An international study led by Amsterdam UMC, the Netherlands, Pasteur Institute of Lille, France and the University of Rouen Normandie, France, has led to the discovery of two new 'Alzheimer genes', and evidence for a third. A genetic alteration in any one of these genes can lead to a significantly increased risk of Alzheimer's disease. The study is published in Nature Genetics.
In a collaborative effort, a large international group of researchers, including Professor Cornelia van Duijn and Dr Najaf Amin from Oxford Population Health, compared more than 32,000 genomes from patients with Alzheimer’s disease and healthy individuals. The researchers found that rare damaging genetic mutations in five genes, SORL1, ABCA7, TREM2, ATP8B4 and ABCA1, led to an increased risk of Alzheimer's disease. While this was already known for the first three genes, the finding that damaging mutations in ATP8B4 and ABCA1 can lead to Alzheimer's disease was not previously observed.
In addition, the researchers found that damaging mutations in a sixth gene, ADAM10, are likely to lead to an increased risk of Alzheimer's disease. However, the authors observed very few individuals with genetic mutations in this gene, such that comparison of an even larger collection of genomes from Alzheimer disease patients and healthy individuals is necessary to classify ADAM10 as an 'Alzheimer gene'.
All of the identified genes are involved in maintaining brain health, and genetic impairment of these genes are indicative of processes that go awry in the brains of those with Alzheimer's disease. The previously discovered Alzheimer genes, SORL1, ABCA7 and TREM2 are involved in the processing of the amyloid-β protein by neurons or in the brain's immune system.
The newly discovered genes expand on this: ABCA1 maintains healthy cholesterol and phospholipid levels in the brain cells, and it is associated with lower levels of aggregated amyloid protein, high levels of which are a hallmark of Alzheimer’s disease. Like ABCA1, the newly discovered gene ATB8B4 is involved in the transport of phospholipids, mainly in the brain's immune cells. ADAM10 is also involved in the processing of the amyloid-β precursor protein, but in such a way that it prevents amyloid-β protein from being formed. Together, the identified genes represent the molecular mechanisms that are most affected in Alzheimer’s patients, providing targets for the design of treatment options.
An estimated 60-80% of the risk of Alzheimer’s disease can be explained by genetic factors, and for early onset Alzheimer's (age at onset less than 65 years) this increases to more than 90%. Therefore, using each person’s unique genome, it may become possible to identify, before symptoms occur, those individuals with an increased risk of Alzheimer’s disease, enabling the timely application of personalised treatment strategies in the future.
Cornelia van Duijn, Professor of Epidemiology at Oxford Population Health, said ‘Genome-wide association studies have recently fueled our knowledge of the pathogenesis of Alzheimer research, but studies of rare variants have always been important in Alzheimer's disease research. This new study demonstrates the value of investigating rare genetic mutations to further our understanding of this devastating disease.
‘The fact that the second phase 3 trial (lecanemab) is providing significant evidence that treatment targeting amyloid works, makes our findings on mutations in ADAM10 and the risk of Alzheimer's disease more exiting. The rare variants in ABCA1 show us that lipids and the immune system are tightly interwoven in the disease.’