"The most groundbreaking aspect of this study is that we found structural changes in the brain many years before the first signs of plaque buildup, which is considered to be the earliest sign of Alzheimer's disease," says Anders Martin Fjell, Professor at the Department of Psychology and head of LCBC.

"These are cognitively well-functioning older individuals," Fjell emphasizes. "What is unique here is that we have examined changes in brain structure in the years before the first scan revealed plaques."

In plain terms, the researchers measured cortical thickness — how thick the brain's outer layer is — and found it changing years before any plaque appeared on PET images. According to Roe, this is the earliest signal anyone has detected on brain scans to date. Such a signal, if confirmed, could help track the disease before symptoms emerge.

Why the finding could reshape treatment research

Alzheimer's remains extremely difficult to treat. Fjell points to one likely reason: the disease is closely tied to aging and is probably shaped by several different biological factors at once.

The new results raise two possible explanations for what the team observed. First, harmful processes that either contribute to plaque accumulation or result from it may already be active in the brain, even while the plaques themselves remain too small or sparse for scanners to detect. Second, other biological processes entirely — unrelated to amyloid — may be driving the structural changes before plaques even begin to accumulate.

The second possibility carries real weight for drug development. Most experimental Alzheimer's therapies target amyloid directly. If brain change starts through mechanisms separate from amyloid buildup, researchers may need treatments aimed elsewhere.

"If the latter is true, it suggests it is important to continue developing drugs that target processes other than amyloid plaque accumulation. But we need more research on this," Fjell cautions.

Early findings, careful steps

Several limitations deserve mention. All participants were cognitively healthy older adults, so the study tracks brain changes rather than diagnosed disease, and the researchers themselves stress that more work is needed before the findings translate into clinical tools. The study shows an early structural signal; it does not yet prove that this signal can predict who will develop Alzheimer's symptoms in daily practice.

Still, the implications are significant. The current gold standard for early Alzheimer's imaging, amyloid-PET, may simply not be sensitive enough to capture the very first stages of the disease. If the Oslo findings hold up, the field may need to recalibrate what it considers the "earliest" sign of Alzheimer's — and how early future treatments should intervene.

The study appears in Nature Neuroscience under the title "Cortical thickness changes precede high levels of amyloid by at least 7 years," with co-authors including researchers from the University of Oslo, the University of California, Berkeley, and Diakonhjemmet Hospital in Oslo.