ACAA1 and early-onset autosomal dominant Alzheimer disease: Over 50 loci/genes involved in a variety of pathways, including endocytosis, cholesterol and lipid metabolism, synaptic function, dendritic and axonal transport, Aβ and tau processing, and microglial and myeloid cell function, have been implicated in AD,14,22,23 suggesting that AD is a systemic disease.24 There are multiple reports for dysfunction of metabolism during the AD pathogenesis.25–28 In this study, we reported an EOFAD-associated rare loss-of-function variant, rs117916664 (p.Asn299Ser [p.N299S]), in peroxisomal ACAA1 (acetyl-CoA acyltransferase 1).