Beyond the Alzheimer's Research Fraud

After 19 years dominated by fraudulent studies, we may finally be making progress against Alzheimer's disease.

Scientists haven’t made much progress against Alzheimer’s disease in this century, in part because of apparent widespread fraud. From the New York Times opinion section last winter:

The Devastating Legacy of Lies in Alzheimer’s Science

By Charles Piller

Mr. Piller is an investigative journalist for Science. This essay is adapted from his upcoming book, “Doctored: Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s.”

Jan. 24, 2025

… Yet despite decades of research, no treatment has been created that arrests Alzheimer’s cognitive deterioration, let alone reverses it. That dismal lack of progress is partly because of the infinite complexity of the human brain, which has posed insurmountable challenges so far. Scientists, funders and drug companies have struggled to justify billions in costs and careers pursuing dead-end paths. But there’s another, sinister, factor at play.

Over the past 25 years, Alzheimer’s research has suffered a litany of ostensible fraud and other misconduct by world-famous researchers and obscure scientists alike, all trying to ascend in a brutally competitive field. During years of investigative reporting, I’ve uncovered many such cases, including several detailed for the first time in my forthcoming book. …

For decades, Alzheimer’s research has been shaped by the dominance of a single theory, the amyloid hypothesis. It holds that amyloid proteins prompt a cascade of biochemical changes in the brain that cause dementia.

Some skeptics, however, wonder whether amyloid proteins are the rubble rather than the bomb.

The supremacy of that hypothesis has exerted enormous pressure toward scientific conformity.

Even many of the most hardened skeptics of the hypothesis believe that amyloids have some association with the disease. But since the early 2000s, doctors, patients and their loved ones have endured decades of therapeutic failures stemming from it, despite billions of dollars spent in grants and investments. …

Still, the hypothesis retains enormous influence. Nearly every drug approved for Alzheimer’s dementia symptoms is based on it, despite producing meager results. The anti-amyloid antibody drugs approved in the United States cost tens of thousands of dollars per patient per year, yet they slow cognitive decline so minutely that many doctors call the benefits imperceptible. The drugs are also not benign, posing risks of death or serious brain injury, and they can shrink the brain faster than Alzheimer’s itself.

The entrenchment of the amyloid hypothesis has fostered a kind of groupthink where grants, corporate riches, career advancement and professional reputations often depend on a central idea largely accepted by institutional authorities on faith. It’s unsurprising, then, that most of the fraudulent or questionable papers uncovered during my reporting have involved aspects of the amyloid hypothesis. It’s easier to publish dubious science that aligns with conventional wisdom. …

Was this a conscious conspiracy?

Or was it a lot of careerists finding themselves unable to replicate the most prestigious results, so they individually altered their studies’ images to make them look valid, not realizing that the gold standard images they were following had had a thumb on the scale too?

That’s a rather nightmarish scenario.

Marc Tessier-Lavigne, the former president of Stanford University, was known as a global leader in research on the brain’s circuitry in Alzheimer’s and other neurological conditions. He resigned in 2023 after an intrepid student journalist revealed numerous altered images in his research. Dr. Tessier-Lavigne didn’t personally falsify data or coerce junior colleagues to do so. But he failed to correct dubious results that came to his attention and may have provided inadequate oversight of his lab — allowing apparently doctored studies that helped build his reputation to remain on the scientific record, according to an investigation by a special committee appointed by the university’s board of trustees. …

Since the amyloid hypothesis became dominant in 2006 due to a doctored study, a lot of other potential treatments have been given short shrift for research dollars.

But here’s a new study in Nature based on a whole new theory of the cause of Alzheimer’s — lithium deficiency — that could be promising:

06 August 2025

Lithium deficiency and the onset of Alzheimer’s disease

Liviu Aron, Zhen Kai Ngian, Chenxi Qiu, Jaejoon Choi, Marianna Liang, Derek M. Drake, Sara E. Hamplova, Ella K. Lacey, Perle Roche, Monlan Yuan, Saba S. Hazaveh, Eunjung A. Lee, David A. Bennett & Bruce A. Yankner

Nature (2025)

Abstract

The earliest molecular changes in Alzheimer’s disease (AD) are poorly understood. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Of the metals we analysed, Li was the only one that was significantly reduced in the brain in individuals with mild cognitive impairment (MCI), a precursor to AD. Li bioavailability was further reduced in AD by amyloid sequestration. We explored the role of endogenous Li in the brain by depleting it from the diet of wild-type and AD mouse models. Reducing endogenous cortical Li by approximately 50% markedly increased the deposition of amyloid-β and the accumulation of phospho-tau, and led to pro-inflammatory microglial activation, the loss of synapses, axons and myelin, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3β. Single-nucleus RNA-seq showed that Li deficiency gives rise to transcriptome changes in multiple brain cell types that overlap with transcriptome changes in AD.

Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice. These findings reveal physiological effects of endogenous Li in the brain and indicate that disruption of Li homeostasis may be an early event in the pathogenesis of AD. Li replacement with amyloid-evading salts is a potential approach to the prevention and treatment of AD.