Publications by authors named "Lori B Chibnik"

92 Publications

Low-coverage sequencing cost-effectively detects known and novel variation in underrepresented populations.

Am J Hum Genet 2021 04 25;108(4):656-668. Epub 2021 Mar 25.

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

Genetic studies in underrepresented populations identify disproportionate numbers of novel associations. However, most genetic studies use genotyping arrays and sequenced reference panels that best capture variation most common in European ancestry populations. To compare data generation strategies best suited for underrepresented populations, we sequenced the whole genomes of 91 individuals to high coverage as part of the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study with participants from Ethiopia, Kenya, South Africa, and Uganda. We used a downsampling approach to evaluate the quality of two cost-effective data generation strategies, GWAS arrays versus low-coverage sequencing, by calculating the concordance of imputed variants from these technologies with those from deep whole-genome sequencing data. We show that low-coverage sequencing at a depth of ≥4× captures variants of all frequencies more accurately than all commonly used GWAS arrays investigated and at a comparable cost. Lower depths of sequencing (0.5-1×) performed comparably to commonly used low-density GWAS arrays. Low-coverage sequencing is also sensitive to novel variation; 4× sequencing detects 45% of singletons and 95% of common variants identified in high-coverage African whole genomes. Low-coverage sequencing approaches surmount the problems induced by the ascertainment of common genotyping arrays, effectively identify novel variation particularly in underrepresented populations, and present opportunities to enhance variant discovery at a cost similar to traditional approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2021.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059370PMC
April 2021

Functional dystonia: A case-control study and risk prediction algorithm.

Ann Clin Transl Neurol 2021 04 16;8(4):732-748. Epub 2021 Mar 16.

Dystonia Center and Movement Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Objective: Functional dystonia (FD) is a disabling and diagnostically challenging functional movement disorder (FMD). We sought to identify historical predictors of FD vs. other primary dystonias (ODs) and develop a practical prediction algorithm to guide neurologists.

Methods: 1475 consecutive new patient medical records were reviewed at an adult/pediatric tertiary-referral dystonia clinic from 2005 to 2017. Ninety-nine met criteria for clinically established FD (85 adults and 14 pediatric), paired with 99 age/dystonia distribution-matched OD. Univariate and multivariate regression analyses were performed to identify predictors of FD and disability. We formed a prediction algorithm, assessed using the area under the receiver operating curve (AUC).

Results: Multivariate logistic regression analysis investigating independent predictors of FD (P < 0.001) followed by development of a prediction algorithm showed that the most robust predictors included abrupt onset, spontaneous resolution/recurrence, pain, cognitive complaints, being on or pursuing disability, lifetime mood/anxiety disorder, comorbid functional somatic disorders, and having ≥3 medication allergies. The prediction algorithm had utility for both adult and pediatric FD, with excellent sensitivity/specificity (89%/92%) and an area under the curve (AUC) 0.95 (0.92-0.98). Greater disability (modified Rankin Scale) independently correlated with a number of functional examination features, unemployment/not attending school, number of medication allergies, and younger age of presentation. FD patients were high health-care utilizers and were more frequently prescribed opiates/opioids and benzodiazepines (P < 0.003).

Interpretation: This case-control study provides an algorithm to guide clinicians in gauging their index of suspicion for a FD, with diagnostic confirmation subsequently informed by neurological examination. While this algorithm requires prospective validation, health-care utilization data underscore the importance and need for more research in FD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.51307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045924PMC
April 2021

Polygenic risk for autism, attention-deficit hyperactivity disorder, schizophrenia, major depressive disorder, and neuroticism is associated with the experience of childhood abuse.

Mol Psychiatry 2021 05 22;26(5):1696-1705. Epub 2021 Jan 22.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

People who experience childhood abuse are at increased risk of mental illness. Twin studies suggest that inherited genetic risk for mental illness may account for some of these associations. Yet, the hypothesis that individuals who have experienced childhood abuse may carry genetic loading for mental illness has never been tested with genetic data. Using polygenic risk scores for six psychiatric disorders-attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), neuroticism, and schizophrenia-we tested whether genetic risk for mental illness was associated with increased risk of experiencing three types of childhood abuse: physical/emotional abuse, physical assault, and sexual abuse, in a cohort of white non-Hispanic women (n = 11,315). ADHD and MDD genetic risk scores were associated with a higher risk of experiencing each type of childhood abuse, while neuroticism, schizophrenia, BPD, and ASD genetic scores were associated with a higher risk of experiencing physical/emotional abuse and physical assault, but not sexual abuse. Sensitivity analyses examining potential bias from the differential recall of childhood trauma, parental socioeconomic status, and population stratification were consistent with the main findings. A one-standard-deviation increase in genetic risk for mental illness was associated with a modestly elevated risk of experiencing childhood abuse (OR range: 1.05-1.19). Therefore, inherited genetic risk may partly account for the association of childhood abuse with mental illness. In addition, future treatments for mental illness will benefit from taking into consideration the co-occurrence of childhood trauma and genetic loading.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-020-00996-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164961PMC
May 2021

A cortical immune network map identifies distinct microglial transcriptional programs associated with β-amyloid and Tau pathologies.

Transl Psychiatry 2021 01 14;11(1):50. Epub 2021 Jan 14.

Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.

Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer's disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 540 subjects from two cohort studies of brain aging. Two of these transcriptional programs-modules 113 and 114-relate to the accumulation of β-amyloid, while module 5 relates to tau pathology. We replicate these associations in brain epigenomic data and in two independent datasets. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that three representative module 5 genes (ACADVL, TRABD, and VASP) encode proteins that are upregulated in activated microglia in AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-020-01175-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809035PMC
January 2021

Posttraumatic Stress Disorder and Likelihood of Hormone Therapy Use among Women in the Nurses' Health Study II: A 26-Year Prospective Analysis.

Cancer Epidemiol Biomarkers Prev 2021 Mar 21;30(3):492-498. Epub 2020 Dec 21.

Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Background: Posttraumatic stress disorder (PTSD) is associated with higher risk of certain chronic diseases, including ovarian cancer, but underlying mechanisms remain unclear. Although prior work has linked menopausal hormone therapy (MHT) use with elevated ovarian cancer risk, little research considers PTSD to likelihood of MHT use. We examined whether PTSD was prospectively associated with greater likelihood of initiating MHT use over 26 years.

Methods: Using data from the Nurses' Health Study II, with trauma and PTSD (symptoms and onset date) assessed by screener in 2008 and MHT assessed via biennial survey (from 1989), we performed Cox proportional regression models with women contributing person-years from age 36 years. Relevant covariates were assessed at biennial surveys. We considered potential effect modification by race/ethnicity, age at baseline, and period (1989-2002 vs. 2003-2015).

Results: Over follow-up, 22,352 of 43,025 women reported initiating MHT use. For example, compared with women with no trauma, the HR for initiating MHT was 1.18 for those with trauma/1-3 PTSD symptoms [95% confidence interval (CI), 1.13-1.22] and 1.31 for those with trauma/4-7 PTSD symptoms (95% CI, 1.25-1.36; trend < 0.001), adjusting for sociodemographic factors. Associations were maintained when adjusting for reproductive factors and health conditions. We found evidence of effect modification by age at baseline.

Conclusions: Trauma and number of PTSD symptoms were associated with greater likelihood of initiating MHT use in a dose-response manner.

Impact: MHT may be a pathway linking PTSD to altered chronic disease risk. It is important to understand why women with PTSD initiate MHT use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-20-1227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049954PMC
March 2021

Association of Posttraumatic Stress and Depressive Symptoms With Mortality in Women.

JAMA Netw Open 2020 12 1;3(12):e2027935. Epub 2020 Dec 1.

Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Importance: Consistent evidence has found associations between posttraumatic stress disorder (PTSD) and increased risk of chronic disease and greater prevalence of health risk factors. However, the association between PTSD and all-cause mortality has not been thoroughly investigated in civilians.

Objective: To investigate the association between PTSD symptoms, with or without comorbid depressive symptoms, and risk of death.

Design, Setting, And Participants: This prospective cohort study was conducted using data on female US nurses in the Nurses' Health Study II followed up from 2008 to 2017. Women who responded to a 2008 questionnaire querying PTSD and depressive symptoms were included. Data were analyzed from September 2018 to November 2020.

Exposures: Symptoms of PTSD, measured using the short screening scale for Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) PTSD, and depression symptoms, measured using the Center for Epidemiologic Studies Depression Scale-10 in 2008.

Main Outcomes And Measures: All-cause mortality was determined via National Death Index, US Postal Service, or report of participant's family. The hypothesis being tested was formulated after data collection. Trauma exposure and PTSD symptoms were jointly coded as no trauma exposure (reference), trauma and no PTSD symptoms, 1 to 3 PTSD symptoms (subclinical), 4 to 5 PTSD symptoms (moderate), and 6 to 7 PTSD symptoms (high).

Results: Among 51 602 women (50 137 [97.2%] White individuals), the mean (range) age was 53.3 (43-64) years at study baseline in 2008. PTSD and probable depression were comorbid; of 4019 women with high PTSD symptoms, 2093 women (52.1%) had probable depression, while of 10 105 women with no trauma exposure, 1215 women (12.0%) had probable depression. Women with high PTSD symptoms and probable depression were at nearly 4-fold greater risk of death compared with women with no trauma exposure and no depression (hazard ratio [HR], 3.80; 95% CI, 2.65-5.45; P < .001). After adjustment for health factors, women with these conditions had a more than 3-fold increased risk (HR, 3.11; 95% CI, 2.16-4.47, P < .001). Women with subclinical PTSD symptoms without probable depression had increased risk of death compared with women with no trauma exposure and no depression (HR, 1.43; 95% CI, 1.06-1.93; P = .02). Among 7565 women with PTSD symptoms and probable depression, 109 deaths (1.4%) occurred for which we obtained cause of death information, compared with 124 such deaths (0.6% ) among 22 215 women with no depression or PTSD symptoms. Women with PTSD symptoms and probable depression, compared with women with no PTSD or depression, had higher rates of death from cardiovascular disease (17 women [0.22%] vs 11 women [0.05%]; P < .001), diabetes (4 women [0.05%] vs 0 women; P < .001), unintentional injury (7 women [0.09%] vs 7 women [0.03%]; P = .03), suicide (9 women [0.12%] vs 1 woman [<0.01%]; P < .001), and other causes of death (14 women [0.19%] vs 17 women [0.08%]; P = .01).

Conclusions And Relevance: These findings suggest that at midlife, women with high PTSD symptoms and co-occurring probable depression are at increased risk of death compared with women without these disorders. Treatment of PTSD and depression in women with symptoms of both disorders and efforts to improve their health behaviors may reduce their increased risk of mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2020.27935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718604PMC
December 2020

Characterizing Clinical and Neuropathological Traits of APOE Haplotypes in African Americans and Europeans.

J Alzheimers Dis 2020 ;78(1):467-477

MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.

Background: The APOEɛ4 allele is the largest genetic risk factor for late-onset Alzheimer's disease (AD). Recent literature suggested that the contribution of APOEɛ4 to AD risk could be population-specific, with ɛ4 conferring a lower risk to Blacks or African Americans.

Objective: To investigate the effect of APOE haplotypes on AD risk in individuals with European ancestry (EU) and Blacks or African Americans (AA).

Methods: We selected data from 1) the National Alzheimer's Coordinating Center: a total of 3,486 AD cases and 4,511 controls (N = 7,997, 60% female) with genotypes from the Alzheimer's Disease Genetics Consortium (ADGC), and 2) the Rush University Religious Orders Study and Memory and Aging Project (ROSMAP) cohort with 578 AD and 670 controls (N = 1,248, 60% female). Using ɛ3 homozygotes as the reference, we compared the association of various APOE haplotypes with the clinical and neuropathological correlates of dementia in AA and EU.

Results: In both cohorts, we find no difference in the odds or age of onset of AD among the ɛ4-linked haplotypes defined by rs769449 within either AA or EU. Additionally, while APOEɛ4 was associated with a faster rate of decline, no differences were found in rate of decline, clinical or neuropathological features among the ɛ4-linked haplotypes. Further analysis with other variants near the APOE locus failed to identify any effect modification.

Conclusion: Our study finds similar effects of the ɛ4-linked haplotypes defined by rs769449 on AD as compared to ɛ3 in both AA and EU. Future studies are required to understand the heterogeneity of APOE conferred risk of AD among various genotypes and populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-200228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774865PMC
January 2020

Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium.

Neurology 2020 08 1;95(5):e519-e531. Epub 2020 Jul 1.

From the Department of Epidemiology (F.J.W., L.B.C., R.W., D. Blacker, D. Bos, J.G., A.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Departments of Epidemiology (F.J.W., D. Bos, S.K.L.D., M.A.I., M.K.I., A.H.), Radiology and Nuclear Medicine (D. Bos), and Neurology (M.K.I.), Erasmus MC, Rotterdam, the Netherlands; Department of Neurology (L.B.C.), Massachusetts General Hospital, Boston; Department of Infectious Disease Epidemiology (R.A., F.d.W., C. Hadjichrysanthou, K.M.-M., M.M.W.), School of Public Health, Imperial College London, UK; Neuropsychiatry and Epidemiology and Clinical Research (C. Berr), INSERM, UMR 1061 Montpellier, Universite de Montpellier, France; Boston University School of Medicine (A.B., M.P.P., C.L.S., S.S.); Framingham Heart Study (A.B., M.P.P., C.L.S., S.S.), MA; Department of Biostatistics (A.B., K.L.D.-P.), Boston University School of Public Health, MA; Cardiovascular Health Research Unit, Departments of Medicine (J.C.B., B.M.P.) and Epidemiology and Health Services (B.M.P.), University of Washington, Seattle; Department of Psychiatry (D. Blacker), Massachusetts General Hospital, Charlestown; University of Cambridge (C. Brayne), UK; Bordeaux Population Health Research Center (J.-F.D., S.D., C.D., L.G., C. Helmer), INSERM, UMR 1219, University of Bordeaux; Department of Neurology (S.D.), Memory Clinic, Bordeaux University Hospital, France; McGovern Medical School (M.F.), University of Texas Health Science Center at Houston; Icelandic Heart Association (V.G.), Kopavogur; Faculty of Medicine (V.G.), University of Iceland, Reykjavik; Institute of Neuroscience and Physiology (E.J., S.K., I.S., H.W., A.Z.), Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Epidemiology, Graduate School of Public Health (L.H.K.), and Departments of Neurology and Psychiatry (O.L.L.), University of Pittsburgh, PA; Laboratory of Epidemiology and Population Sciences (L.L., O.M.), National Institute on Aging, Bethesda, MD; Institute of Health and Society (F.E.M., B.C.M.S.), Newcastle University, Newcastle upon Tyne, UK; MIND Center (T.H.M.), University of Mississippi Medical Center, Jackson; Melbourne Dementia Research Centre (M.P.P.), The Florey Institute for Neuroscience and Mental Health, Melbourne, Australia; Kaiser Permanente Washington Health Research Institute (B.M.P.), Seattle; and The Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., S.S.), UT Health San Antonio, TX.

Objective: To determine changes in the incidence of dementia between 1988 and 2015.

Methods: This analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex.

Results: Of 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65-69 years to 65 per 1,000 person-years for those aged 85-89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval [CI], 7%-19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%-32%] vs 8% [0%-15%]).

Conclusion: The incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000010022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455342PMC
August 2020

Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease.

Nat Med 2020 08 22;26(8):1256-1263. Epub 2020 Jun 22.

Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.

Alzheimer's disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal-based-bioactivity assays to characterize tau in 32 patients with AD. We found striking patient-to-patient heterogeneity in the hyperphosphorylated species of soluble, oligomeric, seed-competent tau. Tau seeding activity correlates with the aggressiveness of the clinical disease, and some post-translational modification (PTM) sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, whereas others are not. These data suggest that different individuals with 'typical' AD may have distinct biochemical features of tau. These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-020-0938-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603860PMC
August 2020

Time Trends in Survival Following First Hemorrhagic or Ischemic Stroke Between 1991 and 2015 in the Rotterdam Study.

Stroke 2020 03 20;51(3):STROKEAHA119027198. Epub 2020 Feb 20.

Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands. (R.W., D.B., A. Heshmatollah, M.A.I., A. Hofman, M.K.I.).

Background and Purpose- The introduction of stroke units and the implementation of evidence-based interventions have been a breakthrough in the management of patients with stroke over the past decade. Survival following stroke is an important indicator in monitoring stroke burden. Recent data on survival by stroke subtype in the general population is scarce. We assessed (1) recent temporal time trends in survival; (2) age-standardized death rates; (3) survival probabilities at 6 months, 1, 2, and 3 years following first hemorrhagic or ischemic stroke. Methods- Within the population-based Rotterdam Study between 1991 and 2015, we assessed time trends in survival among 162 with first-ever hemorrhagic and 988 patients with first-ever ischemic stroke across 3 time periods (1991-1998; 1999-2007; 2008-2015) using time-varying Cox regression model and calculated age-standardized death rates according to the European 2010 census population. Results- In the hemorrhagic stroke group, a total of 144 deaths occurred during 386 person-years. Following a hemorrhagic stroke, we observed similar mortality rates over the years with 30 per 100 person-years in 2015 compared with 25/100 person-years in 1991. Similarly, compared with the earliest study period (1991-1998), mortality rates remained unchanged in the latest study period (2008-2015; hazard ratio, 0.97 [95% CI, 0.61-1.57]; =0.93). In the ischemic stroke group, a total of 711 deaths occurred during 4897 person-years. We observed a decline in mortality rates in 2015 (11 per 100 person-years) compared with 1991 (29/100 person-years). This translated to favorable trends in the latest study period 2008 to 2015 (hazard ratio, 0.71 [95% CI, 0.56-0.90]; <0.01). Conclusions- Survival following ischemic stroke has improved over the past decade, while no change was observed in survival following hemorrhagic stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.119.027198DOI Listing
March 2020

Risk of hemorrhagic and ischemic stroke in patients with Alzheimer disease: A synthesis of the literature.

Neurology 2020 02 16;94(6):265-272. Epub 2020 Jan 16.

From the Department of Epidemiology (R.W., L.B.C., D.B., A.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Epidemiology (R.W., D.B., M.K.I., A.H.), Department of Radiology and Nuclear Medicine (D.B.), and Department of Neurology (M.K.I.), Erasmus Medical Center, Rotterdam, The Netherlands.

Objective: To assess the risk of hemorrhagic and ischemic stroke in patients with Alzheimer disease (AD) compared with non-AD controls with similar risk profiles.

Methods: A search was conducted on EMBASE and MEDLINE for reports published up to September 26, 2018. Studies were included if they (1) assessed the incidence of stroke in patients diagnosed with AD; (2) included patients with no history of stroke; and (3) reported outcomes by stroke subtype. The main outcome was relative risk of ischemic or hemorrhagic stroke. Furthermore, the rate of stroke occurrence per 1,000 person-years was assessed. A random-effects meta-analysis was undertaken. The risk of bias in included studies was assessed in terms of selection, comparability, and outcome.

Results: A total of 3,605 studies were screened in the title and abstract phase after removing duplicates, and 88 eligible studies were screened for full text. Eight studies met the inclusion criteria representing 121,719 individuals (AD = 73,044; non-AD = 48,675). Five studies were included in the relative risk analysis, among which 4 studies applied formal matching criteria of 44,544 AD and 44,660 non-AD controls. The included studies were based on nationwide registries from Finland, Sweden, Taiwan (2), United Kingdom (2), 1 clinic-based study from the Netherlands, and 1 US population-based cohort. Among patients with AD, the incidence rate of hemorrhagic stroke was 3.41/1000 person-years (95% CI 2.70-4.32) and 2.23 (95% CI 1.72-2.88) among AD cases and non-AD controls, respectively. This is in contrast to 13.98 (95% CI 9.86-19.81) and 12.12 (95% CI 7.55-19.46) for ischemic stroke among AD cases and non-AD controls, respectively. Compared with non-AD controls with similar risk profiles, patients with AD had a relative risk of 1.42 (95% CI 1.23-1.64) for hemorrhagic stroke and 1.15 (95% CI 0.89-1.48) for ischemic stroke.

Conclusion: Compared with non-AD controls with similar risk profiles, patients with AD are likely at a higher risk of hemorrhagic but not ischemic stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000008924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136067PMC
February 2020

Posttraumatic stress disorder and changes in diet quality over 20 years among US women.

Psychol Med 2021 01 26;51(2):310-319. Epub 2019 Nov 26.

Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Individuals with posttraumatic stress disorder (PTSD) are at increased risk of various chronic diseases. One hypothesized pathway is via changes in diet quality. This study evaluated whether PTSD was associated with deterioration in diet quality over time.

Methods: Data were from 51 965 women in the Nurses' Health Study II PTSD sub-study followed over 20 years. Diet, assessed at 4-year intervals, was characterized via the Alternative Healthy Eating Index-2010 (AHEI). Based on information from the Brief Trauma Questionnaire and Short Screening Scale for DSM-IV PTSD, trauma/PTSD status was classified as no trauma exposure, prevalent exposure (trauma/PTSD onset before study entry), or new-onset (trauma/PTSD onset during follow-up). We further categorized women with prevalent exposure as having trauma with no PTSD symptoms, trauma with low PTSD symptoms, and trauma with high PTSD symptoms, and created similar categories for women with new-onset exposure, resulting in seven comparison groups. Multivariable linear mixed-effects spline models tested differences in diet quality changes by trauma/PTSD status over follow-up.

Results: Overall, diet quality improved over time regardless of PTSD status. In age-adjusted models, compared to those with no trauma, women with prevalent high PTSD and women with new-onset high PTSD symptoms had 3.3% and 3.6% lower improvement in diet quality, respectively, during follow-up. Associations remained consistent after adjusting for health conditions, sociodemographics, and behavioral characteristics.

Conclusions: PTSD is associated with less healthy changes in overall diet quality over time. Poor diet quality may be one pathway linking PTSD with a higher risk of chronic disease development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S0033291719003246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063582PMC
January 2021

Variation in blood pressure and long-term risk of dementia: A population-based cohort study.

PLoS Med 2019 11 12;16(11):e1002933. Epub 2019 Nov 12.

Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Background: Variation in blood pressure may relate to dementia risk via autonomic disturbance or hemodynamic mechanisms, but the long-term associations are unclear. We aimed to determine whether blood pressure variation over a period of years, considering both magnitude and direction, is associated with the risk of dementia.

Methods And Findings: In a prospective cohort study ongoing since 1989 in the Netherlands, 5,273 dementia-free participants (58.1% women; mean [SD] age, 67.6 [8.0] years) were included. As of 2016, 1,059 dementia cases occurred during a median follow-up of 14.6 years. Absolute variation in systolic blood pressure (SBP) was assessed as the absolute difference in SBP divided by the mean over two sequential visits every 4.2 (median) years, with the first quantile set as the reference level. The direction was the rise or fall in SBP, with the third quantile set as the reference level. We estimated the risk of dementia in relation to SBP variation measured at different time windows (i.e., at least 0, 5, 10, and 15 years) prior to dementia diagnosis, with adjustments for age, sex, education, apolipoprotein E (APOE) genotype, vascular risk factors, and history of cardiovascular disease. We repeated the above analysis for variation in diastolic blood pressure (DBP). A large SBP variation was associated with an increased dementia risk, which became more pronounced with longer intervals between the assessment of SBP variation and the diagnosis of dementia. The hazard ratio (HR) associated with large variation (the highest quintile) increased from 1.08 (95% confidence interval [CI] 0.88-1.34, P = 0.337) for risk within 5 years of SBP variation measurement to 3.13 (95% CI 2.05-4.77; P < 0.001) for risk after at least 15 years since the measurement of SBP variation. The increased long-term risk was associated with both large rises (HR for the highest quintile, 3.31 [95% CI 2.11-5.18], P < 0.001) and large falls in SBP (HR for the lowest quintile, 2.20 [95% CI 1.33-3.63], P = 0.002), whereas the higher short-term risk was only associated with large falls in SBP (HR, 1.21 [95% CI 1.00-1.48], P = 0.017). Similar findings were observed for variation in DBP. Despite our assessment of major confounders, potential residual confounding is possible, and the findings on blood pressure variability over periods of years may not be generalizable to variability over periods of days and other shorter periods.

Conclusions: Results of this study showed that a large blood pressure variation over a period of years was associated with an increased long-term risk of dementia. The association between blood pressure variation and dementia appears most pronounced when this variation occurred long before the diagnosis. An elevated long-term risk of dementia was observed with both a large rise and fall in blood pressure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pmed.1002933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850672PMC
November 2019

Prevalence of parental bereavement among female sex workers (FSW) in Kibra, Kenya.

J Loss Trauma 2019 31;24(2):129-142. Epub 2019 Jan 31.

Kenya Medical Research Institute (KEMRI), P.O. Box 54840 00200, Nairobi, Kenya.

Female sex workers (FSW) residing in Kibra, Kenya experience elevated exposure to adverse events, yet the prevalence of parental bereavement is not well characterized. This cross-sectional pilot study on 301 FSWs residing in Kibra, Kenya found that 67.7% of these women were parentally bereaved. Significantly fewer parentally bereaved women reported historical use of condoms and emergency contraception compared to non-bereaved women, and older age of paternal bereavement was significantly associated with current contraceptive use. Prevalence rates of bereavement among this cohort are well over the national Kenyan average, and further research on the specific impact of bereavement is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15325024.2018.1560692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785239PMC
January 2019

Sex differences in the genetic predictors of Alzheimer's pathology.

Brain 2019 09;142(9):2581-2589

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.

Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awz206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736148PMC
September 2019

Neuropsychiatric Genetics of African Populations-Psychosis (NeuroGAP-Psychosis): a case-control study protocol and GWAS in Ethiopia, Kenya, South Africa and Uganda.

BMJ Open 2019 02 19;9(2):e025469. Epub 2019 Feb 19.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Introduction: Schizophrenia and bipolar disorder account for a large proportion of the global burden of disease. Despite their enormous impact, little is known about their pathophysiology. Given the high heritability of schizophrenia and bipolar disorder, unbiased genetic studies offer the opportunity to gain insight into their neurobiology. However, advances in understanding the genetic architecture of schizophrenia and bipolar disorder have been based almost exclusively on subjects of Northern European ancestry. The Neuropsychiatric Genetics of African Populations-Psychosis (NeuroGAP-Psychosis) project aims to expand our understanding of the causes of schizophrenia and bipolar disorder through large-scale sample collection and analyses in understudied African populations.

Methods And Analysis: NeuroGAP-Psychosis is a case-control study of 34 000 participants recruited across multiple sites within Ethiopia, Kenya, South Africa and Uganda. Participants will include individuals who are at least 18 years old with a clinical diagnosis of schizophrenia or bipolar disorder ('psychosis') or those with no history of psychosis. Research assistants will collect phenotype data and saliva for DNA extraction. Data on mental disorders, history of physical health problems, substance use and history of past traumatic events will be collected from all participants.DNA extraction will take place in-country, with genotyping performed at the Broad Institute. The primary analyses will include identifying major groups of participants with similar ancestry using the computation-efficient programme single nucleotide polymorphisms (SNP) weights. This will be followed by a GWAS within and across ancestry groups.

Ethics And Dissemination: All participants will be assessed for capacity to consent using the University of California, San Diego Brief Assessment of Capacity to Consent. Those demonstrating capacity to consent will be required to provide informed consent. Ethical clearances to conduct this study have been obtained from all participating sites. Findings from this study will be disseminated in publications and shared with controlled access public databases, such as the database of Genotypes and Phenotypes, dbGaP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2018-025469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377543PMC
February 2019

Role of metabolic syndrome and its components as mediators of the genetic effect on type 2 diabetes: A family-based study in China.

J Diabetes 2019 Jul 1;11(7):552-562. Epub 2019 Jan 1.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.

Background: Metabolic syndrome (MetS) share a genetic basis with type 2 diabetes (T2D). However, whether MetS and its components mediate genetic susceptibility to T2D is not completely understood.

Methods: We assessed the effects of MetS and its components on associations T2D and 18 genome-wide association studies-identified variants using a two-stage strategy based on parametric models involving 7110 Chinese participants (2436 were T2D patients) across 2885 families. Multilevel logistic regression was used to account for the intrafamilial correlation.

Results: Metabolic syndrome significantly mediated the effect of a melatonin receptor 1B (MTNR1B) polymorphism on T2D risk (OR of average causal mediation effect [OR ] 1.004; 95% confidence interval [CI] 1.001-1.008; P = 0.018). In addition, low high-density lipoprotein cholesterol (HDL-C) levels mediated the genetic effects of MTNR1B (OR 1.012; 95% CI 1.007-1.015; P < 0.001), solute carrier family 30 member 8 (SLC30A8; OR 1.001; 95% CI 1.000-1.007; P < 0.040), B-cell lymphoma/leukemia 11A (BCL11A; OR 1.009; 95% CI 1.007-1.016; P < 0.001), prospero homeobox 1 (PROX1; OR 1.005; 95% CI 1.003-1.011; P < 0.001) and a disintegrin and metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9; OR 1.006; 95% CI 1.001-1.009; P = 0.022), whereas increased fasting blood glucose (FBG) significantly mediated the genetic effect of BCL11A (OR 1.017; 95% CI 1.003-1.021; P = 0.012).

Conclusions: This study provides evidence that MetS and two of its components (HDL-C, FBG) may be involved in mediating the genetic predisposition to T2D, which emphasize the importance of maintaining normal HDL-C and FBG levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1753-0407.12882DOI Listing
July 2019

Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort study.

Lancet Neurol 2018 09 6;17(9):773-781. Epub 2018 Aug 6.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA. Electronic address:

Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy in older adults frequently coexists with Alzheimer's disease pathology and hippocampal sclerosis. It is unclear whether there is a link between APOE ε4 and TDP-43 proteinopathy, and the role of APOE ε4 in the association of TDP-43 proteinopathy with hippocampal sclerosis remains to be examined. We investigated the relationships of TDP-43 proteinopathy and hippocampal sclerosis with APOE ε4.

Methods: We used data from two community-based cohort studies of ageing and dementia: the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). A battery of cognitive tests examining multiple cognitive domains is given to ROS-MAP participants each year, and a measure of annual global cognitive function for each participant is derived by averaging Z scores of these tests. The final clinical diagnosis is assigned after death by a neurologist using all available clinical data without access to post-mortem pathology. Amyloid-β, paired helical filament tau, Lewy bodies, TDP-43, and hippocampal sclerosis were microscopically evaluated in the midbrain, medial temporal, and neocortical regions that capture the progression of each neuropathology. TDP-43 proteinopathy topographic stage was recorded as an ordinal variable, and TDP-43 burden was defined by averaging a semi-quantitative six-point scale across six brain regions. The relationships among APOE ε4, TDP-43 proteinopathy, and hippocampal sclerosis were tested with regression models controlled for sex and age at death, and they were further explored with a mediation analysis using the quasi-Bayesian Monte Carlo method.

Findings: ROS began data collection in 1994, and MAP began data collection in 1997. The data included in this study were analysed from Jan 16, 2017, to July 12, 2017. When analysis began in January, 2017, a total of 1059 ROS-MAP participants who were deceased had APOE genotype and complete pathological measures for amyloid-β, paired helical filament tau, and TDP-43 proteinopathy stage. After excluding 15 participants with other pathological diagnoses, 1044 participants, 1042 of whom also had measures of Lewy body pathology, were included in this study (470 from ROS and 574 from MAP). APOE ε4 count was associated with higher TDP-43 proteinopathy stage (odds ratio [OR] 2·0, 95% CI 1·6-2·6; p=1·9 × 10) and TDP-43 burden (0·40, 0·28-0·52; p=1·2 × 10). Amyloid-β, paired helical filament tau, or Lewy body pathology did not fully explain this association. APOE ε4 increased the odds of hippocampal sclerosis (OR 2·1, 95% CI 1·4-3·0; p=1·7 × 10); this effect was largely mediated by TDP-43 burden (mediated effect p<1·0 × 10) but not directly by APOE ε4 (direct effect p=0·40). APOE ε4 was associated with worse global cognition proximate to death even after adjusting for amyloid-β and paired helical filament tau (estimated effect -0·18, 95% CI -0·31 to -0·04; p=0·010), but this association was attenuated by additionally adjusting for TDP-43 burden (-0·09, -0·22 to 0·04; p=0·18).

Interpretation: APOE ε4 seems to increase TDP-43 burden, and this effect in turn was associated with higher odds of hippocampal sclerosis, a pathology potentially downstream of TDP-43 proteinopathy. TDP-43 proteinopathy contributes to the detrimental effect of APOE ε4 on late-life cognition through mechanisms independent of Alzheimer's disease pathology, and future research should consider that TDP-43 proteinopathy might be an integral component of APOE-related neurodegeneration.

Funding: US National Institute on Aging and Alzheimer's Association.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(18)30251-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154505PMC
September 2018

Reproductive period and epigenetic modifications of the oxidative phosphorylation pathway in the human prefrontal cortex.

PLoS One 2018 27;13(7):e0199073. Epub 2018 Jul 27.

Harvard Medical School, Boston, MA, United States of America.

Purpose: Human females have a unique duration of post-reproductive longevity, during which sex-specific mechanisms ma influence later-life mechanisms of neuronal resilience and vulnerability. The maintenance of energy metabolism, through the oxidative phosphorylation (OXPHOS) apparatus, is essential for brain health. Given the known association between reproductive period (years from menarche to menopause) and cognitive aging, we examined the hypothesis that cumulative estrogen exposure across the lifetime may be associated with differential methylation of genes in the OXPHOS pathway.

Methods: Using DNA methylation patterns in the post-mortem dorsolateral prefrontal cortex (DLPFC) of 426 women prospectively followed until death in the Religious Orders Study and Rush Memory and Aging Project, we examined the relationship between reproductive period (subtracting age at menarche from age at menopause) and DNA methylation of a published set of autosomal OXPHOS genes previously implicated in stroke susceptibility. We then performed an unsupervised analysis of methylation levels across the Hallmark pathways from the Molecular Signatures Database.

Results: We observed a strong association between reproductive period and DNA methylation status across OXPHOS CpGs. We replicated this association between reproductive period and DNA methylation in a much larger set of OXPHOS genes in our unsupervised analysis. Here, reproductive period also showed associations with methylation in genes related to E2F, MYC and MTORC1 signaling, fatty acid metabolism and DNA repair.

Conclusion: This study provides evidence from both a supervised and unsupervised analyses, that lifetime cumulative endogenous steroid exposures may play a role in maintenance of post-menopausal cellular balance, including in brain tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199073PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063396PMC
December 2018

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Acta Neuropathol 2018 12 2;136(6):857-872. Epub 2018 Jul 2.

Clinic of Psychiatry and Psychotherapy, Saarland University, Homburg/Saar, Germany.

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10; β = 0.03, p = 3.97 × 10) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (p = 0.047; p = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1881-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280657PMC
December 2018

A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer's disease.

Nat Neurosci 2018 06 25;21(6):811-819. Epub 2018 May 25.

Broad Institute, Cambridge, MA, USA.

There is a need for new therapeutic targets with which to prevent Alzheimer's disease (AD), a major contributor to aging-related cognitive decline. Here we report the construction and validation of a molecular network of the aging human frontal cortex. Using RNA sequence data from 478 individuals, we first build a molecular network using modules of coexpressed genes and then relate these modules to AD and its neuropathologic and cognitive endophenotypes. We confirm these associations in two independent AD datasets. We also illustrate the use of the network in prioritizing amyloid- and cognition-associated genes for in vitro validation in human neurons and astrocytes. These analyses based on unique cohorts enable us to resolve the role of distinct cortical modules that have a direct effect on the accumulation of AD pathology from those that have a direct effect on cognitive decline, exemplifying a network approach to complex diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41593-018-0154-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599633PMC
June 2018

Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau.

JAMA Neurol 2018 08;75(8):989-998

Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner.

Objective: To evaluate sex differences in the association between APOE and markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy.

Design, Setting, And Participants: This multicohort study selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals and included population-based and clinic-based samples. Inclusion in our analysis required APOE genotype data and either CSF data available for analysis. Analyses began on November 6, 2017, and were completed on December 20, 2017.

Main Outcomes And Measures: Biomarker analyses included levels of β-amyloid 42, total tau, and phosphorylated tau measured in CSF. Autopsy analyses included Consortium to Establish a Registry for Alzheimer's Disease staging for neuritic plaques and Braak staging for neurofibrillary tangles.

Results: Of the 1798 patients in the CSF biomarker cohort, 862 were women, 226 had AD, 1690 were white, and the mean (SD) age was 70 [9] years. Of the 5109 patients in the autopsy cohort, 2813 were women, 4953 were white, and the mean (SD) age was 84 (9) years. After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction between APOE-ε4 and sex on CSF total tau (β = 0.41; 95% CI, 0.27-0.55; P < .001) and phosphorylated tau (β = 0.24; 95% CI, 0.09-0.38; P = .001), whereby APOE showed a stronger association among women compared with men. Post hoc analyses suggested this sex difference was present in amyloid-positive individuals (β = 0.41; 95% CI, 0.20-0.62; P < .001) but not among amyloid-negative individuals (β = 0.06; 95% CI, -0.18 to 0.31; P = .62). We did not observe sex differences in the association between APOE and β-amyloid 42, neuritic plaque burden, or neurofibrillary tangle burden.

Conclusions And Relevance: We provide robust evidence of a stronger association between APOE-ε4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly, APOE-ε4 is not differentially associated with autopsy measures of neurofibrillary tangles. Together, the sex difference in the association between APOE and CSF measures of tau and the lack of a sex difference in the association with neurofibrillary tangles at autopsy suggest that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2018.0821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142927PMC
August 2018

Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium.

Eur J Epidemiol 2017 10 23;32(10):931-938. Epub 2017 Oct 23.

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.

Several studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10654-017-0320-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680377PMC
October 2017

variants are associated with cerebral amyloid angiopathy.

Neurol Genet 2017 Aug 18;3(4):e176. Epub 2017 Jul 18.

Departments of Neurology and Psychiatry (H.-S.Y., C.C.W., H.-U.K., P.L.D.J.), Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences; Department of Neurology (H.-S.Y.), Center for Alzheimer Research and Treatment, Brigham and Women's Hospital; Harvard Medical School (H.-S.Y., H.-U.K.); Harvard T.H. Chan School of Public Health (L.B.C.), Boston; Program in Medical and Population Genetics (H.-S.Y., C.C.W., L.B.C., H.-U.K., P.L.D.J.), Broad Institute, Cambridge, MA; Rush Alzheimer's Disease Center (J.A.S., D.A.B.) and Department of Neurological Sciences (J.A.S., D.A.B.), Rush University Medical Center, Chicago, IL; and Department of Neurology (P.L.D.J.), Center for Translational & Systems Neuroimmunology, Columbia University Medical Center, New York, NY.

Objective: To determine whether common genetic variants in , a recently identified late-onset Alzheimer disease (LOAD) dementia susceptibility gene, are associated with AD susceptibility or AD-related clinical/pathologic phenotypes.

Methods: We used data from deceased individuals of European descent who participated in the Religious Orders Study or the Rush Memory and Aging Project (n = 1,288). We examined whether there were associations between single nucleotide polymorphisms (SNPs) within ±100 kb of the gene and a diagnosis of AD dementia, global cognitive decline, a pathologic diagnosis of AD, β-amyloid load, neuritic plaque count, diffuse plaque count, paired helical filament tau density, neurofibrillary tangle count, and cerebral amyloid angiopathy (CAA) score. We also evaluated the relation of the CAA-associated variant and dorsolateral prefrontal cortex (DLPFC) RNA expression. Secondary analyses were performed to examine the interaction of the CAA-associated SNP and known genetic risk factors of CAA as well as the association of the SNP with other cerebrovascular pathologies.

Results: A set of SNPs tagged by rs28660566 was associated with a higher CAA score ( = 2.3 × 10): each additional rs28660566 allele was associated with a 0.60 point higher CAA score, which is equivalent to approximately 75% of the higher CAA score associated with each allele of ε4. rs28660566 was weakly associated with lower expression in the human DLPFC ( = 0.036). Moreover, rs28660566 had a synergistic interaction with ε4 on their association with higher CAA severity ( = 0.027) and was associated with more severe arteriolosclerosis ( = 0.0065).

Conclusions: Targeted analysis of the region uncovered a set of SNPs associated with CAA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515600PMC
August 2017

Dissecting the role of non-coding RNAs in the accumulation of amyloid and tau neuropathologies in Alzheimer's disease.

Mol Neurodegener 2017 07 1;12(1):51. Epub 2017 Jul 1.

Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, 77 Avenue Louis Pasteur, NRB 168C, Boston, MA, 02115, USA.

Background: Given multiple studies of brain microRNA (miRNA) in relation to Alzheimer's disease (AD) with few consistent results and the heterogeneity of this disease, the objective of this study was to explore their mechanism by evaluating their relation to different elements of Alzheimer's disease pathology, confounding factors and mRNA expression data from the same subjects in the same brain region.

Methods: We report analyses of expression profiling of miRNA (n = 700 subjects) and lincRNA (n = 540 subjects) from the dorsolateral prefrontal cortex of individuals participating in two longitudinal cohort studies of aging.

Results: We confirm the association of two well-established miRNA (miR-132, miR-129) with pathologic AD in our dataset and then further characterize this association in terms of its component neuritic β-amyloid plaques and neurofibrillary tangle pathologies. Additionally, we identify one new miRNA (miR-99) and four lincRNA that are associated with these traits. Many other previously reported associations of microRNA with AD are associated with the confounders quantified in our longitudinal cohort. Finally, by performing analyses integrating both miRNA and RNA sequence data from the same individuals (525 samples), we characterize the impact of AD associated miRNA on human brain expression: we show that the effects of miR-132 and miR-129-5b converge on certain genes such as EP300 and find a role for miR200 and its target genes in AD using an integrated miRNA/mRNA analysis.

Conclusions: Overall, miRNAs play a modest role in human AD, but we observe robust evidence that a small number of miRNAs are responsible for specific alterations in the cortical transcriptome that are associated with AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13024-017-0191-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494142PMC
July 2017

Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data.

PLoS Med 2017 04 25;14(4):e1002287. Epub 2017 Apr 25.

Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.

Introduction: The molecular underpinnings of the dissociation of cognitive performance and neuropathological burden are poorly understood, and there are currently no known genetic or epigenetic determinants of the dissociation.

Methods And Findings: "Residual cognition" was quantified by regressing out the effects of cerebral pathologies and demographic characteristics on global cognitive performance proximate to death. To identify genes influencing residual cognition, we leveraged neuropathological, genetic, epigenetic, and transcriptional data available for deceased participants of the Religious Orders Study (n = 492) and the Rush Memory and Aging Project (n = 487). Given that our sample size was underpowered to detect genome-wide significance, we applied a multistep approach to identify genes influencing residual cognition, based on our prior observation that independent genetic and epigenetic risk factors can converge on the same locus. In the first step (n = 979), we performed a genome-wide association study with a predefined suggestive p < 10-5, and nine independent loci met this threshold in eight distinct chromosomal regions. Three of the six genes within 100 kb of the lead SNP are expressed in the dorsolateral prefrontal cortex (DLPFC): UNC5C, ENC1, and TMEM106B. In the second step, in the subset of participants with DLPFC DNA methylation data (n = 648), we found that residual cognition was related to differential DNA methylation of UNC5C and ENC1 (false discovery rate < 0.05). In the third step, in the subset of participants with DLPFC RNA sequencing data (n = 469), brain transcription levels of UNC5C and ENC1 were evaluated for their association with residual cognition: RNA levels of both UNC5C (estimated effect = -0.40, 95% CI -0.69 to -0.10, p = 0.0089) and ENC1 (estimated effect = 0.0064, 95% CI 0.0033 to 0.0096, p = 5.7 × 10-5) were associated with residual cognition. In secondary analyses, we explored the mechanism of these associations and found that ENC1 may be related to the previously documented effect of depression on cognitive decline, while UNC5C may alter the composition of presynaptic terminals. Of note, the TMEM106B allele identified in the first step as being associated with better residual cognition is in strong linkage disequilibrium with rs1990622A (r2 = 0.66), a previously identified protective allele for TDP-43 proteinopathy. Limitations include the small sample size for the genetic analysis, which was underpowered to detect genome-wide significance, the evaluation being limited to a single cortical region for epigenetic and transcriptomic data, and the use of categorical measures for certain non-amyloid-plaque, non-neurofibrillary-tangle neuropathologies.

Conclusions: Through a multistep analysis of cognitive, neuropathological, genomic, epigenomic, and transcriptomic data, we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population, and we expanded our understanding of the TMEM106B haplotype that is protective against TDP-43 proteinopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pmed.1002287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404753PMC
April 2017

Diurnal and seasonal molecular rhythms in human neocortex and their relation to Alzheimer's disease.

Nat Commun 2017 04 3;8:14931. Epub 2017 Apr 3.

Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 168c, Boston, Massachusetts 02115, USA.

Circadian and seasonal rhythms are seen in many species, modulate several aspects of human physiology, including brain functions such as mood and cognition, and influence many neurological and psychiatric illnesses. However, there are few data regarding the genome-scale molecular correlates underlying these rhythms, especially in the human brain. Here, we report widespread, site-specific and interrelated diurnal and seasonal rhythms of gene expression in the human brain, and show their relationship with parallel rhythms of epigenetic modification including histone acetylation, and DNA methylation. We also identify transcription factor-binding sites that may drive these effects. Further, we demonstrate that Alzheimer's disease pathology disrupts these rhythms. These data suggest that interrelated diurnal and seasonal epigenetic and transcriptional rhythms may be an important feature of human brain biology, and perhaps human biology more broadly, and that changes in such rhythms may be consequences of, or contributors to, diseases such as Alzheimer's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms14931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382268PMC
April 2017

Genetic epistasis regulates amyloid deposition in resilient aging.

Alzheimers Dement 2017 Oct 17;13(10):1107-1116. Epub 2017 Mar 17.

Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Introduction: The brain-derived neurotrophic factor (BDNF) interacts with important genetic Alzheimer's disease (AD) risk factors. Specifically, variants within the SORL1 gene determine BDNF's ability to reduce amyloid β (Aβ) in vitro. We sought to test whether functional BDNF variation interacts with SORL1 genotypes to influence expression and downstream AD-related processes in humans.

Methods: We analyzed postmortem brain RNA sequencing and neuropathological data for 441 subjects from the Religious Orders Study/Memory and Aging Project and molecular and structural neuroimaging data for 1285 subjects from the Alzheimer's Disease Neuroimaging Initiative.

Results: We found one SORL1 RNA transcript strongly regulated by SORL1-BDNF interactions in elderly without pathological AD and showing stronger associations with diffuse than neuritic Aβ plaques. The same SORL1-BDNF interactions also significantly influenced Aβ load as measured with [F]Florbetapir positron emission tomography.

Discussion: Our results bridge the gap between risk and resilience factors for AD, demonstrating interdependent roles of established SORL1 and BDNF functional genotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jalz.2017.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601013PMC
October 2017

Assessment of Early Evidence of Multiple Sclerosis in a Prospective Study of Asymptomatic High-Risk Family Members.

JAMA Neurol 2017 03;74(3):293-300

Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.

Importance: Subclinical inflammatory demyelination and neurodegeneration often precede symptom onset in multiple sclerosis (MS).

Objective: To investigate the prevalence of brain magnetic resonance imaging (MRI) and subclinical abnormalities among asymptomatic individuals at risk for MS.

Design, Setting, And Participants: The Genes and Environment in Multiple Sclerosis (GEMS) project is a prospective cohort study of first-degree relatives of people with MS. Each participant's risk for MS was assessed using a weighted score (Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility [GERSMS]) comprising an individual's genetic burden and environmental exposures. The study dates were August 2012 to July 2015.

Main Outcomes And Measures: Participants in the top and bottom 10% of the risk distribution underwent standard and quantitative neurological examination, including disability status, visual, cognitive, motor, and sensory testing, as well as qualitative and quantitative neuroimaging with 3-T brain MRI and optical coherence tomography.

Results: This study included 100 participants at risk for MS, with 41 at higher risk (40 women [98%]) and 59 at lower risk (25 women [42%]), at a mean (SD) age of 35.1 (8.7) years. Given the unequal sex distribution between the 2 groups, the analyses were restricted to women (n = 65). When considering all measured outcomes, higher-risk women differed from lower-risk women (P = .01 by omnibus test). Detailed testing with a vibration sensitivity testing device in a subgroup of 47 women showed that higher-risk women exhibited significantly poorer vibration perception in the distal lower extremities (P = .008, adjusting for age, height, and testing date). Furthermore, 5 of 65 women (8%) (4 at higher risk and 1 at lower risk) met the primary neuroimaging outcome of having T2-weighted hyperintense brain lesions consistent with the 2010 McDonald MRI criteria for dissemination in space. A subset of participants harbor many different neuroimaging features associated with MS, including perivenous T2-weighted hyperintense lesions and focal leptomeningeal enhancement, consistent with the hypothesis that these individuals are at higher risk of developing clinical symptoms of MS than the general population.

Conclusions And Relevance: Higher-risk asymptomatic family members of patients with MS are more likely to have early subclinical manifestations of MS. These findings underscore the importance of early detection in high-risk individuals.

Trial Registration: clinicaltrials.gov Identifier: NCT01353547.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2016.5056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348267PMC
March 2017