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New genes linked to Alzheimer’s disease risk

Written by Charlotte Harrison, Science Writer 

The largest genome-wide association study so far on Alzheimer’s disease (AD) has identified numerous new genetic variations implicated in the disease. Including these new genetic variations in AD risk scores makes the prediction more accurate.   

AD is a complex multifactorial condition, yet genetics make up the majority of a person’s risk. This new study, published in Nature Genetics, used genomic data from 111,326 patients with Alzheimer’s disease and 677,663 healthy subjects. Overall, the study found 75 genomic regions associated with AD, 33 of which were known previously and 42 that were newly discovered regions. 

Genes in microglial cells 

One of the key pathological processes in AD is the abnormal build-up of amyloid and tau proteins in the brain. The study confirmed the link between AD and these proteins by identifying several genomic regions associated with amyloid and tau production that influences the risk of AD. 

Several of the newly identified genetic regions are linked to the function of the immune system, particularly microglial cells. This type of immune cell is found in the central nervous system, where it clears out damaged tissue. The genes expressed in microglia and linked to AD include RHOH, BLNK, SIGLEC11, LILRB2, and RASGE1FC; two of these genes (SIGLEC11 and LILRB2) have known links to amyloid peptides or plaques. 

Genes in the TNFa pathway 

One of the study’s most novel findings is the link between the TNFa pathway and AD risk; this is the first time this inflammatory pathway has been linked with the development of AD. In particular, the researchers found that genes that encode for the linear ubiquitin chain assembly complex (LUBAC), which is a major regulator of TNFa signalling, are associated with AD. Genes in this pathway included SHARPIN, RBCK1, and OTULIN

Lastly, the researchers built a new genetic risk score associated with the risk of future AD. The genetic risk score could predict with 84 percent accuracy whether a patient experiencing mild cognitive impairment would progress to Alzheimer’s disease within three years.  

This improved genetic risk score should help prioritize AD patients for emerging treatments.  “While this tool is not at all intended for use in clinical practice at present, it could be very useful when setting up therapeutic trials in order to categorise participants according to their risk and improve the evaluation of the medications being tested,” said the paper’s lead author Jean-Charles Lambert in a news release

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