In a recent study, researchers identified 11 rare genetic variants related to Alzheimer’s disease through high-risk pedigree studies.
Alzheimer’s disease (AD) is the leading cause of global dementia cases. It is a progressive neurodegenerative disease known to cause memory loss, behavioural disorders and shortened lifespan. More than 40% of AD genetic variation remains uncharacterised and scientists believe that pedigree-based designs may show potential for future breakthroughs. Pedigree-based studies have high statistical power and limit gene locus heterogeneity, allowing successful gene discovery for many phenotypes in addition to AD.
A pedigree-based analysis
In a recent study published in Alzheimer’s & Dementia, researchers performed a pedigree-based analysis using exome sequences from 19 AD-affected cousin pairs selected from high-risk AD mortality pedigrees. This revealed candidate variants that were then further evaluated using publicly available datasets. Subsequently, the variants that emerged underwent further testing for co-segregation using affected relatives of the original pedigree members.
From their analyses, the team prioritised 11 variants spanning 10 genes, two of which were previously implicated in AD pathology (ABCA7 and TTR). Their results expanded on the role of previously reported NOTCH3 variants, and also prioritised 7 additional candidate variants. High statistical power was maintained as the small sample size of the study reduced locus heterogeneity.
This study has demonstrated the value of pedigree-based study designs for the identification of rare, high-risk variants for Alzheimer’s disease. The analyses have helped further implicate ABCA7 and TTR variants in AD risk, in addition to the 11 prioritised variants.
The prioritisation methods were based off current understandings of AD pathology. Therefore, it is unlikely that all of the disease-causing variants were recognised. Nevertheless, the study aimed to provide evidence for highly supported candidate variants associated with AD risk, in which it was successful. Moreover, these outcomes indicate that high-risk pedigree approaches, alongside external datasets, can produce meaningful data. In the future, similar methods have the potential to be used for identifying genetic disease risks in AD, as well as in other complex disorders.
Image credit: By Thomas Northcut – canva