In this nationwide Swedish twin study, overweight and obesity at midlife increase the risk of all dementia, AD, and VaD, independently of lifespan diabetes and vascular diseases. Findings from the cotwin matched analyses suggest that familial factors (genetic factors and early life environments) contribute to the association between midlife high adiposity and dementia in late life.
A growing body of evidence suggests that a high level of adiposity is associated with cognitive decline and dementia10,26,27
; however, the relation between BMI and dementia among people aged over 65 is controversial.28–30
Several population-based studies have reported an effect of obesity at middle age on dementia risk.3,4,7,9
Only one study reported an increased dementia risk in people with overweight.5
Despite the fact that high adiposity is associated with dementia, there remains a debate whether this concerns only AD or also VaD. Some prospective studies did find an association between obesity and increased risk of VaD,7,29,31
while others did not.9,32–34
In this Swedish twin cohort, we found that having dementia or AD was associated with more than a 70% higher odds of being overweight at midlife, while the odds of being obese at midlife were higher for those with AD as well as those with VaD. Although the effect of midlife overweight on dementia is not as substantial as that of obesity, its impact on public health and clinical practice is significant due to the fact that there are 1.6 billion overweight adults worldwide.35
Several potential biological mechanisms may explain the association between adiposity and dementia. First, higher BMI is associated with diabetes and vascular diseases, which are related to dementia risk.12
Nonetheless, in our study, the association between midlife high BMI and dementia remained significant after controlling for lifespan vascular diseases, suggesting that nonvascular pathways might play an important role in the adiposity-dementia association. Second, higher adiposity at midlife may reflect a lifetime exposure to an altered metabolic and inflammatory state. Adiposity is one component of the metabolic syndrome which has been related to cognitive decline.36
Further, adipose tissue is the largest endocrine organ and secretes inflammatory cytokines and growth hormones; some of them (such as leptin, interleukin-6, and C-reactive protein) may affect cognitive functioning. Leptin is involved in deposition of amyloid β-42, and plays a role in neurodegenerative process.37
Twin studies involving a life-course approach may help to identify genetic and environmental influences on the development of chronic diseases, as twins provide naturally matched pairs, in which confounding effects of a large number of potentially causal factors (e.g., genetics and childhood environments) may be removed when comparisons are made within twin pairs. In cotwin control analyses, the association between higher midlife BMI and dementia was significantly attenuated, and thus may be attributed in part to genetic and early environmental factors such as childhood socioeconomic situation. However, twins may also experience similar exposures even at midlife and late life. Studies have reported that early life exposure to an imbalanced nutrition and disadvantaged economic status are related to a greater risk of obesity in adult life38
and dementia in late life.39
Our findings suggest that early-life environmental and genetic factors contribute to the link between adiposity and dementia.
Some limitations of the study should be mentioned. First, the use of prevalent dementia cases may have introduced some confounding effect due to differential survival among cases and controls. In addition, midlife obesity is associated with elevated mortality in our study, which would probably lead to an underestimation of the strength of the observed association. Second, compared to participants, the nonresponders were older, less educated, and more likely to be women, but did not differ from participants in terms of vascular risk factors. As old age, low education, and female sex are risk factors for dementia, possible selection bias could arise if the prevalence of dementia in this cohort differs from that in the general population. However, the prevalence of dementia in this study was comparable with several studies of dementia prevalence in Europe and the United States.17
Third, midlife height and weight relied on self-reported information, which, however, were validated by a previous study. In addition, BMI alone might not be an ideal representation of body composition, although BMI has been widely used in population-based studies. Additional anthropometric measures, such as waist circumference, would be useful. Finally, both obesity and AD are genetically influenced disorders with substantial concordance in twins. Thus, the matched pairs could be regarded as overmatched, as twin pairs are similar on many aspects. Nevertheless, the comparison of the results from the entire sample and from matched pairs provides information about the potential role of genetic and familial influences in the observed association. Finally, in the matched analysis, both MZ and DZ twins were included due to limited number of dementia-discordant MZ twin pairs. Hence, genetic effects were not perfectly controlled for.
Our results provide further support for the important role of high adiposity at midlife in the development of dementia, and highlight the need to control body weight as early as midlife for prevention of dementia in late life. These findings have relevant implications for public health, as the risk of dementia could be reduced by midlife weight loss.40
Genetic and early-life environmental factors may contribute to the link of overweight and obesity to dementia, suggesting that the high adiposity-dementia association might develop across the lifespan.