Body mass index, genetic susceptibility, and Alzheimer's disease: a longitudinal study based on 475,813 participants from the UK Biobank

BACKGROUND: The association between body mass index (BMI) and Alzheimer's disease (AD) remains controversial. Genetic and environmental factors are now considered contributors to AD risk. However, little is known about the potential interaction between genetic risk and BMI on AD risk. OBJECTIVE: To study the causal relationship between BMI and AD, and the potential interaction between AD genetic risk and BMI on AD risk. METHODS AND RESULTS: Using the UK Biobank database, 475,813 participants were selected for an average follow-up time of more than 10 years. Main findings: 1) there was a nonlinear relationship between BMI and AD risk in participants aged 60 years or older (p for non-linear < 0.001), but not in participants aged 37–59 years (p for non-linear = 0.717) using restricted cubic splines; 2) for participants aged 60 years and older, compared with the BMI (23–30 kg/m(2)) group, the BMI (< 23 kg/m(2)) group was associated with a higher AD risk (HR = 1.585; 95% CI 1.304–1.928, p < 0.001) and the BMI (> 30 kg/m(2)) group was associated with a lower AD risk (HR = 0.741; 95% CI 0.618–0.888, p < 0.01) analyzed using the Cox proportional risk model; 3) participants with a combination of high AD genetic risk score (AD-GRS) and BMI (< 23 kg/m(2)) were associated with the highest AD risk (HR = 3.034; 95% CI 2.057–4.477, p < 0.001). In addition, compared with the BMI (< 23 kg/m(2)), the higher BMI was associated with a lower risk of AD in participants with the same intermediate or high AD-GRS; 4) there was a reverse causality between BMI and AD when analyzed using bidirectional Mendelian randomization (MR). CONCLUSION: There was a reverse causality between BMI and AD analyzed using MR. For participants aged 60 years and older, the higher BMI was associated with a lower risk of AD in participants with the same intermediate or high AD genetic risk. BMI (23–30 kg/m(2)) may be a potential intervention for AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03621-2.