Depression-an underrecognized target for prevention of dementia in Alzheimer's disease

Abstract

It is broadly acknowledged that the onset of dementia in Alzheimer's disease (AD) may be modifiable by the management of risk factors. While several recent guidelines and multidomain intervention trials on prevention of cognitive decline address lifestyle factors and risk diseases, such as hypertension and diabetes, a special reference to the established risk factor of depression or depressive symptoms is systematically lacking. In this article we review epidemiological studies and biological mechanisms linking depression with AD and cognitive decline. We also emphasize the effects of antidepressive treatment on AD pathology including the molecular effects of antidepressants on neurogenesis, amyloid burden, tau pathology, and inflammation. We advocate moving depression and depressive symptoms into the focus of prevention of cognitive decline and dementia. We constitute that early treatment of depressive symptoms may impact on the disease course of AD and affect the risk of developing dementia and we propose the need for clinical trials.

Fig. 1. The relationship between depression and cognitive decline throughout the development and clinical course of Alzheimer‘s disease (AD).

Depression can occur in three different stages in relation to the process of neurodegeneration in AD. Depression can be a predisposing risk factor occuring before the onset of AD pathology. It might also be an early sign of neurodegenerative changes or a prodromal symptom with or without cognitive deficits. Finally, it may occur at the more advanced dementia stage of AD. In every stage depression is an important accelerating factor contributing to the clinical progression and conversion from a preclinical state to MCI and to dementia.

Fig. 2. Impact of HPA axis dysregulation in depression on AD pathology.

HPA axis: hypothalamic-pituitary-adrenal axis, GR: glucocorticoid receptor, APP: amyloid precursor protein, BDNF: brain-derived neurotrophic factor, AD: Alzheimer’s disease.

Fig. 3. Impact of inflammation in depression on AD pathology.

APP: amyloid precursor protein, BDNF: Brain-derived neurotrophic factor, AD: Alzheimer’s disease.

Fig. 4. Impact of neurotransmitter imbalance in depression on AD pathology.

5-HT: 5-Hydroxytryptamine, DA: Dopamin, BDNF: Brain-derived neurotrophic factor, AD: Alzheimer’s disease.

Fig. 5. Impact of depression-related mechanisms on AD pathology.

AD: Alzheimer’s disease, HPA: Hypothalamic-pituitary-adrenal axis.