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
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 toAPOE genotype and to other sources.
Nonparametric and parametric survival analyses of AD incidence in prospective
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.
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 allelesbut observed no meaningful difference in
100-year lifetime incidence related to number of ϵ4 alleles.
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.