The pathophysiology of Alzheimer’s disease (AD) is based on the amyloid hypothesis: in the brain, the accumulation of amyloid proteins (Aß) and an overproduction of tau proteins leading to neurofibrillary tangles lead to synaptic dysfunctions, neuronal inflammation, neuronal loss and, ultimately, cognitive impairment and dementia. Research has long focused on contributing genetic and lifestyle factors. In recent years, another hypothesis has emerged, highlighting the role of infections in the onset of the disease. It was the subject of a virtual symposium in the United States (“ New Approaches for Understanding the Potential Role of Microbes in Alzheimer’s disease “, organized by The Duke/University of North Carolina (Duke/UNC) Alzheimer’s Disease Research CenterMay 16, 2023), an account of which was recently published in Brain, Behavior & Immunity – Health.
The formation of amyloid plaques would have as its starting point a protective mechanism against pathogens that have managed to cross the blood-brain barrier, by encapsulating them to neutralize them. This would induce abnormalities in the formation of tau proteins, activation of microglial cells and inflammatory reactions. In short, all of these phenomena would be a defective defense mechanism against a viral or microbial infection: this would be effectively blocked, but at the cost of neuronal loss. These processes would nevertheless have been preserved during evolution because they effectively protect against brain infections, cellular degeneration taking time in humans who rarely reached advanced ages.
The infectious hypothesis is supported by several arguments:
- Viral (herpes virus in particular) and microbial (salmonella) transposons have been identified in neuronal cultures from mouse models of AD.
- COVID-19 frequently manifests with neurological disorders and the disease may be associated with a higher probability of AD than in unaffected subjects.
- Cytomegalovirus infections are associated with an increased risk of AD and rapid cognitive decline in adults.
- It is very likely that anti-infection vaccines reduce the risk of AD and other dementias, by reducing the intensity of specific and non-specific immune mechanisms upon the intrusion of a pathogen into brain tissue.
- Age affects immune protection mechanisms and cell renewal. Thus, infections are the main cause of mortality in metazoans (which include humans) and their frequency increases with age, as does the probability of being affected by AD.
Even intestinal flora could play a role, without microbial penetration into brain tissue. Indeed, Gram- bacteria release lipopolysaccharides capable of crossing the endothelial wall of brain capillaries and then attaching to neurons, thus triggering a series of immune reactions similar to those described at the origin of AD.
No speaker at the symposium presented the infectious hypothesis as the exclusive mechanism underlying AD. But they call for serious consideration: in certain cases, the accumulation of amyloid proteins comes from defense processes against infection, conserved by evolution. These processes themselves are not unambiguous, but varied. In any case, a vast field of research is open.
