Change in Depressive Symptoms and Longitudinal Regional Amyloid Accumulation in Unimpaired Older Adults

Depressive symptoms in older adults may be a harbinger of Alzheimer disease (AD), even in preclinical stages. It is unclear whether worsening depressive symptoms are manifestations of regional distributions of core AD pathology (amyloid) and whether cognitive changes affect this relationship.

To evaluate whether increasing depressive symptoms are associated with amyloid accumulation in brain regions important for emotional regulation and whether those associations vary by cognitive performance.

Participants from the Harvard Aging Brain Study, a longitudinal cohort study, underwent annual assessments of depressive symptoms and cognition alongside cortical amyloid positron emission tomography (PET) imaging at baseline and every 2 to 3 years thereafter (mean [SD] follow-up, 8.6 [2.2] years). Data collection was conducted from September 2010 to October 2022 in a convenience sample of community-dwelling older adults who were cognitively unimpaired with, at most, mild baseline depression. Data were analyzed from October 2022 to December 2023.

Depression (Geriatric Depression Scale [GDS]-30-item), cognition (Preclinical Alzheimer Cognitive Composite-5 [PACC]), and a continuous measure of cerebral amyloid (Pittsburgh compound B [PiB] PET) examined in a priori-defined regions (medial orbitofrontal cortex [mOFC], lateral orbitofrontal cortex, middle frontal cortex [MFC], superior frontal cortex, anterior cingulate cortex, isthmus cingulate cortex [IC], posterior cingulate cortex, and amygdala). Associations between longitudinal GDS scores, regional amyloid slopes, and PACC slopes were assessed using linear mixed-effects models.

In this sample of 154 individuals (94 [61%] female; mean [SD] age, 72.6 [6.4] years; mean (SD) education, 15.9 [3.1] years), increasing PiB slopes in the bilateral mOFC, IC, and MFC were associated with increasing GDS scores (mOFC: β = 11.07 [95% CI, 5.26-16.87]; t = 3.74 [SE, 2.96]; P = .004; IC: β = 12.83 [95% CI, 5.68-19.98]; t = 3.51 [SE, 3.65]; P = .004; MFC: β = 9.22 [95% CI, 2.25-16.20]; t = 2.59 [SE, 3.56]; P = .03). Even with PACC slope as an additional covariate, associations remained significant in these regions.

In this cohort study of cognitively unimpaired older adults with, at most, mild baseline depressive symptoms, greater depressive symptoms over time were associated with amyloid accumulation in regions associated with emotional control. Furthermore, these associations persisted in most regions independent of cognitive changes. These results shed light on the neurobiology of depressive symptoms in older individuals and underscore the importance of monitoring for elevated mood symptoms early in AD.