Polygenic Score Models for Alzheimer’s Disease: From Research to Clinical Applications

Abstract

The high prevalence of Alzheimer’s disease (AD) among the elderly population and its lack of effective treatments make this disease a critical threat to human health. Recent epidemiological and genetics studies have revealed the polygenic nature of the disease, which is possibly explainable by a polygenic score model that considers multiple genetic risks. Here, we systemically review the rationale and methods used to construct polygenic score models for studying AD. We also discuss the associations of polygenic risk scores (PRSs) with clinical outcomes, brain imaging findings, and biochemical biomarkers from both the brain and peripheral system. Finally, we discuss the possibility of incorporating polygenic score models into research and clinical practice along with potential challenges.

Stability of polygenic scores across discovery genome-wide association studies

“…One goal is to utilize PGS in clinical settings to facilitate the diagnosis and treatment of a wide range of heritable diseases, 6 such as inflammatory bowel disease, 7 diabetes, 8 cardiovascular disease, 9 , 10 cancer, 11 Alzheimer disease, 12 attention-deficit/hyperactivity disorder, 13 major depressive disorder, 14 bipolar disorder, 15 and schizophrenia. 16 While progress has been made toward reaching this goal, 17 , 18 , 19 , 20 numerous challenges remain to be solved.…”

Stability of Polygenic Scores Across Discovery Genome-Wide Association Studies

“…Numerous methods have been developed for computing PGS for a target population using summary statistics from a discovery genome-wide association study (GWAS) run for an independent population, with newer Bayesian-based techniques such as LDpred, 1 SBayesR, 2 and PRS-CS 3 generally yielding more predictive PGS than those produced using older methodologies that rely on a combination of linkage disequilibrium (LD) clumping and P-value thresholding. 4 One goal is to utilize PGS in clinical settings to facilitate the diagnosis and treatment of a wide range of heritable diseases, 5 such as inflammatory bowel disease, 6 diabetes, 7 cardiovascular disease, 8; 9 cancer, 10 Alzheimer's disease, 11 attention-deficit/hyperactivity disorder, 12 major depressive disorder, 13 bipolar disorder, 14 and schizophrenia. 15 While progress has been made towards reaching this goal, [16][17][18][19] numerous challenges remain to be solved.…”

Polygenic effect on accelerated tau pathology accumulation in Alzheimer’s disease: implications for patient selection in clinical trials

“…We demonstrate that the predictive power of the present PGS is dependent on the effect of tau-PET changes. Overall, the current study substantially adds to previous studies that used a lower number of genome-wide significant SNPs for construing a PGS and were confined to cross-sectional analyses of pathologic tau 15,16, for review see: 18,44 .…”

“…It also remains unclear whether a PGS is predictive of the progression of tau pathology, which underlies cognitive decline. So far, studies examining the value of a PGS for predicting tau pathology have been limited to cross-sectional assessments 13,15-17 , leaving the question unaddressed whether a PGS is associated with faster rates of fibrillar tau progression 18 .…”