Impact of APOE-epsilon 4 and family history of dementia on gray matter atrophy in cognitively healthy middle-aged adults

The apolipoprotein E ε4 allele (APOE4) and family history of dementia (FH) are well-known risk factors for the development of sporadic Alzheimer's disease. We assessed the effects of these risk factors on gray matter (GM) volume in 295 cognitively healthy middle-aged community-dwelling subjects. Voxel-based morphometry was used to study GM volume differences between high- and low-risk subjects, based on APOE4 carriership (n = 74), first-degree FH (n = 228), or both (n = 62). No significant results were found using a corrected p value. Using a more lenient threshold (p < 0.001 and minimum cluster size of 100 voxels), APOE4 carriers had reduced GM in the striatum compared to noncarriers. Subjects with FH had reduced GM in right precuneus compared to subjects without FH. Maternal and paternal FH provided similar atrophy patterns. APOE4 carriers with FH had GM reductions in bilateral insula compared to subjects with neither APOE4 nor FH. We conclude that a family history of dementia and APOE4 carriership are both associated with regional GM decreases in cognitively healthy middle-aged subjects, with differential effects on brain regions typically affected in Alzheimer's disease.