Parallels Between Major Depressive Disorder and Alzheimer’s Disease: Role of Oxidative Stress and Genetic Vulnerability

Abstract

The thesis of this review is that oxidative stress is the central factor in major depressive disorder (MDD) and Alzheimer’s disease (AD). The major elements involved are inflammatory cytokines, the hypothalamic pituitary axis, the hypothalamic pituitary gonadal, and arginine vasopressin systems, which induce glucocorticoid and “oxidopamatergic” cascades when triggered by psychosocial stress, severe life threatening events, and mental-affective and somatic diseases. In individuals with a genomic vulnerability to depression these cascades may result in chronic depression-anxiety-stress spectra, resulting in MDD and other known depressive syndromes. In contrast, in subjects with genomic vulnerability to Alzheimer’s disease, oxidative stress-induced brain damage triggers specific antioxidant defenses, i.e. increased levels of amyloid-β (Aβ) and aggregation of hyper-phosphorylated tau, resulting in paired helical filaments and impaired functions related to the ApoEε4 isoform, leading to complex pathological cascades culminating in AD. Surprisingly, all the AD associated molecular pathways mentioned in this review have been shown to be similar or analogous to those found in depression, including structural damage, i.e. hippocampal and frontal cortex atrophy. Other interacting molecular signals, i.e. GSK-3β, convergent survival factors (brain-derived neurotrophic factor and heat shock proteins), and transition-redox metals are also mentioned to emphasize the vast array of intermediates that could interact via comparable mechanisms in both MDD and AD.

Anxiety is associated with increased risk of dementia in older Swedish twins

“…One possible mechanism is chronic stress that is associated with anxiety, which results in hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, which may damage the hippocampus and frontal cortex [38]. Other possible mechanisms include disruptions to the GABAergic system and thyroid abnormalities.…”

Stability of Genetic and Environmental Contributions to Anxiety Symptoms in Older Adulthood

“…Although varying by domain, cognitive functioning typically starts to decline at a greater rate starting around the age of 60 (Salthouse 2010). It is possible that genes contributing to these physiological changes and cognitive decline may partially explain this genetic innovation in anxiety seen at age 60 as research has hypothesized genetic overlap of the phenotypes of anxiety, depression, and cognitive performance (Rodrigues et al 2014). These explanations are speculative and future research needs to examine this further and the need for future research to investigate genetic contributions to late life anxiety is great.…”

The inverted CD4:CD8 ratio is associated with gender-related changes in oxidative stress during aging

“…During aging, however, there is a clear accumulation of free radicals and associated damage in various tissues [17][18][19] -and this constitutes the basis for the free radical theory of aging. In addition, enhanced oxidative stress (OS) contributes to the pathogenesis of many age-related diseases [20][21][22][23].…”