Alzheimer's and Stress

Could Alzheimer's be influenced by something so ordinary as chronic stress?

According to the August 2008 Neuroscience and Biobehavioral Reviews there is a significant probability of that. The issue has a lengthy summary of over 12 years of research by many different labs that points to a clear link between stress, particularly in early development, and an increase in the risk of Alzheimer's [Pardon 2008] -- a neurotoxic disease that afflicts almost half of the US population (in particular) by age 85 and "some recent studies estimate that it is now the fourth most common cause of death in the developed world" [Ryman 2006]. The thrust of this article is that chronic stress increases sensitivity to stress and increases vulnerability to Alzheimer's as well.
The authors present a great deal of food for thought not just about Alzheimer's, but about the long term effects of stress upon ageing in general. Ageing starts, physiologically, by age 25. [Cansino.2008]
The result of the author's attempt to put together the many pieces of the puzzle involved has produced the hypothesis presented graphically in the figure bekow, and in extensively documented detail in the article itself: (Don't be overwhelmed by the number of 'players' and arrows in the diagram below; it all boils down to the very simple figure below it.)

The red arrow in figure 2 represents the flow of most of the interactions in figure 1 and sums up the indirect effect of stress on Alzheimer's. The 2 arrows together represent a cautionary tale of two vulnerabilities that exacerbate each other: Alzheimer's and stress. The diagrams below each zoom in on a successive piece of the puzzle that makes up the indirect effect.
As figure 3 shows, chronic stress increases the sensitivity to stress and increases the vulnerability to other factors that dispose one to Alzheimers, such as genes, lifestyle, and environment. The thumbnail on the right gives a sense of the context of these interactions among the chain of interactions that link stress (indirectly) to Alzheimer's. /div>
In figure 4 above, the increased cort. (cortisol or corticosterone) produced by chronic stress impairs the ability of it's receptors to provide a 'break' against over-reacting to the stress, a brake against the detrimental effects of stress. The Corticotropin Releasing Hormone (CRH) acts in the opposite direction, ie., by increasing the effects of stress on the body. So when cort. levels are low or infrequent, the cort. and CRH balance each other. butn when the levels of stress are unrelenting (ie, "chronic") the protectiveness of the cort. tends to fall apart.
The impairment of the cortisol or corticosteroid receptors (figure 5) ramps up the Hypothalamus-Pituitary-Adrenal cortex (HPA) axis or cycle of stimulation, and this contributes to a type of neuronal death which itself further impairs the normal 'braking' activity of the cort. receptors.
Figure 6 above shows that the increased neuronal cell death contributes to the decreased cognition which delivers a double whammy. It both contributes to accelerted ageing, and when accompanied by senile plaques and NeuroFibrillary Tangles increases Alzheimer's risk as well.
At the same time that the cortisol is stimulating the HPA axis (Figure 7 above), the Corticotrophic Releasing Hormone, when binding with its own receptor, increases the production of Amyloid Beta -- the stuff of senile plaques -- and changes Tau to a form more favorable for the characteristic 'tangles' of Alzheimer's.
Figure 8 shows the increased propensity for the Tau and Amyloid Beta to change into a form that favors senile plaques and NeuroFibrillary Tangles (NFTs) dovetails with the increased activation of the Tau by the Corticotropin Releasing Hormone, to ultimately increase the likelihood of Alzheimer's.
Figure 9 reassembles all the pieces of the puzzle. It's important to note that this hypothesis is not saying that stress is the cause of Alzheimer's, but only that it increases the risk of this disease that results from many more (again, hypothesized) factors than can be included here, including environmental risk factors covered in this blog. Update: An article in the Aug 18, 2009 New York Times refers a recent study published in the prestigious journal Science about the effect of stress on the brain, including increasing the risk of Alzheimer's. Here is an abstract of the reseach upon which the article reports.



The article upon which this post centers:
[Pardon 2008] Pardon MC, Rattray I, What do we know about the long-term consequences of stress on ageing and the progression of age-related neurodegenerative disorders? Neuroscience & Biobehavioral Reviews, Volume 32, Issue 6, August 2008, Pages 1103-1120. PubMed

[Cansino.2008] Cansino S, Episodic memory decay along the adult lifespan: A review of behavioral and neurophysiological evidence, International Journal of Psychophysiology, 23 July 2008. ( PubMed

[Ryman 2006] Ryman D, Lamb BT, Genetic and Environmental Modifiers of Alzheimer’s Disease Phenotypes in the Mouse, Current Alzheimer Research, 2006, 3, 465-473. PubMed

. More Information: [ScienceDaily 2006] University of California - Irvine (2006, August 30). Stress Significantly Hastens Progression Of Alzheimer's Disease. ScienceDaily. Article

[Wolf 2003] Wolf, OT. HPA axis and memory, Best Practice & Research Clinical Endocrinology & Metabolism, Volume 17, Issue 2, June 2003, Pages 287-299. Abstract

[Cohen 2008] Cohen E, Dillin A, The insulin paradox: aging, proteotoxicity and neurodegeneration, Nature Reviews Neuroscience 9, 759-767 (October 2008) | doi:10.1038/nrn2474. Abstract

[Sotiropoulos 2008] Sotiropoulos I, Cerqueira JJ, Catania C, Takashima A, Sousa N, Almeida OF. Stress and glucocorticoid footprints in the brain-the path from depression to Alzheimer's disease. Neurosci Biobehav Rev. 2008 Aug;32(6):1161-73. PubMed

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