Work

Routine implementation of α-synuclein Seed Amplification Assays reveals high diagnostic performance and the limited value of Alzheimer disease fluid biomarkers for detecting α-synuclein co-pathology

Year: 2026

Type: preprint

Abstract: Background In neurodegenerative diseases, the diagnostic value of α-synuclein seed amplification assay (αSAA) in routine clinical practice and its relationship with cognitive performance and fluid biomarkers remains incompletely characterized. In addition, although Alzheimer disease (AD) CSF and blood biomarkers accurately detect amyloid and tau pathology, their ability to identify concomitant α-synuclein (αSyn) pathology remains unknown. Methods We included 398 patients from the multicenter memory clinic ALZAN cohort. All participants underwent CSF and blood sampling with measurement of CSF biomarkers (Aβ42/40, tau, p-tau181) and plasma biomarkers (Aβ42/40, p-tau181, p-tau217, GFAP, NfL). Cognitive assessment was performed using the Mini-Mental State Examination (MMSE). Clinical diagnoses were independently confirmed by two senior neurologists. αSyn status was determined by αSAA (RT-QuIC). Results Of 398 patients, 19/20 patients with Lewy body dementia (LBD) (95.0%) and 32/203 patients with AD (15.8%) were αSAA+. αSAA-positivity presented a sensitivity of 95.0% (95%CI, 75.1-99.9), a specificity of 93.1% (95%CI, 88.3-96.4) for distinguishing LBD from patients without LBD or AD. In the entire cohort, αSAA+ patients showed lower MMSE scores (p<0.01), lower CSF Aβ42/40 ratio (p<0.01), and elevated plasma GFAP (p<0.05). However, within the AD subgroup, only CSF Aβ42/40 differed marginally between αSAA+ and αSAA- patients, whereas CSF total tau, CSF p-tau181, plasma p-tau217, p-tau181, GFAP, and NfL showed no significant differences. Conclusions αSAA accurately detects αSyn pathology in routine memory clinic practice that is not captured by current AD CSF and blood biomarkers. These findings support αSAA as a complementary biomarker for routine diagnosis and patient stratification. What is already known on this topic α-synuclein seed amplification assay (αSAA) has shown high sensitivity and specificity for detecting Lewy body dementia (LBD) in research cohorts, and α-synuclein co-pathology is frequently observed in Alzheimer’s disease (AD). However, it remains unknown whether currently available AD CSF and blood biomarkers can identify patients with α-synuclein pathology in routine clinical practice. What this study adds In a prospective multicenter memory clinic cohort, αSAA showed high sensitivity (95.0%) and specificity (93.5%) for identifying clinically diagnosed LBD and detected αSyn co-pathology in 15.8% of AD patients. Current AD CSF and blood biomarkers did not discriminate between αSAA-positive and αSAA-negative patients, providing little information on concomitant αSyn pathology. How this study might affect research, practice or policy αSAA provides unique biological information by improving the detection of LBD and identifying AD patients with concomitant αSyn co-pathology that is not captured by current CSF and blood biomarkers, thereby improving patient stratification and informing future precision medicine approaches and therapeutic trials.

Source: medRxiv

DOI: 10.64898/2026.04.21.26351389