Objectives The life course determinants of midlife and later life cognitive function have been studied using longitudinal population-based cohort data, but far less is known about whether the pattern of these pathways is similar or distinct for clinically relevant cognitive state. We investigated this for Addenbrooke’s Cognitive Examination third edition (ACE-III), used in clinical settings to screen for cognitive impairment and dementia. Design Longitudinal birth cohort study. Setting Residential addresses in England, Wales and Scotland. Participants 1762 community-dwelling men and women of European heritage, enrolled since birth in the Medical Research Council (MRC) National Survey of Health and Development (the British 1946 birth cohort). Primary outcome ACE-III. Results Path modelling estimated direct and indirect associations between apolipoprotein E (APOE) status, father’s social class, childhood cognition, education, midlife occupational complexity, midlife verbal ability (National Adult Reading Test; NART), and the total ACE-III score. Controlling for sex, there was a direct negative association between APOE ε4 and the ACE-III score (β=−0.04 [–0.08 to –0.002], p=0.04), but not between APOE ε4 and childhood cognition (β=0.03 [–0.006 to 0.069], p=0.10) or the NART (β=0.0005 [–0.03 to 0.03], p=0.97). The strongest influences on the ACE-III were from childhood cognition (β=0.20 [0.14 to 0.26], p
