Genetic variants in glutamate-, Aβ-, and tau-related pathways determine polygenic risk for Alzheimer's disease

Neurobiol Aging. 2021 May;101:299.e13-299.e21. doi: 10.1016/j.neurobiolaging.2020.11.009. Epub 2020 Nov 12.


Synapse loss is an early event in late-onset Alzheimer's disease (LOAD). In this study, we have assessed the capacity of a polygenic risk score (PRS) restricted to synapse-encoding loci to predict LOAD. We used summary statistics from the International Genetics of Alzheimer's Project genome-wide association meta-analysis of 74,046 patients for model construction and tested the "synaptic PRS" in 2 independent data sets of controls and pathologically confirmed LOAD. The mean synaptic PRS was 2.3-fold higher in LOAD than that in controls (p < 0.0001) with a predictive accuracy of 72% in the target data set (n = 439) and 73% in the validation data set (n = 136), a 5%-6% improvement compared with the APOE locus (p < 0.00001). The model comprises 8 variants from 4 previously identified (BIN1, PTK2B, PICALM, APOE) and 2 novel (DLG2, MINK1) LOAD loci involved in glutamate signaling (p = 0.01) or APP catabolism or tau binding (p = 0.005). As the simplest PRS model with good predictive accuracy to predict LOAD, we conclude that synapse-encoding genes are enriched for LOAD risk-modifying loci. The synaptic PRS could be used to identify individuals at risk of LOAD before symptom onset.

Keywords: Aβ; Glutamate signaling; Late-onset Alzheimer's disease; Polygenic risk score; Tau1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Amyloid beta-Peptides / metabolism*
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genetic Variation / genetics*
  • Genetic Variation / physiology
  • Genome-Wide Association Study*
  • Glutamates / metabolism*
  • Humans
  • Male
  • Multifactorial Inheritance / genetics*
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Signal Transduction / genetics*
  • Signal Transduction / physiology
  • tau Proteins / metabolism*


  • Amyloid beta-Peptides
  • Glutamates
  • tau Proteins