The APOE-ε4 (APOE4) variant is the greatest single risk factor for developing late-onset Alzheimer's disease (AD); however, its involvement in AD is poorly understood. Recently DAB1 was identified as the only genome-wide significant locus in homozygous APOE4 (e4/e4) individuals in the UK Biobank. DAB1's involvement in AD was profoundly dependent on the e4/e4 genotype and also the DAB1 SNP zygosity, which influenced the probability of developing AD and the age of onset. Based on this, we hypothesize that there is a genetic interaction between APOE4 and DAB1 that synergistically augments the likelihood of AD. Both APOE4 and DAB1 act on the endocytosis-signaling receptors in the APOE-receptor family and have consequences for Aβ accumulation and microtubule binding protein τ (MAPT) phosphorylation pointing to potential functional overlap. DAB1 is an obligate adaptor protein on the REELIN signaling pathway that is well characterized for its roles in brain development. The Reln gene has been shown to impact AD-related phenotypes in mouse models of the disease, and in the APOE4 study RELN was nominally associated with AD in e4/e4 individuals pointing to a broader involvement of the RELN-DAB1 pathway in AD. We propose that determining the Dab1 dosage-dependent, AD-related phenotypes that are exaggerated by APOE4 in mouse and culture models will help elucidate how these genes contribute to the increased risk of the disease. We will investigate this by pursuing the following specific aims: Specific Aim 1. To determine if Dab1 heterozygosity alters early and/or late AD-like pathology in an APOE variant-dependent manner. Specific Aim 2. To determine if Dab1-gene dose influences APOE4-dependent endocytic aberrations. Our long term goal is to resolve how DAB1 and other REELIN pathway genes influence APOE4 biology as a means to understand how this apolipoprotein and defects in endocytosis contribute to the progression of AD.