Journal of Alzheimer’s Disease 23 (2011) 177–193 DOI 10.3233/JAD-2010-100390 IOS Press 177 Review Depression and Alzheimer’s Disease: Is Stress the Initiating Factor in a Common Neuropathological Cascade? Susana Aznar ∗ and Gitte M. Knudsen Center for Integrated Molecular Imaging, Neurobiology Research Unit, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark Accepted 29 September 2010 Abstract. The existence of a high co-morbidity between Alzheimer’s disease (AD) and depression has been known for a long time. More interesting though are recent studies indicating that depression and number of depressive episodes earlier in life is associated with increased risk of AD development. This suggests the existence of common neuropathological mechanisms behind depression and AD. Here we propose that the brain changes associated with depressive episodes that compromise the brain’s ability to cope with stress may constitute risk factors for development of AD. Furthermore, in individuals with a genetic linkage to depression, there may be an increased vulnerability towards the initiation of a detrimental neurodegenerative cascade. The following review will deal with the various observations reported within the different neurobiological systems known to be involved and affected in depression, like serotonergic and cholinergic system, hypothalamic-pituitary-adrenal axis and brain derived neurotrophic factor, and discussed in relation to AD. Keywords: 5-HT 1A , 5-HT 2A , BDNF, depression, HPA-axis, monoaminergic hypothesis, serotonin, stress INTRODUCTION Both dementia and major depressive disorders (MDD) are projected to become two of the most burdensome disorders by midway through the 21st century. The worldwide prevalence of both diseases has increased dramatically during the last few decades and will continue to do so primarily due to the steady aging of the world population [1, 2]. Understanding the risk factors associated with these diseases and explor- ing preventive interventions is therefore of uttermost importance in our fight against them. ∗ Correspondence to: Susana Aznar, Ph.D., Neurobiology Re- search Unit, Copenhagen University Hospital, Unit 9201, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel.: +45 35456701; Fax: +45 3545 6713; E-mail: saznar@nru.dk. Alzheimer’s disease (AD) is the most prevalent dementia disease, and together with vascular dementia, it accounts for 85% of dementia related diseases [3]. Epidemiological studies do not always utilize estab- lished criteria for probable AD and even less frequently neuropathological confirmation of the disease is done. MDD is one of the most prevalent neuropsychiatric disorders characterized by the presence of one or more major depressive episodes without a history of manic, mixed, or hypomanic episodes. Interestingly, anxiety disorders, dysthymia, bipolar disorders, and apathy have been associated with AD. A different diagnos- tic criteria for MDD associated with AD has been suggested, where depression may be less severe or per- sistent, with waxing and waning symptomatology [4]. An extract of these extensive studies are represented in Table 1 to illustrate the high co-morbidity between neuropsychiatric disorders and AD. ISSN 1387-2877/11/$27.50 © 2011 – IOS Press and the authors. All rights reserved