Alzheimer's disease (AD) is a pervasive neurodegenerative disorder, and new approaches for its prevention and therapy are critically needed. Here, we elucidate a gut-microbiome-brain axis that offers actionable perspectives for achieving this objective. Using the 5xFAD mouse model, we identify increased Clostridium abundance and decreased Bacteroides abundance as key features associated with β-amyloid (Aβ) burden. Treatment with Bacteroides ovatus, or its associated metabolite lysophosphatidylcholine (LPC), significantly reduces Aβ load and ameliorates cognitive impairment. Mechanistically, LPC acts through the orphan receptor GPR119, inhibiting ACSL4 expression, thereby suppressing ferroptosis and ameliorating AD pathologies. Analysis of fecal and serum samples from individuals with AD also reveals diminished levels of Bacteroides and LPC. This study thus identifies a B.ovatus-triggered pathway regulating AD pathologies and indicates that the use of single gut microbiota, metabolite, or small molecule compound may complement current prevention and treatment approaches for AD.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Genetic studies can offer powerful insights for the development of disease-modifying therapies for Alzheimer's disease. Protective genetic variants that delay the onset of cognitive impairment have been found in people with sporadic Alzheimer's disease and in carriers of mutations that usually cause autosomal-dominant Alzheimer's disease in mid-life. The study of families who carry autosomal dominant mutations provides a unique opportunity to uncover genetic modifiers of disease progression, including rare variants in genes such as APOE and RELN. Understanding how these variants confer protection can help identify the biological pathways that contribute to cognitive resilience, such as the heparan-sulphate proteoglycan-APOE receptor pathway, the TREM-2-driven signalling pathways in the microglia, and phagocytosis. Therapies able to replicate the beneficial effects of these natural defences could provide novel strategies for slowing or preventing the progression of Alzheimer's disease.Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

The Montreal Cognitive Assessment (MoCA) is a cognitive screening instrument growing in popularity, but few studies have conducted psychometric item analyses or attempted to develop abbreviated forms. We sought to derive and validate a short-form MoCA (SF-MoCA) and compare its classification accuracy to the standard MoCA and Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI), Alzheimer disease (AD), and normal aging.408 subjects (MCI n = 169, AD n = 87, and normal n = 152) were randomly divided into derivation and validation samples. Item analysis in the derivation sample identified most sensitive MoCA items. Receiver Operating Characteristic (ROC) analyses were used to develop cut-off scores and evaluate the classification accuracy of the SF-MoCA, standard MoCA, and MMSE. Net Reclassification Improvement (NRI) analyses and comparison of ROC curves were used to compare classification accuracy of the three measures.Serial subtraction (Cramer's V = .408), delayed recall (Cramer's V = .702), and orientation items (Cramer's V = .832) were included in the SF-MoCA based on largest effect sizes in item analyses. Results revealed 72.6% classification accuracy of the SF-MoCA, compared with 71.9% for the standard MoCA and 67.4% for the MMSE. Results of NRI analyses and ROC curve comparisons revealed that classification accuracy of the SF-MoCA was comparable to the standard version and generally superior to the MMSE.Findings suggest the SF-MoCA could be an effective brief tool in detecting cognitive impairment.