PLASMA PROTEOLYTIC IMBALANCE AS A SIGNATURE TO DIFFERENTIATE ALZHEIMER’S DISEASE FROM FRONTOTEMPORAL AND LEWY BODY DEMENTIAS

Differential diagnosis among dementia syndromes remains challenging in clinical practice. The aim of this study is to investigated whether plasma markers of altered proteolysis, particularly ADAM10 and functionally related proteins involved in APP processing, can discriminate Alzheimer’s disease (AD) from frontotemporal dementia (FTD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB).
For that, plasma samples from 35 older adults (AD = 10; FTD = 10; PDD = 8; DLB = 7) were analyzed using ELISA to quantify sADAM10, ADAM9, TIMP1, TIMP3, Aβ40, Aβ42, α-synuclein (α-syn), phosphorylated α-syn (p-α-syn), t-tau, p-tau181, NfL and GFAP. Group comparisons, correlation analyses, elastic net regression and ROC curves were performed to explore diagnostic utility.
Our results showed that ADAM10 levels were consistently lower in AD than in the other dementia groups, whereas ADAM9 levels were higher, indicating a proteolytic imbalance specific to AD. Reduced TIMP3 levels and a decreased ADAM10/ADAM9 ratio further supported impaired non-amyloidogenic APP processing in AD. In contrast, PDD and DLB displayed higher p-α-syn and p-tau181 levels, reflecting a synuclein- and tau-related pathological profile characteristic of synucleinopathies. Elastic net modeling identified biomarker combinations with the highest discriminative value: sADAM10 + ADAM9 + TIMP3 for AD, sADAM10 + p-α-syn + TIMP1 for FTD and sADAM10 + p-tau181 for PDD.
In conclusion, dementia subtypes exhibit distinct plasma biomarker signatures. Altered proteolysis differentiates AD, while phosphorylated α-syn and tau species distinguish synucleinopathies. These findings support the diagnostic potential of integrated biomarker panels to improve differential diagnosis of dementia.