Decoding adipose–brain crosstalk: Distinct lipid cargo in human adipose‐derived extracellular vesicles modulates amyloid aggregation in Alzheimer's disease

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.