Genetics of Alzheimer Disease

This article discusses the spectrum of genetic risk in familial and sporadic forms of early- and late-onset Alzheimer disease (AD). Recent work illuminating the complex genetic architecture of AD is discussed in the context of high and low risk and what is known in different populations.

A small proportion of AD is autosomal dominant familial AD caused by variants in PSEN1, PSEN2, or APP, although more recently described rare genetic changes can also increase risk substantially over the general population, with odds ratios estimated at 2 to 4. APOE remains the strongest genetic risk factor for late-onset AD, and understanding the biology of APOE has yielded mechanistic insights and leads for therapeutic interventions. Genome-wide studies enabled by rapidly developing technologic advances in sequencing have identified numerous risk factors that have a low impact on risk but are widely shared throughout the population and involve a repertoire of cell pathways, again shining light on potential paths to intervention. Population studies aimed at defining and stratifying genetic AD risk have been informative, although they are not yet widely applicable clinically because the studies were not performed in people with diverse ancestry and ethnicity and thus population-wide data are lacking.

The value of genetic information to practitioners in the clinic is distinct from information sought by researchers looking to identify novel therapeutic targets. It is possible to envision a future in which genetic stratification joins other biomarkers to facilitate therapeutic choices and inform prognosis. Genetics already has transformed our understanding of AD pathogenesis and will, no doubt, continue to reveal the complexity of brain biology in health and disease.