Overweight and obesity, as measured with BMI, were associated with regionally specific atrophy in the anterior hippocampus. This is an important finding for several reasons. First, it suggests that generalized BMI related atrophy, which we have identified in the earlier work, may also be localized to specific regions of the hippocampus. This explains some of the atrophy that is a characteristic neuroimaging signature of Alzheimer’s disease [4
]. The specificity of this atrophy is notable as it targets the anterior hippocampus, which is affected in the early course of Alzheimer’s disease [21
]. The anterior hippocampus may have been the place where more effects were detected because of the greater age-related and disease-related variabilities in that part of the structure. Patients with Alzheimer’s disease are more likely to show differences (and have greater variance as a group) in the anterior hippocampus because of the underlying disease process. Some studies report considerable age-related variation in the posterior hippocampus, distinct from the effects of Alzheimer’s pathology [2
]. Even so, the posterior hippocampal structure is generally affected later in Alzheimer’s disease. As such, we would not expect to see BMI to correlate strongly with posterior hippocampal anatomy in either normal aging or in Alzheimer’s disease. The anatomic variance in the anterior hippocampus of our participants with Alzheimer’s disease may also be some-what less than in other cohorts with Alzheimer’s disease, as our patients were so early in their disease course, that is, with an average MMSE of 23.4 points.
Second, our findings add to the growing evidence that higher BMI may contribute to the atrophy caused by Alzheimer’s disease pathology. A higher BMI over the lifespan likely reflects a poorer cardiovascular health and a poorer diet, which may compound the brain atrophy because of Alzheimer’s disease. Midlife obesity is associated with future cognitive decline and Alzheimer’s risk [23
]. Our patients had mild Alzheimer’s disease, as they were well-enough to participate in an imaging study. Inevitably, those with end-state dementia are often frail, have low BMI, and may not maintain minimally adequate caloric intake [24
]. Consequently, the associations found here may be typical of early but not late Alzheimer’s disease, where the advancing disease may eventually promote loss in body and brain mass, causing a positive association between BMI and brain atrophy. As such, these results may be most relevant for those who are early in the course of Alzheimer’s pathophysiology.
Although associations between BMI and hippocampal volumes were significant in patients with Alzheimer’s disease, this relationship was not found in 204 matched healthy control participants from the same dataset (results not shown). If BMI only correlates with anterior hippocampal volume in patients with Alzheimer’s disease, cardiovascular risk factors may be compounding the level of atrophy caused by the disease, and may be affecting the brain’s ability to resist disease-related atrophy; this is plausible if high BMI causes neurovascular insufficiency. The BMI effect may not be detectable in healthy controls; further studies with larger samples are needed to confirm this.
We also investigated if cognitive scores from the MMSE differed among BMI groups, but there was no significant group difference (P
value = 0.35, F
statistic = 1.057). The MMSE is a clinical measure of the global cognitive function that is in many ways an outcome measure of the hippocampal volume [15
]. That is, when hippocampal volume shrinks, it is often because of the underlying neuronal pathology, which leads to cognitive decline and results with a reduced MMSE score. Thus, adjusting for differences in MMSE scores in BMI studies and hippocampal volume may be difficult as MMSE tends to track hippocampal volume and is highly correlated with it, especially in disease.
Finally, this study shows how the radial atrophy mapping in the hippocampus can complement other whole-brain mapping techniques such as tensor-based morphometry in providing greater specificity on structural brain differences. Future studies may benefit from this approach, using tensor-based morphometry to identify atrophic regions that may then be examined in greater detail with structure-specific mapping methods.
The main strengths of this study were a well-defined cohort, high resolution MRI scans of the brain, and well-validated computational methods. The main weakness is lack of longitudinal information to determine whether obesity-related anterior hippocampal atrophy preceded clinical Alzheimer’s in the same patients. As the ADNI has a longitudinal design, studies relating BMI to atrophic rates over time will be possible in the future.