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Risk of incident clinical diagnosis of Alzheimer's disease-type dementia attributable to pathology-confirmed vascular disease.

ABSTRACT: INTRODUCTION:The presence of cerebrovascular pathology may increase the risk of clinical diagnosis of Alzheimer's disease (AD). METHODS:We examined excess risk of incident clinical diagnosis of AD (probable and possible AD) posed by the presence of lacunes and large infarcts beyond AD pathology using data from the Statistical Modeling of Aging and Risk of Transition study, a consortium of longitudinal cohort studies with more than 2000 autopsies. We created six mutually exclusive pathology patterns combining three levels of AD pathology (low, moderate, or high AD pathology) and two levels of vascular pathology (without lacunes and large infarcts or with lacunes and/or large infarcts). RESULTS:The coexistence of lacunes and large infarcts results in higher likelihood of clinical diagnosis of AD only when AD pathology burden is low. DISCUSSION:Our results reinforce the diagnostic importance of AD pathology in clinical AD. Further harmonization of assessment approaches for vascular pathologies is required.

SUBMITTER: Dodge HH

PROVIDER: S-EPMC5466467 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Risk of incident clinical diagnosis of Alzheimer's disease-type dementia attributable to pathology-confirmed vascular disease.

Dodge Hiroko H HH Zhu Jian J Woltjer Randy R Nelson Peter T PT Bennett David A DA Cairns Nigel J NJ Fardo David W DW Kaye Jeffrey A JA Lyons Deniz-Erten DE Mattek Nora N Schneider Julie A JA Silbert Lisa C LC Xiong Chengjie C Yu Lei L Schmitt Frederick A FA Kryscio Richard J RJ Abner Erin L EL

Alzheimer's & dementia : the journal of the Alzheimer's Association 20161223 6

<h4>Introduction</h4>The presence of cerebrovascular pathology may increase the risk of clinical diagnosis of Alzheimer's disease (AD).<h4>Methods</h4>We examined excess risk of incident clinical diagnosis of AD (probable and possible AD) posed by the presence of lacunes and large infarcts beyond AD pathology using data from the Statistical Modeling of Aging and Risk of Transition study, a consortium of longitudinal cohort studies with more than 2000 autopsies. We created six mutually exclusive ...[more]

PMID: 28017827

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Project description:Growing evidence suggests overlap between Alzheimer's disease (AD) and Parkinson's disease (PD) pathophysiology in a subset of patients. Indeed, 50-80% of autopsy cases with a primary clinicopathological diagnosis of Lewy body disease (LBD)-most commonly manifesting during life as PD-have concomitant amyloid-beta and tau pathology, the defining pathologies of AD. Here we evaluated common genetic variants in genome-wide association with AD as predictors of concomitant AD pathology in the brains of people with a primary clinicopathological diagnosis of PD or Dementia with Lewy Bodies (DLB), diseases both characterized by neuronal Lewy bodies. In the first stage of our study, 127 consecutive autopsy-confirmed cases of PD or DLB from a single center were assessed for AD neuropathological change (ADNC), and these same cases were genotyped at 20 single nucleotide polymorphisms (SNPs) found by genome-wide association study to associate with risk for AD. In these 127 training set individuals, we developed a logistic regression model predicting the presence of ADNC, using backward stepwise regression for model selection and tenfold cross-validation to estimate performance. The best-fit model generated a risk score for ADNC (ADNC-RS) based on age at disease onset and genotype at three SNPs (APOE, BIN1, and SORL1 loci), with an area under the receiver operating curve (AUC) of 0.751 in our training set. In the replication stage of our study, we assessed model performance in a separate test set of the next 81 individuals genotyped in our center. In the test set, the AUC was 0.781, and individuals with ADNC-RS in the top quintile had four-fold increased likelihood of having AD pathology at autopsy compared with those in each of the lowest two quintiles. Finally, in the validation stage of our study, we applied our ADNC-RS model to 70 LBD individuals from 20 Alzheimer's Disease Research Centers (ADRC) whose autopsy and genetic data were available in the National Alzheimer's Coordinating Center (NACC) database. In this validation set, the AUC was 0.754. Thus, in patients with autopsy-confirmed PD or DLB, a simple model incorporating three AD-risk SNPs and age at disease onset substantially enriches for concomitant AD pathology at autopsy, with implications for identifying LBD patients in which targeting amyloid-beta or tau is a therapeutic strategy.

Project description:ObjectiveWe evaluated dementia and Alzheimer's disease (AD) risks after a cancer diagnosis in a population-based prospective cohort, the Adult Changes in Thought (ACT) study.MethodsWe followed community-dwelling people aged ?65 years without dementia at study entry for incident dementia and AD from 1994-2015. We linked study data with cancer registry data and categorized cancer diagnoses as prevalent (diagnosed before ACT study enrollment) or incident (diagnosed during follow-up). We used Cox regression to estimate cause-specific hazard ratios (HRs) with 95% confidence intervals (CIs) for dementia or AD risk comparing people with a cancer diagnosis to people without cancer. We conducted sensitivity analyses restricted to people surviving beyond age 80, and stratified by cancer stage, type, and whether the cancer was smoking-related.ResultsAmong 4,357 people, 756 (17.4%) had prevalent cancer; 583 (13.4%) developed incident cancer, 1,091 (25.0%) developed dementia, and 877 (20.1%) developed AD over a median 6.4 years (34,482 total person-years) of follow-up. Among complete cases (no missing covariates) with at least one follow-up assessment, adjusted HRs for dementia following prevalent and incident cancer diagnoses were 0.92 (95%CI: 0.76, 1.11) and 0.87 (95%CI: 0.64, 1.04), compared to no cancer history. HRs for AD were 0.95 (95%CI: 0.77, 1.17) for prevalent cancer and 0.73 (95%CI: 0.55, 0.96) for incident cancer. In sensitivity analyses, prevalent late-stage cancers were associated with reduced risks of dementia (HR = 0.51, 95%CI: 0.30, 0.89) and AD (HR = 0.50, 95%CI: 0.27, 0.94). When limited to people who survived beyond age 80, incident cancers were still associated with reduced AD risk (HR = 0.69, 95%CI: 0.51, 0.92).ConclusionsOur results do not support an inverse association between prevalent cancer diagnoses, which were primarily early-stage, less aggressive cancers, and risk of dementia or AD. A reduced risk of AD following an incident cancer diagnosis is biologically plausible but may reflect selective mortality.

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Risk of incident clinical diagnosis of Alzheimer's disease-type dementia attributable to pathology-confirmed vascular disease.

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Risk of incident clinical diagnosis of Alzheimer's disease-type dementia attributable to pathology-confirmed vascular disease.

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