Association of Genetic Variants Linked to Late-Onset Alzheimer Disease With Cognitive Test Performance by Midlife

JAMA Netw Open. 2022 Apr 1;5(4):e225491. doi: 10.1001/jamanetworkopen.2022.5491.


Importance: Identifying the youngest age when Alzheimer disease (AD) influences cognition and the earliest affected cognitive domains will improve understanding of the natural history of AD and approaches to early diagnosis.

Objective: To evaluate the age at which cognitive differences between individuals with higher compared with lower genetic risk of AD are first apparent and which cognitive assessments show the earliest difference.

Design, setting, and participants: This cross-sectional study used data from UK Biobank participants of European genetic ancestry, aged 40 years or older, who contributed genotypic and cognitive test data from January 1, 2006, to December 31, 2015. Data analysis was performed from March 10, 2020, to January 4, 2022.

Exposure: The AD genetic risk score (GRS), which is a weighted sum of 23 single-nucleotide variations.

Main outcomes and measures: Seven cognitive tests were administered via touchscreen at in-person visits or online. Cognitive domains assessed included fluid intelligence, episodic memory, processing speed, executive functioning, and prospective memory. Multiple cognitive measures were derived from some tests, yielding 32 separate measures. Interactions between age and AD-GRS for each of the 32 cognitive measures were tested with linear regression using a Bonferroni-corrected P value threshold. For cognitive measures with significant evidence of age by AD-GRS interaction, the youngest age of interaction was assessed with new regression models, with nonlinear specification of age terms. Models with youngest age of interaction from 40 to 70 years, in 1-year increments, were compared, and the best-fitting model for each cognitive measure was chosen. Results across cognitive measures were compared to determine which cognitive indicators showed earliest AD-related change.

Results: A total of 405 050 participants (mean [SD] age, 57.1 [7.9] years; 54.1% female) were included. Sample sizes differed across cognitive tests (from 12 455 to 404 682 participants). The AD-GRS significantly modified the association with age on 13 measures derived from the pairs matching (range in difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 2.5%-11.5%), symbol digit substitution (range in difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 2.0%-5.8%), and numeric memory tests (difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 8.8%) (P = 1.56 × 10-3). Best-fitting models suggested that cognitive scores of individuals with a high vs low AD-GRS began to diverge by 56 years of age for all 13 measures and by 47 years of age for 9 measures.

Conclusions and relevance: In this cross-sectional study, by early midlife, subtle differences in memory and attention were detectable among individuals with higher genetic risk of AD.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alzheimer Disease* / diagnosis
  • Cognition Disorders* / psychology
  • Cross-Sectional Studies
  • Executive Function
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neuropsychological Tests