Cerebrovascular risk factors and preclinical memory decline in healthy APOE ε4 homozygotes

Abstract

Objective: To characterize the effects of cerebrovascular (CV) risk factors on preclinical memory decline in cognitively normal individuals at 3 levels of genetic risk for Alzheimer disease (AD) based on APOE genotype.

Methods: We performed longitudinal neuropsychological testing on an APOE ε4 enriched cohort, ages 21-97. The long-term memory (LTM) score of the Auditory Verbal Learning Test (AVLT) was the primary outcome measure. Any of 4 CV risk factors (CVany), including hypercholesterolemia (CHOL), prior cigarette use (CIG), diabetes mellitus (DM), and hypertension (HTN), was treated as a dichotomized variable. We estimated the longitudinal effect of age using statistical models that simultaneously modeled the cross-sectional and longitudinal effects of age on AVLT LTM by APOE genotype, CVany, and the interaction between the two.

Results: A total of 74 APOE ε4 homozygotes (HMZ), 239 ε4 heterozygotes (HTZ), and 494 ε4 noncarriers were included. APOE ε4 carrier status showed a significant quadratic effect with age-related LTM decline in all models as previously reported. CVany was associated with further longitudinal AVLT LTM decline in APOE ε4 carriers (p=0.02), but had no effect in noncarriers. When ε4 HTZ and HMZ were considered separately, there was a striking effect in HMZ (p<0.001) but not in HTZ. In exploratory analyses, significant deleterious effects were found for CIG (p=0.001), DM (p=0.03), and HTN (p=0.05) in APOE ε4 carriers only that remained significant only for CIG after correction for multiple comparisons.

Conclusion: CV risk factors influence age-related memory decline in APOE ε4 HMZ.

Figure. Cerebrovascular risk factors and APOE ε4 homozygotes

Longitudinal performance in Auditory Verbal Learning Test (AVLT)–long-term memory scores improves in younger ε4 homozygotes without CV risk factors, but shows little improvement to frank decline even in the youngest age deciles of homozygotes with cerebrovascular risk factors. Solid black lines = without any of 4 cerebrovascular risk factors (CVany); dashed red lines = with CVany.