Global neuropathologic severity of Alzheimer's disease and locus coeruleus vulnerability influences plasma phosphorylated tau levels

Background: Advances in ultrasensitive detection of phosphorylated tau (p-tau) in plasma has enabled the use of blood tests to measure Alzheimer's disease (AD) biomarker changes. Examination of postmortem brains of participants with antemortem plasma p-tau levels remains critical to understanding comorbid and AD-specific contribution to these biomarker changes. Methods: We analyzed 35 population-based Mayo Clinic Study of Aging participants with plasma p-tau at threonine 181 and threonine 217 (p-tau181, p-tau217) available within 3 years of death. Autopsied participants included cognitively unimpaired, mild cognitive impairment, AD dementia, and non-AD neurodegenerative disorders. Global neuropathologic scales of tau, amyloid-beta, TDP-43, and cerebrovascular disease were examined. Regional digital pathology measures of tau (phosphorylated threonine 181 and 217 [pT181, pT217]) and amyloid-beta (6F/3D) were quantified in hippocampus and parietal cortex. Neurotransmitter hubs reported to influence development of tangles (nucleus basalis of Meynert) and amyloid-beta plaques (locus coeruleus) were evaluated. Results: The strongest regional associations were with parietal cortex for tau burden (p-tau181 R = 0.55, p = 0.003; p-tau217 R = 0.66, p < 0.001) and amyloid-beta burden (p-tau181 R = 0.59, p < 0.001; p-tau217 R = 0.71, p < 0.001). Linear regression analysis of global neuropathologic scales explained 31% of variability in plasma p-tau181 (Adj. R-2 = 0.31) and 59% in plasma p-tau217 (Adj. R-2 = 0.59). Neither TDP-43 nor cerebrovascular disease global scales independently contributed to variability. Global scales of tau pathology (beta-coefficient = 0.060, p = 0.016) and amyloid-beta pathology (beta-coefficient = 0.080, p < 0.001) independently predicted plasma p-tau217 when modeled together with co-pathologies, but only amyloid-beta (beta-coefficient = 0.33, p = 0.021) significantly predicted plasma p-tau181. While nucleus basalis of Meynert neuron count/mm(2) was not associated with plasma p-tau levels, a lower locus coeruleus neuron count/mm(2) was associated with higher plasma p-tau181 (R = -0.50, p = 0.007) and higher plasma p-tau217 (R = -0.55, p = 0.002). Cognitive scores (Adj. R-2 = 0.25-0.32) were predicted by the global tau scale, but not by the global amyloid-beta scale or plasma p-tau when modeled simultaneously. Conclusions: Higher soluble plasma p-tau levels may be the result of an intersection between insoluble deposits of amyloid-beta and tau accumulation in brain, and may be associated with locus coeruleus degeneration.