The Spectrum of Genetic Risk in Alzheimer Disease

Abstract

Alzheimer disease (AD), the most common dementing syndrome in the United States, is currently established by the presence of amyloid-β and tau protein biomarkers in the setting of clinical cognitive impairment. These straightforward diagnostic parameters belie an immense complexity of genetic architecture underlying risk and presentation in AD. In this review, we provide a focused overview of the current state of AD genetics. We discuss the discovery of familial autosomal dominant genes, the identification of candidate genes associated with AD, and genetic variants conferring higher risk of developing AD compared with the general population. In particular, we discuss important features of AD risk due to the APOE ε4 allele. In addition to risk, we describe how the field has made headway understanding genetic factors that may protect from AD. The biological implications and practical limitations of information gleaned from genome-wide association studies in AD over the years are also discussed. The readers will have an up-to-date understanding of where we are in our efforts to understand the layers of genetic complexity in AD.

Figure. Schematic of Interrelated Biological Pathways and Their Comprising Genes in the Context of AD Pathogenesis (in eReferences e87 and e122)

Known processes contributing to AD pathogenesis are represented with red arrows and boxes. Pathologic processes that may exacerbate AD pathogenesis but that are also associated with aging more generally are shown in boxes with gray background. Potential relationships between pathways that are relatively less well understood and may provide new avenues into understanding the genetics of AD risk are shown as dashed arrows. Created in BioRender. Jayadev, S. (2024) BioRender.com/q00h227. AD = Alzheimer disease.