Every year brings hopeful news about brain disease. Scientists discover drugs that remove toxic proteins. Experimental treatments rescue neurons in animals. Brain scans now reveal damage to extraordinary precision. From the outside, it feels as if cures for Alzheimer’s disease and Parkinson’s disease must already exist somewhere, waiting only to reach patients. Yet inside clinics, the conversation sounds very different.
Doctors can help reduce tremors, improve mobility, and temporarily slow memory decline. But stopping the disease itself remains rare. Families struggle to understand this contradiction. If science is advancing so rapidly, why does the illness continue to progress? This question has quietly become one of the central challenges of modern medicine.
Across all areas of drug development, treatments for brain disorders fail more often than therapies for heart disease, infections, or cancer. Large analyses of pharmaceutical pipelines published in Nature Biotechnology, Biostatistics, and BIO industry reports show that only about 6 to 8 percent of neurological drugs entering clinical trials eventually reach approval. Most fail during Phase II clinical trials; the stage designed to prove that treatment improves human life rather than laboratory biology. In the laboratory, disease looks solvable. In real people, it behaves differently.
When the brain looks better, but the person does not
For decades, Alzheimer’s research focused on amyloid plaques and sticky protein deposits in the brain. The logic seemed simple: remove the plaques and the disease should slow. After many failures, medicine finally succeeded biologically.
Antibody therapies now visibly clear amyloid on brain scans. The EMERGE and ENGAGE trials of Aducanumab showed plaque removal but inconsistent clinical benefit, leading to controversial approval based on biomarker change rather than functional improvement. The CLARITY-AD trial of Lecanemab, published in The New England Journal of Medicine in 2022, showed a statistically significant slowing of decline by about 27 percent, yet the difference in daily life remained modest. The TRAILBLAZER-ALZ 2 trial of Donanemab, published in JAMA in 2023, reported similar results. For families, the outcome felt confusing. The scans improved clearly. Life improved only slightly.
Researchers eventually understood why. Long-term biomarker studies summarized in Lancet Neurology show Alzheimer’s disease begins 15 to 20 years before forgetfulness appears. By the time treatment starts, large parts of the brain network are already lost. Removing plaques changes biology, but it cannot restore neurons that have already died. The treatment works. It simply arrives too late.
Parkinson’s disease, which involves degeneration of dopamine neurons, taught the same lesson. Scientists hoped that protecting these cells would slow progression. In animals, the strategy repeatedly succeeded. In patients, it did not work.
The PRECEPT trial testing CEP-1347 showed no disease-modifying benefit. The STEADY-PD III trial of Isradipine, published in The New England Journal of Medicine in 2020, confirmed that a drug protective in laboratory models did not prevent disability in humans. More recently, anti-alpha-synuclein antibody trials such as PASADENA and PADOVA demonstrated target engagement but failed to produce meaningful clinical improvement.
Pathology studies had already hinted at the explanation. By the time tremor appears, roughly half of substantia nigra dopamine neurons and most striatal dopamine are already lost. A drug cannot protect cells that no longer exist.
The disease begins long before diagnosis
In laboratory models, disease is fast and clear. Toxin damages neurons within days. A mutation produces symptoms within months. Cause and effect are visible. Human neurodegeneration behaves differently. It resembles slow aging under a microscope. Sleep disruption, inflammation, metabolism, environmental exposure, and genetics interact quietly for decades before symptoms appear. By the time someone notices tremor or memory loss, the brain has been compensating for injury for years. Many drugs were designed for early disease but tested in late disease. The medicine did not necessarily fail. The timing did.
One name, many diseases
Another discovery of a further complicated treatment. Alzheimer’s disease and Parkinson’s disease are not single, uniform disorders. Research in Nature Reviews Neurology and Neuron shows multiple biological subtypes involving inflammation, mitochondrial dysfunction, vascular injury, and immune signaling. Parkinson’s may even begin in the gut in some patients and in the brain in others.
Two patients may look identical in clinics but have different underlying biology. When placed in the same clinical trial, a drug helping one subgroup can appear ineffective overall. Cancer treatment improved only after medical science accepted that one diagnosis could contain many diseases. Neurology is now learning the same lesson.
Why this matters even more in Nepal
The gap between discovery and benefit becomes wider in countries like Nepal. As life expectancy rises, dementia and Parkinson’s disease are increasing. Early symptoms such as loss of smell, constipation, sleep disturbance, or slowed movement are often dismissed as normal aging. Medical care is usually sought only after tremors, falls, or major memory problems appear, indicating that the disease has already advanced. At such a stage, treatments designed to slow early degeneration can do little. Scientific progress exists globally, but its impact depends on timing. The challenge is not only access to medicine, but access early enough for medicine to matter.
Why failed trials still move science forward
A failed clinical trial sounds discouraging, but it rarely means the idea was wrong. Often, it means the treatment was given too late, to the wrong subgroup, or measured over too short a period. Because of these lessons, neuroscience is changing direction. Blood biomarkers, imaging, and genetic screening are being developed to detect disease years before symptoms appear. Prevention trials such as AHEAD 3-45 and DIAN-TU now test therapies in people who are biologically positive but still healthy. The central question is shifting from "Does the drug work? To whom should it be administered, and when?”
The real meaning of progress
For families living with brain disease, progress feels painfully slow. Yet decades of disappointing trials revealed something profound: these illnesses begin long before diagnosis. Many treatments did not fail because hope was misplaced. They failed because they met the disease at the wrong moment. The future of brain medicine may depend less on discovering a miracle cure and more on matching the right therapy to the right person at the right stage. When early detection, precise diagnosis, and timely treatment finally align, scientific breakthroughs will stop fading after headlines and begin changing everyday life both around the world and in Nepal.
The author is a PhD candidate in the Department of Neurosciences and Neurological Disorders at the University of Toledo
