The way the brain shrinks in people who develop Alzheimer’s disease does not follow a specific or uniform pattern, according to a new study from researchers at UCL and Radboud University in the Netherlands.
Published in Alzheimer’s and dementiathe study is the first to compare individual patterns of brain shrinkage over time in people with mild memory problems or Alzheimer’s disease against a healthy benchmark.
When assessing brain scans for ‘fingerprints’ of diseases, researchers found that among people with mild memory problems, those who develop a greater number of ‘outlier’ changes more quickly are more likely to develop Alzheimer’s disease. An outlier is classified as a specific brain region that has shrunk more than normal when adjusted for age and gender.
However, researchers also found that, despite some overlap, there was no uniform pattern in the way the brain shrank in those who developed Alzheimer’s disease.
The scientists say this new finding could make it possible to develop more personalized medicines, targeting the specific range of brain areas affected in an individual.
We know that Alzheimer’s affects everyone differently. Understanding and quantifying this variability has important implications for the design and interpretation of clinical trials, and potentially, eventually, for counseling patients and developing personalized approaches to treatment.”
Jonathan Schott, Study author, professor, UCL Queen Square Institute of Neurology
Alzheimer’s disease is the most common cause of dementia and accounts for 60-80% of the 944,000 people with dementia in Britain.
Previous group-level studies have shown that patients with Alzheimer’s disease collectively have excessive brain shrinkage compared to healthy controls, and this can be measured using MRI scans.
However, these studies may overlook how the pattern of shrinkage varies between individuals, and researchers believe this information could provide valuable information about how an individual’s cognitive performance (thinking/memory) changes over time.
To overcome this, researchers at UCL used normative modelling1 approach to gain insight into the individual variability between Alzheimer’s patients.
Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), they compared 3,233 MRI brain scans from 1,181 people with Alzheimer’s disease or mild memory problems to compare the brain scan data of 58,836 healthy people. The MRI scans were typically done at annual intervals, with most participants having two or three scans.
Each scan was then processed using special imaging tools, which can assess the structure (thickness and volume) of the brain in 168 different regions.
This data allowed researchers to develop individualized brain maps for each participant, which could be mapped against healthy maps over time (the benchmark).
The analysis found that despite most participants starting out with brains of similar size, different patterns (progression/affected regions) of brain shrinkage were observed between individuals over time.
Patients with Alzheimer’s disease had an average of 15 to 20 outliers in the brain at the beginning of the study and after three years there were about 30. In contrast, patients with mild memory problems started with about five to 10 outliers and accumulated an average of over this period only two to three outliers. Importantly, having a greater number of outliers was associated with poorer memory in both groups.
Among people with mild memory problems, those who developed dementia (within three years) accumulated four new outliers each year, while among people who continued to have mild problems the average was less than one new outlier per year.
Researchers say this new insight could ultimately help predict how Alzheimer’s disease will progress in an individual based on the early changes in their brain identified in scans. However, further research is needed to determine which changes in the brain are predictive of which future symptoms.
Professor James Cole, senior author of the study from UCL Computer Science and UCL Queen Square Institute of Neurology, said: “When we look at which parts of the brain have shrunk the most in different people with Alzheimer’s disease, there is no cartridge.
“The approach we took in our study means we can get a better picture of the individual variability in the progression of Alzheimer’s disease. By creating these brain maps, which are unique “fingerprints” of a patient’s brain health, we can see whether individual brain areas are changing and how quickly.
“While we are far from being able to predict exactly how an individual’s disease will progress, this approach should help us monitor the different ways in which people’s brains may change as symptoms develop and worsen. Hopefully this is a step towards a more personalized approach to diagnosis and treatment.”
All people experience some form of cognitive decline as they age, and the results showed that there is an overlap in brain shrinkage between healthy people and those with Alzheimer’s disease and/or mild memory problems. These overlapping areas include the hippocampus, amygdala, and other parts of the medial temporal lobe known to be crucial for memory, spatial cognition, and emotion.
But the authors argue that focusing on certain areas over others can detract from the big picture.
Dr. Serena Verdi, first author of the study from UCL Computer Science and UCL Queen Square Institute of Neurology, said: “While it is true that some brain areas, such as the hippocampus, are particularly important in Alzheimer’s disease, we wanted to avoid this by By focusing on specific regions in this study, our results confirm that everyone is different; the regions affected by disease in one person may not be the same in the next person.
“I think we need to shift to a new way of thinking to get rid of the idea that ‘this area is important, but this area is not’. The big picture and the individual variability inherent in it is what counts.”
The authors say that some of this individual variability may stem from the fact that many people with Alzheimer’s disease have more than one cause of cognitive disease, such as vascular dementia or fronto-temporal dementia. Genetic and environmental factors, such as brain injury, alcohol consumption or smoking habits, probably also play a role.
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Magazine reference:
Verdi, S., et al. (2024). Personalizing progressive brain structure changes in Alzheimer’s disease using normative modeling. Alzheimer’s and dementia. doi.org/10.1002/alz.14174.