New Genetic Variant Implicated in Alzheimer's Disease

Neurology Today
20 December 2012; Volume 12(24); pp 1,13–14

Talan, Jamie

A genetic variant, TREM2, previously associated with an autosomal recessive form of early-onset dementia presenting with bone cysts and fractures, was implicated as a risk gene for Alzheimer's disease in genome-wide association studies by two separate international research groups.

PATHOLOGICAL FINDINGS from the study by Hardy et al. are shown here in samples containing variant D87N (panels A to D) and variant R47H (panels E to L) obtained from patients with Alzheimer's disease. A carrier of the D87N variant had mature plaques (panel A, arrow), along with more diffuse plaques and a moderate degree of cerebral amyloid angiopathy (panel B). Amyloid beta was found deposited in leptomeningeal blood vessels. Tau immunohistochemical analysis revealed neuritic plaques (panel C) in the hippocampus and numerous neurofibrillary tangles throughout the cortical regions (panel D). Two carriers of the R47H variant also showed pathological features of Alzheimer's disease (with sections obtained from one patient in panels E to H and from the other in panels I to L) in the form of mature and diffuse plaques (panels E and J, arrow). Severe cerebral amyloid angiopathy was evident with the presence of parenchymal capillary involvement (panel F) and circumferential deposition of beta amyloid (panel K). Also present were neuritic plaques (panels G and L, arrow in panel L), neurofibrillary tangles (panels H and L), and abundant neuropil threads. However, one carrier of the R47H variant showed only moderate cerebral amyloid angiopathy with no other pathological abnormalities (panel I, inset).

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Two teams of scientists have identified a genetic variant — TREM2 (encoding the triggering receptor expressed on myeloid cells 2 protein) — that puts people at risk for Alzheimer's disease (AD). The variant associated with late-onset AD may be as strong a risk factor as apolipoprotein E4 (APOE4), according to the study investigators, though the variant is not as common. The papers were published in the Nov. 14 online edition of The New England Journal of Medicine.

TREM2 controls two signaling pathways: one that regulates phagocytosis, stimulating the expression of microglia that then removes cell debris, including amyloid proteins, and another that suppresses inflammatory reactivity and dampens down cytokine production and secretion, explained John Hardy, PhD, chair of the department of molecular neuroscience at University College London's Institute of Neurology, who led one of the studies.

Dr. Hardy and his colleagues reported in the current study that TREM2 rises in parallel with an increase in cortical levels of amyloid beta. “We believe that TREM2 controls microglial responses and when it is not working properly it can lead to a build-up of cellular debris and the beta amyloid present in AD,” said Dr. Hardy. “The variants can also fuel inflammatory cascades, which can lead to an overblown inflammatory response and neuronal death.”

TREM2 is a receptor and the hope is that it may be possible to activate it and protect the brain from a microglia attack, said Dr. Hardy who collaborated with research teams from the NIH, the Mayo Clinic, and the University of Toronto, as well as institutions in the United Kingdom.

Investigators were interested in the variant because homozygous loss-of-function mutations in TREM2 had been associated with an autosomal recessive form of early-onset dementia presenting with bone cysts and fractures called polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, or Nasu-Hakola disease.

The clinical phenotype in Nasu-Hakola patients looks like frontotemporal dementia. Patients are apathetic, disinhibited and exhibit inappropriate behavior that over time is followed by increasing memory loss and cognitive problems. The bone fractures begin in early adulthood but once dementia sets in during the fourth or fifth decade the patients die within seven years. At autopsy, all of the white matter beneath the cortex is damaged. (See “TREM2 and Nasu-Hakola Disease.”)

The investigators had identified homozygous TREM2 mutations in three Turkish patients presenting with a clinical phenotype associated with frontotemporal dementia and leukodystrophy but without any bone-associated symptoms. In addition, a genome-wide meta-analysis pooling linkage results for late-onset Alzheimer's disease identified eight linkage regions with nominally significant associations.

With new genomic technology in hand, Dr. Hardy and his colleagues sought to understand whether there were obvious consequences for people who inherited one copy of the mutated TREM2.

In their study, Dr. Hardy, Rita Guerreiro, PhD, and their colleagues used sequencing methods to analyze the genetic variability of TREM2 variants in 1,092 people with AD and 1,107 people without any form of dementia. It was known from the genomic data on Nasu-Hakola patients that the TREM2 variant rs75932628 was predicted to cause a R47H substitution. They then mined three genome-wide association studies (GWAS) of AD and looked for the association of the R47H variant. They also performed a GWAS analysis on another 1,887 AD cases and 4,061 controls. To understand how the variant affected brain tissue they assayed TREM2 expression across many brain regions of the human brain and in mouse models of AD and controls and found genes that were differentially expressed in the variant and not in the controls.

They reported in the current paper that there were 22 variant alleles in the 1,092 AD patients compared with five variant alleles in the 1107 controls (p<0.001). The most common variant in those with AD was rs75932628. The GWAS meta-analysis confirmed the finding, as did their other genomic studies. They also found six other variants that were only in the AD cases and two variants that were only in controls.

DR. JOHN HARDY: “We believe that TREM2 controls microglial responses and when it is not working properly it can lead to a build-up of cellular debris and the beta amyloid present in AD. The variants can also fuel inflammatory cascades, which can lead to an overblown inflammatory response and neuronal death.”

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They went on to conduct pathological examinations of five brains with the variants and found that these brains had the hallmarks of Braak stage 6, indicative of full-blown AD. Two of the samples tested showed mild Lewy-body disease and another had TDP-43 (TAR DNA-binding protein 43) disease.

In another study published in the same issue of the journal, Kari Stefansson, MD, PhD, chief operating officer of deCODE Genetics, teamed up with colleagues at Illumina; scientists from the National Hospital of Iceland; and geneticists from Holland, Germany, and the United States to conduct genome sequencing and genotyping on blood samples from thousands of people living in Iceland. Once they identified TREM2's role in AD, they branched out to colleagues throughout the world to analyze the variants in the genomes of 3,550 people with AD and a control population of people over 85 with no signs of clinical dementia.

The researchers identified approximately 41 million markers, including 191,777 functional variants, in 2,261 Icelandic samples. Variants of TREM2 emerged as a strong risk factor for AD. Other samples tested confirmed the gene's role in AD.

The team also identified four people in their Icelandic cohort with two mutated copies of TREM2. Two had AD and two others, both in their early 50s, did not. They also conducted cognitive tests on normal elderly people with and without TREM2 variants and found poorer cognitive among those with a TREM2 variant.

“The discovery of variant TREM2 is important because it confers high risk for Alzheimer's and because the gene's normal biological function has been shown to reduce immune response that may contribute to the disease,” Dr. Stefansson said. “These combined factors make TREM2 an attractive target for drug development.”

In an accompanying editorial, Harald Neumann, MD, of the European Neuroscience Institute Göttingen in Germany, and Mark J. Daly, PhD, of Harvard Medical School's Center for Human Genetics Research, wrote that these “two groups of researchers convincingly show in the Journal that rare variants in TREM2, encoding triggering receptor expressed on myeloid cells 2 protein, cause susceptibility to late-onset Alzheimer's disease, with an odds ratio similar to that of the APOe4 allele. Although the most compelling TREM2 variant (encoding a substitution of arginine by histidine at residue 47 [R47H] of the TREM2 protein) is rare, with an allelic prevalence of 0.63% in Iceland, these findings implicate a gene and naturally arising perturbation that may generate new insights into the pathogenesis of late-onset Alzheimer's disease.” (Dr. Hardy said the prevalence of the disease variants in their heterogeneous population is around one percent.)

“The biologic effect of the variant was consistent across the many populations studied by the two groups,” they added.

Thomas Bird, MD, professor of medicine, neurology, and medical genetics at the University of Washington, described the two current studies as “impressive and remarkable.”

“It's plausible biology,” Dr. Bird said. “It is a gene and a protein that is active in microglia and we now know that microglia are involved in AD.”

Rudolph Tanzi, PhD, the Joseph P. and Rose F. Kennedy professor of child neurology and mental retardation at Massachusetts General Hospital, said: “TREM2 fits very nicely with the developing story in AD genetics that the innate immune system is important. From a biological standpoint, TREM2 is very interesting. The state of microglial cells is part of the innate immune system. If we had a therapy that kept microglia in a protected state it could be a great way to push back AD.”

LISTEN UP, TUNE IN: John Hardy, PhD, chair of the department of molecular neuroscience at University College London's Institute of Neurology, who led one of two international genome-wide association studies implicating TREM2 in Alzheimer's disease, discusses the variant's role in microglial responses and inflammatory cascades, which can lead to an overblown inflammatory response and neuronal death: http://bit.ly/dy2KLx .

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Since 1973, when Nasu-Hakola was first described, a handful of families in Scandinavia and Japan with the disease were reported. In 1983, Thomas Bird, MD, professor of medicine, neurology, and medical genetics at the University of Washington, published the case of a 48-year old born into a family where others had Nasu-Hakola. An autopsy revealed plaques and tangles.

DR. THOMAS BIRD

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Dr. Bird, who believed that this was only the second family described in the US, sent the Japanese scientists DNA from his patient. When Dr. Bird diagnosed his patient, the man told him about one of his brothers, who had died at 48. An autopsy had been done on the man's brother and the slides were sent to University of Washington for review. That is when pathologists saw the hallmark signs of Alzheimer's disease. In 2002, it was confirmed that Dr. Bird's patient had had the TREM2 mutation. Dr. Bird serves on the editorial advisory board of Neurology Today.

—Jamie Talan

• Guerreiro R, Wojtas A, Hardy J, et al, for the Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer's disease. 2012; E-pub 2012 Nov. 14.

• Jonsson T, Stefansson H, Stefansson K, et al. Variant of TREM2 associated with the risk of Alzheimer's disease. 2012; E-pub 2012 Nov. 14.

• Neumann H, Daly MJ. Editorial: Variant TREM2 as risk factor for Alzheimer's disease. 2012; E-pub 2012 Nov. 14.

• Chouery E, Delague V, Mégarbané A, et al. Mutations in TREM2 lead to pure early-onset dementia without bone cysts. 2008;29(9):E194–204.