A newly identified protein marker in the blood shows promise for earlier detection of Alzheimer’s disease, potentially years before the onset of clinical symptoms, according to a study published this month in Cell Reports Medicine. Researchers found that declining levels of protein phosphatase 2 regulatory subunit B’β (PPP2R5C) correlate with the early stages of Alzheimer’s pathology.
Alzheimer’s disease, the most prevalent form of dementia, is characterized by a slow, progressive decline in cognitive function. Current diagnostic methods, such as positron emission tomography (PET) scans and cerebrospinal fluid (CSF) analysis, are invasive and expensive, hindering widespread employ. This creates a critical need for accessible and reliable biomarkers that can identify the disease in its preclinical phases, when interventions may be most effective.
The study focused on the role of tau protein, a key component of the neurofibrillary tangles that accumulate in the brains of Alzheimer’s patients. Hyperphosphorylation of tau disrupts its normal function, leading to neuronal dysfunction and cell death. PPP2R5C, a regulatory subunit of protein phosphatase 2A (PP2A) – an enzyme responsible for approximately 70% of tau phosphatase activity in the human brain – emerged as a potential candidate for an early biomarker.
Researchers initially analyzed neuron-derived exosomes (NDEs) isolated from plasma samples of four cognitively normal individuals, four individuals with presymptomatic familial Alzheimer’s disease, and five with familial Alzheimer’s disease. Proteomic analysis revealed a progressive decrease in a PPP2R5C-specific peptide as the disease progressed from the presymptomatic stage to full-blown familial Alzheimer’s, compared to the cognitively normal group. This observation was then validated in a larger cohort of 32 cognitively normal controls, 20 sporadic Alzheimer’s patients, and 12 individuals with amnestic mild cognitive impairment (aMCI).
Recognizing the technical challenges of isolating NDEs from plasma, the researchers also examined total plasma PPP2R5C levels. Analysis of a cohort of 15 familial Alzheimer’s patients and 15 cognitively normal controls showed significantly lower PPP2R5C levels in the Alzheimer’s group. Further analysis indicated that PPP2R5C levels were approximately 61.3% lower in aMCI patients and 31.6% lower in Alzheimer’s patients compared to cognitively normal controls. Alzheimer’s patients exhibited 52.1% lower plasma PPP2R5C levels than those with aMCI.
The biomarker demonstrated a moderate ability to distinguish between groups. Plasma PPP2R5C distinguished Alzheimer’s disease from cognitively normal controls with an area under the receiver operating characteristic curve (AUROC) of 0.8494, and differentiated aMCI from controls with an AUROC of 0.7360. However, its ability to differentiate between aMCI and Alzheimer’s disease was limited, with an AUROC of 0.5931.
Importantly, plasma PPP2R5C levels correlated with cognitive performance, as measured by the Mini-Mental State Examination (MMSE), and were inversely related to levels of phosphorylated tau proteins (p-tau181, p-tau217, and p-tau231) in the plasma, reinforcing its connection to Alzheimer’s pathology. Postmortem brain tissue analysis revealed lower PPP2R5C levels in aged Alzheimer’s patients compared to younger, cognitively normal individuals and aged, cognitively normal individuals, suggesting that aging alone does not significantly reduce PPP2R5C expression.
Further investigation into the mechanism of action revealed that PPP2R5C interacts directly with tau protein. Increasing PPP2R5C expression reduced phosphorylated tau and total tau levels, while simultaneously enhancing PP2A enzymatic activity. Conversely, silencing PPP2R5C decreased PP2A activity, suggesting a direct regulatory role rather than a mere correlation. The study also found that PPP2R5C promotes tau degradation through the autophagolysosomal pathway, a cellular process responsible for clearing damaged proteins.
Researchers demonstrated that PPP2R5C expression decreased as early as Braak stage II, a relatively early stage of Alzheimer’s pathology characterized by limited neurofibrillary tangle formation. PPP2R5C levels remained consistently low in later Braak stages (II and IV) despite increasing tangle accumulation, suggesting that the reduction in PPP2R5C may occur before widespread tau pathology.
While the findings are promising, the researchers emphasize the need for larger, longitudinal studies with more diverse populations to validate these results. Standardization of the assay and ensuring reproducibility are also crucial steps before plasma PPP2R5C can be implemented in clinical practice for early Alzheimer’s diagnosis.