P2-194: Presymptomatic longitudinal decline in frontally mediated cognitive skills and memory in cognitively normal late middle aged APOE e4 carriers

Abstract

APOE e4 is a major genetic risk factor for Alzheimer's disease (AD). Cross sectional studies suggest that frontally mediated cognitive skills decline with age in cognitively normal APOE e4 carriers more than in noncarriers (Caselli et al 1999; Caselli et al 2001) although longitudinal studies of late middle age APOE e4 carriers under 3 years in duration have failed to confirm this (Caselli et al, 2004). To assess frontally mediated cognitive skills in cognitively normal late middle age APOE e4 carriers and noncarriers who have undergone longitudinal neuropsychological testing for 6 years or more. Cognitively normal individuals age 50–65 years at entry underwent biannual neuropsychological testing for at least 6 years, and linear changes in cognitive skills were correlated with APOE e4 carrier status among those who remained healthy. We excluded anyone at entry, or who during the course of the study period, developed mild cognitive impairment (MCI), AD, any other form of symptomatic cognitive impairment, or anyone with more than 30% decline on any test score even in the absence of symptoms. 35 carriers and 33 noncarriers who completed at least six years of longitudinal neuropsychological assessment did not differ in entry age (56±4.2 years), education (16.3±2.3 years), gender (63% female), or duration of followup (77.8±6.9 months). Carriers performed slightly better on Auditory Verbal Learning Test (AVLT) memory measures at entry (p<0.05 on total learning, short term recall, long term recall, and % recall). Longitudinally, carriers declined significantly more than noncarriers on frontally mediated tests: WAIS–R mental arithmetic (p=0.04), digit symbol substitution (p=0.03), and on a composite Freedom from Distractibility measure (p=0.01) that includes mental arithmetic and digit span. Carriers also declined more on AVLT short term recall (p=0.009). There were no differences or declines in other cognitive domains. Longitudinal observation of late middle aged cognitively normal APOE e4 carriers confirms that in addition to memory, frontally mediated cognitive skills decline significantly more than in noncarriers even in the absence of emerging clinical symptoms or signs of MCI or AD.