Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by extracellular amyloid β (Aβ) and intraneuronal tau protein aggregations. One risk factor for developing AD is the APOE gene coding for the apolipoprotein E protein (apoE). Humans have three versions of APOE gene: ε2, ε3, and ε4 allele. Carrying the ε4 allele is an AD risk factor while carrying the ε2 allele is protective. ApoE is a component of lipoprotein particles in the plasma at the periphery, as well as in the cerebrospinal fluid (CSF) and in the interstitial fluid (ISF) of brain parenchyma in the central nervous system (CNS). ApoE is a major lipid transporter that plays a pivotal role in the development, maintenance, and repair of the CNS, and that regulates multiple important signaling pathways. This review will focus on the critical role of apoE in AD pathogenesis and some of the currently apoE-based therapeutics developed in the treatment of AD.
Highlights
Reviewed by: Leon Maing Tai, University of Illinois at Chicago, United States Muthuswamy Anusuyadevi, Bharathidasan University, India
Polymorphism in the apolipoprotein E (APOE) gene is a major risk for developing late onset Alzheimer disease (LOAD), whose symptoms are more frequently appearing after the age of 65 years (Yamazaki et al, 2019)
APOE2 homozygotes have a 66% reduction in Alzheimer’s disease (AD) risk compared to ε2/ε3 carriers, an 87% reduction in AD risk compared to APOE3 homozygotes, and a 99.6% reduction in AD risk when compared to APOE4 homozygotes (Reiman et al, 2020)
Summary
All species have one version of APOE gene while humans have three versions: APOE-ε2 (APOE2), APOE-ε3 (APOE3), and APOE-ε4 (APOE4) allele (McIntosh et al, 2012). In non-human mammals, APOE genotype is (Thr61/Arg112/Arg158) while all human APOE alleles have an Arginine in position 61 (Arg). In non-human mammals, APOE genotype is (Thr61/Arg112/Arg158) while all human APOE alleles have an Arginine in position 61 (Arg61) Combinations of these specific amino acids modify the protein structure and functions. The world-wide frequency of human APOE alleles varies considerably (Figure 1). APOE3 is the most common among all human populations and its frequency ranges from 85% (Asia) to 69% (Africa) (Singh et al, 2006). APOE4 allele frequency varies considerably in native populations of Central Africa (40%), Oceania (37%), and Australia (26%) (Corbo and Scacchi, 1999). APOE2 is the least common allele with a global prevalence of 7.3% and is absent in many indigenous people without any clear regional pattern (Corbo and Scacchi, 1999; Singh et al, 2006)
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