New markers identified to detect preclinical phase of Alzheimer's
An international team of researchers, led at Barcelonaβeta Brain Research Center (BBRC), together with the support of the La Caixa Foundation, has discovered that a series of biomarkers, recently described to detect the most advanced phase of Alzheimer's, can also detect the preclinical phase of the disease in the cerebrospinal fluid and in the blood.
The results point to the potential role of tau protein as a therapeutic target even for the prevention of dementia associated with Alzheimer's, and will make it possible to improve the selection of participants in clinical trials for the disease.
An international study led by the Pasqual Maragall Foundation's research centre, the Barcelonaβeta Brain Research Center (BBRC), promoted by the "la Caixa" Foundation, has analysed a series of new biomarkers of phosphorylated tau protein (or p-tau, its acronym in English), which is one of the hallmarks of Alzheimer's, to find out if they are also capable of detecting the preclinical phase of the disease.
The results of the study show that some of the biomarkers that have recently been described to diagnose Alzheimer's in the dementia phase can also detect the initial phase of the disease in blood plasma (this is the case of the p-tau181 biomarker), and in the cerebrospinal fluid (p-tau217 and p-tau231).
According to the neurologist and first author of the study at the BBRC, Dr. Marc Suárez-Calvet, "our findings open the door to developing new ways of detecting the preclinical phase of Alzheimer's and to enriching the selection of participants for intervention or observational studies aimed at this asymptomatic phase of the disease".
In this sense, Dr. Thomas Karikari, co-leader of the study at the University of Gothenburg, points out that "one of the possible ways to improve the success of developing drugs to treat Alzheimer's is to test them on people who are at the beginning of the preclinical phase, when very subtle changes occur in the brain that are very difficult to measure. Our findings also show the potential of the highly sensitive tools we have developed to advance in the early detection and clinical trials of the disease.
The study was published in the EMBO Molecular Medicine journal, and involved researchers from the University of Gothenburg, the Hospital del Mar and Hospital del Mar Medical Research Institute (IMIM), and the Center for Biomedical Research on the Fragility and Healthy Aging Network (CIBERFES).
Many years before the onset of Alzheimer's symptoms, two neuropathological events occur in the brain that currently confirm the diagnosis of the disease: the formation of neurofibrillary tangles of the tau protein, and the accumulation of plaques of the beta amyloid protein.
The tau protein added to the tangles formed in the brain is abnormally hyperphosphorylated in the Alzheimer's disease continuum. One of the most widespread ways of detecting it, both in the preclinical phase and when there are already symptoms, is by measuring the p-tau181 biomarker in the cerebrospinal fluid.
In recent months different studies have come to light that suggest that it is possible to diagnose Alzheimer's and define the degree of the disease by analysing other biomarkers of the tau protein. The aim of this study has been to check whether these new biomarkers discovered are also effective in detecting the preclinical phase of the disease.
The research was carried out on 381 participants in the BBRC's Alfa + Study, promoted by the "la Caixa" Foundation. These participants are between 45 and 75 years of age, most of whom are descendants of people with Alzheimer's disease, and regularly attend the BBRC for clinical, nursing, neuroimaging and cognitive tests. The participants do not have cognitive alterations, but some do have biomarkers associated with the preclinical phase of the disease.
The Alpha Study is one of the largest and best characterized cohorts in the world dedicated to research into the preclinical phase of Alzheimer's. Thanks to the extensive data available to the participants, the researchers have been able to analyse the presence of these new tau protein biomarkers and contrast it with measurements of other biomarkers in samples of cerebrospinal fluid, blood and neuroimaging tests such as positron emission tomography.
The results of the research have revealed that the biomarkers p-tau181, p- tau217 and p-tau231 serve to detect the preclinical phase of Alzheimer's, even when only very subtle changes in the pathology of the beta amyloid protein are detected. Likewise, they are capable of differentiating participants with and without amyloid pathology. "Our research suggests that in the preclinical phase of Alzheimer's disease very early changes in tau metabolism occur, following changes in the metabolism of the beta amyloid protein. Therefore, this suggests the potential role of tau protein as a therapeutic target even for the prevention of dementia associated with Alzheimer's," explains Dr. José Luis Molinuevo, driving force behind the BBRC's Alzheimer's Prevention Programme and lead author of the study.
On the other hand, Dr. Suárez-Calvet points out that the biomarker detected in blood "may change clinical practice in the coming years, as it will make it possible to improve the diagnosis of patients with Alzheimer's disease, both in its asymptomatic and symptomatic phases". BBRC researchers will continue to develop this line of research in a new laboratory equipped with the most advanced techniques for determining these and other Alzheimer's disease biomarkers.
Suárez-Calvet M, Karikari T, Ashton N, Lantero-Rodríguez J, Milà-Alomà M, Gispert JD, Salvadó G, Minguillón C, Fauria K, Shekari M, Grau-Rivera O, Arenaza-Urquijo E, Sala-Vila A, Sánchez-Benavides G, González-de-Echábarri J, Kollmorgen G, Stoops E, Vanmechelen E, Zetterberg H, Blennow K, Molinuevo JL. Novel tau biomarkers phosphorylated at T81, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Aβ pathology are detected. EMBO. Molecular Medicine. November 2020