Alzheimer's as the Endpoint of a Life-Long Burden of Infectious Disease
The long years of failure in Alzheimer's research, in which trial after trial of immunotherapies targeting amyloid-β produced no meaningful benefits in Alzheimer's patients, has sown the seeds of change in the research community. In the past couple of years, promising human data for amyloid-β clearance has finally arrived, but the damage is done. The amyloid hypothesis for Alzheimer's disease is now challenged, and alternative theories are thriving. One of particular note is built upon the point that generation of amyloid in the brain appears to be a defensive mechanism of the innate immune system, and thus its proponents see Alzheimer's as the end result of persistent infection, such as by herpesviruses or the bacteria of lyme disease.
In this view of the world, Alzheimer's is just another of the many unpleasant late consequences of a high disease burden sustained throughout life. We are, after all, far better off than our recent ancestors thanks to increased control over infectious disease. Chronic inflammation and other consequences of the burden of parasitism and infectious disease resulted in earlier frailty in later life and shortened life expectancy until the advent of widespread antibiotics and other, similarly influential 20th century medical advances. Nonetheless, many infectious agents remain uncontrolled or poorly controlled - the ones whose effects are sufficiently subtle and slow to have evaded early notice. Numerous herpesviruses have few to no immediate symptoms, but may be slowly corroding the immune system or other aspects of our biology over the years, as cytomegalovirus is thought to do.
Why do only some people develop full blown Alzheimer's disease, while others never progress beyond the symptoms of mild cognitive impairment? Those researchers who favor an infectious disease model would say that it is because only some people carry a high burden of the most relevant infectious agents, such as lyme spirochetes. It is a compelling argument in many ways.
Historically, infectious diseases were the cause of morbidity and mortality. Infectious disease arguably continues to be the major driver of morbidity and mortality however this connection is largely ignored because of the occult nature of many of the causative agents and the cryptic cause and effect between organism and disease. The concept of evolutionary fitness actually points to infection as being the major cause of disease in modern society. Genetic traits that may be unfavorable to an organism's survival or reproduction do not persist in the gene pool for very long. Natural selection weeds them out and any inherited disease or trait that has a serious impact on fitness must fade over time. Therefore, when diseases have been present in human populations for many generations and still have a substantial negative impact on people's fitness, they are likely to have infectious causes.
Immune system vitality may be the most important risk factor in any chronic disease including Alzheimer's. Apart from symbiotic coexistence of human with micro-organisms, disease causing organisms breed in man-made unhygienic conditions of air water and soil. People with low immunity, weak, and living in unhygienic conditions are at greater risk for contracting the infections from surroundings. This model of disease fits equally well with Alzheimer's and other chronic diseases but has been limited because source of the infection is less obvious and diagnosis is not frequently enough made or considered.
Chronic inflammation is considered a cause of chronic disease, including Alzheimer's. Chronic inflammation continues to be blamed for tissue damage but this complex cascade, stimulated by internal and external mediators, results in the release of danger signals that promote immune responses to antigens. Chronic, occult infection is a significant stimulator of chronic inflammation. Any chronic disease, then, is potentially a measure of the stress on the biological system and its ability, or lack thereof, to cope.
Chronic disease incidences, including Alzheimer's, increases with older age and are linked to immunosenescence. Numerous studies show that the pathology of Alzheimer's disease is present decades before a clinical diagnosis of dementia can be made. Predisposition to Alzheimer's, therefore, is established prior to the acceleration of immunosenescence that starts around age 65. The vulnerability to disease due to an immature immune system during the ages 0-5 is also relevant. It is during these times that the antecedents of Alzheimer's and other chronic diseases, specifically occult infections, may opportunistically infiltrate such vulnerable hosts only to express as disease across the spectrum of time and lead to the a significant upswing in Alzheimer's.