Age, APOE and sex: Triad of risk of Alzheimer's disease

Abstract

Age, apolipoprotein E ε4 (APOE) and chromosomal sex are well-established risk factors for late-onset Alzheimer's disease (LOAD; AD). Over 60% of persons with AD harbor at least one APOE-ε4 allele. The sex-based prevalence of AD is well documented with over 60% of persons with AD being female. Evidence indicates that the APOE-ε4 risk for AD is greater in women than men, which is particularly evident in heterozygous women carrying one APOE-ε4 allele. Paradoxically, men homozygous for APOE-ε4 are reported to be at greater risk for mild cognitive impairment and AD. Herein, we discuss the complex interplay between the three greatest risk factors for Alzheimer's disease, age, APOE-ε4 genotype and chromosomal sex. We propose that the convergence of these three risk factors, and specifically the bioenergetic aging perimenopause to menopause transition unique to the female, creates a risk profile for AD unique to the female. Further, we discuss the specific risk of the APOE-ε4 positive male which appears to emerge early in the aging process. Evidence for impact of the triad of AD risk factors is most evident in the temporal trajectory of AD progression and burden of pathology in relation to APOE genotype, age and sex. Collectively, the data indicate complex interactions between age, APOE genotype and gender that belies a one size fits all approach and argues for a precision medicine approach that integrates across the three main risk factors for Alzheimer's disease.

Keywords: Age; Alzheimer's disease; ApoE; Bioenergetics; Brain; Mitochondria; Sex difference.

Figure 1

Sex-specific incidence estimates of Alzheimer’s per 1,000 person years. Obtained with data from the Cache County Study [12]. Data reported in Ruitenberg et al., [12] indicate that men are at greater risk than women for developing earlier onset AD. However, this sex difference is reversed by age 75, with women at a 2 fold greater risk for AD, thereafter.

Figure 2

ApoE NMR protein structure. Created from the RCSB Protein Databank and the PyMol graphics viewer (PDB ID: PO2649) [186]. This figure shows the nuclear magnetic resonance protein structure of apoE ɛ3. Lipoprotein binding (1) and Aβ-binding (2) motif regions are delineated [34, 78]. Residues 112 and 158, which are altered between (and therefore determine) the differing isoforms, are also labeled [42–43].

Figure 3

ApoE serum concentrations by sex and age (N=6,934). From data collected in the ApoEurope project, obtained with permissions from [48]. Data indicate that men have greater apoE concentrations than women until age 50–54. While men experience progressive declines in apoE concentrations following this age, apoE concentrations rise in women. As low serum levels of apoE are associated with an increased risk for AD, this tipping point might explain the discordant findings in risk by sex, such that men are at risk due to a reduced production of apoE, while ɛ4 women produce an overabundance of as isoform with impaired function.