A rare genetic variant that protects against Alzheimer disease (AD) is also associated with reduced risks of other dementias, according to a new study published in Acta Neuropathologica. The finding could lead to the development of preventive treatments.

A specific variant of PLCG2, which is the gene that encodes phospholipase Cγ2 (PLCγ2), has previously been associated with a reduced risk of AD. The PLCγ2 protein is involved in the transduction of immune signals across cell membranes and is highly expressed in microglia. Given that the immune response is thought to have a role in multiple neurodegenerative diseases, the new study was designed to test whether the PLCG2 variant protects against other diseases as well as AD.

“The variant in PLCG2 is rare — it occurs in about 1% of the Dutch population,” notes Sven van der Lee, who led the new study alongside Henne Holstege. “We reached out to collaborators worldwide and requested the genotype of the PLCG2 variant in patients with neurodegenerative diseases and controls.” Using this approach, the team were able to analyse data from 53,000 patients, each of whom had one of seven different neurodegenerative diseases, and almost 150,000 healthy controls.

The presence of the PLCG2 variant was associated not only with a reduced risk of AD but also with a reduced risk of dementia with Lewy bodies and frontotemporal dementia. The team did not detect an effect of the variant on the risk of progressive supranuclear palsy, amyotrophic lateral sclerosis, Parkinson disease or multiple sclerosis.

The variant was also associated with an increased chance of reaching at least 90 years of age and specifically with becoming a cognitively healthy centenarian, in whom the absence of dementia and extreme longevity is combined.

Now we need to find out how this variant keeps our brains healthy

More work is required to understand the mechanism underlying the protective effect of the PLCG2 variant. “We suspect that the genetic variant leads to a change in the PLCγ2 protein structure, which likely alters the functioning of PLCγ2 in immune response processes,” explains Holstege. “Now we need to find out how this variant keeps our brains healthy by investigating the effect of the PLCG2 variant in the relevant immune cells. Ultimately, we hope that mimicking the effect of the genetic variant might represent a first lead to agents that could decrease disease risk.”