Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Aug 1.
Published in final edited form as: Neurobiol Aging. 2015 Apr 25;36(8):2443.e21–2443.e26. doi: 10.1016/j.neurobiolaging.2015.04.012

More evidence for association of a rare TREM2 mutation (R47H) with Alzheimer’s disease risk

Samantha L Rosenthal 1, Mikhil N Bamne 1, Xingbin Wang 1, Sarah Berman 2, Beth E Snitz 2, William E Klunk 3, Robert A Sweet 2,3,4, F Yesim Demirci 1, Oscar L Lopez 2, M Ilyas Kamboh 1
PMCID: PMC4465085  NIHMSID: NIHMS684666  PMID: 26058841

Abstract

Over twenty risk loci have been identified for late onset Alzheimer’s disease (LOAD), most of which display relatively small effect sizes. Recently, a rare missense (R47H) variant, rs75932628 in TREM2, has been shown to mediate LOAD risk substantially in Icelandic and Caucasian populations. Here we present more evidence for the association of the R47H with LOAD risk in a Caucasian population comprising 4,567 LOAD cases and controls. Our results show that carriers of the R47H variant have a significantly increased risk for LOAD (OR=7.40, P=3.66E-06). In addition to AD risk, we also examined the association of R47H with AD-related phenotypes, including age-at-onset, psychosis, and amyloid deposition, but found no significant association. Our results corroborate those of other studies implicating TREM2 as a LOAD risk locus and indicate the need to determine its biological role in the context of neurodegeneration.

Keywords: TREM2, rare variants, LOAD

Introduction

Late-onset Alzheimer’s disease (LOAD) is a fatal neurodegenerative disorder affecting more than 5 million Americans (http://www.alz.org/alzheimers_disease_facts_and_figures.asp#quickFacts, [accessed 12 Jan 2015]). Alzheimer’s patients exhibit progressive deficits in cognitive function thought to be caused by the combination of abnormal aggregation of beta-amyloid (Aβ) and hyperphosphorylation of the microtubule-stabilizing tau protein in the brain. The full molecular mechanism of disease has yet to be determined. Previously, 21 risk loci—APOE, CR1, BIN1, INPP5D, MEF2C, CD2AP, HLA-DRB1/HLA-DRB5, EPHA1, NME8, ZCWPW1, CLU, PTK2B, PICALM, SORL1, CELF1, MS4A4/MS4A6E, SLC24A4/RIN3, FERMT2, CD33, ABCA7, and CASS4 —have been identified for LOAD in large genome-wide association studies (GWAS) (Harold et al., 2009, Hollingworth et al., 2011, Lambert et al., 2013, Naj et al., 2011, and Seshardi et al., 2010). These loci are varied in genomic location, biological function, and cellular localization and expression. Rare mutations affecting LOAD risk also have been identified with sequencing methods in the APP and PLD3 genes (Bamne et al., 2014, Cruchaga et al., 2014, Jonsson et al., 2012, and Kero et al., 2013).

Triggering receptor expressed on myeloid cells 2 (TREM2) is differentially expressed by microglia among different brain regions (Schmid et al., 2002). Two independent groups found a rare missense variant, rs75932628, in exon 2 of TREM2 (Guerreiro et al., 2013a and Jonsson et al., 2013). This substitution of histidine for arginine at residue 47 (R47H) increases LOAD risk at a magnitude similar to that of APOE*4. Other groups have found similar associations in Caucasian populations from both Europe and North America (Benitez et al., 2013, Giraldo et al., 2013, Gonzalez et al., 2013, and Roussos et al., 2014). This variant has also been associated with early-onset Alzheimer’s disease (EOAD) in a case/control study of Caucasian individuals of French descent (Pottier et al., 2013). An association between R47H carriers with both history of parental LOAD and earlier maternal age- at -onset in a cohort of middle-aged unaffected individuals has been described as well (Engelman et al., 2014).

In addition to its association with LOAD, variants in TREM2 have been shown to cause autosomal recessive Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL), a disease which counts among its features early onset neurodegeneration (Paloneva et al., 2002 and Sorgana et al., 2003). Risk for other neurodegenerative diseases, including frontotemporal dementia (FTD) (Cuyvers et al., 2013, Guerreiro 2013b, 2013c, and Rayaprolu 2013), Parkinson’s disease (PD) (Rayaprolu et al., 2013), and sporadic amyotrophic lateral sclerosis (ALS) (Cady et al., 2014), also appears to be mediated by TREM2 variation. Network analysis revealed connections of other known AD genes to TREM2, as well as genes with known functions in other neurological diseases, suggesting a microglial link among these diseases (Forbosco et al., 2013).

Neuroinflammation is thought to play a key role in LOAD pathogenesis (reviewed by Latta et al., 2014). TREM2 is expressed primarily by microglial cells of the brain, is involved in neuroinflammatory responses, and complexes with DAP12 (aka TYROBP) for intracellular signaling (reviewed by Ma et al., 2014). Ligands for TREM2 have yet to be identified, although one study shows an increase of these unknown ligands on apoptotic cells, including neurons (Hsieh et al., 2009). An examination of TREM2 in senescence-accelerated mice showed TREM2 levels increase with age. The same study demonstrated decreased levels of TREM2 are responsible for increased expression of pro-inflammatory cytokines, tumor necrosis factor (TNF) –α and interleukin (IL)-6 and decreased expression of anti-inflammatory cytokine, IL-10 (Jiang et al., 2014). The aim of this study is to replicate the association of the TREM2 R47H variant in a large AD case/control sample. Additionally, the associations of this variant with psychosis (a common LOAD endophenotype), fibrillar amyloid-beta (Aβ) deposition determined by Pittsburgh Compound-B (PiB) positron emission tomography (PET), and age-at-onset (AAO) are examined.

Methods

Study Population

The study population and informed consent procedures have been described previously (DeKosky et al., 2008 and Kamboh et al., 2012). Briefly, 4,885 individuals from two cohorts, the University of Pittsburgh Alzheimer’s Disease Research Center (ADRC) and Gingko Evaluation of Memory (GEM) study, were used in this study. The ADRC cohort was comprised of 1,283 cases (mean AAO 72.8±6.5, 63% female, 25% autopsy confirmed) and 996 controls (mean age 75.6 ± 6.4, 64% female). The GEM cohort consisted of 338 cases (48% female) and 1,950 controls (mean age 78.3 ± 3.1, 44% female). Diagnosis of LOAD in cases for both cohorts was determined based upon DSM-IV criteria. Following quality control procedures and removal of non-Caucasian samples, 4,567 samples remained for analysis. These samples were comprised of 1,621 cases (59.8% female) and 2,946 controls (51% female).

Genotyping

Genotyping was performed with a custom designed TaqMan® assay for TREM2/rs75932628 according to the manufacturer's protocol. (Life Technologies, Grand Island, NY, USA). For each cohort 10% replicates were included for quality control. Two control samples that are heterozygous for the R47H variant (courtesy of Dr. Carlos Cruchaga, Washington University) also were included on each plate. Assayed plates were read using a 7900 HT Fast Real Time PCR (Applied Biosystems). Genotyping calls were made using Applied Biosystems TaqMan® Genotyper Software (v1.0.1, Life Technologies, Inc., 2010). Automated calls were manually reviewed for discrepancies in replicate samples. There were no discrepancies for the ADRC cohort and a discrepancy of rate of 0.0042 for the GEM cohort. We removed those discrepant samples prior to analysis. Twenty-seven samples failed genotyping, bringing the effective sample size for association analysis to 4,540.

Determination of Psychosis in AD Patients

We evaluated the association of psychosis in 1,204 ADRC participants with AD who had been genotyped for the TREM2 ‘T’ allele, 1,069 of whom were characterized during life for cognition and for psychotic symptoms by the Clinical Core of the ADRC, as previously used successfully to examine antemortem (DeMichele-Sweet et al., 2011 and Hollingworth et al., 2011) and post-mortem correlates of AD+P (Murray et al., 2012). The presence or absence of delusions and hallucinations are indicated as part of the semi-structured examinations, and ratings scored on the CERAD Behavioral Rating Scale (Tariot et al., 1995). Delusions are defined as a false belief, not attributable to membership in a social or cultural group, based on incorrect inference about external reality. Delusions are differentiated from confabulations due to cognitive impairment by their persistence and their resistance to persuasion or contrary evidence. Hallucinations are defined as sensory perceptions for which there is no reality basis. Hallucinations occurring when the subject is not fully awake (i.e. hypnagogic or hypnapompic) are not considered hallucinations for the purpose of diagnosis or ratings of psychopathology.

The CERAD Behavioral Rating Scale was administered at initial and annual visits and in some subjects between annual visits by telephone (DeMichele-Sweet et al., 2011). AD+P was considered present when any of the CBRS items #33 - #45 were rated as occurring ≥3 times in the past month at any visit. Individuals with scores of 0 on the same CBRS items at all visits were classified as AD-P. Inter-rater reliability of the psychosis assessments used, including telephone assessments, has been previously described (Sweet et al., 2010 and Wilkosz et al., 2007). Psychotic symptoms typically emerge in the moderate stages of AD (Hollingworth et al. 2006, and Sweet et al., 2010), therefore those categorized as AD-P who were in the mild stages of disease at their last assessment (mini-mental state examination score (Folstein et al., 1975) >20) were considered to be at substantial risk of going on to develop delusional or hallucinatory behaviour. These individuals were therefore excluded from the analysis, leaving 547 AD+P and 356 AD-P subjects available for analysis.

Measurement of Amyloid Deposition in the Brain

Deposition of amyloid-beta in the brain was measured by positron emission tomography (PET) scanning with 11C-labeled Pittsburgh Compound- B (PiB) (Klunk et al., 2004). PiB data was available in 321 subjects that were also genotyped for R47H. PiB retention values from anterior cingulate cortex, frontal cortex, lateral temporal cortex, parietal cortex, and precuneus (areas typically highest in AD) were averaged in each subject to calculate a mean global score (GBL5) as the quantitative phenotype.

Statistical Analyses

The association between AD disease status and the R47H variant was tested using an additive logistic regression model that included age, gender, and APOE*4 status as covariates. Association of this variant with AAO was analyzed using an additive linear regression model adjusted for sex and APOE*4 status. Association of this variant with the average PiB uptake derived from five brain regions was analyzed using an additive linear regression model adjusted for sex, age, and AD status as covariates. Psychosis in AD was analyzed using a Pearson Chi-Square test with sex and AAO as covariates. All analyses were implemented in PLINK or R.

Results

Table 1 presents the distribution of R47H variant in cases and controls. A total of 37 individuals of the 4,567 successfully genotyped samples were carriers of the R47H variant (29 cases, 8 controls). Consistent with previous findings, the minor allele frequency (MAF) for TREM2/rs75932628 in the total sample was less than 0.01 (MAF=0.008), which explains why no homozygous individuals were observed in this population. The MAF was over six times higher in cases as compared to controls (0.0180 versus 0.0027, respectively). The odds ratio (OR) for association of the TREM2 variant with LOAD risk adjusted for age, sex, and APOE*4 status was 7.40 (95% CI: 3.171-17.26, P=3.66E-06). These results are consistent with previous findings that the minor ‘T’ allele of TREM2/rs75932628 significantly and substantially increases risk for LOAD. Table 2 presents the association results of R47H variant with AAO and psychosis in AD and with PiB deposition in the brain. There was no significant association with any of these AD-related phenotypes.

Table 1.

Association of R47H variant with LOAD risk

Genotype MAF OR (95% CI) P
CC CT TT
Controls 2919 8 0 0.0027 ----- -----
Cases 1584 29 0 0.018 7.40 (3.171-17.26) 3.66E-06
Total 4503 37 0 0.008
Open in a new tab

Table 2.

Association of R47H variant with AAO (A), Amyloid deposition (B), and Psychosis in AD (C)

A. Age-at-Onset*
Genotype N Mean AAO
(SD)
CC 1253 72.8 (6.51)
CT 25 73.0 (6.29)
Total 1278 P=0.94
B. Amyloid Deposition
Genotype N Mean PIB value (SD)
CC 314 1.89 (0.58)
CT 7 2.10 (0.99)
Total 321 P=0.287
C. Psychosis in AD
Genotype AD + P AD - P
CC 533 352
CT 14 4
Total 547 356
P=0.13
Open in a new tab
*

Age at onset only available for ADRC samples

Discussion

A rare TREM2 (R47H) variant that considerably increases LOAD risk has been identified in populations of European descent (Benitez et al., 2013, Giraldo et al., 2013, Guerreiro et al., 2013, Jonsson et al., 2013, Gonzalez et al., 2013). In this study, the association between this rare variant, rs75932628, and LOAD risk has been replicated in an independent population. While these results show the same direction of effect for this single nucleotide polymorphism (SNP), our odds ratio is dramatically higher than most other studies have reported. (Table 3) It is possible that this population was enriched for affected carriers, likely by chance rather than by a true difference in this population compared to others. Of note, the MAF of R47H seems to be even lower in the northern Han Chinese population (Yu et al., 2014) compared to European populations, and was not associated with LOAD risk in a Japanese population (Miyashita et al., 2014), suggesting this variant’s effect may be limited to European populations. More recently, a meta-analysis of family-based and case-control data supported the association of the R47H variant with increased LOAD risk, however the effect was much smaller (OR=1.67, 95% CI= 0.95-2.92) than that seen in other studies, including our own (Hooli et al., 2014). Slattery et al (2014) also confirmed this association while reporting a smaller odds ratio (OR=2.19, 95% CI= 1.04-4.51), while Finelli et al. (2015) observed an odds ratio even higher than ours (OR=7.87, 95% CI=1.75-35.34). The association of TREM2 with LOAD risk appears to be real and should be vetted with the same intensity as other risk loci, especially with respect to its effect size. Future studies should aim to characterize better this variant’s effects in other populations and to determine TREM2’s function in neurodegeneration, including how it interacts with other established LOAD risk loci.

Table 3.

Published of odds ratios for association of R47H variant with LOAD

Cases Controls Odds Ratio (95% CI) P Publication
474 608 7.87 (1.75-35.34) 0.007 Finelli et al, 2015
265 225 4.76 (1.37-16.54) 0.014 Roussos et al, 2014
3220 3112 1.67 (0.95-2.92) 0.034 Hooli et al, 2014a
917 199 4.97 (1.18-20.80) 0.004 Hooli et al, 2014, NIMHb
860 1036 3.03 (0.5-18.0) 0.39 Hooli et al, 2014, NIA-LOADb
1002 534 2.19 (1.04-4.51) 0.03 Slattery et al, 2014
2082 1648 2.63 (1.44-4.81) 0.000917 Jin et al, 2014
2190 2498 0.57 (0.05-6.30) 1.00 Miyashita et al, 2014
2037 9727 2.83 (1.45-4.50) 0.002 Jonsson et al, 2013
1091 1105 4.5 (1.7-11.90) <0.001 Guerreiro et al, 2013
1541 1132 3.30 (1.3-9.80) 0.0044 Giraldo et al, 2013a
504c 550 not reported 0.009 Benitez et al, 2013
427 2540 3.5 (1.30-8.80) 0.0076 Gonzalez et al, 2013
1216 1094 3.01 (0.83-10.94) 0.08 Cuyvers et al, 2013
1613 2927 7.40 (3.171-17.26) 0.00000366 This study
Open in a new tab
a

meta-analysis

b

family-based sample

c

LOAD and EOAD combined

Slattery et al. (2014) suggested the association of R47H variant with earlier disease onset. However, in our sample, we found no association between the R47H variant and AAO. In addition to association of TREM2 with LOAD risk and AAO, we also examined the association of this variant with deposition of amyloid, a hallmark of the disease, and psychosis, which can emerge during the progression of LOAD (reviewed by Murray et al., 2014). We found no evidence for either association, possibly due to small sample size and subsequently, lack of power to detect association.

A GWAS of Alzheimer’s endophenotypes revealed associations with the TREM region on chromosome 6 and cerebrospinal fluid (CSF) tau and ptau levels, two biomarkers of LOAD. Included among these associations was that of the R47H variant with CSF ptau levels (Cruchaga et al., 2014). Our results showed no association between amyloid deposition and the R47H variant, further suggesting TREM2’s role in LOAD risk is a function of its interaction with or effect on tau. However, Aβ1-42 clearance is significantly diminished in primary microglia from TREM2 knockout mice, and TREM2 causative mutations for other neurodegenerative diseases have been shown to alter general phagocytic ability, albeit to a greater degree than the R47H variant (Kleinberger et al., 2014). Furthermore, TREM2 has been shown to be a "hub" gene in the hippocampus, and its expression has been linked to the molecular signature of microglia, the cells responsible for clearing Aβ in the brain (Forbasco et al., 2013). Thus, the exact mechanism by which TREM2 affects LOAD risk remains to be determined.

Highlights.

  • We replicated the association of the rare TREM2 R47H variant with LOAD in Caucasians.

  • No association of this variant with age-at-onset was observed.

  • This variant did not affect amyloid deposition or psychosis in AD in our sample.

  • We provide further evidence that the R47H variant confers significant LOAD risk.

Acknowledgements

This study was supported by the National Institute on Aging grants AG041718, AG030653, AG027224, AG005133, and P01 AG025204, and by U01 AT000162 from the National Center for Complementary and Alternative Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health, the National Institutes of Health, the Department of Veterans Affairs, or the United States Government.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Disclosure

The authors report no conflict of interests.

References

  1. Alzheimer’s Facts and Figures: Quick Facts. Chicago: [accessed 12 Jan 2015]. Alzheimers Association. [Internet] c2015. Available from: http://www.alz.org/alzheimers_disease_facts_and_figures.asp#quickFacts. [Google Scholar]
  2. Benitez BA, Cooper B, Pastor P, Jin SC, Lorenzo E, Cervantes S, et al. TREM2 is associated with the risk of Alzheimer's disease in Spanish population. Neurobiol Aging. 2013;34:1711.e15–1711.e17. doi: 10.1016/j.neurobiolaging.2012.12.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cady J, Koval ED, Benitez BA, Zaidman C, Jockel-Balsarotti J, Allred P, et al. TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol. 2014;71:449–453. doi: 10.1001/jamaneurol.2013.6237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cruchaga C, Kauwe JS, Harari O, Jin SC, Cai Y, Karch CM, et al. GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease. Neuron. 2013;78:256–268. doi: 10.1016/j.neuron.2013.02.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cuyvers E, Bettens K, Philtjens S, Van Langenhove T, Gijselinck I, van der Zee J, et al. Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia. Neurobiol Aging. 2014;35:726.e11–726.e19. doi: 10.1016/j.neurobiolaging.2013.09.009. [DOI] [PubMed] [Google Scholar]
  6. DeKosky ST, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, Saxton JA, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA. 2008;300(19):2253–2262. doi: 10.1001/jama.2008.683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. DeMichele-Sweet MA, Klei L, Devlin B, Ferrell RE, Weamer EA, Emanuel JE, et al. No association of psychosis in Alzheimer disease with neurodegenerative pathway genes. Neurobiol Aging. 2011;32:555.e9–555.e11. doi: 10.1016/j.neurobiolaging.2010.10.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Emanuel JE, Lopez OL, Houck PR, Becker JT, Weamer EA, DeMichele-Sweet MA, et al. Trajectory of cognitive decline as a predictor of psychosis in early Alzheimer disease in the cardiovascular health study. Am J Geriatr Psychiatry. 2011;19:160–168. doi: 10.1097/JGP.0b013e3181e446c8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Engelman CD, Koscik RL, Jonaitis EM, Hermann BP, La Rue A, Sager MA. Investigation of triggering receptor expressed on myeloid cells 2 variant in the Wisconsin Registry for Alzheimer's Prevention. Neurobiol Aging. 2014;35:1252–1254. doi: 10.1016/j.neurobiolaging.2013.11.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Finelli D, Rollinson S, Harris J, Jones M, Richardson A, Gerhard A, et al. TREM2 analysis and increased risk of Alzheimer's disease. Neurobiol Aging. 2015;36:546.e9–546.e13. doi: 10.1016/j.neurobiolaging.2014.08.001. [DOI] [PubMed] [Google Scholar]
  11. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–198. doi: 10.1016/0022-3956(75)90026-6. [DOI] [PubMed] [Google Scholar]
  12. Forabosco P, Ramasamy A, Trabzuni D, Walker R, Smith C, Bras J, et al. Insights into TREM2 biology by network analysis of human brain gene expression data. Neurobiol Aging. 2013;34:2699–2714. doi: 10.1016/j.neurobiolaging.2013.05.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Giraldo M, Lopera F, Siniard AL, Corneveaux JJ, Schrauwen I, Carvajal J, et al. Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease. Neurobiol Aging. 2013;34:2077.e11–2077.e18. doi: 10.1016/j.neurobiolaging.2013.02.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gonzalez Murcia JD, Schmutz C, Munger C, Perkes A, Gustin A, Peterson M, et al. Assessment of TREM2 rs75932628 association with Alzheimer's disease in a population-based sample: the Cache County Study. Neurobiol Aging. 2013;34:2889.e11–2889.e13. doi: 10.1016/j.neurobiolaging.2013.06.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. a.Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013;368:117–127. doi: 10.1056/NEJMoa1211851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. b.Guerreiro RJ, Lohmann E, Bras JM, Gibbs JR, Rohrer JD, Gurunlian N, et al. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol. 2013;70:78–84. doi: 10.1001/jamaneurol.2013.579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. c.Guerreiro R, Bilgic B, Guven G, Bras J, Rohrer J, Lohmann E, et al. Novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family. Neurobiol Aging. 2013;34:2890.e1–2890.e5. doi: 10.1016/j.neurobiolaging.2013.06.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009;41:1088–1093. doi: 10.1038/ng.440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. 2011;43:429–435. doi: 10.1038/ng.803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hollingworth P, Hamshere ML, Moskvina V, Dowzell K, Moore PJ, Foy C, et al. Four components describe behavioral symptoms in 1,120 individuals with late-onset Alzheimer's disease. J Am Geriatr Soc. 2006;54:1348–1354. doi: 10.1111/j.1532-5415.2006.00854.x. [DOI] [PubMed] [Google Scholar]
  21. Hooli BV, Parrado AR, Mullin K, Yip WK, Liu T, Roehr JT, et al. The rare TREM2 R47H variant exerts only a modest effect on Alzheimer disease risk. Neurology. 2014;83:1353–1358. doi: 10.1212/WNL.0000000000000855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hsieh CL, Koike M, Spusta SC, Niemi EC, Yenari M, Nakamura MC, et al. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem. 2009;109:1144–1156. doi: 10.1111/j.1471-4159.2009.06042.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Jiang T, Yu JT, Zhu XC, Tan MS, Gu LZ, Zhang YD, et al. Triggering receptor expressed on myeloid cells 2 knockdown exacerbates aging-related neuroinflammation and cognitive deficiency in senescenceaccelerated mouse prone 8 mice. Neurobiol Aging. 2014;35:1243–1251. doi: 10.1016/j.neurobiolaging.2013.11.026. [DOI] [PubMed] [Google Scholar]
  24. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med. 2013;368:107–116. doi: 10.1056/NEJMoa1211103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012;488:96–99. doi: 10.1038/nature11283. [DOI] [PubMed] [Google Scholar]
  26. Kamboh MI, Demirci FY, Wang X, Minster RL, Carrasquillo MM, Pankratz VS, et al. Genome-wide association study of Alzheimer's disease. Transl Psychiatry. 2012;2:e117. doi: 10.1038/tp.2012.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kero M, Paetau A, Polvikoski T, Tanskanen M, Sulkava R, Jansson L, et al. Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population. Neurobiol Aging. 2013;34:1518.e1–1518.e3. doi: 10.1016/j.neurobiolaging.2012.09.017. [DOI] [PubMed] [Google Scholar]
  28. Kleinberger G, Yamanishi Y, Suarez-Calvet M, Czirr E, Lohmann E, Cuyvers E, et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014 Jul 2;6(243):243ra86. doi: 10.1126/scitranslmed.3009093. [DOI] [PubMed] [Google Scholar]
  29. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306–319. doi: 10.1002/ana.20009. [DOI] [PubMed] [Google Scholar]
  30. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013;45:1452–1458. doi: 10.1038/ng.2802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Latta CH, Brothers HM, Wilcock DM. Neuroinflammation in Alzheimer's disease; A source of heterogeneity and target for personalized therapy. Neuroscience. 2014 doi: 10.1016/j.neuroscience.2014.09.061. pii: S0306-4522(14)00820-3. [Epub ahead of print]. ~Review. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ma J, Jiang T, Tan L, Yu JT. TYROBP in Alzheimer's Disease. Mol Neurobiol. 2014 doi: 10.1007/s12035-014-8811-9. [Epub ahead of print]. ~Review. [DOI] [PubMed] [Google Scholar]
  33. Miyashita A, Wen Y, Kitamura N, Matsubara E, Kawarabayashi T, Shoji M, et al. Lack of genetic association between TREM2 and late-onset Alzheimer's disease in a Japanese population. J Alzheimers Dis. 2014;41:1031–1038. doi: 10.3233/JAD-140225. [DOI] [PubMed] [Google Scholar]
  34. Murray PS, Kumar S, Demichele-Sweet MA, Sweet RA. Psychosis in Alzheimer's disease. Biol Psychiatry. 2014;75:542–552. doi: 10.1016/j.biopsych.2013.08.020. ~Review. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Murray PS, Kirkwood CM, Gray MC, Ikonomovic MD, Paljug WR, Abrahamson EE, et al. beta-Amyloid 42/40 ratio and kalirin expression in Alzheimer disease with psychosis. Neurobiol Aging. 2012;33:2807–2816. doi: 10.1016/j.neurobiolaging.2012.02.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet. 2011;43:436–441. doi: 10.1038/ng.801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet. 2002;71:656–662. doi: 10.1086/342259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Pottier C, Wallon D, Rousseau S, Rovelet-Lecrux A, Richard AC, Rollin-Sillaire A, et al. TREM2 R47H variant as a risk factor for early-onset Alzheimer's disease. J Alzheimers Dis. 2013;35:45–49. doi: 10.3233/JAD-122311. [DOI] [PubMed] [Google Scholar]
  39. Rayaprolu S, Mullen B, Baker M, Lynch T, Finger E, Seeley WW, et al. TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease. Mol Neurodegener. 2013;8:19. doi: 10.1186/1750-1326-8-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Roussos P, Katsel P, Fam P, Tan W, Purohit DP, Haroutunian V. The triggering receptor expressed on myeloid cells 2 (TREM2) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer's dementia. Alzheimers Dement. 2014 doi: 10.1016/j.jalz.2014.10.013. pii: S1552-5260(14)02868-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Schmid CD, Sautkulis LN, Danielson PE, Cooper J, Hasel KW, Hilbush BS, et al. Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J Neurochem. 2002;83:1309–1320. doi: 10.1046/j.1471-4159.2002.01243.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010;303:1832–1840. doi: 10.1001/jama.2010.574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Soragna D, Papi L, Ratti MT, Sestini R, Tupler R, Montalbetti L. An Italian family affected by Nasu-Hakola disease with a novel genetic mutation in the TREM2 gene. J Neurol Neurosurg Psychiatry. 2003;74:825–826. doi: 10.1136/jnnp.74.6.825-a. ~Erratum. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Slattery CF, Beck JA, Harper L, Adamson G, Abdi Z, Uphill J, et al. R47H TREM2 variant increases risk of typical early-onset Alzheimer's disease but not of prion or frontotemporal dementia. Alzheimers Dement. 2014;10:602–608. doi: 10.1016/j.jalz.2014.05.1751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Sweet RA, Bennett DA, Graff-Radford NR, Mayeux R National Institute on Aging Late-Onset Alzheimer's Disease Family Study Group. Assessment and familial aggregation of psychosis in Alzheimer's disease from the National Institute on Aging Late Onset Alzheimer's Disease Family Study. Brain. 2010;133:1155–1162. doi: 10.1093/brain/awq001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Tariot PN, Mack JL, Patterson MB, Edland SD, Weiner MF, Fillenbaum G, et al. The behavior rating scale for dementia of the Consortium to Establish a Registry for Alzheimer's Disease. Am J Psychiatry. 1995;152:1349–1357. doi: 10.1176/ajp.152.9.1349. [DOI] [PubMed] [Google Scholar]
  47. Wilkosz PA, Kodavali C, Weamer EA, Miyahara S, Lopez OL, Nimgaonkar VL, et al. Prediction of psychosis onset in Alzheimer disease: the role of depression symptom severity and the HTR2A T102C polymorphism. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:1054–1062. doi: 10.1002/ajmg.b.30549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Yu JT, Jiang T, Wang YL, Wang HF, Zhang W, Hu N, et al. Triggering receptor expressed on myeloid cells 2 variant is rare in late-onset Alzheimer's disease in Han Chinese individuals. Neurobiol Aging. 2014;35:937.e1–937.e3. doi: 10.1016/j.neurobiolaging.2013.10.075. [DOI] [PubMed] [Google Scholar]

RESOURCES