Advances in peripheral blood biomarkers of patients with Alzheimer’s disease: Moving closer to personalized therapies

Recently, measurable peripheral biomarkers in the plasma of patients with Alzheimer's disease (AD) have gained considerable clinical interest. Several studies have identified one or more blood signatures that may facilitate the development of novel diagnostic and therapeutic strategies. For instance, changes in peripheral amyloid β42 (Aβ42) levels have been largely investigated in patients with AD and correlated with the progression of the pathology, although with controversial results. In addition, tumor necrosis factor α (TNFα) has been identified as an inflammatory biomarker strongly associated with AD, and several studies have consistently suggested the pharmacological targeting of TNFα to reduce systemic inflammation and prevent neurotoxicity in AD. Moreover, alterations in plasma metabolite levels appear to predict the progression of systemic processes relevant to brain functions. In this study, we analyzed the changes in the levels of Aβ42, TNFα, and plasma metabolites in subjects with AD and compared the results with those in healthy elderly (HE) subjects. Differences in plasma metabolites of patients with AD were analyzed with respect to Aβ42, TNFα, and the Mini-Mental State Examination (MMSE) score, searching for plasma signatures that changed simultaneously. In addition, the phosphorylation levels of the Tyr682 residue of the amyloid precursor protein (APP), which we previously proposed as a biomarker of AD, were measured in five HE and five AD patients, in whom the levels of Aβ42, TNFα, and two plasma lipid metabolites increased simultaneously. Overall, this study highlights the potential of combining different plasma signatures to define specific clinical phenotypes of patient subgroups, thus paving the way for the stratification of patients with AD and development of personalized approaches.