Specific association of worry with amyloid-β but not tau in cognitively unimpaired older adults

INTRODUCTION Anxiety disorders and subsyndromal anxiety symptoms are highly prevalent in late life. Recent studies support that anxiety may be a neuropsychiatric symptom during preclinical Alzheimer's disease (AD) and that higher anxiety is associated with more rapid cognitive decline and progression to cognitive impairment. However, the associations of specific anxiety symptoms with AD pathologies and with co-occurring subjective and objective cognitive changes have not yet been established. METHODS Baseline data from the A4 and LEARN studies were analyzed. Older adult participants (n=4486) underwent assessments of anxiety (State-Trait Anxiety Scale–6 item version [STAI]), and cerebral amyloid-beta (Aβ; 18F-florbetapir) PET and a subset underwent tau (18F-flortaucipir) PET. Linear regressions estimated associations of Aβ in a cortical composite and tau in amygdala, entorhinal and inferior temporal regions with STAI-Total and individual STAI item scores. Models adjusted for age, sex, education, marital status, depression, Apolipoprotein ε4 genotype, and subjective and objective cognition (Cognitive Function Index-participant; Preclinical Alzheimer Cognitive Composite). RESULTS Greater Aβ deposition was significantly associated with higher STAI-Worry, adjusting for all covariates, but not with other STAI items or STAI-Total scores. In mediation analyses, the association of Aβ with STAI-Worry was partially mediated by subjective cognition with a stronger direct effect. No associations were found for regional tau deposition with STAI-Total or STAI-Worry score. CONCLUSION Greater worry was associated with Aβ but not tau deposition, independent of subjective and objective cognition in cognitively unimpaired older adults. These findings implicate worry as an early, specific behavioral marker and a possible therapeutic target in preclinical AD. Summary Higher anxiety is associated with accelerated cognitive decline in preclinical Alzheimer's disease, but associations of specific symptoms with hallmark pathologies are poorly understood. In a large sample of cognitively unimpaired older adults, greater amyloid-β deposition was independently associated with greater worry but not global anxiety. Regional tau deposition was not associated with worry or global anxiety. These findings support that worry may be an early behavioral marker and possible therapeutic target in preclinical Alzheimer's disease. Tweet Worry is specifically and independently associated with amyloid-β, suggesting that worry could be an early behavioral marker and possible therapeutic target in preclinical Alzheimer's disease.