Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy Can immunization with Bacillus Calmette-Guérin (BCG) protect against Alzheimer’s disease? Ofer N. Gofrit a,d, ⁎ , Herve Bercovier b,d , Benjamin Y. Klein b,d , Irun R. Cohen c,d , Tamir Ben-Hur c,d , Charles L. Greenblatt b,d a Department of Urology, Jerusalem, Israel b Department of Microbiology and Molecular Genetics, Hebrew University-Hadassah Faculty of Medicine, Jerusalem, Israel c Department of Immunology, Weizmann Institute, Rehovot Israel, Rehovot, Israel d Department of Neurology, Hadassah – Hebrew University Medical Center, Jerusalem, Israel ABSTRACT Alzheimer’s disease (AD) is a neurodegenerative disorder which is the most prevalent cause of dementia in the western world. Currently, it is the most expensive disease in America, costing more than heart diseases and cancer and as the world population is getting older it is expected to become the most expensive medical disorder in the world. AD is characterized by three core pathologies: accumulation of amyloid β (Aβ) plaques, neurofibrillary tangles (NFT) and sustained in- flammation. It is now believed that inflammation provides the link between Aβ and NFT. The immune system is therefore, a major player in the pathogenesis of AD. Here we propose that Bacillus Calmette-Guérin (BCG) could affect the incidence of AD. Bacillus Calmette-Guérin (BCG) is a live attenuated Mycobacterium bovis preparation first developed as a vaccine against M. tuberculosis. It has been shown to be moderately effective in preventing tuberculosis, while noted to induce modifications in inflammatory response and to regulate the immune system. Intra-vesical administration of BCG is used successfully in the past four decades to prevent recurrence of non-muscle invasive bladder cancer. In this manuscript we investigate the hypothesis that exposure to BCG decreases the prevalence of AD in elderly population and that this occurs through modulation of the immune system. Our hypothesis is based on several lines of evidence: lower prevalence of AD in countries with high BCG coverage, ability of BCG to ameliorate several conditions involving the immune system like type 1 diabetes mellitus and multiple sclerosis, animal models of AD in which BCG shows therapeutic potential and a plausible molecular mechanism which may be the basis for this hypothesis. Namely, elevated systemic levels of IL-2 (as found when BCG is given intra-vesically) that amplify Treg cells that inhibit AD associated inflammation, decreased plaque formation and restore cognitive function. To test this hypothesis one may study cognition in the large available “natural adult population” exposed to high dose of BCG through the bladder. Bladder cancer survivors not given BCG can serve as control group. This population can be used without adding any medical intervention. Alzheimer’s disease Alzheimer’s disease (AD) is the major cause of chronic progressive dementia in the western world accounting for 60–70% of all cases of dementia. It currently affects over 5 million Americans [1] and as the number of people older than 65 is expected to triple between 2000 and 2030 the prevalence of AD is expected to rise accordingly. As a result, the cost of AD care to Medicare and Medicaid is expected to rise from 186 billion dollar in 2018 to 750 billion in 2050 [2]. AD is marked by several characteristic brain pathological features including the accumulation of amyloid β (Aβ) plaques and neurofi- brillary tangles (NFT) and sustained inflammation [3]. It is now be- lieved that inflammation is not just a response of the immune system to neuronal loss but a major player in AD pathogenesis. The current ac- cepted role of the immune system in AD is as follows: the presence of Aβ activates microglia cells. They migrate and phagocytiz the Aβ. Early in AD development this process clears the Aβ but later, the microglia are no longer able to process the Aβ. This leads to a condition of sus- tained activation termed “reactive microgliosis”. The results of this process are the sustained production of pro-inflammatory cytokines and neurotoxins. While the ability of the microglia to process the Aβ de- creases, their immune activation abilities persist. Thus a continuous loop of neurotoxicity and response to neurotoxicity perdures. In later stages of AD peripheral macrophages are also recruited to the brain further amplifying the pathology. Multiple immune cells and cytokines participate in AD. Worth mentioning are the CD4 + CD25 + Foxp3 + regulatory T cells (Treg). They represent a small proportion of the total lymphocyte population that can regulate immune response critical for maintenance of self-tolerance [4]. These cells have a neuroprotective effect shown in animal models of AD [5]. The key cytokines partici- pating in AD include the pro-inflammatory TNF-α, IL-1β and the double action cytokine IL-6 that in low levels reduces microglia activity and in https://doi.org/10.1016/j.mehy.2019.01.007 Received 22 November 2018; Accepted 10 January 2019 ⁎ Corresponding author at: Department of Urology, Hadassah Hebrew University Hospital, POBox 12000, Jerusalem 91120, Israel. E-mail address: roferg@hadassah.org.il (O.N. Gofrit). Medical Hypotheses 123 (2019) 95–97 0306-9877/ © 2019 Elsevier Ltd. All rights reserved. T