New insights into Alzheimer's disease biomarkers
How are emerging plasma biomarkers related to the diagnostic tests currently used in clinical routines? And does the earlier evidence from highly selective research cohorts translate to the heterogeneous real-world data? Researchers at Karolinska Institutet have sought to answer these questions in a study published in eBioMedicine with Dr. Marina Bluma from the Department of Neurobiology, Care Sciences and Society as the first author.
As of November 14, 2024, the European Medicines Agency (EMA) has, for the first time, recommended a drug designed to slow the progression of Alzheimer's disease. This development once again highlights the need for screening tests able to detect individuals at the asymptomatic, early stage of the disease - before irreversible changes occur.
Blood-based tests promising
In Alzheimer's disease (AD), certain proteins in the brain, called tau proteins, play an important role. Normally, tau proteins help stabilise structures in brain cells, but in AD these proteins become abnormally altered (phosphorylated) and start to clump together. This causes the brain cells to function less well and eventually die.
Blood-based tests are promising biomarker candidates that currently show high accuracy in research cohorts. But how changes in the levels of these plasma biomarkers truly correspond to the underlying pathology of AD - and how their results can be interpreted in relation to the biological changes and disease stages tracked by diagnostic tools in clinical routine in hospitals for years - remains unclear.
Diverse group of patients
In this study, researchers analyzed data from a memory clinic cohort, examining the levels of plasma biomarkers in association to standard diagnostic tests and the biological staging of the disease.
The cohort, thus, consisted of a diverse group of patients with various pathologies, selected from individuals who sought medical attention at Karolinska university hospital due to memory complaints.
Dr. Marina Bluma, postdoctoral fellow at the Department of Neurobiology, Care Sciences and Society explains,
"Earlier studies on plasma biomarkers have mostly been conducted in well-controlled, research-based cohorts where patients are strictly selected based on specific inclusion and exclusion criteria. While this is of utmost importance — ensuring high homogeneity, boosting the statistical power of analyses, and providing better control over confounding factors —once we move to the next step of biomarker validation, we seek real-world evidence to generate insights that improve the interpretability and applicability of these tests in their target populations”.
pTau217 is a dual marker
The study found that all tested plasma biomarkers (except for NfL) were associated with accumulation of misfolded amyloid in the brain, highlighting the role of amyloid in the phosphorylation of tau.
“These findings are in line with the other recent reports on this topic, and add to the emerging body of evidence that plasma pTau217 is a dual marker of amyloid and tau pathology. “ says Dr. Bluma. "Unlike these biomarkers, increased NfL levels were more indicative of brain atrophy and older age."
Among the biomarkers tested, only plasma levels of pTau217 were well explained by clinical variables, while over 70% of the variation in other plasma biomarkers remained unexplained.
These studies provide a deeper understanding of complex relationships between novel plasma biomarkers and current traditional diagnostic tools. The researchers hope that this new knowledge will lead to increased availability of early diagnostic markers and thus increased treatment in Alzheimer's disease in the future.
The project was founded by the Swedish Research Council (projects 2017–06086, 2020-4-3018,2024-2027), Swedish Brain foundation (2022-0272), Swedish Alzheimer foundation (AF-96918), CIMED Region Stockholm/KI ( FOUI-988916 ), the Region Stockholm - Karolinska Instituteregional agreement on medical training and clinical research (ALF grant), (FOUI- 987525), Fondation Recherche sur Alzheimer,the Swedish Dementia Foundation (Demensfonden), the Gun och Bertil Stohnes foundation.
Publication
Disentangling relationships between AD plasma biomarkers and established biomarkers in patients of tertiary memory clinics. Marina Bluma, Konstantinos Chiotis, Marco Bucci, Irina Savitcheva, Anna Matton, Miia Kivipelto, Andreas Jeromin, Giovanni De Santis, Guglielmo Di Molfetta, Nicholas J. Ashton, Kaj Blennow, Henrik Zetterberg, Agneta K Nordberg, eBioMedicine, online December 2024, doi: 10.1016/j.ebiom.2024.105504.