller, C and Blanc, F and Chabran, É},
title = {Language performances in dementia with Lewy bodies and Alzheimer's disease: A longitudinal comparative study of naming and fluency.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261427500},
doi = {10.1177/13872877261427500},
pmid = {41885701},
issn = {1875-8908},
abstract = {BackgroundWhile language impairments are well-documented in Alzheimer's disease (AD), their longitudinal progression in dementia with Lewy bodies (DLB) remains poorly understood.ObjectiveTo compare four-year trajectories of naming and verbal fluency in DLB, AD, and healthy controls (HC), and to identify the cognitive correlates underlying naming performance over time.MethodsThis study included 111 participants (62 DLB, 26 AD, 23 HC) followed at baseline, 12, 24, and 48 months. Primary outcomes were naming (DO-80) and verbal fluency (letter/semantic) scores. Secondary assessments included verbal memory, executive, and visuospatial functions. Linear Mixed Models compared longitudinal trajectories, and Spearman correlations explored cognitive associations.ResultsA significant Visit x Group interaction (p < 0.001) revealed that naming remained stable in DLB (-1.15 points) and HC, whereas AD patients showed a steep decline (-7.77 points). In DLB, letter fluency remained stable over 48 months, while semantic fluency significantly decreased (p = 0.002). Conversely, AD patients deteriorated across all tasks. By month 48, DLB patients significantly outperformed AD patients in naming (p = 0.002) and semantic fluency (p = 0.015). Naming in DLB was positively and increasingly correlated with executive functions (Frontal Assessment Battery: rho 0.416 to 0.578) and Mini-Mental State Examination, whereas in AD, it was tied to episodic memory. No correlation was found with attentional fluctuations in DLB.ConclusionsThese findings highlight distinct language trajectories: naming abilities are relatively preserved in DLB compared to the global collapse in AD. This preservation in DLB appears increasingly dependent on executive control, underscoring the need for tailored, domain-specific interventions.},
}

@article {pmid41885816,
year = {2026},
author = {VanCleef, TR and Jones, EJ},
title = {The Theoretical Intersection of Plant-Based Diets, Alzheimer's, and Cardiovascular Disease.},
journal = {Biological research for nursing},
volume = {},
number = {},
pages = {10998004261439115},
doi = {10.1177/10998004261439115},
pmid = {41885816},
issn = {1552-4175},
abstract = {Alzheimer's disease (AD) and cardiovascular disease (CVD) are significant health concerns for older adults globally. Plant-based diets (PBDs) are a potential non-invasive lifestyle strategy to address the risk factors common to both conditions. Research on plant-based diets and older adults is limited, especially when it comes to the overlap between the development of CVD and AD. This theoretical paper examines the relationships between PBDs, AD, and CVD through the integration of six theories and concepts: the vascular hypothesis, microbiota-gut-brain axis (MGBA) theory, neurovascular unit (NVU) theory, antioxidant theory, metabolic syndrome (MetS), and mitochondrial dysfunction. By integrating these theories and concepts, a comprehensive model is provided for understanding how plant-based diets may mitigate both AD and CVD through shared pathophysiological pathways.},
}

@article {pmid41885876,
year = {2026},
author = {Wang, J and Zhang, B and Liu, L and Li, X and Xie, Z and Yang, X},
title = {Vanadyl Complexes (VOp-Dmada) Promote Healthy Aging by Regulating Electron Transport Mediated by Mitochondrial Complex II.},
journal = {ChemMedChem},
volume = {21},
number = {6},
pages = {e202600003},
doi = {10.1002/cmdc.202600003},
pmid = {41885876},
issn = {1860-7187},
support = {22177007//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Mice ; *Electron Transport Complex II/metabolism/antagonists & inhibitors ; Electron Transport/drug effects ; *Mitochondria/metabolism/drug effects ; *Healthy Aging/drug effects ; *Coordination Complexes/pharmacology/chemistry/chemical synthesis ; Caenorhabditis elegans/drug effects ; Reactive Oxygen Species/metabolism ; Molecular Structure ; Structure-Activity Relationship ; Dose-Response Relationship, Drug ; *Vanadium Compounds/pharmacology/chemistry ; },
abstract = {Vanadium compounds are promising metallodrug candidates, with well-documented antidiabetic, antitumor, and anti-Alzheimer's activities. In search for the long-term beneficial or adverse effects of antidiabetic vanadyl complexes, we serendipitously discovered that the vanadyl complexes VOp-dmada exerted pro-healthy aging effects across a diverse panel of model organisms, i.e., yeast, C. elegans, and SAMP8 mice. Furthermore, VOp-dmada attenuated replicative senescence in mouse embryonic fibroblasts and alleviated thymic epithelial cell aging while preserving thymic architecture and function in a mouse model of dexamethasone-induced acute thymic atrophy. Mechanistic investigations revealed that VOp-dmada improved the structural integrity and functional capacity of mitochondrial complex II. This effect was mediated by activation of the c-Myc/S-phase kinase-associated protein 2 (SKP2)/sirtuin 3 (SIRT3) signaling axis, which in turn upregulated succinate dehydrogenase subunit A (SDHA) expression. Thus, vanadyl complexes suppressed reactive oxygen species (ROS) generation at the source, disrupted the deleterious ROS-thioredoxin-interacting protein (TXNIP) vicious cycle, and ultimately decelerated the aging process. Our findings highlight the potential application of antidiabetic vanadium complexes in the treatment of other aging-related disorders and corroborate the chronic safety profile. Moreover, these results support the targeting of mitochondrial complex II function and integrity as a novel strategy for the discovery of pro-healthy aging agents.},
}

Animals
Mice
*Electron Transport Complex II/metabolism/antagonists & inhibitors
Electron Transport/drug effects
*Mitochondria/metabolism/drug effects
*Healthy Aging/drug effects
*Coordination Complexes/pharmacology/chemistry/chemical synthesis
Caenorhabditis elegans/drug effects
Reactive Oxygen Species/metabolism
Molecular Structure
Structure-Activity Relationship
Dose-Response Relationship, Drug
*Vanadium Compounds/pharmacology/chemistry

@article {pmid41885908,
year = {2026},
author = {Zhang, M and Cui, Q and Lü, Y and Pan, Y and Yu, W and Li, W},
title = {A large language model-based self-learning and critical agent framework for multimodal Alzheimer's disease diagnosis.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001079},
pmid = {41885908},
issn = {1931-1559},
support = {//Science Innovation Programs/ ; //Chongqing Talent Plan/ ; //Chongqing Science and Technology Bureau/ ; //Chongqing Medical University; Program for Youth Innovation in Future Medicine/ ; },
abstract = {OBJECTIVE: We developed and evaluated a training-free, large language model (LLM) multiagent framework, consisting of role-prompted LLM instances, that simulates hospital-style team diagnosis for Alzheimer's disease, improving interpretability and generalizability for multimodal data.

METHOD: We designed a self-learning and critical multiagent workflow comprising nine single-dimension agents and five senior agents that iteratively validate, retrieve experience, and refine decisions via self-evaluation and critique. Agents are augmented with an "intelligence" module and an experience-retrieval module. Participants were 1,362 Alzheimer's Disease Neuroimaging Initiative (ADNI) records spanning cognitively normal, mild cognitive impairment, and Alzheimer's disease from ADNI GO, ADNI 1, ADNI 2, ADNI 3, ADNI 4. The decision layer is not supervised on ADNI labels, and no end-to-end fine-tuning is performed on ADNI within this study.

RESULTS: The full self-learning and critical multiagent framework achieved an F1 score = 88%, sensitivity = 88%, and precision = 90% for three-way cognitively normal/mild cognitive impairment/Alzheimer's disease classification, providing case-level rationales. Relative to early agents, sequential self-learning and critique produced large effect gains. Single-dimension agents varied widely, while the integrated framework yielded the most balanced performance and higher answer relevancy on LLM-based metrics.

CONCLUSIONS: A label-free LLM multiagent approach can integrate heterogeneous modalities, retain diagnostic "experience," and generate transparent reasoning while delivering competitive accuracy on ADNI. The framework shows promise for real-world support of complex neuropsychological diagnosis; future work should incorporate fully multimodal LLMs for imaging and repeated, graph-driven iterations to further enhance performance. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid41886174,
year = {2026},
author = {Tsougos, I and Valotassiou, V and Tsivaka, D and Satra, M and Angelidis, G and Papatriantafyllou, J and Panagiotidis, E and Dardiotis, E and Hadjigeorgiou, G and Georgoulias, P},
title = {SPECT and PET imaging of Alzheimer's disease revisited: from biomarkers to artificial intelligence-based prediction.},
journal = {Annals of nuclear medicine},
volume = {},
number = {},
pages = {},
pmid = {41886174},
issn = {1864-6433},
}

@article {pmid41886471,
year = {2026},
author = {Luo, N and Pandit, H and Kalra, S and Tran, E and Mandelblatt, J and Vicini, S and Rebeck, GW},
title = {APOE4 and doxorubicin impair inhibitory interneuron function and homeostatic regulation in the entorhinal cortex.},
journal = {PloS one},
volume = {21},
number = {3},
pages = {e0343276},
doi = {10.1371/journal.pone.0343276},
pmid = {41886471},
issn = {1932-6203},
mesh = {Animals ; *Doxorubicin/pharmacology/adverse effects ; *Apolipoprotein E4/genetics/metabolism ; *Entorhinal Cortex/drug effects/metabolism/physiology ; *Interneurons/drug effects/metabolism/physiology ; Mice ; *Homeostasis/drug effects ; Pyramidal Cells/drug effects/metabolism/physiology ; Humans ; Parvalbumins/metabolism ; Male ; Female ; Genotype ; Mice, Transgenic ; },
abstract = {APOE4 is a risk factor for several disease states associated with cognitive impairment, including Alzheimer's disease and cancer-chemotherapy induced cognitive impairment. Using mouse knock-in models of human APOE alleles, we examined the effects of APOE genotype and chemotherapy on the ex vivo electrophysiological characteristics of excitatory and inhibitory neurons in the entorhinal cortex (EC). We found that APOE4 is associated with a significantly higher excitatory/inhibitory ratio (0.33 ± 0.04) in the layer 2/3 pyramidal cells of the entorhinal cortex compared to APOE3 (0.19 ± 0.04). We crossed APOE mice to mice with parvalbumin (PV) interneurons tagged with tdTomato, allowing us to measure effects specifically on this inhibitory cell type. For EC pyramidal neurons, the chemotherapeutic agent doxorubicin caused increases in the amplitudes of both spontaneous excitatory and inhibitory post-synaptic currents, with significant responses (***p < 0.001; **p < 0.01 respectively) in APOE3 brains. For EC PV neurons, APOE4 genotype was associated with significantly lower firing rates at injections of high currents (**p < 0.01), but rates were unaffected by doxorubicin. Doxorubicin doubled the percentage of PV cells that showed inactivation block in APOE3 brains (25% to 52%) but had no effect on APOE4 brains (50% to 54%). This ex vivo study suggests that APOE4 impairs homeostatic synaptic transmission in pyramidal cells under control conditions and causes a lack of responsiveness to a stressor (doxorubicin treatment) in PV cells.},
}

Animals
*Doxorubicin/pharmacology/adverse effects
*Apolipoprotein E4/genetics/metabolism
*Entorhinal Cortex/drug effects/metabolism/physiology
*Interneurons/drug effects/metabolism/physiology
Mice
*Homeostasis/drug effects
Pyramidal Cells/drug effects/metabolism/physiology
Humans
Parvalbumins/metabolism
Male
Female
Genotype
Mice, Transgenic

@article {pmid41886678,
year = {2026},
author = {Easter, B and Gore, J and Fields, J and Epps, F},
title = {African American Adolescents' Experiences Providing Care for a Family Member with Dementia.},
journal = {Issues in mental health nursing},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/01612840.2026.2642087},
pmid = {41886678},
issn = {1096-4673},
abstract = {This study explores the experiences of African American adolescents aged 14-17 who provide care for family members with Alzheimer's disease and related dementias (ADRD). The research utilizes a qualitative approach, conducting semi-structured interviews with 10 participants recruited through two ADRD service organizations. Analysis of interview data revealed five key themes: 1) experiencing and recognizing caregiver stress, 2) conflicting roles within the African American family system, 3) knowledge of ADRD behavioral symptoms through direct caregiving experiences, 4) seeking supportive groups instead of traditional support groups, and finally 5) the positive impact of caregiving. The results of this study show the variety of emotions experienced by these adolescents, including relief, joy, sadness, and stress. Results also highlight the cultural expectations within the families of each caregiver. This research addresses a vital gap in the literature and provides valuable insight into the unique needs and experiences of African American adolescent caregivers.},
}

@article {pmid41886735,
year = {2026},
author = {Taherinezhad, F and Momeni Nezhad, MJ and Karimi, S and Rashidi, S and Zolnour, A and Dadkhah, M and Haghbin, Y and Azadmaleki, H and Zolnoori, M},
title = {Large Language Model Adaptation Strategies in Speech-Based Cognitive Screening: Systematic Evaluation.},
journal = {JMIR AI},
volume = {5},
number = {},
pages = {e82608},
doi = {10.2196/82608},
pmid = {41886735},
issn = {2817-1705},
abstract = {BACKGROUND: Over half of US adults with Alzheimer disease and related dementias (ADRD) remain undiagnosed. Speech-based screening algorithms offer a scalable approach, but the relative value of large language model (LLM) adaptation strategies is unclear.

OBJECTIVE: The study aimed to compare LLM adaptation strategies for cognitive impairment detection across DementiaBank speech datasets using both text-only and multimodal models.

METHODS: We analyzed audio-recorded speech from 237 participants in the ADReSSo subset of DementiaBank (ADRD vs cognitive normal [CN]) and report performance on a held-out test set (n=71). Nine text-only LLMs (3B-405B; open-weight and commercial) and 3 multimodal audio-text models were evaluated. Adaptations included (1) in-context learning (ICL) with 4 demonstration selection strategies (most similar, least similar, average similar or prototype, and random), (2) reasoning-augmented prompting (self- or teacher-generated rationales, self-consistency, tree-of-thought with domain experts), (3) parameter-efficient fine-tuning (token-level vs added classification head), and (4) multimodal audio-text integration. Generalizability of the adaptation strategies was evaluated on the DementiaBank Delaware dataset (n=205; mild cognitive impairment vs CN) using the first 3 strategies. The primary outcome was the F1-score for the cognitive impaired class; the area under the receiver operating characteristic curve was reported when available.

RESULTS: On the ADReSSo dataset, average similar (prototype) demonstrations achieved the highest ICL performance across model sizes (F1-score up to 0.81). Reasoning primarily benefited smaller models: teacher-generated rationales increased LLaMA 8B from F1-score 0.72 to 0.76; expert-role tree-of-thought improved its zero-shot score from 0.65 to 0.71. Token-level fine-tuning produced the highest scores (LLaMA 3B: F1=0.83, 95% CI 0.01, area under the curve [AUC]=0.91; LLaMA 70B: F1=0.82, 95% CI 0.02, AUC=0.86; GPT-4o: F1=0.79, 95% CI 0.01, AUC=0.87). A classification head markedly improved MedAlpaca 7B (F1=0.06, 95% CI 0.02 to F1=0.81, 95% CI 0.04), indicating model-dependent benefits of this approach. Among multimodal models, fine-tuned Phi-4 Multimodal reached an F1-score of 0.80 (cognitive impaired) and 0.75 (CN) but did not exceed the top text-only systems. On the Delaware dataset, ICL achieved a high performance (LLaMA 8B: F1=0.74; GPT-4o: F1=0.80). Reasoning-augmented ICL improved LLaMA 8B to an F1-score of 0.75. Token-level fine-tuning produced the highest scores (LLaMA 8B: F1=0.76, 95% CI 0.02; GPT-4o: F1=0.82, 95% CI 0.03).

CONCLUSIONS: Detection accuracy is influenced by demonstration selection, reasoning design, and tuning method. Token-level fine-tuning is generally most effective, while a classification head benefits models that perform poorly under token-based supervision. Properly adapted open-weight models can match or exceed commercial LLMs, supporting their use in scalable speech-based ADRD and mild cognitive impairment screening. Current multimodal models may require improved audio-text alignment and/or larger training corpora.},
}

@article {pmid41886887,
year = {2026},
author = {Kumar, V and Shukla, R and Gangani, S and Joseph, R and Jain, S and Yadav, H},
title = {Epigenetics and the gut-brain axis: Insights into DNA methylation, aging, and Alzheimer disease.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {393},
number = {4},
pages = {104299},
doi = {10.1016/j.jpet.2026.104299},
pmid = {41886887},
issn = {1521-0103},
abstract = {Alzheimer disease (AD) and aging have similar molecular mechanisms that are affected by genetic as well as environmental variables. Based on current research, gut microbiomes contribute to age-specific biological processes and play an essential role in maintaining host homeostasis. Several molecular processes, including the host DNA methylation mechanism, are affected by microbially derived metabolites such as short-chain fatty acids, folate, and choline. This interaction establishes a mechanistic causal relationship that further shapes gene expression, inflammatory balance, and neuronal function in aging and related diseases. In this review, we looked at recent research showing how gut dysbiosis and its associated metabolites impact DNA methylation, which consequently contributes to disease progression in AD and aging. We also talked about how the DNA clock and age-associated methylation drifts can be used for forecasting biological aging. In addition, we discussed recent findings on how microbial and diet-based interventions may restore the methylation patterns that might be involved in aging and neurodegenerative processes. We also implicated the possible use of methylation-based biomarkers in the diagnosis of AD. Additionally, we have also explored the potential therapeutic benefits of using microbiome modulators, dietary modifications, and pharmacological interventions. Next, we highlighted the importance of multiomics and longitudinal studies to build the causal connection underlying methylation dynamics and microbial changes in neurodegeneration. Altogether, this review highlights the potential of the microbiome-methylation axis as an approach to understanding aging and establishing precision strategies to maintain cognitive health. SIGNIFICANCE STATEMENT: This review explores the interplay between DNA methylation and gut microbiota in aging and Alzheimer's disease. It highlights the gut-brain axis and summarizes recent findings on microbiome-driven epigenetic changes and metabolites influencing cognitive decline. The review also emphasizes microbiome-targeted therapeutic strategies for age-related disorders. Overall, it integrates current molecular insights with emerging approaches for the detection, prevention, and management of Alzheimer's disease and associated cognitive challenges.},
}

@article {pmid41886893,
year = {2026},
author = {Wang, M and Zhang, B and Guo, R and Wang, H and Wu, D and Peng, X and Guo, H and Duan, J and Yang, W and Ren, P and Zhang, S},
title = {Restoration of autophagy-lysosomal function via transcranial focused ultrasound stimulation ameliorates β-amyloid pathology and cognitive deficits in an Alzheimer's disease model.},
journal = {Ultrasonics},
volume = {165},
number = {},
pages = {108075},
doi = {10.1016/j.ultras.2026.108075},
pmid = {41886893},
issn = {1874-9968},
abstract = {Transcranial focused ultrasound (FUS) is a non-invasive neuromodulation technique that regulates intracellular functions and treats brain disorders. In Alzheimer's disease (AD), impaired autophagy-lysosomal pathway (ALP) function leads to the accumulation of β-amyloid (Aβ). However, the potential of FUS alone to alleviate AD pathology by restoring ALP function remains unexplored. In this study, sixteen male transgenic mice with five familial Alzheimer's disease mutations (5×FAD) received bilateral FUS targeting the hippocampus and were compared with sixteen age-matched untreated male 5×FAD mice. Cognitive function was evaluated using behavioral tests, and Aβ pathology was analyzed by immunofluorescence. RNA sequencing, western blotting, and electron microscopy were employed to assess the effects of FUS on the ALP. The results indicated that FUS reduced Aβ deposition and ameliorated cognitive deficits. Compared with the AD group, FUS treatment significantly reduced escape latency by 40.9% (p = 0.010), increased the novel object recognition index by 38.2% (p = 0.016), and increased spontaneous alternation by 18.2% (p = 0.009). Critically, FUS enhanced lysosomal biogenesis and improved autophagosome-lysosome fusion, increasing colocalization efficiency from 28.07 ± 3.73% to 53.22 ± 4.85% in the cortex (p = 0.009) and from 31.95 ± 3.65% to 48.00 ± 2.18% in the hippocampus (p = 0.026). It also promoted the nuclear translocation of transcription factor EB (TFEB). Moreover, the ALP antagonist chloroquine (CQ) suppressed the beneficial effects of FUS, indicating that FUS exerts therapeutic effects in an ALP-dependent manner. Our findings demonstrate that restoring ALP via FUS is a crucial mechanism for mitigating Aβ pathology.},
}

@article {pmid41886952,
year = {2026},
author = {Honaramouz, B and Imenshahidi, M and Hosseinzadeh, H},
title = {A review of plant-derived products regulating amyloid beta-degrading enzymes in Alzheimer's disease.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {155},
number = {},
pages = {158053},
doi = {10.1016/j.phymed.2026.158053},
pmid = {41886952},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent form of dementia that affects elderly individuals, characterized by cognitive dysfunction and behavioral impairments. Cerebral amyloid beta-peptide (Aβ) is a critical precipitating factor in AD development. Aβ exists in a dynamic equilibrium between biosynthesis and clearance in the CNS. Disruption of this balance leads to increased Aβ deposition in the brain and the development of AD.

PURPOSE: In recent years, there has been a growing emphasis on stimulating Aβ-degrading enzymes (ADEs). Evidence suggests that enhancing Aβ degradation is more effective than preventing Aβ accumulation. Different strategies have been developed for the upregulation of ADEs; we provide a summary of the research on the benefits of bioactive plant constituents for enhancing the activity of ADEs.

METHODS: Electronic databases, including Scopus, PubMed, and Web of Science, were searched for articles. Using the articles that dealt with the effect of plant-derived products on ADEs were identified, and the most recent evidence regarding their influence on the expression and/or activity of ADEs was summarized and discussed.

RESULTS: The results indicated that a total of 39 plant-derived products can regulate ADEs, including Curcuma longa, Vitis vinifera, Panax ginseng, Cichorium intybus, and Crocus sativus, among others. Among ADEs, neprelesin, with 13 medicinal plants that are effective in regulating its activity, is the most important enzyme.

CONCLUSIONS: It appears that upregulating the levels of ADEs with plant-derived products is a promising strategy for the prevention or reversal of AD. However, pharmacological approaches face several challenges, including the necessity for enzyme stimulation instead of enzyme inhibition and the potential for dysregulation of other related substrates.},
}

@article {pmid41887009,
year = {2026},
author = {Hortsch, S and Domenico, AD and Borlinghaus, N and Caley, D and Kaminioti-Dumont, L and Jeppesen, SB and González-Escalante, A and Ritchie, C and Frederiksen, KS and Suárez-Calvet, M},
title = {Performance of a fully automated plasma tau phosphorylated at threonine 217 immunoassay to reflect amyloid-beta burden in an unselected cohort representative of clinical practice.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {5},
pages = {100534},
doi = {10.1016/j.tjpad.2026.100534},
pmid = {41887009},
issn = {2426-0266},
abstract = {BACKGROUND: With the emergence of disease-modifying anti-amyloid-beta (Aβ) therapies for Alzheimer's disease (AD), early and accurate quantitative measures of Aβ burden are critical. Blood-based biomarkers are a scalable and minimally invasive diagnostic solution; plasma tau phosphorylated at threonine 217 (pTau217) is a promising marker for Aβ pathology. The clinical performance of the prototype Elecsys[Ⓡ] Phospho-Tau (217P) Plasma immunoassay (Roche Diagnostics) to detect Aβ burden was investigated in an unselected cohort reflective of clinical practice.

METHODS: Plasma was prospectively collected from participants aged 55 to 80 years with objective or subjective cognitive decline under evaluation for AD. Participants were recruited at multiple clinical sites spanning primary and secondary care. Plasma pTau217 concentrations measured using the prototype pTau217 plasma immunoassay were compared with amyloid positron emission tomography centiloid-based classification at different cutoffs, with further analyses performed at centiloid cutoff 30.

OUTCOMES: Among 588 participants, plasma pTau217 demonstrated high concordance with centiloid-based classification at selected cutoffs. The discriminative ability of plasma pTau217 to detect Aβ pathology peaked at centiloid cutoff 32 (area under the curve=0.933). Subgroup analyses at centiloid cutoff 30 demonstrated good discrimination of Aβ positivity/negativity by clinical diagnosis, age, and sex. Moderately decreased kidney function to kidney failure was found to influence plasma pTau217 levels.

INTERPRETATION: The prototype pTau217 plasma immunoassay showed high accuracy in reflecting Aβ burden among individuals presenting with cognitive complaints across diverse clinical settings. These findings support its potential implementation into routine clinical practice for early detection of AD, alongside standard clinical and neuropsychologic assessments.},
}

@article {pmid41887535,
year = {2026},
author = {Leikin-Frenkel, A and Ravid, O and Liberman, M and Atrakchi, D and Lamport, V and Rand, D and Harats, D and Yassine, HN and Sampath, H and Michaelson, DM and Schnaider-Beeri, M and Liraz-Zaltsman, S and Cooper, I},
title = {α-linolenic acid-rich diet boosts docosahexaenoic acid levels and restores lipid balance in the brain parenchyma and vasculature of APOE4 mice.},
journal = {The Journal of nutritional biochemistry},
volume = {},
number = {},
pages = {110352},
doi = {10.1016/j.jnutbio.2026.110352},
pmid = {41887535},
issn = {1873-4847},
abstract = {The APOE4 allele significantly increases Alzheimer's disease (AD) risk, often linked to brain lipid imbalance. This study investigated lipid profiles in the brain parenchyma and brain blood vessels (BBV) of APOE3 and APOE4-humanized female mice, assessing the protective effects of an alpha-linolenic acid (ALA)-rich diet on lipid composition and memory in APOE4 mice. Mice received either a Control or an ALA-rich flaxseed oil diet for six months. Lipid profiles were analyzed in brain parenchyma, BBV, plasma, and liver, alongside memory performance. In vitro studies explored human brain endothelial cell conversion of ALA to docosahexaenoic acid (DHA). APOE4 mice, compared to APOE3 controls, exhibited significant lipid depletion in brain parenchyma, including reduced cholesterol (32%), phospholipids (10%), and DHA (57%). The ALA-rich diet beneficially restored lipid levels in APOE4 brain parenchyma, increased DHA-containing phospholipids, and improved memory. This diet also elevated n-3 fatty acids and DHA within the BBV, particularly in APOE4 phosphatidylserine, and upregulated lipid-related genes (PLA2, LDLR). In vitro data confirmed brain endothelial cells synthesize DHA via the ∆6 desaturase pathway, a process suppressed by desaturase inhibitors or external DHA. Collectively, these findings suggest the BBV acts as a crucial hub for lipid homeostasis. An ALA-rich diet effectively mitigates lipid imbalance in APOE4 mice by promoting lipid unsaturation, enhancing DHA synthesis and its incorporation into complex lipids, thereby improving cognitive performance. This research positions dietary ALA as a promising nutritional intervention for APOE4 carriers.},
}

@article {pmid41870711,
year = {2026},
author = {Garland, IJZ and Engel, S and Scalf, M and Payne, NR and Lee, AM and Graves, SM},
title = {Decreased Length of Locus Coeruleus Norepinephrine Axons and Increased Amyloid Beta Pathology in Male APP/PS1 Mice During Protracted Abstinence From Alcohol.},
journal = {Neurotoxicity research},
volume = {44},
number = {2},
pages = {},
pmid = {41870711},
issn = {1476-3524},
abstract = {Alzheimer’s disease (AD) is the leading cause of dementia and evidence suggests that alcohol, the most commonly used addictive substance, may increase AD risk. Locus coeruleus (LC) neurons are the primary source of norepinephrine in the brain and these neurons degenerate early in AD. In rodent models, lesioning the LC increases amyloid beta (Aβ) pathology suggesting that LC integrity and norepinephrine signaling obstruct Aβ pathogenesis. We recently reported a decrease in the number of LC norepinephrine neurons and increased Aβ pathology when measured after protracted abstinence from chronic intermittent alcohol consumption in female APP/PS1 mice. Clinically, female subjects are at a higher risk for AD; additionally, female mice consume more alcohol than male mice making it unclear as to whether alcohol consumption would produce similar adverse outcomes in male subjects. To address this gap, male APP/PS1 and non-transgenic mice underwent chronic intermittent access (IA) to alcohol followed by protracted abstinence with water drinking controls run in parallel, consistent with our prior study. In contrast to our previous results with female mice, the number of LC norepinephrine neurons was unchanged in male APP/PS1 mice that had IA to alcohol; however, the length of LC axons was decreased and Aβ pathology was increased in male APP/PS1 mice that consumed alcohol. These data demonstrate that alcohol consumption during early adulthood results in negative consequences in male APP/PS1 mice, although the effect may not be as severe as previously observed in female mice.},
}

@article {pmid41876055,
year = {2026},
author = {Wang, Y and Sun, ZP and Zhou, P and Tu, T and Zhang, XJ and Tu, E and Chen, HP and Cheng, HY and Pan, A and Zhang, QL and Wang, J and Yan, XX},
title = {Early-onset axonal pathology and β-amyloidosis in human brains with hematological malignances and cardiovascular diseases.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.03.032},
pmid = {41876055},
issn = {1873-7544},
abstract = {β-Amyloid (Aβ) and tau pathologies are hallmark lesions of Alzheimer's disease (AD) and they develop in human brain following differential spatiotemporal trajectories. Accordingly, young/adult-onset tau-independent β-amyloidosis is rare. We encountered four such cases among 397 banked brains, with the donors died of hematological malignances (blood cancers) or cardiovascular diseases. To explore the pathological implication, we examined 17 brains (10-87 year-old, y) from blood cancer patients and three (52-82 y) with cardiovascular diseases, focusing on vascular injury, axonal pathology and Aβ formation. Aβ plaques occurred in two adult brains (31 y, 63 y) with blood cancers and two (52 y, 65 y) with cardiovascular diseases in the absence of tau pathology. In the blood cancer brains, 17/17 had vascular injuries seen in hematoxylin-eosin stained sections, 13/17 had iron leakage, and 13/17 had axonal pathology. Malignant cell infiltration was found in 5/14 brains with myeloid, lymphocytic and lymphoma malignances, with light chain infiltration in 3/3 brains with multiple myeloma. In the cardiovascular disease brains, Aβ deposition primarily as diffuse plaques occurred in the cerebral cortex, with vascular and axonal pathologies in the white matter, striatum and internal capsule. Using a multi-labeling approach, the injury/stress induced axonal pathology was associated with β-amyloid processor protein and β-secretase 1 upregulation, but not with intra-axonal amyloid tracer staining. The current findings suggest that hematological malignances and cardiovascular diseases are risk conditions for early-onset cerebral axonal pathology and β-amyloidosis, potentially attributable to vascular injury.},
}

@article {pmid41876395,
year = {2026},
author = {Rosa-Grilo, M and Mallon, D and Thomas, DL and Beament, M and Chughtai, HR and Liu, W and Magill, N and Malone, IB and Meyer, H and Parker, GJM and Triantafyllou, C and Barkhof, F and Fox, NC and Mummery, CJ},
title = {Accelerated 3D MRI for ARIA monitoring in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71297},
doi = {10.1002/alz.71297},
pmid = {41876395},
issn = {1552-5279},
support = {577 [AS-PG-21-045]//Alzheimer's Society Heather Corrie Impact Fund/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; CF-2022-2/128//Rosetrees Trust/ ; //Biogen Idec UK/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Male ; Female ; Aged ; *Imaging, Three-Dimensional/methods ; Sensitivity and Specificity ; *Brain/diagnostic imaging/pathology ; Middle Aged ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Amyloid-targeting therapies for Alzheimer's disease require regular MRI monitoring for amyloid-related imaging abnormalities (ARIA). 3D scans are more sensitive but time intensive; ultra-fast implementations could improve access and reduce burden.

METHODS: Eighty scans from 20 participants were acquired with standard 2D fluid-attenuated inversion recovery (FLAIR) and T2*-gradient recalled echo (T2*-GRE), or accelerated Wave-controlled aliasing in parallel imaging (Wave-CAIPI) 3D FLAIR and susceptibility-weighted imaging (SWI) at 3 T. Two neuroradiologists graded ARIA-E (edema/effusion) and ARIA-H (hemosiderin deposits). Bayesian models estimated sensitivity, specificity, severity agreement, and interchangeability between acquisitions.

RESULTS: Accelerated sequences reduced acquisition time by up to 56%. Four participants had ARIA-E and microbleeds; five had microbleeds alone. Sensitivity and specificity for ARIA-E were identical (1.00; 0.94-0.95); severity was comparable. Replacing standard with accelerated FLAIR did not decrease severity agreement (interchangeability 1.4; 95% highest-density interval [HDI] -3.6% to 5.4%). Fast SWI showed higher microbleed severity gradings.

DISCUSSION: Wave-CAIPI offers fast high-resolution FLAIR acquisitions with comparable performance for ARIA-E monitoring. Wave-CAIPI SWI provides high-quality scans that may aid ARIA-H interpretation.},
}

Humans
*Alzheimer Disease/diagnostic imaging
*Magnetic Resonance Imaging/methods
Male
Female
Aged
*Imaging, Three-Dimensional/methods
Sensitivity and Specificity
*Brain/diagnostic imaging/pathology
Middle Aged
Aged, 80 and over

@article {pmid41876548,
year = {2026},
author = {Kuragano, M and Nishishita, N and Araya, K and Kobayashi, A and Noguchi, TQP and Watanabe, K and Watanabe, S and Baar, S and Uwai, K and Tokuraku, K},
title = {A high-throughput conditioned-media-based screening system identifies inhibitors of aggregation induced by iPSC-secreted amyloid β.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-71078-8},
pmid = {41876548},
issn = {2041-1723},
support = {JPMJPF2213//MEXT | JST | Center of Innovation Program (COI)/ ; },
abstract = {In early drug discovery, in vitro screening is frequently used, but selected candidates often fail in vivo. Induced pluripotent stem cell (iPSC)-based disease models offer improved physiological relevance; however, the high costs of media and differentiation procedures limit large-scale testing. Here, we develop a high-throughput conditioned-media-based screening system-the High-throughput screening technology for Aggregation Inhibitors of Diseased cell-derived Aggregative Proteins (HaiDap) system-to identify inhibitors of aggregation induced by iPSC-secreted amyloid β (Aβ). Using conditioned media derived from differentiated iPSCs of a male Alzheimer's disease patient, we screen extracts from 22 edible plants. Whereas PBS-based assays showed 40.9% (9/22) apparent selectivity, the HaiDap system demonstrates higher specificity (13.6%; 3/22). All three identified extracts (O. aristatus, S. aromaticum, and G. yesoense) significantly delay Aβ aggregation on neuronal surfaces in an iPSC-based assay. These findings suggest that the HaiDap system enables efficient, accurate, and low-cost screening of amyloid aggregation inhibitors.},
}

@article {pmid41876672,
year = {2026},
author = {Prókay, AP and Konkoly, J and Kormos, V and Biró-Sütő, T and Kriszta, G and Szentmártoni, HP and Berta, G and Gaszner, B and Zelena, D and Pintér, E},
title = {Age-dependent alterations of TRPA1 and urocortin 1 signaling in the Edinger-Westphal nucleus in a mouse model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-44022-5},
pmid = {41876672},
issn = {2045-2322},
abstract = {Cholinergic neurons of the preganglionic Edinger-Westphal nucleus (EW) are involved in Alzheimer's disease (AD), however, the role of urocortin 1 (UCN1) positive peptidergic neurons of the centrally projecting EW (EWcp) remains unclear. EWcp cells exclusively express transient receptor potential ankyrin 1 (TRPA1) ion channels, implicated in neurodegenerative disorders. We hypothesized that the EWcp/UCN1/Trpa1 neurons may be involved in AD-related pathologies. Age-dependent (2, 6, 9, 12 and 18 months) Trpa1 mRNA expression (RNAscope in situ hybridization) and UCN1 peptide (immunostaining) content of the EWcp were examined in male triple transgenic mouse (3xTg-AD) model of AD. [1]H-MRI spectroscopy was performed in the hippocampus at 6, 12 and 18 months to evaluate the taurine and N-acetylaspartate levels, metabolites reflecting neuroprotection and neuronal integrity as AD prognostic markers. Trpa1 expression was lower in 2 and 6-months-old 3xTg-AD than controls. Later the genotype differences disappeared due to the progressive, age-related reduction of Trpa1 mRNA transcripts in the controls. In contrast, the Trpa1 expression of transgenic mice remained persistently low. Similarly, the UCN1 peptide content was also lower in the 2 and 6-months-old 3xTg-AD compared to controls. However, UCN1 level increased with age, which was more pronounced in 3xTg-AD than controls abolishing the genotype differences. Age-dependent decrease in taurine level was detected in transgenic animals leading to significantly lower taurine/creatine ratio in 12 and 18-months-old 3xTg-AD animals compared to the controls. This age-related dynamics of Trpa1 and UCN1 expression of 3xTg-AD mice suggests that altered UCN1 signaling may contribute to AD-associated mood disorders and memory decline.},
}

@article {pmid41876811,
year = {2026},
author = {Chaung, W and Ma, G and Lapin, D and Sharma, A and Wang, P and Brenner, M},
title = {Radiation-induced eCIRP Causes Alzheimer's Disease-like Neuronal Tau Phosphorylation.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41876811},
issn = {1559-1182},
support = {R35GM11833/GM/NIGMS NIH HHS/United States ; R01AA028947/AA/NIAAA NIH HHS/United States ; U01AI186997//National Institute of Allergy and Infectious Diseases/ ; U01AI170018//National Institute of Allergy and Infectious Diseases/ ; },
mesh = {*tau Proteins/metabolism ; Animals ; Phosphorylation/radiation effects/drug effects ; *Alzheimer Disease/metabolism/pathology ; *Neurons/metabolism/pathology/radiation effects/drug effects ; Mice, Inbred C57BL ; Cyclin-Dependent Kinase 5/metabolism ; *RNA-Binding Proteins/metabolism/antagonists & inhibitors ; Hippocampus/metabolism/pathology ; Male ; Mice ; },
abstract = {Cranial radiotherapy is associated with neuroinflammation, cognitive dysfunction, and dementia. Tau pathology plays a key role in Alzheimer's disease (AD) but has not been studied in the context of radiation injury. Extracellular cold-inducible RNA-binding protein (eCIRP) is a novel neuroinflammatory mediator that activates neuronal IL6Rα/p25/Cdk5, leading to tau hyperphosphorylation. We hypothesized that radiation promotes pathological tau phosphorylation via the eCIRP/IL6Rα/p25/Cdk5 pathway, which can be mitigated by the eCIRP inhibitor C23. Adult C57BL/6 and CIRP[-/-] mice were exposed to a single dose of 10-Gy X-rays at a dose-rate of 1 Gy/min. Hippocampal tissue lysates were analyzed for p25, phosphorylated tau, and CIRP using Western blotting. Cdk5 activity was assessed utilizing a modified Cdk5/p35 kinase enzyme system. Serum and cerebrospinal fluid (CSF) eCIRP was quantified using ELISA. eCIRP (1 µg) was injected intracerebroventricularly (icv) and C23 (8 mg/kg BW) retro-orbitally. N2a and primary neurons were pre-treated with 3 μg/ml IL-6Rα neutralizing Abs or IgG control, or 25 µg/mL C23 and stimulated with up to 2.5 μg/mL eCIRP for 48 h. Irradiation significantly increased hippocampal p25 expression, Cdk5 activity, and tau phosphorylation [AT-8 (Ser202/Thr205/Ser208), and combined Ser199/Ser202 and Ser396 p-tau antibodies] at 48 h post-irradiation. eCIRP increased by 1.2-fold in the serum and 2.6-fold in the CSF, and CIRP increased by 65% in hippocampal lysates after irradiation. Irradiated CIRP[-/-] mice had a 44% reduction in hippocampal p25 and a 59% reduction in hippocampal phosphorylated tau. Mice icv-injected with eCIRP presented p25 and p-tau protein levels as high as irradiated mice. eCIRP increased p-tau in N2a and primary neurons and was inhibited by IL-6Rα Abs and by C23. C23 markedly attenuated the radiation-induced increase in hippocampal p25 and tau phosphorylation. Radiation causes AD-like tau phosphorylation via the eCIRP/IL-6Rα/p25/Cdk5 pathway, which is effectively mitigated by targeting eCIRP with C23. eCIRP is a novel neuroinflammatory mediator with consequential effects for tau pathology and cognitive dysfunction. These novel findings are directly relevant to the pathogenesis and mitigation of radiation-induced cognitive dysfunction, as well as to the etiopathogenesis of AD.},
}

*tau Proteins/metabolism
Animals
Phosphorylation/radiation effects/drug effects
*Alzheimer Disease/metabolism/pathology
*Neurons/metabolism/pathology/radiation effects/drug effects
Mice, Inbred C57BL
Cyclin-Dependent Kinase 5/metabolism
*RNA-Binding Proteins/metabolism/antagonists & inhibitors
Hippocampus/metabolism/pathology
Male
Mice

@article {pmid41876895,
year = {2026},
author = {Luzzi, S and Cherubini, V and Rosettani, P and Baldinelli, S and Fiori, C and Silvestrini, M and Scandola, M},
title = {An updated italian normative data for a short version of the stroop colour word test.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {4},
pages = {},
pmid = {41876895},
issn = {1590-3478},
}

@article {pmid41876945,
year = {2026},
author = {Malin, SK and Battillo, DJ and Beeri, MS and Mustapic, M and Kapogiannis, D},
title = {A Single Bout of Aerobic Exercise Increases Neuronal Extracellular Vesicle-Derived Insulin Signaling Biomarkers in Adults With Cardiometabolic Risk.},
journal = {Comprehensive Physiology},
volume = {16},
number = {2},
pages = {e70131},
doi = {10.1002/cph4.70131},
pmid = {41876945},
issn = {2040-4603},
support = {//Brain Health Institute, Rutgers University/ ; R01DK133598-01A1/DK/NIDDK NIH HHS/United States ; },
mesh = {Humans ; *Insulin/metabolism/blood ; *Exercise/physiology ; Male ; *Extracellular Vesicles/metabolism ; Female ; Adult ; Middle Aged ; Biomarkers/blood/metabolism ; Signal Transduction ; *Neurons/metabolism ; Obesity/metabolism/blood ; Blood Glucose/metabolism ; Cardiometabolic Risk Factors ; },
abstract = {UNLABELLED: Exercise may lower Alzheimer's Disease and Related Dementia (ADRD) risk. While insulin has been proposed to benefit cognition, the effect of exercise on neuronal insulin signaling in humans is unclear.

PURPOSE: We tested the hypothesis that a single bout of aerobic exercise would raise insulin signaling mediators from plasma-derived neuronal extracellular vesicles (nEVs).

METHODS: Fifteen sedentary adults with obesity (12F; ~56y; ~31 kg/m[2]) completed an evening rest and acute exercise condition (70% maximal oxygen consumption (VO2max)) in a randomized, counterbalanced order. Following an overnight fast, plasma was collected for analysis of nEV insulin signaling biomarkers before and after intranasal insulin spray (INI, 40 IU) as well as 60 min following a 75 g oral glucose tolerance test (OGTT). Plasma glucose and insulin were also measured at 30 and 60 min during the OGTT, and total area under the curve (tAUC) was calculated.

RESULTS: Exercise tended to lower glucose tAUC0-150min (p = 0.08, d = 0.50), independent of insulin tAUC0-150min (p = 0.99, d = 0.00). Exercise increased pIR-Tyr1162/Tyr1163 (p = 0.05, η[2] = 0.05), pIRS-1-Ser636 (p = 0.02, η[2] = 0.07), pAkt-Ser473 (p = 0.03, η[2] = 0.06), and pTSC2-Ser939 (p = 0.01, η[2] = 0.08) with medium effect sizes across blood draws, compared with the resting condition. Exercise also raised fasting and decreased pp70S6K-Thr412 before and after the OGTT, compared with increased levels after rest during the OGTT (p = 0.02, η[2] = 0.10). Exercise had no effect on other insulin signaling proteins (e.g., pmTOR-Ser2448, pGSK3β-Ser9, etc.).

CONCLUSIONS: A single bout of aerobic exercise increases some nEV-associated insulin signaling phosphoproteins in people with cardiometabolic risk. Additional work is warranted to determine if changes in brain insulin signaling translate to lower ADRD risk.

CLINICAL TRIALS REGISTRATION: NCT05853913.},
}

Humans
*Insulin/metabolism/blood
*Exercise/physiology
Male
*Extracellular Vesicles/metabolism
Female
Adult
Middle Aged
Biomarkers/blood/metabolism
Signal Transduction
*Neurons/metabolism
Obesity/metabolism/blood
Blood Glucose/metabolism
Cardiometabolic Risk Factors

@article {pmid41876971,
year = {2026},
author = {Chondur, R and Zhao, Y and Unnikrishnan, R and Wright, A and Burgess, P and Lamba, G},
title = {Tobacco Smoking-Attributable Burden of Disease in the Adult Northern Territory Population, 2014-18.},
journal = {The Australian journal of rural health},
volume = {34},
number = {2},
pages = {e70155},
doi = {10.1111/ajr.70155},
pmid = {41876971},
issn = {1440-1584},
mesh = {Humans ; Northern Territory/epidemiology ; Adult ; Middle Aged ; Male ; Female ; Aged ; *Cost of Illness ; Prevalence ; *Tobacco Smoking/adverse effects/mortality/epidemiology ; *Smoking ; },
abstract = {INTRODUCTION: Tobacco smoking is an important preventable cause of death and disease in Australia. Smoking rates are higher in the Northern Territory (NT) among Aboriginal peoples living in remote areas. Understanding smoking-attributable mortality and burden of disease in the NT population is important for building awareness and implementing targeted public health strategies.

OBJECTIVE: To estimate the impact of tobacco smoking on mortality and morbidity in the NT Aboriginal and non-Aboriginal populations aged 30 years and above between 2014 and 2018.

SETTING: NT, Australia.

PARTICIPANTS: Adults (> 30 years) who were NT residents.

METHODS: We used the NT Burden of Disease study (2014-2018) results and Global Burden of Disease methods to estimate smoking-attributable deaths and smoking-attributable burden of disease for the NT Aboriginal and non-Aboriginal populations. The smoking prevalence data were based on 2018-19 National Aboriginal and Torres Strait Islander Heath Survey and 2016 National Drugs Strategy Household Survey.

RESULTS: Smoking was attributable to 18.3% of the total deaths for NT adults aged 30 years and above with 23.8% in Aboriginal and 13.9% in the non-Aboriginal population. Smoking explained 19.5% and 10.7% of total disability adjusted life years among the NT Aboriginal and non-Aboriginal populations respectively. The top three smoking-attributable burden of diseases for the Aboriginal population were ischaemic heart disease, diabetes and chronic obstructive pulmonary disease. In the non-Aboriginal population, lung cancer, chronic obstructive pulmonary disease and back pain were the leading causes of smoking-attributable burden. Leading causes of smoking-related mortality in the Aboriginal population were ischaemic heart disease, chronic obstructive pulmonary disease, lung cancer and diabetes, while in non-Aboriginal population the most common causes were lung cancer, chronic obstructive pulmonary disease, ischaemic heart disease, and Alzheimer's disease.

CONCLUSIONS: Tobacco smoking was associated with a higher burden of disease among the Aboriginal population than the non-Aboriginal population. Our study quantifies the disproportionate impact of tobacco smoking within the Aboriginal population and the NT as a whole compared to the rest of Australia.},
}

Humans
Northern Territory/epidemiology
Adult
Middle Aged
Male
Female
Aged
*Cost of Illness
Prevalence
*Tobacco Smoking/adverse effects/mortality/epidemiology
*Smoking

@article {pmid41877131,
year = {2026},
author = {Wang, N and Yu, G and Wang, Z and Alnobani, A and Jeevaratnam, S and Zhang, X and McReynolds, M and Chang, Y and Qi, F and Tauer, W and Rosenberg, C and Wren, M and Ikezu, TC and Martens, YA and Wang, M and Zhang, B and Carter, GW and Sasner, M and Holtzman, DM and Peng, J and Wu, LJ and Kanekiyo, T and Liu, CC and Bu, G},
title = {Molecular characterization of humanized APOE mouse models reveals source and genotype dependent differences.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00940-6},
pmid = {41877131},
issn = {1750-1326},
support = {U54AG054345//NIH/NIA/ ; 1RF1AG055104//NIH/NIA/ ; U19AG069701//NIH/NIA/ ; },
}

@article {pmid41877170,
year = {2026},
author = {Younas, N and Younas, A and Hermann, P and Flores, LCF and Dittmar, K and Zafar, S and Budde, H and Legler, TJ and Saleem, T and Schmitz, M and Zerr, I},
title = {Reduced plasma TIA-1: bridging established pathology and novel biomarker potential.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02020-9},
pmid = {41877170},
issn = {1758-9193},
}

@article {pmid41877246,
year = {2026},
author = {Shen, R and Sung, K and Ding, J and Wu, C},
title = {Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {41877246},
issn = {2047-9158},
mesh = {Humans ; *Neurodegenerative Diseases/pathology/therapy ; *Axons/pathology ; Animals ; },
abstract = {Axons are unique structural and functional features of nerve cells, which play a critical role in regulating neuronal homeostasis. Dysfunction and degeneration of axons (axonopathy) has been established as an early and prominent contributing mechanism to the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In this review, we briefly summarize the structure and function of axons, and highlight recent advances in the understanding of the role of axons in health and disease. We argue that axons are a potential target for developing novel therapies for neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/pathology/therapy
*Axons/pathology
Animals

@article {pmid41877272,
year = {2026},
author = {Scenna, MS and Maceroni, E and Cimini, A and Castelli, V and d'Angelo, M},
title = {Hypertension and brain damage: evidence from rodent models.},
journal = {Laboratory animal research},
volume = {42},
number = {1},
pages = {},
pmid = {41877272},
issn = {1738-6055},
abstract = {Hypertension is a prevalent condition that significantly raises the incidence of cerebrovascular and cognitive disorders. This review focuses on the factors most closely linked to stroke, cognitive impairment, and Alzheimer's disease. Research into pathophysiology and treatment of hypertensive brain damage has greatly benefited from rodent models, which have been crucial in uncovering the underlying mechanisms and developing effective therapeutic strategies. Rodent models, particularly spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHR-SP), have been essential in elucidating the pathophysiological mechanisms connecting hypertension to brain damage. These models exhibit structural and functional cerebrovascular alterations, including blood-brain barrier disruption, microvascular rarefaction, and neuroinflammation. Interventions targeting the renin-angiotensin system have shown promise in mitigating these adverse effects. This review synthesizes current findings from rodent studies, underscoring the pivotal impact of hypertension in brain pathology and the potential therapeutic benefits of antihypertensive treatments.},
}

@article {pmid41877277,
year = {2026},
author = {Lao, ZK and Xu, NJ},
title = {Deciphering the microenvironment of adult neurogenesis: a perspective from neurodegenerative diseases.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {41877277},
issn = {2047-9158},
support = {2021ZD0202801//National Major Science and Technology Projects of China/ ; 32030042//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Neurogenesis/physiology ; *Neurodegenerative Diseases/pathology/physiopathology ; Animals ; *Neural Stem Cells/physiology ; *Stem Cell Niche/physiology ; *Brain/pathology ; },
abstract = {Neurodegenerative diseases are characterized by progressive neuron loss and brain atrophy. While conventional studies focused on neuronal death as the primary cause of these diseases, accumulating evidence suggests that impaired neurogenesis, particularly the dysfunction of adult neural stem cells (NSCs), may also contribute significantly to disease pathogenesis. Adult neurogenesis occurs primarily in two adult NSC niches. These specialized niches are enriched with complex cytokine networks, neuronal activity, and non-cellular components such as the extracellular matrix. Understanding the regulation of NSCs in the adult brain and how their dysregulation exacerbates neurodegeneration provides novel insights into therapeutic strategies. This review proposes that dysfunction of the NSC microenvironment, rather than neuronal death alone, may drive neurodegeneration, and that restoring this microenvironment offers a novel research direction of stem cell-based therapies.},
}

Humans
*Neurogenesis/physiology
*Neurodegenerative Diseases/pathology/physiopathology
Animals
*Neural Stem Cells/physiology
*Stem Cell Niche/physiology
*Brain/pathology

@article {pmid41877305,
year = {2026},
author = {Wu, X and Lu, C and Kong, H and Chen, R and Wang, Z and Deng, Z and Xiao, W and Huang, Z and Li, Q and Yao, D and Ding, X and Zhao, C},
title = {Recalibrating the epigenetic clock reveals divergent DNA methylation age signatures across schizophrenia, bipolar disorder and major depressive disorder.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {},
number = {},
pages = {1-9},
doi = {10.1192/bjp.2025.10508},
pmid = {41877305},
issn = {1472-1465},
abstract = {BACKGROUND: Few studies have quantitatively characterised the shared and distinct features of the epigenetic age signature of schizophrenia, bipolar disorder and major depressive disorder.

AIMS: To construct a multi-platform epigenetic clock tailored to human blood and brain tissues, and to characterise variations in epigenetic age acceleration across these three common psychiatric disorders.

METHOD: We integrated 31 publicly available DNA methylation data-sets generated on the platforms Illumina 27K, 450K and EPIC (850K) from patients with schizophrenia, bipolar disorder or major depressive disorder, and from matched controls. Using elastic net regression combined with sure independence screening, we developed the blood–brain clock and applied it to assess disorder-specific epigenetic age acceleration in blood and brain.

RESULTS: The blood–brain clock achieved high accuracy across tissues and outperformed established predictors, particularly in brain samples. Epigenetic age acceleration was reduced in schizophrenia, increased in bipolar disorder and major depressive disorder and strongly elevated in Alzheimer’s disease (positive control). Alterations appeared earlier in blood than in brain. Meta-analysis confirmed that both reduced acceleration (schizophrenia) and increased acceleration (bipolar disorder, major depressive disorder, Alzheimer’s disease) were significantly associated with disease prevalence. Differential methylation analyses further revealed that the blood–brain clock probes captured disease-associated signals, with schizophrenia showing the greatest overlap with causal risk loci, and opposite methylation patterns distinguishing schizophrenia from bipolar disorder or major depressive disorder. A subset of blood DNA methylation probes enabled high-precision classification between schizophrenia and bipolar disorder or major depressive disorder.

CONCLUSIONS: This blood–brain clock reveals distinct patterns of epigenetic age acceleration across psychiatric disorders, reflecting disorder-specific and shared biological ageing signatures. The manifestation of these alterations in peripheral blood highlights its potential as a non-invasive biomarker for early detection, risk stratification and differential classification of schizophrenia, bipolar disorder and major depressive disorder.},
}

@article {pmid41877517,
year = {2026},
author = {Oliveira, FF and Miraldo, MC and Castro-Neto, EF and Almeida, SS and Matas, SLA and Bertolucci, PHF and Naffah-Mazzacoratti, MDG},
title = {Fluid Biomarkers of Motor and Non-Motor Experiences of Daily Living in Dementia with Lewy Bodies and Alzheimer's Disease.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-10},
doi = {10.1017/cjn.2026.10559},
pmid = {41877517},
issn = {0317-1671},
abstract = {BACKGROUND: Associations of cerebrospinal fluid biomarkers with sleep, functionality and the MDS-UPDRS in dementia with Lewy bodies (DLB) and late-onset Alzheimer's disease (AD) help elucidate their pathophysiological underpinnings.

METHODS: Consecutive outpatients with DLB and AD were matched by sex, cognitive scores and dementia stage, along with cognitively healthy controls matched by age and sex to investigate associations of cerebrospinal fluid amyloid-β (Aβ42,Aβ40,Aβ38), tau, phospho-tauThr181, ubiquitin, α-synuclein and neurofilament light (NfL) with sleep duration, Schwab & England scale and MDS-UPDRS, adjusted for sex, age and APOE-ϵ4 alleles.

RESULTS: Patients with DLB (APOE-ϵ4+:n=11, 76.64±9.0years; APOE-ϵ4-:n=16, 79.75±9.0years) were paired with patients with AD (APOE-ϵ4+:n=12, 80.17±5.7years; APOE-ϵ4-:n=15, 81.67±5.9years) and controls (APOE-ϵ4+:n=4, 82.00±6.4years; APOE-ϵ4-:n=23, 77.87±9.0years); two-thirds were women. APOE-ϵ4 carriers with dementia had more amyloidosis, higher phospho-tauThr181/Aβ42 and α-synuclein/Aβ42. In DLB, APOE-ϵ4 non-carriers had lower Schwab & England scores and higher MDS-UPDRS-I&II scores, lower tau/phospho-tauThr181 and higher ubiquitin and NfL than APOE-ϵ4 carriers. In controls, APOE-ϵ4 non-carriers had lower Aβ42 and Aβ42/Aβ38, higher phospho-tauThr181/Aβ42 and α-synuclein/Aβ42 than APOE-ϵ4 carriers. In DLB, sleep duration was associated with Aβ38 and α-synuclein and inversely associated with tau/phospho-tauThr181 and tau/ubiquitin; Schwab & England scores were associated with tau/ubiquitin and inversely associated with tau/phospho-tauThr181; MDS-UPDRS-I&II was associated with Aβ42/Aβ38; MDS-UPDRS-III was associated with tau/phospho-tauThr181; MDS-UPDRS-V ON was associated with Aβ42 and Aβ42/Aβ40, and MDS-UPDRS-V OFF was associated with Aβ42, Aβ42/Aβ40 and Aβ42/Aβ38. In AD, MDS-UPDRS-III was associated with ubiquitin.

CONCLUSION: Biomarker ratios were superior to isolated biomarkers in associations with motor and non-motor experiences in DLB, though not so prominently in AD due to less motor impairment.},
}

@article {pmid41877619,
year = {2026},
author = {Fisher, DW and Mehta, R and Morrow, CB and Kerr, KF and Jayadev, S and Domoto-Reilly, K and Schrift, MJ and Darvas, M},
title = {Affective neuropsychiatric symptom metrics in the National Alzheimer's Coordinating Center dataset.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261427462},
doi = {10.1177/13872877261427462},
pmid = {41877619},
issn = {1875-8908},
abstract = {BackgroundIn dementia research, affective neuropsychiatric symptoms (NPS)-depression, anxiety, and apathy-remain understudied. Improving strategies to ensure robust and comparable identification of clinically relevant NPS is essential for better research.ObjectiveWe sought to determine how often objective metrics and clinical gestalt metrics agree on NPS presence or absence. We further sought to determine optimal cut-offs for affective NPS presence/absence using the Neuropsychiatric Inventory Questionnaire (NPIQ) severity ratings.MethodsWe assessed agreement for NPS presence/absence among 5 different depression metrics, 4 anxiety metrics, and 2 apathy metrics via Jaccard indices using the National Alzheimer's Coordinating Center (NACC) dataset. Analysis included exploring four different NPIQ severity rating thresholds of ">0", ">1", ">2", and "=0 and >1".ResultsNPIQ cut-off >1 for presence and =0 for absence of an NPS led to the best agreement with other metrics. However, there was poor agreement for NPS presence across depression metrics (6%) and across anxiety metrics (7%). Choice of metric could greatly skew the frequency of an NPS being present. All 3 affective NPS were more common in Lewy body disorder compared to Alzheimer's disease or vascular cognitive impairment, regardless of metric.ConclusionsThough NPIQ severity rating cut-off choice should depend on study design, using a severity score of >1 for presence and =0 for absence may best fit clinical gestalt for affective NPS. Lewy body disorders present with more affective NPS than other common dementia etiologies. Future consensus on criteria for depression and anxiety syndromes in dementia may improve their identification.},
}

@article {pmid41877626,
year = {2026},
author = {Zhou, X and Wang, R and Yan, J and Wu, X and Yuan, D and Wang, Q and Li, H and Zhao, W},
title = {Atractylenolide I mitigates Alzheimer's disease pathology in ApoE [-/-] mice via ARG1/nNOS axis and lipid homeostasis regulation.},
journal = {Acta biochimica et biophysica Sinica},
volume = {},
number = {},
pages = {},
doi = {10.3724/abbs.2026055},
pmid = {41877626},
issn = {1745-7270},
abstract = {Apolipoprotein E (ApoE) serves as a critical molecular nexus between Alzheimer's disease (AD) and atherosclerosis, two age-associated inflammatory disorders that share vascular pathology, amyloid-beta (Aβ) deposition, and lipid dysregulation. Atractylenolide I (AI), a promising therapeutic candidate derived from Atractylodes macrocephalaKoidz., exhibits multimodal bioactivities with demonstrated anti-inflammatory and neuroprotective properties. To explore its therapeutic potential against AD pathology, we use high-fat diet (HFD)-fed ApoE knockout (ApoE [-/-]) mice treated with or without AI for 12 weeks. Integrated bioinformatics analyses and experimental validation reveal that AI treatment markedly attenuates systemic lipid dyshomeostasis, particularly cerebral lipid deposition, suppresses neuroinflammation via downregulation of M1 macrophage polarization markers, and restores cognitive function through neuronal preservation in hippocampal regions. Mechanistically, AI orchestrates cholesterol efflux by upregulating ATP-binding cassette transporter A1 (ABCA1) and liver X receptor (LXR) expression, while concurrently modulating the abundance of arginine biosynthesis metabolites (urea, malic acid, and creatinine) to rebalance neurovascular homeostasis. Notably, western blot and RT-qPCR analyses reveal that AI differentially regulates key enzymes including arginase 1 (ARG1) and simultaneously upregulates the expression of neuronal nitric oxide synthase (nNOS). Further molecular docking and surface plasmon resonance (SPR) analyses confirm the direct binding of AI to ARG1, indicating a novel neuroprotective mechanism involving the modulation of arginine metabolism. These findings delineate the pleiotropic effects of AI against AD pathology and establish a preclinical foundation for the development of AI-based therapeutics targeting neurodegenerative-cardiovascular comorbidities.},
}

@article {pmid41877657,
year = {2026},
author = {Arwini, A and Kirk, A and O'Connell, M and Morgan, D},
title = {Predictors of long-term care admission in a rural and remote memory clinic.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261434989},
doi = {10.1177/13872877261434989},
pmid = {41877657},
issn = {1875-8908},
abstract = {BackgroundCaregivers face unique challenges when the care recipient transitions from at-home care to long-term care (LTC).ObjectiveWe aimed to elucidate predictors of LTC admission within two years of initial presentation to a Rural and Remote Memory Clinic in Saskatchewan.MethodsAnalysis included 635 patients seen between March 2004 and June 2019 (admitted to LTC within two years = 222, not admitted = 413). Patients were assessed neuropsychologically and administered questionnaires.ResultsThe majority of those who moved to LTC were diagnosed with Alzheimer's disease. The multivariate logistic regression model revealed no statistically significant results. However, univariate logistic regressions showed that advanced age (OR = 1.05, CI = 1.04-1.07), female sex (OR = 1.79, CI = 1.28-2.52), higher Functional Activities Questionnaire (OR = 1.09, CI = 1.06-1.11), lower Mini-Mental State Examination (OR = 0.861, CI = 0.827-0.897), and higher Clinical Dementia Rating score (OR = 1.13, CI = 1.06-1.21) were significant predictors (p < 0.001).ConclusionsBeing older, female, more dependent in activities of daily living, and having more severe dementia predicted LTC admission, potentially helping in planning care.},
}

@article {pmid41877664,
year = {2026},
author = {Pennington, C and Apurva, P and Chen, A and Duncan, A and Mackay, G and Masters, H and Paramore, K and Russ, T and Skinner, H and Zeidler, M},
title = {Disease modifying treatments for Alzheimer's disease: Clinician perspectives.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261429859},
doi = {10.1177/13872877261429859},
pmid = {41877664},
issn = {1875-8908},
abstract = {In recent years there have been exciting developments in the diagnosis and treatment of mild cognitive impairment and dementia due to Alzheimer's disease. Robust biomarkers and potentially disease modifying therapies are now available, with multiple other agents in clinical trials alongside on-going validation studies of blood-based biomarkers. Recent and probable future developments in the diagnosis and care of people with Alzheimer's disease pathology warrants serious re-evaluation of the structure and function of cognitive clinical services. Here we report recommendations from the November 2024 Brain Health Scotland roundtable discussion of opportunities and challenges for modern memory services.},
}

@article {pmid41877687,
year = {2025},
author = {Hayat, B and Alone, DP},
title = {Unfolded proteins and aggregates: The role of proteostasis in pseudoexfoliation pathology.},
journal = {Molecular vision},
volume = {31},
number = {},
pages = {463-484},
pmid = {41877687},
issn = {1090-0535},
mesh = {Humans ; *Exfoliation Syndrome/metabolism/pathology ; *Proteostasis ; *Unfolded Protein Response ; *Protein Aggregates ; Animals ; Autophagy ; *Protein Aggregation, Pathological/metabolism/pathology ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/metabolism ; Endoplasmic Reticulum Stress ; Protein Folding ; Aging/metabolism ; },
abstract = {BACKGROUND: Proteostasis impairment is central to cellular dysfunction in protein aggregation disorders such as Alzheimer disease, Parkinson disease, and age-related macular degeneration. Pseudoexfoliation (PEX), a systemic age-related disorder and a leading cause of secondary glaucoma, is increasingly recognized as a protein aggregation disease. It is characterized by the deposition of pseudoexfoliative material (PEXM) in ocular tissues, leading to elevated intraocular pressure and optic neuropathy.

OBJECTIVE: This review synthesizes current evidence on the role of proteostasis failure in PEX pathogenesis, with a focus on molecular mechanisms, stress response pathways, and potential therapeutic interventions.

METHODS: We conducted a comprehensive literature review of studies examining proteostasis mechanisms in PEX. Emphasis was placed on cellular pathways regulating protein synthesis, folding, and degradation, including the unfolded protein response (UPR), ubiquitin-proteasome system (UPS), and autophagy, as well as environmental and aging-related triggers of proteotoxic stress.

RESULTS: Evidence indicates that chronic proteotoxic stress, arising from aging, oxidative damage, and environmental influences, disrupts the proteostasis network (PN). Dysregulation of ER stress signaling, cytosolic stress responses, and protein degradation pathways contributes to the accumulation of misfolded proteins and extracellular matrix deposits in ocular tissues. These molecular alterations underlie disease onset and progression in PEX syndrome (PEXS) and PEX glaucoma (PEXG).

CONCLUSIONS: Proteostasis dysfunction plays a pivotal role in PEX pathogenesis by promoting protein misfolding, aggregation, and extracellular deposition. Targeting the proteostasis network, through modulation of stress responses and enhancement of degradation pathways, represents a promising therapeutic strategy for PEXS and PEXG.},
}

Humans
*Exfoliation Syndrome/metabolism/pathology
*Proteostasis
*Unfolded Protein Response
*Protein Aggregates
Animals
Autophagy
*Protein Aggregation, Pathological/metabolism/pathology
Proteasome Endopeptidase Complex/metabolism
Ubiquitin/metabolism
Endoplasmic Reticulum Stress
Protein Folding
Aging/metabolism

@article {pmid41878054,
year = {2026},
author = {Mi, F and Ren, L and Pan, D and Yu, C},
title = {Advancements in Therapy for Alzheimer's Disease Based on the Cerebral Lymphatic System.},
journal = {Degenerative neurological and neuromuscular disease},
volume = {16},
number = {},
pages = {574901},
pmid = {41878054},
issn = {1179-9900},
abstract = {BACKGROUND: Conventional therapeutic interventions for Alzheimer's disease (AD) are limited by multiple drawbacks, including anticholinesterase inhibitors, glutamate receptor antagonists, intestinal flora regulators and Aβ-targeting monoclonal antibodies, which only achieve modest symptomatic relief, are accompanied by notable adverse events (e.g., intracerebral hemorrhage, cerebral edema) and have suboptimal clinical efficacy. In recent years, the cerebral lymphatic system, consisting of the glial lymphatic system (GLS) and meningeal lymphatic vessels (MLVs), has been identified as a key mediator of amyloid β-protein (Aβ) clearance and a critical driver of AD pathogenesis. Lymphatic dysfunction in this system precedes and exacerbates Aβ deposition and cognitive decline in AD patients, revealing the close association between cerebral lymphatic system impairment and AD progression.

PURPOSE: This study aims to focus on the emerging therapeutic advancements for AD targeting the cerebral lymphatic system, moving beyond the conventional symptomatic treatments and Aβ-centric interventions. It also intends to systematically summarize the relevant mechanisms of the cerebral lymphatic system in AD and the diverse therapeutic strategies targeting this system, thus providing a framework for developing innovative clinical interventions for AD.

METHODS: This study adopted a review approach, systematically collating and analyzing existing research on the cerebral lymphatic system and AD, including the cerebral lymphatic pathway of Aβ clearance, the pathological consequences of lymphatic impairment in AD, and various therapeutic strategies targeting the cerebral lymphatic system that have been reported in current studies.

RESULTS: The review identified and summarized multiple categories of effective therapeutic strategies targeting the cerebral lymphatic system for AD, covering pharmacological agents (VEGF-C, traditional Chinese medicines, oxytocin), photobiotherapies (808 nm near-infrared light, 40 Hz multisensory stimulation), physiotherapies (aerobic exercise, rTMS), gene therapy (DSCR1 upregulation), and surgical interventions (lymphatic-venous anastomosis). All these strategies are designed to optimize cerebral lymphatic function and thereby enhance Aβ drainage in the brain.

CONCLUSION: Optimizing cerebral lymphatic function to enhance Aβ drainage is a viable, disease-modifying therapeutic direction for AD. This therapeutic approach targeting the cerebral lymphatic system can serve as a complementary or alternative method to current symptomatic or Aβ-targeted treatments for AD, and also provides a theoretical and practical framework for the development of innovative clinical interventions for the disease.},
}

@article {pmid41878314,
year = {2026},
author = {Tang, S and Liao, Y and Yang, M and Yue, R},
title = {Brain insulin resistance: a key pathological hub linking metabolic and neuropsychiatric comorbidities.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1716291},
pmid = {41878314},
issn = {1663-4365},
abstract = {The high rate of comorbidity between metabolic diseases and neuropsychiatric disorders suggests a shared underlying pathogenic mechanism. However, the biological basis of this relationship remains unclear. This study aims to clarify the role of brain insulin resistance (BIR) in linking metabolic dysfunction to neuropsychiatric symptoms based on existing evidence. The analysis shows that BIR disrupts limbic system function through two primary molecular pathways: (1) impairment of the PI3K/Akt/mTOR pathway, which decreases the expression of synaptic plasticity-related proteins and causes deficits in long-term potentiation (LTP); (2) activation of the TLR4/MyD88 inflammatory axis, promoting pro-inflammatory cytokine release from glial cells. These changes result in characteristic neuropsychiatric phenotypes, including amygdala hyperactivity (emotional disorders), hippocampal atrophy (memory impairment), and decreased prefrontal cortex (PFC) function (executive dysfunction). This review highlights that interventions targeting BIR might simultaneously improve metabolic outcomes and neuropsychiatric symptoms, providing a theoretical foundation for trans-diagnostic treatment models. The findings support the view of BIR as a modifiable interface for metabolic- neuropsychiatric comorbidities and advocate for the development of a multidisciplinary collaborative framework to facilitate mechanism-based precision therapy.},
}

@article {pmid41878379,
year = {2026},
author = {Hersch, GG and Leka, G and Acosta, GE and Xicota, L and Lee, JH and Pulsifer, MB and Hom, CL and Lai, F and Rosas, HD},
title = {A Tale of Monozygotic Twins With Down Syndrome: Divergent Clinical Paths to Dementia.},
journal = {Neurology open access},
volume = {2},
number = {1},
pages = {},
pmid = {41878379},
issn = {2998-7601},
abstract = {OBJECTIVES: Individuals with Down syndrome (DS) have a very high risk for developing Alzheimer's disease (AD) due to the triplication of the amyloid precursor protein gene on chromosome 21. We describe a unique set of female monozygotic twins with Trisomy 21 and mild intellectual disability with significantly discordant rates of cognitive decline.

METHODS: The twins were followed longitudinally, starting at age 42, using cognitive assessments (Down Syndrome Mental Status Examination and Modified Cued Recall). Caregiver assessments included the Dementia Questionnaire for People with Learning Disabilities, National Task Group - Early Detection Screen for Dementia and the Neuropsychiatric Inventory. Blood was collected for AD biomarkers.

RESULTS: Performance on baseline cognitive assessments was similar; however, by Timepoint 1, Twin 2 met criteria for mild cognitive impairment (MCI) and by Timepoint 2 met criteria for dementia due to AD. In contrast, Twin 1 remained cognitively stable. Caregiver assessment at baseline showed concerns about Twin 2's social skills, which remained stable across timepoints. AD protein biomarker levels were similar.

DISCUSSION: Discordant cognitive decline could not be explained by clinical co-morbidities, medications, or environment, suggesting that other factors, such as epigenetics, could underlie phenotypic variability and variable risk for AD in DS and deserves further study.},
}

@article {pmid41878504,
year = {2026},
author = {Kempuraj, D and Ramesh Babu, PR and Jayakumar, N and Belur, MG and Cohan, CH and Sharma, A and Sanchez-Guerrero, E and Anderson, T and Kong, D and Chinnappan, B and Pena, C and Klimas, NG and Theoharides, TC},
title = {Neurosenescence, inflammaging and neuroinflammation in neurodegenerative disorders.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1756670},
pmid = {41878504},
issn = {2673-6217},
abstract = {Senescence is the biological aging associated with the gradual deterioration of cells and functions of various organs over time. This irreversible process is caused by genetic, metabolic, and environmental factors, such as telomere shortening, exposure to cytotoxic substances, and accumulated cellular damage over time, although the rate of degradation can be modified by lifestyle factors. Immunosenescence specifically refers to senescent changes in the innate and adaptive immunity and is associated with low inflammation known as inflammaging. As immunosenescence implies, reduced immune function leads to impaired tissue function and an increased risk of infection and heightened susceptibility to chronic, autoimmune, and neurodegenerative disorders, such as Alzheimer's disease (AD) in the elderly. An increase in senescent cells is common in aging, which leads to age-associated diseases. Cellular senescence may also contribute to the onset and severity of Parkinson's disease (PD) neuropathology. Inflammaging with high levels of proinflammatory marker expression may result from changes in immune responses, chronic antigenic stimulation, and senescence-associated secretory phenotype (SASP) factors, such as increased expression of interleukin-6 (IL-6), insulin-like growth factor binding proteins (IGFBPs), transforming growth factor-beta (TGF-β) and matrix metalloproteinase-10 (MMP-10) has been reported in AD patients. The levels of the senescence marker p16INK4a and several SASP factors, such as MMP-3, IL-6, IL-1α and IL-8 are elevated along with low levels of astrocytic lamin B1 in the substantia nigra of PD. This review discusses recent developments in neurosenescence and immunosenescence in AD and PD, as well as potential senolytic therapies.},
}

@article {pmid41878543,
year = {2026},
author = {Jaeger, A and Carreira, EX and Gomide, G and da Gama, NAS and de Queiroz, MC and Caramelli, P and Schilling, LP and de Souza, LC},
title = {Spatial memory retrieval under cueing in behavioral frontotemporal dementia and Alzheimer's disease.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e20250413},
pmid = {41878543},
issn = {1980-5764},
abstract = {UNLABELLED: Recent studies indicate that episodic memory is impaired in behavioral variant frontotemporal dementia (bvFTD), with deficits as severe as those seen in Alzheimer's disease (AD). Also, both bvFTD and AD patients exhibit executive dysfunction, but the extent to which such dysfunction contributes to memory impairments remains unclear.

OBJECTIVE: The aim of this study was to investigate interactions between executive functions and episodic memory in AD and bvFTD by manipulating executive control in a spatial source memory task.

METHODS: Twenty bvFTD patients, 18 AD patients, and 20 healthy controls completed a source memory test in which they should remember whether objects were previously seen on the left or right side of a computer screen. Critically, arrow cues (66.7% valid, 33.3% invalid) indicated the likely prior location of each object during retrieval.

RESULTS: bvFTD and AD patients showed overall similar memory performances but were impaired compared to controls. While cueing affected memory performances of controls and bvFTD patients, AD patients showed undistinguishable performances after valid and invalid cueing.

CONCLUSION: These findings support the notion that episodic memory deficits in bvFTD can be as severe as in AD and demonstrate that, unlike bvFTD patients, patients with AD show difficulties in using information conveyed by cues during memory judgments, probably because of underlying attentional deficits.},
}

@article {pmid41878908,
year = {2026},
author = {Álvarez Velásquez, C and Álvarez Mercado, M and Negrón López, R and Neira-Maldonado, C and Salazar-Méndez, J and Coronado, JC and Cuyul-Vásquez, I and Ponce-Fuentes, F},
title = {Effects and reporting quality of the vitamin supplementation on cognitive function in older adults with Alzheimer's disease ‒ A systematic review.},
journal = {Nutricion hospitalaria},
volume = {},
number = {},
pages = {},
doi = {10.20960/nh.06434},
pmid = {41878908},
issn = {1699-5198},
abstract = {BACKGROUND: evidence supporting the effectiveness of vitamin supplementation on cognitive function in older adults with Alzheimer's disease (AD) is limited, and the reporting quality of existing research is often overlooked.

OBJECTIVES: to a) evaluate the effectiveness of vitamin supplementation on cognitive function in older adults with AD; b) describe the characteristics of supplementation protocols; and c) assess the reporting quality of these interventions.

METHODS: a systematic search of seven databases was conducted for randomized controlled trials (RCTs) up to February 2026. Included studies involved vitamin supplementation for patients with AD and assessed cognitive outcomes. The risk of bias and reporting quality were evaluated.

RESULTS: seventeen RCTs (n = 2,478 participants) were included. While eight studies reported some cognitive improvements or stabilization with vitamin B3, D, E, folic acid or specialized multi-nutrient formulations, nine found no significant benefit. A high risk of bias was identified in seven studies, while only five were rated as low risk. The median TIDieR score of 10/12 indicates a good description of the vitamin supplementation protocols.

CONCLUSIONS: the current evidence for vitamin supplementation in older adults with AD is inconclusive. While some protocols show potential for stabilizing or improving cognitive domains, results are compromised by methodological heterogeneity and a high risk of bias. Future research must focus on enhancing methodological quality and achieving greater homogeneity in vitamin supplementation prescription and dosing to ensure robust clinical evidence for patients with AD.},
}

@article {pmid41878910,
year = {2026},
author = {Liu, Y and Liu, H and Chen, Y and Cheng, D and Zhao, Y and Lv, Z and Li, P},
title = {Interpretable machine learning models predict cognitive impairment in adults aged 50 and over with diabetes: influence of dietary nutrients.},
journal = {Nutricion hospitalaria},
volume = {},
number = {},
pages = {},
doi = {10.20960/nh.06195},
pmid = {41878910},
issn = {1699-5198},
abstract = {INTRODUCTION: diabetes mellitus increases the risk of cognitive impairment, but the role of dietary nutrients remains unclear.

OBJECTIVES: to develop interpretable machine learning (ML) models to identify associations with cognitive impairment in adults aged 50 years and older with diabetes, and to identify key dietary nutrients associated with cognitive outcomes.

METHODS: data from the 2011-2014 National Health and Nutrition Examination Survey were analyzed. Cognitive function was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning Test, the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). A total of 46 dietary nutrients and other covariates were included. Feature selection was performed using the Boruta algorithm. Six ML models were trained with ten-fold cross-validation. SHapley Additive Explanations and Local Interpretable Model-Agnostic Explanations were applied for model interpretation.

RESULTS: XGBoost achieved the highest performance in the CERAD model (AUC = 0.982), whereas Random Forest outperformed other models in the AFT and DSST models (AUC = 0.958 and 0.856, respectively). Caffeine emerged as a key protective factor. Copper, zinc, and moisture intake were also associated with reduced risk of cognitive impairment.

CONCLUSIONS: interpretable ML models can effectively predict cognitive impairment in older adults with diabetes. Nutritional profiling may support early screening and targeted intervention strategies based on observed associations.},
}

@article {pmid41879199,
year = {2026},
author = {Urso, D and Valguarnera, A and Volpe, G and Rollo, E and Barone, R and Vilella, D and Gnoni, V and Giugno, A and Giannoni, S and Andersson, N and Hachinski, V and Logroscino, G},
title = {A simple translational metric of integral brain health: Preliminary results.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431799},
doi = {10.1177/13872877261431799},
pmid = {41879199},
issn = {1875-8908},
abstract = {BackgroundComprehensive real-world tools for evaluating brain health are increasingly needed to complement established cognitive assessments and to capture multidimensional aspects of functioning relevant to dementia risk. The Integral Brain Health Questionnaire is a brief three-question, self-referenced multidomain self-assessment, not yet validated in clinical populations.ObjectiveAssess feasibility and construct validity of the Integral Brain Health Questionnaire in patients with cognitive impairment and assess its association with severity of cognitive loss and dementia risk factors.MethodsA consecutive series of 169 individuals with subjective memory complaints, mild cognitive impairment, or mild dementia at a tertiary care center in Southern Italy. Participants completed the Integral Brain Health Questionnaire, Mini-Mental State Examination (MMSE), the Clinical Dementia Rating (CDR) scale, and evaluations of dementia risk factors, including depression, social engagement, and sleep health.ResultsThe questionnaire showed good internal consistency (Cronbach's α = 0.843). Total scores correlated with MMSE (r = 0.322, p < 0.001), and CDR Sum of Boxes (r = -0.165, p = 0.041). Lower scores were associated with depression, poor sleep, and social isolation, while higher scores correlated with social engagement and sleep health. Women reported lower mental and social health scores. The tool showed moderate discriminative ability between mild cognitive impairment and mild dementia.ConclusionsThe Integral Brain Health Questionnaire is a simple, reliable proxy for assessing multidimensional brain health and cognitive loss severity. Apparent independence from age and education and associations with modifiable risk factors support its potential utility in clinical and population settings.},
}

@article {pmid41879255,
year = {2026},
author = {Rivero, M and Pacheco-Garcia, JL and Vankova, P and Loginov, D and Quereda-Moraleda, I and Martin-Garcia, JM and Man, P and Pey, AL and Medina, M},
title = {Tyrosine residues at the substrate binding site in human NQO1 homodimer: Protein conformational dynamics and optimization of substrate binding geometry.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70511},
pmid = {41879255},
issn = {1742-4658},
support = {PID2022-136369NB-I00//Spanish State Research Agency, AEI/ ; PID2023-151100NB-I00//Spanish State Research Agency, AEI/ ; RTI2018-096246-B-I00//Spanish State Research Agency, AEI/ ; E35_23R//Departamento de Educación, Cultura y Deporte, Gobierno de Aragón/ ; P18-RT-2413//Consejería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía/ ; CNS2022-135713//European Union Next Generation/ ; B-BIO-84-UGR20//ERDF/Counseling of Economic transformation, Industry, Knowledge and Universities/ ; },
abstract = {Human NQO1 is a homodimeric flavoenzyme essential for the redox metabolism of many substances and implicated in major global health challenges such as cancer and Alzheimer's disease. X-ray crystallographic studies have identified several residues within its substrate binding site (including Tyr126 and Tyr128) that may regulate catalytic competent binding of substrates, cofactor redox properties, half-site reactivity, and/or functional inter-active site negative cooperativity. To elucidate the functional role of Tyr126 and Tyr128, we generated point mutants at these positions and assessed their dynamics and kinetic properties. Hydrogen-deuterium exchange coupled to mass spectrometry revealed that non-conservative mutations, particularly at Tyr126, notably disrupted dynamics not only within the substrate binding site but also in structural elements connecting the two active sites of the NQO1 homodimer. Rapid-mixing pre-steady-state kinetics experiments of the reduction of NQO1 by NAD(P)H showed that mutations to Phe caused a mild decrease in hydride transfer (HT) efficiency from the coenzyme to the FAD cofactor. In contrast, mutations to Ala resulted in a significantly greater impact and mutations to Glu nearly abolished HT. Despite these effects, some mutations moderately affected the non-synchronous catalysis between the two alternating active sites, but hardly produced an impact on the selectivity for NADPH versus NADH as hydride donor coenzymes. However, all variants exhibited markedly impaired enzyme turnover, highlighting alterations in the enzyme's substrate specificity toward quinones. The data presented here demonstrate that Tyr126 and Tyr128 optimize both substrate binding geometry as well as overall enzyme conformational dynamics during the asymmetric catalytic cycle of the NQO1 homodimer.},
}

@article {pmid41879263,
year = {2026},
author = {Li, X and Zeng, X and Li, J and Zheng, Y and Tian, S and Wang, Z and Ma, C and Lin, Y and Lin, G and Zeng, Y and Xiao, Z and Tan, H and Yang, M and Liang, S and Liu, Z and Gao, P and Wang, Q and Lu, H and Zhong, X and Chen, B and Ning, Y},
title = {Altered temporal dynamics of intrinsic brain activity in mild cognitive impairment with olfactory dysfunction.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431797},
doi = {10.1177/13872877261431797},
pmid = {41879263},
issn = {1875-8908},
abstract = {BackgroundOdor identification (OI) impairment in mild cognitive impairment (MCI) elevates the risk for Alzheimer's disease (AD). The present study was designed to clarify the underlying neural mechanisms by investigating brain network aberrations in MCI patients with OI impairment using dynamic resting-state functional magnetic resonance imaging (rs-fMRI).ObjectiveThis study aimed to delineate the profile of dynamic intrinsic brain activity in MCI patients with and without OI impairment. It further aimed to establish the clinical relevance of these dynamic neural signatures by linking them to cognitive and olfactory function.MethodsIn 194 participants (97 MCI and 97 healthy controls [HC]), we analyzed dynamic metrics including dynamic fractional Amplitude of Low-Frequency Fluctuations (dfALFF), dynamic Amplitude of Low-Frequency Fluctuations (dALFF), dynamic Degree Centrality (dDC), and dynamic Regional Homogeneity (dReHo), and their correlation with cognitive performance and OI.ResultsThe MCI with OI impairment (MCI-OII) group (n = 22) performed worse across all cognitive domains than both HC and the MCI without OI impairment (MCI-NOII) group (n = 75, p < 0.001). These patients exhibited elevated dALFF, dfALFF, dDC, and dReHo variability in regions including the fusiform gyrus, insula, precuneus, and cingulate cortex (p < 0.001). These dynamic metrics correlated with olfactory and cognitive scores (p < 0.05). Additionally, dReHo in the right precuneus partially mediated the relationship between olfactory function and delayed recall memory.ConclusionsThis study demonstrates that MCI patients with OI impairment exhibit widespread disruptions in dynamic brain activity. These alterations correlate with clinical deficits, and precuneus dReHo may partially link olfactory and cognitive decline in MCI.},
}

@article {pmid41879271,
year = {2026},
author = {Luca, A and Piccoli, T and Tomaselli, A and Di Marco, S and Nicoletti, A and Lo Coco, D and Rolandi, E and Sensi, SL and Sucapane, P and Bruni, AC and Perani, D and Guarnieri, B and , },
title = {Cognitive and behavioral determinants of burden in caregivers of patients with Alzheimer's disease: A focus on sex and gender. The SexDemCare Multicentric Italian Study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261435213},
doi = {10.1177/13872877261435213},
pmid = {41879271},
issn = {1875-8908},
abstract = {BackgroundPrevious studies assessed the relationship between caregivers' characteristics and caregiver burden. However, comprehensive evaluations of caregivers' behavioral and psychological traits remain comparatively limited.ObjectiveTo explore the possible association between the cognitive and behavioral characteristics of caregivers of patients with Alzheimer's disease (AD) and the burden they experience, with a focus on sex/gender differences.MethodsIn this multicenter cross-sectional study within the SINdem "Sex and Gender Differences in Dementia" group, informal caregivers of non-institutionalized AD patients attending the Italian Memory Clinics were enrolled. Caregivers completed the Montreal Cognitive Assessment, Revised Scale for Caregiver Self-Efficacy, 20-Item Toronto Alexithymia Scale, Barratt Impulsiveness Scale-11, Brief COPE, 14-Item Resilience Scale, Ten-Item Big Five Inventory, Five Facet Mindfulness Questionnaire, Empathy Quotient-Short, and the Caregiver Burden Inventory. Sex was considered as a binary variable (female/male); gender-related dimensions were explored indirectly through caregivers' behavioral and psychological characteristics.Results238 caregivers and 238 AD patients were enrolled. A higher burden was associated with more daily caregiving hours, lower self-efficacy, greater impulsivity, difficulties identifying feelings, acting without awareness, a stronger tendency to judge, and higher neuroticism. Female caregiver burden was associated with attentional/motor impulsiveness, lower mindfulness, lower resilience, and lower emotional empathy. Male caregivers showed associations with lower self-efficacy, greater reliance on emotion-focused coping, difficulties identifying feelings, lower non-judging, lower agreeableness, and reduced cognitive empathy.ConclusionsCaregiver burden was associated with caregivers' own behavioral and psychological profiles and sex, beyond patient-related factors. These findings support the importance of integrating sex/gender perspectives and targeted interventions into caregiver assessment and support.},
}

@article {pmid41879275,
year = {2026},
author = {Zhang, H and Zeng, QY and Liu, C and Wu, Y and Liu, JK and Wang, FH and Luo, X},
title = {Association between omeprazole and memory impairment: Insights from NHANES data analysis and network pharmacology studies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261435988},
doi = {10.1177/13872877261435988},
pmid = {41879275},
issn = {1875-8908},
abstract = {BackgroundPost-marketing surveillance indicates a possible link between omeprazole consumption and changes in cognitive abilities; however, existing observational studies have yielded conflicting outcomes. This highlights the lack of consensus and underscores the imperative for further systematic investigation to elucidate this relationship.ObjectiveThis investigation thoroughly examined the connection between omeprazole administration and reported memory issues, with the goal of supplying empirical support for evaluating the medication's safety profile and determining its risk-benefit balance in clinical practice.MethodsWe employed a range of analytical approaches, including descriptive statistics, multivariable logistic regression, and receiver operating characteristic curve analysis, to systematically evaluate the association between omeprazole use and memory function. Network pharmacology further characterized omeprazole's molecular targets and pathways linked to memory deficits.ResultsIn the National Health and Nutrition Examination Survey (NHANES) analysis, it revealed a significant positive association between omeprazole consumption and memory impairment (OR [95% CI] = 3.51 [1.87, 6.59]). Through network pharmacology, 342 core targets related to Alzheimer's disease were identified. The top 10 potential binding targets of omeprazole-UBA52, RPL23, RPS18, RPL4, RPL15, RPL11, RPS6, EGFR, RPL13, and RPS20-exhibited strong binding affinities. The enrichment analysis implies a role for omeprazole in causing memory issues, possibly by affecting processes like carboxylic acid metabolism and membrane transportation.ConclusionsMounting research from both large-scale population studies and drug safety surveillance reports paints a clear picture: regular omeprazole consumption appears to hike the chances of experiencing cognitive hiccups related to memory function.},
}

@article {pmid41879277,
year = {2026},
author = {Tavan, Y and Roozegar, S and Mohammadi, ZF and Akbari, A and Nasiri, K and Memarmoghaddam, M and Talebi, V and Patel, DI},
title = {Aerobic exercise significantly alters Notch1 signaling in a neurotoxic hippocampal rat model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261434058},
doi = {10.1177/13872877261434058},
pmid = {41879277},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder and a major cause of dementia.ObjectiveThe aim of this study was to investigate the effect of aerobic training on the expression changes of Notch1, Rbpjk, Hes1, and Hey1genes in the hippocampus of Alzheimer rats.MethodsForty, 8-week-old male Wistar rats were divided into four groups: control (n = 10), exercise (n = 10), AD (n = 10), AD + exercise (n = 10). Endurance training was implemented with increasing intensity starting at 15 m/min in the first week and progressing to speeds of 16-20 m/min over the next five weeks with increased durations each week. After 6 weeks, animals were euthanized and hippocampus was collected, frozen and RNA was isolated to quantify Notch1, Rbpjk, Hes1, and Hey1 expression. All statistical analyses and graphs were conducted using SPSS and visualized using GraphPad Prism, with significance set at p < 0.05.ResultsOne-way analysis of variance with Tukey's post-hoc analysis found that the Alz group had significantly lower expression of Notch1 with increased expression of Rbpjk and Hes1. Conversely, the AD + Ex group was observed to have significantly higher Notch1 and significantly lower Rbpjk compared to the AD group.ConclusionsThese findings suggest that exercise may serve as a complementary neuroprotective intervention via manipulation of Notch1 signaling. Overall, the study highlights the need for further research on the relationship between physical activity and gene expression in the context of AD.},
}

@article {pmid41879312,
year = {2026},
author = {Wang, J and Liu, H and Lai, H and Bao, Y and Shen, M and Li, C and Ma, L and Wu, T and Yang, S and Du, X and O'Brien, TJ and Zhang, J and Zhang, L},
title = {Identifying candidate gut microbiota indicators for Alzheimer's disease through integrated data.},
journal = {mSystems},
volume = {},
number = {},
pages = {e0175425},
doi = {10.1128/msystems.01754-25},
pmid = {41879312},
issn = {2379-5077},
abstract = {UNLABELLED: Alzheimer's disease (AD) is associated with the gut microbiota, and identifying reliable gut microbiota biomarkers enhances AD diagnosis. We aim to characterize the gut microbiota in AD patients by integrating data from multiple populations and identifying key candidate gut microbiota indicators with diagnostic value for AD. Public data from studies on AD and gut microbiota were collected, including participants from AD dementia, mild cognitive impairment (MCI), and normal control (NC) groups. Microbiota composition, diversity, and network analyses were used to characterize the gut microbiota of the three groups. Differential bacterial genera identified simultaneously by seven common methods served as candidate indicators. The study included 799 AD dementia, 170 MCI, and 731 NC participants. The AD dementia group demonstrated a lower relative abundance of Bacteroides and Faecalibacterium and lower α-diversity than the MCI and NC groups (P < 0.05). The microbial network density in the AD dementia group was reduced by 1.5% and 1.6% compared with the NC and MCI groups, respectively. We identified 35 bacterial genera as candidate indicators for AD, including first-time reports of RF39 and Oligella. Faecalibacterium was the most important candidate indicator in the overall population, Akkermansia in the Chinese population, Collinsella in the "Turkish and Kazakh" population, and Actinomyces in the "American and Canadian" population. Our findings contribute to the development of non-invasive biomarkers for AD diagnosis and targeted microbiota therapies and provide a valuable reference for selecting specific biomarkers for different application scenarios.

IMPORTANCE: This study characterized the gut microbiota of Alzheimer's disease (AD) patients and identified candidate indicators for AD diagnosis using a large, multi-population data set. The AD dementia group consistently showed lower α-diversity and a sparser microbiota interaction network than the other groups. We identified 35 bacterial genera as candidate indicators for AD, including first-time reports of RF39 and Oligella. Faecalibacterium was the most important candidate indicator in the overall population, Akkermansia in the Chinese population, Collinsella in the "Turkish and Kazakh" population, and Actinomyces in the "American and Canadian" population. These findings provide a valuable reference for selecting biomarkers for different application scenarios.},
}

@article {pmid41879387,
year = {2026},
author = {Cheng, J and Zhang, C and Yang, L and Li, G and Jiang, X and Chen, P and Duan, X},
title = {An integrated strategy including chemical profiling, network pharmacology and experimental evaluation was used to investigate the effects of Rubia yunnanensis water decoction on vascular dementia.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {5},
pages = {1262-1283},
doi = {10.36721/PJPS.2026.39.5.REG.14029.1},
pmid = {41879387},
issn = {1011-601X},
mesh = {Animals ; *Network Pharmacology/methods ; *Dementia, Vascular/drug therapy/metabolism/pathology/psychology ; *Drugs, Chinese Herbal/pharmacology/chemistry ; Rats ; *Neuroprotective Agents/pharmacology ; Male ; Rats, Sprague-Dawley ; Disease Models, Animal ; Signal Transduction/drug effects ; Apoptosis/drug effects ; },
abstract = {BACKGROUND: Vascular dementia (VaD) is the second most prevalent cause of dementia following Alzheimer's disease. Rubia yunnanensis, a medicinal plant recorded in the Chinese Materia Medica, has historically been utilized for managing cerebral ischaemia-related disorders. While recent attention has focused on its neuroprotective potential, the specific mechanisms underlying the effects of Rubia yunnanensis water decoction (RY-W) on VaD remain unelucidated.

OBJECTIVES: This study aimed to identify the active chemical components and elucidate the molecular mechanisms of RY-W in the treatment of VaD by integrating network pharmacology with experimental validation.

METHODS: The chemical constituents of RY-W and their potential therapeutic targets were analyzed using UPLC-MS/MS and network pharmacology techniques. To validate these findings, the cerebral protective effects of RY-W were assessed in a rat model of VaD. Cognitive function was evaluated using the Morris Water Maze (MWM) test. Pathological changes and molecular markers were analyzed via Hematoxylin and Eosin (HE) staining, Nissl staining, TUNEL fluorescence staining, Immunohistochemistry (IHC), and Western blotting.

RESULTS: Network pharmacology analysis identified IL-6, IL-1β, ALB, TNF, and AKT1 as potential core targets for RY-W. Experimental results demonstrated that RY-W significantly alleviated cognitive deficits in VaD rats. Furthermore, RY-W exhibited anti-inflammatory properties and reduced neuronal apoptosis. These neuroprotective effects appear to be mediated through the regulation of ALB and the PI3K-Akt signaling pathway.

CONCLUSION: RY-W effectively ameliorates VaD pathology by exerting anti-inflammatory and anti-apoptotic effects. These findings highlight the involvement of ALB and the PI3K-Akt signaling pathway in the therapeutic action of RY-W, supporting its potential as a treatment for vascular dementia.},
}

Animals
*Network Pharmacology/methods
*Dementia, Vascular/drug therapy/metabolism/pathology/psychology
*Drugs, Chinese Herbal/pharmacology/chemistry
Rats
*Neuroprotective Agents/pharmacology
Male
Rats, Sprague-Dawley
Disease Models, Animal
Signal Transduction/drug effects
Apoptosis/drug effects

@article {pmid41879392,
year = {2026},
author = {Fu, C and Guo, K and Liu, T and Gong, J and Dong, H},
title = {Unveiling AKT1 as a key target of β-asarone in Alzheimer's disease through network pharmacology and molecular dynamics simulations.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {5},
pages = {1340-1349},
doi = {10.36721/PJPS.2026.39.5.REG.15243.1},
pmid = {41879392},
issn = {1011-601X},
mesh = {Allylbenzene Derivatives ; *Anisoles/pharmacology/therapeutic use/chemistry/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; Molecular Dynamics Simulation ; *Alzheimer Disease/drug therapy/metabolism/enzymology ; Network Pharmacology/methods ; Humans ; Molecular Docking Simulation ; Signal Transduction/drug effects ; *Neuroprotective Agents/pharmacology ; Protein Interaction Maps/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and complex, multi-factorial pathology. Current single-target drugs provide only limited benefits, and there is a need for more effective therapeutic strategies. β-asarone, a major volatile component of Acorus tatarinowii used in traditional Chinese medicine (TCM), has demonstrated neuroprotective effects, including anti-apoptotic, anti-inflammatory, and anti-amyloid β (Aβ) toxicity properties. However, the molecular targets and signaling mechanisms of β-asarone in AD remain underexplored.

OBJECTIVE: This study aims to explore the molecular targets and signaling mechanisms of β-asarone in AD by integrating network pharmacology, molecular docking, and molecular dynamics simulations.

METHODS: Network pharmacology was used to identify overlapping targets between β-asarone and AD. Protein-protein interaction networks were constructed using STRING, and key targets were analyzed for enrichment in the PI3K-AKT/MAPK pathways. Molecular docking was conducted to assess the binding affinity of β-asarone with multiple targets along the PI3K-AKT axis. Additionally, molecular dynamics (MD) simulations of the β-asarone-AKT1 complex were performed for 100 ns to assess the stability of the interaction.

RESULTS: Seventy-four overlapping targets of β-asarone and AD were identified, with key hub genes enriched in the PI3K-AKT/MAPK pathways. Molecular docking revealed that β-asarone binds to critical nodes along the PI3K-AKT axis with binding free energies (ΔG) of approximately -6.2 kcal/mol and to HRAS/IGF1 with ΔG ≈ -5.2/-4.1 kcal/mol. MD simulations showed stable trajectories for the β-asarone-AKT1 complex (RMSD ~3.5-4.0 Å) with persistent hydrogen bonds, indicating a durable interaction in the ATP-binding pocket.

CONCLUSION: β-asarone interacts with multiple interconnected signaling nodes, particularly the PI3K-AKT pathway, to modulate apoptosis, neuroinflammation, and cellular energetics. These findings support the potential of β-asarone as a TCM-derived candidate for the development of therapeutic strategies for AD.},
}

Allylbenzene Derivatives
*Anisoles/pharmacology/therapeutic use/chemistry/metabolism
*Proto-Oncogene Proteins c-akt/metabolism
Molecular Dynamics Simulation
*Alzheimer Disease/drug therapy/metabolism/enzymology
Network Pharmacology/methods
Humans
Molecular Docking Simulation
Signal Transduction/drug effects
*Neuroprotective Agents/pharmacology
Protein Interaction Maps/drug effects
Phosphatidylinositol 3-Kinases/metabolism