Abstract
INTRODUCTION: Developing biomarker tools for identification of individuals at high-risk for late-onset Alzheimer's disease (LOAD) is important for prognosis and early treatment. This review focuses on genetic factors and their potential role for precision medicine in LOAD. AREAS COVERED: APOEe4 is the strongest genetic risk factor for non-Mendelian LOAD, and the APOE-linkage disequilibrium (LD) region has produced the most significant association signal in multi-center genome-wide-association-studies (GWAS). Consideration of extended haplotypes in the APOE-LD region and specifically, non-coding variants in putative enhancer elements, such as the TOMM40-polyT, in-addition to the coding variants that comprise the APOE-genotypes, may be useful for predicting subjects at high-risk of developing LOAD and estimating age-of-onset of early disease-stage symptoms. A genetic-biomarker based on APOE-TOMM40-polyT haplotypes, and age is currently applied in a clinical trial for prevention/delay of LOAD onset. Additionally, we discuss LOAD-GWAS discoveries and the development of new genetic risk scores based on LOAD-GWAS findings other than the APOE-LD region. EXPERT COMMENTARY: Deciphering the precise causal genetic-variants within LOAD-GWAS regions will advance the development of genetic-biomarkers to complement and refine the APOE-LD region based prediction model. Collectively, the genetic-biomarkers will be translational for early diagnosis and enrichment of clinical trials with subjects at high-risk.