Cognitive stimulation in the workplace, plasma proteins, and risk of dementia: three analyses of population cohort studies.
Level 3 - non-randomized controlled study
Individual participant data meta-analysis of prospective cohort studies
PubMed 34407988 · doi:10.1136/bmj.n1804
What was done
An individual participant data meta-analysis evaluated the association between cognitively stimulating work and incident dementia across seven prospective cohort studies from the UK, Europe, and the US (n = 107,896; 1.8 million person-years; follow-up 13.7 to 30.1 years). Cognitive stimulation was assessed at baseline using standard questionnaires (active versus passive jobs) and over time via a job exposure matrix. Dementia was identified via linked electronic health records and repeated clinical examinations. Secondary analyses examined associations between cognitive stimulation and 4,953 plasma proteins in 2,261 participants, and candidate proteins with dementia risk in 13,656 participants.
What was found
During follow-up, 1,143 dementia cases were recorded. Crude dementia incidence per 10,000 person-years was 4.8 in the high stimulation group versus 7.3 in the low stimulation group (age- and sex-adjusted hazard ratio [HR] 0.77, 95% CI 0.65 to 0.92; I2 = 0%). After adjusting for education, adult dementia risk factors (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, baseline diabetes), and cardiometabolic diseases, the association remained significant (fully adjusted HR 0.82, 95% CI 0.68 to 0.98). Findings held for follow-up under 10 years (HR 0.60, 95% CI 0.37 to 0.95) and from year 10 onwards (HR 0.79, 95% CI 0.66 to 0.95), and when using the job exposure matrix (HR per 1 SD increase 0.77, 95% CI 0.69 to 0.86). Higher cognitive stimulation was associated with lower levels of axonogenesis/synaptogenesis inhibitors: SLIT2 (fully adjusted beta -0.34, P < 0.001), CHSTC (beta -0.33, P < 0.001), and AMD (beta -0.32, P < 0.001). Higher levels of these proteins were associated with increased dementia risk (fully adjusted HR per 1 SD: 1.16 [95% CI 1.05 to 1.28] for SLIT2; 1.13 [95% CI 1.00 to 1.27] for CHSTC; 1.04 [95% CI 0.97 to 1.13] for AMD).
Why it matters
This study provides large-scale prospective evidence that mentally stimulating occupations are associated with a reduced risk of clinical dementia and identifies specific circulating neurodevelopmental proteins as plausible biological markers.
Limits
The design is observational, meaning residual confounding or reverse causation cannot be fully ruled out. Proteomic analyses were conducted in smaller subsets (n = 2,261 and n = 13,656) rather than the entire cohort, plasma protein levels may not fully reflect central nervous system processes, and reliance on electronic health record linkage may miss mild or undiagnosed dementia cases.
Cited by
- supports Working in an occupation that does not require new learning is associated with an increased risk of memory problems.