Mutation type shapes early Alzheimer’s
How hereditary Alzheimer’s disease develops in its early stages depends on which genetic mutation a person carries. This is shown in a new study from Karolinska Institutet, published in the journal Translational Psychiatry.
Researchers followed 45 individuals from Swedish families with hereditary Alzheimer’s disease for an average of seven years. Participants underwent repeated assessments including brain PET imaging, cognitive tests and blood sampling. The researchers found that the two mutation types that were included in the study were linked to different patterns of glucose use in the brain.
People with the PSEN1 mutation showed a period of increased glucose use in the brain around 20–10 years before the expected onset of symptoms, followed by a decline. In contrast, individuals with the APP mutation did not show such a peak but instead had a slower and more gradual decrease in glucose use over time.
Differences in early biomarker changes
Early increases in the blood astrocyte marker GFAP were seen in both PSEN1 and APP mutation carriers. Astrocytes are support cells in the brain that help nerve cells function. However, in people with the APP mutation, rising GFAP levels were more strongly linked to both lower brain glucose use and declining performance on cognitive tests. This stronger link may reflect early differences in how the disease develops in APP compared with PSEN1 mutations.
“Being able to follow individuals with hereditary Alzheimer’s disease over such a long period allows us to identify patterns that would otherwise be difficult to detect. Our results show that different mutations follow different early disease courses, offering a new picture of how and when key changes occur. This knowledge may be important when developing and interpreting biomarkers in future research,” says Mariola Zapater-Fajari, first author of the study and postdoctoral researcher at the Department of Neurobiology, Care Sciences and Society.
Strengths and limitations of the study
The researchers emphasise that the number of participants is limited because the specific hereditary mutations included in the study are very rare and found in only a small number of families. The findings should therefore be interpreted with some caution. At the same time, the long follow‑up period allows the study to provide a broad picture of how the disease changes during its early phase, from many years before symptoms appear to the period after onset.
“These insights may also be relevant for understanding early changes in sporadic forms of Alzheimer’s disease, the much more common form that is not caused by inherited mutations,” says Agneta Nordberg, professor at the same department and the study’s last author.
The study was conducted in collaboration with Uppsala University, the University of Gothenburg and several international research groups. The research was funded by the Swedish Research Council, the Swedish Foundation for Strategic Research, the Swedish Brain Foundation and the Swedish Alzheimer Foundation, among others. Some researchers have received fees from pharmaceutical companies, as disclosed in the scientific article.
Publication
“Early functional changes and plasma GFAP in Swedish families with Autosomal
2 Dominant Alzheimer’s disease mutations”, Emma S. Luckett, Mariola Zapater-Fajari, Ove Almkvist, Charlotte Johansson, Konstantinos Chiotis, Marco Bucci, Anders Wall, Nicholas J. Ashton, Kaj Blennow, Henrik Zetterberg, Elena Rodriguez-Vieitez, Caroline Graff, Agneta Nordberg, Translational Psychiatry, online 5 February 2026, doi: 10.1038/s41398-026-03829-6.