Alison Goate, DPhil, on the Genetics of Alzheimer Disease

Genetics is one of the most important risk factors of Alzheimer disease (AD). Our understanding of the key genes associated with Alzheimer disease has advanced over the years, and it is important to continue learning about how genes influence disease.

The genetics of AD is one topic of discussion during the Presidential Session at the 144th Annual Meeting of the American Neurological Association (ANA) in October 2019.1 Speaker Alison Goate, DPhil, answered our questions about this important topic.

Alison Goate, DPhil, is the Willard T.C. Johnson Research Professor of Neurogenetics and director of the Ronald M. Loeb Center for Alzheimer’s disease at the Icahn School of Medicine at Mt. Sinai in New York, New York.

NEUROLOGY CONSULTANT: What genetics underlie inherited and late-onset AD?

Alison Goate: The rare monogenic form of AD is usually associated with a dominant inheritance pattern and early age at onset (generally 30 to 60 years). It can be caused by mutations in one of 3 genes: ß-amyloid precursor protein, presenilin 1, or presenilin 2. Approximately 80% of cases with this form of disease have a mutation in presenilin 1. Approximately 2% of late-onset AD families can also carry a mutation in one of these genes. Sporadic early-onset AD can also result from a de novo mutation in one of these genes.

The vast majority of AD cases are multifactorial—result of both genetic and environmental factors. For most of these cases, the genetic component may be highly polygenic. The most common risk factor in this category is apolipoprotein E (APOE). There are 3 APOE alleles: E3 (the most common), E4, and E2. The APOE-e4 allele shows a dose-dependent effect on risk and age at onset. Each APOE-e4 allele is associated with a 3-fold increased risk and an earlier age at onset, while the APOE-e2 allele shows a dose-dependent decreased risk and delayed onset.

Beyond APOE, there are more than 40 other regions of the genome that are associated with AD risk, each contributing a small amount to an individual’s risk. Although we do not know the specific genes for much of this risk, we do know that many of these regions contain genes that are expressed in microglia, and likely affect efferocytosis, clearance of lipid rich debris. A polygenic risk score can be calculated to express an individual’s overall risk of developing AD. This score is largely driven by APOE genotype but, in individuals with an APOE 33 genotype, can provide additional information about risk.

Polygenic risk scores (PRS) have similar predictive value in sporadic AD with onset at younger than 60 years and older than 60 years, suggesting that the overall genetic architecture of sporadic AD is similar across the age spectrum. Indeed, APOE genotype is the strongest predictor of risk in any age group and has been shown to influence age at onset even in families carrying mutations in amyloid precursor protein or the presenilins.

NEURO CON: What advances have been made in the detection of genetic biomarkers?

AG: As noted previously, sporadic and familial late-onset AD is highly polygenic. Using modern genomic approaches, such as genome-wide single nucleotide polymorphism arrays and whole genome sequencing, we have made substantial progress in identifying both common variants and rare variants that contribute to disease risk. In particular, the rare variants have pin-pointed genes that play a role in microglial response to damage in the brain, including that caused by Aß aggregation.

The most well-studied of these genes is TREM2, a protein expressed on the cell surface of microglia that is required for microglial response to damage. Mutations in TREM2 that reduce TREM2 activity, lead to an increase in risk of AD, suggesting that the microglial response is beneficial, at least at early stages of the disease.

Although we have known about APOE as a risk factor since 1993, we have only recently discovered that APOE is not only expressed in astrocytes but also in microglia activated by cellular damage. This links APOE and TREM2 to the same biological processes. Based on these genetic studies implicating microglial function, many laboratories are now seeking to develop novel therapeutics that target modulation of the innate immune system using both small molecules and biologics.

NEURO CON: What are the key take-home messages from your session?

AG: AD genetics is complex, but similar underlying processes are occurring regardless of the age at onset or the pattern of inheritance—the clinical and pathological pictures are largely similar, and the impact of individual genes spans both early- and late-onset disease. Genes identified in both early- and late-onset forms of the disease implicate Aß metabolism as a key component. Variants in many genes implicate activation of microglia in AD, particularly in the process of efferocytosis—clearance of lipid rich debris. Lastly, genetics has and will identify many new potential therapeutic targets, allowing drug discovery to move beyond amyloid and τ.

For more information about the ANA’s Annual Meeting or to read more about Dr Goate’s session, visit the ANA’s website:


  1. Goate A. Genetics of Alzheimer’s disease: similarities and differences between dominantly inherited and late onset Alzheimer’s disease. Talk will be presented at: ANA 2019; October 13-15, 2019: St. Louis, MO.