Summary: Researchers have identified two new genes, ATP8B4 and ABCA1, that are implicated in Alzheimer’s disease. The genes impact the brain’s immune system and cholesterol processing, leading to an increased risk of developing Alzheimer’s disease.
Source: Cardiff University
Two new genes that raise a person’s risk of developing Alzheimer’s Disease have been discovered by researchers.
An international team, involving Cardiff University’s Dementia Research Institute, compared 32,000 genetic codes from patients with Alzheimer’s disease and healthy individuals.
The research uncovered several new genes and specific mutations in those genes that lead to the development of Alzheimer’s disease. They found rare, damaging genetic mutations in the genes known as ATP8B4 and ABCA1 which could lead to an increased risk of Alzheimer’s disease.
The researchers also found evidence of genetic alternation in a further gene, ADAM10.
Professor Julie Williams, Director of the Dementia Research Institute at Cardiff University, and a co-author on the study said, “These findings point us towards very specific processing in the brain, which includes differences in the brain’s immune system and how the brain processes cholesterol. These differences impact brain functioning and leads to the development of Alzheimer’s disease.”
Alzheimer’s disease is the most common form of dementia in the UK. An estimated 60–80% of the risk of Alzheimer’s disease can be explained by genetic factors. For early onset Alzheimer’s (under 65 years), this increases to more than 90%.
Professor Williams added, “This study helps expand our knowledge about who is at risk of developing this form of dementia. These genetic discoveries also allow us to understand the mechanisms underlying Alzheimer’s, as well as create genetic models of the disease to develop targeted therapies in the future—through new drug-based treatments or even gene therapy.
“The Dementia Research Institute at Cardiff University is well-placed to apply this research and take it forward into developing disease models. We are the biggest investment in dementia research in Wales, with over 100 researchers focused on developing our understanding of dementia and delivering new treatments.
About this genetics and Alzheimer’s disease research news
Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease
Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants.
Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls.
Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10.
Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases.
Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.