Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages

Alzheimers Dement. 2018 May;14(5):623-633. doi: 10.1016/j.jalz.2017.11.006. Epub 2017 Dec 20.


Introduction: Genetic associations for endophenotypes of Alzheimer's disease (AD) in cognitive stages preceding AD have not been thoroughly evaluated.

Methods: We conducted genome-wide association studies for AD-related endophenotypes including hippocampal volume, logical memory scores, and cerebrospinal fluid Aβ42 and total/phosphorylated tau in cognitively normal (CN), mild cognitive impairment, and AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative study.

Results: In CN subjects, study-wide significant (P < 8.3 × 10-9) loci were identified for total tau near SRRM4 and C14orf79 and for hippocampal volume near MTUS1. In mild cognitive impairment subjects, study-wide significant association was found with single nucleotide polymorphisms (SNPs) near ZNF804B for logical memory test of delayed recall scores. We found consistent expression patterns of C14orf40 and MTUS1 in carriers with risk alleles of expression SNPs and in brains of AD patients, compared with in the noncarriers and in brains of controls.

Discussion: Our findings for AD-related brain changes before AD provide insight about early AD-related biological processes.

Keywords: ADNI; Alzheimer's disease; Biomarker; Cerebrospinal fluid; Coexpression network; Endophenotypes; Genome-wide association; Logical memory; MRI; Tau.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / diagnosis*
  • Alzheimer Disease / genetics
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Amyloid beta-Peptides / genetics*
  • Biomarkers / cerebrospinal fluid
  • Cognitive Dysfunction / cerebrospinal fluid
  • Cognitive Dysfunction / diagnosis
  • Cognitive Dysfunction / genetics
  • Early Diagnosis
  • Endophenotypes*
  • Female
  • Genome-Wide Association Study*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Nerve Tissue Proteins / genetics
  • Phosphorylation
  • Polymorphism, Single Nucleotide*
  • tau Proteins / cerebrospinal fluid
  • tau Proteins / genetics*


  • Amyloid beta-Peptides
  • Biomarkers
  • Nerve Tissue Proteins
  • tau Proteins