How a Genetic Variant May Protect Against Early-Onset Alzheimer’s

How a Genetic Variant May Protect Against Early-Onset Alzheimer’s

Table of Contents

Inheritance Patterns of Alzheimer’s Disease

In spite of its status as a top ten cause of death in the United States, Alzheimer’s Disease (AD) has proven remarkably challenging to understand. Memory loss and confusion are hallmarks of AD, but their exact molecular causes remain unknown. A prominent but controversial hypothesis for the cause of AD points to amyloid plaques as a major contributor. These plaques are aggregates of misfolded proteins that are commonly found in the brains of AD patients.

One branch of supporting evidence for the ‘amyloid hypothesis’ comes from some of the studies of AD inheritance. Around 60% of AD cases have a family history of AD, with around 10% exhibiting an autosomal dominant inheritance pattern. This has led to the discovery of genetic variants that predict an increased risk of AD (APOE4, for example), as well as genes related to amyloid formation and processing, including APP, PSEN1, and PSEN2. 

One variant, the PSEN1-E260A mutation, was identified from the largest known cohort of families with autosomal dominant AD. Based on an analysis of 1,200 individuals carrying the PSEN1-E260A mutation, researchers found that carriers develop mild cognitive impairment by a median age of 44 and dementia by 49 years of age. However, there are rare exceptions – people who do not develop early-onset AD and dementia. These outliers may provide insight into the underlying mechanisms driving AD and how to prevent it.

New Genetic Variant Identified that Delays Onset of Alzheimer’s

In a paper published this week in Nature Medicine, Lopera et. al. detailed their findings of a man with the PSEN1-E260A mutation who did not experience any cognitive decline until the age of 67 which was followed by moderate dementia at the age of 73, a full 24 years later than the expected onset for a carrier. According to his family, his sister, who also carried the mutation, did not experience cognitive decline until she was 58, 14 years later than expected.

What could be protecting their brains? The researchers found a very high burden of amyloid plaques in the man’s brain, but a surprisingly low burden of tangled Tau proteins in certain regions of the brain where Tau tangles were typically high in mutation carriers. Tau tangles are another piece of the AD puzzle and are frequently found in addition to amyloid plaques.

Genetic analysis identified a genetic variant in the RELN gene, which they named RELN-COLBOS after the COLBOS biomarker studies the work is part of. The variant is involved in Tau phosphorylation and is functionally related to APOE, the gene family which contains variants closely associated with AD pathogenesis both in protective and driving roles. RELN-COLBOS was found in the individual and in his sister, a strong indication that it may be the variant responsible for their protection from early-onset AD.

The Changing Landscape of Alzheimer’s Research

This study provides exciting new avenues for hypotheses in AD research, potentially pointing researchers to new cellular mechanisms that may be involved in AD pathogenesis. What this study also highlights is that AD, like many complex diseases, likely does not stem from a single cause. The individual in the study had a high concentration of amyloid plaques but only mild cognitive impairment, and Tau tangles seemed to be the key to this patient’s specific case.

A few high-profile Alzheimer’s drugs have attempted to launch in the last few years that eliminate amyloid plaques from the brain. Biogen’s now-infamous drug aducanumab was the center of contentious FDA approval which was later subject to a congressional hearing due to concerns about the drug’s efficacy. However, two recent drugs, lecanemab (developed by Eisai) and donanemab (developed by Eli Lilly) have shown mild cognitive improvement in early-onset AD. The puzzle of what causes AD and how to treat it has not yet been solved, but pieces are beginning to come together.

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Jane Cook, Biochemist & Content Writer, Bridge Informatics

Jane Cook, the leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email [email protected] or [email protected].

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