Cerebrospinal fluid tau and ptau₁₈₁ increase with cortical amyloid deposition in cognitively normal individuals: Implications for future clinical trials of Alzheimer's disease

Alzheimer's disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. We previously reported that cerebrospinal fluid (CSF) levels of amyloid-β₄₂ (Aβ₄₂) serve as an excellent marker for brain amyloid as detected by the amyloid tracer, Pittsburgh compound B (PIB). Using data from 189 cognitively normal participants, we now report a positive linear relation ship between CSF tau/ptau₁₈₁ (primary constituents of neurofibrillary tangles) with the amount of cortical amyloid. We observe a strong inverse relationship of cortical PIB binding with CSF Aβ₄₂ but not for plasma Aβ species. Some individuals have low CSF Aβ₄₂ but no cortical PIB binding. Together, these data suggest that changes in brain Aβ₄₂ metabolism and amyloid formation are early pathogenic events in AD, and that significant disruptions in CSF tau metabolism likely occur after Aβ₄₂ initially aggregates and increases as amyloid accumulates. These findings have important implications for preclinical AD diagnosis and treatment.