Scientists identify gene variant that may protect against APOE ε4-related Alzheimer’s risk

Certain versions of the fibronectin 1 gene may protect people with the APOE ε4 gene from increased Alzheimer's disease risk, according to an NIA-funded study. The findings, published in Acta Neuropathologica, could help scientists better understand how Alzheimer's develops, and help them determine potential new research strategies.

Previous research has shown that certain genetic variations are one of several possible risk or protective factors for Alzheimer's. The strongest known genetic risk factor for this disease is a form of the apolipoprotein E (APOE) gene called APOE ɛ4. People inherit two copies of the APOE gene, one from each biological parent. Overall, those with two copies of the APOE ɛ4 form of the APOE gene have a higher risk of developing Alzheimer's compared to people with two different forms of the APOE gene.

However, some older adults with two copies of APOE ɛ4 remain cognitively healthy. This suggests that these individuals have some protective factor that counteracts the disease-linked effects of APOE ε4. Led by Columbia University researchers, an international scientific team analyzed DNA sequences of cognitively healthy older adults with APOE ε4 to determine if they had another gene that was protecting them from developing Alzheimer's.

The team analyzed whole genome sequence data from three NIA-funded studies: the NIA Alzheimer's Disease Family Based Study, the Washington Heights/Inwood Columbia Aging Project, and the Estudio Familiar de Influencia Genetica en Alzheimer. Specifically, the scientists looked at DNA from adults older than 70 who had two copies of APOE ε4 but remained cognitively healthy. They found that many of these individuals had rare versions of the fibronectin 1 gene.

Next, the researchers wanted to confirm their findings that certain fibronectin versions were protective against Alzheimer's in APOE ε4 carriers. In a second analysis, the scientists examined genetic data from more than 7,000 people with two copies of APOE ε4 to determine which versions of the fibronectin 1 gene were protective against the increased risk conferred by APOE ε4.They discovered that a particular version of the fibronectin 1gene (rs140926439) reduced the odds of developing Alzheimer's by 71%.

Next, the scientists looked at how these genetic differences played out in postmortem brain tissue of people with zero, one, or two copies of APOEε4. They found that, in general, people with one or two copies of APOE ε4 (carriers) who developed Alzheimer's had more fibronectin 1 protein in the blood-brain barrier, a protective shield made up of tightly packed cells lining the blood vessels in the brain. The barrier controls what can pass from the bloodstream into the brain, letting in only substances that are necessary (e.g., water, oxygen, carbon dioxide, and general anesthetics) and keeping out harmful ones, such as bacteria and toxins. APOE ε4 carriers who did not develop Alzheimer's had less fibronectin 1 protein in the blood-brain barrier. These findings suggest that versions of the fibronectin 1 gene that cause less protein to build up in the blood vessels that line the brain could protect against Alzheimer's in APOE ε4 carriers.

Overall, these results suggest that certain forms of the fibronectin 1 gene may protect some individuals from APOE ε4-related Alzheimer's risk. These findings will help scientists better understand how genetics influence Alzheimer's risk - or provide protection - and could also provide insights for new therapeutic strategies. Future studies may explore why having less fibronectin 1 protein at the blood-brain barrier is protective.

This research was supported in part by NIA grants R01AG067501, RF1AG066107, R01AG072474, U01AG066752, R01AG061796, U19AG074879, U01AG046139, R00AG075238, U24AG056270, R01AG028786, R01AG027944, RF1AG054074, U01AG052410, R56AG063908, R01AG060747, P50AG047366, R01AG059013, and RF1AG015473.

These activities relate to NIH's AD+ADRD Research Implementation NIH's AD+ADRD Research Implementation Milestone 1.A "Population Studies: Endophenotyping at-risk and resistant cohorts."

Reference: Bhattarai P, et al. Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer's disease. Acta Neuropathologica. 2024;147(1):70. doi:10.1007/s00401-024-02721-1.