Neurodegenerative Disease Research

Alzheimer’s is personal for me. I think of my dad and his impact on my life all the time. That’s one of the reasons I’m excited about the investments we’re making to accelerate Alzheimer’s R&D, particularly by enabling more data sharing and global collaboration among researchers. Recently, our partners at the Alzheimer's Disease Data Initiative surveyed Alzheimer’s researchers at AAIC24 to learn what they’re most excited about—and what they view as the greatest barriers to progress. Their responses were interesting. Researchers are excited about the potential for new therapeutics and diagnostic tools, including blood-based biomarkers. They believe we need to break down barriers to data access, data sharing, and global research collaboration across academia, research agencies, and pharmaceutical companies to continue to drive and accelerate breakthroughs. I agree.   The potential for AI and machine learning to speed up Alzheimer’s research is also something that excites me. In the next couple months, the ADDI will be launching applications for a fellowship cohort with this exact focus. I’m eager to see how all these efforts will help us make even more progress and eventually find a cure. 

𝗕𝗿𝗲𝗮𝗸𝘁𝗵𝗿𝗼𝘂𝗴𝗵 𝗶𝗻 𝗡𝗲𝘂𝗿𝗼𝗹𝗼𝗴𝘆: Gene Therapy Slows Huntington’s Disease👇 Jack May-Davis, 30, always knew he carried the gene for Huntington’s - a devastating hereditary brain disease that claimed his father and grandmother. Then came a breakthrough. Jack joined a pioneering clinical trial led by Professors Sarah Tabrizi and Ed Wild at UCL. 👉 Using advanced gene therapy, a specially designed virus was delivered into his brain to reduce the toxic huntingtin protein that destroys neurons. Early trial data from UniQure, the developer, shows Huntington’s disease progression slowed by up to 75% which is astonishing. Jack, who was previously at risk of losing mobility, has regained function, is walking longer distances, and even returning to work. Great to see gene therapy impacting neurodegenerative diseases. UniQure plans to apply for US approval for the gene therapy in early 2026. Congrats to Jack and UniQure along with the HD community! #neurology #biotech #genetherapy #CGTweekly

Nine in ten drug programs that enter the clinic fail, most often when we first test for efficacy - when the mechanism did not drive the disease. The best-validated fix has been known for a decade: targets with human genetic support are 2 to 4 times more likely to succeed in the clinic. Yet only 3.6% of genetically supported targets have ever been pursued for an indication the genetics supports. The genetic window is foggy. A disease map yields dozens or hundreds of associated genes, most with muted effects, because evolution selects against variants of massive impact. Part 2 of my Deep Phenotype manifesto, out today, describes the AI we built at insitro to cut through that fog. Specialized ML models turn high-content measurements, from whole-body imaging in large human cohorts to genome-scale perturbation screens in human cells, into a library of precision phenotypes: quantitative traits that sharply raise the power of human genetics. In MASH, they surfaced over 30x more genetic associations than clinical staging. On top of this library sits a causal AI model, our Virtual Human, that integrates evidence across data modalities, disease biologies, and physical scales. The premise is that this integration gives rise to higher conviction, which in turn we believe will give rise to higher clinical success rates. To assess that hypothesis,we asked the model to predict success of historical phase 2 trials, zero-shot, with no trial outcomes in training. In its top decile of target-indication pairs, the false-positive rate was 10% in metabolic disease and 21% in cardiac, against a historical failure rate of 57% in both. We recognize, of course, that a retrospective benchmark is no guarantee of prospective success. Conviction is only half the value. Because the same phenotypes span from patient to cell, a genetic hit becomes an experiment we can run: the platform tells us in which cells a gene acts, which pathways it perturbs, whether a drug should inhibit or activate it. The assays that credential a target become the assays we optimize molecules against; the biomarkers that found the mechanism follow the drug into the clinic. The piece traces one example end to end: MASH, from the UK Biobank to a validated liver program. If this works, the payoff arrives twice. The first is economic: every medicine that reaches a patient carries the cost of the failures behind it, and nothing lowers that burden more than mechanisms that survive phase 2. The larger prize is measured in patients: the many diseases that still lack any disease-modifying therapy because we have not known which mechanisms drive them. If we can generate causally credentialed targets repeatably, disease after disease, the question changes: from whether the next program will fare better to how many diseases we can take on at once. That is the wager behind the Virtual Human: a repeatable path to medicines for the many who have none today. https://lnkd.in/gxFt-Fst

Neuroscience should improve the real-world characterization of health & disease. We present a computational whole-body exposome framework that integrates multilevel brain activity (via generative + biophysical models) with extracerebral information (multi-omics, organ clocks, cardiometabolic pathways, and lifelong physical & social exposomes). These components can be integrated within computational architectures designed to handle heterogeneity, multimodal integration, and individual trajectories. The framework outlines future pathways to capture nonlinear brain–body–environment neurosyndemics, enabling individualized predictions for precision brain health across populations. https://lnkd.in/dmfD8UJu At Nature Portfolio with a unique dream team: Claudia Duran-Aniotz Joaquín Migeot  Sandra Báez Sol Fittipaldi Carlos Coronel Harris Eyre Dr Chi Udeh-Momoh Henrik Zetterberg Suvarna Alladi  Carmen Sandi Ian Robertson Sanne Franzen Temitope Farombi MD, PhD Janitza Montalvo-Ortiz Sudha Seshadri Felipe Court Pedro A. Valdes-Sosa Jiayuan Xu  Chunshui Yu Lea Tenenholz Grinberg, M.D, P.hD Brian Lawlor  perminder sachdev Kristine Yaffe vladimir hachinski Karl Friston Enzo Tagliazucchi Hernando Santamaría-García

"Your mother seems fine when I examine her." This is what the doctor told my patient's daughter after a 15-minute office visit. The daughter knew something was wrong. Mom was getting lost driving to familiar places, struggling with her checkbook, and repeating the same stories. But in the clinic, mom was charming, articulate, and passed the basic cognitive screening. The problem? We're looking for dementia in the wrong places. After diagnosing 1000+ cases, here's the #1 early sign missed in medical visits: Loss of executive function in complex daily activities Not memory loss. Not confusion. Executive function. What this looks like in real life: 1. Financial management becomes impossible ↳ Checkbook balancing that took 10 minutes now takes 2 hours ↳ Bills get paid twice or not at all despite good intentions ↳ Complex financial decisions get avoided or delegated suddenly 2. Driving skills deteriorate in subtle ways ↳ Getting lost in familiar neighborhoods ↳ Difficulty with left turns or parking ↳ Family notices increased anxiety about driving 3. Multi-step tasks become overwhelming ↳ Cooking elaborate meals they've made for decades ↳ Managing multiple medications correctly ↳ Planning and executing social events Why providers miss this: 1. Office cognitive tests don't capture real-world complexity ↳ MoCA and MMSE test basic cognitive functions ↳ Patients can pass these while struggling at home ↳ Executive function requires complex task assessment 2. Patients compensate during medical visits ↳ Motivated to appear competent to providers ↳ Spouses often answer questions for them ↳ Social skills remain intact longer than cognitive abilities 3. Providers focus on obvious red flags ↳ Severe memory loss that hasn't developed yet ↳ Clear confusion that comes in later stages ↳ Behavioral changes that family hasn't reported A better approach: 1. Ask about specific functional changes - "Has bill-paying become more difficult in the past year?" - "Do you feel less confident planning dinner parties?" - "Have you stopped doing activities you used to enjoy?" 2. Include caregivers in the assessment Family members notice functional decline months before cognitive tests detect problems. 3. Use technology that tests executive function Digital cognitive assessments can capture complex decision-making deficits that paper tests miss. When families say "something's not right," they're detecting executive function changes that our medical system isn't designed to measure. The most important question for early detection: "What activities have become more difficult in the past year?" Executive function decline predicts future cognitive decline better than memory complaints. And it's detectable years before traditional dementia symptoms appear. ⁉️ What early changes did you notice that providers initially dismissed? ♻️ Share if you think we need better ways to detect early dementia signs 👉 Follow me (Reza Hosseini Ghomi, MD, MSE) for insights on dementia

❗ This is huge: A groundbreaking study connects key pieces of the Alzheimer’s puzzle and points to a potentially powerful solution. For the first time, researchers found that the reduction of Li concentration is associated with memory loss and the neurological hallmarks of Alzheimer’s disease - amyloid plaques and tau tangles. Essentially, Li has an important physiological role in our brain. Previously, epidemiological studies hinted at it. People who drink water with trace amounts of lithium have relatively low dementia rates. But proper studies were missing. 📍 Fundamental discoveries: 1. Lithium levels were lower in parts of the human brain affected by Alzheimer’s disease than in unaffected regions. 2. In people with mild cognitive impairment (a precursor to Alzheimer’s), lithium is already being trapped inside amyloid plaques. This leaving too little “free” lithium to perform its normal brain functions. 3. In mice, lithium deficiency worsened progressively as the disease advanced, mirroring the human condition. “This approach targets all the major pathologies of concern in the disease” - Ashley Bush, a neuroscientist at the University of Melbourne. 📍 Now the mystery is unveiled: Mice with lithium-deficient brains developed significantly more amyloid plaques than those with normal lithium levels. This seems to trigger the progression of Alzheimer’s disease: less Li → more amyloids → even less Li Earlier clinical tries showed mixed results. Now, we know why! They used lithium carbonate, which we now understand gets trapped inside amyloid plaques. This reduces lithium content in the brain and leads to even MORE plaques, which leads to even less lithium. This is a vicious cycle that results in the Alzheimer’s. Scientists found that lithium orotate (instead of carbonate) actually works very well because it doesn’t get trapped by amyloid plaques. Just stunning! 👍 Implications: Lithium salts are very cheap. VERY cheap. This study may start a huge shift in how we prevent & treat dementia (if confirmed by clinical trials). “I don’t think there’s much more in the pipeline that that would have this level of evidence and that would be as safe,” says Hajek. “Lithium is dirty cheap. And it could be tremendously beneficial to people.” I am very excited by this fundamental work, so I will keep an eye on the follow-up studies. They are way too promising to miss. p.s. Yes, mice studies do not always translate into humans. But clinical trials are easy to do with Li salts. I'm sure many groups will begin them now.

Groundbreaking Alzheimer’s research reveals the disease isn't a brain disorder, but rather an autoimmune condition. For decades, scientists believed the buildup of beta-amyloid plaques was the root cause of Alzheimer’s. However, new insights based on 30 years of research propose that beta-amyloid is not an abnormal protein, but a key part of the brain’s immune system. Normally, it acts as a defense against infection or injury—but due to structural similarities between certain bacteria and brain cells, beta-amyloid can mistakenly turn on its host, triggering a slow and devastating autoimmune attack. This new framework redefines Alzheimer’s as a malfunction of the immune system, where the brain’s own protective mechanisms go rogue. It’s a compelling pivot that could revolutionize treatment strategies by targeting immune regulation rather than trying to eliminate beta-amyloid itself. By aligning Alzheimer’s with other autoimmune diseases like lupus or multiple sclerosis, this theory offers fresh hope for more effective therapies and a better understanding of how to prevent or slow the progression of dementia. Source: Donald Weaver, Professor of Chemistry and Director of Krembil Research Institute, University Health Network, University of Toronto. In The Conversation.

Researchers say abnormal proteins actually travel from somewhere else to the brain. A groundbreaking study from Wuhan University suggests that Parkinson’s disease may originate in the kidneys, challenging long-held assumptions that it begins in the brain. Researchers found abnormal clusters of alpha-synuclein (α-Syn) proteins—known to play a central role in Parkinson’s—in the kidneys of patients with the disease. In animal experiments, healthy kidneys were able to clear these proteins, but malfunctioning kidneys allowed α-Syn to accumulate and spread to the brain, leading to neurological damage. The study also found α-Syn buildup in patients with chronic kidney disease, even when no neurological symptoms were present. This raises the possibility that the kidneys may act as an early reservoir for pathological proteins, which later travel via blood or nerve pathways to the brain. Though the research is preliminary and based on small sample sizes, it opens a new frontier in Parkinson’s research—suggesting that kidney health could be a target for early intervention and new treatments. As researchers continue exploring non-brain origins of neurodegenerative diseases, these findings could reshape how we understand and manage Parkinson’s. Source: Yuan, Y., et al. (2025). Peripheral α-synucleinopathy in kidneys contributes to Lewy body pathogenesis. Nature Neuroscience.

New research shows a protein blamed for Alzheimer’s may actually be crucial for building newborn brains, shaking long-held beliefs A surprising new study has turned decades of Alzheimer’s dogma on its head. Scientists have discovered that p-tau217, a form of the tau protein long thought to be purely destructive in the brain, is found in astonishingly high levels in healthy newborn babies — even more than in Alzheimer’s patients. This finding suggests p-tau217 isn’t just a marker of disease but may actually be vital for early brain development. Tau normally acts like scaffolding inside nerve cells, keeping them stable and helping them communicate. But in Alzheimer’s, tau becomes chemically altered into p-tau217, which clumps into tangles that choke brain cells, causing the memory loss and confusion typical of dementia. For years, high levels of p-tau217 have been viewed as a surefire sign of trouble. But this new research, led by the University of Gothenburg, shows that’s not the whole story. Analyzing blood samples from over 400 people — from premature babies to seniors with Alzheimer’s — researchers found premature infants had the highest p-tau217 levels of all. These levels then plunged during the first months of life, stayed very low through adulthood, and only rose modestly again in Alzheimer’s patients. The fact that newborns can handle sky-high p-tau217 without damage suggests it plays a key role in wiring up the brain’s early networks, especially in regions tied to movement and touch. This discovery could completely reshape how we diagnose and treat Alzheimer’s. It means high p-tau217 isn’t always a red flag — in babies, it’s part of healthy growth. More importantly, if we can figure out why infant brains tolerate or even need these levels without forming harmful tangles, we might uncover new ways to protect aging brains. Instead of only attacking tau as the villain, researchers may start asking how to keep its youthful, brain-building properties alive for longer. Research References : PMID: 40574977 PMCID: PMC12198956 The potential dual role of tau phosphorylation: plasma phosphorylated-tau217 in newborns and Alzheimer’s disease, Brain Communications, Volume 7, Issue 3, 2025, fcaf221,

𝗥𝗲𝘃𝗲𝗿𝘀𝗲 𝗣𝗮𝗿𝗸𝗶𝗻𝘀𝗼𝗻’𝘀 𝗨𝘀𝗶𝗻𝗴 𝗡𝗮𝗻𝗼𝗽𝗮𝗿𝘁𝗶𝗰𝗹𝗲𝘀? Scientists have developed a promising technique using gold nanoparticles to repair brain damage in Parkinson’s disease. Parkinson’s is caused by toxic alpha-synuclein protein clumps that damage dopamine-producing neurons. The new approach uses nanoparticles coated with antibodies and peptides to target and dissolve these clumps. Once in the brain, the nanoparticles attach to affected neurons. A near-infrared light beam activates them, generating mild heat that triggers cell repair and releases therapeutic peptides to clear harmful proteins. This restores dopamine production naturally. Unlike traditional drugs with side effects, this method addresses the root cause. Tested successfully in mice, it showed significant recovery without side effects. Though human trials are still ahead, this breakthrough offers hope for a non-invasive, long-term Parkinson’s treatment. #Discovery #Scientist #Work #Element #Newage