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  • PMID: 23075538 was deleted because it is a duplicate of PMID: 23570886
Am J Geriatr Psychiatry. 2013 May;21(5):418-32. doi: 10.1016/j.jagp.2013.01.053. Epub 2013 Feb 6.

The age-by-disease interaction hypothesis of late-life depression.

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Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15219, USA.


The phenomenologic diagnosis of depression is successful in increasing diagnostic reliability, but it is a classification scheme without biologic bases. One subtype of depression for which evidence suggests a unique biologic 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 biologic processes. Here, we briefly review current LLD hypotheses and then describe the characteristics of molecular brain aging and their overlap with disease processes. Furthermore, 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 biologic processes that are pushed in LLD-promoting directions by changes in gene expression naturally occurring in the brain during aging. Hence, the brain is led to a physiological state that is more susceptible to LLD, because 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 biologic changes of the brain can shift the repertoire of available functional states in a prodepression 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 biologic processes affected during normal aging may inform the development of new interventions for the prevention and treatment of LLD.

[Indexed for MEDLINE]

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