Mild Cognitive Impairment (MCI) is a syndrome characterized by cognitive deficits that lie on the spectrum between normal aging and dementia. The clinical course of MCI at diagnosis is not easily predictable, because it represents a heterogeneous population. Neuropsychiatric symptoms (NPS) and midlife obesity increase the likelihood of developing Alzheimer's disease; yet, these two risk factors have not been studied together in MCI. The goal of this dissertation is to examine the relationships of weight measured by body mass index (BMI), with behavior, brain structure, and longitudinal changes in MCI. First, we examined the relationship of obesity and NPS in MCI. It is unknown whether obesity or related health conditions modify the risk of NPS or severity of cognitive impairment in MCI. We found that in MCI, obese subjects were younger and had a higher frequency and severity of affective (depression and anxiety) symptoms near the time of diagnosis. In addition, we examined a number of obesity-related disorders to determine if the relationship between BMI and NPS was more strongly mediated by these secondary factors than BMI itself. We found that type-2-diabetes mellitus (T2DM) and obstructive sleep apnea, also exhibited a specific frequency and severity of NPS. While there were no effects of obesity on cognition, T2D subjects had lower cognitive scores and nearly double the NPS burden. Next, we wanted to determine whether BMI had an effect on brain structure. We selected 36 regional brain volumes related to MCI or weight from the Alzheimer's disease Neuroimaging Initiative (ADNI) dataset. The ADNI sample provided over 600 MCI subjects and we found a main effect of BMI on brain volume in 14 out of 36 regions. Surprisingly, normal weight subjects had lower brain volumes. Since normal weight subjects were significantly older we separated the sample by middle age (55-65 years) and Seniors (>65 years) to determine if age group mediated the effects on brain structure and found that Seniors had lower brain volumes and there was no difference in brain structure for middle-aged subjects. Finally, we measured the relationship of BMI on longitudinal behavioral and cognitive changes over two years and measured the survival distributions of BMI, age, and NPS groups. Over two years NW subjects had greater cognitive deficits. Senior subjects with low baseline NPS showed a faster progression to Alzheimer's dementia. These findings indicate that in MCI obese subjects may have a higher likelihood of NPS and those that have T2D may be at risk for cognitive impairment. In addition, NW MCI subjects may be at an increased risk for brain atrophy and lower cognitive scores. This research may inform lifestyle interventions in regards to obesity, and clinical treatment for NPS prior to the establishment of irreversible cognitive impairments. Further, low body weight should be monitored in old age for progressive gray matter atrophy and cognitive decline.
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