Alzheimer Disease: Genetic and Environmental Influences

Abstract

Abstract Alzheimer disease (AD) is a complex, progressive neurodegenerative disease. Prevalence of AD is expected to grow substantially, although predictions may shift given future treatment interventions or higher levels of engagement in lifestyle delaying factors that may reduce risk. Several mutations have been characterised and susceptibility genes implicated as playing a role in the disorder. The apolipoprotein E (APOE) ε4 allele remains the best‐established susceptibility gene for late‐onset AD. Although a substantial proportion of the liability for AD may be accounted for by genetic factors, heterogeneity or differences in aetiology are important to consider. Environmental factors probably play a significant role, such as education, head injury and nonsteroidal anti‐inflammatory drugs (NSAIDs) use, as well as obesity, diabetes, physical activity and cognitively engaging leisure activities. The extent to which susceptibility genes interact with environmental factors may provide further clues to aetiology. Lastly, a developmental longitudinal perspective on the salience of particular risk and protective factors across the life course may illuminate etiologies and potential points of intervention. Key Concepts: The prevalence of Alzheimer disease (AD) will continue to rise globally, quadrupling by 2050. The aetiology of AD is multifactorial. Early‐onset Alzheimer disease (AD) is caused by rare mutations in three genes: APP, PSEN1 and PSEN2 . Late‐onset AD is complex whereby the genetic contribution to the liability for AD may be as high as 79%. The APOE ɛ4 allele increases the risk for late‐onset Alzheimer disease. Genome‐wide gene association studies (GWAS) were instrumental in identifying new susceptibility genes for late‐onset AD beyond the APOE and SORL1 candidates, including: ABCA7 , BIN1 , CD33 , CD2AP , CLU , CR1 , EPHA1 , MS4A4E/MS4A6A and PICALM . Risk and protective factors appear to play a role in AD risk, such as education, head injury, physical activity, cognitively engaging leisure activities and NSAIDs use.