Over 50% of adults are obese or overweight and current trends suggest these numbers will increase in the coming decades.23
The rising prevalence of overweight and obesity is likely to have important public health implications on the cognitive health of the aging population. We found that biomarker levels reflective of AD pathophysiology were associated with lower BMI in a sample of cognitively normal, MCI, and AD participants enrolled in ADNI. This relationship was most strongly evident in individuals with MCI, a heterogeneous pathologic state, suggesting that individuals with MCI who are normal or low weight (BMI 18.5–25 kg/m2
) are more likely to have amyloid-based cognitive impairment compared to those who are overweight (BMI >25 kg/m2
). This relationship was also evident in cognitively normal adults, of which a portion (>38%) had significant cerebral amyloid burden without associated functional and clinical symptoms.
Conflicting findings have obscured a precise definition of the relationship between body mass and late-life cognitive decline. Being overweight (BMI >25) in midlife is associated with an increased risk of cognitive impairment and dementia1,5
while being overweight in late life is associated with reduced cognitive risk.6–8
Mortality studies suggest the chronic disease associated with obesity drives mortality risk while the association of low BMI (<20) with mortality may be an artifact of preexisting disease.24,25
Our data in cognitively healthy participants demonstrate that low BMI is associated with AD pathophysiologic markers. Interestingly, the vast majority of our cohort was not at the extremes of BMI, with less than 17% of the overweight group classified as obese (BMI >30) and few participants (3.6%) with a BMI <20. Nevertheless, we observed robust relationships between BMI and the presence and burden of AD biomarkers.
We observed that lower BMI (<25 kg/m2
) was associated with a higher burden of AD biomarkers and greater prevalence of AD biomarker “positivity” in both the cognitively normal and MCI groups. Surprisingly, we found no evidence of change in BMI or weight over 2 years in biomarker “positive” vs “negative” groups although multiple studies have demonstrated that weight loss is a nonspecific preclinical marker of AD that may be present 6–10 years prior to the onset of clinically recognizable cognitive and functional symptoms.11,26
Both autopsy and imaging data suggest that weight loss may in part be related to brain pathology. An autopsy study of individuals with and without dementia found that AD plaque and tangle pathology was associated with both low BMI and declining BMI in the years preceding death.15
Imaging data also suggest that structural brain changes, including whole brain and hippocampal atrophy, are associated with alterations in body composition, including reductions in more specific measures of lean mass and bone density.9,27
As BMI is also a marker of systemic energy metabolism, our findings are consistent with others that suggest that systemic metabolic changes are present early in the disease process.28
Potential mechanisms underlying the relationship of BMI and AD pathophysiology include neuropathologic changes known to occur in areas such as the hypothalamus that play a role in regulating energy metabolism and food intake.29
It is also important to consider mechanisms that influence both weight loss and cognitive impairment, including systemic anabolic and inflammatory abnormalities that are common to both AD and wasting states such as sarcopenia.30,31
Behavioral and cognitive changes associated with dementia can also influence body composition by interfering with nutrition (i.e., forgetting to eat) or through reductions in physical activity, a strong predictive factor of sarcopenia.32
Our observations were strongest in those without significant cognitive and functional limitations and we found no evidence of weight loss in any group, reducing this likelihood.
The substrate for cognitive impairment across selected populations of individuals with MCI is heterogeneous and includes both AD and vascular changes. Our data suggest that the underlying etiology of cognitive impairment in MCI participants with higher BMI is less likely to be related to amyloid pathophysiology than those with normal or low BMI. For example, more individuals with MCI who had a BMI below 25 kg/m2
were PiB-positive than individuals who were overweight (85.2% vs 48.3%). The same was true with regard to elevated tau/Aβ (80.2% vs 60.7%). Prior studies in healthy older adults have found that high BMI is associated with structural and metabolic brain changes. Higher BMI in participants in the ADNI cohort has previously been associated with brain atrophy, although this association was observed predominantly in the cerebellum, brainstem, frontal, temporal, and occipital lobes and spared those areas most commonly affected by AD pathophysiology such as the medial temporal lobe or default mode network.33
It is possible that being overweight may contribute to cognitive impairment through comorbidities such as cerebrovascular disease. Additionally, cerebrovascular burden influences the expression of clinical symptoms at lower levels of AD pathophysiology in an additive fashion.34,35
High BMI in individuals with cognitive impairment similar to that of normal weight individuals such as in the present study may thus be associated with an increased likelihood of underlying mixed or nonamyloid pathologies.
This study has several important limitations. Given that multiple secondary analyses were performed there is an increased chance of type I error and spurious observations. BMI is a nonspecific measure of body composition that does not adequately reflect distribution of body fat and important components of body composition. This is an increasingly important limitation given variable risks associated with the location of adipose tissue,7
weight stability despite sarcopenia in older age,36
and the possibility that AD may be specifically associated with sarcopenia.9
However, BMI continues to be a useful heuristic associated with adverse health outcomes including coronary artery disease, diabetes, and hypertension.37
Additionally, our findings were confined to associations between AD biomarkers and BMI at baseline and we did not observe an association with change in BMI over time. These data were collected from a selected group of research participants which may affect the study's generalizability. These data should not be interpreted as establishing evidence of a causal or temporal relationship between body composition and AD pathology.
Our in vivo results extend previous autopsy findings to demonstrate a relationship between BMI and AD pathophysiology in the earliest stages of AD. Importantly, this relationship of higher AD pathophysiology with lower BMI was most strongly evident in those without major cognitive or functional change. These results provide further support that AD has systemic manifestations that may be the result of longstanding neuropathologic change or lifestyle patterns. Further, cognitive impairment in those who are overweight may be more likely to be the result of heterogenous pathophysiology. Future investigations should investigate if the association between BMI and AD reflects a systemic response to unrecognized disease or a longstanding trait that predisposes one to developing the disease.