The association between adiposity and incident dementia varied with the measure used, the outcome considered, and was modified by age. The only association that clearly resembled a linear pattern (higher risk with higher quartile) was that of WC and DAS. However, the fourth WC quartile was related to a higher dementia and AD risk in persons < 76 years, but not in the oldest old. The association of BMI to dementia resembled a U-shape in those < 76 years. Weight loss was associated with a higher dementia risk. This association stronger for DAS, and weight gain was also associated with DAS.
AD and vascular dementia are the most common forms of dementia 37
. AD is probably caused by brain deposition of amyloid beta 38
, and peripheral hyperinsulinemia may have an important role in its clearance 39
. Vascular risk factors and stroke cause vascular dementia 40–43
, but they may also cause AD 44,45
. There are conflicting data relating hyperinsulinemia 7,8,46–48
, diabetes 49–52
and hyperinsulinemia features such as hyperlipidemia 53
and hypertension 53–57
to a higher risk of cognitive decline and AD. Higher adiposity are related to hyperinsulinemia, diabetes, hypertension, dyslipidemia, heart disease, and stroke 32,58
. Thus, we hypothesized that high BMI and WC are associated with higher dementia, AD, and DAS risk.
High BMI in middle age is associated with higher dementia risk 59,60
. Higher BMI at ages 70, 75 and 79 years also predicts higher dementia risk 15
. However, there have been reports of no association 14
and of lower BMI related to higher AD risk 13
. These paradoxical findings could be explained by different age groups in different studies; those conducted in middle age show a relation of high BMI to increased dementia risk, while those in older populations are conflicting. The association of high BMI to cardiovascular and general mortality is attenuated in older age groups, and high BMI becomes a predictor of decreased mortality in the oldest old 17
. This is possibly due to survival bias and to decreased value of BMI as an adiposity measure in the oldest old. Aging is characterized by lean body mass loss and adipose tissue increase without weight gain that may not be captured by BMI, and traditional adiposity measures are less useful in the elderly 61
. Another potential explanation for paradoxical findings is the possibility of a U-shape association between BMI and dementia as has been reported for other outcomes 34
. Low BMI related to worse outcomes is usually ascribed to conditions associated with weight loss. Higher BMI related to worse outcomes is usually interpreted as evidence of the consequences of high adiposity. The results of our study suggest a U-shape association between BMI and dementia in the younger elderly, while higher BMI is related to lower dementia risk in the oldest old. It is possible that persons with the lowest BMI lost weight due to pre-morbid dementia. It is also possible that low BMI is the consequence of hyperinsulinemia, which precede weight loss 62
and is related to higher dementia risk 7,8
WC has been proposed as a better adiposity measure in the elderly than BMI 16,61,63
. We found that higher WC was associated to higher DAS risk for all age groups. The association between vascular risk factors and dementia is clearly stronger for DAS compared to AD 44
, and this may explain why WC only predicted DAS in the whole sample. However, higher WC was associated with higher dementia and AD risk in younger elderly, consistent with the notion that adiposity measures lose their predictive ability in the oldest old 61
Persons may lose weight prior to dementia diagnosis14,64
and this has been interpreted as a consequence of the disease rather than a direct cause 14
. We did not have enough data to assess weight change up to dementia diagnosis. We had weights at 2 time points for a sub-sample and explored how weight change predicted dementia prospectively. We found that weight loss predicted higher dementia risk in agreement with previous work. As mentioned previously, this could be a consequence of the dementia process, but could also be the consequence and a marker of hyperinsulinemia 64
, an emerging dementia risk factor7,8
. We also found that weight gain predicted higher DAS risk, which has not been reported to the best of our knowledge. This could reflect increase in vascular risk factors with weight gain32
, but could also be a consequence of cardiovascular disease, such as heart failure causing edema and weight gain 65
We must consider the possibility that confounding, chance or bias explain the results of this study. We conducted analyses excluding current smokers and persons with short follow-up and the results were essentially unchanged. We adjusted for years of education and ethnic group as indices of socioeconomic background without change in our findings, but we cannot rule out residual confounding. The ascertainment of covariates such as smoking were made by self-report, likely resulting in some misclassification that could have resulted in residual confounding. Another consideration is the fact that we conducted multiple comparisons, including those in stratified analyses. Invocation of multiple comparisons as an explanation of results is a controversial issue 66
, but it is possible that our results could be explained by chance. The most striking results occurred in the stratified analyses. Finding of significant results for some quartiles by chance could lead to identification of patterns that also occurred by chance. Despite the results not being unexpected, and consistent with previous publications in the aging literature, chance due to multiple comparisons is a possibility as an explanation for our findings, and our analyses should be replicated in other samples. The number of persons developing DAS was appreciably smaller than those developing AD, and this could have resulted in chance findings due to sparse data. When interpreting and generalizing the results, it is important to take into account that this study occurred in the context of a cohort study of the elderly with multiple ethnic groups, in an urban setting, with a high prevalence of vascular risk factors. It is a cohort with potential selection biases, particularly because high adiposity is related to increased morbidity and mortality that could have limited participation to persons who were less likely to have this risk factor.
Our study has several strengths. We had comprehensive research procedures for the diagnosis of dementia. We also had measures of BMI and WC, and weight at two time-points, but did not have a weight history prior to inclusion in the cohort. To the best of our knowledge, this is the first study examining the relation between WC and dementia in the elderly.
Our results show that high adiposity may be associated with higher dementia risk, particularly in younger elderly. However, this association could be confounded by low weight and weight loss due to pre-clinical disease and is attenuated in older age groups. This may explain conflicts in previous studies. Our results need to be replicated in other studies. Similar studies are needed with imaging or biomarkers of adipose tissue.