Alzheimer’s disease (AD) is a neurodegenerative disorder associated with progressive damage in brain functions. It is the most prevalent form of dementia, with about 1 in 20 people over the age of 65 developing the condition. "AD is probably caused by a complex interplay between both genetic and environmental factors," explains BioALFA project coordinator Marc Suárez-Calvet, a neurologist at the BarcelonaBeta Brain Research Center (BBRC), Spain. “Although we have made considerable advances in our understanding of the mechanisms of AD, there has been little progress in translating this knowledge to therapies that modify disease progression.” Suárez-Calvet notes that therapies targeting the main risk factor of AD – ageing – have been relatively underexplored. This, he says, is probably due to a lack of knowledge of the mechanisms that link ageing with AD. “Another important issue is that most clinical trials have been done in patients that have already developed dementia,” he adds. “AD has a long asymptomatic preclinical stage and it is becoming clear that the earlier we treat AD, the higher the chances of success.”
Observing preclinical stages
To address this research gap, BioALFA sought to learn more about the preclinical stages of AD. His research was undertaken with the support of the Marie Skłodowska-Curie Actions programme. A key aim was to detect, in humans, certain factors in blood that were found to have a rejuvenating or ageing effect on the brains of mice. Analytical procedures were developed and applied to a group of 400 cognitively unimpaired individuals, some of them in the preclinical stage of AD. “During the first phase of the project we focused on developing and validating blood biomarker assays,” explains Suárez-Calvet. “We tested different antibodies and trialled a range of commercial assays. This enabled us to select those which rendered the more robust results.” The project team next conducted a pilot study in which rejuvenating and ageing blood factors were measured across a range of ages. The group included teenagers, young adults and older adults. Umbilical cord plasma was also used. In this pilot study, Suárez-Calvet and his colleagues observed that certain ageing blood factors – beta2-microglobulin (beta2-M), Eotaxin-1 and MCP1 – increase with ageing. On the other hand, oxytocin, a rejuvenating blood factor, was found at much higher levels in umbilical cord plasma. Interestingly, higher levels of oxytocin were associated with lower levels of neurofilament (NfL), a marker of neuronal injury, in younger adults. Higher levels of beta2-M and MCP1 were linked with higher levels of NfL in older adults.
New therapeutic targets
By the end of the project, BioALFA had achieved its key aim, which was to measure all rejuvenating and ageing blood factors within the target group. Moreover, this project also measured other blood and cerebrospinal fluid (CSF) biomarkers in participants, which could have relevance for AD development and neurodegeneration. The results have just been accepted for publication in ‘Alzheimer’s and Dementia’. “We are optimistic that we will be able to publish our results later this year,” Suárez-Calvet adds. “Once we have finished analysing the data, we are also confident that we will be able to see whether the ageing and rejuvenating blood factors are associated with neurodegeneration in preclinical AD.” Over the long term, this will help to confirm whether certain blood factors have an effect on brain health and are therapeutic targets worth pursuing.
BioALFA, Alzheimer’s, neurodegenerative, brain, disease, ageing, blood, dementia, cognitively