The orchestra plays a funeral march, and the conductor is not to blame for the choice of notes. But if he waves his baton more energetically, the music grows louder and the walls of the hall shake. Likewise, microglia, the brain's immune cells, don't start the disease, but they can turn a quiet fading into a collapse.
At center stage stands the hippocampus, the brain region responsible for memory. With age, it often shrinks, and scientists have long been looking for culprits. Two main suspects: Alzheimer's proteins (amyloid and tau) and TDP-43 protein, which accumulates in LATE disease. But the role of microglia remained unclear. They become activated in both cases, like a fire crew that responds to every call but sometimes soaks not only the fire but also the furniture.
To see the whole picture, the brain was scanned on a tomograph with a resolution of less than a millimeter, and then thin sections were stained with a special antibody that highlights microglia. A computer program counted the cells and divided them into resting and activated. Manual verification showed agreement in 93 out of 100 cases, meaning the machine wasn't hallucinating.
The result was unexpected. Microglial density by itself is almost unrelated to hippocampal volume when other pathologies are taken into account. But when TDP-43 accumulates, each additional unit of microglial density intensified atrophy by 0.019 conventional units. In other words, the conductor doesn't play himself, but when the orchestra performs that particular melody, his baton strikes the nerves.
The practical takeaway is simple: anti-inflammatory drugs may not help everyone, but only those whose brains are accumulating TDP-43. Today such patients can be identified only after death, but once life-time markers appear, treatment will become more precise. For now, the orchestra keeps playing, and we are learning to hear exactly where the conductor amplifies the sound.
The average age of participants at death was 90.1 years, and the average duration of education was 16 years. These are among the oldest and best-educated cohorts in the world.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.