Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

Abstract

BCG vaccine has been used for 100 years to prevent tuberculosis. Not all countries, including the United States, adopted the initial World Health Organization recommendation to use BCG. Moreover, many Western countries that had routinely used BCG have discontinued its use. Recent population studies demonstrate lower prevalence of Alzheimer’s disease (AD) in countries with high BCG coverage. Intravesicular instillation of BCG is also used to treat bladder cancer that has not invaded the bladder muscle wall and has been shown to reduce recurrence. Several retrospective studies of bladder cancer patients demonstrated that BCG treatment was associated with a significantly reduced risk of developing AD. Plasma amyloid β assessment has become a fertile area of study for an AD biomarker that is predictive of a positive amyloid PET scan. Mass spectrometry-based plasma amyloid 42/40 ratio has proven to be accurate and robust, and when combined with age and ApoE, is shown to accurately predict current and future brain amyloid status. These parameters, amyloid 42/40 ratio, age and ApoE genotype are incorporated into an Amyloid Probability Score (APS)–a score that identifies low, intermediate or high risk of having a PET scan positive for cerebral amyloid. Community recruitment was used for this open-label pilot study. Forty-nine BCG-naïve, immunocompetent individuals completed our study: prior to BCG prime and boost, as determined by the APS, 34 had low risk (APS 0–35), 5 had intermediate risk (APS 36–57) and 10 had high risk (APS 58–100). The APS range for the participant group was 0 to 94. Follow-up plasma amyloid testing 9 months after vaccination revealed a reduction in the APS in all the risk groups: low risk group (p = 0. 37), intermediate risk group (p = 0.13) and the high-risk group (statistically significant, p = 0.016). Greater benefit was seen in younger participants and those with the highest risk. The small number of participants and the nascent status of plasma amyloid testing will rightfully temper embracement of these results. However, both the favorable direction of change after BCG as well as the utility of the APS—a valuable surrogate AD biomarker—may prompt a definitive large-scale multicenter investigation of BCG and AD risk as determined by plasma amyloid peptide ratios and APS.

BCG Vaccine—The Road Not Taken

“…These studies mirror investigations that show benefit of a variety of vaccinations in AD [ 78 , 79 , 80 , 81 , 82 ].…”

“…In a follow-up, multi-cohort study again it was shown that intravesicular BCG imparted a protective benefit against risk of AD; interestingly, it also showed protection against Parkinson’s disease [ 72 ]. A recent open-label, non-placebo-controlled study employing BCG in cognitively normal participants showed a reduction of AD risk as measured by plasma amyloid [ 78 ].…”

Vaccines and Dementia: Part II. Efficacy of BCG and Other Vaccines Against Dementia

“…In those who completed 9 months following vaccination, their APS scores revealed a reduction in all the risk groups, but of different statistical significances: low-risk group ( p = 0.37), intermediate-risk group ( p = 0.13), and the high-risk group (statistically significant, p = 0.016). Greater benefit was seen in younger participants and those with the highest risk [ 56 ].…”

Alzheimer’s disease and its treatment–yesterday, today, and tomorrow

“…Other herpetic vaccinations, for instance for shingles (varicella-zoster) have been associated with a 15% reduced risk of AD and other neurodegenerative diseases ( Lehrer and Rheinstein, 2022 ). A prospective study (albeit proof of concept with n = 49) with the Bacillus Calmette–Guérin (BCG) vaccine for tuberculosis has also provided positive data that will stimulate additional interest in the role of vaccines as a protection against AD ( Dow et al, 2022 ). Whether benefits are seen with COVID-19 vaccinations remains to be analysed.…”