Since the time of Selye, we have known that excessive levels of stress can cause and exacerbate disease, in large part through the activation of the Hypothalamic-Pituitary-Adrenal (HPA) axis which elevates circulating corticosteroid (Cort) levels. This produces a constellation of symptoms that occur in response to any form of stress, which he terms the “general adaptation syndrome” (Selye, 1950). With recent advances, we have come to more fully understand both how stress exacerbates disease symptoms and drives disease progression, and how diseases disrupt stress responses to produce neuropsychiatric symptoms. I term this feed-forward relationship between stress and disease, “The Vicious Cycle of Stress” (Fig. 1). In the Vicious Cycle of Stress, the right arc of the cycle represents the influence of stress on disease. Countless studies have experimentally demonstrated the negative impact stress has on disease progression, from cancer to cardiovascular disease, neurodegenerative disease and symptoms of aging (for review, see: Bjorntorp, 1997; Wahrborg, 1998; Girod and Brotman, 2004; Reiche et al., 2004; DiMicco et al., 2006; Pasquali et al., 2006; Goosens and Sapolsky, 2007; El Husseini and Laskowitz, 2014; Gupta and Morley, 2014; Prenderville et al., 2015; Herbert and Lucassen, 2016; Martocchia et al., 2016; Shin et al., 2016; Bortolato et al., 2017; Crestani, 2017). However, there are far fewer studies that address the left arc of the cycle. The left arc represents mechanisms by which advancing disease disrupts neural and endocrine circuits that mediate the stress response, producing neuropsychiatric symptoms such as depression, anxiety, insomnia and malaise (for review, see: Pedersen et al., 2001a; Silverman et al., 2005; Du and Pang, 2015; Michael Caudle, 2016; Wulsin et al., 2016). A clear example of this is pituitary tumors that release excess hormones to cause physiologic and psychologic pathologies secondary to tumor growth (e.g. pituitary adenomas release excess ACTH thereby chronically elevating circulating Cort, resulting in Cushing’s disease; Boscaro et al., 2001). The recent extensive dissection of the neural circuitry that mediates behavioral and hormonal stress responses has uncovered a plethora of brain regions in which disease-associated dysfunction can produce neuropsychiatric symptoms, particularly in the context of neurodegeneration (Kolanowski et al., 2017; Ross et al., 2017). The “Vicious Cycle of Stress” posits that stress drives disease and disease causes stress, feeding forward to accelerate disease progression while producing neuropsychiatric complications. Although this is an oversimplified construct, I use it here to illuminate the relationship between stress and Alzheimer’s disease (AD) that most certainly is much more complicated. Below, I present both clinical and experimental data using this framework to illustrate how stress and AD interact to drive progression of AD-related dementias.