By Makoto Ishii, MD, PhD
Assistant Professor of Neuroscience and Neurology, Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medical College
SYNOPSIS: Among cognitively intact individuals, those who develop mild cognitive impairment (MCI) had faster body mass index (BMI) decline and significantly lower BMI seven years before MCI diagnosis. However, after MCI diagnosis, there was no difference in BMI decline between patients who developed dementia and those who did not.
SOURCE: Guo J, Wang J, Dove A, et al. Body mass index trajectories preceding incident mild cognitive impairment and dementia. JAMA Psychiatry 2022;79:1180-1187.
Changes in systemic metabolism during midlife, such as obesity or high body mass index (BMI) and insulin resistance caused by diabetes mellitus, are emerging as important modifiable risk factors for mild cognitive impairment (MCI) and dementia in late life. Interestingly, in late life, the association of BMI and the development of MCI and dementia appear to be the opposite, with accumulating evidence suggesting that weight loss can precede the dementia.
In this study by Guo and colleagues, the authors sought to further clarify the relationship of BMI and the development of cognitive impairment in older adults by using data from the Rush Memory and Aging Project, a long-term, community-based longitudinal cohort study, to examine the BMI trajectories preceding the transition from normal cognition to MCI and from MCI to dementia and to investigate the association between BMI trajectories and brain pathologies.
A total of 1,390 participants were included initially in this study. After excluding 22 participants who developed dementia without a previous diagnosis of MCI and 429 participants with fewer than three repeated BMI measurements, the BMI trajectories were measured in 939 cognitively intact individuals. During the follow-up period (median duration, 6 years [3-9]), 371 participants (39.5%) developed MCI, with 88 (23.7%) subsequently developing dementia.
The authors found that the BMI trajectories significantly differed between cognitively intact participants who developed MCI compared to those who remained cognitively intact, with an earlier and more pronounced BMI decline in those who developed MCI. The differences in BMI were seen approximately seven years prior to the MCI diagnosis (difference in mean BMI at year -7, -0.96; 95% confidence interval [CI], -1.85 to -0.07).
When the authors examined the BMI trajectories among participants with incident MCI and compared those who developed dementia to those who did not, there was a significant decline in BMI in both groups but no significant difference in the BMI decline between the two groups (β, -0.04; 95% CI, -0.23 to 0.14; P = 0.63). Finally, among the 520 participants who underwent brain autopsy, BMI decline before death was significantly faster for those with the highest burden of global Alzheimer’s disease (AD) pathology compared to those with the lowest burden. Similar results were obtained with cerebral vascular pathology, since BMI decline was fastest in those with the highest burden of cerebral vascular pathology compared to those with the lowest burden.
COMMENTARY
This study provides further evidence supporting observations that faster BMI decline occurs during the preclinical or prodromal stages of dementia, with brain autopsy findings suggesting that the faster BMI decline may be the result of a higher burden of AD and/or cerebral vascular pathology. Major strengths of this study include the use of a relatively large community-based cohort with long-term follow-up, annual BMI measurements, and the availability of brain autopsy data.
Why is midlife obesity associated with MCI and dementia, while late life weight loss is associated with MCI and dementia? One possible explanation is that obesity and its associated metabolic dysfunction earlier in life could contribute to the development of AD and cerebral vascular pathology over time and, therefore, increase the risk for developing MCI and dementia. In contrast, as seen in this study of older adults, if BMI declines faster around seven years prior to MCI diagnosis, this presumably is during the preclinical stage of dementia, where AD and other pathologies already are accumulating in the brain decades prior to any significant cognitive decline. Therefore, the late-life weight loss could be an early manifestation of AD and related dementias caused by disruption of brain circuits involved in regulating body weight. Supporting this possibility, in mouse models of AD pathology, amyloid-beta can cause dysfunction of hypothalamic neurons that are important regulators of body weight and metabolism.
Additional studies clearly are needed to validate findings from this study and to further elucidate the mechanisms underlying the changes in BMI during the preclinical and prodromal stages of dementia. As changes in body weight and systemic metabolism increasingly are recognized as important factors contributing to the pathogenesis of MCI and dementia, regular monitoring of body weight and systemic metabolic factors in older adults may help identify and prioritize those individuals who need cognitive assessments and early interventions.
