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INTRODUCTION: We evaluated differences in p-tau levels between Alzheimer's disease (AD), a condition with brain-specific changes in p-tau, and amyotrophic lateral sclerosis (ALS), a condition associated with increases in peripheral p-tau levels.

METHODS: Cerebrospinal fluid and plasma from 668 participants were analyzed using immunoassays specific for the low-molecular-weight (LMW) tau isoforms present in the brain (i.e., p-tau217Lilly, p-tau181Lilly) and those that detect both LMW- and high-molecular-weight (HMW) tau expressed in the peripheral nervous system (i.e., p-tau217AlzPath, p-tau181UGOT).

RESULTS: Increases in plasma p-tau in ALS versus controls were significantly smaller for the LMW-specific p-tau assays (15.9%–20.5%) compared with non-specific assays (92.0%–121.3%). The LMW-specific p-tau assays showed significantly larger plasma p-tau increases in AD versus ALS, discriminating AD from ALS with areas under the curve (AUCs; 0.890.93) higher than the AUCs of the non-specific assays (0.54–0.74).

DISCUSSION: LMW-specific p-tau assays could be more useful in the diagnostic workup of AD, especially in population-based communities where conditions causing peripheral neuropathy are frequent.