Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease

AbstractImportanceFew studies have measured the effect of genetic factors on dementia and cognitive decline in a population of healthy older individuals followed prospectively.ObjectiveTo examine the effect of Apolipoprotein E (APOE) genotypes and a polygenic risk score (PRS) on incident dementia and cognitive decline in a longitudinal cohort of healthy older people.Design, Setting and ParticipantsPost-hoc genetic analysis of a randomized clinical trial population - the ASPirin in Reducing Events in the Elderly (ASPREE) trial. At enrollment, participants had no history of diagnosed dementia, atherothrombotic cardiovascular disease, or permanent physical disability and were without cognitive impairment.Main Outcomes and MeasuresDementia (adjudicated trial endpoint) and cognitive decline, defined as a >1.5 standard deviation decline in test score for either global cognition, episodic memory, language/executive function or psychomotor speed, versus baseline scores. Cumulative incidence curves for all-cause dementia and cognitive decline were calculated with mortality as a competing event, stratified by APOE genotypes and tertiles of a PRS based on 23 common non-APOE variants.Results12,978 participants with European ancestry were included; 54.8% were female, and average age at baseline was 75 years (range 70 to 96). During a median 4.5 years of follow-up, 324 (2.5%) participants developed dementia and 503 (3.8%) died. Cumulative incidence of dementia to age 85 years was estimated to be 7.4% in all participants, 12.6% in APOE ε4 heterozygotes, 26.6% in ε4 homozygotes, 9.6% in the high PRS tertile, and 7.3% in the low PRS tertile. APOE ε4 heterozygosity/homozygosity was associated with a 2.5/6.3-fold increased risk of dementia and a 1.4/1.8-fold increased risk of cognitive decline, versus ε3/ε3 (P<0.001 for both). A high PRS (top tertile) was associated with a 1.4-fold increase risk of dementia, versus the low tertile (CI 1.04-1.76, P=0.02), but was not associated with cognitive decline risk (CI 0.96-1.22, P = 0.18).Conclusions and RelevanceIncidence of dementia among healthy older individuals is low across all genotypes; however, APOE ε4 and high PRS increase relative risk. APOE ε4 is associated with cognitive decline, but PRS is not.KEY POINTSQuestionHow do genetic factors influence the risk of dementia and cognitive decline among healthy older individuals?FindingsWe studied cumulative incidence of dementia and cognitive decline in 12,978 healthy older individuals without cardiovascular disease or cognitive impairment at enrollment, stratified by APOE genotype and a polygenic risk score (PRS). APOE ε4 and PRS increased the relative risk of dementia, but cumulative incidence was low across all genotypes. APOE genotypes were associated with cognitive decline, but PRS was not.MeaningIncidence of dementia is low among healthy older individuals; however, genetic factors still increase relative risk.

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HOW THE IMPACT OF CHRONIC PAIN ON COGNITION VARIES BY POLYGENIC RISK SCORE (PRS)

Innovation in Aging ◽

10.1093/geroni/igz038.3521 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S971-S971

Author(s):

Jieun Song

Keyword(s):

Chronic Pain ◽

Cognitive Decline ◽

Risk Score ◽

Genetic Risk ◽

Cognitive Change ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Severe Chronic Pain ◽

Nationally Representative ◽

The Impact

Abstract While prior research has found associations between chronic pain and cognition and genetic risk of cognitive decline, little research examined moderating effects of genetic risk on the association between chronic pain and cognition. This study investigate whether genetic risk of accelerated cognitive decline, assessed by polygenic risk score (PRS) of Alzheimer disease (AD), moderates the association between severe chronic pain and cognitive decline. The data are drawn from Midlife in the US (MIDUS), a survey of a nationally representative sample of US adults. The analytic sample consists of two groups: 201 individuals who reported severe chronic pain (116 women, 85 men) and 404 individuals without severe chronic pain (215 women, 189 men) who completed MIDUS 2 (2004-06) and MIDUS 3 (2013-14) surveys and participated in biomarker data collection. The findings showed that men who suffered from severe chronic pain were more vulnerable to genetic risk of cognitive decline than men who did not experience severe chronic pain. Specifically, men who suffered from severe chronic pain and had higher level of PRS of AD experienced a greater decline of episodic memory than men who experienced chronic pain with lower level of PRS of AD. This association was not found in women sufferers. For both men and women who did not have chronic pain, cognitive change was not a function of the level of genetic risk of cognitive decline. Findings suggest that genetic risk of cognitive decline would be manifested contingent on life circumstances as well as gender of individuals.

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A/T/N polygenic risk score for cognitive decline in old age

10.1101/838847 ◽

2019 ◽

Author(s):

Annah M. Moore ◽

Teresa J. Filshtein ◽

Logan Dumitrescu ◽

Amal Harrati ◽

Fanny Elahi ◽

...

Keyword(s):

Executive Function ◽

Cognitive Decline ◽

Risk Score ◽

Genetic Risk ◽

Clinical Utility ◽

Association Studies ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Phosphorylated Tau ◽

Polygenic Risk

AbstractINTRODUCTIONWe developed a novel polygenic risk score (PRS) based on the A/T/N (amyloid plaques (A), phosphorylated tau tangles (T), and neurodegeneration (N)) framework and compared a PRS based on clinical AD diagnosis to assess which was a better predictor of cognitive decline.METHODSWe used summary statistics from genome wide association studies of cerebrospinal fluid amyloid-β (Aβ42) and phosphorylated-tau (ptau181), left hippocampal volume (LHIPV), and late-onset AD dementia to calculate PRS for 1181 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Individual PRS were averaged to generate a composite A/T/N PRS. We assessed the association of PRS with baseline and longitudinal cognitive composites of executive function and memory.RESULTSThe A/T/N PRS showed superior predictive performance on AD biomarkers and executive function decline compared to the clinical AD PRS.DISCUSSIONResults suggest that integration of genetic risk across AD biomarkers may improve prediction of disease progression.Research in ContextSystematic ReviewAuthors reviewed relevant literature using PubMed and Google Scholar. Key studies that generated and validated polygenic risk scores (PRS) for clinical and pathologic AD were cited. PRS scores have been increasingly used in the literature but clinical utility continues to be questioned.InterpretationIn the current research landscape concerning PRS clinical utility in the AD space, there is room for model improvement and our hypothesis was that a PRS with integrated risk for AD biomarkers could yield a better model for cognitive decline.Future DirectionsThis study serves as proof-of-concept that encourages future study of integrated PRS across disease markers and utility in taking an A/T/N (amyloidosis, tauopathy and neurodegeneration) focused approach to genetic risk for cognitive decline and AD.

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