APOE Genotype and Alzheimer’s Disease: The Influence of Lifestyle and Environmental Factors

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder with obscure pathogenesis and no disease-modifying therapy to date. AD is multifactorial disease that develops from the complex interplay of genetic factors and environmental exposures. The E4 allele of the gene encoding apolipoprotein E (APOE) is the most common genetic risk factor for AD, whereas the E2 allele acts in a protective manner. A growing amount of epidemiological evidence suggests that several lifestyle habits and environmental factors may interact with APOE alleles to synergistically affect the risk of AD development. Among them, physical exercise, dietary habits including fat intake and ketogenic diet, higher education, traumatic brain injury, cigarette smoking, coffee consumption, alcohol intake, and exposure to pesticides and sunlight have gained increasing attention. Although the current evidence is inconsistent, it seems that younger APOE4 carriers in preclinical stages may benefit mostly from preventive lifestyle interventions, whereas older APOE4 noncarriers with dementia may show the most pronounced effects. The large discrepancies between the epidemiological studies may be attributed to differences in the sample sizes, the demographic characteristics of the participants, including age and sex, the methodological design, and potential related exposures and comorbidities as possible cofounding factors. In this Review, we aim to discuss available evidence of the prominent APOE genotype–environment interactions in regard to cognitive decline with a focus on AD, providing an overview of the current landscape in this field and suggesting future directions.

Alzheimer’s Disease Classification Using Cluster-based Labelling for Graph Neural Network on Heterogeneous Data

“…Cluster AD membership was associated with having 2 copies of APoE ε4 allele or had high tau level in the left fusiform cortex, consistent with genetic risk factor (e.g. Angelopoulou et al, 2021) and late-stage AD brain changes (e.g. Huang et al 2020, 2021), respectively.…”

“…First, the algorithm revealed that if there were 2 copies of the APoE ε4 allele, a known risk genetic factor (e.g. Angelopoulou et al, 2021), then 90% of the cases would belong to Cluster AD. We next apply the classifier on the remaining cases, and observed that if there was high tau level in the left fusiform cortex with no APoE ε4 allele, then the algorithm predicted about 94% of the data to again be in Cluster AD.…”

Psychosis in Parkinson’s Disease: A Lesson from Genetics

“…Apolipoprotein E (APOE) is a lipoprotein abundantly found in the brain, being implicated in several cellular processes including the metabolism and clearance of β-amyloid [ 88 ]. APOE gene has three alleles, named ε2, ε3 and ε4.…”

Increase in Mitochondrial D-Loop Region Methylation Levels in Mild Cognitive Impairment Individuals

“…Pathogenetic mutations in three genes, namely beta-amyloid precursor protein ( APP ), presenilin 1 ( PSEN1 ), and presenilin 2 ( PSEN2 ), which induce an overproduction of the Aβ peptide, cause an early-onset (before age 65) autosomal dominant familial inherited form of the disease, representing a small percentage (<1%) of AD cases [ 11 ]. The sporadic late-onset (onset after 65 years of age) form of AD, which accounts for the majority of AD cases, is likely due to the interaction of several genetic factors, with apolipoprotein E ε4 ( APOEε4 ) as the main genetic risk factor, and environmental factors, including brain injury, diabetes, cardiovascular disease, and exposure to various pollutants, and especially increasing age [ 12 ]. Although the exact etiology of sporadic AD is not well understood, several pieces of evidence indicate a pivotal role played by mitochondrial dysfunction, which has been suggested as the primum movens for the further development of the molecular alterations that characterize the disease, such as impaired apoptosis, disruption of calcium homeostasis, inflammation, oxidative stress, and deficient glucose metabolism, ultimately leading to neuronal death [ 13 ].…”