NEW YORK – A team from Iceland, the US, and Spain has identified blood protein markers that coincide with late-onset Alzheimer's disease (LOAD), including those dependent or independent of individuals' APOE4 risk status.
"Our results add considerably to the number of circulating proteins that have been associated specifically with Alzheimer's disease, and remarkably, some of these are already known to be highly altered in the brains of Alzheimer’s patients," co-senior and co-corresponding authors Vilmundur Gudnason and Valborg Gudmundsdottir, both researchers at the University of Iceland, said in a joint email.
For a study appearing in Nature Aging on Wednesday, researchers at the University of Iceland, Emory University, the International University of Catalonia, and elsewhere used SomaLogic SomaScan-based high-throughput proteomic analyses to assess protein patterns in blood serum samples from 5,127 elderly Icelandic individuals participating in the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES).
"This large prospective cohort study, using both a longitudinal and a cross-sectional design, represents a unified and comprehensive reference analysis with which past and future serum protein biomarkers can be considered, compared, and evaluated," the authors wrote.
The team noted that all of the participants in AGES were evaluated for subsequent dementia via medical records, nursing home reports, or death certificates, while 3,411 of the individuals actively took part in a follow-up visit at the five year mark.
Along with clinical data spanning nearly 13 years of follow-up time, on average, the researchers focused in on 303 proteins that coincided with LOAD development.
Of these blood protein markers, 43 percent appeared to be independent of APOE4 risk factors — a set that encompassed proteins involved in neuronal pathways such as neuron morphogenesis, axon development, or neural cell adhesion in a subsequent gene set enrichment analysis.
Intriguingly, at least some blood protein changes that preceded the clinical symptoms associated with Alzheimer's disease overlapped with Alzheimer's-associated proteins previously found in the brain or cerebrospinal fluid.
Together, Gudmundsdottir and Gudnason explained, the results suggest presymptomatic blood proteins involved in neurological processes "can potentially be harnessed as biomarkers to inform on prodromal Alzheimer’s disease and its progression."
Within the remaining LOAD-related protein set, the team highlighted 17 proteins with strong ties to APOE4 status, including four that were upregulated in LOAD but nevertheless appeared to be dialed down prior to the development of symptoms in participants carrying the APOE4 allele.
"[W]e are, in particular, interested in a set of proteins that are strongly downregulated by APOE4 but yet seem to be upregulated as a response to the disease onset, hinting at a potentially protective pathway," Gudmundsdottir and Gudnason noted.
The duo explained that further study of the potential blood protein markers "may reveal specific pathways that contribute to Alzheimer's disease pathogenesis and could even be therapeutically targeted in the future," though they warned that the current findings argue against a "one size fits all" approach to biomarker use and drug targeting.
"This is an important consideration when developing therapeutic interventions," Gudmundsdottir and Gudnason said, "as their effectiveness may vary based on a patient's genetic and molecular risk profile."