In addition to the appearance of senile plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by aberrant lipid metabolism and early mitochondrial dysfunction. We recently showed that there was increased functionality of mitochondriaâassociated endoplasmic reticulum (ER) membranes (MAM), a subdomain of the ER involved in lipid and cholesterol homeostasis, in presenilinâdeficient cells and in fibroblasts from familial and sporadic AD patients. Individuals carrying the Îľ4 allele of apolipoprotein E (ApoE4) are at increased risk for developing AD compared to those carrying ApoE3. While the reason for this increased risk is unknown, we hypothesized that it might be associated with elevated MAM function. Using an astrocyteâconditioned media (ACM) model, we now show that ERâmitochondrial communication and MAM functionâas measured by the synthesis of phospholipids and of cholesteryl esters, respectivelyâare increased significantly in cells treated with ApoE4âcontaining ACM as compared to those treated with ApoE3âcontaining ACM. Notably, this effect was seen with lipoproteinâenriched preparations, but not with lipidâfree ApoE protein. These data are consistent with a role of upregulated MAM function in the pathogenesis of AD and may help explain, in part, the contribution of ApoE4 as a risk factor in the disease.