Alzheimer’s is a complex neurodegenerative disease, and although many cases are not due to a single genetic cause, evidence suggests that genes play a significant role in its risk and development. Below, I review the main genetic pathways involved, recent evidence, and current challenges.
Inheritance and genetic risk estimates
- Twin and family studies have estimated that the heritability of Alzheimer’s disease (i.e., the proportion of variation attributable to genetic factors) could be around 70% in some populations. ( The Lancet )
- However, this estimate varies: genetics doesn’t explain everything, and environmental factors, lifestyle, and other epigenetic modulators also play a role.
Types of genes involved
We can group the genes related to Alzheimer’s into two large categories:
- Deterministic genes (or direct cause, although rare)
- Risk genes (variants that increase the likelihood of developing the disease, but do not guarantee it)
Deterministic genes (direct cause)
They are very rare, but when present they usually cause early-onset hereditary forms of Alzheimer’s (before age 65).
The best known are:
- APP (amyloid precursor protein)
- PSEN1 (Presenilin 1)
- PSEN2 (Presenilina 2)
Mutations in these genes disrupt the processing of β-amyloid protein, promoting its accumulation in the brain. ( PMC )
A historical example is the “Swedish mutation” in the APP gene , identified in families with familial Alzheimer’s. ( Wikipedia )
Although these cases are very valuable for research (because they allow us to understand biological mechanisms), they constitute a tiny fraction of all Alzheimer’s cases.
Risk genes
Most cases of Alzheimer’s (especially late-onset Alzheimer’s, after age 65) are associated with genetic variants that are not deterministic, but rather increase risk.
APOE
The most studied gene is APOE (apolipoprotein E). It has several allelic variants: ε2, ε3, and ε4. ( Mayo Clinic )
- The ε4 variant is the one that confers the greatest risk: Having one copy of APOE-ε4 can double or triple the risk of late-onset Alzheimer’s, and having two copies increases it even more. ( Mayo Clinic )
- However, not all ε4 carriers develop Alzheimer’s, and many people with Alzheimer’s do not have this variant. This indicates that the presence of APOE-ε4 alone is neither sufficient nor necessary. ( Mayo Clinic )
- Recently, a study suggested that people with two copies of APOE ε4 have a very high likelihood of developing Alzheimer’s disease over time, leading some authors to consider it almost a “more direct” genetic form in certain cases. ( National Institutes of Health (NIH) )
- Additionally, some research has found that diets such as the Mediterranean diet may partially mitigate the risk in people with APOE-ε4. ( massgeneralbrigham.org )
Other variants discovered by genomic studies (GWAS)
With the advancement of genome-wide association studies (GWAS), dozens of loci that modestly increase the risk of Alzheimer’s have been identified. ( ScienceDirect )
Some examples:
- CLU, CR1, PICALM, TREM2, ABCA7, SORL1
- These variants tend to be involved in β-amyloid clearance, lipid metabolism, immune response/neuroinflammation, and cellular transport. ( Nature )
- A recent study identified 54 significant gene clusters that grouped pathways involving amyloid/tau, lipids, immunity, and endocytosis. ( Nature )
A recent article titled “The Spectrum of Genetic Risk in Alzheimer’s Disease” reviews the current landscape of these risk variants. ( PMC )
Gene-environment interaction and modifying factors
A key point is that genetic variants interact with environmental factors, lifestyle habits, and other modulators. There is no genetic “mandate” that ensures Alzheimer’s (except in the few deterministic cases), but rather a “predisposed environment.”
Some relevant aspects:
- The outcome of carrying a risk variant may depend on other genes, epigenetic factors, environmental exposure, diet, exercise, vascular comorbidities, etc.
- For example, as I mentioned, there is evidence that a Mediterranean-style diet might buffer risk even in APOE-ε4 carriers. ( massgeneralbrigham.org )
- Protective genetic variants have also begun to be explored. For example, Columbia researchers described a genetic variant that reduces the likelihood of Alzheimer’s by up to 70% . ( cuimc.columbia.edu )
In addition, a recent review titled “Alzheimer’s Disease: An Updated Overview of Its Genetics” examines the latest findings on the genes involved and their possible mechanisms. ( PMC )
Another recent clinically useful study evaluated Mendelian genes and risk genes and made recommendations for genetic screening in clinical settings. ( ScienceDirect )
Implications for diagnosis, prevention and treatment
The genetics of Alzheimer’s are not only interesting from a scientific point of view, but also have practical implications:
- Knowing the risk variants can help estimate individual predisposition and guide early intervention strategies (although it is not yet widely used as a clinical tool).
- In clinical research, genetic stratification allows for the design of more precise drug trials (e.g., enrolling APOE-ε4 carriers).
- In the future, therapies targeting specific genes, epigenetic intervention, or gene editing could be options.
- However, there are ethical and practical challenges: screening for genetic risks can cause anxiety, have implications for insurance or employment, and there is still no guarantee of curative intervention.
Limits, challenges and recent findings
- Although many risk genes have been discovered, their individual effects are small; the current challenge is understanding how they combine with each other and with non-genetic factors.
- There is something called “genetic dark matter”: rare or infrequent variants that have not yet been properly catalogued.
- Most studies have been conducted in populations of European descent; applicability to other populations may vary.
- A recent study found that a risk variant for Alzheimer’s is primarily associated with people of African descent, underscoring the need for more diverse genetic studies. ( Stanford Medicine )
- Another recent finding suggests that a gene implicated in Alzheimer’s (APOE ε4) may also increase the risk for other neurodegenerative disorders, through mechanisms of chronic inflammation. ( Nature )
- Some recent studies suggest that carriers with two copies of APOE ε4 may have a more “genetic” or predictable form of Alzheimer’s, which could reframe disease categories. ( The Guardian )
Date 09/29/25
Photo: Pixabay
Note: The Nutrigenomics Institute is not responsible for the opinions expressed in this article.
