Lipid rafts are highly dynamic membrane microdomains intimately associated with cell signaling. Compelling evidence has demonstrated that alterations in lipid rafts are associated with neurodegenerative diseases such Alzheimer's disease, but at present, whether alterations in lipid raft microdomains occurs in other types of dementia such Dementia with Lewy Bodies (DLB) remains unknown. Our analyses reveal that lipid rafts from DLB exhibit aberrant lipid profiles including low levels of n3 long chain polyunsaturated fatty acids (mainly docosahexaenoic acid), plasmalogens and cholesterol, and reduced unsaturation and peroxidability indexes. As a consequence, lipid raft resident proteins holding principal factors of the βamyloidogenic pathway, including β-amyloid precursor protein, presenilin 1, βsecretase and PrP, are redistributed between lipid rafts and non-raft domains in DLB frontal cortex. Meta-analysis discloses certain similarities in the altered composition of lipid rafts between DLB and Parkinson's disease which are in line with the spectrum of Lewy Body Diseases. In addition, redistribution of proteins linked to the β-amyloidogenic pathway in DLB can facilitate generation of β-amyloid, thus providing mechanistic clues to the intriguing convergence of Alzheimer's disease pathology, particularly β-amyloid deposition, in DLB.