{"doi":"10.1002/alz.70603","title":"Decoding adipose–brain crosstalk: Distinct lipid cargo in human adipose‐derived extracellular vesicles modulates amyloid aggregation in Alzheimer's disease","abstract":"INTRODUCTION: Obesity is a major modifiable risk factor for Alzheimer's disease (AD), but the mechanistic link between peripheral metabolic dysfunction and AD progression remains unclear. Adipose-derived extracellular vesicles (EVs) may penetrate the brain and alter lipid homeostasis, contributing to neurodegeneration. METHODS: We isolated exosome-enriched EVs from subcutaneous and visceral fat of lean and obese individuals, followed by lipidomic profiling. An in vitro amyloid-β (Aβ) aggregation assay using purified Aβ40 and Aβ42 peptides was performed under lipid environments mimicking physiological and pathological states. RESULTS: Obese-derived EVs exhibited distinct lipid profiles, particularly in lysophosphatidylcholine (LPC) and sphingomyelin (SM) species. Functional assays demonstrated that lipid identity and concentration critically influenced Aβ aggregation kinetics. DISCUSSION: Our study reveals that obesity-associated EV lipids modulate Aβ aggregation, linking adipose metabolism to AD pathology. These findings support lipid-targeted strategies as potential therapeutics for neurodegenerative diseases. HIGHLIGHTS: Human adipose-derived extracellular vesicles (EVs) from obese individuals exhibit distinct lipidomic profiles. EV lipids modulate amyloid-β (Aβ) 40 and Aβ42 aggregation in a lipid-type- and concentration-dependent manner. Lysophosphatidylcholine (LPC) and sphingomyelin (SM) species from obese EVs significantly deregulate Aβ fibrillization in vitro. EV lipid cargo links peripheral metabolic state to amyloid pathology in Alzheimer's disease.","journal":"Alzheimer s & Dementia","year":2025,"id":520164,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.951,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":546996,"name":"Michael W.Y. Chan","orcid":"0000-0003-1431-322X","position":1,"is_corresponding":false},{"id":310685,"name":"Jianting Sheng","orcid":"0000-0003-3532-3259","position":2,"is_corresponding":false},{"id":641555,"name":"Shaohua Qi","orcid":null,"position":3,"is_corresponding":false},{"id":1389737,"name":"Bill Chan","orcid":null,"position":4,"is_corresponding":false},{"id":851744,"name":"Dharti Shantaram","orcid":"0000-0003-2637-8039","position":5,"is_corresponding":false},{"id":446157,"name":"Xilal Y. Rima","orcid":"0000-0001-5633-5887","position":6,"is_corresponding":false},{"id":446159,"name":"Eduardo Reátegui","orcid":"0000-0002-8271-8205","position":7,"is_corresponding":false},{"id":232153,"name":"Xianlin Han","orcid":"0000-0002-8615-2413","position":8,"is_corresponding":false},{"id":350528,"name":"Willa A. Hsueh","orcid":"0000-0002-7321-4398","position":9,"is_corresponding":false},{"id":1114097,"name":"Stephen Wong","orcid":null,"position":10,"is_corresponding":false},{"id":1389188,"name":"Li Yang","orcid":"0000-0003-1421-7377","position":0,"is_corresponding":true}],"reference_count":99,"raw_metadata":null,"created_at":"2026-07-19T02:49:23.618703Z","pmid":"41036709","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}