By Ralph Sanchez, MTCM, CNS, D.Hom.
Recently (11/13), a rare variant of the TREM2 gene, designated as R47H, was shown to increase the risk of developing Alzheimer’s disease. Individuals with the variant may be up to 3 to 5 times more likely to develop late-onset Alzheimer’s disease (LOAD). This susceptibility to LOAD in R47H genotypes, is similar to that conferred by the ApoE4 gene.
The TREM2 gene is involved in immune regulatory processes in the brain and the R47H mutation impairs the gene’s ability to contain inflammation. One of the roles of the TREM2 gene that encodes for TREM 2 protein receptor on microglia, is to aid the brain in efficiently eliminating beta amyloid–the toxic protein that forms plaques associated with Alzheimer’s disease.
Evidence indicates that TREM2 may repress the secretion and production of pro-inflammatory molecules, cytokines,* which are mediated by the central nervous system’s immune cells, the microglia** TREM2 would thus reduce the pro-inflammatory cascade associated with the activation of microglia, and the subsequent damage to neurons (1).
The R47H variant of the TREM2 gene essentially negates the protective action of TREM2 on the brain’s inflammatory processes. In addition, he R47H mutation inhibits the brain’s microglia role of clearing (phagocytosis) beta amyloid (2). These studies reinforce the linkage between Alzheimer’s disease and pro-inflammatory processes linked to the disease process.
Neurons and neuroglial cells. Glial cells are non-neuronal cells in brain. There are different types of glial cells: oligodendrocyte, microglia, astrocytes and Schwann cells.
The microglia function is central to the immune defense of the central nervous system and chronic activation of microglia is a component to the proinflammatory mechanisms associated with Alzheimer’s disease.
One study discovered the mutation when it examined the genome sequences of 2,261 individuals from Iceland to look for gene variations that affect when nursing home care is needed. The researchers then looked for this gene variant in two samples; 110,050 Icelandic individuals from the general population and 3,550 Icelandic individuals with Alzheimer’s disease. Within the general population sample the researchers looked at 8,888 individuals who had lived until at least their 85th birthday without an Alzheimer’s disease diagnosis and 1,236 that did not show any impairment at comparable age.
The R47H variant was discovered in both samples, and it was associated with worse cognitive performance regardless of Alzheimer’s disease diagnosis. A gradual diminishment of cognitive performance was present in the non-carriers indicated by slight increases in cognitive performance scores (2.2 at 81 years of age vs. 2.7 at 99 years of age), however this cognitive decline was much more severe in those that carried the variant as evidenced by the more dramatic increase in scores (2.3 at 81 vs. 4 at 97).
These researchers also examined the TREM2 gene variant frequency in groups of controls and patients with Alzheimer’s disease from the U.S., Netherlands, Norway, and Germany with 9727 controls and 2037 individuals with Alzheimer’s disease. They found the gene variant was three times more frequent in the patients with Alzheimer’s disease (2).
Another study led by the University College London initially looked at 1,092 individuals with Alzheimer’s disease and 1,107 individuals without the disease. The researchers discovered that those with the R47H gene variant of TREM2 were found in about 1.9% of those with the disease, but only .37% of those without the disease. They confirmed their results in a larger sample of 6700 with the disease and 16,200 without the disease (3).
Genetic Risk Susceptibility
The mutation only occurs in .3% – .5% of the general population (1,2,3). As in the susceptibility risk associated with the ApoE4 variant, not everyone who carries the R47H mutation will develop Alzheimer’s disease because the mutation isn’t fully penetrant.***
Advisory Council on Alzheimer’s Research, Care, and Services
January 14, 2013
Based on the findings in these studies, the TREM2 gene variant may have a similar risk influence on the onset of Alzheimer’s disease as does the APOE4 gene variant. Individuals with TREM2 variant, R47H, were shown to be three to five times more likely to get Alzheimer’s than those without the mutation. Studies exploring the ApoE4 gene variant, and increased susceptibility to AD , demonstrated a 2 to 10 times increased risk in carriers of one, or two copies of the gene, respectively.
*Cytokines… “chemical messengers” secreted by immune cells. Cytokines are immune system modulators, and a set of them that stimulate inflammatory responses, are often referred to as proinflammatory cytokines.
** Microglia…Microglial cells are one of the three main types of central nervous system glia. The central nervous system (CNS) consists of neurons and glial cells. The three types of CNS Glial cells are Astrocytes, Oligodendrocytes, and Microglia. Glial are commonly described as the “supporting cells” of the nervous system.
***Fully penetrant…In genetics, Penetrance describes the effect a gene variant will have on the manifestation of the disease. If not “fully penetrant”, not all individuals who have the variant will develop a disease. The Trem2 variant, R47H, is not fully penetrant for Alzheimer’s disease. Other risk factors, genes and environmental factors will also influence risk for disease onset.
1. TREM2 in Alzheimer’s disease.
Teng Jiang, Jin-Tai Yu, Xi-Chen Zhu, Lan Tan
Mol Neurobiol. 2013 Aug;48(1):180-5.
2. Variant of TREM2 associated with the risk of Alzheimer’s disease.
N Engl J Med. 2013 Jan 10;368(2):107-16.
Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K.
3. TREM2 variants in Alzheimer’s disease.
N Engl J Med. 2013 Jan 10;368(2):117-27.
Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J; Alzheimer Genetic Analysis Group.