Search

Justina P Tavana,1,* Matthew Rosene,2,* Nick O Jensen,2 Perry G Ridge,1 John SK Kauwe,1,3 Celeste M Karch2,4 1Department of Biology, Brigham Young University, Provo, UT 84602, USA; 2Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA; 3Department of Neuroscience, Brigham Young University, Provo, UT 84602, USA; 4Hope Center for Neurological Disorders, Washington University in St Louis, St Louis, MO, USA *These authors contributed equally to this work Abstract: Alzheimer’s disease (AD) is mainly a late-onset neurodegenerative disorder. Substantial efforts have been made to solve the complex genetic architecture of AD as a means to identify therapeutic targets. Unfortunately, to date, no disease-altering therapeutics have been developed. As therapeutics are likely to be most effective in the early stages of disease (ie, before the onset of symptoms), a recent focus of AD research has been the identification of protective factors that prevent disease. One example is the discovery of a rare variant in the 3'-UTR of RAB10 that is protective for AD. Here, we review the possible genetic, molecular, and functional role of RAB10 in AD and potential therapeutic approaches to target RAB10. Keywords: Alzheimer’s disease, RAB10, retromer, APP, resilience, GTPase

Objective: Aggregation and deposition of amyloid beta (Abeta) in the brain is thought to be central to the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that cerebrospinal fluid (CSF) Abeta levels are strongly correlated with AD status and progression, and may be a meaningful endophenotype for AD. Mutations in presenilin 1 (PSEN1) are known to cause AD and change Abeta levels. In this study, we have investigated DNA sequence variation in the presenilin (PSEN1) gene using CSF Abeta levels as an endophenotype for AD.Methods: We sequenced the exons and flanking intronic regions of PSEN1 in clinically characterized research subjects with extreme values of CSF Abeta levels.Results: This novel approach led directly to the identification of a disease-causing mutation in a family with late-onset AD.Interpretation: This finding suggests that CSF Abeta may be a useful endophenotype for genetic studies of AD. Our results also suggest that PSEN1 mutations can cause AD with a large range in age of onset, spanning both early- and late-onset AD. [ABSTRACT FROM AUTHOR]

Brain arteriolosclerosis (B-ASC) is characterized by pathologically altered brain parenchymal arterioles. B-ASC is associated with cognitive impairment and increased likelihood of clinical dementia. To date, no study has been conducted on genome-wide genetic risk of autopsy-proven B-ASC. We performed a genome-wide association study (GWAS) of the B-ASC phenotype using multiple independent aged neuropathologic cohorts. Included in the study were participants with B-ASC autopsy and genotype data available from the NACC, ROSMAP, ADNI, and ACT data sets. Initial Stage 1 GWAS ( n  = 3382) and Stage 2 mega-analysis ( n  = 4569) were performed using data from the two largest cohorts (NACC and ROSMAP). Replication of top variants and additional Stage 3 mega-analysis were performed incorporating two smaller cohorts (ADNI and ACT). Lead variants in the top two loci in the Stage 2 mega-analysis (rs7902929, p  =  1.8 × 10 - 7 ; rs2603462, p  =  4 × 10 - 7 ) were significant in the ADNI cohort (rs7902929, p  =  0.012 ; rs2603462, p = 0.012 ). The rs2603462 lead variant colocalized with ELOVL4 expression in the cerebellum (posterior probability = 90.1%). Suggestive associations were also found near SORCS1 and SORCS3 . We thus identified putative loci associated with B-ASC risk, but additional replication is needed.

Introduction: MAPT H1 haplotype is implicated as a risk factor for neurodegenerative diseases including Alzheimer's disease (AD)., Methods: Using Alzheimer's Disease Genetics Consortium (ADGC) genome-wide association study (GWAS) data (n = 18,841), we conducted a MAPT H1/H2 haplotype-stratified association to discover MAPT haplotype-specific AD risk loci., Results: We identified 11 loci-5 in H2-non-carriers and 6 in H2-carriers-although none of the MAPT haplotype-specific associations achieved genome-wide significance. The most significant H2 non-carrier-specific association was with a NECTIN2 intronic (P = 1.33E-07) variant, and that for H2 carriers was near NKX6-1 (P = 1.99E-06). The GABRG2 locus had the strongest epistasis with MAPT H1/H2 variant rs8070723 (P = 3.91E-06). Eight of the 12 genes at these loci had transcriptome-wide significant differential expression in AD versus control temporal cortex (q < 0.05). Six genes were members of the brain transcriptional co-expression network implicated in "synaptic transmission" (P = 9.85E-59), which is also enriched for neuronal genes (P = 1.0E-164), including MAPT., Discussion: This stratified GWAS identified loci that may confer AD risk in a MAPT haplotype-specific manner. This approach may preferentially enrich for neuronal genes implicated in synaptic transmission., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer's disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis (1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10, and TAU) at 5 different developmental stages (embryo [E15], 2, 4, 8, and 18 months), (2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant-based and single-gene-based (c-alpha test and sequence kernel association test (SKAT)) genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (log2FC > 1, adj. p-value < 0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ dense-core plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H, and p.H703Y) in our discovery and validation cohort, composed of 465 AD and mild cognitive impairment (MCI) Caucasian patients from the United Kingdom. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-value = 0.01). Adult-onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R, and sporadic late-onset AD, which warrants further investigation., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The Opioid Abuse Risk Screener was developed to support well-informed decision-making in opioid analgesic prescribing by extending the breadth of psychiatric risk factors evaluated relative to other non-clinician-administered measures. We examined the preliminary predictive validity of the Opioid Abuse Risk Screener relative to the widely used Screener and Opioid Assessment for Patients with Pain-Revised in predicting aberrant urine drug tests and controlled substance database checks. The Opioid Abuse Risk Screener is significantly different from the Screener and Opioid Assessment for Patients with Pain-Revised in predicting aberrant same-day urine drug tests ( Z  = 2.912, p  = 0.0036) and controlled substance database checks within 1 year of assessment ( Z  = 3.731, p  = 0.0002). Promising preliminary analyses using machine learning methods are also discussed., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Three authors (LAA, CLA, and PHB) are affiliated with InteraSolutions, a startup psychological assessment company that intends to market the OARS as a commercial product. IRB review was obtained and none of the authors had any contact with any study participants as all data used is archival in nature only. These authors have no additional potential conflicts and all other authors deny any potential conflicts.

More than 20 genetic loci have been associated with risk for Alzheimer's disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ 42 ), tau, and phosphorylated tau (ptau 181 ) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau 181 , including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ 42 near GLIS1 on 1p32.3 (β = -0.059, P = 2.08 × 10 -8 ) and within SERPINB1 on 6p25 (β = -0.025, P = 1.72 × 10 -8 ) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10 -2 ), disease progression (GLIS1: β = 0.277, P = 1.92 × 10 -2 ), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10 -3 ). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ 42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau 181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.

Background: Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations., Methods and Findings: Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case-control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999-2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer's Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984-2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005-2007 and longitudinal cognitive data from the Alzheimer's Disease Neuroimaging Initiative (n = 346, mean follow-up 3.15 ± 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 (p = 9.6 x 10-4, odds ratio [OR] [95% confidence interval] = 1.21 [1.08-1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E (APOE) ɛ4. Separate analyses of class I and II haplotypes further supported the role of class I haplotype A*03:01~B*07:02 (p = 0.03, OR = 1.11 [1.01-1.23]) and class II haplotype DRB1*15:01- DQA1*01:02- DQB1*06:02 (DR15) (p = 0.03, OR = 1.08 [1.01-1.15]) as risk factors for AD. We followed up these findings in the clinical dataset representing the spectrum of cognitively normal controls, individuals with mild cognitive impairment, and individuals with AD to assess their relevance to disease. Carrying A*03:01~B*07:02 was associated with higher CSF amyloid levels (p = 0.03, β ± standard error = 47.19 ± 21.78). We also found a dose-dependent association between the DR15 haplotype and greater rates of cognitive decline (greater impairment on the 11-item Alzheimer's Disease Assessment Scale cognitive subscale [ADAS11] over time [p = 0.03, β ± standard error = 0.7 ± 0.3]; worse forgetting score on the Rey Auditory Verbal Learning Test (RAVLT) over time [p = 0.02, β ± standard error = -0.2 ± 0.06]). In a subset of the same cohort, dose of DR15 was also associated with higher baseline levels of chemokine CC-4, a biomarker of inflammation (p = 0.005, β ± standard error = 0.08 ± 0.03). The main study limitations are that the results represent only individuals of European-ancestry and clinically diagnosed individuals, and that our study used imputed genotypes for a subset of HLA genes., Conclusions: We provide evidence that variation in the HLA locus-including risk haplotype DR15-contributes to AD risk. DR15 has also been associated with multiple sclerosis, and its component alleles have been implicated in Parkinson disease and narcolepsy. Our findings thus raise the possibility that DR15-associated mechanisms may contribute to pan-neuronal disease vulnerability.

The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer's disease subjects in an IL6R allele dependent manner. We conducted a screen to identify variants associated with the age of onset of Alzheimer's disease in APOE ɛ4 carriers. Across five datasets, p.D358A had a meta P = 3 ×10-4 and an odds ratio = 1.3, 95% confidence interval 1.12 -1.48. Our study suggests that a common coding region variant of the IL-6 receptor results in neuroinflammatory changes that may influence the age of onset of Alzheimer's disease in APOE ɛ4 carriers.

Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer's disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyze the single independent and joint effect of rare and low-frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, and CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North-American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low-frequency coding variant (p.G215S, rs72973581, minor allele frequency = 4.3%) conferring a modest but statistically significant protection against AD (p-value = 0.024, odds ratio = 0.57, 95% confidence interval = 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provides new insights that should address functional studies., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Analyzing next-generation sequencing data is difficult because datasets are large, second generation sequencing platforms have high error rates, and because each position in the target genome (exome, transcriptome, etc.) is sequenced multiple times. Given these challenges, numerous bioinformatic algorithms have been developed to analyze these data. These algorithms aim to find an appropriate balance between data loss, errors, analysis time, and memory footprint. Typical analysis pipelines require multiple steps. If one or more of these steps is unnecessary, it would significantly decrease compute time and data manipulation to remove the step. One step in many pipelines is PCR duplicate removal, where PCR duplicates arise from multiple PCR products from the same template molecule binding on the flowcell. These are often removed because there is concern they can lead to false positive variant calls. Picard (MarkDuplicates) and SAMTools (rmdup) are the two main softwares used for PCR duplicate removal., Results: Approximately 92 % of the 17+ million variants called were called whether we removed duplicates with Picard or SAMTools, or left the PCR duplicates in the dataset. There were no significant differences between the unique variant sets when comparing the transition/transversion ratios (p = 1.0), percentage of novel variants (p = 0.99), average population frequencies (p = 0.99), and the percentage of protein-changing variants (p = 1.0). Results were similar for variants in the American College of Medical Genetics genes. Genotype concordance between NGS and SNP chips was above 99 % for all genotype groups (e.g., homozygous reference)., Conclusions: Our results suggest that PCR duplicate removal has minimal effect on the accuracy of subsequent variant calls.

Background: Alzheimer's disease is the leading cause of dementia in the elderly and the third most common cause of death in the United States. A vast number of genes regulate Alzheimer's disease, including Presenilin 1 (PSEN1). Multiple studies have attempted to locate novel variants in the PSEN1 gene that affect Alzheimer's disease status. A recent study suggested that one of these variants, PSEN1 E318G (rs17125721), significantly affects Alzheimer's disease status in a large case-control dataset, particularly in connection with the APOEε4 allele., Methods: Our study looks at the same variant in the Cache County Study on Memory and Aging, a large population-based dataset. We tested for association between E318G genotype and Alzheimer's disease status by running a series of Fisher's exact tests. We also performed logistic regression to test for an additive effect of E318G genotype on Alzheimer's disease status and for the existence of an interaction between E318G and APOEε4., Results: In our Fisher's exact test, it appeared that APOEε4 carriers with an E318G allele have slightly higher risk for AD than those without the allele (3.3 vs. 3.8); however, the 95 % confidence intervals of those estimates overlapped completely, indicating non-significance. Our logistic regression model found a positive but non-significant main effect for E318G (p = 0.895). The interaction term between E318G and APOEε4 was also non-significant (p = 0.689)., Conclusions: Our findings do not provide significant support for E318G as a risk factor for AD in APOEε4 carriers. Our calculations indicated that the overall sample used in the logistic regression models was adequately powered to detect the sort of effect sizes observed previously. However, the power analyses of our Fisher's exact tests indicate that our partitioned data was underpowered, particularly in regards to the low number of E318G carriers, both AD cases and controls, in the Cache county dataset. Thus, the differences in types of datasets used may help to explain the difference in effect magnitudes seen. Analyses in additional case-control datasets will be required to understand fully the effect of E318G on Alzheimer's disease status.

Background: Prostatic Acid Phosphatase (PAP) is an enzyme that is produced primarily in the prostate and functions as a cell growth regulator and potential tumor suppressor. Understanding the genetic regulation of this enzyme is important because PAP plays an important role in prostate cancer and is expressed in other tissues such as the brain., Methods: We tested association between 5.8 M SNPs and PAP levels in cerebrospinal fluid across 543 individuals in two datasets using linear regression. We then performed meta-analyses using METAL =with a significance threshold of p < 5 × 10(-8) and removed SNPs where the direction of the effect was different between the two datasets, identifying 289 candidate SNPs that affect PAP cerebrospinal fluid levels. We analyzed each of these SNPs individually and prioritized SNPs that had biologically meaningful functional annotations in wANNOVAR (e.g. non-synonymous, stop gain, 3' UTR, etc.) or had a RegulomeDB score less than 3., Results: Thirteen SNPs met our criteria, suggesting they are candidate causal alleles that underlie ACPP regulation and expression., Conclusions: Given PAP's expression in the brain and its role as a cell-growth regulator and tumor suppressor, our results have important implications in brain health such as cancer and other brain diseases including neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease) and mental health (e.g., anxiety, depression, and schizophrenia).

Background: Prolactin is a polypeptide hormone secreted by the anterior pituitary gland that plays an essential role in lactation, tissue growth, and suppressing apoptosis to increase cell survival. Prolactin serves as a key player in many life-critical processes, including immune system and reproduction. Prolactin is also found in multiple fluids throughout the body, including plasma and cerebrospinal fluid (CSF)., Methods: In this study, we measured prolactin levels in both plasma and CSF, and performed a genome-wide association study. We then performed meta-analyses using METAL with a significance threshold of p < 5 × 10(-8) and removed SNPs where the direction of the effect was different between the two datasets., Results: We identified 12 SNPs associated with increased prolactin levels in both biological fluids., Conclusions: Our efforts will help researchers understand how prolactin is regulated in both CSF and plasma, which could be beneficial in research for the immune system and reproduction.

Background: CCL16 is a chemokine predominantly expressed in the liver, but is also found in the blood and brain, and is known to play important roles in immune response and angiogenesis. Little is known about the gene's regulation., Methods: Here, we test for potential causal SNPs that affect CCL16 protein levels in both blood plasma and cerebrospinal fluid in a genome-wide association study across two datasets. We then use METAL to performed meta-analyses with a significance threshold of p < 5x10(-8). We removed SNPs where the direction of the effect was different between the two datasets., Results: We identify 10 SNPs associated with increased CCL16 protein levels in both biological fluids., Conclusions: Our results will help understand CCL16's regulation, allowing researchers to better understand the gene's effects on human health.

Identifying accurate biomarkers of cognitive decline is essential for advancing early diagnosis and prevention therapies in Alzheimer's disease. The Alzheimer's disease DREAM Challenge was designed as a computational crowdsourced project to benchmark the current state-of-the-art in predicting cognitive outcomes in Alzheimer's disease based on high dimensional, publicly available genetic and structural imaging data. This meta-analysis failed to identify a meaningful predictor developed from either data modality, suggesting that alternate approaches should be considered for prediction of cognitive performance., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The cerebral deposition of Aβ42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-Aβ metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aβ degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e-4

Late-onset Alzheimer's disease (LOAD) can present heterogeneously, with several subtypes recognized, including dysexecutive AD. One way to identify people with dysexecutive AD is to consider the difference between memory and executive functioning, which we refer to as the executive prominent/memory prominent spectrum. We aimed to determine if this spectrum was heritable. We used neuropsychological and genetic data from people with mild LOAD (Clinical Dementia Rating 0.5 or 1.0) from the National Alzheimer's Coordinating Center and the Alzheimer's Disease Neuroimaging Initiative. We cocalibrated the neuropsychological data to obtain executive functioning and memory scores and used their difference as a continuous phenotype to calculate its heritability overall and by chromosome. Narrow-sense heritability of the difference between memory and executive functioning scores was 0.68 (standard error 0.12). Single nucleotide polymorphisms on chromosomes 1, 2, 4, 11, 12, and 18 explained the largest fraction of phenotypic variance, with signals from each chromosome accounting for 5%-7%. The chromosomal pattern of heritability differed substantially from that of LOAD itself., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Skeletal muscle-specific liver kinase B1 (LKB1) knockout mice (skmLKB1-KO) exhibit elevated mitogen-activated protein kinase (MAPK) signaling after treadmill running. MAPK activation is also associated with inflammation-related signaling in skeletal muscle. Since exercise can induce muscle damage, and inflammation is a response triggered by damaged tissue, we therefore hypothesized that LKB1 plays an important role in dampening the inflammatory response to muscle contraction, and that this may be due in part to increased susceptibility to muscle damage with contractions in LKB1-deficient muscle. Here we studied the inflammatory response and muscle damage with in situ muscle contraction or downhill running. After in situ muscle contractions, the phosphorylation of both NF-κB and STAT3 was increased more in skmLKB1-KO vs. wild-type (WT) muscles. Analysis of gene expression via microarray and RT-PCR shows that expression of many inflammation-related genes increased after contraction only in skmLKB1-KO muscles. This was associated with mild skeletal muscle fiber membrane damage in skmLKB1-KO muscles. Gene markers of oxidative stress were also elevated in skmLKB1-KO muscles after contraction. Using the downhill running model, we observed significantly more muscle damage after running in skmLKB1-KO mice, and this was associated with greater phosphorylation of both Jnk and STAT3 and increased expression of SOCS3 and Fos. In conclusion, we have shown that the lack of LKB1 in skeletal muscle leads to an increased inflammatory state in skeletal muscle that is exacerbated by muscle contraction. Increased susceptibility of the muscle to damage may underlie part of this response., (Copyright © 2016 the American Physiological Society.)

Background: Alzheimer's disease (AD) remains challenging to diagnose, especially early disease. Having serum AD biomarkers would be of significant interest both in the clinical setting and in drug development efforts., Objective: We applied a novel serum proteomic approach to interrogate the low-molecular weight proteome for serum AD biomarkers., Methods: A discovery study used sera from 58 any-stage AD cases and 55 matched controls analyzed by capillary liquid chromatography-electrospray ionization-tandem mass spectrometry. Candidate biomarkers were statistically modeled and promising biomarkers were retested in a second, blinded confirmatory study (AD cases = 68, controls = 57). Biomarkers that replicated in the second study were modeled for the diagnosis of any-stage and very early stage AD. Further, they were chemically identified by tandem MS., Results: The initial discovery study found 59 novel potential AD biomarkers. Thirteen recurred in more than one multi-marker panel. In a second, blinded, confirmatory study, these same biomarkers were retested in separate specimens. In that study, four markers validated comparing controls to patients with any-stage AD and also with very early AD. The four biomarkers with replicable ability to diagnose AD were then chemically identified., Conclusion: These results suggest novel serum AD diagnostic biomarkers can be found using this approach.

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

The missense P39L variant in the prion protein gene (PRNP) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may be an extremely rare cause of FTD (0.13%).

Introduction: Genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) have been crucial in advancing the understanding of Alzheimer's disease (AD) pathophysiology. Here, we provide an update on sample collection, scientific progress and opportunities, conceptual issues, and future plans., Methods: Lymphoblastoid cell lines and DNA and RNA samples from blood have been collected and banked, and data and biosamples have been widely disseminated. To date, APOE genotyping, genome-wide association study (GWAS), and whole exome and whole genome sequencing data have been obtained and disseminated., Results: ADNI genetic data have been downloaded thousands of times, and >300 publications have resulted, including reports of large-scale GWAS by consortia to which ADNI contributed. Many of the first applications of quantitative endophenotype association studies used ADNI data, including some of the earliest GWAS and pathway-based studies of biospecimen and imaging biomarkers, as well as memory and other clinical/cognitive variables. Other contributions include some of the first whole exome and whole genome sequencing data sets and reports in healthy controls, mild cognitive impairment, and AD., Discussion: Numerous genetic susceptibility and protective markers for AD and disease biomarkers have been identified and replicated using ADNI data and have heavily implicated immune, mitochondrial, cell cycle/fate, and other biological processes. Early sequencing studies suggest that rare and structural variants are likely to account for significant additional phenotypic variation. Longitudinal analyses of transcriptomic, proteomic, metabolomic, and epigenomic changes will also further elucidate dynamic processes underlying preclinical and prodromal stages of disease. Integration of this unique collection of multiomics data within a systems biology framework will help to separate truly informative markers of early disease mechanisms and potential novel therapeutic targets from the vast background of less relevant biological processes. Fortunately, a broad swath of the scientific community has accepted this grand challenge., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR)., Methods and Findings: We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP-AD associations from the International Genomics of Alzheimer's Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 × 10(-3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(-8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51-0.89]; p = 6.5 × 10(-3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses., Conclusions: Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure--or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications--may reduce AD risk.

Importance: Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States., Objective: To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden., Design, Setting, and Participants: Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources., Main Outcomes and Measures: Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies)., Results: The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673., Conclusions and Relevance: The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations.

Cholesterol has been implicated in the pathogenesis of late-onset Alzheimer's disease (LOAD) and the cholesteryl ester transfer protein (CETP) is critical to cholesterol regulation within the cell, making CETP an Alzheimer's disease candidate gene. Several studies have suggested that CETP I405V (rs5882) is associated with cognitive function and LOAD risk, but findings vary and most studies have been conducted using relatively small numbers of samples. To test whether this variant is involved in cognitive function and LOAD progression, we genotyped 4486 subjects with up to 12 years of longitudinal cognitive assessment. Analyses revealed an average 0.6-point decrease per year in the rate of cognitive decline for each additional valine (p < 0.011). We failed to detect the association between CETP I405V and LOAD status (p < 0.28). We conclude that CETP I405V is associated with preserved cognition over time but is not associated with LOAD status., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Alzheimer's disease affects millions of people worldwide and incidence is expected to rise as the population ages, but no effective therapies exist despite decades of research and more than 20 known disease markers. Research has shown that Alzheimer's disease's missing heritability remains extensive with an estimated 25% of phenotypic variance unexplained by known variants. The missing heritability may be explained by missing variants or by epistasis. Researchers often focus on individual loci rather than epistatic interactions, which is likely an oversimplification of the underlying biology since most phenotypes are affected by multiple genes. Focusing research efforts on epistasis will be critical to resolving Alzheimer's disease etiology, and a major key to identifying and properly interpreting key epistatic interactions will be bridging the gap between statistical and biological epistasis. This review covers the current state of epistasis research in Alzheimer's disease and how researchers can bridge the gap between statistical and biological epistasis to help resolve Alzheimer's disease etiology.

Importance: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants., Objectives: To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium., Design, Setting, and Participants: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes., Main Outcomes and Measures: Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria., Results: Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242)., Conclusions and Relevance: We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10-10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.

Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls., Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci., Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p.R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). In addition, common single nucleotide polymorphisms in this genomic region are associated with cerebrospinal fluid biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p.R47H. Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p.S144G (rs3747742) as a potential driver of the meta-analysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The Genetics Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI), formally established in 2009, aims to provide resources and facilitate research related to genetic predictors of multidimensional Alzheimer's disease (AD)-related phenotypes. Here, we provide a systematic review of genetic studies published between 2009 and 2012 where either ADNI APOE genotype or genome-wide association study (GWAS) data were used. We review and synthesize ADNI genetic associations with disease status or quantitative disease endophenotypes including structural and functional neuroimaging, fluid biomarker assays, and cognitive performance. We also discuss the diverse analytical strategies used in these studies, including univariate and multivariate analysis, meta-analysis, pathway analysis, and interaction and network analysis. Finally, we perform pathway and network enrichment analyses of these ADNI genetic associations to highlight key mechanisms that may drive disease onset and trajectory. Major ADNI findings included all the top 10 AD genes and several of these (e.g., APOE, BIN1, CLU, CR1, and PICALM) were corroborated by ADNI imaging, fluid and cognitive phenotypes. ADNI imaging genetics studies discovered novel findings (e.g., FRMD6) that were later replicated on different data sets. Several other genes (e.g., APOC1, FTO, GRIN2B, MAGI2, and TOMM40) were associated with multiple ADNI phenotypes, warranting further investigation on other data sets. The broad availability and wide scope of ADNI genetic and phenotypic data has advanced our understanding of the genetic basis of AD and has nominated novel targets for future studies employing next-generation sequencing and convergent multi-omics approaches, and for clinical drug and biomarker development.

Background: Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome., Methods: A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and Aβ42 was used as a continuous trait in these analyses., Results: The ptau181-Aβ42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low Aβ42) compared with elderly control subjects with no pathology (low ptau181, high Aβ42). The FABP-Aβ42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aβ42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD., Conclusions: Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Reported odds ratios and population attributable fractions (PAF) for late-onset Alzheimer's disease (LOAD) risk loci (BIN1, ABCA7, CR1, MS4A4E, CD2AP, PICALM, MS4A6A, CD33, and CLU) come from clinically ascertained samples. Little is known about the combined PAF for these LOAD risk alleles and the utility of these combined markers for case-control prediction. Here we evaluate these loci in a large population-based sample to estimate PAF and explore the effects of additive and nonadditive interactions on LOAD status prediction performance., Methods: 2419 samples from the Cache County Memory Study were genotyped for APOE and nine LOAD risk loci from AlzGene.org. We used logistic regression and receiver operator characteristic analysis to assess the LOAD status prediction performance of these loci using additive and nonadditive models and compared odds ratios and PAFs between AlzGene.org and Cache County., Results: Odds ratios were comparable between Cache County and AlzGene.org when identical single nucleotide polymorphisms were genotyped. PAFs from AlzGene.org ranged from 2.25% to 37%; those from Cache County ranged from .05% to 20%. Including non-APOE alleles significantly improved LOAD status prediction performance (area under the curve = .80) over APOE alone (area under the curve = .78) when not constrained to an additive relationship (p < .03). We identified potential allelic interactions (p values uncorrected): CD33-MS4A4E (synergy factor = 5.31; p < .003) and CLU-MS4A4E (synergy factor = 3.81; p < .016)., Conclusions: Although nonadditive interactions between loci significantly improve diagnostic ability, the improvement does not reach the desired sensitivity or specificity for clinical use. Nevertheless, these results suggest that understanding gene-gene interactions may be important in resolving Alzheimer's disease etiology., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Single-nucleotide polymorphisms (SNPs) located in the gene encoding the regulatory subunit of the protein phosphatase 2B (PPP3R1, rs1868402) and the microtubule-associated protein tau (MAPT, rs3785883) gene were recently associated with higher cerebrospinal fluid (CSF) tau levels in samples from the Knight Alzheimer's Disease Research Center at Washington University (WU) and Alzheimer's Disease Neuroimaging Initiative (ADNI). In these same samples, these SNPs were also associated with faster functional decline, or progression of Alzheimer's disease (AD) as measured by the Clinical Dementia Rating sum of boxes scores (CDR-sb). We attempted to validate the latter association in an independent, population-based sample of incident AD cases from the Cache County Dementia Progression Study (DPS)., Methods: All 92 AD cases from the DPS with a global CDR-sb ≤1 (mild) at initial clinical assessment who were later assessed on CDR-sb data on at least two other time points were genotyped at the two SNPs of interest (rs1868402 and rs3785883). We used linear mixed models to estimate associations between these SNPs and CDR-sb trajectory. All analyses were performed using Proc Mixed in SAS., Results: Although we observed no association between rs3785883 or rs1868402 alone and change in CDR-sb (P > .10), there was a significant association between a combined genotype model and change in CDR-sb: carriers of the high-risk genotypes at both loci progressed >2.9 times faster than noncarriers (P = .015). When data from DPS were combined with previously published data from WU and ADNI, change in CDR-sb was 30% faster for each copy of the high-risk allele at rs3785883 (P = .0082) and carriers of both high-risk genotypes at both loci progressed 6 times faster (P < .0001) than all others combined., Conclusions: We replicate a previous report by Cruchaga et al that specific variations in rs3785883 and rs1868402 are associated with accelerated progression of AD. Further characterization of this association will provide a better understanding of how genetic factors influence the rate of progression of AD and could provide novel insights into preventative and therapeutic strategies., (Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

We observed the changes in the angular measurements commonly used in the evaluation of the first metatarsal and first metatarsophalangeal joint in cadaveric specimens before and after frontal plane rotation of the first metatarsal. Measurements of the first and second intermetatarsal angle (IMA), hallux abductus angle, proximal articular set angle, and tibial sesamoid position (TSP) were taken after varying degrees of varus and valgus rotation of the first metatarsal. Standard dorsoplantar radiographs were taken at 0°, 10°, 20°, and 30° of valgus rotation of the first metatarsal and repeated at 10°, 20°, and 30° varus rotation of the first metatarsal. The data were analyzed using a mixed linear model to compare the change in each angle measurement over the range of valgus and varus rotation. The change in the TSP was significant in both valgus and varus rotations (p = .0004 and p = .028, respectively), an increase in valgus rotation causing an increase in the TSP and an increase in varus rotation causing a decrease in TSP. The change in the IMA was significant compared with valgus rotation (p = .028), showing that as the valgus rotation increased, the IMA also increased. However, compared with the varus rotation, the correlation was not significant (p = .18). The proximal articular set angle and hallux abductus angle measurements, compared with metatarsal rotation, showed positive trends but were not statistically significant. From our results and a review of the published data, we have hypothesized that frontal plane rotation of the first metatarsal is an integral component of hallux abducto valgus pathologic features, specifically in relation to the TSP and IMA., (Copyright © 2014 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

The use of cerebrospinal fluid levels of Aβ42 and pTau181 as endophenotypes for genetic studies of Alzheimer's disease (AD) has led to successful identification of both rare and common AD risk variants. In addition, this approach has provided meaningful hypotheses for the biological mechanisms by which known AD risk variants modulate the disease process. In this article we discuss these successes and outline challenges to effective and continued applications of this approach. We contrast the statistical power of this approach with traditional case-control designs and discuss solutions to address challenges in quality control and data analysis for these phenotypes. Finally, we discuss the potential for the use of this approach with larger samples as well as the incorporation of next generation sequencing and for future work with other endophenotypes for AD.

Background: Since the advent of next-generation sequencing many previously untestable hypotheses have been realized. Next-generation sequencing has been used for a wide range of studies in diverse fields such as population and medical genetics, phylogenetics, microbiology, and others. However, this novel technology has created unanticipated challenges such as the large numbers of genetic variants. Each caucasian genome has more than four million single nucleotide variants, insertions and deletions, copy number variants, and structural variants. Several formats have been suggested for storing these variants; however, the variant call format (VCF) has become the community standard., Results: We developed new software called the Variant Tool Chest (VTC) to provide much needed tools to work with VCF files. VTC provides a variety of tools for manipulating, comparing, and analyzing VCF files beyond the functionality of existing tools. In addition, VTC was written to be easily extended with new tools., Conclusions: Variant Tool Chest brings new and important functionality that complements and integrates well with existing software. VTC is available at https://github.com/mebbert/VariantToolChest.

Background: We sought to identify optimal approaches by calibrating longitudinal cognitive performance across studies with different neuropsychological batteries., Methods: We examined four approaches to calibrate cognitive performance in nine longitudinal studies of Alzheimer's disease (AD) (n = 10,875): (1) common test, (2) standardize and average available tests, (3) confirmatory factor analysis (CFA) with continuous indicators, and (4) CFA with categorical indicators. To compare precision, we determined the minimum sample sizes needed to detect 25% cognitive decline with 80% power. To compare criterion validity, we correlated cognitive change from each approach with 6-year changes in average cortical thickness and hippocampal volume using available MRI data from the AD Neuroimaging Initiative., Results: CFA with categorical indicators required the smallest sample size to detect 25% cognitive decline with 80% power (n = 232) compared to common test (n = 277), standardize-and-average (n = 291), and CFA with continuous indicators (n = 315) approaches. Associations with changes in biomarkers changes were the strongest for CFA with categorical indicators., Conclusions: CFA with categorical indicators demonstrated greater power to detect change and superior criterion validity compared to other approaches. It has wide applicability to directly compare cognitive performance across studies, making it a good way to obtain operational phenotypes for genetic analyses of cognitive decline among people with AD., (© 2014 S. Karger AG, Basel.)

The first intermetatarsal angle (IMA) is known to decrease after first metatarsophalangeal joint arthrodesis, although the exact mechanism by which this decrease occurs is not known. We measured the first IMA and obliquity of the medial cuneiform on anteroposterior weightbearing preoperative and postoperative radiographs in 86 feet and analyzed the statistical correlation between the IMA and the medial cuneiform angle. A change in the first IMA after first metatarsophalangeal joint fusion showed a strong positive correlation with a change in cuneiform obliquity (p < .0001). This finding was consistent in the direction and magnitude in each of 3 clinical subgroups: normal, p = .087; moderate deformity, p = .011; and severe deformity, p = .10. A comparison of the preoperative IMA and cuneiform obliquity revealed a trend toward a positive relationship but did not reach statistical significance (p = .08). The preoperative association between the IMA and medial cuneiform obliquity was not significant in any clinical subgroup, and the postoperative association between the IMA and cuneiform obliquity was not significant (p = .65). Clinical subgroup analysis showed no significant association between the IMA and the normal (p = .73) and moderately (p = .69) deformed feet, although the postoperative association between the IMA and cuneiform obliquity in the severely deformed group was significantly (p = .034) positive. A linear relationship between the reduction of the first IMA and medial cuneiform obliquity after metatarsophalangeal joint fusion was observed. Our findings suggest that frontal plane rotation influences cuneiform obliquity., (Copyright © 2014 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The mitochondria are essential organelles and are the location of cellular respiration, which is responsible for the majority of ATP production. Each cell contains multiple mitochondria, and each mitochondrion contains multiple copies of its own circular genome. The ratio of mitochondrial genomes to nuclear genomes is referred to as mitochondrial copy number. Decreases in mitochondrial copy number are known to occur in many tissues as people age, and in certain diseases. The regulation of mitochondrial copy number by nuclear genes has been studied extensively. While mitochondrial variation has been associated with longevity and some of the diseases known to have reduced mitochondrial copy number, the role that the mitochondrial genome itself has in regulating mitochondrial copy number remains poorly understood., Results: We analyzed the complete mitochondrial genomes from 1007 individuals randomly selected from the Cache County Study on Memory Health and Aging utilizing the inferred evolutionary history of the mitochondrial haplotypes present in our dataset to identify sequence variation and mitochondrial haplotypes associated with changes in mitochondrial copy number. Three variants belonging to mitochondrial haplogroups U5A1 and T2 were significantly associated with higher mitochondrial copy number in our dataset., Conclusions: We identified three variants associated with higher mitochondrial copy number and suggest several hypotheses for how these variants influence mitochondrial copy number by interacting with known regulators of mitochondrial copy number. Our results are the first to report sequence variation in the mitochondrial genome that causes changes in mitochondrial copy number. The identification of these variants that increase mtDNA copy number has important implications in understanding the pathological processes that underlie these phenotypes.

Background: Population stratification is a key concern for genetic association analyses. In addition, extreme homogeneity of ethnic origins of a population can make it difficult to interpret how genetic associations in that population may translate into other populations. Here we have evaluated the genetic substructure of samples from the Cache County study relative to the HapMap Reference populations and data from the Alzheimer's Disease Neuroimaging Initiative (ADNI)., Results: Our findings show that the Cache County study is similar in ethnic diversity to the self-reported "Whites" in the ADNI sample and less homogenous than the HapMap CEU population., Conclusions: We conclude that the Cache County study is genetically representative of the general European American population in the USA and is an appropriate population for conducting broadly applicable genetic studies.

Recent studies have identified the rs75932628 (R47H) variant in TREM2 as an Alzheimer's disease risk factor with estimated odds ratio ranging from 2.9 to 5.1. The Cache County Memory Study is a large, population-based sample designed for the study of memory and aging. We genotyped R47H in 2974 samples (427 cases and 2540 control subjects) from the Cache County study using a custom TaqMan assay. We observed 7 heterozygous cases and 12 heterozygous control subjects with an odds ratio of 3.5 (95% confidence interval, 1.3-8.8; p = 0.0076). The minor allele frequency and population attributable fraction for R47H were 0.0029 and 0.004, respectively. This study replicates the association between R47H and Alzheimer's disease risk in a large, population-based sample, and estimates the population frequency and attributable risk of this rare variant., (Copyright © 2013 Elsevier Inc. All rights reserved.)