Apolipoprotein E ε4 Count Affects Age at Onset of Alzheimer Disease, but Not Lifetime Susceptibility: The Cache County Study

Background: The incidence of Alzheimer disease (AD) increases strongly with age, but little is known about the cumulative incidence of AD over a lifetime of 100 years, or its relationship to the polymorphic APOE locus that encodes apolipoprotein E. APOE is a strong genetic risk factor for AD. Objectives: To estimate the occurrence of AD as a function of age and number of APOE ε4 alleles; and to explore evidence for heterogeneity of AD risk related to APOE genotype and to other sources. Design: Nonparametric and parametric survival analyses of AD incidence in prospective longitudinal study. Setting and Participants: A total of 3308 elderly residents of Cache County, Utah. Main Outcome Measures: Cumulative incidence of AD: in mixture models assuming susceptible and nonsusceptible individuals, the proportion of individuals not susceptible to AD at any age. Results: Models that assumed a proportion of invulnerable individuals provided strongly improved fit to the data. These models estimated the 100-year lifetime incidence of AD at 72%, implying that 28% of individuals would not develop AD over any reasonable life expectancy. We confirmed the acceleration of AD onset in individuals with 1 or, especially, 2 APOE ε4 alleles, but observed no meaningful difference in 100-year lifetime incidence related to number of ε4 alleles. Conclusions: The APOE ε4 allele acts as a potent risk factor for AD by accelerating onset. However, the risk of AD appears heterogeneous in ways independent of APOE. Some individuals seem destined to escape AD, even over an extended lifespan. Their relative invulnerability may reflect other genes or environmental factors that can be investigated.