In this narrative review, we delved into the intricate interplay between Apolipoprotein E (APOE) alleles (typically associated with Alzheimer’s disease—AD) and alpha-synucleinopathies (aS-pathies), involving Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA). This evidence concerns the gene APOE and early-onset autosomal dominant Alzheimer disease.