Do we have Alzheimer’s disease all wrong?

Plus: Post Malone is everywhere, 30% of US food ends up wasted, and more. June 17, 2024 [View in browser]( Welcome back! Today, senior correspondent Dylan Scott is here to talk about the maddening state of Alzheimer's research. —Caroline Houck, senior editor of news   [brain image] Getty Images Where is our Alzheimer’s cure? Every step toward [an effective Alzheimer’s treatment]( seems to be followed by another step back. It’s hard not to feel as if we are running in place, as millions of patients and their families suffer through one of the most harrowing diseases known to humanity. We went through that two-step again over the past two weeks when the retraction of a landmark study was followed by federal scientific advisers [endorsing]( a new treatment. This treatment has led to modest clinical improvements for patients but also comes with the same safety concerns that have dogged other recent drug candidates. The authors of the retracted paper in question, which was published in Nature in 2006 and claimed to identify a specific target for future drug development, [agreed to withdraw their research in full](, two years after [a stunning investigation by Science]( found that key images had been doctored. The retraction adds to the crisis of confidence in scientific research overall, which my colleague Kelsey Piper has [documented]( [extensively](. As Science [noted]( last week, the Alzheimer’s study is [among the most cited papers]( ever to be retracted after accumulating nearly 2,500 citations over the past 18 years. The 2006 paper had appeared to be an important breakthrough in our understanding of how Alzheimer’s works, providing the precise mechanisms that undergirded the prevailing theory of the disease. But that was, as we now know, a fraudulent discovery. Instead, the retraction adds to the nagging doubts that we may be somehow misunderstanding this most pernicious of afflictions. [computer showing mri brain scans] Brian B. Bettencourt/Toronto Star via Getty Images The amyloid hypothesis has struggled to translate into effective treatments When I saw the news about the decision to retract the Nature paper, I thought of two people: [Sharon Begley](, my former colleague at STAT who is sadly no longer with us, and Sarah Gilbert, the daughter of a mother with Alzheimer’s whom I connected with three years ago amid another Alzheimer’s research controversy. I thought of Begley because in 2019 she published [an incisive investigation into the stagnant state of Alzheimer’s research]( that cuts to the core of the Nature paper’s retracted findings. For years, since the 1990s, the field has been dominated by the so-called amyloid hypothesis. To keep it simple: Scientists noticed that people with Alzheimer’s had a lot of plaque in their brains primarily made up of amyloid proteins. They theorized that this build-up could be responsible for Alzheimer’s uniquely devastating symptoms, which over time will rob a person of their very identity and always lead to death. The 2006 Nature paper had purported to identify the exact amyloid protein in question, offering in theory a more specific target for future therapies. Research and drug development have been targeting for years those amyloid plaques and aiming to wipe them out, reducing or even reversing the person’s cognitive decline. The problem, as Begley documented, is that those efforts struggled to yield promising results. Even as science made exciting progress treating cancer and heart disease, Alzheimer’s research stayed stuck in the mud. Her investigation revealed an institutional inertia that dismissed any alternative theories of the disease and quashed funding that might support outside-of-the-box investigations. Is it possible a different approach to treating the disease might lead to more impressive clinical improvements, as Begley’s story suggested? We still don’t know. Last week, donanemab, which targets amyloid plaque, received a recommendation for FDA approval from the agency’s scientific advisers, but it was [not an unqualified one](. As Science noted in [its story on the retracted paper](, scientists are still debating whether the amyloid theory is viable. The skeptics cite the fraudulent research and lack of a genuine breakthrough; supporters can point to this new class of drugs including donanemab that have led to some improvement in some patients. [scientist holding a blood sample during a clinical trial with a MRI on screen] Getty Images We need a better strategy for finding Alzheimer’s treatments In 2019, Begley mentioned a failed drug that appeared to be an avatar for the amyloid hypothesis’s shortcomings: aducanumab. Biogen, the drug’s developer, had halted clinical trials because of the scant evidence of its effectiveness and the risk of dangerous side effects. Two years later, that same drug created the next crisis of confidence in Alzheimer’s research. Biogen, with questionable assistance from the FDA and some statistical skullduggery I won’t bore you with, had changed its position. It identified a subset of patients who did appear to see a slower cognitive decline while taking aducanumab and decided that was enough to seek FDA approval. The federal agency responsible for safeguarding patients from ineffective — or worse, dangerous — drugs agreed. And aducanumab, branded as Aduhelm, was approved. But news of the first FDA-approved drug that claimed to slow the progress of Alzheimer’s disease, which you’d think would be greeted with jubilation, instead sparked a firestorm. Those questionable methods used to justify its approval were criticized by doctors, nurses, and others, including family and friends, who care for patients. The upside seemed marginal, while the risks — specifically serious brain bleeding — were harrowing. It was in [reporting on the fallout of Aduhelm’s approval]( that I met Sarah Gilbert. Her mom had recently been diagnosed. And now she had to endure the whiplash of being promised a breakthrough treatment only to learn it was no such thing. “It was like having the rug pulled out from under you because you want some hope,” she told me at the time. In the years since, new drugs based on the same theory of the disease have followed — with somewhat better clinical results but persistent safety concerns. Leqembi was [approved]( in 2023. Donanemab now has FDA approval. [More drugs]( are in the pipeline that appear to be effective at eliminating the amyloid plaques but have undetermined clinical efficacy and safety profiles. Any progress is welcome. Alzheimer’s disease afflicts around 6.7 million Americans and [nearly 50 million]( may be living with preclinical iterations of the disease. So many people need help. But as America’s population ages, and the number of Alzheimer’s patients grows with it, we don’t need an either/or approach to finding a cure. We need an all-of-the-above strategy. Researchers like the University of Pittsburgh’s Karl Herrup have [argued]( for a fundamental overhaul of how we approach the disease. It’s long overdue. —[Dylan Scott, senior correspondent](   [Listen]( Will LGBTQ voters come out for Biden? The LGBTQ+ voting bloc has traditionally favored Democrats, but as Vox's Christian Paz explains, this year their support may be slipping. California Rep. Robert Garcia says the Biden campaign is on it. [Listen now](   CULTURE - Why is Post Malone seemingly everywhere?: An investigation into this summer’s hottest musical collaborator. 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