AD is influenced by genetics, but there are many details that add context to that. Although relatively rare, early-onset AD affects patients younger than age 65, including some individuals as young as in their late 30s or early 40s. In approximately 1% or fewer of AD cases, a genetic mutation in the PSEN1, PSEN2, or APP gene directly causes the disease, often with a very early age of onset and a familial pattern. There may be additional causal mutations for early-onset AD that have not been identified yet. For most AD cases, however, genetic factors do not directly cause the disease but may increase or decrease the risk of developing it, alongside influences from environmental and lifestyle factors.

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The strongest known genetic risk factor for sporadic (ie, not familial) AD is the APOEɛ4 (APOE4) allele. If someone has 1 copy of the APOE4 allele, their risk of developing AD is 2 to 4 times higher, and having 2 copies of the APOE4 allele increases their risk by more than 10 times compared with having 2 copies of the APOEε3 allele. However, the APOE4 allele alone is not necessary or sufficient to cause AD or cognitive impairment more generally. In fact, some individuals can have 2 copies of the APOE4 allele and remain cognitively intact throughout the course of their lives. Conversely, patients can develop AD without having an APOE4 allele.

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Currently, we do not recommend testing for APOE alleles as part of the diagnostic process, since the presence or absence of APOE4 does not meaningfully indicate whether a given patient has AD vs another cause of cognitive impairment. We also do not recommend APOE testing for future risk stratification in asymptomatic individuals, primarily because the results would not alter clinical management at this time. Familiar lifestyle and other approaches to promote brain health are applicable regardless of someone’s APOE status. We now test for APOE allele status when anti-amyloid therapies are being considered for early AD because the presence of APOE4 is associated with a higher risk of side effects (known as amyloid-related imaging abnormalities, or ARIA) with those therapies.

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Beyond APOE4, studies have compared the genetic profiles of large numbers of individuals diagnosed clinically with probable AD against those without a cognitive diagnosis. These studies have identified additional genetic factors associated with AD risk, typically with fairly modest effect sizes in isolation. An increasing number of genetic variants is being discovered through research, and ongoing work is evaluating how to combine the collective effects of these variants into polygenic risk scores. I can envision a future in which knowing a person’s overall genetic risk for developing AD could potentially help guide the use of medication to prevent or delay AD development or help guide entry into a clinical trial. However, there are many steps of further research required to get to that point.