Newly Discovered Genetic Variant Protects Against Alzheimer's Disease

(Posted on Saturday, July 20, 2024)

A new genetic variant has been uncovered that may protect individuals at high risk from developing Alzheimer’s disease. Researchers at Columbia University found that this gene can reduce one’s risk by 70%. Previously in this series on Alzheimer’s, we focused on the blood-brain barrier as a potential treatment target. Here, we explore an alternative approach to delaying the onset of Alzheimer’s disease: our genes.

While no single gene is directly responsible for Alzheimer’s, having an affected sibling or parent can increase one’s risk, suggesting that there are genetic factors at play. Numerous studies have implicated variants in a gene called apolipoprotein E, or APOE, as the leading genetic risk factor for Alzheimer’s. This gene plays a critical role in facilitating the movement of cholesterol and other fats through the bloodstream. In addition to the obvious risk for cardiovascular complications, select variants of this gene have been found to correlate with increased amyloid plaques in the brain, a key characteristic of Alzheimer’s disease. This only adds to the plethora of evidence linking heart and brain health.

Researchers estimate that up to 65% of people diagnosed with Alzheimer’s have the disease-linked variant. Among non-Hispanic white populations in particular, there is a strong correlation between late-onset Alzheimer’s disease and the APOEε4 allele, or form, of this gene. Above the age of 65, carriers are susceptible to cognitive decline and dementia, albeit the risk is highest for individuals who have two copies of this allele, one inherited from each parent.

The age at onset and severity of Alzheimer’s symptoms, however, can vary significantly between carriers. In fact, some individuals with the APOEε4 disease-linked allele seem to never develop symptoms at all. While genetic predispositions can be influenced by lifestyle and environmental factors, researchers speculate that other genes may counteract the impact of the APOEε4 allele, allowing these individuals to be resilient to cognitive decline. Now, a new study from Colombia University may have identified the gene that protects the brain from neurodegeneration.

Investigators began the search by comparing the genes of over 3,500 individuals across more than 700 families. Through whole genome sequencing, the team was able to obtain their full genetic code from a few drops of blood. The cohort was comprised of individuals known to have two copies of the APOEε4 disease-linked allele, as well as carriers that only have one copy. Those above 70 years without dementia symptoms were considered resilient to Alzheimer’s disease. Among these participants, the team identified 510 variants across 276 genes that were not present in non-carriers or those that developed Alzheimer’s disease.

Further filtration and analysis revealed that many of these genes are involved in maintaining the extracellular matrix, a network of proteins that support and provide structure between cells. Most commonly, individuals that appeared resilient to Alzheimer’s were found to have unique variant in a gene called fibronectin 1. This gene encodes a protein that supports the extracellular matrix of the blood-brain barrier.

To determine if and how this gene may interact with APOE, Bhattarai et. al obtained 27 brain samples from the New York Brain Bank. Normally, the blood-brain barrier contains very few fibronectin proteins. These protein levels, however, seem to increase significantly in Alzheimer’s disease. When researchers compared the brains of individuals with two copies of the APOEε4 disease-linked allele, they found that those who also carried the fibronectin disease-resistant variant exhibited significantly less protein accumulation, similar to protein levels seen in healthy individuals without the high-risk allele.

The team further confirmed these findings in a cohort of zebrafish that exhibit Alzheimer ’s-like changes in the brain. Knocking out, or removing, the fibronectin gene protected the zebrafish from developing amyloid plaques. This evidence suggests that impairing the production of fibronectin may enhance resilience to Alzheimer’s disease. Researchers speculate that elevated protein levels in Alzheimer’s disease block the clearance of amyloid plaques. Therefore, a loss-of-function variant that impairs the production of fibronectin may prevent the accumulation of these disease-causing plaques and protect against neurodegeneration.

Among the 1 to 3% of individuals that carry the APOEε4 allele, researchers estimate that close to 620,000 people may also have the Alzheimer’s-resistant fibronectin variant. A drug that reduces fibronectin levels in the brain-brain barrier has significant therapeutic potential for delaying the onset of Alzheimer’s disease and preventing cognitive decline. In the meantime, additional studies are needed to determine whether those without the APOEε4 disease-linked allele may also benefit from this novel therapeutic approach.