The impact of maternal smoking during pregnancy and the age of smoking initiation on incident dementia: A prospective cohort study

Abstract

Introduction: The impact of early-life tobacco exposure on dementia has remained unknown.

Methods: Using the UK Biobank, the associations of maternal smoking during pregnancy (MSDP) and age of smoking initiation (ASI) with the onset time of all-cause dementia were estimated with accelerated failure time models. The effects of MSDP and ASI on brain structure and their genetic correlation to Alzheimer's disease (AD) were analyzed. A Mendelian randomization (MR) analysis was conducted.

Results: The time ratios for smokers starting in childhood, adolescence, and adulthood (vs never smokers) were 0.87 (0.76 to 0.99), 0.92 (0.88 to 0.96), and 0.95 (0.89 to 1.01). MSDP and smoking in adolescence altered many brain regions, including the hippocampus. In genetic analysis, MSDP was genetically and causally linked to AD, and a younger ASI was genetically correlated to a higher AD risk.

Discussion: Early-life smoking accelerated dementia onset and was genetically correlated to AD. MSDP demonstrated genetic and causal linkage to AD risks.

Highlights: Unlike the commonly used Cox proportional hazards model, this article uses a parametric survival analysis method - the accelerated failure model - to explore the relationship between exposure to onset time. It can be used as an alternative method when the proportional hazards assumption is not met. Genetic analyses including genetic correlation study and MR analysis and brain structure analyses were conducted to support our findings and explore the potential mechanisms. The study reveals the relationship between different smoking initiation periods and the onset time of dementia and shows that earlier smoking exposure has a more significant impact on dementia. It emphasizes the importance of preventing early smoking. In the future, more research focusing on the relationship between early exposure and dementia is called for to provide more detailed prevention measures for dementia that cover all age groups.

Keywords: Alzheimer's disease; dementia; early‐life tobacco exposure; smoking; vascular dementia.

FIGURE 1

Workflow of study design. Abbreviations: AD, Alzheimer's disease; ASI, age of smoking initiation; MSDP, maternal smoking during pregnancy; TDI, Townsend deprivation index; VaD, vascular disease.

FIGURE 2

Independent impact of MSDP, ASI on ACD. Rhombuses represent time ratios and horizontal lines indicate corresponding 95% confidence intervals around time ratios. Time ratios were calculated after adjustments for age, sex, educational levels, APOE e4 status, drinking status, physical activities, BMI, birth weight, comparative body size at age 10, comparative body height at age 10, Townsend deprivation index, cardiovascular disease, diabetes, and cancer (Model 3). Abbreviations: ACD, all‐cause dementia; ASI, age of smoking initiation; LCI, lower confidence interval; MSDP, maternal smoking during pregnancy; UCI, upper confidence interval.

FIGURE 3

Joint effect of MSDP and ASI on onset time of ACD, AD, and VaD. Rhombuses represent time ratios; horizontal lines indicate corresponding 95% confidence intervals around time ratios. Time ratios were calculated after adjustments for age, sex, educational levels, APOE e4 status, drinking status, physical activities, BMI, birth weight, comparative body size at age 10, comparative body height at age 10, Townsend deprivation index, cardiovascular disease, diabetes, and cancer (Model 3). Abbreviations: ACD, all‐cause dementia; AD, Alzheimer's disease; ASI, age of smoking initiation; LCI, lower confidence interval; MSDP, maternal smoking during pregnancy; UCI, upper confidence interval; VaD = vascular disease.

FIGURE 4

Subgroup analyses under MSDP. The p values for interaction were calculated with multiplicative interaction terms. Time ratios were calculated after adjustments for age, sex, educational levels, APOE e4 status, drinking status, physical activities, BMI, birth weight, comparative body size at age 10, comparative body height at age 10, Townsend deprivation index, cardiovascular disease, diabetes, and cancer (Model 3). Abbreviations: ACD, all‐cause dementia; LCI, lower confidence interval; MSDP, maternal smoking during pregnancy; UCI, upper confidence interval.

FIGURE 5

Subgroup analyses under ASI. The p values for interaction were calculated with multiplicative interaction terms. Time ratios were calculated after adjustments for age, sex, educational levels, APOE e4 status, drinking status, physical activities, BMI, birth weight, comparative body size at age 10, comparative body height at age 10, Townsend deprivation index, cardiovascular disease, diabetes, and cancer (Model 3). Abbreviations: ACD, all‐cause dementia; ASI, age of smoking initiation; LCI, lower confidence interval; UCI, upper confidence interval.

FIGURE 6

Association between MSDP/ASI and gray matter (GM) volume in imaging analyses (false discovery rate‐adjusted, *p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.001). (A) Cortical GM volume alteration under MSDP; (B) subcortical GM volume alteration under MSDP; (C) GM volume alteration in participants starting to smoke during adolescence; (D) subcortical GM volume alteration in participants starting to smoke during adolescence. Linear models were applied with adjustment of age, sex, educational levels, APOE e4 status, drinking status, physical activities, BMI, birth weight, comparative body size at age 10, comparative body height at age 10, Townsend deprivation index, cardiovascular disease, diabetes, and cancer (Model 3).