Abelard Lindsay

Spouses of Alzheimer's patients are 6 times more likely to develop Alzheimer's themselves. They share daily saliva exchange for decades. Their oral bacteria converges to the same strains. In 2019 Cortexyme published a paper in Science Advances showing Porphyromonas gingivalis, the bacterium behind gum disease, was present in over 90% of postmortem Alzheimer's brains. They also found its DNA in the cerebrospinal fluid of living Alzheimer's patients. P. gingivalis is the keystone pathogen of periodontitis. The CDC says 47% of American adults over 30 have periodontitis right now. The mechanism is specific. P. gingivalis produces enzymes called gingipains. Two types: one cuts proteins at lysine residues, the other at arginine. Tau, the protein that holds your neuronal scaffolding together, is loaded with both amino acids. In cell culture, gingipains shred soluble tau within one hour of infection. The fragments seed the paired helical filaments that become tangles. Tangles are Alzheimer's. Mice fed P. gingivalis through the mouth grew amyloid plaques in their brains. Hippocampal neurons died. The bacteria crossed the blood-brain barrier and started chewing through the same proteins that fail in human Alzheimer's patients. Cortexyme built a drug called atuzaginstat to block gingipains. Phase 1 was clean. They ran a 643-patient Phase 2/3 trial called GAIN. The FDA hit it with a partial clinical hold for liver toxicity. The drug missed both primary endpoints. In August 2022 Cortexyme shut the program down, renamed itself Quince, and pivoted to bone disease. The subgroup with the highest baseline P. gingivalis loads still showed cognitive improvement on secondary endpoints. The bacteria itself kept showing up in postmortem brains across independent studies after the trial closed. Periodontal disease shows up 10 to 20 years before cognitive symptoms in people who later develop Alzheimer's. By the time someone forgets a name, the bacteria has been working for two decades. The intervention point is upstream of your skull.

The math on this project should mass-humble every AI lab on the planet. 1 cubic millimeter. One-millionth of a human brain. Harvard and Google spent 10 years mapping it. The imaging alone took 326 days. They sliced the tissue into 5,000 wafers each 30 nanometers thick, ran them through a $6 million electron microscope, then needed Google’s ML models to stitch the 3D reconstruction because no human team could process the output. The result: 57,000 cells, 150 million synapses, 230 millimeters of blood vessels, compressed into 1.4 petabytes of raw data. For context, 1.4 petabytes is roughly 1.4 million gigabytes. From a speck smaller than a grain of rice. Now scale that. The full human brain is one million times larger. Mapping the whole thing at this resolution would produce approximately 1.4 zettabytes of data. That’s roughly equal to all the data generated on Earth in a single year. The storage alone would cost an estimated $50 billion and require a 140-acre data center, which would make it the largest on the planet. And they found things textbooks don’t contain. One neuron had over 5,000 connection points. Some axons had coiled themselves into tight whorls for completely unknown reasons. Pairs of cell clusters grew in mirror images of each other. Jeff Lichtman, the Harvard lead, said there’s “a chasm between what we already know and what we need to know.” This is why the next step isn’t a human brain. It’s a mouse hippocampus, 10 cubic millimeters, over the next five years. Because even a mouse brain is 1,000x larger than what they just mapped, and the full mouse connectome is the proof of concept before anyone attempts the human one. We’re building AI systems that loosely mimic neural networks while still unable to fully read the wiring diagram of a single cubic millimeter of the thing we’re trying to imitate. The original is 1.4 petabytes per millionth of its volume. Every AI model on Earth fits in a fraction of that. The brain runs on 20 watts and fits in your skull. The data center required to merely describe one-millionth of it would span 140 acres.