Aim: To elucidate the effect of midlife smoking on the risk of dementia and Alzheimer’s disease (AD), and the possible modification of this relation by the apolipoprotein E (APOE) Ε4. Methods: Participants of the Cardiovascular Risk Factors, Aging and Dementia study were randomly selected from population-based samples originally studied in midlife (1972, 1977, 1982 or 1988). After an average follow-up of 21 years, 1,449 persons (73%) aged 65–79 years took part in a reexamination in 1998. Results: Smoking in midlife increased the risk of dementia (odds ratio, OR: 4.93; 95% CI: 1.51–16.11) and AD (OR: 6.56; 95% CI: 1.80–23.94) among the APOE Ε4 carriers, but not among the APOE Ε4 noncarriers. Conclusion: Midlife smoking was associated with an increased risk of dementia and AD later in life only among those individuals carrying the APOE Ε4 allele. These results suggest that the association between smoking and AD may be complex and vary according to genotype.

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