A Proposal to Evaluate the Effect of Bacillus Calmette-Guérin Vaccination on Alzheimer’s Disease Development

Alzheimer’s disease (AD) pathology comprises the accumulation of incorrectly folded proteins accompanied by oxidative stress and sustained inflammation that result in a neurodegenerative disease. This pathological process develops in the brain starting approximately 20 years before the appearance of symptomatic dementia. These years should be regarded as an incubation period of a deadly condition. Mounting evidence suggests that early intervention increases the likelihood of obtaining a significant disease-modifying effect.  

More and more data argue for the critical role of the immune system in the course of AD. The Bacillus Calmette-Guérin (BCG) vaccine, through its immune-modulation properties, may prevent the development of AD. Indeed, the BCG vaccine seems to reduce dramatically (by 30% to 50%) the risk of dementia in elderly patients with bladder cancer who were treated with multiple BCG instillations. These historical retrospective studies in bladder cancer patients need to be challenged by a prospective interventional study in the aging population who are at risk for developing Alzheimer’s dementia. This population will receive the BCG vaccine via the commonly used nonaggressive intradermic route (jab/shot). Currently, the lack of any significantly disease-modifying drug in AD urges us to test whether BCG can be a significant player in preventing, or at least postponing, AD.  

As various brain pathologies can cause dementia, the use of specific and early biomarkers of AD for selecting a proper aging population without cognitive impairment yet is essential to evaluate any intervention. Recently evaluated blood markers like phosphorylated-tau (p-tau) levels seem to specify preclinical AD, especially when combined with the determination of another blood marker, the amyloid beta 42/40 ratio. By evaluating these blood markers in a selected aging population, we will identify individuals with preclinical AD—those who display underlying Alzheimer’s disease brain pathology while they still are cognitively intact.  

This proposal aims to evaluate, in a small population (60 individuals) who is potentially at risk for AD: (i) whether BCG safely delivered in the skin will, during a follow-up of two years, stabilize or slow down the progression of the levels of these blood markers indicating a reduced risk of developing AD, and (ii) whether it will impact the appearance of mild cognitive impairment, thereby providing additional evidence that AD is delayed significantly or even prevented. If the data obtained is promising, it will be the basis for a larger control clinical trial in the near future.