The Next Alzheimer’s Treatments May Spur the Brain to Protect Itself

Niels Plath, chief scientific officer, Muna Therapeutics

The Alzheimer’s research community has tried for decades to get rid of amyloid plaques in the brain, in hopes of slowing down or preventing the memory-robbing disease. But amyloid might not be an insurmountable enemy after all.

A remarkable group of people whose ability to resist the cognitive decline of Alzheimer’s was, until recently, completely invisible. These were individuals who lived long, cognitively healthy lives despite their brains harboring the very amyloid plaques we have long considered to be a death sentence.

Advances in our scientific toolkit made it possible to study postmortem brain tissue directly. And this wasn’t a rare fluke; the finding of plaques in healthy people appeared again and again. It was the first real evidence of a bona fide, innate mechanism of resilience in the brain–an ability to thrive despite what looks like a devastating tangled web of amyloid plaques.  

This concept was powerfully reinforced by the astonishing finding that a rare genetic variant (the “Christchurch mutation”) can protect individuals from dementia, even when they carry a mutation in a different gene PSEN1 (presenilin 1) that would otherwise spell certain doom.

That discovery was made in a single individual back in 1987, but the significance wasn’t fully appreciated by the scientific community until more evidence buttressed the finding in 2019 and 2024. The question began to shift from ‘How do we clear the plaques?’ to the far more profound ‘How do these brains successfully fight back?’

The idea of being resilient to disease is common in immunology, where we credit a ‘stronger immune system’ for protecting our bodies from the invasion and spread of bugs. This concept is more nuanced in areas like oncology and neurodegeneration. What does resilience mean in an Alzheimer’s context?

A recent landmark study published in Nature provides a credible blueprint for what this resilience looks like at a molecular level. It was a signpost, providing concrete, human-derived data that proves that we can, in fact, identify biological pathways that protect the brain.

Researchers at Harvard Medical School analyzed human brains with single-cell RNA-seq resolution, and discovered that, of 27 different metals measured in brain cells, the brain’s innate level of lithium was the one most relevant to Alzheimer’s. Lithium levels were significantly reduced in individuals with mild cognitive impairment, a precursor to Alzheimer’s. The study revealed that amyloid plaques act like sponges, sequestering the brain’s natural lithium and reducing its bioavailability.

Further experiments in mouse models confirmed this link: reducing lithium levels by about half markedly accelerated the deposit of amyloid and tau, activated inflammation and sped up cognitive decline. Aging-related decline in learning and memory was largely reversed by treatment with lithium. In normally aging humans, the study showed that higher natural lithium levels were positively correlated with better scores on cognitive tests, offering a direct molecular link to cognitive resilience.

This is not a lifestyle fad; it is rigorous molecular biology revealing key pathways that offer actionable therapeutic targets. Lithium orotate, a salt with reduced amyloid binding, could be given as a replacement therapy. This insight – that we can perturb brains to overcome what looks like a disease pathology — stems directly from our new technological tools that have made it possible to ask and answer questions at an unprecedented speed and volume.

The tools that enable us to study these mechanisms are only just becoming widely available to neuroscientists. Single-cell RNA-seq, and spatial transcriptomics are a couple examples.

This is the most auspicious time to be studying the basic pathophysiology of Alzheimer’s disease and other neurodegenerative disorders. Progress in Alzheimer’s has been stymied by the lack of critical tools to interrogate cells and molecular mechanisms in the human brain itself. We have been forced to translate our findings across from mouse models, where these animals do not even experience Alzheimer’s disease.

To build on this newfound momentum, we must wage a collective campaign to amass, harmonize, and share our data.

The alternative is to let it sit idle and unconnected to today’s fervent research efforts. Brilliant research, including the discovery of the Christchurch mutation, the recent lithium study, and the continued characterization of key brain cells in neurodegeneration, has opened a door.

But to walk through it, we must confront the critical bottleneck: the scarcity and siloing of brain tissue samples and the rich clinical metadata from the individuals who donated them. Without large-scale data sharing and analysis, we will be stuck looking at samples that might represent a few anecdotes. We might miss the larger patterns that could point to promising therapeutic targets.

For decades, our goal was to wage a defensive war against damage. Now, we have a more profound and promising path forward: harnessing the body’s innate, protective mechanisms leading to resilience. The future of Alzheimer’s therapy may not be a drug that simply fights the disease, but one that empowers the brain to protect itself.