Longitudinal Association of Amyloid Beta and Anxious-Depressive Symptoms in Cognitively Normal Older Adults
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Updated: Feb 15, 2026
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Nancy J Donovan1, Joseph J Locascio1, Gad A Marshall1
1From the Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston; the Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston; the Division of Geriatric Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Mass.; the Department of Neurology, Cliniques Universitaires Saint-Luc, Institute of Neurosciences, Université Catholique de Louvain, Brussels; the Department of Psychiatry, the Department of Neurology, and the Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston.
Objective:
To understand the role of depressive symptoms in preclinical Alzheimer's disease, it is essential to define their temporal relationship to Alzheimer's proteinopathies in cognitively normal older adults. The study objective was to examine associations of brain amyloid beta and longitudinal measures of depression and depressive symptom clusters in a cognitively normal sample of older adults.
Method:
A total of 270 community-dwelling, cognitively normal elderly individuals underwent baseline Pittsburgh compound B (PiB) positron emission tomography (PET) measures of cortical aggregate amyloid beta and annual assessments with the 30-item Geriatric Depression Scale (GDS). The authors evaluated continuous PiB binding as a predictor of GDS score or GDS cluster, calculated as total scores and mean scores for three GDS item clusters (apathy-anhedonia, dysphoria, and anxiety-concentration), across time (1-5 years; mean=3.8 years) in separate mixed-effects models with backward elimination. Initial predictors included PiB binding, age, sex, Hollingshead score, American National Adult Reading Test (AMNART) score, apolipoprotein E ε4 status, depression history, and their interactions with time.
Results:
Higher PiB binding predicted accelerated rates of increase in GDS score over time, adjusting for depression history. Higher PiB binding also predicted steeper rates of increase for anxiety-concentration scores, adjusting for depression history and the AMNART score-by-time interaction. In a post hoc model estimating anxiety scores without concentration disturbance items, the PiB binding-by-time interaction remained significant.
Conclusions:
Higher amyloid beta burden was associated with increasing anxious-depressive symptoms over time in cognitively normal older individuals. Prior depression history was related to higher but not worsening symptom ratings. These results suggest a direct or indirect association of elevated amyloid beta levels with worsening anxious-depressive symptoms and support the hypothesis that emerging neuropsychiatric symptoms represent an early manifestation of preclinical Alzheimer's disease.
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