Assessing the Merits of Trained Immunity via BCG Vaccination to Treat or Prevent Alzheimer's Disease
Vaccinations can produce a lasting effect known as trained immunity, altering the behavior of the innate immune system and resulting in both a reduction in the chronic inflammation of aging and a more effective immune response to unrelated infectious agents. Arguably the largest body of research into trained immunity involves the BCG vaccine for tuberculosis, widely used outside the United States. A lesser body of work examines the trained immunity effects of a small number of other vaccines that are more commonly provided to adults rather than children. For most vaccines, there is no human data, and trained immunity itself is well documented, but not well understood in detail. Here, researchers report on a small trial to assess the effects of BCG vaccination on older people with and without Alzheimer's disease, to see whether the changes produced by trained immunity are sizable enough to justify further trials and widespread use.
Immune aging may contribute to Alzheimer's disease. Bacillus Calmette-Guérin (BCG), a vaccine known to induce trained immunity, has been linked to reduced Alzheimer's risk in prior studies. However, whether trained immunity can be observed in the human central nervous system remains unclear. We conducted two related one-year, open-label clinical trials in adults aged 55 years or older (n = 12 without Alzheimer's-related pathology; n = 11 with Alzheimer's-related pathology) recruited at a single center. Participants received two intradermal BCG vaccinations one month apart.
We show that BCG induces persistent, trained immunity-like changes in immune cells in cerebrospinal fluid, including enhanced innate responsiveness and associated transcriptional programs. These responses differ from blood, suggesting compartment-specific immune imprinting. In participants without Alzheimer's-related changes, these immune shifts are accompanied by decreased amyloid-β levels in cerebrospinal fluid and increased levels in blood. BCG was well tolerated, with no unexpected safety signals observed. This approach may represent an early neurodegenerative intervention strategy, although larger controlled studies are needed to confirm these observations.