AD FAMILY HISTORY MODULATES EFFECTS OF TOMM40 ‘523’ POLY-T ON MTL ATROPHY AND HYPOMETABOLISM IN PRECLINICAL AND AD COHORTS

Abstract

There is tremendous interest in finding novel genetic risk factors for Alzheimer's disease (AD) among individuals lacking the Apolipoprotein E ε4 allele (non-APOE4's). Translocase of Outer Mitochondrial Membrane-kD40 (TOMM40), which affects mitochondrial function, is a gene with strong linkage disequilibrium to APOE. A TOMM40 variable poly-T length polymorphism at rs10524523 within intron 6 may increase risk for late onset AD. Few studies have examined how a “very long” (VL) versus “short” (S) poly-T length is related to neural outcomes. Furthermore, we found recently that AD family history (FH) changes the association between VL poly-T length and cognitive decline in cognitively normal middle-aged and aged adults across the AD spectrum. Thus, we examined TOMM40 poly-T genotype, FH, and their interaction on changes in medial temporal lobe (MTL) gray matter (GM) and glucose metabolism across time. Longitudinal linear mixed modeling assessed FH and TOMM40 main effects and interactions, among non-APOE4's, for subsets of 913 middle-aged subjects from the Wisconsin Registry for Alzheimer's Prevention (WRAP) over 7–10 years and 334 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) over 3 years. FreeSurfer was used to derive mean MTL volume and cortical thickness (CT). Arterial spin labeling (ASL) in WRAP and fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in ADNI were used to gauge MTL glucose metabolism. Significant TOMM40 x FH interactions indicated that TOMM40 VL's who were FH- and FH+ respectively showed robust step-wise protective or detrimental effects for GM, ASL, and FDG-PET. Figure 1 and Figure 2 illustrate this association in MTL volume for WRAP and MTL CT for ADNI. Figure 3 illustrates this association for MTL versus global cerebral blood flow in WRAP, with comparable associations seen for FDG-PET in ADNI.