The Genetics of Alzheimer’s Disease

Scientist Explains Dr. Ekaterina Rogaeva

Is Alzheimer’s disease hereditary, and how does family history affect risk?

Alzheimer’s disease is the most common type of dementia, making up about 75% of all cases. It happens when certain proteins—called Aβ-peptides and tau—build up in the brain and cause damage.

There are two main types of Alzheimer’s:

1. Early-onset Alzheimer’s disease: This type starts before age 65 and affects about 1 in 10 people with Alzheimer’s. It is strongly linked to genes passed down in families. In fact, heritability is estimated to be between 92% and 100%, and about 60% of people with early-onset Alzheimer’s have a close family member (a first-degree relative) who also had the disease. Genes play a big role in early-onset Alzheimer’s, but not all causes are known yet. Fewer than 20% of these cases are caused by known gene mutations, so researchers are still looking for other genetic factors.
2. Late-onset Alzheimer’s disease: This more common type usually begins after age 65. It also tends to run in families, but it is caused by many small risk genetic changes working together. About 70% to 80% of the risk for late-onset Alzheimer’s is believed to come from genes [1].

So yes—Alzheimer’s can be hereditary. Having a family history can increase your risk, but other things like age, lifestyle, and environment also play an important role.

What genes are linked to Alzheimer’s disease?

Genes are segments of DNA that act like instructions, telling our cells how to grow, function, and stay healthy. We inherit these instructions from our parents, and sometimes small changes in certain genes can affect our risk for certain diseases, including Alzheimer’s.

Some cases of early-onset Alzheimer’s are caused by inherited changes (called mutations) in three genes:

• APP (Amyloid Precursor Protein)
• PSEN1 (Presenilin 1)
• PSEN2 (Presenilin 2)

These gene mutations follow an autosomal dominant pattern. This means a person only needs to inherit one copy of the changed gene from one parent to be at high risk of developing the disease during aging. Over 500 different mutations in these genes have been found. PSEN1 mutations are the most common and often cause symptoms as early as a person’s 30s. PSEN2 mutations are rare.

All three genes are involved in how the brain makes something called Aβ-peptides. When too much Aβ builds up, it can form sticky clumps called amyloid plaques that damage brain cells. These plaques are the earliest feature of Alzheimer’s brain pathology. Interestingly, a rare version of the APP gene (one of the three genes linked to early-onset disease) found in Iceland helps protect against Alzheimer’s by lowering Aβ levels by about 40% [1].

Even people with the same gene mutation can have different experiences with the disease. This may be due to other genetic factors. For example, a gene called APOE has a version known as APOE4 that increases the risk of late-onset Alzheimer’s disease. APOE4 may also lead to symptoms appearing earlier. On the other hand, the rare versions of APOE (APOE2 or APOE with a specific mutation called Arg136Ser) may help protect the brain—even in people who already have high levels of the Aβ sticky protein [1].

Sometimes, genes are linked to both early- and late-onset Alzheimer’s disease. For example, the changes in a gene called SORL1 can slightly increase the risk of late-onset disease in some people, while rare harmful versions of the gene can lead to early-onset disease in families [2].

Researchers around the world are studying both rare and common gene changes to better understand Alzheimer’s disease. So far, they have found 75 regions of the genome—which is the complete set of a person’s genetic material—linked to late-onset Alzheimer’s disease [3]. These discoveries have helped develop a tool called the Polygenic Risk Score (PRS), which adds up many small genetic risks to estimate a person’s overall chance of developing Alzheimer’s. In some groups, PRS can correctly identify people with the disease up to 84% of the time, making it a promising tool for research and future diagnosis [4].

Can genetic testing predict or prevent Alzheimer’s disease?

Genetic testing is being used to help diagnose Alzheimer's disease and find possible treatments. For example, the Dominantly Inherited Alzheimer Network (DIAN) is a long-term study with people who have specific genetic mutations (in the APP, PSEN1, or PSEN2 genes). The study is testing treatments aimed at reducing Aβ levels, one of the proteins linked to Alzheimer’s.

While most cases of Alzheimer’s have complex or unknown genetic causes, studies like DIAN help researchers understand how genes, lifestyle, and other factors contribute to the disease. For example, in one large family with the PSEN2 mutation, one person did not show symptoms of Alzheimer’s for 18 years despite high levels of amyloid plaques in the brain. This person likely has protective genetic or lifestyle factors that may have helped delay the disease [5].

However, genetic testing can be challenging. Even when new mutations are found, it is hard to predict exactly when or if Alzheimer’s will develop. The age at which Alzheimer’s begins can vary greatly, even among individuals with the same genetic makeup, such as in identical twins or triplets. This shows that other factors, beyond just genetics, can influence the disease [6].

How is research advancing our understanding of genetics and Alzheimer’s disease?

Alzheimer’s disease is a complex condition that starts many years before symptoms appear. Researchers are using genetic data to improve how we diagnose the disease and find ways to prevent it. Advances in technology over the past decade have helped us better understand the genetic causes of Alzheimer’s, which could lead to more personalized treatments in the future [7].

While we have learned a lot about early-onset Alzheimer’s disease, more work is needed to understand the genetic causes of late-onset Alzheimer’s disease, and to find better ways to diagnose and treat it. Some missing genetic information may be linked to rare types of mutations, which scientists are still studying. To move forward, research needs to look at all types of genetic changes and consider differences in sex, ancestry, and other factors [8].

Looking ahead, TDRA is focused on improving our understanding of the genetics of dementia and how to better treat people by combining lab research with real-world care.

References:

1. Reitz C, Rogaeva E, Beecham GW. Late-onset vs nonmendelian early-onset Alzheimer disease: A distinction without a difference? Neurol Genet. 2020 Oct 6;6(5):e512. PMID: 33225065.
2. Rogaeva E, Meng Y, Lee JH, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007 Feb;39(2):168-77. PMID: 17220890.
3. Guo MH, Lee WP, Vardarajan B, et al. Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer's disease. Nat Commun. 2025 Jan 28;16(1):1126. PMID: 39875385.
4. Zhang M, Dilliott AA, Khallaf R, et al. Genetic and epigenetic study of an Alzheimer's disease family with monozygotic triplets. Brain. 2019 Nov 1;142(11):3375-3381. PMID: 31580390.
5. Llibre-Guerra JJ, Fernandez MV, Joseph-Mathurin N, et al. Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia. Nat Med. 2025 Feb 10; Epub 2025 Feb 10, PMID: 39930140.
6. Pottier C, Hannequin D, Coutant S, et al. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry. 2012 Sep;17(9):875-9. PMID: 22472873.
7. Guo MH, Lee WP, Vardarajan B, et al. Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer's disease. Nat Commun. 2025 Jan 28;16(1):1126. PMID: 39875385.
8. Reitz C, Rogaeva E, Beecham GW. Late-onset vs nonmendelian early-onset Alzheimer disease: A distinction without a difference? Neurol Genet. 2020 Oct 6;6(5):e512. PMID: 33225065.