The Neurobiology and Age-Related Prevalence of the ε4 Allele of Apolipoprotein E in Alzheimer's Disease Cohorts

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterised by amyloid beta (Aβ) plaques and tau neurofibrillary tangles in the brain. Human apolipoprotein E (ApoE) is a lipid transport protein coded by the polymorphic APOE gene, with three major alleles: ε2, ε3 and ε4. After age, the ε4 allele is the greatest risk factor for developing sporadic AD, conferring an increased risk of 3-4 and 8-12 times for one or two copies of the allele, respectively. This risk is reported to vary by demographic factors including sex, ethnicity and geography. In order to understand the risk of ApoE ε4 in relation to age, the primary risk factor for developing AD, we need to understand how the prevalence of APOE genotypes changes with age. Here, we present the first data on age-related prevalence of APOE ε4 in AD in three AD cohorts in Australia and the USA. There is a significant association between age and ε4 prevalence, particularly for ε4 homozygotes, such that as age increases the prevalence of ε4 decreases. Further studies on a random, population-based sample of the population are needed to provide more generalizable data, particularly in the >90-year-old age group.

Keywords: APOE; Alzheimer’s disease; Apolipoprotein E; Population demographics.

Fig. 1

Structure of human ApoE (Protein Data Bank 2L7B, Chen et al. 2011), with 10-kDa C-terminal shown in blue (a) and removed (b), and 22-kDa N-terminal separated by a flexible hinge region. The major lipid-binding region is shown in green, and the LDL receptor-binding region is shown in pink (b). The sites of isoform-specific cysteine-to-arginine amino acid substitution is shown in red at positions 112 and 158, such that ApoE2 (Cys112/Cys158), ApoE3 (Cys112/Arg158) and ApoE4 (Arg112/Arg158). Graphics were prepared using The PyMOL Molecular Graphics System, Version 1.7 Schrödinger, LLC

Fig. 2

APOE ε4 allele frequency by cognitive status (normal/MCI/ severe) for three Alzheimer’s disease cohorts. a the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. b the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL). c Uniform Data Set of the Alzheimer’s Disease Centers (UDS) program. Assignment of cognitive status was based on total MMSE score (normal 24–30, MCI 23–18, severe ≤17). Allele frequency (%) of ε4^+/+ carriers is indicated at the top of each bar. Total number of participants per group is indicated below the x-axis. MCI: mild cognitive impairment; MMSE: mini mental state exam

Fig. 3

APOE ε4 allele frequency by decade of life for three Alzheimer’s disease cohorts. a The Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. b the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL). c Uniform Data Set of the Alzheimer’s Disease Centers (UDS) program. Allele frequency (%) of ε4^+/+ carriers in indicated at the top of each bar. Total number of participants per decade of life is indicated below the x-axis