An international study led by Amsterdam UMC, the Netherlands, Pasteur Institute of Lille, France and the University of Rouen Normandy, 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.

The collaborative effort of a large international group of researchers allowed for the comparison of more than 32,000 genomes from both patients with Alzheimer’s disease and healthy individuals. The researchers found that rare damaging genetic mutations in five genes, SORL1ABCA7TREM2ATP8B4 and ABCA1, lead 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, likely also lead to an increased risk of Alzheimer's disease. However, the authors observed very few individuals with genetic mutations in the ADAM10 gene and research with an even larger dataset is necessary to classify it as an 'Alzheimer gene'.

Gene Function

All of the identified genes are involved in maintaining brain health, and genetic impairment of these genes, as identified in Alzheimer patients, are indicative of how these processes go awry in the brains of those with Alzheimer's disease. The previously discovered Alzheimer genesSORL1ABCA7 and TREM2 are involved in the processing of the amyloid-β protein by neurons and 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. Without these phospholipids, the brain's immune system doesn't function as well. ADAM10 is also involved in the processing of the amyloid-β precursor protein, but in such a way that prevents amyloid-β protein from being formed.

Towards a future without Alzheimer's

An estimated 60-80% of the risk of late onset Alzheimer’s disease (age at onset >65) is thought to be genetic, and for early onset Alzheimer's (age at onset <65 years) this increases to 90%. Each person’s unique genome can therefore estimate their level of vulnerability for the disease allowing doctors to identify those with an increased risk of Alzheimer’s disease, before symptoms occur. This will allow for the timely application of personalised treatment strategies in the future. Importantly, pinpointing the genes and proteins that are most affected in Alzheimer’s patients, as done in this study and in other recent Amsterdam Neuroscience studies, provides a window of opportunity to design and implement these strategies for those affected.

Read the full publication on the discovery of new Alzheimer's genes in Nature Genetics.