image: This work demonstrates that the entorhinal cortex, in blue, and the amygdala, in red, predict early Alzheimer’s disease better than the hippocampus, shown in green.
Credit: Johns Hopkins University
Johns Hopkins University researchers have identified two areas of the brain that show significant signs of Alzheimer’s disease before it reaches the hippocampus, possibly providing new biomarkers that could get people diagnosed and started on treatment before symptoms begin, when interventions may be most effective.
The team analyzed hundreds of brain scans from people in various stages of Alzheimer’s and found that the entorhinal cortex and amygdala began to shrink before the hippocampus, the main region of the brain responsible for memory, where doctors typically look for evidence of Alzheimer’s.
“We have found that there are early changes in the brain manifesting the clinical biomarkers of atrophy as much as a decade before there are clinical symptoms,” said biomedical engineer and senior author Michael Miller. “It’s at least a 5-to-10-year play where your brain is changing. Imagine if we could start to treat the neurodegenerative changes at the 2, 3 or 4-year point rather than after 15 years when the changes are manifesting in memory symptoms. That’s the great promise here for your loved ones who are at risk.”
The work, recently published in NeuroImage Reports, is being presented this week at Neuroscience 2026, the annual meeting of the Society for Neuroscience.
Alzheimer’s disease is the leading cause of dementia worldwide. Researchers know that the disease begins to build in the brain decades before symptoms of memory loss appear, and they suspect that treatments would be most effective during those early years. So, developing reliable biomarkers for the earliest stages of the disease is critical.
“Our goal is to be able to treat individuals before the symptoms of Alzheimer’s disease develop so that they may delayed or even stopped’, said Marilyn Albert, co-author and director of the Johns Hopkins Alzheimer’s Disease Research Center.
The team analyzed hundreds of magnetic resonance imaging (MRI) and Positron Emission Tomography (PET) scans from two independent cohorts, the Alzheimer’s Disease Neuroimaging Initiative and the Biomarkers of Cognitive Decline Among Normal Individuals study. The scans were taken over time of Alzheimer’s patients who were symptom-free, who suffered cognitive impairment, and who died from the disease.
Across patients from both studies, two brain regions near the hippocampus, the entorhinal cortex and the amygdala, showed greater relative atrophy and volume loss relative to the hippocampus during the early phase of the disease, the team found.
The entorhinal cortex is responsible for retrieving old memories. The amygdala is linked to emotional memory.
The team also demonstrated that gray matter atrophy shrinkage was spatially localized with changes in tau protein as measured by PET imaging and digital pathology, Tau pathology a known hallmark of Alzheimer’s.
The team believes measuring atrophy shrinkage in these two regions together could be a better early predictor of Alzheimer’s disease and a promising new biomarker, especially as brain scanning technology becomes more available and affordable.
For people with a family history of Alzheimer’s or other concerns, doctors might start scanning those new brain regions when patients are in their 30s and 40s.
“As biomarkers and treatments become increasingly available, knowing who is going to have cognitive decline is going to be really important,” said co-author Meaghan Morris, a neuropathologist who studies Alzheimer’s and other dementias. “This could really play into better risk stratification for identifying who is going to have cognitive decline in the near future—and treating people earlier and earlier to hopefully slow the course of the disease.”
More work is needed before the findings can be used to help diagnose Alzheimer’s.
The team hopes to zoom in on these key brain areas to learn more about what’s happening at the molecular level as the disease begins to progress.
“Our future work is to better show the molecular neighborhoods associated with these Tau protein changes as localized by these clinical biomarkers of atrophy,” Miller said. “Once we know more about the molecular neighborhoods, we can develop therapies.”
Journal
Neuroimage Reports