Alzheimer’s disease affects millions of people worldwide, and scientists have long known that genes play a role in who develops it. A large study led by researchers at Vrije Universiteit Amsterdam has identified several rare genetic variants that raise the risk, and the findings point to the biological processes that may drive the disease.
How genes and Alzheimer’s connect
Most people who develop Alzheimer’s have a mix of genetic and lifestyle risk factors rather than a single cause. The best-known risk gene is APOE4, which raises risk but doesn’t guarantee the disease. Most earlier genetic research looked at common gene variants, each of which nudges risk up only slightly. This study took a different approach, searching for rare variants that are uncommon but can have a much bigger effect.
What the researchers did
Published in Nature Genetics in 2022, the study compared the genes of thousands of people with early-onset or late-onset Alzheimer’s against people without dementia. Instead of looking at single genetic letters one at a time, the team grouped together all the rare, damaging changes within each gene to see whether carrying any of them raised risk.
What they found
Rare damaging variants in several genes were linked to a higher risk of Alzheimer’s. The strongest signals included:
- ATP8B4: damaging variants were found in about 3.6% of people with early-onset Alzheimer’s, compared with about 2.1% of people without dementia. Certain changes in this gene raised risk by about 1.6 times.
- ABCA1: a gene involved in moving cholesterol and other fats. Variants that knocked out the gene’s function raised risk by nearly 5 times.
- ADAM10: damaging variants were very rare, found in well under 1% of people, but carrying one raised risk about 9-fold.
The team also found evidence for rare variants in several other genes, including CLU, RIN3, ZCWPW1 and ACE.
What the genes reveal about the disease
Together, the genes point to a handful of biological processes: how the body makes and clears amyloid-beta (the protein that forms plaques in the brain), how it handles fats and cholesterol, and how the brain’s immune cells, called microglia, do their job. This supports the long-standing idea that amyloid plays a central role in Alzheimer’s, an idea that has been debated but has gained ground with newer drugs that clear amyloid from the brain.
The researchers suggest that treatments supporting the brain’s natural ways of processing and clearing proteins, given early to people at higher risk, might one day help prevent the disease from developing.
What this means for you
- Genes aren’t destiny. These variants are rare, and most people who carry them won’t develop Alzheimer’s because of them alone.
- Focus on what you can change. Research suggests a substantial share of dementia risk is linked to modifiable factors, including high blood pressure, diabetes, smoking, physical inactivity, hearing loss, heavy drinking and social isolation.
- Protect your heart to protect your brain. Managing blood pressure, cholesterol and blood sugar supports brain health too.
- Talk to a professional about genetic testing. If Alzheimer’s runs in your family, especially at younger ages, a doctor or genetic counselor can explain whether testing makes sense and what the results would mean.
- Don’t ignore memory changes. Worsening memory or thinking problems deserve a medical check. Some causes are treatable.
The bottom line
This study uncovered rare genetic variants that can sharply raise Alzheimer’s risk and shed light on how the disease develops. It’s a step toward earlier detection and better treatments, while lifestyle choices remain a powerful way to protect your brain today.
This article is for general information and isn’t medical advice. Talk with your healthcare provider about your individual needs.
