31 May 2019

The lucky carriers of a coding variant in the phospholipase Cγ2 (PLCG2) gene may reap even more benefits than previously thought. In the May 27 Acta Neuropathologica, researchers confirm that people with the rs72824905-G allele not only enjoy protection from Alzheimer’s disease, but also from frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB). What’s more, they are more likely to be nonagenarians or even centenarians.

A protective PLCG2 mutation was previously found to reduce AD risk.

New data indicate it protects against FTD and DLB.

People who live past 90 are more likely to carry the mutation.

Scientists led by Henne Holstege, Alzheimer Center of the Amsterdam UMC, studied this rare mutation in 16 cohorts comprising more than 53,000 patients with various diseases, 149,000 controls, and 3,500 people who lived past 90. The nonsynonymous cytosine-to-guanine change yields an arginine at amino acid 522 instead of a proline. How this change affects the lipase is unknown. The authors urge the field to investigate the mechanism to see if it can be replicated with a drug.

“Collectively, these findings further strengthen the role of the microglial-enriched gene PLCG2 in AD and DLB, whose neuropathologies can co-occur,” wrote co-author Nilüfer Ertekin-Taner, Mayo Clinic, Jacksonville, Florida, to Alzforum. “It also raises the intriguing possibility that innate immunity, protection from several neurodegenerative diseases, and longevity are connected.” Ertekin-Taner is one of 108 named authors and consortia on the paper. Rita Guerreiro, Van Andel Institute, Grand Rapids, Michigan, was more cautious. She noted that establishing an association between AD-related variants and other neurodegenerative disease can be confounded by the much lower prevalence of diseases such as FTD and DLB, and by the variable frequencies of rare variants in populations. “Consequently, it is difficult to assess if the nominal associations found for DLB and FTD are real, or if they result from the absence of population stratification corrections, or if they represent residual associations, with possible AD contaminations in these cohorts,” she wrote (see comment below).

Cognitively Normal. Despite hippocampal and posterior cortical atrophy (top) and amyloid in the precuneus and frontal lobes (bottom), this 102-year-old ApoE4 homozygote performs normally on all neuropsychological tests. She carries the rs72824905-G variant. [Courtesy of van der Lee et al., 2019. Acta Neuropath.]

Two years ago, first author Sven van der Lee and colleagues from the International Genomics of Alzheimer’s Disease Consortium reported that the rs72824905-G allele of PLCG2 protected against AD (Sims et al., 2017; Aug 2017 conference news). The PLCG2 protein is highly expressed in microglia and more so in the brains of AD patients in areas with pathology (Friedman et al., 2018; Conway et al., 2018). Phospholipases help transduce signals from activated cell surface receptors (Rhee, 2001).

It is still unclear, however, if or how the phospholipase modulates microglial function. Some reports suggest it activates the NLRP3 inflammasome, which spurs the production of pro-inflammatory cytokines (Chae et al., 2015).

In the current study, the authors wondered whether the allele protects against other neurodegenerative diseases (Apr 2019 conference news; Apr 2019 news). Because the variant is so rare, van der Lee and colleagues assembled genomic data from a dozen disease cohorts, totaling 4,985 patients with AD, 2,437 with FTD, 1,446 with DLB, 882 with PSP, 28,448 with PD, 10,953 with ALS, and 4,476 with MS. Each cohort had its own control group.

The researchers found that rs72824905-G lowered the risk for AD, DLB, and FTD, with odds ratios of 0.57, 0.54, and 0.61, respectively. Despite plumbing such a large patient sample, the researchers found no correlation between the mutation and multiple sclerosis, amyotrophic lateral sclerosis, or Parkinson’s disease. The variant had been associated previously with increased risk for progressive supranuclear palsy, but there weren’t enough PSP patients in van der Lee’s sample to confirm or refute that finding (Conway et al., 2018).

In addition, according to data from five cohorts, people with the rs72824905-G variant were more likely to live to age 90, and the scientists discovered even greater prevalence of the allele among centenarians. The odds ratios for nonagenarians and centenarians having the allele were 1.49 and 2.36, respectively. It is unclear whether the mutation is associated with longer lifespan because it reduces the chances of developing certain dementias or if it has an independent effect on longevity. One 102-year-old carrier performed as well on neuropsychological tests as did age-matched peers who had no signs of dementia, despite being homozygous for ApoE4 and having brain atrophy and amyloid plaques on MRI and PET scans (see image above). Eighty percent of ApoE4 homozygotes develop dementia by age 90 and very few live past 100.

“We found that in centenarians, the variant is enriched, whereas in several forms of dementia, the variant is depleted,” Holstege told Alzforum. She thinks that although AD, DLB, and FTD have different pathologies, they may share some common biology involving PLCG2. “There is probably some overlapping etiology between AD, DLB, and FTD that is different from ALS, MS and PD.” Van der Lee agreed the commonality must be overarching, saying, “We think immunity is the most obvious candidate.”

What does the rs72824905-G mutation do to PLCG2? Scientists don’t know. Its effect is most likely subtle, the authors wrote, because other mutations that hyperactivate the enzyme can cause inflammatory immunodeficiency disorders (Zhou et al., 2012; Schade et al., 2016). One publication reported a slight increase in phospholipase activity in vitro with the rs72824905-G variant (Magno et al., 2019).

Oleg Butovsky, Brigham and Women's Hospital, Boston, speculated that, because AD, FTD, and DLB tend to strike later than ALS and MS, rs72824905-G may affect processes of aging. For example, the variant might bolster the microglial response to amyloid, neurofibrillary tangles, and α-synuclein pathology.—Gwyneth Dickey Zakaib