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Song of Myself By 1819-1892 1 I celebrate myself, and sing myself, And what I assume you shall assume, For every atom belonging to me as good belongs to you. I loafe and invite my soul, I lean and loafe at my ease observing a spear of summer grass. My tongue, every atom of my blood, form'd from this soil, this air, Born here of parents born here from parents the same, and their parents the same, I, now thirty-seven years old in perfect health begin, Hoping to cease not till death. Creeds and schools in abeyance, Retiring back a while sufficed at what they are, but never forgotten, I harbor for good or bad, I permit to speak at every hazard, Nature without check with original energy. 2 Houses and rooms are full of perfumes, the shelves are crowded with perfumes, I breathe the fragrance myself and know it and like it, The distillation would intoxicate me also, but I shall not let it. The atmosphere is not a perfume, it has no taste of the distillation, it is odorless, It is for my mouth forever, I am in love with it, I will go to the bank by the wood and become undisguised and naked, I am mad for it to be in contact with me.

Name of textbook: Mader Biology. Edition: 10 th. Author: McGraw-Hill. Copyright: 2011. Big Idea 1: The process of evolution drives the diversity and unity of life. Essential knowledge. Illustrative examples covered. 1.a.1 Natural selection is a major mechanism of evolution. 15.1-3 & 16.1-3. 1 I celebrate myself, and sing myself, And what I assume you shall assume, For every atom belonging to me as good belongs to you. I loafe and invite my soul.

Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Variant of TREM2 Associated with the Risk of Alzheimer's Disease Thorlakur Jonsson, Ph.D., Hreinn Stefansson, Ph.D., Stacy Steinberg, Ph.D., Ingileif Jonsdottir, Ph.D., Palmi V.

Jonsson, M.D., Jon Snaedal, M.D., Sigurbjorn Bjornsson, M.D., Johanna Huttenlocher, B.S., Allan I. Levey, M.D., Ph.D., James J. Lah, M.D., Ph.D., Dan Rujescu, M.D., Harald Hampel, M.D., Ina Giegling, Ph.D., Ole A.

Andreassen, M.D., Ph.D., Knut Engedal, M.D., Ph.D., Ingun Ulstein, M.D., Ph.D., Srdjan Djurovic, Ph.D., Carla Ibrahim-Verbaas, M.D., Albert Hofman, M.D., Ph.D., M. Arfan Ikram, M.D., Ph.D., Cornelia M van Duijn, Ph.D., Unnur Thorsteinsdottir, Ph.D., Augustine Kong, Ph.D., and Kari Stefansson, M.D., Ph.D. N Engl J Med 2013; 368:107-116 DOI: 10.1056/NEJMoa1211103. Methods We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function.

We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease. We performed replication tests using case–control series from the United States, Norway, the Netherlands, and Germany.

We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. Results A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 ( TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P=3.42×10 −10). The mutation had a frequency of 0.46% in controls 85 years of age or older.

We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10 −12 in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P=0.003). Figure 1 Cognition as a Function of Age in Controls Who Were Carriers or Noncarriers of the rs75932628-T Variant Associated with the Risk of Alzheimer's Disease. Shown are scores on the Cognitive Performance Scale (CPS) for carriers and noncarriers of the rs75932628-T variant associated with Alzheimer's disease, according to age.

Scores on the CPS range from 0 to 6, with higher scores indicating more severe impairment. Values are shown in 2-year bins (i.e., the data point for 81 years of age contains data for ages 80 and 81), except for the last bin, which represents ages of 98, 99, and 100 years.

No CPS data were available for carriers in the last age bin. Each data point represents the average CPS score for participants in the respective age bin. The I bars represent standard errors. The graph is based on 307 measurements from 53 carriers and 24,152 measurements from 3699 noncarriers. Patients in whom Alzheimer's disease had been diagnosed were not included in the analysis.

Alzheimer's disease, the most common form of dementia in the elderly, is a neurodegenerative disorder that is characterized by a slow but progressive loss of cognitive function. Extracellular amyloid plaques, intracellular neurofibrillary tangles, and loss of neurons and synapses resulting in brain atrophy are the main pathological hallmarks of Alzheimer's disease.

Disease onset is usually after the age of 70 years, although the prevalence increases exponentially with age after the age of 65 years and exceeds 25% in those over the age of 90 years. The vast majority of variants in the sequence of the genome that have been shown to markedly affect the risk of Alzheimer's disease are rare variants in APP, PSEN1, and PSEN2 (encoding amyloid precursor protein, presenilin 1, and presenilin 2, respectively). These variants appear to be fully penetrant and result in Alzheimer's disease with an early onset, in most cases before the age of 60 years. However, these variants do not shed light on the most common, late-onset form of the disease. Although a number of common, low-risk variants have been associated with late-onset Alzheimer's disease, the ε4 allele of apolipoprotein E (ApoE), originally discovered as a risk factor for Alzheimer's disease in 1993, remains by far the most important sequence variant affecting the risk of late-onset Alzheimer's disease because of its prevalence and the size of its effect on risk, with reported odds ratios ranging from 3 to 4 (a meta-analysis is available at ).

To search for sequence variants that influence the risk of Alzheimer's disease, we performed a genomewide association analysis with variants (found by whole-genome sequencing of samples from 2261 Icelanders) that were likely to affect protein function. These variants were imputed in patients with Alzheimer's disease and controls with the use of long-range haplotype phasing and chip-genotype information. Using this approach, we have recently reported variants that greatly influence the risk of the sick sinus syndrome, gout, gliomas, ovarian cancer, and Alzheimer's disease. Icelandic Population Approval for these studies was obtained from the National Bioethics Committee and the Icelandic Data Protection Authority. Written informed consent was obtained from all participants or their guardians before blood samples were drawn, and all sample identifiers were encrypted in accordance with the regulations of the Icelandic Data Protection Authority. In 1062 patients, the diagnosis of Alzheimer's disease was established according to the criteria for definite, probable, or possible Alzheimer's disease of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA).

In another 2697 patients, the diagnosis was established according to the criteria for code F00 of the International Classification of Diseases, 10th Revision (ICD-10). We assessed cognitive function using data from the Resident Assessment Instrument (RAI), with which assessment is performed on an individual basis and recorded in a Minimum Data Set (MDS 2.0) form. Data were primarily obtained through RAI 2.0 for Nursing Homes, which is a comprehensive and standardized instrument originally developed for residential facilities for the elderly, with additional information provided by the InterRAI Assessment for Home Care. We assessed cognitive function using the MDS Cognitive Performance Scale (CPS), which combines selected MDS 2.0 items expressing different measures of cognitive function on a seven-category scale, ranging from 0 (intact) to 6 (severe impairment). The CPS is hierarchical and based on an assessment of several measures of cognitive function; a 1-unit change is a reflection of distinct and measurable changes in at least one cognitive domain. A total of 1236 study participants with a score of 0 on the CPS scale were used as cognitively intact controls. We selected 110,050 population controls from among participants in various research projects at deCODE Genetics, excluding those in whom Alzheimer's disease had been diagnosed.

Rip Rig And Panic God Rar on this page. Norwegian Population The Regional Ethical Committee and the Norwegian Data Protection Agency approved the studies. The sample of patients with Alzheimer's disease consisted of home-dwelling outpatients referred to three memory clinics in the Southeast Health Region of Norway for suspicious dementia.

The patients underwent a standardized comprehensive assessment, which consisted of taking a medical history from the patient as well as a close family member, comprehensive neuropsychological testing, a physical and psychiatric examination with the use of standardized assessment scales, blood sample analyses, and brain imaging. Diagnoses of Alzheimer's disease were established in accordance with the ICD-10 criteria for research. Controls were recruited as a part of the Thematically Organized Psychosis study (enrolling 700 patients and 291 controls) and two Norwegian studies of attention deficit–hyperactivity disorder (enrolling 626 patients and 898 controls). Emory Population All participants underwent a research evaluation in the Emory Alzheimer's Disease Research Center in Atlanta. Participants were classified as controls or as having probable Alzheimer's disease after a review of the history, physical examination, neuropsychological testing, and available clinical records in a consensus conference among neurologists, neuropsychologists, and other health care professionals.

Munich Population Patients with Alzheimer's disease were recruited at the memory clinic of the Department of Psychiatry, University of Munich, Germany. Participants in whom dementia associated with Alzheimer's disease was diagnosed fulfilled the criteria for probable Alzheimer's disease, according to the NINCDS-ADRDA criteria.

The control group included participants who were randomly selected from the general population of Munich. Controls who had a disease of the central nervous system or a psychotic disorder or who had a first-degree relative with a psychotic disorder were excluded. Rotterdam Population The Rotterdam Study I is a prospective, population-based cohort study enrolling 7983 residents who are 55 years of age or older and live in Ommoord, a suburb of Rotterdam, the Netherlands. Baseline examinations took place between 1991 and 1993; follow-up examinations were performed between 1997 and 1999 and between 2002 and 2006; a final follow-up examination was performed between 2009 and 2011.

Participants were screened for prevalent dementia with the use of a three-stage process; those free of dementia remained under surveillance for incident dementia, a determination that was made with the use of record linkage and assessment at three subsequent examinations. We included all patients in whom Alzheimer's disease was diagnosed before December 31, 2011; a subset of those in whom Alzheimer's disease was not diagnosed served as controls. Screening was done with the MMSE and Geriatric Mental Schedule (GMS) for organic (i.e., medical or physical) mental illness for all participants.

Participants who were deemed to be positive on screening (a score of 0 on the GMS organic level) underwent the Cambridge Mental Disorders of the Elderly Examination (CAMDEX) schedule. Participants in whom dementia was suspected underwent more extensive neuropsychological testing. When available, imaging data were used. In addition, all participants were continuously monitored for major events (including dementia) through automated linkage of the study database with digitized medical records from general practitioners, the Regional Institute for Outpatient Mental Health Care, and the municipality. In addition, physicians' files from nursing homes and general practitioners' records for participants who moved out of the Ommoord district were reviewed twice a year. For suspected dementia events, additional information (including neuroimaging) was obtained from hospital records, and research physicians discussed available information with a neurologist experienced in dementia diagnosis and research to verify all diagnoses. Dementia was diagnosed in accordance with internationally accepted criteria for dementia in the revised third edition of the Diagnostic and Statistical Manual of Mental Disorders, and Alzheimer's disease was diagnosed on the basis of the NINCDS-ADRDA criteria for possible, probable, or definite disease.

The criteria of the National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) were used to diagnose vascular dementia. The final diagnosis was determined by a panel consisting of a neurologist, a neurophysiologist, and a research physician. The diagnoses of Alzheimer's disease and vascular dementia were not mutually exclusive. Whole-Genome Sequencing, SNP Calling, and Imputation We performed whole-genome sequencing on samples obtained from 2261 Icelandic participants, followed by single-nucleotide-polymorphism (SNP) calling and genotype imputation, using methods that were described previously. The chip-genotype imputation was based on chip genotypes from 95,085 persons.

Approximately 34 million markers (SNPs and insertion–deletion polymorphisms), including the 191,777 functional variants identified through whole-genome sequencing, were imputed in the Icelandic cases and controls. The information content for rs75932628 in the imputed data was 0.999 (as compared with 1.0 for perfect information). Single-Track Assay SNP Genotyping We performed single SNP genotyping of rs75932628 using the Centaurus (Nanogen) platform.

No mismatches resulted from a comparison of genotypes determined through imputation and Centaurus genotyping of 964 participants, including 30 participants who were predicted to be heterozygous for the rare allele and 2 who were predicted to be homozygous for the rare allele. Samples from the United States, Germany, and Norway were also typed with the use of Centaurus assays. Before analysis, we excluded samples with a genotype yield of less than 90% and one member of each pair of duplicate samples. The genotyping yield was at least 95% in both cases and controls in samples from all study locations, and all genotypes were in Hardy–Weinberg equilibrium.

Samples from the Netherlands were genotyped for rs75932628 with Taqman allelic discrimination Assays-by-Design (Applied Biosystems). All measurements were performed in accordance with the manufacturer's protocols; primer and probe sequences are available from the manufacturer.

Imputation of Genomewide Data We downloaded genotype and phenotype data from the Genetic Alzheimer's Disease Associations (GenADA) study, the National Institute on Aging Late Onset Alzheimer's Disease and National Cell Repository for Alzheimer's Disease Family Study (NIA-LOAD), and the Electronic Medical Records and Genomics (eMERGE) genomewide association study of dementia from the controlled-access portal of the National Institutes of Health Genotype and Phenotype database (dbGAP, accession number phs000234.v1.p1). Two small components of NIA-LOAD, phs000168.v1.p1.c2 (involving 28 participants) and phs000168.v1.p1.c1 (involving 570 participants), could not be included because consent from participants was for nonprofit use only. In addition, rs75932628 could not be successfully imputed on the basis of the GenADA data (information content associated with the additive test.

Statistical Analysis For the Icelandic data, we performed case–control association testing of imputed genotypes using methods that were described previously. Odds ratios were calculated on the basis of a multiplicative model for the two chromosomes of each individual. The method of genomic control was used to correct for relatedness and potential population stratification.

We used logistic regression to perform association analysis that was based on the NIA-LOAD and eMERGE data sets, with the first three principal components included as covariates to adjust for population stratification. Before the analysis, we removed data for participants with genotyped sex inconsistent with reported sex, the lower-yield sample in each pair of duplicates, genetically related older cases and younger controls (to eliminate the inclusion of first- or second-degree relatives), and participants with an estimated fraction of less than 0.9 European ancestry in analysis with STRUCTURE software and using as a reference HapMap samples of Utah residents with ancestry from northern and western Europe (CEU), Han Chinese in Beijing and Japanese in Tokyo (CHB+JPT), and Yoruba in Ibadan, Nigeria (YRI). We used Fisher's exact test to perform other association analyses. We combined results from the various replication groups, and from the discovery group and the replication groups, using inverse-variance–weighted meta-analysis. The relationship between the age at onset and rs75932628-T was examined with the use of a linear model with the age at onset as the response and rs75932628-T and the ApoE ε4 count as predictors. We analyzed the effect of age on the CPS score, using determinations made at several ages for each participant.

The CPS score is based on the Resident Assessment Instrument for Nursing Homes, which is applied on average three times per year in Icelandic nursing homes. Since the residency time in nursing homes in Iceland is on average 3 to 4 years, many determinations of CPS that are performed at different times are available for most persons. Clinical Kinesiology And Anatomy 5th Edition Quizzes Buzzfeed.

We assessed the difference in CPS score between rs75932628-T carriers and noncarriers in the age range from 80 to 100 years using a mixed model with age and carrier status as fixed effects and the individual as a random effect. We used bootstrapping methods to calculate standard errors for the analysis of the CPS score versus age. Association of Variant with Alzheimer's Disease Through whole-genome sequencing of samples from 2261 Icelanders, we found 191,777 nonsynonymous SNPs, frameshift variants, splicing variants, and stop gain–loss variants and imputed these variants in patients with Alzheimer's disease and controls. A total of 3550 patients with Alzheimer's disease were included in the analysis. Our control group included persons who had reached the age of 85 without a diagnosis of Alzheimer's disease. With the exclusion of the ApoE locus and the A673T variant in APP, only one marker, rs75932628, showed a genomewide association, on the basis of either the Bonferroni-adjusted threshold of P. Replication Series In an attempt to replicate the association between rs75932628-T and Alzheimer's disease, we genotyped rs75932628 in cohorts from the United States (Emory), Germany, the Netherlands (Rotterdam Study), and Norway.

We found that rs75932628-T conferred a risk of Alzheimer's disease in all replication cohorts, with a combined odds ratio of 2.83 (95% CI, 1.45 to 5.40; P=0.002 ( Table 2 Replication Analysis of the Association between the rs75932628-T Variant and Alzheimer's Disease. Combining results from Iceland (using population controls who were at least 85 years of age) and the replication cohorts, we found that the overall association between rs75932628-T and Alzheimer's disease was highly significant (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10 −12). We also estimated the effect of rs75932628-T on the risk of Alzheimer's disease by imputing the variant in two publicly available data sets (NIA-LOAD and eMERGE). Association results that were based on imputed genotypes for rs75932628-T in these data sets were found to be consistent with the observed effect of rs75932628-T on disease risk in the genotyped cohorts (odds ratio, 2.66; 95% CI, 1.46 to 4.84; P=0.001) (Table S2 in the ). Association with ApoE ε4 We investigated the effect of the ε4 allele of ApoE on the association between rs75932628-T and Alzheimer's disease. We found a somewhat higher odds ratio in ε4 noncarriers (4.03) than in ε4 carriers (2.38) (Table S3 in the ). The difference in the frequency of rs75932628-T in ApoE ε4 carriers, as compared with noncarriers, had borderline significance (odds ratio, 0.60; 95% CI, 0.37 to 0.98; P=0.04).

However, in a logistic-regression model, the interaction between rs75932628-T and ApoE ε4 was not significant (P=0.18), and the difference in frequency according to ApoE ε4 status in cases did not replicate in the additional data sets (odds ratio, 1.79; 95% CI, 0.73 to 4.43; P=0.20) (Table S4 in the ). Although the population frequency of rs75932628-T was low (0.63% in Iceland), it conferred a risk of Alzheimer's disease that was similar to the risk the ApoE ε4 allele, which has a population frequency of 17.3% in Iceland. (As compared with controls 85 years of age or older, the odds ratio for Alzheimer's disease was 2.92 for rs75932628-T and 3.08 for the ApoE ε4 allele.) We also found that in Iceland, each copy of rs75932628-T was associated with an age at onset of Alzheimer's disease that was lower by 3.18 years than in controls without the variant (P=0.20). Although this effect was similar to that of ApoE ε4 (3.22 years; P=4.1×10 −8), it was not significant, owing to the low frequency of the variant, which resulted in a reduced effective sample size and an elevated standard error (2.49 for rs75932628-T vs.

0.58 for ApoE ε4). We found a similar result in the Dutch data (3.65 years per allele, P=0.13), and the combined effect was found to be 3.4 years per allele (P=0.048). Association According to Age We also investigated how rs75932628-T affects cognitive function in elderly controls in whom Alzheimer's disease had not been diagnosed. Cognitive function declined steadily with age in elderly persons between the ages of 80 and 100 ( Figure 1 Cognition as a Function of Age in Controls Who Were Carriers or Noncarriers of the rs75932628-T Variant Associated with the Risk of Alzheimer's Disease. Shown are scores on the Cognitive Performance Scale (CPS) for carriers and noncarriers of the rs75932628-T variant associated with Alzheimer's disease, according to age. Scores on the CPS range from 0 to 6, with higher scores indicating more severe impairment.

Values are shown in 2-year bins (i.e., the data point for 81 years of age contains data for ages 80 and 81), except for the last bin, which represents ages of 98, 99, and 100 years. No CPS data were available for carriers in the last age bin.

Each data point represents the average CPS score for participants in the respective age bin. The I bars represent standard errors. The graph is based on 307 measurements from 53 carriers and 24,152 measurements from 3699 noncarriers.

Patients in whom Alzheimer's disease had been diagnosed were not included in the analysis. We found that carriers of rs75932628-T showed worse cognition (a mean increase of 0.87 units on the CPS) than did noncarriers (P=0.003). Clinical determination of Alzheimer's disease is partially based on progressive loss of cognitive function, in particular memory, with time. Thus, the decline in cognitive function that we observed in rs75932628-T carriers may be due to early cognitive deficits that ultimately result in Alzheimer's disease.

Alternatively, the decline may at least partially be due to a loss of cognitive function in old age that is not associated with Alzheimer's disease. The latter explanation is in keeping with the hypothesis that Alzheimer's disease may be the extreme of the cognitive decline of the elderly and caused by the same biochemical mechanism. Discussion Inflammation is a well-established histologic feature in the brains of patients with Alzheimer's disease. Complement factors were identified in amyloid plaques in the 1980s, followed by reports of clusters of activated microglia, complement-activation products, and cytokines in and near amyloid plaques. There is evidence that inflammation is an early event in the brains of patients with Alzheimer's disease. It has also been noted that the expression of genes associated with inflammation in the brain is increased in aging and that this effect is accentuated in patients with Alzheimer's disease. According to the amyloid hypothesis, which is the predominant theory about the pathogenesis of this disease, inflammation is a downstream effect of amyloidogenesis, which provides a trigger for the inflammatory response.

Genomewide association studies have also provided evidence of the importance of inflammation in Alzheimer's disease. Thus, low-risk variants have been found in CR1, which belongs to the complement factor family of genes; in MS4A6A and MS4A4E, which are members of a cell-surface gene family expressed in lymphoid tissue; and in CD33, which encodes a myeloid cell-surface receptor. TREM2 was originally identified as a DAP12-associated receptor that was expressed on macrophages and dendritic cells and was later shown to be expressed on osteoclasts and microglia. TREM2 is a transmembrane glycoprotein, consisting of an extracellular immunoglobulin-like domain, a transmembrane domain, and a cytoplasmic tail, which associates with DAP12 for its signaling function. TREM2 has both exogenous ligands on pathogens and endogenous ligands that remain largely unknown, although a recent study has shown that Hsp60 is an agonist of TREM2 in neuroblastoma cells and astrocytes. In addition, an endogenous ligand on dendritic cells has been found. In brain cells, TREM2 is primarily expressed on microglia, the resident histiocytes of the central nervous system.

Activation of microglia may lead to phagocytosis of cell debris and amyloid, but microglia can also be activated to promote the production of proinflammatory cytokines, or they may differentiate into antigen-presenting cells. A recent study showed that TREM2 expression is induced concomitantly with the formation of amyloid plaques in APP transgenic mice expressing the Swedish mutation (K670N/M671L) in APP, and this expression was found to correlate positively with amyloid phagocytosis by unactivated microglia. The expression of TREM2 also correlated positively with the ability of microglia to stimulate the proliferation of CD4+ T cells, as well as the secretion of tumor necrosis factor and CCL2, but not interferon-γ, into the extracellular milieu.

This led the authors to speculate that TREM2-positive microglia on plaques capture and present self-antigens to lymphocytes infiltrating the central nervous system without promoting proinflammatory responses. Furthermore, knockdown of TREM2 or DAP12 in microglia resulted in reduced phagocytosis of apoptotic neurons, whereas the overexpression of TREM2 increased such phagocytosis, suggesting that microglia recognize and phagocytose apoptotic neurons through TREM2 ligation. TREM2 has an antiinflammatory function; it inhibits macrophage response to ligation of toll-like receptor (TLR), and it negatively regulates TLR-mediated maturation of dendritic cells, type I interferon responses, and the induction of antigen-specific T-cell proliferation. Furthermore, TREM2 stimulation of dendritic cells induces partial activation without any production of proinflammatory cytokines.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, which produces increased signals from the deep white matter of the brain on T 2-weighted magnetic resonance imaging, is called Nasu–Hakola disease. It is a rare recessively inherited disease that is characterized by painful bone cysts in wrists and ankles, psychotic symptoms, and progressive presenile dementia with onset in the fourth decade of life, usually leading to death in the fifth decade of life. Loss-of-function mutations in DAP12 and TREM2 were originally found in patients with Nasu–Hakola disease about a decade ago, suggesting that the TREM2–DAP12–mediated pathway may be important for human brain and bone tissue. Nasu–Hakola disease and Alzheimer's disease are distinct from each other, and the clinical symptoms of Nasu–Hakola disease (early onset, painful bone cysts, fractures of bones of the limbs, and sclerosing leukoencephalopathy) are incompatible with the diagnosis of Alzheimer's disease. Bearing in mind that it is possible that rare mutations accounting for a small proportion of cases of common diseases may define a clinical subgroup, we looked for but did not find clinical features (e.g., sex distribution, radiographic features, and rate of disease progression) that clearly separate carriers of the R47H mutation from noncarriers with Alzheimer's disease, although the age at disease onset was on average 3.18 years earlier in the carriers than in the noncarriers. A homozygous mutation in the 5′ consensus donor splice site in intron 1 of TREM2 in a Lebanese family, leading to early-onset dementia without bone cysts, has been reported.

Furthermore, three homozygous mutations in TREM2 have recently been reported in three Turkish probands with frontotemporal dementia-like disease in the absence of bone cysts, and there is also a report of memory deficits in heterozygous carriers of a loss-of-function mutation in TREM2 in an Italian family. These findings suggest that TREM2 may be crucial for the integrity of cognitive function. The R47H substitution encoded by rs75932628-T is located within the extracellular immunoglobulin-like domain of TREM2. The amino acid substitution may result in decreased affinity of TREM2 for its natural ligands and affect its signaling. It has recently been proposed that TREM2 may represent a proteolytic substrate for γ-secretase, although the exact cleavage site was not identified.

If this proteolytic activity is confirmed, processing of TREM2 may be affected by the R47H substitution. In conclusion, we have found a new risk variant, rs75932628-T, for Alzheimer's disease. Although this variant occurs with less frequency than the ApoE ε4 allele, it confers a risk of Alzheimer's disease with an effect size that is similar to that of ApoE ε4.

Given the involvement of TREM2 in the phagocytic role of microglia on amyloid plaques, it is possible that reduced TREM2 activity caused by the R47H substitution may lead to brain damage through the inability of the brain to clear these toxic products. References • 1 Castellani RJ, Rolston RK, Smith MA. Alzheimer disease. Dis Mon 2010;56:484-546 • 2 Qiu C, Kivipelto M, von Strauss E. Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci 2009;11:111-128 • 3 Cruts M, Theuns J, Van Broeckhoven C.

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Nat Genet 2011;43:316-320 • 8 Sulem P, Gudbjartsson DF, Walters GB, et al. Identification of low-frequency variants associated with gout and serum uric acid levels. Nat Genet 20-1130 • 9 Stacey SN, Sulem P, Jonasdottir A, et al. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. Nat Genet 2011;4.