A Quarter Century of APOE and Alzheimer's Disease: Progress to Date and the Path Forward

Abstract

Alzheimer's disease (AD) is considered a polygenic disorder. This view is clouded, however, by lingering uncertainty over how to treat the quasi "monogenic" role of apolipoprotein E (APOE). The APOE4 allele is not only the strongest genetic risk factor for AD, it also affects risk for cardiovascular disease, stroke, and other neurodegenerative disorders. This review, based mostly on data from human studies, ranges across a variety of APOE-related pathologies, touching on evolutionary genetics and risk mitigation by ethnicity and sex. The authors also address one of the most fundamental question pertaining to APOE4 and AD: does APOE4 increase AD risk via a loss or gain of function? The answer will be of the utmost importance in guiding future research in AD.

Keywords: AD; APOE; ASO; Alzheimer’s disease; Apolipoprotein E; anti-sense oligonucleotide; cardiovascular disease; ethnicity; evolutionary genetics; gene-based therapy; neurodegenerative disease; pleiotropy; sex.

Figure 1.. APOE isoforms, allele frequencies, and protein structures.

A) The three main APOE isoforms APOE2, APOE3, and APOE4, respectively encoded by the Apolipoprotein E2, E3, and E4 alleles, are the result of non-synonymous polymorphisms that cause amino acid changes at position 112 and 158 of the APOE protein (Rall et al., 1982; Weisgraber et al., 1981). APOE3 is the most common variant in the general population. The APOE4 variant is a major genetic risk factor for AD, while APOE2 is protective (Farrer et al., 1997). B) Structural models of lipid-free APOE are shown for each major isoform, based on X-ray crystallography, structure prediction, and circular dichroism spectroscopy (Zhong and Weisgraber, 2009). The N-terminal domain contains APOE’s low-density lipoprotein receptor (LDLR) region at amino acid residues 134 to 150, while the C-terminal holds the lipid-binding region at residues 244 to 272. Amino acid substitutions in APOE4 promote a salt-bridge between Arg61 and Glu255, which, compared to the APOE2 and APOE3 variants, drives increased domain interaction between the N- and C-terminal domains. In figure panel A, APOE allele frequencies are obtained, with permission, from American Medical Association © Farrer, L. et al. JAMA. 278, 1349–1356 (1997). Figure panel B is a reprint, with permission, from Annual Reviews © Yu, J. et al. Annu. Rev. Neurosci. 37, 79–100 (2014).

Figure 2.. APOE4 drives amyloid accumulation.

Binding of Pittsburgh Compound-B (PIB) reflects cerebral amyloid accumulation. Graph displays, per age group and stratified by presence of APOE4 allele (number of subjects indicated at bottom of bars), frequency of PIB-positive subjects in a cohort of cognitively normal individuals. APOE4 carriers more frequently display amyloid accumulation, an effect that becomes more pronounced with age. Figure is adapted, with permission, from John Wiley and Sons © Morris, J. C. et al. Ann. Neurol. 67, 122–131 (2010).

Figure 3.. APOE is a pleiotropic gene.

The table illustrates the relationship between the three major APOE genotypes and their association with various diseases and pathologies. Position on the matrix, from left to right, indicates the strength of association, while color marks the APOE genotype relationship. Abbreviations: AD, Alzheimer’s Disease; DLB, Dementia with Lewy Bodies; FTLD, Frontotemporal Lobar Degeneration; ALS, Amyotrophic Lateral Sclerosis; PD, Parkinson’s Disease; MSA, Multiple Systems Atrophy; MS, Multiple Sclerosis; FH III, familial hypolipoproteinemia type III; TG, Triglycerides; CAD, Coronary Artery Disease; T-C; Total Cholesterol; MI, Myocardial Infarction; CAA, Cerebral Amyloid Angiopathy; HS, Hemorrhagic Stroke; IS, Ischemic Stroke; VAD, Vascular Dementia.

Figure 4.. Parametric associations of APOE alleles with Alzheimer’s disease, cardiovascular traits, and cerebrovascular pathology.

Across all six combination of APOE alleles, clear parametric decreases can be observed for plasma APOE levels (A) and increases for low density lipoprotein cholesterol (LDL-C) levels [mean ± standard error of mean (SEM)] (B), while triglyceride (TG) levels are marked by a U-shape (geometric mean ± SEM) (C), indicating risk for hypertriglyceridemia in APOE2 and APOE4 carriers (Rasmussen, 2016). The parametric association of APOE genotypes with lipid traits is also reflected in the association with risk, indicated by the odds ratio (OR ± SE), for AD (Caucasians, pathology-confirmed; Farrer et al., 1997) (D) and Myocardial Infarction (MI) (Wang et al., 2015) (E). While the APOE-related risk for AD follows APOE2 > APOE3 > APOE4, cerebral amyloid angiopathy (CAA) and related risk for intracerebral lobar hemorrhage display a U-shape (% probability of cases versus controls; median ± min/max) (F), indicating increased risk for both APOE2 and APOE4 carriers (Biffi et al., 2010). In panels C, D, and F, the position of the APOE (2/4) genotype is shifted to better indicate the combined effect of the two detrimental APOE alleles. Figure panel A is a graphical representation, and B&C are adaptations, with permission, from Elsevier © Rasmussen, K. Atherosceloris. 255, 145–155 (2016). Figure panel D is a visual adaptation of data, with permission, from American Medical Association © Farrer, L. et al. JAMA. 278, 1349–1356 (1997). Figure panel E is a visual adaptation of data, under CC BY, from Wang, Y. et al. FEBS open bio. 5, 852–858 (2015). Figure panel F is a visual adaptation, with permission, from John Wiley and Sons © Biffi, A. et al. Ann. Neurol. 68, 934–943 (2010).

Figure 5.. Geographical differences in APOE4 frequency and ethnic risk mitigation.

A) Worldwide APOE4 allele frequency (For methods and references, see Supplementary text). B) APOE-related risk for Alzheimer’s disease (clinically defined) across all six APOE genotypes, for Caucasians (left), African-Americans (second from left), Hispanics (second from right), and Japanese (right) patient groups (Farrer et al., 1997). Figure panel B is a visual adaptation of data, with permission, from American Medical Association © Farrer, L. et al. JAMA. 278, 1349–1356 (1997).

Figure 6.. Sex interacts with APOE to affect risk of Alzheimer’s disease, clinical decline and biomarker levels

A) Risk for Alzheimer’s disease based on APOE genotype, stratified by male and female sex (Farrer et al., 1997). B) Risk of clinical decline, defined as conversion from healthy controls to mild cognitive impairment (MCI) or Alzheimer’s disease (AD), across the age range, stratified by sex. Inset shows the hazard ratio for conversion as determined for each sex independently, marking higher risk in women (Altmann et al., 2014). * p<0.05; *** p<0.001. C) In MCI patients, the APOE4 allele’s effect on increasing tau levels was significantly greater in women than in men. [Analysis was adjusted for age and education; blue squares correspond to men and red circles to women]. Panels display levels of CSF Abeta (left) and tau (right). ** p<0.01. Figure panel A is a reprint, with permission, from American Medical Association © Farrer, L. et al. JAMA. 278, 1349–1356 (1997). Figure panel B&C are reprints, with permission, from John Wiley and Sons © Altmann, A. et al. Ann. Neurol. 75, 563–573 (2014).