Apolipoprotein E, survival in Alzheimer's disease patients, and the competing risks of death and Alzheimer's disease

Abstract

The apolipoprotein E (APOE) epsilon 4 allele carries an increased risk of a patient developing Alzheimer's disease (AD) while the epsilon 2 allele carries a decreased risk. We compared survival from the onset of AD in subjects with different numbers of epsilon 4 alleles and evaluated changes in genotypic frequencies with age. Two subject groups were investigated: unrelated AD case and control subjects, and affected and unaffected members from 74 multiplex AD families. In both subject groups, survival from onset decreased with increasing onset age, was longer in women, and was unrelated to epsilon 4 gene dose. The epsilon 2/epsilon 3 genotype became more common with age (p = 0.004). The epsilon 4 allele decreased in frequency with age in all patient groups but, unexpectedly, remained unchanged in control subjects. We conclude that the progression of AD is not strongly related to epsilon 4 gene dose, that the higher prevalence of AD in women may involve the longer survival of affected women, and that AD and death are competing risks involving APOE that change over time.

Neuropsychological deficits associated with Alzheimer's disease in the very-old: Discrepancies in raw vs. standardized scores

“…Consistent with previous studies (Basun et al, 1995;Bondi et al, 1999;Corder et al, 1995;Normann et al, 1995;Dal Forno et al, 1996;DeKosky et al, 1995;Gomez-Isla et al, 1996;Growdon et al, 1996;Kurz et al, 1996;Small et al, 1998;Smith et al, 1998), there was little overall effect of APOE genotype on the cognitive performance of the NC participants or AD patients in the Very-Old or Young-Old cohorts (e.g., no main effect of APOE genotype in the multivariate analysis and in all but one of the ANOVAs). However, there were interactions between age and the presence of the APOE ε4 allele on the severity of impairment exhibited by patients with AD on some measures of memory, visuomotor sequencing, and perseverative responding, but these interaction effects were not consistent across measures.…”

“…The APOE ε4 allele has been identified as a major risk factor for late-onset AD (Corder et al, 1993;Saunders et al, 1993;Strittmatter et al, 1993Strittmatter et al, , 1994, but there is evidence that the associated risk wanes with advancing age (Corder et al, , 1995(Corder et al, , 1996Rebeck et al, 1994; but see Gebner et al, 1997;Payami et al, 1997). This change in risk suggests that the phenotypic expression of the APOE ε4 allele may be age dependent.…”

Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice

“…Individuals that succumb to sporadic AD, accounting for the vast majority of all AD cases, do not possess mutations in the previously mentioned genes. Expression of the ε4 allele of the apoE gene is considered a risk factor for the development of sporadic AD [9,34]. Although risk factors have been identified, the early initiating events leading to the development of the sporadic form of AD have yet to be determined [22].…”

Susceptibility Genetics in the Etiopathogenesis of Alzheimer's Disease: Role for Potential Confounding Factors

“…The mechanism by which APOE exerts its influence on AD is not known. A consistent increase in the deposition of AP that is linked to increasing ~4 gene dosage (Gomez-Isla, 1996;Polvikoski et al, 1995;Rebeck et al, 1993), that is not due to a differential survival effect (Corder et al, 1995). Duration and progression of AD are not related to APOE4, suggesting that the higher AP load is not a major determinant of the course of the disease.…”

“…Sociological factors may be directly relevant to AD or might act as surrogate markers of some other process with a genetic component (e.g., educational level may reflect intellect, a complex phenome- (Corder et al, 1995;Growdon et al, 1996;Kurz et al, 1996). The strongest evidence that nongenetic, environmental factors are involved in A D comes from the observation that some monozygotic twin pairs, including shared ~4 alleles, have remained discordant for A D for up to 20 years (Breitner et al, 1995).…”