Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders

Abstract

The importance of apolipoprotein E (APOE) in late-onset Alzheimer's disease (LOAD) has been firmly established, but the mechanisms through which it exerts its pathogenic effects remain elusive. In addition, the sex-dependent effects of APOE on LOAD risk and endophenotypes have yet to be explained. In this Review, we revisit the different aspects of APOE involvement in neurodegeneration and neurological diseases, with particular attention to sex differences in the contribution of APOE to LOAD susceptibility. We discuss the role of APOE in a broader range of age-related neurodegenerative diseases, and summarize the biological factors linking APOE to sex hormones, drawing on supportive findings from rodent models to identify major mechanistic themes underlying the exacerbation of LOAD-associated neurodegeneration and pathology in the female brain. Additionally, we list sex-by-genotype interactions identified across neurodegenerative diseases, proposing APOE variants as a shared etiology for sex differences in the manifestation of these diseases. Finally, we present recent advancements in 'omics' technologies, which provide a new platform for more in-depth investigations of how dysregulation of this gene affects the development and progression of neurodegenerative diseases. Collectively, the evidence summarized in this Review highlights the interplay between APOE and sex as a key factor in the etiology of LOAD and other age-related neurodegenerative diseases. We emphasize the importance of careful examination of sex as a contributing factor in studying the underpinning genetics of neurodegenerative diseases in general, but particularly for LOAD.

Keywords: APOE; Alzheimer's disease; Gene-by-sex interaction; Late-onset; Neurodegenerative diseases; Sex effect.

Fig. 1.

APOE variants differentially affect its conformational properties and biological effects in the brain. (A) Diagram of APOE pre-mRNA, which consists of four exons to encode a 317-residue pre-APOE protein. An 18-residue signal peptide is co-translationally removed from pre-APOE (Lin-Lee et al., 1981; Zannis et al., 1984) to produce the mature 299-aa APOE, which consists of N-terminal and C-terminal arms connected by a hinge region (Wetterau et al., 1988). A receptor-binding domain (RBD) is located in the N-terminal arm (Wilson et al., 1991), while a lipid-binding domain (LBD) is located in the C-terminal arm (Weisgraber, 1990). Two single-nucleotide variants affect the aa sequence around the RBD – rs42958 (aa 112, C→R, ε4, 14% allele frequency) and rs7412 (aa 158, R→C, ε2, 7% allele frequency) (Bertram et al., 2007). These aa changes result in different APOE isoforms with altered functions. The schematic drawings of the three isoforms illustrate the shapes as described in B. (B) Table listing the effects of aa changes in the ε2 and ε4 isoforms of APOE relative to ε3, except where otherwise specified. aa, amino acids; BBB, blood-brain barrier; kb, kilobases; NMDAR, N-methyl-D-aspartate receptor.

Fig. 2.

Exacerbation of LOAD neurodegeneration and pathology by female sex and APOE ε4, and hypothesized mechanisms. (A) The healthy APOE ε3/ε3 brain benefits from neuroprotection conferred by sex hormones, with abundant mitochondria at synapses, intact myelin, intact NMDAR-mediated neuroplasticity and homeostatic microglia. (B) The male LOAD brain exhibits degeneration, neuropathology, reduced mitochondria and pro-inflammatory signature in microglia, in part due to the gradual loss of sex hormones during andropause. (C) With fluctuations and declines in sex hormones at peri- and post-menopause, in addition to reduced estrogen sensitivity, the female LOAD brain exhibits more severe atrophy and neuropathology, loss of mitochondria and myelin abnormalities. (D) APOE ε4 is associated with defective estrogen signaling and a delay in menopause, which may lengthen the perimenopausal transition period of intense estrogen level fluctuations. Therefore, the female APOE ε4-positive LOAD brain exhibits the most severe atrophy and neuropathology, disruption of the myelin sheath, mitochondrial deficits, impairments in neuroplasticity and increased activation of AP-1, which drives APP expression and, consequently, Aβ deposition. LDLR, low-density lipoprotein receptor; LRP1, LDLR-related protein 1; NMDAR, N-methyl-D-aspartate receptor.