In the past several years, researchers have discovered several genes and loci — the specific positions of a gene on a chromosome — associated with Alzheimer’s disease. ABCA7 only being one of many potential culprits. How do researchers all over the world still see the wood for the trees? Kristel is happy to explain.
Why did your research focus on this particular gene?
We decided to investigate 9 of the new Alzheimer risk genes in more detail, to understand which genetic variation in these genes contributes to increased risk. From these analyses ABCA7 leaped out, because we saw a large number of rare mutations in Alzheimer’s patients. Previous studies strongly suggest that ABCA7 plays a role in the clearance of amyloids. Amyloid is a major constituent of abnormal protein depositsin brain tissue of Alzheimer’s patients, causing the nerve damage that underpins Alzheimer’s disease. This implies that a decline in functional ABCA7 might increase the risk of getting Alzheimer’s. In addition, ABCA7 was among the most significant loci identified in our previous research on Belgian patients. Yet another reason why we decided to study it in more detail.
How did you go about investigating this?
We used a technique called ‘massive parallel resequencing’. That way, we tested for ABCA7 mutations in 772 Alzheimer’s patients, from two Belgian memory clinics. Our research group has a longstanding very close relationship with a network of Belgian neurologists, which was indispensible for this study. We compared the results with similar tests on 757 Belgians that are unaffected by the disease. After bioinformatics analysis, we were able to pinpoint several types of mutations — both common and rare genetic variations — that might be linked to Alzheimer’s disease. In particular, we investigated various ‘loss-of-function’ mutations: variants where ABCA7 completely or partially loses its function, possibly including its capability of clearing
“Our research provides further evidence for therole of both common and rare ABCA7 mutationsin the pathogenesis of Alzheimer’s disease.” Kristel Sleegers
How does your study contribute to the research on Alzheimer’s disease?
Our findings provide genetic evidence that loss-offunction mutations of ABCA7 make a person more susceptible for Alzheimer’s disease. For some of the ABCA7 variants, including one that seems particularly enriched in Flanders, the effect on disease risk is so pronounced that it may mimic the pattern of inheritance of disease-causing mutations in APP, PSEN1 and PSEN2, well-known causes of familial Alzheimer’s. In other words: this gene is definitely one of the main avenues to explore in hopes of developing an efficient therapy to treat Alzheimer’s.