Age-dependent effects of body mass index across the adult life span on the risk of dementia: a cohort study with a genetic approach

Abstract

Background: While a high body mass index (BMI) in midlife is associated with higher risk of dementia, high BMI in late-life may be associated with lower risk. This study combined genetic designs with longitudinal data to achieve a better understanding of this paradox. Methods: We used longitudinal data from 22,156 individuals in the Swedish Twin Registry (STR) and 25,698 from the Health and Retirement Study (HRS). The STR sample had information about BMI from early adulthood through late-life, and the HRS sample from age 50 through late-life. Survival analysis was applied to investigate age-specific associations between BMI and dementia risk. To examine if the associations are influenced by genetic susceptibility to higher BMI, an interaction between BMI and a polygenic score for BMI (PGS BMI) was included in the models and results stratified into those with genetic predisposition to low, medium, and higher BMI. In the STR, co-twin control models were applied to adjust for familial factors beyond those captured by the PGS BMI. Results: At age 35-49, 5 units higher BMI was associated with 15% (95% CI 7-24%) higher risk of dementia in the STR. There was a significant interaction (p = 0.04) between BMI and the PGS BMI , and the association present only among those with genetic predisposition to low BMI (HR 1.38, 95% CI 1.08-1.78). Co-twin control analyses indicated genetic influences. After age 80, 5 units higher BMI was associated with 10-11% lower risk of dementia in both samples. There was a significant interaction between late-life BMI and the PGS BMI in the STR (p = 0.01), but not the HRS, with the inverse association present only among those with a high PGS BMI (HR 0.70, 95% CI 0.52-0.94). No genetic influences were evident from co-twin control models of late-life BMI. Conclusions: Not only does the association between BMI and dementia differ depending on age at BMI measurement, but also the effect of genetic influences. In STR, the associations were only present among those with a BMI in opposite direction of their genetic predisposition, indicating that the association between BMI and dementia across the life course might be driven by environmental factors and hence likely modifiable.

The dynamic association between body mass index and cognition from midlife through late-life, and the effect of sex and genetic influences

“…Our findings indicated small but significant genetic influences assessed by the PGS BMI , such that the effects of BMI on cognitive abilities were most prominent among those with genetic predisposition to a low BMI. Similarly, we have previously shown that a higher BMI in midlife predicts dementia only among those with a genetic predisposition to a low BMI 19 . This may indicate that a higher BMI due to environmental factors (such as a sedentary lifestyle and diet) has different consequences than a higher BMI due to genetic predisposition.…”

“…Use of self-reported height and weight to calculate BMI, specifically in longitudinal aging studies, has been validated against in-person measures previously 18 . The BMI data were cleaned prior to analyses, the process described in detail elsewhere 19 , removing outliers (1515 individuals, or 4% of the total HRS sample) including those that had values considered out-of-range (e.g., height below 1.47 or above 2.10 m, BMI below 15 or above 55) and unreasonably large changes between waves. BMI at baseline was categorized into normal weight (18.5–24.9), overweight (25–29.9), and obesity (30 and above).…”

The dynamic association between body mass index and cognition from midlife through late-life, and the effect of sex and genetic influences

“…Our findings indicated small but significant genetic influences assessed by the PGSBMI, such that the effects of BMI on cognitive abilities were most prominent among those with genetic predisposition to a low BMI. Similarly, we have previously shown that a higher BMI in midlife predicts dementia only among those with a genetic predisposition to a low BMI [19]. This may indicate that a higher BMI due to environmental factors (such as a sedentary lifestyle and diet) has different consequences than a higher BMI due to genetic predisposition.…”

“…Use of self-reported height and weight to calculate BMI, specifically in longitudinal aging studies, has been validated against in-person measures previously [18]. The BMI data were cleaned prior to analyses, the process described in detail elsewhere [19], removing outliers (1,515 individuals, or 4% of the total HRS sample) including those that had values considered out-of-range (e.g., height below 1.47 or above 2.10 meters, BMI below 15 or above 55) and unreasonably large changes between waves. BMI at baseline was categorized into normal weight (18.5-24.9), overweight (25-29.9), and obesity (30 and above).…”

Change in cognition and body mass index in relation to preclinical dementia

“…Height and weight were measured by trained research nurses as part of the health examinations during each in-person testing occasion. The measures have been thoroughly examined for outliers, both quantitatively and visually by plotting individual trajectories over time, as described in detail previously [12]. BMI was calculated as kilograms divided by height (in meters) squared.…”