Early‐onset APOE‐ε4 carriers show greater decline in memory, language and executive function than late‐onset carriers

Abstract

AbstractBackgroundApolipoprotein‐ε4 (APOE‐ε4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). However, whether APOE‐ε4 accelerates cognitive decline in AD has not been firmly established. We studied the rate of cognitive decline among early‐ (EOAD) and late‐onset (LOAD) APOE‐ε4 carriers vs non‐carriers on measures of memory, attention, language, and executive function.MethodEOAD and LOAD (onset‐age < or ≥65) subjects were selected from the National Alzheimer’s Coordinating Center (NACC) database. Mixed‐effects models were run separately for EOAD and LOAD with longitudinal neuropsychological measures as dependent variables. APOE‐ε4 carrier status, follow‐up time, and an APOE*time interaction were included as independent variables adjusting for age, sex, education, and disease severity (CDR‐SB) at baseline. For measures where ε4‐carriers had significantly more decline in both groups, mixed‐effects models in the combined samples were used with a three‐way interaction among APOE status, follow‐up time and onset‐age variables to determine whether APOE‐ε4 associated decline was similar between EOAD and LOAD.ResultSubject demographics are shown in Table 1. The estimated differences in annual cognitive change between ε4‐carriers and non‐carriers are shown in Table 2. Both EOAD and LOAD APOE‐ε4 carriers showed significant decline in Craft Immediate (p=0.0065 and p=0.0134, respectively), semantic fluency (p=0.0001 and p<0.0001, respectively), and Trail‐Making B scores (p=0.0028 and 0.0206, respectively) than non‐ε4 carriers. Only EOAD APOE‐ε4 carriers showed significantly greater decline in Craft Delayed recall than non‐ε4 carriers (p=0.0189). Only LOAD APOE‐ε4 carriers showed significantly greater decline on MoCA (p<0.0001), MINT (p<0.0001), and Trail‐Making A (p<0.0001) than non‐carriers. The accelerated rate of decline in two of the three cognitive tests that showed faster decline in APOE‐ε4 carriers in both EOAD and LOAD was significantly greater in EOAD, while one was trending (Craft Immediate, p=0.0042; semantic fluency, p<0.0001; Trail‐Making B, p=0.0942).ConclusionThese results suggest that APOE‐ε4 is associated with accelerated rate of decline in both LOAD and EOAD; however, the magnitude of the rate of decline is more pronounced in EOAD. Investigation in other large research consortia such as LEADS and ADNI can further characterize the genetic influences of APOE‐ε4 and other genetic risk factors on AD.