The Age-by-Disease Interaction Hypothesis of Late-Life Depression

Abstract

The phenomenological diagnosis of depression is successful in increasing diagnostic reliability, but it is a classification scheme without biological bases. One subtype of depression for which evidence suggests a unique biological basis is late-life depression (LLD), with first onset of symptoms after the age of 65. LLD is common and poses a significant burden on affected individuals, caretakers, and society. The pathophysiology of LLD includes disruptions of the neural network underlying mood, which can be conceptualized as the result of dysfunction in multiple underlying biological processes. Here, we briefly review current LLD hypotheses and then describe the characteristics of molecular brain aging and their overlap with disease processes. Further, we propose a new hypothesis for LLD, the Age-by-Disease Interaction hypothesis, which posits that the clinical presentation of LLD is the integrated output of specific biological processes that are pushed in LLD-promoting directions by changes in gene expression naturally occurring during brain aging, hence leading the brain to a physiological state that is more susceptible to LLD, since additional pushes by genetic, environmental and biochemical factors may now be sufficient to generate dysfunctional states that produce depressive symptoms. We put our propositions together into a decanalization model to aid in illustrating how age-related biological changes of the brain can shift the repertoire of available functional states in a pro-depression direction, and how additional factors can readily lead the system into distinct and stable maladaptive phenotypes, including LLD. This model brings together basic research on neuropsychiatric and neurodegenerative diseases more closely with the investigation of normal aging. Specifically, identifying biological processes affected during normal aging may inform the development of new interventions for the prevention and treatment of LLD.

Neuroanatomical correlates of late-life depression and associated cognitive changes

“…As it was mentioned previously, the reason for the discrepancy between the results may be because of the mixed sample used in Colloby's study, containing subjects with and without current depression, whereas our study had a more homogeneous sample of patientsdwith only current depression. Our finding is in-line with the age-by-disease interaction hypothesis of the LLD, which posits that the clinical presentation of LLD is the integrated output of specific biologic processes that are pushed in LLD-promoting directions by changes in gene expression naturally occurring in the brain during aging (Freret et al, 2014;McKinney and Sibille, 2013). This hypothesis was further supported by genome studies (Verhoeven et al, 2014).…”

“…Emerging evidence suggests that pathophysiology of depression is strongly connected with brain aging (Koutsouleris et al, 2014;McKinney and Sibille, 2013;Verhoeven et al, 2014). In the present study, significant differences in the ageecortical thickness correlations between the LLD and control groups were observed.…”

Brain-derived neurotrophic factor levels in late-life depression and comorbid mild cognitive impairment: A longitudinal study

“…Previous studies have consistently shown a significant reduction of BDNF levels in subjects with neurodegenerative disorders, such as Alzheimer’s disease and amnestic mild cognitive impairment (Forlenza et al, 2010; Lee et al, 2009). Recent studies suggest that the molecular changes associated with depression may lead to accelerated brain aging and changes in the expression of the BDNF gene might play an important role in this process (McKinney and Sibille, 2013). In a recent post-mortem study, Douillard-Guilloux et al (2013) found that the expression of BDNF mRNA was negatively correlated with age; moreover, the mean reduction was significantly higher in participants with history of major depression.…”

The Moderating Effect of Age on the 12-Month Prevalence of Anxiety and Depressive Disorders in Adults with a Lifetime History of Cancer

“…Third, there may be biological differences with regard to age-associated diseases and medications that alter the vulnerability to anxiety and depression. 16, 29, 30 Finally, coping styles may differ by age, and older adults may rely more on internal adjustments to cope with loss (e.g., altering their perception of the situation) because they presumably have fewer opportunities to change their life situation than younger adults. 31 Perhaps due to differing coping styles, as well as a tendency to focus on the positive 32 and having more life experiences to draw upon, older adults were better at adapting to loss than younger adults in a bereavement study.…”