A mechanistic explanation of how two genes may influence Alzheimer’s disease risk has been identified, researchers reported.
The genes, known as MS4A4 (membrane-spanning 4-domains subfamily A) and TREM2 (triggering receptor expressed on myeloid cells 2), operate in the microglia and appeared to influence Alzheimer’s risk by altering levels of TREM2, a protein that may help microglia cells clear excessive amounts of brain amyloid and tau, reported Carlos Cruchaga, PhD, Celeste Karch, PhD, and Laura Piccio, MD, PhD, of Washington University School of Medicine in St. Louis, and colleagues, in Science Translational Medicine.
“Before this study, it was known that rare variants in TREM2 increase risk for Alzheimer’s disease, but it was not clear if TREM2 [protein] was involved in Alzheimer’s in general, in those individuals without the rare TREM2 variants,” said Karch. “It was not clear if higher or lower levels of TREM2 were good or bad in relation to Alzheimer’s.”
Previous studies also reported that MS4A4A was associated with Alzheimer’s risk, but the function or mechanism of MS4A4A was unknown. “In this study, we reported for the first time that MS4A4A is the major regulator of TREM2 levels,” Karch told MedPage Today. “This is important, because we are now able to explain the reason why MS4A4A is associated with Alzheimer’s disease, which is by regulating TREM2.”
“One of the most important findings of this study is that we demonstrate that TREM2 is involved in Alzheimer’s disease in general, and that higher TREM2 levels are protective,” she added. “These findings open the door to new therapeutic strategies.”
In 2013, two groups of researchers independently identified a rare variant in TREM2 that increased risk for Alzheimer’s disease almost three-fold, making it the strongest genetic risk factor for late-onset Alzheimer’s disease since the identification of APOE4. Concentrations of soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) changes with Alzheimer’s progression, but genetic modifiers of the protein were unknown.
In this study, researchers measured soluble TREM2 levels in the CSF of 813 older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort: 172 with Alzheimer’s disease, 169 cognitively normal, 183 with early mild cognitive impairment, 221 with late mild cognitive impairment, and 68 with significant memory concern. People with previously identified risk mutations in TREM2 were excluded.
The investigators identified common genetic variants and genes associated with CSF sTREM2 in this group and also in a replication group of 580 CSF samples from Alzheimer’s cases and healthy individuals.
“We observed TREM2 risk variants more often in people who had Alzheimer’s or were mildly cognitively impaired, compared with those who were cognitively normal,” Karch said. “It turns out that about 30% of the population in the study had variations in the MS4A4A gene that appear to affect their risk for developing Alzheimer’s disease. Some variants protected people from Alzheimer’s or made them more resilient, while others increased their risk.”
Common variants in the MS4A gene region were associated with CSF sTREM2 concentrations in both the ADNI group and the replication cohort. Variants associated with increased CSF sTREM2 concentrations were linked to reduced Alzheimer’s risk and delayed age at onset of disease; ones associated with lower levels of soluble TREM2 were tied to increased Alzheimer’s risk.
“This study is telling us that if we are able to regulate TREM2 levels, we can also modify the risk of developing Alzheimer’s disease,” Cruchaga said. “It is also telling us that we do not need to target TREM2 directly, but if we target another gene that is part of the biological pathway of TREM2, such as MS4A4A, we can obtain similar results,” he told MedPage Today.
“Our study provides a strong evidence of a biological link between TREM2 and MS4A4A in microglia in the context of Alzheimer’s disease,” Piccio added. “However, we know that TREM2 is an important molecule in microglia and TREM2 and MS4A4A pathways could potentially modulate microglia functions in other neurological and neurodegenerative diseases. Our study opens new direction of research not only in the Alzheimer’s field, but with a much broader view for a better understanding of microglia biology in the context of several neurological disorders.”
The study was supported by the National Institute on Aging, the National Heart, Lung, and Blood Institute, and the National Institute of Mental Health, and funded by the Alzheimer’s Association; the Fondazione Italiana Sclerosi Multipla; the National Multiple Sclerosis Society; a Fondazione Veronesi fellowship; the Hope Center for Neurological Disorders and the Danforth Foundation Challenge at Washington University; the Swedish Alzheimer Foundation; the Research Council, Sweden; Hjarnfonden, Sweden; the LUA/ALF project, Vastra Gotalandsregionen, Sweden; the Swedish and European Research Councils; and the UK Dementia Research Institute.
Source: MedicalNewsToday.com
