In recent years, researchers have made major strides in understanding the relationship between genetics and Alzheimer’s disease. Jagan Pillai, MD, PhD is the Director of the Lou Ruvo Center for Brain Health, Director of the Cleveland Alzheimer’s Disease Research Center, and the The Iversen Family Endowed Chair in Alzheimer’s Disease Research. He helped us make sense of this complicated scientific subject.
Read the interview with Dr. Pillai below.
WAM: Can you explain the current understanding of how genetics contributes to Alzheimer’s disease and other forms of dementia?
Dr. Pillai: Genetics plays a significant role in Alzheimer’s disease (AD). Genetic mutations in APP, PSEN1, and PSEN2 genes are known to cause rare young-onset familial forms of AD where multiple members of the family develop the disease. The APOE ε4 gene is another genetic risk factor for late-onset AD. In this case, the gene increases the risk but those with the risk gene do not always get AD in their lifetimes. There are many other genes that contribute smaller effects, often through inflammation, lipid metabolism, or immune function. Frontotemporal dementia also has strong genetic links, while other dementias like Lewy body dementia are also related to genetic factors.
WAM: What is the significance of the APOE gene, particularly the APOE4 variant, in Alzheimer’s disease risk? Will someone with the APOE4 variant definitely develop Alzheimer’s disease? Are there other genes associated with Alzheimer’s risk?
Dr. Pillai: The APOE4 gene one is the most common risk factor genes for AD. About 25% of people carry one copy of APOE ε4, and 2-3% carry two copies. The risk of developing mild cognitive impairment or dementia by age 85 years is approximately 10-15% for APOE ε4 noncarriers, 20-25% for those with one copy of APOE ε4, and 30-55% for those with two copies of APOE ε4. However, many APOE ε4 carriers never develop AD. Ethnicity, race, age, sex, protective genetic variants, and other factors have the potential to modify the effect of APOE ε4 on AD. Many other genes like ABCA7, CLU, and PICALM, also contribute smaller risks.
WAM: Are there any protective genetic variants that researchers have identified?
Dr. Pillai: Yes, there are some protective genetic variants that have been identified. A rare mutation in the APOE3 allele was found in a woman with a strong familial AD mutation who remained symptom-free for decades longer than expected. A mutation in the APP gene among Icelandic individuals appears to reduce the production of amyloid-beta, a key protein involved in AD, offering protection even into old age.
WAM: How do genetic factors interact with environmental and lifestyle factors
Dr. Pillai: For example, a high-risk gene like APOE ε4 may increase risk for AD, but healthy lifestyle choices such as regular exercise, a Mediterranean-style diet, good quality sleep, and strong social engagement, can delay or even prevent symptom onset in vulnerable individuals. Alternatively, poor lifestyle factors (e.g., smoking, hypertension, high cholesterol obesity, air pollution, or chronic stress) may amplify genetic risk of AD and other dementias.
WAM: Lots of people ask us at WAM about whether or not they should get tested for genetic risk of Alzheimer’s. What are the factors to consider before deciding to do it? What is the value in knowing you have a diagnosis for a disease that has no cure?
Dr. Pillai: Genetic tests are recommended in those individuals who have been diagnosed with young onset AD and have a family history of multiple immediate members in the family who have developed the disease for genes including APP, PSEN1, and PSEN2. In other cases, knowing your genetic risk (like carrying APOE ε4) doesn’t guarantee if a person will or will not get AD. However, knowing one is at higher risk can cause anxiety, and there’s currently no cure. For some, it is a motivation to pursue a healthier lifestyle. A genetic counselor can help assess whether testing is truly beneficial in the right context. However, choosing a healthy lifestyle to decrease the risk of AD does not need prior genetic testing results. It is a choice one makes knowing that genes alone don’t provide all the answers.
WAM: What genetic tests are currently available for Alzheimer’s risk assessment and what are their limitations?
Dr. Pillai: Currently, genetic tests for Alzheimer’s risk assessment include APOE genotyping and, in rare cases, testing for mutations in APP, PSEN1, and PSEN2 genes that were discussed before. APOE testing can estimate the risk of late-onset Alzheimer’s, but it cannot predict with certainty who will or won’t develop the disease. Limitations include no guaranteed prediction of AD after APOE genotyping, potential emotional distress, possible implications for insurance or privacy and may cause more anxiety for some individuals.