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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. We used summary statistics from genome wide association studies of cerebrospinal fluid amyloid β (A β 42) and phosphorylated tau (ptau181), left hippocampal volume (LHIPV), and late-onset AD dementia to calculate PRS for 1181 participants in the Alzheimers 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. The A/T/N PRS showed superior predictive performance on AD biomarkers and executive function decline compared to the clinical AD PRS. Results suggest that integration of genetic risk across AD biomarkers may improve prediction of disease progression.

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