scholarly journals Genome-wide screen to identify genetic loci associated with cognitive decline in late-life depression

2020 ◽  
pp. 1-9
Author(s):  
D. C. Steffens ◽  
M. E. Garrett ◽  
K. L. Soldano ◽  
D. R. McQuoid ◽  
A. E. Ashley-Koch ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Multiple Testing ◽  
Academic Medical Center ◽  
Late Life ◽  
Late Life Depression ◽  
Gwas Analysis ◽  
Genome Wide ◽  
A Genome

ABSTRACT Objective: This study sought to conduct a comprehensive search for genetic risk of cognitive decline in the context of geriatric depression. Design: A genome-wide association study (GWAS) analysis in the Neurocognitive Outcomes of Depression in the Elderly (NCODE) study. Setting: Longitudinal, naturalistic follow-up study. Participants: Older depressed adults, both outpatients and inpatients, receiving care at an academic medical center. Measurements: The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery was administered to the study participants at baseline and a minimum of twice within a subsequent 3-year period in order to measure cognitive decline. A GWAS analysis was conducted to identify genetic variation that is associated with baseline and change in the CERAD Total Score (CERAD-TS) in NCODE. Results: The GWAS of baseline CERAD-TS revealed a significant association with an intergenic single-nucleotide polymorphism (SNP) on chromosome 6, rs17662598, that surpassed adjustment for multiple testing (p = 3.7 × 10−7; false discovery rate q = 0.0371). For each additional G allele, average baseline CERAD-TS decreased by 8.656 points. The most significant SNP that lies within a gene was rs11666579 in SLC27A1 (p = 1.1 × 10−5). Each additional copy of the G allele was associated with an average decrease of baseline CERAD-TS of 4.829 points. SLC27A1 is involved with processing docosahexaenoic acid (DHA), an endogenous neuroprotective compound in the brain. Decreased levels of DHA have been associated with the development of Alzheimer’s disease. The most significant SNP associated with CERAD-TS decline over time was rs73240021 in GRXCR1 (p = 1.1 × 10−6), a gene previously linked with deafness. However, none of the associations within genes survived adjustment for multiple testing. Conclusions: Our GWAS of cognitive function and decline among individuals with late-life depression (LLD) has identified promising candidate genes that, upon replication in other cohorts of LLD, may be potential biomarkers for cognitive decline and suggests DHA supplementation as a possible therapy of interest.

scholarly journals When Cognitive Decline and Depression Coexist in the Elderly: CSF Biomarkers Analysis Can Differentiate Alzheimer's Disease from Late-Life Depression

2018 ◽  
Vol 10 ◽  
Author(s):  
Claudio Liguori ◽  
Mariangela Pierantozzi ◽  
Agostino Chiaravalloti ◽  
Giulia M. Sancesario ◽  
Nicola B. Mercuri ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Late Life ◽  
The Elderly ◽  
Csf Biomarkers ◽  
Late Life Depression

scholarly journals Genetic Effects on Longitudinal Cognitive Decline During the Early Stages of Alzheimer's Disease

2021 ◽  
Author(s):  
Atul Kumar ◽  
Maryam Shoai ◽  
Sebastian Palmqvist ◽  
Erik Stomrud ◽  
John Hardy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Genome Wide Association Study ◽  
Early Stage ◽  
Cognitive Change ◽  
Preclinical Ad ◽  
Genome Wide ◽  
A Genome ◽  
Polygenic Scores

Abstract Background Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. Methods In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence and educational attainment), and genetic variants (in a genome-wide association study [GWAS]) to predict longitudinal cognitive change (measured by MMSE) over a mean of 4.2 years. We included 555 β-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 206 Aβ-positive CU (preclinical AD), 110 Aβ-negative mild cognitive impairment (MCI) patients, and 146 Aβ-positive MCI patients (prodromal AD). Results Polygenic scores for AD (in Aβ-positive individuals) and intelligence (independent of Aβ-status) were associated with cognitive decline. Eight genes were associated with cognitive decline in GWAS (3 independent of Aβ-status). Conclusions AD risk genes may influence cognitive decline in early AD, while genes related to intelligence may modulate cognitive decline irrespective of disease. Therapies targeting the implicated biological pathways may modulate the clinical course of AD.

scholarly journals Genetic Effects on Longitudinal Cognitive Decline During the Early Stages of Alzheimer's Disease

2021 ◽  
Author(s):  
Atul Kumar ◽  
Maryam Shoai ◽  
Sebastian Palmqvist ◽  
Erik Stomrud ◽  
John Hardy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Genome Wide Association Study ◽  
Early Stage ◽  
Cognitive Change ◽  
Preclinical Ad ◽  
Genome Wide ◽  
A Genome ◽  
Polygenic Scores

Abstract Background Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. Methods In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence and educational attainment), and genetic variants (in a genome-wide association study [GWAS]) to predict longitudinal cognitive change (measured by MMSE) over a mean of 4.2 years. We included 555 β-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 206 Aβ-positive CU (preclinical AD), 110 Aβ-negative mild cognitive impairment (MCI) patients, and 146 Aβ-positive MCI patients (prodromal AD). Results Polygenic scores for AD (in Aβ-positive individuals) and intelligence (independent of Aβ-status) were associated with cognitive decline. Eight genes were associated with cognitive decline in GWAS (3 independent of Aβ-status). Conclusions AD risk genes may influence cognitive decline in early AD, while genes related to intelligence may modulate cognitive decline irrespective of disease. Therapies targeting the implicated biological pathways may modulate the clinical course of AD.

scholarly journals Cognitive Decline in Alzheimer’s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 501
Author(s):  
Jack Euesden ◽  
Sivakumar Gowrisankar ◽  
Angela Xiaoyan Qu ◽  
Pamela St. Jean ◽  
Arlene R. Hughes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Decline ◽  
Clinical Utility ◽  
Phase Iii ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome

Introduction: Alzheimer’s disease (AD) is a progressive and irreversible neurological disease. The genetics and molecular mechanisms underpinning differential cognitive decline in AD are not well understood; the genetics of AD risk have been studied far more assiduously. Materials and Methods: Two phase III clinical trials measuring cognitive decline over 48 weeks using Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog, n = 2060) and Clinical Dementia Rating-Sum of Boxes (CDR-SB, n = 1996) were retrospectively genotyped. A Genome-Wide Association Study (GWAS) was performed to identify and replicate genetic variants associated with cognitive decline. The relationship between polygenic risk score (PRS) and cognitive decline was tested to investigate the predictive power of aggregating many variants of individually small effect. Results: No loci met candidate gene or genome-wide significance. PRS explained a very small percentage of variance in rates of cognitive decline (ADAS-cog: 0.54%). Conclusions: These results suggest that incorporating genetic information in the prediction of cognitive decline in AD currently appears to have limited utility in clinical trials, consistent with small effect sizes estimated elsewhere. If AD progression is more heritable soon after disease onset, genetics may have more clinical utility.

scholarly journals 110 - Investigations of Risk, Resilience and Novel Therapeutics of Late Life Neuropsychiatric Disease

2020 ◽  
Vol 32 (S1) ◽  
pp. 22-22
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Imaging ◽  
Animal Models ◽  
Cognitive Decline ◽  
Cognitive Deficits ◽  
Neuropsychiatric Symptoms ◽  
Late Life ◽  
Late Life Depression ◽  
Neuropsychiatric Disease

Converging data from multiple domains of preclinical and human studies has underscored the importance of focusing on genetic, synaptic and neural circuity as critical neurobiological mechanisms of late life neuropsychiatric disease. These complementary research approaches have been applied to identify novel molecular mechanisms that may represent early intervention targets, as well as promising new treatments. The symposium will include four speakers who span the range of studies in animal models, post-mortem brain tissue, molecular imaging and clinical trials combined with biomarkers. Dr Etienne Sibille will present his research on the procognitive, neurotrophic and neurogenic effects of novel compounds augmenting dendritic inhibition and restoring neuronal connectivity, which is affected in aging and in neurodegenerative disorders, such as Alzheimer’s disease. Dr. Robert Sweet will present new GWAS and human postmortem findings regarding risk/resilience to psychosis in Alzheimer's Disease, with an emphasis on synaptic mechanisms of resilience. Dr Helen Lavretsky will present a study of the neuroimaging, genetic and epigenetic effects of memantine and escitalopram treatment in late life depression. The strategy of incorporating biological measures into a clinical trial is an important opportunity to understanding the neurobiological mechanisms. Dr Gwenn Smith will present multi-modality molecular imaging data to understand the synaptic changes associated with Alzheimer’s Disease pathology in late life depression and mild cognitive impairment. Consideration of interdisciplinary research approaches and applications to different neuropsychiatric conditions may have particular relevance to understanding the neurobiological mechanisms underlying neuropsychiatric symptoms as risk factors or complications of neurodegenerative disease.Molecular imaging methods to visualize the neuropathology of Alzheimer’s disease (AD) in vivo provide an unprecedented opportunity to understand the neuropsychiatric (NPS) and cognitive symptoms observed in early stage AD by testing hypotheses informed by human neuropathology and animal models. A fuller understanding of the neurobiology of early AD and its clinical progression is essential to identify individuals at risk and to identify targets for prevention and treatment. Numerous neuroimaging studies have shown that beta-amyloid and tau is necessary but not sufficient to explain cognitive decline and that models to explain cognitive decline must also include measures associated with synaptic dysfunction (eg cerebral glucose metabolism or brain volumes). Human data and animal models support the further investigation of serotonin (5-HT) degeneration. Relative to other molecular targets, there is stronger evidence for 5-HT loss in both cognitive deficits and neuropsychiatric symptoms (NPS) in Alzheimer’s Disease. 5-HT compounds are the only agents with preclinical evidence of multiple therapeutic mechanisms relevant to prevention and symptomatic treatment: blockade of amyloid precursor protein processing or neuroprotection, synaptic plasticity and improvement in both cognitive deficits and NPS. Multi-radiotracer PET studies of beta-amyloid (Aβ), tau and 5-HT have been performed longitudinally in amnestic, multi -domain, MCI (aMCI-MD) and cognitively normal elderly. Cortical and limbic 5-HT degeneration was a more powerful predictor of longitudinal memory decline than Aβ or Tau. Elucidating the role of 5-HT, in relation to Tau and Aβ in cognitive decline in aMCI-MD will have fundamental implications for the design of prevention and intervention studies targeting 5-HT.

scholarly journals Genetic Interactions Explain Variance in Cingulate Amyloid Burden: An AV-45 PET Genome-Wide Association and Interaction Study in the ADNI Cohort

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Jin Li ◽  
Qiushi Zhang ◽  
Feng Chen ◽  
Jingwen Yan ◽  
Sungeun Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genome Wide Association Study ◽  
Neurodegenerative Disorder ◽  
Genome Wide Association ◽  
Interaction Study ◽  
Gwas Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Single Marker

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. Using discrete disease status as the phenotype and computing statistics at the single marker level may not be able to address the underlying biological interactions that contribute to disease mechanism and may contribute to the issue of “missing heritability.” We performed a genome-wide association study (GWAS) and a genome-wide interaction study (GWIS) of an amyloid imaging phenotype, using the data from Alzheimer’s Disease Neuroimaging Initiative. We investigated the genetic main effects and interaction effects on cingulate amyloid-beta (Aβ) load in an effort to better understand the genetic etiology of Aβdeposition that is a widely studied AD biomarker. PLINK was used in the single marker GWAS, and INTERSNP was used to perform the two-marker GWIS, focusing only on SNPs withp≤0.01for the GWAS analysis. Age, sex, and diagnosis were used as covariates in both analyses. Correctedpvalues using the Bonferroni method were reported. The GWAS analysis revealed significant hits within or proximal toAPOE,APOC1, andTOMM40genes, which were previously implicated in AD. The GWIS analysis yielded 8 novel SNP-SNP interaction findings that warrant replication and further investigation.

scholarly journals Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Joseph S. Reddy ◽  
Mariet Allen ◽  
Charlotte C. G. Ho ◽  
Stephanie R. Oatman ◽  
Özkan İş ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genome Wide Association Study ◽  
Transcriptome Profiling ◽  
Brain Regions ◽  
Common Finding ◽  
Amyloid Angiopathy ◽  
Genome Wide ◽  
A Genome ◽  
Male Sex

AbstractCerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer’s disease (AD) dementia and is a common finding at autopsy. The APOEε4 allele and male sex have previously been reported to associate with increased CAA in AD. To inform biomarker and therapeutic target discovery, we aimed to identify additional genetic risk factors and biological pathways involved in this vascular component of AD etiology. We present a genome-wide association study of CAA pathology in AD cases and report sex- and APOE-stratified assessment of this phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed AD cases scored for CAA across five brain regions, and imputed to the Haplotype Reference Consortium panel. Key variables and genome-wide genotypes were tested for association with CAA in all individuals and in sex and APOEε4 stratified subsets. Pathway enrichment was run for each of the genetic analyses. Implicated loci were further investigated for functional consequences using brain transcriptome data from 1,186 samples representing seven brain regions profiled as part of the AMP-AD consortium. We confirmed association of male sex, AD neuropathology and APOEε4 with increased CAA, and identified a novel locus, LINC-PINT, associated with lower CAA amongst APOEε4-negative individuals (rs10234094-C, beta = −3.70 [95% CI −0.49—−0.24]; p = 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels in AD cases, and association of rs10234094-C with altered LINC-PINT splicing. Pathway analysis indicates variation in genes involved in neuronal health and function are linked to CAA in AD patients. Further studies in additional and diverse cohorts are needed to assess broader translation of our findings.

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