Unravelling the plasma proteome: Pioneering biomarkers for differential dementia diagnosis

Diagnosing Alzheimer's disease (AD) is challenging due to overlapping symptoms with other dementias and the invasiveness of current biomarkers. This study introduces the NULISA platform, a novel proteomics technology, to evaluate diagnostic accuracy of known biomarkers and uncover novel biomarkers underlying different dementias.

We analyzed plasma and cerebrospinal fluid (CSF) samples from 248 participants diagnosed with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and mild cognitive impairment (MCI). Plasma biomarkers were evaluated using regression models, receiver operating characteristics curve (ROC) analysis, and pathway enrichment.

Plasma phosphorylated Tau217 (pTau217) demonstrated the highest diagnostic accuracy for AD, DLB, and FTD (area under the curve [AUCs]: 0.9, 0.84, and 0.79, respectively). CXCL1 (fractalkine), synaptosomal-associated protein 25 (SNAP25), triggering receptor expressed on myeloid cells 1 (TREM1), β-synuclein, and tyrosine kinase (TEK) are expressed differently in DLB and FTD than AD. Ingenuity pathway analyses revealed astrocytic, synaptic, and inflammatory pathways as shared and distinct mechanisms across these dementia types.

Our findings establish plasma pTau217 as a robust diagnostic marker. This study provides new plasma biomarkers for differential diagnosis of dementias with a noninvasive method.

Plasma pTau217 showed high diagnostic accuracy for AD, DLB, and FTD. CXCL1, SNAP25, TREM1, β-synuclein, and TEK are novel markers distinguishing other dementias from AD. Noninvasive plasma biomarkers enable diagnosis and differentiation of dementias.