Researchers have identified a potential blood biomarker, PPP2R5C, that may help detect Alzheimer’s disease (AD) at an earlier stage. The findings were published in Cell Reports Medicine and highlight the importance of early diagnosis in AD, which often begins years before symptoms appear.
Alzheimer’s disease is the most common form of dementia and primarily affects older adults. Current diagnostic methods such as PET imaging and cerebrospinal fluid analysis are invasive and expensive, making them difficult to use widely. Scientists have been searching for more accessible biomarkers that could signal the onset of AD before significant cognitive decline occurs.
The study focused on tau protein hyperphosphorylation—a key feature in AD that leads to neurofibrillary tangles and neuronal damage. Since regulators of tau phosphorylation might serve as effective biomarkers, researchers examined PPP2R5C, a regulatory subunit of protein phosphatase 2A (PP2A), which is responsible for most tau dephosphorylation activity in the brain.
The research involved analyzing neuron-derived exosomes from plasma samples across several groups: cognitively normal individuals, presymptomatic familial AD participants, and patients with familial AD. The results showed that levels of a specific PPP2R5C peptide decreased progressively from healthy controls to those with advanced disease.
These findings were validated in another group including cognitively normal controls, sporadic AD patients, and people with amnestic mild cognitive impairment (aMCI). Reduced PPP2R5C expression was observed in those with early signs of Alzheimer’s pathology.
To simplify testing for clinical settings, researchers also measured total plasma PPP2R5C rather than isolating neuron-derived exosomes. In this analysis, lower levels of plasma PPP2R5C were found among AD patients compared to controls. Specifically, plasma PPP2R5C was about 61% lower in individuals with aMCI and 32% lower in those with diagnosed AD when compared to healthy controls; there was also a notable difference between aMCI and AD groups.
Plasma PPP2R5C distinguished Alzheimer’s patients from healthy controls with good accuracy based on area under the receiver operating characteristic curve (AUROC) values but had limited ability to differentiate between stages within affected groups.
Further tests revealed positive associations between plasma PPP2R5C levels and cognitive function scores while showing negative correlations with established markers of tau pathology. Postmortem brain tissue analysis confirmed reduced expression of PPP2R5C specifically among aged Alzheimer’s patients but not simply due to aging alone.
Laboratory experiments demonstrated that increasing PPP2R5C led to less phosphorylated tau protein through enhanced PP2A activity. Additional tests indicated this process depended on autophagy-lysosome pathways involving ULK1 kinase signaling.
The authors noted: “Collectively, findings suggest PPP2R5C may serve as a plasma biomarker candidate associated with early AD pathological processes. Reduced PPP2R5C appeared to precede tau hyperphosphorylation and was not observed in cognitively normal aged individuals.”
However, they cautioned: “Larger, longitudinal, and ethnically diverse cohort studies are needed to validate these findings. Assay standardization and reproducibility studies will be essential before plasma PPP2R5C can be incorporated into routine clinical screening or early diagnostic workflows for Alzheimer’s disease.”
