UC San Diego

Rationale: Presently, there are over 5 million Americans living with Alzheimer’s disease (AD); this number is projected to grow to over 7 million by 2025. In the absence of effective treatments, and difficulty reversing the neuropathological changes once they emerge, finding modifiable risk factors early in the course of the disorder is one of the most promising strategies to delay or prevent the progression of predementia [i.e., Mild Cognitive Impairment (MCI)] and dementia syndromes. Two factors that may be particularly important in influencing phenotype and rate of progression to MCI and AD are neuropsychiatric and cardiovascular symptoms.

Design: This study included 549 cognitively normal, MCI, and AD volunteers from the UC San Diego Alzheimer’s Disease Research Center (ADRC). Participants were seen annually and underwent a one-hour neurological examination, comprehensive neuropsychological testing, ApoE genotyping, and assessments of cardiovascular symptoms, medication use and neuropsychiatric functioning. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals. Separate analogous models were conducted for individuals that converted to MCI and individuals that converted to AD and ApoE-e4 interaction terms were tested. Multilevel modeling analyses were performed separately for cognitively normal, MCI, and AD subgroups to identify any differential sensitivity among neuropsychological domains most sensitive to neuropsychiatric and vascular risk factors across time.

Results: There were 22 individuals that converted to MCI and 57 individuals that converted to AD during the course of the study. Apathy at baseline was found to significantly increase the risk of MCI after adjusting for age, sex, and education. Individuals endorsing agitation were more than two times as likely to convert to AD and individuals with at least mild depression were 2.5 times as likely to convert to AD. There were no significant interactions between neuropsychiatric symptoms and APoE-e4; cardiovascular risk factors did not predict change in cognitive status. Within-person increases in depressive symptoms were significantly related to decreases on memory and executive functioning among cognitively normal individuals; within-person increases in neuropsychiatric symptoms among AD patients were associated with worse attention, language, visuospatial skills, and processing speed. Moreover, AD patients with higher levels of neuropsychiatric symptoms across time had worse executive functioning relative to AD patients with lower levels of neuropsychiatric symptoms.

Conclusions: Results suggest that apathy, and agitation and depression at baseline are associated with increased risk of future MCI and AD, respectively. As such, clinicians should monitor individuals presenting with both cognitive complaints and new neuropsychiatric symptoms closely, as these individuals may be at higher risk of developing MCI or AD. This study also found that higher reports of neuropsychiatric symptoms in cognitively normal and AD patients were associated with worse performance across time in specific cognitive domains. Additional studies are warranted that investigate whether treatments designed to improve neuropsychiatric symptoms result in subsequent improvements in specific areas of cognition.