The development of diagnostic tools to identify disease risk is critical to enable selection of suitable individuals for inclusion in clinical trials and cohort studies. The utility of PRS is gaining increasing attention for generating an individual genetic risk profile and subsequent estimation of future disease risk in Alzheimer’s disease (AD). In this work we have analysed whether the PRS can predict substantial cognitive decline towards AD and longitudinal changes to protein biomarkers that precede the onset of cognitive decline.

Genotype data available from longitudinal cohorts including the Wisconsin Registry for Alzheimer’s Prevention (WRAP) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were used to calculate a PRS for each participant. The risk distribution profile for each cohort was calculated and compared. Furthermore, where available, performance for predicting change in cerebrospinal fluid biomarkers and cognitive decline due to Alzheimer’s disease were assessed.

Genetically high risk individuals as determined by setting a threshold for polygenic risk were shown, on average, to experience greater cognitive decline than the low risk group in the ADNI cohort. Furthermore, on average a higher Increase in the pTau/β-amyloid ratio as measured in CSF samples of participants in WRAP were seen in those individuals with high polygenic risk.

Using DNA easily accessible from saliva, can provide a more efficient manner for identifying participants most likely to decline cognitively. Importantly for preventative trials PRS may be used for stratifying individuals most at risk of changing biomarker status prior to manifestation of risks. The use of PRS algorithms for stratifying patients prior to more invasive, expensive or burdensome procedures provides a strategy to screen out unsuitable patients very early in the recruitment process.