Effect of APOE and family history of dementia on Alzheimer's disease imaging biomarkers in cognitively normal subjects

Abstract

To investigate the effect of APOE and family history of dementia on biomarkers of AD pathophysiology in cognitively normal (CN) subjects. The biomarkers evaluated were brain beta-amyloid load via PIB-PET and neurodegeneration via FDG-PET and structural MRI. We analyzed 940 Mayo Clinic Study of Aging CN participants with PET or MRI, APOE, and self-reported parental medical history. For a subject to be classified as having no family history of dementia, both parents had to survive to at least age 65 and remain dementia free through life. We fit univariate and multivariate linear regression models to test for associations between APOE e4 status, family history, and the interaction of the two with the imaging outcome variables. We found that amyloid load differed by APOE status (p<0.001) and family history (p=0.002) but FDG-PET and MRI did not (p>0.1). While there was no evidence of an interaction between APOE and family history in terms of amyloid load, both APOE and family history independently added to the prediction of amyloid load after adjusting for the other. In a multivariate model, APOE e4 genotype was associated with an 11% increase in amyloid load compared to e4 non-carriers (7%-16%, 95% CI; p<0.001) and parental family history of dementia was associated with a 5% increase in amyloid load compared to no parental history (1%-9%, 95% CI; p=0.02). 1) APOE status and family history were significantly associated with amyloid load but not with neurodegeneration. 2) While APOE genotype appears to be the larger driver of amyloid levels, family history of dementia, which reflects a composite risk factor encompassing known and unknown genetic and environmental risk of dementia, appears to be independently associated with higher levels of amyloid. 3) An individual subject's risk of brain amyloid given by their APOE status may be more precise than their family history. 4) Higher levels of amyloid load seen in asymptomatic APOE e4 carriers as well as cognitively normal individuals with a family history of dementia without neurodegeneration provides evidence that increasing amyloid levels may be the earliest indicator of AD.