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A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease.

ABSTRACT: Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain A?-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRSc?APOE) or excluding APOE (emPRSs?APOE ). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer's cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRSc? APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRSs? APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ?4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ?4 or one ?4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ?4 allele. Overall, the described novel emPRS has utility for the prediction of decline in cognition in preclinical AD. This study provides evidence to support the further use and evaluation of phenotype weightings in PRS development.

SUBMITTER: Porter T

PROVIDER: S-EPMC6305908 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease.

Porter Tenielle T Burnham Samantha C SC Savage Greg G Lim Yen Ying YY Maruff Paul P Milicic Lidija L Peretti Madeline M Ames David D Masters Colin L CL Martins Ralph N RN Rainey-Smith Stephanie S Rowe Christopher C CC Salvado Olivier O Taddei Kevin K Groth David D Verdile Giuseppe G Villemagne Victor L VL Laws Simon M SM

Frontiers in aging neuroscience 20181219

Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of <i>APOE</i> genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (<i>em</i>PRS) was derived and assessed against decline in cognitive pe ...[more]

PMID: 30620773

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Project description:An unfortunate result of the rapid rise in geriatric populations worldwide is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that is characterized by a profound impairment of cognitive function, marked physical disability, and an enormous economic burden on the afflicted individual, caregivers, and society in general. The rise in elderly populations is also resulting in an increase in individuals with related (potentially treatable) conditions such as "Mild Cognitive Impairment" (MCI) which is characterized by a less severe (but abnormal) level of cognitive impairment and a high-risk for developing dementia. Even in the absence of a diagnosable disorder of cognition (e.g., AD and MCI), the perception of increased forgetfulness and declining mental function is a clear source of apprehension in the elderly. This is a valid concern given that even a modest impairment of cognitive function is likely to be associated with significant disability in a rapidly evolving, technology-based society. Unfortunately, the currently available therapies designed to improve cognition (i.e., for AD and other forms of dementia) are limited by modest efficacy and adverse side effects, and their effects on cognitive function are not sustained over time. Accordingly, it is incumbent on the scientific community to develop safer and more effective therapies that improve and/or sustain cognitive function in the elderly allowing them to remain mentally active and productive for as long as possible. As diagnostic criteria for memory disorders evolve, the demand for pro-cognitive therapeutic agents is likely to surpass AD and dementia to include MCI and potentially even less severe forms of memory decline. The purpose of this review is to provide an overview of the contemporary therapeutic targets and preclinical pharmacologic approaches (with representative drug examples) designed to enhance memory function.

Project description:BackgroundWhat combination of risk factors for Alzheimer's disease (AD) are most predictive of cognitive decline in cognitively unimpaired individuals remains largely unclear. We studied associations between APOE genotype, AD-Polygenic Risk Scores (AD-PRS), amyloid-β pathology and decline in cognitive functioning over time in a large sample of cognitively unimpaired older individuals.MethodsWe included 276 cognitively unimpaired older individuals (75 ± 10 years, 63% female) from the EMIF-AD PreclinAD cohort. An AD-PRS was calculated including 83 genome-wide significant variants. The APOE gene was not included in the PRS and was analyzed separately. Baseline amyloid-β status was assessed by visual read of [18F]flutemetamol-PET standardized uptake value images. At baseline and follow-up (2.0 ± 0.4 years), the cognitive domains of memory, attention, executive function, and language were measured. We used generalized estimating equations corrected for age, sex and center to examine associations between APOE genotype and AD-PRS with amyloid-β status. Linear mixed models corrected for age, sex, center and education were used to examine associations between APOE genotype, AD-PRS and amyloid-β status, and their interaction on changes in cognitive functioning over time.ResultsFifty-two participants (19%) had abnormal amyloid-β, and 84 participants (31%) carried at least one APOE ε4 allele. APOE genotype and AD-PRS were both associated with abnormal amyloid-β status. Increasingly more risk-full APOE genotype, a high AD-PRS and an abnormal amyloid-β status were associated with steeper decline in memory functioning in separate models (all p ≤ 0.02). A model including 4-way interaction term (APOE×AD-PRS×amyloid-β×time) was not significant. When modelled together, both APOE genotype and AD-PRS predicted steeper decline in memory functioning (APOE β(SE)=-0.05(0.02); AD-PRS β(SE)=-0.04(0.01)). Additionally, when modelled together, both amyloid-β status and AD-PRS predicted a steeper decline in memory functioning (amyloid-β β(SE)=-0.07(0.04); AD-PRS β(SE)=-0.04(0.01)). Modelling both APOE genotype and amyloid-β status, we observed an interaction, in which APOE genotype was related to steeper decline in memory and language functioning in amyloid-β abnormal individuals only (β(SE)=-0.13(0.06); β(SE)=-0.22(0.07), respectively).ConclusionOur results suggest that APOE genotype is related to steeper decline in memory and language functioning in individuals with abnormal amyloid-β only. Furthermore, independent of amyloid-β status other genetic risk variants contribute to memory decline in initially cognitively unimpaired older individuals.

Project description:Evidence suggests exposure to particulate matter with aerodynamic diameter <2.5 μm (PM2.5) may increase the risk for Alzheimer's disease and related dementias. Whether PM2.5 alters brain structure and accelerates the preclinical neuropsychological processes remains unknown. Early decline of episodic memory is detectable in preclinical Alzheimer's disease. Therefore, we conducted a longitudinal study to examine whether PM2.5 affects the episodic memory decline, and also explored the potential mediating role of increased neuroanatomic risk of Alzheimer's disease associated with exposure. Participants included older females (n = 998; aged 73-87) enrolled in both the Women's Health Initiative Study of Cognitive Aging and the Women's Health Initiative Memory Study of Magnetic Resonance Imaging, with annual (1999-2010) episodic memory assessment by the California Verbal Learning Test, including measures of immediate free recall/new learning (List A Trials 1-3; List B) and delayed free recall (short- and long-delay), and up to two brain scans (MRI-1: 2005-06; MRI-2: 2009-10). Subjects were assigned Alzheimer's disease pattern similarity scores (a brain-MRI measured neuroanatomical risk for Alzheimer's disease), developed by supervised machine learning and validated with data from the Alzheimer's Disease Neuroimaging Initiative. Based on residential histories and environmental data on air monitoring and simulated atmospheric chemistry, we used a spatiotemporal model to estimate 3-year average PM2.5 exposure preceding MRI-1. In multilevel structural equation models, PM2.5 was associated with greater declines in immediate recall and new learning, but no association was found with decline in delayed-recall or composite scores. For each interquartile increment (2.81 μg/m3) of PM2.5, the annual decline rate was significantly accelerated by 19.3% [95% confidence interval (CI) = 1.9% to 36.2%] for Trials 1-3 and 14.8% (4.4% to 24.9%) for List B performance, adjusting for multiple potential confounders. Long-term PM2.5 exposure was associated with increased Alzheimer's disease pattern similarity scores, which accounted for 22.6% (95% CI: 1% to 68.9%) and 10.7% (95% CI: 1.0% to 30.3%) of the total adverse PM2.5 effects on Trials 1-3 and List B, respectively. The observed associations remained after excluding incident cases of dementia and stroke during the follow-up, or further adjusting for small-vessel ischaemic disease volumes. Our findings illustrate the continuum of PM2.5 neurotoxicity that contributes to early decline of immediate free recall/new learning at the preclinical stage, which is mediated by progressive atrophy of grey matter indicative of increased Alzheimer's disease risk, independent of cerebrovascular damage.

Project description:ImportanceGenetic factors have a well-known influence on Parkinson disease (PD) susceptibility. The largest genome-wide association study (GWAS) identified 26 independent single-nucleotide polymorphisms (SNPs) associated with PD risk. Among patients, the course and severity of symptom progression is variable, and little is known about the potential association of genetic factors with phenotypic variance.ObjectiveTo assess whether GWAS-identified PD risk SNPs also have a cumulative association with the progression of cognitive and motor symptoms in patients with PD.Design, setting, and participantsThis longitudinal population-based cohort study of 285 patients of European ancestry with incident PD genotyped 23 GWAS SNPs. One hundred ninety-nine patients were followed up for a mean (SD) of 5.3 (2.1) years for progression (baseline: June 1, 2001, through November 31, 2007; follow-up: June 1, 2007, through August 31, 2013, with mortality surveillance through December 31, 2016); 57 patients had died or were too ill for follow-up, and 29 withdrew or could not be contacted. Movement disorder specialists repeatedly assessed PD symptom progression.Main outcomes measuresThe combined association of PD risk loci, after creating a weighted polygenic risk score (PRS), with cognitive decline, motor progression, and survival, relying on Cox proportional hazards regression models and inverse probability weights to account for censoring.ResultsOf the 285 patients undergoing genotyping, 160 were men (56.1%) and 125 were women (43.9%); the mean (SD) age at diagnosis was 69.1 (10.4) years. The weighted PRS was associated with significantly faster cognitive decline, measured by change in the Mini-Mental State Examination (hazard ratio [HR] per 1 SD, 1.44; 95% CI, 1.00-2.07). The PRS was also associated with faster motor decline, measured by time to Hoehn & Yahr Scale stage 3 (HR, 1.34; 95% CI, 1.00-1.79) and change in Unified Parkinson's Disease Rating Scale part III score (HR, 1.42; 95% CI, 1.00-2.01).Conclusions and relevanceSusceptibility SNPs for PD combined with a cumulative PRS were associated with faster motor and cognitive decline in patients. Thus, these genetic markers may be associated with not only PD susceptibility but also disease progression in multiple domains.

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A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease.

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A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease.

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