Summary Alzheimer’s disease (AD) and AD related dementias (ADRD) are unpreventable, incurable and remain poorly understood. Their hallmark pathology consists of misfolded proteins in characteristic “inclusions” within subsets of neurons and glial cells of the brain. Misfolding of the membrane-associated protein α-synuclein (αS) is central to ADRD. Inclusions rich in αS in cortical and dopaminergic (DA) neurons are the hallmark lesions of dementia with Lewy bodies (DLB) and Parkinson disease with dementia (PDD). But αS inclusions are also found in >50% of AD cases, correlating with cognitive decline and frequently colocalizing with tau pathology. αS pathology is strikingly heterogeneous and poorly understood. Common αS pathology comprises vesicle-rich “pale bodies” (PBs), amyloid-rich Lewy bodies (LBs), or combinations of these. PBs have indeed been discussed as precursors of LBs, but what gives rise to PBs and how they may convert into LBs remains enigmatic. The ultrastructural features of PBs and LBs parallel enormous interest in the field in both amyloid and vesicle- trafficking pathologies in PD. In experimental settings, the seeding of neurons with pre-formed fibrils leads to LB- like amyloid aggregates. These aggregates can under certain conditions spread and self-template in adjacent cells. Different amyloid fiber conformers (“strains”) lead to different patterns of neurodegeneration, with differing levels of phosphorylated αS and tau. Human genetic studies have repeatedly implicated perturbed vesicle trafficking and (membrane) lipid homeostasis as a fundamental and unifying feature in disparate forms of ADRD. We hypothesize that altered cellular, and especially lipid, microenvironments can trigger αS amyloid formation and the development of different strains and pathologies. An increasing body of evidence, including work from our groups, indeed suggests that αS toxicity and aggregation can be modulated by altering cellular fatty acid (FA) saturation or sphingolipid (SL) composition through manipulation of glucocerebrosidase (GBA) and stearoyl- coA desaturase (SCD), respectively. We propose to dissect the influence of these pathways on PB and LB formation and transition in the most disease-relevant patient-derived induced pluripotent stem cell (iPSC) models. Importantly, we will employ patient brain-derived “seed” as the most relevant trigger for neuronal αS aggregation. The use of both patient-specific cell types and misfolded protein conformers will allow us to capture “in the dish” both sides of the toxic equation in neurodegeneration. We recognize the importance, but also the limitations, of postmortem end-stage pathology in delineating disease mechanisms, and propose to establish cross-corre...