Depression Synergy With Amyloid and Increased Risk of Cognitive Decline in Preclinical Alzheimer Disease

There is increasing evidence that depression in late life is a risk factor for dementia.¹ The association of late-life depression with Alzheimer disease (AD) has been a growing area of interest in our attempts to identify at-risk individuals to better target interventions. While the evidence is not always consistent, findings suggest that late-life depression, as opposed to depression earlier in life, is more strongly associated with cognitive decline.² These observations have led to 2 main theories regarding the association between depression and dementia. Depression in late life has been hypothesized to represent (1) an early noncognitive manifestation of AD with a shared neurodegenerative etiology or (2) a risk factor for AD caused by concurrent non-AD pathology. While it is probable that both pathological processes are at play, distinguishing between the 2 is important for the development of future interventions.

Gatchel et al³ present an analysis of participants from the Harvard Aging Brain Study (HABS), a longitudinal observational study of cognition in aging and preclinical AD. In a cohort with normal cognition at baseline, the authors sought to examine the association of depressive symptoms in the presence of amyloid with change in cognition over time. Amyloid burden was determined using amyloid positron emission tomographic imaging at baseline, while cognition and depression were assessed annually. The Geriatric Depression Scale (GDS), a self-report scale, was used to assess depressive symptoms. Cognition was assessed with the Preclinical Alzheimer Cognitive Composite (PACC), a composite of 4 neuropsychological tests weighted toward episodic free recall and designed to be sensitive to early cognitive change in preclinical AD.

In these cognitively unimpaired individuals, Gatchel et al³ found that increasing subsyndromal depressive symptoms were associated with worsening cognition over time only in the presence of higher amyloid (distribution volume ratio, 1.06) at baseline. These findings remained significant after adjusting for baseline antidepressant use and depression history and removing items from the depression assessment relating to cognition. Lagged-time analyses found that depressive symptoms in the setting of high amyloid loading at baseline were associated with cognitive decline at 1-year follow-up.

These findings expand on the current literature on depression and its association with cognitive decline. This cohort notably had low severity of depressive symptoms at baseline (mean [SD] GDS score, 3.0 [2.8]),³ consistent with subsyndromal to mild depressive symptoms. Mild behavioral impairment has been proposed as a construct describing the emergence of persistent, mild, subsyndromal neuropsychiatric symptoms in middle age as an early marker of cognitive decline.⁴ The findings by Gatchel et al³ add to the growing body of evidence that neuropsychiatric symptoms in older adults may be a marker of progression along the neurodegenerative spectrum.

While the observed association of depressive symptoms with cognitive decline is consistent with most prior research, the finding by Gatchel et al³ that this association exists in the presence of higher but not lower amyloid burden provides new evidence for a shared etiology between depressive symptoms and cognitive decline, and that subsyndromal depressive symptoms may have a synergistic association with amyloid in progression along the AD spectrum. In other words, these findings lend support to the hypothesis that depressive symptoms represent a prodrome or early noncognitive manifestation of dementia. However, it should be noted that the measurements of amyloid used in these analyses were collected at baseline only; therefore, we cannot rule out other mechanisms through which depressive symptoms can lead to cognitive decline in individuals who have amyloid pathology. For example, vascular disease was not accounted for. Because tau is increasingly understood as an important downstream mechanism in AD pathology, its role in the association between depression and dementia would also be of interest for future studies.

Among 582 participants in the Religious Orders Study and Rush Memory and Aging Project, depressive symptoms, as measured by the Center for Epidemiological Studies Depression Scale (CES-D) averaged across all visits over a mean of 7.8 years, did not modify the association between neuropathological markers of dementia (including amyloid plaques, infarcts, neurofibrillary tangles, and hippocampal sclerosis) and cognitive decline.⁵ Some of the differences in findings may be accounted for by methodological and study population differences. First, Gatchel et al³ assessed the change in depressive symptoms, as opposed to an average of symptom severity, over time. Second, the HABS cohort consisted of cognitively unimpaired individuals, of whom 93.5% remained cognitively normal during follow-up,³ while only 35.7% of the cohort in the study by Wilson et al⁵ consisted of cognitively unimpaired individuals, leading to differences in timing of pathological assessments relative to cognitive symptom onset. It should also be noted that the association between increasing depressive symptoms and worsening cognition over time was observed at a level below the previously published threshold for amyloid positivity in the HABS cohort.³ Taken together, these findings suggest that the synergistic association of depression and neuropathology with cognitive decline may be limited to the preclinical or earlier phase of the AD pathological spectrum. Future studies investigating the link between change in depressive symptoms and cognitive decline using preclinical AD markers in cognitively unimpaired individuals⁶ may help clarify this association and provide further evidence for potential interventions in this at-risk population.

It is still uncertain whether the treatment of depression will ameliorate the risk of progression in cognitive decline. This was explored in the study by Gatchel et al,³ in which 14.9% of the cohort were receiving antidepressant treatment, including selective serotonin reuptake inhibitors (SSRIs), dual serotonin and norepinephrine reuptake inhibitors, bupropion, and nortriptyline hydrochloride. Findings remained significant after adjustment for antidepressant treatment in sensitivity analysis, suggesting that the association between depression and cognitive decline was not influenced by the presence of antidepressant use. Analyses derived from the longitudinal Alzheimer Disease Neuroimaging Initiative demonstrated that antidepressant treatment with SSRIs of more than 4 years was protective against progression to AD compared with SSRI treatment for 1 to 4 years or other antidepressant treatments.⁷ Further understanding of the biological mechanisms underpinning the association between depression and delirium is needed before pursuit of prevention trials.

In summary, while there is mounting evidence of an association between late-life depressive symptoms and progression to cognitive decline, the mechanisms underlying this are still unclear, although there is emerging information that there may be an interaction between AD pathology and depressive symptoms. Future studies focusing on understanding this interaction in at-risk populations may assist with identification of treatment targets.

Published: August 9, 2019. doi:10.1001/jamanetworkopen.2019.8970

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Chan C et al. JAMA Network Open.

Corresponding Author: Paul B. Rosenberg, MD, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, 5300 Alpha Commons Dr, Ste 429, Baltimore, MD 21224 (prosenb9@jhmi.edu).

Conflict of Interest Disclosures: Dr Rosenberg reported receiving grants from the National Institute on Aging, Lilly, and Functional Neuromodulation and reported receiving other support from Otsuka and Avanir. No other disclosures were reported.