Summary: Researchers identified a genetic variant that significantly lowers the risk of Alzheimer’s disease by up to 70%, potentially benefiting hundreds of thousands in the U.S. The variant, found in the fibronectin gene involved in the blood-brain barrier’s function, aids in preventing amyloid accumulation in the brain, a hallmark of Alzheimer’s.
This discovery emphasizes the vital role of the brain’s vasculature in the disease and opens up promising avenues for drug development aimed at mimicking this protective effect. The research not only offers insights into preventing Alzheimer’s in those at high risk but also underscores the potential for therapies targeting fibronectin to benefit a broader population regardless of their APOE status.
Key Facts:
- The protective genetic variant in the fibronectin gene reduces Alzheimer’s disease risk by 71% in APOEe4 carriers and may delay disease onset.
- Researchers demonstrated that reducing fibronectin in zebrafish models enhances amyloid clearance, suggesting a direct link to Alzheimer’s pathology.
- The discovery, supported by further validation from Stanford and Washington universities, estimates that 1% to 3% of APOEe4 carriers in the U.S. may carry this protective mutation, highlighting its widespread impact.
Source: Columbia University
Columbia researchers have discovered a genetic variant that reduces the odds of developing Alzheimer’s disease by up to 70% and may be protecting thousands of people in the United States from the disease.
The discovery of the protective variant, which appears to allow toxic forms of amyloid out of the brain and through the blood-brain barrier, supports emerging evidence that the brain’s blood vessels play a large role in Alzheimer’s disease and could herald a new direction in therapeutic development.
“Alzheimer’s disease may get started with amyloid deposits in the brain, but the disease manifestations are the result of changes that happen after the deposits appear,” says Caghan Kizil, PhD, a co-leader of the study that identified the variant and associate professor of neurological sciences (in neurology and in the Taub Institute) at Columbia University Vagelos College of Physicians and Surgeons.
“Our findings suggest that some of these changes occur in the brain’s vasculature and that we may be able to develop new types of therapies that mimic the gene’s protective effect to prevent or treat the disease.”
An attractive drug target?
The protective variant identified by the study occurs in a gene that makes fibronectin, a component of the blood-brain barrier, a lining surrounding the brain’s blood vessels that controls the movement of substances in and out of the brain.
Fibronectin is usually present in the blood-brain barrier in very minute amounts, but it is increased in large amounts in people with Alzheimer’s disease. The variant identified in the fibronectin gene seems to protect against Alzheimer’s disease by preventing the buildup of excess fibronectin at the blood-brain barrier.
“It’s a classic case of too much of a good thing,” Kizil says. “It made us think that excess fibronectin could be preventing the clearance of amyloid deposits from the brain.”
The researchers confirmed that hypothesis in a zebrafish model of Alzheimer’s disease and have additional studies in mice underway. They also found that reducing fibronectin in the animals increased amyloid clearance and improved other damage caused by Alzheimer’s disease.
“These results gave us the idea that a therapy targeting fibronectin and mimicking the protective variant could provide a strong defense against the disease in people,” says study co-leader Richard Mayeux, MD, chair of neurology and the Gertrude H. Sergievsky Professor of Neurology, Psychiatry, and Epidemiology.
The newest treatments for Alzheimer’s disease target the amyloid deposits directly and are very efficient at removing the deposits via the immune system. However, simply removing the deposits this way doesn’t improve symptoms or repair other damage.
“We may need to start clearing amyloid much earlier and we think that can be done through the bloodstream,” Mayeux adds.
“That’s why we are excited about the discovery of this variant in fibronectin, which may be a good target for drug development.”
Protective gene was found in people resilient to Alzheimer’s disease
The researchers discovered the protective variant in people who never developed symptoms but who had inherited the e4 form of the APOE gene, which significantly increases the risk of developing Alzheimer’s disease.
“These resilient people can tell us a lot about the disease and what genetic and non-genetic factors might provide protection,” says study co-leader Badri N. Vardarajan, PhD, assistant professor of neurological science (in neurology, the Gertrude H. Sergievsky Center, and the Taub Institute), who is an expert in using computational approaches to discover Alzheimer’s disease genes.
“We hypothesized that these resilient people may have genetic variants that protect them from APOEe4.”
To find protective mutations, the Columbia researchers sequenced the genomes of several hundred APOEe4 carriers over age 70 of various ethnic backgrounds, including those with and without Alzheimer’s disease.
Many participants were residents of Northern Manhattan who were enrolled in the Washington Heights/Inwood Columbia Aging Project, an ongoing study that has been conducted by Columbia University’s Department of Neurology for more than 30 years.
The study identified the fibronectin variant, and the Columbia team publicized their results in a preprint for other researchers to view. Based on the Columbia team’s observations, another group from Stanford and Washington universities replicated the study in an independent cohort of APOEe4 carriers, mostly of European origin.
“They found the same fibronectin variant, which confirmed our finding and gave us even more confidence in our result,” Vardarajan says.
The two groups combined the data on their 11,000 participants, which allowed them to calculate that the mutation reduces the odds of developing Alzheimer’s in APOE4 carriers by 71% and forestalls the disease by roughly four years in those who eventually develop the disease.
The researchers estimate that 1% to 3% of APOEe4 carriers in the United States—roughly 200,000 to 620,000 people—may also carry the protective fibronectin mutation.
Wide therapeutic potential
The fibronectin variant, though discovered in APOEe4 carriers, could protect against Alzheimer’s disease in people with other forms of APOE.
“There’s a significant difference in fibronectin levels in the blood-brain barrier between cognitively healthy individuals and those with Alzheimer’s disease, independent of their APOEe4 status,” Kizil says.
“Anything that reduces excess fibronectin should provide some protection, and a drug that does this could be a significant step forward in the fight against this debilitating condition.”
Richard Mayeux, MD, is also director of the Gertrude H. Sergievsky Center and co-director of the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University Vagelos College of Physicians and Surgeons and neurologist-in-chief at NewYork-Presbyterian/Columbia University Irving Medical Center. (Other contributors are listed in the paper.)
About this genetics and Alzheimer’s disease research news
Author: Helen Garey
Source: Columbia University
Contact: Helen Garey – Columbia University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Rare genetic variation in Fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease” by Caghan Kizil et al. Acta Neuropathologica
Abstract
Rare genetic variation in Fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease
The risk of developing Alzheimer’s disease (AD) significantly increases in individuals carrying the APOEε4 allele. Elderly cognitively healthy individuals with APOEε4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOEε4; however, these mechanisms are unknown.
We hypothesized that APOEε4 carriers without dementia might carry genetic variations that could protect them from developing APOEε4-mediated AD pathology.
To test this, we leveraged whole-genome sequencing (WGS) data in the National Institute on Aging Alzheimer’s Disease Family Based Study (NIA-AD FBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts and identified potentially protective variants segregating exclusively among unaffected APOEε4 carriers.
In homozygous unaffected carriers above 70 years old, we identified 510 rare coding variants. Pathway analysis of the genes harboring these variants showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting protective effects of functional modifications in ECM proteins.
We prioritized two genes that were highly represented in the ECM-related gene ontology terms, (FN1) and collagen type VI alpha 2 chain (COL6A2) and are known to be expressed at the blood–brain barrier (BBB), for postmortem validation and in vivo functional studies. An independent analysis in a large cohort of 7185 APOEε4 homozygous carriers found that rs140926439 variant in FN1 was protective of AD (OR = 0.29; 95% CI [0.11, 0.78], P = 0.014) and delayed age at onset of disease by 3.37 years (95% CI [0.42, 6.32], P = 0.025).
The FN1 and COL6A2 protein levels were increased at the BBB in APOEε4 carriers with AD. Brain expression of cognitively unaffected homozygous APOEε4 carriers had significantly lower FN1 deposition and less reactive gliosis compared to homozygous APOEε4 carriers with AD, suggesting that FN1 might be a downstream driver of APOEε4-mediated AD-related pathology and cognitive decline.
To validate our findings, we used zebrafish models with loss-of-function (LOF) mutations in fn1b—the ortholog for human FN1.
We found that fibronectin LOF reduced gliosis, enhanced gliovascular remodeling, and potentiated the microglial response, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF.
Our study suggests that vascular deposition of FN1 is related to the pathogenicity of APOEε4, and LOF variants in FN1 may reduce APOEε4-related AD risk, providing novel clues to potential therapeutic interventions targeting the ECM to mitigate AD risk.
