Metadata

• Authors: Lesha Pretorius, Douglas B Kell, Etheresia Pretorius
• Publication Date: November 16, 2018
• Journal/Source: Frontiers in Neuroscience
• URL: 10.3389/fnins.2018.00851

Abstract

Alzheimer’s disease and other similar dementias are debilitating neurodegenerative disorders whose etiology and pathogenesis remain largely unknown, even after decades of research. With the anticipated increase in prevalence of Alzheimer’s type dementias among the more susceptible aging population, the need for disease-modifying treatments is urgent. While various hypotheses have been put forward over the last few decades, we suggest that Alzheimer’s type dementias are triggered by external environmental factors, co-expressing in individuals with specific genetic susceptibilities. These external stressors are defined in the Iron Dysregulation and Dormant Microbes (IDDM) hypothesis, previously put forward. This hypothesis is consistent with current literature in which serum ferritin levels of individuals diagnosed with Alzheimer’s disease are significantly higher compared to those of age- and gender-matched controls. While iron dysregulation contributes to oxidative stress, it also causes microbial reactivation and virulence of the so-called dormant blood (and tissue) microbiome. Dysbiosis (changes in the microbiome) or previous infections can contribute to the dormant blood microbiome (atopobiosis1), and also directly promotes systemic inflammation via the amyloidogenic formation and shedding of potent inflammagens such as lipopolysaccharides. The simultaneous iron dysregulation and microbial aberrations affect the hematological system, promoting fibrin amylodiogenesis, and pathological clotting. Systemic inflammation and oxidative stress can contribute to blood-brain barrier permeability and the ensuing neuro-inflammation, characteristic of Alzheimer’s type dementias. While large inter-individual variability exists, especially concerning disease pathogenesis, the IDDM hypothesis acknowledges primary causative factors which can be targeted for early diagnosis and/or for prevention of disease progression.

Key Findings

• Alzheimer’s type dementias may be triggered by external environmental factors in individuals with genetic susceptibilities.
• The Iron Dysregulation and Dormant Microbes (IDDM) hypothesis highlights the role of iron dysregulation and microbial reactivation in Alzheimer’s disease.
• Serum ferritin levels are significantly higher in Alzheimer’s patients, linked to oxidative stress, systemic inflammation, and pathological clotting.

Notes

• The paper proposes the IDDM hypothesis as a coherent explanation aligning with observed higher serum ferritin levels in Alzheimer’s patients.
• Increased oxidative stress due to iron dysregulation can lead to microbial reactivation, which in turn promotes systemic inflammation and contributes to Alzheimer’s pathogenesis.
• Understanding these underlying mechanisms can aid in developing strategies for early diagnosis and prevention.