The contribution of cardiovascular disease (CV) and cerebrovascular disease to the risk for late-onset Alzheimer disease (LOAD) has been long debated. Investigations have shown that antecedent CV risk factors increase the risk for LOAD, although other investigations have failed to validate this association.
To study the contribution of CV risk factors (type 2 diabetes, hypertension, and heart disease) and the history of stroke to LOAD in a data set of large families multiply affected by LOAD.
Design, Setting, and Participants
The National Institute on Aging Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease family study (hereinafter referred to as NIA-LOAD study) is a longitudinal study of families with multiple members affected with LOAD. A multiethnic community-based longitudinal study (Washington Heights–Inwood Columbia Aging Project [WHICAP]) was used to replicate findings. The 6553 participants in the NIA-LOAD study were recruited from 23 US Alzheimer disease centers with ongoing data collection since 2003; the 5972 WHICAP participants were recruited at Columbia University with ongoing data collection since 1992. Data analysis was performed from 2003 to 2015.
Main Outcomes and Measures
Generalized mixed logistic regression models tested the association of CV risk factors (primary association) with LOAD. History of stroke was used for the secondary association. A secondary model adjusted for the presence of an apolipoprotein E (APOE) ε4 allele. A genetic risk score, based on common variants associated with LOAD, was used to account for LOAD genetic risk beyond the APOE ε4 effect. Mediation analyses evaluated stroke as a mediating factor between the primary association and LOAD.
A total of 6553 NIA-LOAD participants were included in the analyses (4044 women [61.7%]; 2509 men [38.3%]; mean [SD] age, 77.0  years), with 5972 individuals from the WHICAP study included in the replication sample (4072 women [68.2%]; 1900 men [31.8%]; mean [SD] age, 76.5 [7.0] years). Hypertension was associated with decreased LOAD risk (odds ratio [OR], 0.63; 95% CI, 0.55-0.72); type 2 diabetes and heart disease were not. History of stroke conferred greater than 2-fold increased risk for LOAD (OR, 2.23; 95% CI, 1.75-2.83). Adjustment for APOE ε4 did not alter results. The genetic risk score was associated with LOAD (OR, 2.85; 95% CI, 2.05-3.97) but did not change the independent association of LOAD with hypertension or stroke. In the WHICAP sample, hypertension was not associated with LOAD (OR, 0.99; 95% CI, 0.88-1.11), whereas history of stroke increased the risk for LOAD (OR, 1.96; 95% CI, 1.56-2.46). The effect of hypertension on LOAD risk was also mediated by stroke in the NIA-LOAD and the WHICAP samples.
Conclusions and Relevance
In familial and sporadic LOAD, a history of stroke was significantly associated with increased disease risk and mediated the association between selected CV risk factors and LOAD, which appears to be independent of the LOAD-related genetic background.
Late Onset Alzheimer Disease; psychosis; genome-wide linkage analysis; association analysis; Non-Hispanic Caucasian and Caribbean Hispanic ancestry populations
The present study identified potential genetic modifiers that may delay or accelerate age at onset of familial Alzheimer disease (AD) by examining age at onset in PSEN1 mutation carrier families, and further investigation of these modifiers may provide insight into the pathobiology of AD and potential therapeutic measures.
To identify genetic variants that modify age at onset of AD.
Design, Setting, And Participants
Using a subset of Caribbean Hispanic families that carry the PSEN1 p.G206A mutation, we performed a 2-stage genome study. The mutation carrier families from an ongoing genetic study served as a discovery set, and the cohort of those with LOAD served as a confirmation set. To identify candidate loci, we performed linkage analysis using 5 p.G206A carrier families (n = 56), and we also performed whole-exome association analysis using 31 p.G206A carriers from 26 families. To confirm the genetic modifiers identified from the p.G206A carrier families, we analyzed the GWAS data for 2888 elderly individuals with LOAD. All study participants were Caribbean Hispanics.
Main Outcomes and Measures
Age at onset of AD.
Linkage analysis of AD identified the strongest linkage support at 4q35 (LOD [logarithm of odds] score, 3.69), and the GWAS of age at onset identified variants on 1p13.1, 2q13, 4q25, and 17p11. In the confirmation stage, genewise analysis identified SNX25, PDLIM3, and 3 SH3 domain genes (SORBS2, SH3RF3, and NPHP1) to be significantly associated with LOAD. Subsequent allelic association analysis confirmed SNX25, PDLIM3, and SORBS2 as genetic modifiers of age at onset of EOAD and LOAD and provided modest support for SH3RF3 and NPHP1.
Conclusions and Relevance
Our 2-stage analysis revealed that SNX25, PDLIM3, and SORBS2 may serve as genetic modifiers of age at onset in both EOAD and LOAD.
To detect rare coding variants underlying loci detected by genome-wide association studies (GWASs) of late-onset Alzheimer’s disease (LOAD).
We conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A and PICALM in three independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 NIA-LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least two datasets were genotyped in independent groups of ancestry matched controls. Additionally, the Exome Aggregation Consortium (ExAC) was used as a reference dataset for population-based allele frequencies.
Overall we detected a statistically significant 3.1-fold enrichment of the non-synonymous mutations in the Caucasian LOAD cases compared with controls (p=0.002) and no difference in synonymous variants. A stopgain mutation in ABCA7 (E1769X) and missense mutation in CD2AP (T374A) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in two of the six Caribbean Hispanic families where the mutations were discovered.
Targeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease related mechanisms and potential therapies.
Targeted sequencing; GWAS and rare variants; Alzheimer’s disease
In the context of late‐onset Alzheimer's disease (LOAD) over 20 genes have been identified but, aside APOE, all show small effect sizes, leaving a large part of the genetic component unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD.
About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome‐wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (n = 5300). Two AD‐like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non‐Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets.
A novel locus, rs75002042 in FBXL7 (5p15.1), was found genome‐wide significant in the case–control cohort (odd ratio [OR] = 0.61, P = 6.19E‐09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E‐08). Fbxl7 protein was overexpressed in both AD‐like transgenic mice compared to wild‐type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single‐nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non‐Hispanic White and African American data sets (0.0005 < P < 0.02) used for replication.
FBXL7, encodes a subcellular protein involved in phosphorylation‐dependent ubiquitination processes and displays proapoptotic activity. F‐box proteins also modulate inflammation and innate immunity, which may be important in LOAD pathogenesis. Further investigations are needed to validate and understand its role in this and other populations.
To detect rare coding variants underlying loci detected by genome‐wide association studies (GWAS) of late onset Alzheimer disease (LOAD).
We conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry‐matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population‐based allele frequencies.
Overall we detected a statistically significant 3.1‐fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop‐gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered.
Targeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease‐related mechanisms and potential therapies. Ann Neurol 2015;78:487–498
Interpersonal Counseling (IPC) comes directly from interpersonal psychotherapy (IPT), an evidenced-based psychotherapy developed by Klerman and Weissman. It [IPC?] is a briefer, more structured version for use primarily in non-mental health settings, such as primary care clinics when treating patients with symptoms of depression. National health-care reform, which will bring previously uninsured persons into care and provide mechanisms to support mental health training of primary care providers, will increase interest in briefer psychotherapy. This paper describes the rationale, development, evidence for efficacy, and basic structure of IPC and also presents an illustrated clinical vignette. The evidence suggests that IPC is efficacious in reducing symptoms of depression; that it can be used by mental health personnel of different levels of training, and that the number of sessions is flexible depending on the context and resources. More clinical trials are needed, especially ones comparing IPC to other types of care used in the delivery of mental health services in primary care.
interpersonal psychotherapy; interpersonal counseling; depression; primary care
In the context of late-onset Alzheimer’s disease (LOAD) over 20 genes have been identified but, aside APOE, all show small effect sizes, leaving a large part of the genetic component unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD.
About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome-wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (n = 5300). Two AD-like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non-Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets.
A novel locus, rs75002042 in FBXL7 (5p15.1), was found genome-wide significant in the case–control cohort (odd ratio [OR] = 0.61, P = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E-08). Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005 < P < 0.02) used for replication.
FBXL7, encodes a subcellular protein involved in phosphorylation-dependent ubiquitination processes and displays proapoptotic activity. F-box proteins also modulate inflammation and innate immunity, which may be important in LOAD pathogenesis. Further investigations are needed to validate and understand its role in this and other populations.
Pathogenic mutations in the three known genes – the amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2) – are known to cause familial Alzheimer's disease (AD) and tend to be associated with early-onset AD. However, the frequency and risk associated with these mutations vary widely. In addition, mutations in the frontotemporal lobar degeneration (FTLD) genes – the microtubule-associated protein tau (MAPT), granulin (GRN) – have also been found to be associated with clinical AD. Here, we conducted targeted resequencing of the exons in genes encoding APP, PSEN1, PSEN2, GRN, and MAPT in 183 individuals from families with four or more affected relatives, presumed to be AD, and living in the Dominican Republic and Puerto Rico. We then performed linkage and family-based association analyses in carrier families, and genotyped 498 similarly aged unrelated controls from the same ethnic background. Twelve potentially pathogenic mutations were found to be associated with disease in 53 individuals in the five genes. The most frequently observed mutation was the p.Gly206Ala variant in PSEN1 present in 30 (57%) of those sequenced. In the combined linkage and association analyses several rare variants were associated with dementia. In Caribbean Hispanics with familial AD, potentially pathogenic variants were present in 29.2%, four were novel mutations, while eight had been previously observed. In addition, some family members carried variants in the GRN and MAPT genes which are associated with FTLD.
Alzheimer's disease; Caribbean Hispanics; familial dementia; mutations; next-generation sequencing
Late-onset Alzheimer disease (LOAD), defined as onset of symptoms after age 65 years, is the most common form of dementia. Few reports investigate incidence rates in large family-based studies in which the participants were selected for family history of LOAD.
To determine the incidence rates of dementia and LOAD in unaffected members in the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) family studies.
DESIGN, SETTING, AND PARTICIPANTS
Families with 2 or more affected siblings who had a clinical or pathological diagnosis of LOAD were recruited as a part of the NIA-LOAD/NCRAD Family Study. A cohort of Caribbean Hispanics with familial LOAD was recruited in a different study at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain in New York and from clinics in the Dominican Republic as part of the EFIGA study.
MAIN OUTCOMES AND MEASURES
Age-specific incidence rates of LOAD were estimated in the unaffected family members in the NIA-LOAD/NCRAD and EFIGA data sets. We restricted analyses to families with follow-up and complete phenotype information, including 396 NIA-LOAD/NCRAD and 242 EFIGA families. Among the 943 at-risk family members in the NIA-LOAD/NCRAD families, 126 (13.4%) developed dementia, of whom 109 (86.5%) met criteria for LOAD. Among 683 at-risk family members in the EFIGA families, 174 (25.5%) developed dementia during the study period, of whom 145 (83.3%) had LOAD.
The annual incidence rates of dementia and LOAD in the NIA-LOAD/NCRAD families per person-year were 0.03 and 0.03, respectively, in participants aged 65 to 74 years; 0.07 and 0.06, respectively, in those aged 75 to 84 years; and 0.08 and 0.07, respectively, in those 85 years or older. Incidence rates in the EFIGA families were slightly higher, at 0.03 and 0.02, 0.06 and 0.05, 0.10 and 0.08, and 0.10 and 0.07, respectively, in the same age groups. Contrasting these results with the population-based estimates, the incidence was increased by 3-fold for NIA-LOAD/NCRAD families (standardized incidence ratio, 3.44) and 2-fold among the EFIGA compared with the NIA-LOAD/NCRAD families (1.71).
CONCLUSIONS AND RELEVANCE
The incidence rates for familial dementia and LOAD in the NIA-LOAD/NCRAD and EFIGA families are significantly higher than population-based estimates. The incidence rates in all groups increase with age. The higher incidence of LOAD can be explained by segregation of Alzheimer disease–related genes in these families or shared environmental risks.
The magnitude of the September 11, 2001 (9/11) attacks was without precedent in the United States, but long-term longitudinal research on its health consequences for primary care patients is limited. We assessed the prevalence and exposure-related determinants of mental disorders, functioning, general medical conditions and service utilization, 1 and 4 years after the 9/11 attacks, in an urban primary care cohort (N = 444) in Manhattan. Although the prevalence of posttraumatic stress disorder (PTSD) and levels of functional impairment declined over time, a substantial increase in suicidal ideation and missed work was observed. Most medical outcomes and service utilization indicators demonstrated a short-term increase after the 9/11 attacks (mean change of +20.3%), followed by a minor decrease in the subsequent year (mean change of −3.2%). Loss of a close person was associated with the highest risk for poor mental health and functional status over time. These findings highlight the importance of longitudinal assessments of mental, functional, and medical outcomes in urban populations exposed to mass trauma and terrorism.
Debate surrounds the nature of gender differences in rates of posttraumatic stress disorder (PTSD).
The goal of this study was to quantify and explore the reasons for gender differences in rates of PTSD in low income, primary care patients after the World Trade Center (WTC) attack of September 11, 2001.
A survey was conducted at a large primary care practice in New York City 7 to 16 months after the WTC attack. The study involved a systematic sample of primary care patients aged 18 to 70 years. The main outcome measures were the Life Events Checklist, the Posttraumatic Stress Disorder Checklist–Civilian Version, and the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire, all administered by a bilingual research staff.
A total of 3807 patients were approached at the primary care clinic. Of the 1347 who met eligibility criteria, 1157 (85.9%) consented to participate. After the addition of the WTC/PTSD supplement to the study, the total number of patients was 992, of whom 982 (99.0%) completed the survey. Both sexes had high rates of direct exposure to the WTC attack and high rates of lifetime exposure to stressful life events. Overall, females had lower rates of exposure to the attack compared with males (P < 0.05). Hispanic females had the highest rate of PTSD in the full sample. Gender differences in rates of PTSD were largely accounted for by differences in marital status and education. The rate of current major depressive disorder (MDD) was higher in females than in males (P < 0.001), and the reverse was true for substance abuse (P < 0.001). Gender differences for MDD and substance abuse persisted even after adjustments for demographic differences between the sexes.
The increased rate of PTSD in women attending a primary care clinic was mediated by their social and economic circumstances, such as living alone without a permanent relationship and with little education or income. The increased rate of MDD in women appeared to be less dependent on these circumstances. These findings have implications for the treatment of women with PTSD in primary care and for research on gender differences in rates of psychiatric disorders.
posttraumatic stress disorder; gender; World Trade Center; primary care
Screening for psychiatric disorders has gained acceptance in some general medical settings, but critics argue about its value. The purpose of this study was to determine the clinical utility of screening by conducting a long-term follow-up of patients who screened positive for psychiatric disorders but who were initially not in treatment.
A cohort of 519 low-income, adult primary care patients were screened for major depression and bipolar, anxiety, and substance use disorders and reassessed with the Structured Clinical Interview for DSM-IV after a mean of 3.7 years by a clinician blind to the initial screen. Data on treatment utilization was obtained through hospital records. The sample consisted of 348 patients who had not received psychiatric care in the year before screening.
Among 39 patients who screened positive for major depression, 62% (95% confidence interval=45.5%–77.6%) met criteria for current major depressive disorder at follow-up. Those who screened positive reported significantly poorer mental and social functioning and worse general health at follow-up than the screen-negative patients and were more likely to have visited the emergency department for psychiatric reasons (12.1% and 3.0%, odds ratio [OR]=6.4) and to have major depression (OR=7.6). Generally similar results were observed for patients who screened positive for other disorders.
Commonly used screening methods identified patients with psychiatric disorders; about four years later, those not initially in treatment were likely to have enduring symptoms and to use emergency psychiatric services. Screening should be followed up by clinical diagnostic assessment in the context of available mental health treatment.
This study examines the long-term psychiatric consequences, pain interference in daily activities, work loss, and functional impairment associated with 9/11-related loss among low-income, minority primary care patients in New York City. A systematic sample of 929 adult patients completed a survey that included a sociodemographic questionnaire, the PTSD Checklist, the PRIME-MD Patient Health Questionnaire, and the Medical Outcomes Study Short Form-12 (SF-12).
Approximately one-quarter of the sample reported knowing someone who was killed in the attacks of 9/11, and these patients were sociodemographically similar to the rest of the sample. Compared to patients who had not experienced 9/11-related loss, patients who experienced loss were roughly twice as likely (OR = 1.97, 95%; CI = 1.40, 2.77) to screen positive for at least one mental disorder, including major depressive disorder (MDD; 29.2%), generalized anxiety disorder (GAD; 19.4%), and posttraumatic stress disorder (PTSD; 17.1%). After controlling for pre-9/11 trauma, 9/11-related loss was significantly related to extreme pain interference, work loss, and functional impairment. The results suggest that disaster-related mental health care in this clinical population should emphasize evidence-based treatments for mood and anxiety disorders.
To examine relationships between exposure to trauma, bipolar spectrum disorder (BD) and posttraumatic stress disorder (PTSD) in a sample of primary care patients.
A systematic sample (n = 977) of adult primary care patients from an urban general medicine practice were interviewed with measures including the Mood Disorders Questionnaire, the PTSD Checklist–Civilian Version, and the Medical Outcomes Study 12-Item Short Form Health Survey.
Compared with patients who screened negative for BD (n = 881), those who screened positive (n = 96) were 2.6 times [95% confidence interval (CI): 1.6–4.2] as likely to report physical or sexual assault, and 2.9 times (95% CI: 1.6–5.1) as likely to screen positive for current PTSD. Among those screening positive for BD, comorbid PTSD was associated with significantly worse social functioning. These results controlled for selected background characteristics, current major depressive episode, and current alcohol/drug use disorder.
In an urban general medicine setting, trauma exposure was related to BD, and the frequency of PTSD among patients with BD appears to be common and clinically significant. These results suggest an unmet need for mental health care in this specific population and are especially important in view of available treatments for BD and PTSD.
bipolar disorder; posttraumatic stress disorder; primary care; trauma exposure
To screen for posttraumatic stress disorder (PTSD) in primary care patients 7–16 months after 9/11 attacks and to examine its comorbidity, clinical presentation and relationships with mental health treatment and service utilization.
A systematic sample (n = 930) of adult primary care patients who were seeking primary care at an urban general medicine clinic were interviewed using the PTSD Checklist: the Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire and the Medical Outcome Study 12-Item Short Form Health Survey (SF-12). Health care utilization data were obtained by a cross linkage to the administrative computerized database.
Prevalence estimates of current 9/11-related probable PTSD ranged from 4.7% (based on a cutoff PCL-C score of 50 and over) to 10.2% (based on the DSM-IV criteria). A comorbid mental disorder was more common among patients with PTSD than patients without PTSD (80% vs. 30%). Patients with PTSD were more functionally impaired and reported increased use of mental health medication as compared to patients without PTSD (70% vs. 18%). Among patients with PTSD there was no increase in hospital and emergency room (ER) admissions or outpatient care during the first year after the attacks.
In an urban general medicine setting, 1 year after 9/11, the frequency of probable PTSD appears to be common and clinically significant. These results suggest an unmet need for mental health care in this clinical population and are especially important in view of available treatments for PTSD.
Primary care; Posttraumatic stress disorder; 9/11 attacks
Familial aggregation of dementia with Lewy bodies (DLB) remains unclear.
To determine the degree of family aggregation of DLB by comparing DLB risk between siblings of probands with clinically diagnosed DLB and siblings of probands with clinically diagnosed Alzheimer disease in a cohort of Caribbean Hispanic families and to explore the degree of aggregation of specific clinical manifestations (ie, cognitive fluctuations, visual hallucinations, and parkinsonism) in DLB.
Familial cohort study.
We separately compared risks of possible DLB, probable DLB, and clinical core features of DLB (cognitive fluctuations, visual hallucinations, and parkinsonism) between siblings of probands with clinically diagnosed DLB (n=344) and siblings of probands with clinically diagnosed Alzheimer disease (n=280) in 214 Caribbean Hispanic families with extended neurologic and neuropsychological assessment.
Main Outcome Measures
We applied general estimating equations to adjust for clustering within families. In these models, age and proband disease status were independent variables, and disease status of siblings was the measure of disease risk and the dependent variable.
Compared with siblings of probands having clinically diagnosed Alzheimer disease, siblings of probands having clinically diagnosed DLB had higher risks of probable DLB (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.04–5.04) and visual hallucinations (2.32; 1.16–4.64). They also had increased risks of possible DLB (OR, 1.51; 95% CI, 0.97–2.34) and cognitive fluctuations (1.55; 0.95–2.53).
Dementia with Lewy bodies and core features of DLB aggregate in families. Compared with siblings of probands having clinically diagnosed AD, siblings of probands having clinically diagnosed DLB are at increased risks of DLB and visual hallucinations. These findings are an important step in elucidating the genetic risk factors underlying DLB and in delineating DLB from other neurodegenerative diseases, such as Alzheimer disease.
To identify novel loci for late-onset Alzheimer disease (LOAD) in Caribbean Hispanic individuals and to replicate the findings in a publicly available data set from the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study.
Nested case-control genome-wide association study.
The Washington Heights–Inwood Columbia Aging Project and the Estudio Familiar de Influencia Genetica de Alzheimer study.
Five hundred forty-nine affected and 544 unaffected individuals of Caribbean Hispanic ancestry.
The Illumina HumanHap 650Y chip for genotyping.
Main Outcome Measure
Clinical diagnosis or pathologically confirmed diagnosis of LOAD.
The strongest support for allelic association was for rs9945493 on 18q23 (P=1.7 × 10−7), but 22 additional single-nucleotide polymorphisms (SNPs) had a P value less than 9 × 10−6 under 3 different analyses: unadjusted and stratified by the presence or absence of the APOE ε4 allele. Of these SNPs, 5 SNPs (rs4669573 and rs10197851 on 2p25.1; rs11711889 on 3q25.2; rs1117750 on 7p21.1; and rs7908652 on 10q23.1) were associated with LOAD in an independent cohort from the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study. We also replicated genetic associations for CLU, PICALM, and BIN1.
Our genome-wide search of Caribbean Hispanic individuals identified several novel genetic variants associated with LOAD and replicated these associations in a white cohort. We also replicated associations in CLU, PICALM, and BIN1 in the Caribbean Hispanic cohort.
To determine whether a diabetes case management telemedicine intervention reduced healthcare expenditures, as measured by Medicare claims, and to assess the costs of developing and implementing the telemedicine intervention.
We studied 1665 participants in the Informatics for Diabetes Education and Telemedicine (IDEATel), a randomized controlled trial comparing telemedicine case management of diabetes to usual care. Participants were aged 55 years or older, and resided in federally designated medically underserved areas of New York State.
We analyzed Medicare claims payments for each participant for up to 60 study months from date of randomization, until their death, or until December 31, 2006 (whichever happened first). We also analyzed study expenditures for the telemedicine intervention over six budget years (February 28, 2000– February 27, 2006).
Mean annual Medicare payments (SE) were similar in the usual care and telemedicine groups, $9040 ($386) and $9669 ($443) per participant, respectively (p>0.05). Sensitivity analyses, including stratification by censored status, adjustment by enrollment site, and semi-parametric weighting by probability of dropping-out, rendered similar results. Over six budget years 28 821 participant/months of telemedicine intervention were delivered, at an estimated cost of $622 per participant/month.
Telemedicine case management was not associated with a reduction in Medicare claims in this medically underserved population. The cost of implementing the telemedicine intervention was high, largely representing special purpose hardware and software costs required at the time. Lower implementation costs will need to be achieved using lower cost technology in order for telemedicine case management to be more widely used.
Diabetes; informatics; telemedicine
Colorectal cancer (CRC) screening remains underutilized in the United States. Prior studies reporting the cost effectiveness of randomized interventions to improve CRC screening have not been replicated in the setting of small physician practices. We recently conducted a randomized trial evaluating an academic detailing intervention in 264 small practices in geographically diverse New York City communities. The objective of this secondary analysis is to assess the cost effectiveness of this intervention.
A total of 264 physician offices were randomly assigned to usual care or to a series of visits from trained physician educators. CRC screening rates were measured at baseline and 12 months. The intervention costs were measured and the incremental cost-effectiveness ratio (ICER) was derived. Sensitivity analyses were based on varying cost and effectiveness estimates.
Academic detailing was associated with a 7% increase in CRC screening with colonoscopy. The total intervention cost was $147,865, and the ICER was $21,124 per percentage point increase in CRC screening rate. Sensitivity analyses that varied the costs of the intervention and the average medical practice size were associated with ICERs ranging from $13,631 to $36,109 per percentage point increase in CRC screening rates.
A comprehensive, multicomponent academic detailing intervention conducted in small practices in metropolitan New York was clinically effective in improving CRC screening rates, but was not cost effective.
Supported by a supplement to our Clinical and Translational Science Award, we studied the feasibility of implementing clinical research in Northern Manhattan community practices that primarily serve Hispanic patients.
We applied a mixed methods approach (surveys, focus groups, interviews) based upon the PRECEDE-PROCEED model to determine the level of interest in clinical research among community clinicians (Practice-based Research Network (PBRN) and non-PBRN members), the perceived barriers that hamper participation in clinical research, and the perceived facilitators for conducting research in such practices.
Survey and qualitative data indicated strong interest in clinical research among current and potential PBRN members if it was relevant to improving quality of care in their practice or community. They also identified important perceived barriers (lack of time, inadequate training in research methods, lack of collaborators and support staff, institutional review board hurdles, and community distrust of research) and the necessary requirements for overcoming barriers to conducting research in busy clinical settings: collaborators, mentors, research support staff, and trusting patient-clinician relationship.
It is feasible to conduct clinical research studies in urban community medical practices if the topics are relevant to the community and appropriate enabling structures and processes are put into place.
The aim of the study was to identify chromosomal regions containing putative genetic variants influencing age-at-onset in familial late-onset Alzheimer’s disease. Data from a genome-wide scan that included genotyping of APOE was analyzed in 1,161 individuals from 209 families of Caribbean Hispanic ancestry with a mean age-at-onset of 73.3 years multiply affected by late-onset Alzheimer’s disease. Two-point and multipoint analyses were conducted using variance component methods from 376 microsatellite markers with an average inter-marker distance of 9.3 cM. Family-based test of association were also conducted for the same set of markers. Age-at-onset of symptoms among affected individuals was used as the quantitative trait. Our results showed that the presence of APOE-ε4 lowered the age-at-onset by three years. Using linkage analysis strategy, the highest LOD scores were obtained using a conservative definition of LOAD at 5q15 (LOD 3.1) 17q25.1 (LOD=2.94) and 14q32.12 (LOD=2.36) and 7q36.3 (LOD=2.29) in covariate adjusted models that included APOE-ε4. Both linkage and family-based association identified 17p13 as a candidate region. In addition, family-based association analysis showed markers at 12q13 (p=0.00002), 13q (p=0.00043) and 14q23 (p=0.00046) to be significantly associated with age at onset. The current study supports the hypothesis that there are additional genetic loci that could influence age-at-onset of late onset Alzheimer’s disease. The novel loci at 5q15, 17q25.1, 13q and 17p13, and the previously reported loci at 7q36.3, 12q13, 14q23 and 14q32 need further investigation.
Alzheimer’s disease; age-at-onset; linkage analysis; family-based association analysis; APOE
Variants in 3′ and 5′ regions of SORL1, the neuronal sorting protein-related receptor, were recently found to be associated with late onset familial and sporadic Alzheimer’s disease in several datasets that were selected for familial aggregation or were ethnically diverse or clinic-based selected series.
To investigate the association between Alzheimer’s disease and variant alleles in SORL1 using a series of single nucleotide polymorphisms (SNPs) in an urban, multiethnic community-based population.
Design & Setting
We used a nested case-control analysis in a population-based, prospective study of aging and dementia in Medicare recipients, 65 years and older, residing in northern Manhattan.
There were 296 patients with probable Alzheimer’s disease and 428 healthy elderly controls. The participants were of African American (34%), Caribbean Hispanic (51%) or non-Hispanic whites (15%).
Main Outcome Measures
We genotyped all 29 SNPs in SORL1 that were examined in the earlier report. We assessed allelic association with AD using standard case-control methods which included APOE genotype as a covariate.
Several individual SNPs and SNP haplotypes were significantly associated with AD in this prospectively collected community-based cohort, confirming the previously reported positive association of SORL1 with Alzheimer’s disease. SNP 12 near the 5′ region was associated with AD in African-Americans and Hispanics. Two SNPs in the 3′ region were also associated with AD in African-Americans (SNP 26) and Whites (SNP 20). A single haplotype in the 3′ region was associated with AD in Hispanics. However, several different haplotypes were associated with AD in the African-Americans and Whites, including the “TTC” haplotypes at SNPs 23–25 (p=0.035) that was significantly associated with AD in the North European Whites in the previous report.
This study confirms the association between genetic variants in SORL1 and AD. While the associations observed in these datasets overlap with those previously reported, the finding of novel SNP and haplotype associations suggest that there may be extensive allelic heterogeneity in SORL1. Broad regions of the SORL1 gene will therefore need to be scrutinized for functional pathogenic variants.
SORL1; Alzheimer’s disease; sporadic; African American; Caribbean Hispanic
Factors that modify risk related to APOE variants have been examined primarily in unrelated patients and controls, but seldom in family-based studies. Stroke, vascular risk factors, estrogen replacement therapy (ERT), head injury (HI) and smoking have been reported to influence risk of sporadic but not familial AD.
To examine the potential relationship between these risk factors and APOE, we used a family study design in a population in which the APOE-ε4 variant is strongly associated with risk of AD.
Latino families primarily from the Caribbean Islands in which two or more living relatives had dementia were identified in the New York City metropolitan area, the Dominican Republic and Puerto Rico. 1,498 participants from 350 families underwent a clinical interview, medical and neurological examinations, neuropsychological testing and APOE genotyping. Diagnosis was made by consensus using research criteria for AD.
APOE-ε4 was associated with a nearly two-fold increased risk of AD. A history of stroke was also associated with a four-fold increased risk. A statistical interaction between APOE-ε4 and stroke was observed. Women with an APOE-ε4 who took ERT did not have an increased risk of AD, but in women with a history of stroke ERT was a deleterious effect modifier.
APOE-ε4 and stroke independently increase risk of familial AD among Latinos, and may interact to further increase AD risk. Among women, the risk of AD associated with APOE-ε4 may be attenuated by a history of ERT.
Alzheimer disease; estrogen; stroke; APOE
A broad region on chromosome 12p13 has been intensely investigated for novel genetic variants associated with Alzheimer disease (AD). We examined this region with 23 microsatellite markers using 124 North European (NE) families and 209 Caribbean Hispanic families with late-onset AD (FAD). Significant evidence for linkage was present in a 5 cM interval near 20 cM in both the NE FAD (LOD=3.5) and the Caribbean Hispanic FAD (LOD=2.2) datasets. We further investigated these families and an independent NE case-control dataset using 14 single nucleotide polymorphisms (SNPs). The initial screening of the region at ~20 cM in the NE case-control dataset revealed significant association between AD and seven SNPs in several genes, with the strongest result for rs2532500 in TAPBPL (p=0.006). For rs3741916 in GAPDH, the C allele, rather than the G allele as was observed by Li and colleagues (2004), was the risk allele. When the two family datasets were examined, none of the SNPs were significant in NE families, but two SNPs were associated with AD in Caribbean Hispanics: rs740850 in NCAPD2 (p=0.0097) and rs1060620 in GAPDH (p=0.042). In a separate analysis combining the Caribbean Hispanic families and NE cases and controls, rs740850 was significant after correcting for multiple testing (empirical p=0.0048). Subsequent haplotype analyses revealed that two haplotype sets -- haplotype C-A at SNPs 6-7 within NCAPD2 in Caribbean Hispanics, and haplotypes containing C-A-T at SNPs 8-10 within GAPDH in Caribbean Hispanic family and NE case-control datasets -- were associated with AD. Taken together, these SNPs may be in linkage disequilibrium with a pathogenic variant(s) on or near NCAPD2 and GAPDH.
Alzheimer disease; GAPDH; NCAPD2; linkage; association