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. (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 134-150, while the C-terminal holds the lipid-binding region at residues 244-272. 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 (A), APOE allele frequencies are obtained, with permission, from American

Functional connectivity between the entorhinal and posterior cingulate cortices associated with navigation impairment following path integration in at-genetic-risk Alzheimer’s disease

“…The role of reduced EC -PCC functional connectivity in preclinical AD discovered here is not be surprising, as typically intracellular tau projects from the hippocampus and surrounding areas, to the PCC in the first stages of disease (Belloy et al, 2019;Jacobs et al, 2018). This spread is consistent with animal models that show in amyloid positive rodents, tau pathology propagation begins in the EC before spreading to the parietal cortex (Ahmed et al, 2014;Khan et al, 2013).…”

Human-lineage-specific genomic elements: relevance to neurodegenerative disease andAPOEtranscript usage

“…We noted that APOE was among the genes with the highest CNCR density across the genome and carried the highest CNCR density of all genes implicated in complex brain-relevant phenotypes (defined within the STOPGAP database 31 ). Given that genetic variation within this gene and specifically APOE-4 status is not only the principal genetic risk factor for Alzheimer's disease 48 but also associated with risk for other neurodegenerative disorders, stroke and reduced lifespan 36 , this finding provides evidence for the value of CNCR annotation. Furthermore, within APOE, the CNCR annotation highlighted an intron-3 retention event not currently within annotation but which has been previously reported 38,39 .…”

“…Given the high CNCR density of APOE, its importance as a disease locus for Alzheimer's disease and other neurodegenerative diseases 36 and the long-standing interest in the lineage specificity of APOE 8,37 (specifically the differences in the ɛ4 allele between humans and non-human primates 1 ), we chose to focus on this gene. We tested whether intragenic analysis of APOE could identify specific exons or transcripts of interest.…”

“Bridging the Gap” Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era

“…Several genetic contributors to the AD risk have been identified, including gene mutations, splice variants, or single nucleotide polymorphisms (SNPs) [149]. Among the strongest genetic factor involved in AD, the E4 allele of the Apolipoprotein E gene (APOE), has been deeply investigated and it is now widely recognized as the strongest genetic factor in determining AD risk in the common late-onset form [150]. Its involvement in other forms of dementia is now also emerging [151][152][153][154].…”