Polygenic Risk Score for Alzheimer’s Disease: Implications for Memory Performance and Hippocampal Volumes in Early Life

Axelrud, Luiza Kvitko; Santoro, Marcos; Pine, Daniel S.; Talarico, Fernanda; Gadelha, Ary; Manfro, Gisele Gus; Pan, Pedro Mário; Jackowski, Andrea Parolin; Picon, Felipe Almeida; Brietzke, Elisa; Grassi‐Oliveira, Rodrigo; Bressan, Rodrigo; Miguel, Eurípedes C.; Rohde, Luís Augusto; Hákonarson, Hákon; Pausová, Zdenka; Belangero, Síntia Iole; Paus, Tomáš; Salum, Giovanni Abrahão

doi:10.1176/appi.ajp.2017.17050529

Cited by 65 publications

(82 citation statements)

References 34 publications

(44 reference statements)

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“…Previous work has shown that the clinical AD PRS derived from IGAP summary statistics was predictive of bilateral hippocampal volume in a Brazilian youth cohort [43], aligning with the clinical AD PRS association with left hippocampal volume demonstrated in this study. Together, these results may suggest that genetic drivers of hippocampal volume are influential throughout life.…”

Section: Discussionsupporting

confidence: 89%

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

Moore

Filshtein²,

Dumitrescu

et al. 2019

Preprint

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Research in Context Systematic 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. Abstract INTRODUCTION: We 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. METHODS: We 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. RESULTS: The A/T/N PRS showed superior predictive performance on AD biomarkers and executive function decline compared to the clinical AD PRS. DISCUSSION: Results suggest that integration of genetic risk across AD biomarkers may improve prediction of disease progression. Boldface indicates P < 0.05. *P<1.25E-03 Bonferroni threshold. N=1,182 unless noted otherwise. No APOE denotes PRS excluding APOE region results. NC/MCI and NC indicate sensitivity analysis results with the denoted diagnostic groups (as assessed at baseline).

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Section: Discussionsupporting

confidence: 89%

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

Moore

Filshtein²,

Dumitrescu

et al. 2019

Preprint

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“…We found no support for the link between AD genetic burden and global, hippocampal. and temporal regions although previous studies have provided evidence for such links during infancy (28,29), childhood (25,30,52,53), and early adulthood (27,(54)(55)(56)(57)(58)(59)(60)(61). The support for such associations does seem stronger in studies during early adulthood than during childhood.…”

Section: Discussionmentioning

confidence: 89%

“…Furthermore, they report that APOE affects regions that are very different from those reported by Chang and colleagues (30). More recently, Axelrud and colleagues reported that the AD PGRS relates to hippocampal volume in Brazilian children aged 6 to 14 years old (53). However, the source GWAS on which the PGRS in the latter study was based was performed in a population of European ancestry (37).…”

Section: Discussionmentioning

confidence: 94%

Genetic Burden for Late-Life Neurodegenerative Disease and Its Association With Early-Life Lipids, Brain, Behavior, and Cognition

et al. 2020

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“…The genes associated with intelligence are highly expressed in medium spiny neurons of the striatum and pyramidal neurons of the CA1 hippocampus (14), early targets of degeneration in HD and AD respectively, potentially contributing to the severe cognitive decline seen in these diseases. Surprisingly, there is no significant association between the presence of cognitive deficits in HD and genetic risk for AD, though AD PRS predicts memory decline and poorer cognitive performance in healthy children and adults well before the age of risk for AD (39,40). In children, HTT CAG repeat length itself shows a J-shaped relationship with cognition, with maximum cognition at 40-41 repeats (37).…”

Section: Discussionmentioning

confidence: 96%

Genetic risk underlying psychiatric and cognitive symptoms in Huntington’s Disease

Ellis

Tee

McAllister

et al. 2019

Preprint

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Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized exam of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown. We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders, and of intelligence, and testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n=5160) of HD patients. Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence. In general, polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.

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Polygenic Risk Score for Alzheimer’s Disease: Implications for Memory Performance and Hippocampal Volumes in Early Life

Cited by 65 publications

References 34 publications

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

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

Genetic Burden for Late-Life Neurodegenerative Disease and Its Association With Early-Life Lipids, Brain, Behavior, and Cognition

Genetic risk underlying psychiatric and cognitive symptoms in Huntington’s Disease

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