Serum brain-derived p-tau 217 and SV2A Reduce Peripheral Interference in Alzheimer's Disease: A Multicohort Study

Abstract Importance Recently, increasing studies have demonstrated that blood p-tau 217, the most promising diagnostic biomarker for Alzheimer's disease (AD), is increased and originated from muscle damage in amyotrophic lateral sclerosis (ALS) patients. These findings suggested that blood total p-tau 217 may partly derive from muscle damage. Thus, there is an urgent need for identifying blood brain-derived p-tau 217, but not blood total p-tau 217 which may contain muscle-derived p-tau 217, and other brain-derived biomarkers in order to reduce the potential peripheral interference in its adoption in assisting early diagnosis in AD patients. Objective To explore whether serum brain-derived p-tau 217 is a more promising diagnostic biomarker and has less peripheral interference than total p-tau 217 for AD patients in a large multicentre cohort. To examine whether serum synaptic vesicle glycoprotein 2A (SV2A) is a potential biomarker for assessing brain damage in AD patients. To examine whether serum p-tau 217 is a specific lower motor neuron (LMN) damage biomarker for ALS patients. Design, Setting, and Participants This cross-sectional study was conducted in 3 independent cohorts and a total of 1198 participants, including 325 AD patients, 235 ALS patients, 289 LMN disease controls (LMNDCs), 145 dementia controls (DDCs), and 204 cognitive intact healthy controls (CIHCs). Main Outcomes and Measures Serum brain-derived p-tau 217, total p-tau 217, SV2A, and NfL were measured based on single molecular detection technique. Results Serum brain-derived p-tau 217 was significantly increased in AD patients compared to ALS patients, DDCs, LMNDCs and CIHCs, while serum p-tau 217 was significantly increased in both ALS patients and AD patients compared to DDCs, LMNDCs and CIHCs after familywise error correction (p < 0.05). Serum SV2A was significantly decreased in AD patients than in other groups. Moreover, area under the curve for serum brain-derived p-tau 217 in differentiating AD from other groups were 0.927-0.954. Conclusions and Relevance Our findings suggest that serum brain-derived p-tau 217 and SV2A are more specific diagnostic biomarkers for reflecting brain damage and may not be disturbed by peripheral damage for AD patients. Moreover, we suggest that serum p-tau 217 is a specific LMN damage biomarker for ALS patients. Keywords: AD, ALS, p-tau 217, brain-derived p-tau 217, SV2A