Psychiatric symptoms, including depression, are common among individuals with Alzheimer’s disease (AD) and may precede the onset of significant cognitive symptoms. Recent research has suggested that elevated depressive symptoms are related in part to the pathophysiologic changes that occur in the brains of those with AD. While there is growing evidence supporting an association between emerging depressive symptoms and the preclinical stages of AD (before the emergence of cognitive impairment), most of this work has come from cross-sectional studies utilizing less sensitive measures of brain function and pathophysiology.
In a recent study published in JAMA Network Open, Jennifer Gatchel, MD, PhD and her research team including members of the Harvard Aging Brain study and Massachusetts General Hospital, examined the relationship between emerging depressive symptoms and early regional amyloid accumulation in cognitively unimpaired older adults. The research aimed to determine whether increasing depressive symptoms are associated with amyloid accumulation in brain regions important for emotional regulation and whether these associations vary by cognitive performance.
All participants were in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of cognitively unimpaired individuals aged 60 years and older at baseline. The study included 154 participants who were cognitively unimpaired and had mild or no depressive symptoms at baseline. Participants underwent annual assessments of depressive symptoms using the Geriatric Depression Scale (GDS) and cognitive performance using the Preclinical Alzheimer Cognitive Composite-5 (PACC). They also had cortical amyloid positron emission tomography (PET) imaging at baseline and every 2-3 years thereafter, with a mean follow-up of 8.6 years.
The researchers focused on specific brain regions of interest (ROIs) linked to emotional regulation and commonly affected by Alzheimer’s disease (AD) pathology. These included the medial orbitofrontal cortex (mOFC), lateral orbitofrontal cortex (lOFC), middle frontal cortex (MFC), superior frontal cortex (SFC), anterior cingulate cortex (ACC), isthmus cingulate cortex (IC), posterior cingulate cortex (PCC), and amygdala.
The Main Findings
- Accumulation of amyloid in the bilateral mOFC, IC, and MFC was significantly associated with increasing depressive symptoms.
- These associations remained significant even after adjusting for changes in cognitive performance.
- The effect sizes of the observed associations were small but consistent with previous findings in the Harvard Aging Brain Study cohort.
Clinical Implications
In this cohort study of cognitively unimpaired older adults with no, or at most mild, depressive symptoms at baseline, greater depressive symptoms over time were associated with amyloid accumulation in regions associated with emotional regulation. In addition, these associations persisted in most regions and were independent of changes in cognitive performance.
The findings of the current study shed light on the neurobiology of depressive symptoms in individuals with preclinical Alzheimer’s disease. The results suggest that emerging depressive symptoms in older adults may not only represent a psychological reaction to cognitive decline but might also have a neurological basis and may reflect amyloid accumulation in frontal and cingulate cortices.
The research adds to the growing body of evidence linking new-onset depression in later life with the development of Alzheimer’s disease and related cerebral pathophysiology. It is among the first studies to use PET imaging to examine in vivo regional accumulation of amyloid in older adults with preclinical AD.
The researchers acknowledged several limitations of their study.The sample size was relatively small and primarily composed of highly educated, White, non-Hispanic individuals; future studies will include larger and more diverse samples, particularly racial and ethnic minorities who are at higher risk of developing dementia. Other biopsychosocial risk factors for depression and Alzheimer’s disease were not examined in this study, and the study was too small to fully explore sex differences in psychiatric illness vulnerability and associations between cognitive decline and Alzheimer’s disease pathology.
The current study underscores the importance of monitoring for depressive symptoms, in addition to cognitive changes, when screening for early Alzheimer’s disease, particularly in those who may have risk factors for AD. In addition, the findings provide support for considering depressive symptoms as an early feature of preclinical Alzheimer’s disease, a shift that may help to facilitate the early identification of those with AD, at a time when interventions are more likely to be more effective in slowing the progression of the disease.
Researchers involved in this project included Catherine E. Munro, PhD; Michelle Farrell, PhD; Bernard Hanseeuw, MD, PhD; Dorene M. Rentz, PsyD; Rachel Buckley, PhD; Michael Properzi, BS; Ziwen Yuan, MS; Patrizia Vannini, PhD; Rebecca E. Amariglio, PhD; Yakeel T. Quiroz, PhD; Deborah Blacker, MD, ScD; Reisa A. Sperling, MD, MMSc; Keith A. Johnson, MD; Gad A. Marshall, MD; and Jennifer Gatchel, MD PhD.
Read More
Munro CE, Farrell M, Hanseeuw B, Rentz DM, Buckley R, Properzi M, Yuan Z, Vannini P, Amariglio RE, Quiroz YT, Blacker D, Sperling RA, Johnson KA, Marshall GA, Gatchel JR. Change in Depressive Symptoms and Longitudinal Regional Amyloid Accumulation in Unimpaired Older Adults. JAMA Netw Open. 2024 Aug 1;7(8):e2427248.
Jennifer Gatchel, MD, PhD, is a neuroscientist and geriatric psychiatrist practicing at Massachusetts General Hospital and an Assistant Professor of Psychiatry at Harvard Medical School. Dr. Gatchel’s research focuses on understanding the relationships among Alzheimer’s Disease (AD)-associated proteins amyloid and tau, neuropsychiatric symptoms, and cognitive decline in the preclinical and prodromal stages of AD and related dementias.
