Dataset Information

Pupillary dilation responses as a midlife indicator of risk for Alzheimer's disease: association with Alzheimer's disease polygenic risk.

ABSTRACT: Locus coeruleus (LC) tau accumulation begins early. Targeting LC (dys)function might improve early identification for Alzheimer's disease (AD) risk. Pupillary responses during cognitive tasks are driven by the LC and index cognitive effort. Despite equivalent task performance, adults with mild cognitive impairment have greater pupil dilation/effort during digit span than cognitively normal (CN) individuals. We hypothesized that AD polygenic risk scores (AD-PRSs) would be associated with pupillary responses in middle-aged CN adults. Pupillary responses during digit span tasks were heritable (h2 = 0.30-0.36) in 1119 men aged 56-66 years. In a CN subset-all with comparable span capacities (n = 539)-higher AD-PRSs were associated with greater pupil dilation/effort in a high (9-digit) cognitive load condition (Cohen's d = 0.36 for upper vs. lower quartile of AD-PRS distribution). Results held up after controlling for APOE genotype. Results support pupillary response-and by inference, LC dysfunction-as a genetically mediated biomarker of early mild cognitive impairment/AD risk. In combination with other biomarkers, task-evoked pupillary responses may provide additional information for early screening of genetically at-risk individuals even before cognitive declines.

SUBMITTER: Kremen WS

PROVIDER: S-EPMC6931134 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pupillary dilation responses as a midlife indicator of risk for Alzheimer's disease: association with Alzheimer's disease polygenic risk.

Kremen William S WS Panizzon Matthew S MS Elman Jeremy A JA Granholm Eric L EL Andreassen Ole A OA Dale Anders M AM Gillespie Nathan A NA Gustavson Daniel E DE Logue Mark W MW Lyons Michael J MJ Neale Michael C MC Reynolds Chandra A CA Whitsel Nathan N Franz Carol E CE

Neurobiology of aging 20190909

Locus coeruleus (LC) tau accumulation begins early. Targeting LC (dys)function might improve early identification for Alzheimer's disease (AD) risk. Pupillary responses during cognitive tasks are driven by the LC and index cognitive effort. Despite equivalent task performance, adults with mild cognitive impairment have greater pupil dilation/effort during digit span than cognitively normal (CN) individuals. We hypothesized that AD polygenic risk scores (AD-PRSs) would be associated with pupillar ...[more]

PMID: 31585363

Similar Datasets

Project description:BackgroundRecent studies suggest that plasma phosphorylated tau181 (p-tau181) is a highly specific biomarker for Alzheimer's disease (AD)-related tau pathology. It has great potential for the diagnostic and prognostic evaluation of AD, since it identifies AD with the same accuracy as tau PET and CSF p-tau181 and predicts the development of AD dementia in cognitively unimpaired (CU) individuals and in those with mild cognitive impairment (MCI). Plasma p-tau181 may also be used as a biomarker in studies exploring disease pathogenesis, such as genetic or environmental risk factors for AD-type tau pathology. The aim of the present study was to investigate the relation between polygenic risk scores (PRSs) for AD and plasma p-tau181.MethodsData from the Alzheimer's Disease Neuroimaging Initiative (ADNI) was used to examine the relation between AD PRSs, constructed based on findings in recent genome-wide association studies, and plasma p-tau181, using linear regression models. Analyses were performed in the total sample (n = 818), after stratification on diagnostic status (CU (n = 236), MCI (n = 434), AD dementia (n = 148)), and after stratification on Aβ pathology status (Aβ positives (n = 322), Aβ negatives (n = 409)).ResultsAssociations between plasma p-tau181 and APOE PRSs (p = 3e-18-7e-15) and non-APOE PRSs (p = 3e-4-0.03) were seen in the total sample. The APOE PRSs were associated with plasma p-tau181 in all diagnostic groups (CU, MCI, and AD dementia), while the non-APOE PRSs were associated only in the MCI group. The APOE PRSs showed similar results in amyloid-β (Aβ)-positive and negative individuals (p = 5e-5-1e-3), while the non-APOE PRSs were associated with plasma p-tau181 in Aβ positives only (p = 0.02).ConclusionsPolygenic risk for AD including APOE was found to associate with plasma p-tau181 independent of diagnostic and Aβ pathology status, while polygenic risk for AD beyond APOE was associated with plasma p-tau181 only in MCI and Aβ-positive individuals. These results extend the knowledge about the relation between genetic risk for AD and p-tau181, and further support the usefulness of plasma p-tau181 as a biomarker of AD.

Project description:Alzheimer's disease (AD) is the most common form of dementia and a growing public health burden in the United States. Significant progress has been made in identifying genetic risk for AD, but limited studies have investigated how AD genetic risk may be associated with other disease conditions in an unbiased fashion. In this study, we conducted a phenome-wide association study (PheWAS) by genetic ancestry groups within a large academic health system using the polygenic risk score (PRS) for AD. PRS was calculated using LDpred2 with genome-wide association study (GWAS) summary statistics. Phenotypes were extracted from electronic health record (EHR) diagnosis codes and mapped to more clinically meaningful phecodes. Logistic regression with Firth's bias correction was used for PRS phenotype analyses. Mendelian randomization was used to examine causality in significant PheWAS associations. Our results showed a strong association between AD PRS and AD phenotype in European ancestry (OR = 1.26, 95% CI: 1.13, 1.40). Among a total of 1,515 PheWAS tests within the European sample, we observed strong associations of AD PRS with AD and related phenotypes, which include mild cognitive impairment (MCI), memory loss, and dementias. We observed a phenome-wide significant association between AD PRS and gouty arthropathy (OR = 0.90, adjusted p = 0.05). Further causal inference tests with Mendelian randomization showed that gout was not causally associated with AD. We concluded that genetic predisposition of AD was negatively associated with gout, but gout was not a causal risk factor for AD. Our study evaluated AD PRS in a real-world EHR setting and provided evidence that AD PRS may help to identify individuals who are genetically at risk of AD and other related phenotypes. We identified non-neurodegenerative diseases associated with AD PRS, which is essential to understand the genetic architecture of AD and potential side effects of drugs targeting genetic risk factors of AD. Together, these findings expand our understanding of AD genetic and clinical risk factors, which provide a framework for continued research in aging with the growing number of real-world EHR linked with genetic data.

Dataset Information

Pupillary dilation responses as a midlife indicator of risk for Alzheimer's disease: association with Alzheimer's disease polygenic risk.

Publications

Pupillary dilation responses as a midlife indicator of risk for Alzheimer's disease: association with Alzheimer's disease polygenic risk.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets