Multimodal Brain Imaging Reveals Structural Differences in Alzheimer’s Disease Polygenic Risk Carriers: A Study in Healthy Young Adults

Foley, Sonya; Tansey, Katherine E.; Caseras, Xavier; Lancaster, Thomas; Bracht, Tobias; Parker, Greg D.; Hall, Jérémy; Williams, Julie; Linden, David

doi:10.1016/j.biopsych.2016.02.033

Cited by 86 publications

(116 citation statements)

References 75 publications

(97 reference statements)

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“…While this A/T/N framework has emerged in studies of preclinical disease, it has not been integrated into PRS for AD despite the availability of GWAS summary statistics for autopsy and in vivo measures of A/T/N [20,21]. Indeed, a previous study suggested that shared genetic drivers for hippocampal volume (a marker of neurodegeneration) and AD may exist [22]. Thus, integrating the common and independent genetic drivers of clinical AD and A/T/N could produce models with higher predictive capacity for cognitive decline in late life.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

Moore

Filshtein²,

Dumitrescu

et al. 2019

Preprint

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“…The AD PGRS has been found to be associated with the risk of familial late-onset AD (Tosto et al, 2017), accelerated progression from mild cognitive impairment (MCI) to AD (Rodriguez-Rodriguez et al, 2013), cognitive scores (Verhaaren et al, 2013), and neuroimaging measures, including total brain volume (Chauhan et al, 2015), hippocampal volume (Chauhan et al, 2015;Foley et al, 2017;Lupton et al, 2016;Mormino et al, 2016), the cortical thickness in AD-vulnerable regions (Sabuncu et al, 2012), and the fractional anisotropy of the right cingulum (Foley et al, 2017). These studies, especially the neuroimaging studies, help to elucidate the mechanisms of the M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 5 genetic contribution to AD risk.…”

mentioning

confidence: 99%

Polygenic risk for Alzheimer's disease influences precuneal volume in two independent general populations

Zhang

et al. 2018

Neurobiology of Aging

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Alzheimer's disease (AD) is heritable with complex genetic underpinnings. Based on previous results from large-scale genome-wide association studies, recent studies found an association between the polygenic risk score (PGRS) of AD and the structure of some preselected brain regions, but the effects of AD PGRS on all voxels of the brain have not been fully investigated. In the present study, we examined the voxel-wise effect of AD PGRS on the entire brain and the influence of AD PGRS on cognitive function in 2 independent healthy young cohorts. In both cohorts, an elevated AD PGRS was associated with a smaller precuneal volume, and the effect remained after excluding the APOE genotype. No correlation was found between AD PGRS and any cognitive measure in either sample. Finding a negative correlation between the AD PGRS and the precuneal volume could help to elucidate the mechanism of the genetic risk for AD and could provide a potential biomarker for early detection and possible interventions in AD.

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“…Here, these prior observations are expanded on to show that these alterations are also present in early life process. Together, accumulating evidence now suggests that both common and rare variations that confer risk for AD may converge on pathophysiological mechanisms such as alterations in subcortical volumetry in early life [6,8]. Furthermore, there was a negative association between the TREM2 risk allele and volume of putamen.…”

Section: Discussionmentioning

confidence: 99%

Associations between rare microglia‐linked Alzheimer's disease risk variants and subcortical brain volumes in young individuals

Lancaster

2019

Alz & Dem Diag Ass & Dis Mo

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Introduction Recent exome sequencing studies have identified three novel risk variants associated with Alzheimer's disease (AD). However, the mechanisms by which these variants confer risk are largely unknown. Methods In the present study, the impact of these rare coding variants (in ABI3, PLCG2 , and TREM2 ) on all subcortical volumes is determined in a large sample of young healthy individuals (N = 756–765; aged 22–35 years). Results After multiple testing correction ( P CORRECTED < .05), rare variants were associated with basal ganglia volumes ( TREM2 and PLCG2 effects within the putamen and pallidum, respectively). Nominal associations between TREM2 and reduced hippocampal and thalamic volumes were also observed. Discussion Our observations suggest that rare variants in microglia-mediated immunity pathway may contribute to the subcortical alterations observed in AD cases. These observations provide further evidence that genetic risk for AD may influence the volume of subcortical volumes and increase AD risk in early life processes.

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Multimodal Brain Imaging Reveals Structural Differences in Alzheimer’s Disease Polygenic Risk Carriers: A Study in Healthy Young Adults

Cited by 86 publications

References 75 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

Polygenic risk for Alzheimer's disease influences precuneal volume in two independent general populations

Associations between rare microglia‐linked Alzheimer's disease risk variants and subcortical brain volumes in young individuals

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