Timing of cognitive decline onset and life-course trajectories A pooled longitudinal analysis of 14,389 adults across three cohorts.

Background: Population ageing is driving a global surge in cognitive impairment. While late-life decline is well-characterized, the onset of measurable cognitive changes across the full adult lifespan remains uncertain. We aimed to estimate the age at which detectable decline begins using longitudinal data from three population-based cohorts from three countries spanning three continents.

Methods: We analyzed participant-level longitudinal data from the China Health and Retirement Longitudinal Study (CHARLS; China), Midlife in the United States (MIDUS; USA), and Kardiovize (KV; Czech Republic). Cognitive performance was assessed using validated instruments (TICS, BTACT, and MoCA). Scores were harmonized using the percent of maximum possible method (0-100 metric). Linear mixed-effects models, adjusted for age group, sex, and education estimated change over an average 7-9-year follow-up.

Findings: In pooled sample of 14,389 participants (baseline age 22-94 years), a detectable decline in total cognition first emerged in the 31-40 age group (mean change -1.2 points, 95% CI -2.1 to -0.3). Decline magnitude increased progressively with age, reaching -11.4-points in the oldest strata (all p<0.001). Non-memory domains showed earlier vulnerability (detectable from age 31), while significant memory decline emerged after age 50. Individual trajectories showed substantial heterogeneity, suggesting that chronological age is not a deterministic proxy for decline.

Interpretation: Population-level cognitive decline became detectable in early midlife, decades before the traditional clinical focus on older age. Across three population-based cohorts from Asia, North America, and Europe, we observed consistent early decline in non-memory domains followed by later memory decline. These findings support evaluation of midlife cognitive monitoring and life-course approaches to brain health.

Funding: European Union Next Generation EU; European Regional Development Fund; European Social Fund; Barrow Neurological Foundation; NIH.