Knowing in advance which diseases are looming and being able to act on them is one of the goals of scientists. This is especially necessary in the cerebral field, specifically in neurodegenerative diseases like Alzheimer's. Searching for clues in healthy individuals and anticipating years before the first dementia symptoms is a challenge that was set 12 years ago by a team of researchers from CIEN (Center for Research in Neurological Diseases) and the Reina Sofía Foundation.
They decided to conduct a thorough follow-up of nearly a thousand cognitively healthy individuals in the Madrid area. The results of this work have now been published in the journal Alzheimer's & Dementia and demonstrate that a blood test can estimate the risk of cognitive decline in healthy individuals up to a decade before the first symptoms appear.
A key to achieving this revelation has been a blood biomarker: %p-tau217, a minimally invasive tool that allows stratifying the population according to their long-term clinical progression risk. The research, coordinated by Jesús Silva Rodríguez, head of the Neuroimaging Platform at CIEN, is disruptive due to its ability to rule out neuronal disease.
What does the research reveal about Alzheimer's prediction?
As Silva Rodríguez points out, the main value of the study "lies in the high negative predictive value of plasma biomarkers, as a negative result allows us to ensure, with over 90% reliability, that the person will not develop clinical symptoms over the next decade, enabling resources and monitoring to be focused on those at risk."
This "ruling out" capability will allow healthcare systems to focus resources and monitoring exclusively on those individuals who do present a real risk, avoiding costly and invasive tests like lumbar punctures for those at minimal risk.
Unlike a negative result, a positive result in %p-tau217 should not be seen as an inevitable sentence. In the highest-risk group identified by the study, a positive result was associated with a 55% probability of progressing to mild cognitive impairment or dementia within five years and a 72% probability within 10 years. The researcher clarifies that, although this represents a risk four to seven times higher than average, "even among individuals with the highest biomarker levels, a significant portion will not develop symptoms."
By "clinical progression" or "symptom onset," it is understood that a person transitions from being cognitively healthy to receiving a diagnosis of mild cognitive impairment (MCI) or dementia, notes the head of the Neuroimaging Platform at CIEN. Regarding how many people actually progressed, he provides some figures from the study: "Throughout the follow-up, 16.2% of the cohort developed mild cognitive impairment or dementia, and 6.7% specifically progressed to dementia, figures that align well with expected numbers for this age range."
Silva Rodríguez mentions that clinical manifestation depends on a complex interaction of biological, sociodemographic, and lifestyle factors. "Until now, we knew that these biomarkers provided a biological diagnosis (who has amyloid or tau protein), but we knew little about how to interpret this in a healthy individual; now we can precisely contextualize what these results mean at the individual risk level," Silva Rodríguez points out.
What will this advancement translate into?
The long-term implications of the biomarker will help in two aspects, as the expert summarises: identifying ideal candidates for prevention clinical trials and allowing high-risk patients to be closely monitored to receive treatment as soon as they meet clinical criteria.
According to Pascual Sánchez-Juan, scientific director of CIEN and senior author of the study, "this study marks a significant change: blood biomarkers not only help us detect Alzheimer's biology but also estimate the risk of long-term clinical progression in asymptomatic individuals."
Its current utility lies not so much in deterministically predicting who will develop the disease, "but in identifying with great reliability most individuals with very low risk and better selecting those who can benefit from closer monitoring or participate in prevention studies," Sánchez-Juan adds.
Silva Rodríguez contextualises the findings: "It is important to understand that what we knew until now about these biomarkers is that they could provide a biological diagnosis of the disease with great precision (who has amyloid or tau protein accumulating in the brain). However, we knew very little about how to interpret these results, especially in the context of a healthy individual."