For years, scientists have known that Alzheimer’s disease can quietly develop long before a person becomes forgetful.
Now researchers in Norway have found evidence that changes in the brain may begin even earlier than one of today’s best Alzheimer’s scans can detect. The difference could be at least seven years.
The discovery comes from the University of Oslo, where researchers followed healthy older adults with repeated brain imaging for almost two decades. Their unusual collection of long-term scans allowed them to watch the years leading up to the first detectable buildup of amyloid, one of the best-known features of Alzheimer’s disease. The research was published in Nature Neuroscience.
Alzheimer’s gradually damages brain cells and is the leading cause of dementia. People eventually develop problems with memory, reasoning, language and everyday tasks. But by the time these symptoms become noticeable, changes inside the brain may have been developing for many years.
Scientists have spent decades searching for ways to identify this silent stage. One major target is amyloid, a substance that can build up between brain cells and form sticky plaques. High levels of these plaques are a major biological sign associated with Alzheimer’s disease.
Doctors and researchers can look for amyloid using a special form of imaging called a PET scan. A small tracer is introduced into the body and makes amyloid deposits easier to see in the brain. Amyloid PET has been considered one of the most sensitive ways to identify very early Alzheimer’s-related changes.
The new study suggests there may be an important period that PET scans miss. James Michael Roe and colleagues found measurable changes in brain structure years before amyloid levels became high enough to show up on PET. Roe carried out the work while he was a postdoctoral researcher at the University of Oslo’s Center for Lifespan Changes in Brain and Cognition.
The team did not simply scan people once and compare those with and without Alzheimer’s. Instead, participants returned for brain imaging over many years. This long follow-up gave researchers a rare opportunity to estimate when amyloid first crossed the level at which it could be detected.
Once they knew approximately when plaques appeared, the researchers turned to MRI scans taken during the previous decade. MRI provides detailed images of the brain’s physical structure. The team looked for differences between people who would later develop detectable amyloid and those who remained without it.
A pattern emerged well before the amyloid scans turned positive. Structural changes could be seen at least seven years earlier, even though the people involved were still functioning normally in terms of thinking and memory. This suggests that the brain may already be on a different path before conventional amyloid imaging raises an alarm.
The finding is important because it challenges a simple picture of how Alzheimer’s begins. Amyloid plaque buildup is often placed near the start of the disease process, followed by other changes and eventually memory loss. The new results suggest that something measurable may be happening before visible plaque accumulation.
There are at least two broad explanations. Very small amounts of amyloid, below the detection limit of current PET scans, might already be causing or accompanying changes in brain tissue. If so, better ways of detecting tiny amounts of amyloid could reveal an even earlier stage.
But there is another possibility. Some other biological process may begin changing the brain before major amyloid buildup starts. That process could potentially contribute to the later development of plaques or could represent another pathway involved in Alzheimer’s disease.
Professor Anders Martin Fjell, head of the Center for Lifespan Changes in Brain and Cognition, said the disease is likely driven by several factors and is deeply connected with aging. If changes unrelated to amyloid truly come first, treatments aimed only at amyloid may not address every important early process. This strengthens the case for investigating other targets as well.
That does not mean amyloid is unimportant. Amyloid remains one of the central features of Alzheimer’s biology, and treatments that reduce it have become an important area of medicine. Instead, the study suggests that researchers may need to understand what happens both before and alongside amyloid buildup.
The possibility of detecting Alzheimer’s earlier is attractive because timing may be crucial for treatment. Brain cells that have already been badly damaged or lost are difficult to replace. In theory, treatments given during a much earlier stage could have a better chance of preserving brain function.
However, this research is not yet a method for telling an individual healthy person that they will develop Alzheimer’s. The early structural changes were discovered through detailed analysis of repeated scans in a research setting. Normal aging also changes the brain, so any future test would need to distinguish disease-related patterns from harmless age-related changes.
The study’s long follow-up is a major advantage because it gives researchers information about the same people before and after amyloid becomes detectable. At the same time, the work does not establish exactly what produced the earlier MRI changes. A link in timing is not the same as proof of cause.
Future studies will need to combine brain imaging with blood tests, spinal fluid markers and other measures of Alzheimer’s biology. Researchers will also need to test more diverse groups and determine whether the early changes predict who later develops memory problems, rather than only who develops detectable amyloid.
The most important message is that Alzheimer’s may have a longer hidden phase than scientists previously recognized through imaging. The years before amyloid PET becomes positive could contain valuable clues about how the disease starts. If researchers can understand those clues, they may eventually find better ways to detect, prevent or treat Alzheimer’s before major damage is done.
Source: University of Oslo.
