Rare genetic variant shields brain from Alzheimer’s disease

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A groundbreaking study published in Acta Neuropathologica has identified a genetic variant that can reduce the risk of developing Alzheimer’s disease by up to 70%. This variant appears to help in removing toxic amyloid from the brain through the blood-brain barrier, highlighting the significant role that blood vessels in the brain may play in Alzheimer’s disease. These findings could pave the way for new therapeutic approaches to prevent or treat Alzheimer’s disease.

“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,” said Caghan Kizil, a co-leader of the study and associate professor of neurological sciences 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.”

Alzheimer’s disease, a progressive neurodegenerative disorder, currently lacks effective treatments that can halt or reverse its course. Despite extensive research, the precise mechanisms driving the disease remain incompletely understood, which hampers drug development. Most therapies target amyloid deposits in the brain, yet they offer limited success in mitigating the symptoms or progression of the disease.

By identifying genetic factors that influence the risk of Alzheimer’s disease, researchers hope to uncover new pathways for therapeutic intervention. The discovery of the APOEε4 allele as a significant risk factor in various populations has spurred the search for genetic variants that can modify or mitigate its effects. The new study aimed to find such protective genetic factors, potentially leading to the development of novel treatment strategies.

The researchers conducted an extensive genetic analysis using whole-genome sequencing data from over 3,500 individuals across more than 700 families affected by Alzheimer’s disease. The study participants were selected from diverse ethnic backgrounds, including non-Hispanic Whites and Caribbean Hispanics, to ensure the findings were broadly applicable. These participants were part of three major cohorts: the NIA-AD Family Based Study, the Washington Heights/Inwood Columbia Aging Project, and the Estudio Familiar de Influencia Genetica en Alzheimer.

Whole-genome sequencing was performed to identify rare genetic variants in APOEε4 carriers who remained cognitively healthy into old age. The researchers focused on variants that were present in healthy APOEε4 carriers but absent in those with Alzheimer’s disease. They prioritized variants that were likely to affect protein function, using various bioinformatics tools to predict the impact of these genetic changes.

The study also included animal models to validate the findings. Zebrafish were used to study the effects of amyloid toxicity and to investigate the role of the identified genetic variant in fibronectin, a protein found in the blood-brain barrier. The researchers performed immunohistochemistry to analyze brain tissues and determine the levels of fibronectin and other related proteins.

The study identified a rare genetic variant in the FN1 gene, which encodes fibronectin-1, that appears to offer protection against Alzheimer’s disease. This variant was found in cognitively healthy APOEε4 carriers and was associated with a significant reduction in Alzheimer’s disease risk. Specifically, the presence of this variant was linked to a 70% reduction in the likelihood of developing the disease.

Fibronectin-1 is a component of the blood-brain barrier, and the researchers discovered that this variant helps prevent the excessive accumulation of fibronectin in the brains of Alzheimer’s patients. This excess fibronectin may hinder the clearance of amyloid deposits from the brain, contributing to the progression of the disease. By reducing fibronectin levels, the protective variant may facilitate the removal of toxic amyloid, thereby reducing the risk of Alzheimer’s disease.

In their zebrafish model, the researchers confirmed that reducing fibronectin levels led to increased amyloid clearance and improved other pathological features associated with Alzheimer’s disease. These findings suggest that targeting fibronectin could be a promising therapeutic strategy for preventing or treating Alzheimer’s disease.

While the findings of this study are promising, there are several limitations that need to be addressed in future research. Firstly, the identified variant is rare, and its protective effect needs to be validated in larger, more diverse populations. Additionally, the precise mechanisms by which fibronectin influences amyloid clearance and other aspects of Alzheimer’s pathology remain unclear and require further investigation.

Another limitation is the reliance on animal models to validate the findings. While zebrafish provide a useful model for studying genetic and molecular processes, their physiology differs significantly from humans. Future studies should include additional animal models, such as mice, and ultimately, clinical trials in humans to confirm the therapeutic potential of targeting fibronectin.

Moreover, the study focused primarily on non-Hispanic White and Caribbean Hispanic populations. Further research is needed to determine whether the protective variant has similar effects in other ethnic groups. Understanding the broader applicability of these findings is crucial for developing inclusive and effective treatments.

Finally, the researchers highlighted the need for early intervention in Alzheimer’s disease. Most current therapies target amyloid deposits directly but fail to significantly improve symptoms or halt disease progression. The discovery of the protective fibronectin variant suggests a new avenue for early therapeutic intervention through the bloodstream, which could complement existing treatments.

“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,” explained study co-leader Richard Mayeux, the chair of neurology and the Gertrude H. Sergievsky Professor of Neurology, Psychiatry, and Epidemiology. “We may need to start clearing amyloid much earlier and we think that can be done through the bloodstream. That’s why we are excited about the discovery of this variant in fibronectin, which may be a good target for drug development.”

The study, “Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease,” was authored by Prabesh Bhattarai, Tamil Iniyan Gunasekaran, Michael E. Belloy, Dolly Reyes-Dumeyer, Dörthe Jülich, Hüseyin Tayran, Elanur Yilmaz, Delaney Flaherty, Bengisu Turgutalp, Gauthaman Sukumar, Camille Alba, Elisa Martinez McGrath, Daniel N. Hupalo, Dagmar Bacikova, Yann Le Guen, Rafael Lantigua, Martin Medrano, Diones Rivera, Patricia Recio, Tal Nuriel, Nilüfer Ertekin-Taner, Andrew F. Teich, Dennis W. Dickson, Scott Holley, Michael Greicius, Clifton L. Dalgard, Michael Zody, Richard Mayeux, Caghan Kizil, and Badri N. Vardarajan.

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