Amyloid-β, Anxiety, and Cognitive Decline in Preclinical Alzheimer Disease A Multicenter, Prospective Cohort Study

IMPORTANCE Alzheimer disease (AD) is now known to have a long preclinical phase in which pathophysiologic processes develop many years, even decades, before the onset of clinical symptoms. Although the presence of abnormal levels of amyloid-beta (A beta) is associated with higher rates of progression to clinically classified mild cognitive impairment or dementia, little research has evaluated potentially modifiable moderators of A beta-related cognitive decline, such as anxiety and depressive symptoms. OBJECTIVE To evaluate the association between A beta status and cognitive changes, and the role of anxiety and depressive symptoms in moderating A beta-related cognitive changes in the preclinical phase of AD. DESIGN, SETTING, AND PARTICIPANTS In this multicenter, prospective cohort study with baseline and 18-, 36-, and 54-month follow-up assessments, we studied 333 healthy, older adults at hospital-based research clinics. MAIN OUTCOMES AND MEASURES Carbon 11-labeled Pittsburgh Compound B (PiB)-, florbetapir F 18-, or flutemetamol F 18-derived measures of A beta, Hospital Anxiety and Depression Scale scores, and comprehensive neuropsychological evaluation that yielded measures of global cognition, verbal memory, visual memory, attention, language, executive function, and visuospatial ability. RESULTS A positive A beta (A beta+) status at baseline was associated with a significant decline in global cognition, verbal memory, language, and executive function, and elevated anxiety symptoms moderated these associations. Compared with the A beta+, low-anxiety group, slopes of cognitive decline were significantly more pronounced in the A beta+, high-anxiety group, with Cohen d values of 0.78 (95% CI, 0.33-1.23) for global cognition, 0.54 (95% CI, 0.10-0.98) for verbal memory, 0.51 (95% CI, 0.07-0.96) for language, and 0.39 (95% CI, 0.05-0.83) for executive function. These effects were independent of age, educational level, IQ, APOE genotype, subjective memory complaints, vascular risk factors, and depressive symptoms; furthermore, depressive symptoms and subjective memory complaints did not moderate the association between A beta and cognitive decline. CONCLUSIONS AND RELEVANCE These results provide additional support for the deleterious effect of elevated A beta levels on cognitive function in preclinical AD. They further suggest that elevated anxiety symptoms moderate the effect of A beta on cognitive decline in preclinical AD, resulting in more rapid decline in several cognitive domains. Given that there is currently no standard antiamyloid therapy and that anxiety symptoms are amenable to treatment, these findings may help inform risk stratification and management of the preclinical phase of AD.