RT Journal Article
SR Electronic
T1 A/T/N polygenic risk score for cognitive decline in old age
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 838847
DO 10.1101/838847
A1 Annah M. Moore
A1 Teresa J. Filshtein
A1 Logan Dumitrescu
A1 Amal Harrati
A1 Fanny Elahi
A1 Elizabeth C. Mormino
A1 Yuetiva Deming
A1 Brian W. Kunkle
A1 Dan M. Mungas
A1 Trey Hedden
A1 Liana G. Apostolova
A1 Andrew J. Saykin
A1 Danai Chasioti
A1 Qiongshi Lu
A1 Jessica Dennis
A1 Julia Sealock
A1 Lea K. Davis
A1 David W. Fardo
A1 Rachel Buckley
A1 Timothy J. Hohman
YR 2019
UL http://biorxiv.org/content/early/2019/11/12/838847.abstract
AB 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.Systematic Review Authors 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.Interpretation In 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 Directions This 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.