DECODING VARIABILITY IN AGE-AT-SYMPTOMATIC-ONSET BETWEEN PARENTS AND CHILDREN WITH SPORADIC ALZHEIMER DISEASE DEMENTIA

Abstract

Adult children of demented individuals harbor an increased risk of developing AD dementia, with ages-at-symptomatic-onset (AAO) that may differ from those of their affected parent(s). Factors responsible for differences in AAO within families remain unknown. We hypothesized that participant-specific factors may account for a proportion of this variability. The prevalence of putative dementia risk factors was determined in 482 participants with symptomatic AD dementia and a reported parental history of dementia. All participants were enrolled within Knight Alzheimer Disease Research Center longitudinal studies of memory and aging between August 1979 and February 2016. For each participant, the difference between the (reported) parental AAO, and the (observed) participant AAO was determined, and used to stratify participants. “Early” participants manifested with AD dementia >10 years before parental AAO (n=79), while “late” participants were diagnosed >10 years after parental AAO (n=73). The prevalence of putative dementia risk factors were compared across groups, including female gender; years of education; race; body mass index; and past or present history of cardiovascular disease, hypertension, hypercholesterolemia, diabetes, depression, traumatic brain injury, and tobacco and/or alcohol abuse. APOEallele status was also considered, given its recognized association with dementia risk. Participants were diagnosed with AD dementia, on average, 6.1±10.9 years earlier than their parent(s) (p<0.001). Maternal history of dementia was most common, reported amongst 74% of participants (p<0.001). Both parents were affected in 7% of cases. Despite differences in frequency, the pattern of inheritance did not account for the earlier-than-expected AAO in participants (p=0.6). Likewise, although putative risk factors were commonly represented in our sample, no single factor was over-represented in participants with earlier- versus later-than-expected AAO. Unexpectedly, participants with later-than-expected AAO were more likely to be APOEε4 allele carriers (p=0.04). The prevalence of measured dementia risk factors did not account for the earlier-than-expected AD dementia AAO observed in participants with a parental history of dementia. These findings imply that other participant-specific risk factors account for the variability observed in this cohort. Studies quantifying the impact of known and unknown genetic factors on AAO are required.