Do Depressive Symptoms Across the Lifespan Affect Dementia Risk?

Up to 20% of adults experience an episode of clinical depression in their lifetimes. These trends are likely to be exacerbated by the COIVD-19 pandemic and response. According to a CDC report in June 2020, 40.9% of respondents reported an adverse mental or behavioral health condition. Although older adults in the same survey reported more resilience to COVID-19 than did younger adults, depressive symptoms often follow a U-shaped curve, such that the highest level of symptoms are reported in young adulthood and in late life (e.g., ages 65 and older). Depression and higher reported depressive symptoms in late life are associated with a higher risk of dementia and cognitive decline, yet few studies have examined a similar association between depression earlier in life and risk of dementia.

Depression as a Risk Factor for Dementia

Increasing evidence suggests that there are multiple risk factors for dementia that may accumulate across an individual’s lifespan. A recent consensus document by The Lancet estimated that up to 40% of dementia cases may be attributable to behavioral and lifestyle factors, as well as comorbid health conditions, spanning from early life (e.g., low educational attainment) to midlife (e.g., vascular risk factors) and later life (e.g., social isolation).

Depression was considered a potential late-life risk factor for dementia—4% of dementia cases are estimated to be attributable to depression in late life. This estimate would suggest that interventions to target depression could reduce dementia risk; however, scientific debate remains about the relationship between depression and dementia.

One of the key challenges to understanding the depression/dementia relationship is that epidemiologic studies on dementia often recruit adults ages 65 or older, which makes it difficult to clearly establish cause and effect, because dementia can take 15 to 20 years to develop. Neuropsychiatric symptoms, including depressive symptoms, apathy and irritability are common in individuals living with dementia: one study reported symptoms in 43% of older adults with mild cognitive impairment and 75% of older adults with dementia. This may be due to early cognitive changes or brain atrophy.

There is some evidence that vascular and cerebrovascular disease may be a common cause of depression and dementia, (called the “Vascular Depression” hypothesis). Yet there also are plausible mechanisms through which depression may affect dementia risk; depression is associated with higher levels of stress hormones (cortisol), which may affect brain regions that are important for memory. Examining associations with depression earlier in life could help rule out some of these alternative pathways.

Life-course Research Challenges and Approaches

Few studies that follow research participants across their entire adult life course have measured depressive symptoms and cognition. There are observational studies that follow cohorts of individuals; but these generally span only one to two decades at most. My colleagues at the University of California San Francisco (UCSF) and Columbia University developed methods to pool several cohort studies that span the adult life course and impute (e.g., fill-in) life-course exposure trajectories.

Initial studies suggested cardiovascular risk factors and higher body mass index in early adulthood were associated with late-life dementia risk, independent of other time periods. In a recent study, published in the Journal of Alzheimer’s Disease, we further applied these same methods to examine depressive symptoms. We pooled four such population-based cohorts, which together spanned the adult lifespan. More than 15,000 Black and White Americans were followed, ranging in age from 20 to 89. Participants had reported depressive symptoms on the Center for Epidemiologic Studies Depression Scale as part of prior study visits.

We used this information to estimate average depressive symptoms across all ages and then predict trajectories for 6,122 older participants who also had cognitive measures. This approach essentially borrows information from younger individuals and applies it to older individuals with otherwise similar characteristics. Such a procedure is often used to predict likelihood of future outcomes, in this case we predicted the past. This rests on important assumptions but is a best guess estimate at this point in time.

We then conducted validation procedures that suggest a relatively good fit, and the imputed depressive symptom trajectories fit a U-shaped curve by age, similar to age-related trends in prevalence data. This same approach also has been developed and implemented to study life-course cardiovascular risk factors and risk of dementia.

Estimated Depressive Symptoms and the Association with Cognitive Impairment

We averaged imputed depressive symptom trajectories over early adulthood (ages 20 to 49), midlife (ages 50 to 69), and late life (70 to 89) and examined associations with incidence of cognitive impairment and rates of cognitive decline. Higher depressive symptoms in each life-course period were associated with 33% to 94% higher odds of developing cognitive impairment in late life (see Table 1, below) as well as faster rates of cognitive decline

However, only early adulthood and late-life depressive symptoms remained significantly associated (p<0.05) with cognitive impairment independent of other life-course stages. These associations were independent of antidepressant use and adjustment for age, sex, race and imputed cardiovascular risk factors. Antidepressant use also was associated with increased odds of incident cognitive impairment, but there should be caution in interpreting this as an effect of medication use because antidepressant use could be cofounded by depression severity.

Our finding that higher imputed depressive symptoms in early adulthood are independently associated with cognitive impairment apart from mid- or late-life depressive symptoms is consistent with the hypothesis that early adulthood depression increases risk for dementia.

Conclusions and Future Research Directions

This approach offers insights into depressive symptoms as a life-course risk factor for dementia by pooling available cohort data; and adds to the evidence that depressive symptoms may increase risk for late-life cognitive impairment. However, the imputation procedure was extensive and rests upon important assumptions that will need to be verified. For example, there may be some underestimation of early adult estimates, which could result in a conservative estimate of the association of higher depressive symptoms in early adulthood associated with late-life cognitive impairment. We examined depressive symptoms, not diagnosed depression, and findings may not be generalizable to clinical settings.

Future studies will be needed to determine underlying mechanisms and whether treatment of depression in early adulthood may be a strategy to reduce dementia burden. However, creative use of multiple cohort studies and advanced statistical imputation procedures may help bridge the gap in assessing life-course risk factors for dementia.

Table 1. Estimated Odds of Incident Cognitive Impairment

OR: Odds Ratio *No participants had imputed young adulthood depressive symptoms in this range.

Source: This table is reprinted from the Journal of Alzheimer’s Disease, 83(3), Brenowitz, W.D., Zeki Al Hazzouri, A., Vittinghoff, E., Golden, S.H., Fitzpatrick, A.L. and Yaffe, K. “Depressive Symptoms Imputed Across the Life Course Are Associated with Cognitive Impairment and Cognitive Decline.” 1379–89. Copyright 2021, with permission from IOS Press. The publication is available at IOS Press through http://dx.doi.org/10.3233/JAD-210588.

Willa Brenowitz, PhD, MPH, is an assistant professor in the Department of Psychiatry and Behavioral Sciences, University of California San Francisco.