Extra-cranial factors in the development of Alzheimer's disease

The development of Alzheimer's Disease (AD) likely involves dysfunction in more than one extra-cranial organ system. AD appears to depend on several functional organ impairments that develops frequently during aging: lack of normal hepatic synthesis, defective detoxification of ammonia, gut microbiome dysbiosis, the development of insulin resistance, diminished adrenal production of dehydroepiandrosterone, nutrient depletion, impaired immune processes with persistent chronic neuro-inflammation, and persistent infectious processes are important components of this system-wide disorder. By reviewing these abnormalities in different organ systems, this review intends to suggest that clinical research into the prevention of dementia needs to take this interplay of organ system dysfunction into account. The design of therapeutic interventions needs to address dysfunction in more than one system at a time. We have singled out one aberrant signaling pathway, NF-kB, that seems common to several of the dysfunctional organ systems and suggest some potential interventions that may be effective when combined with others. Clinical research may need to shift from single factor interventions to studies that include multiple simultaneous interventions that restore health in multiple impaired organ systems in the aging human in order to avert future epidemics of AD.