On the design of early-phase Alzheimer’s disease clinical trials with cerebrospinal fluid tau outcomes

Abstract

Background/Aims: The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power. Methods: We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes. Results: Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau. Conclusion: Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.

Treatment of Alzheimer’s disease by combination of acupuncture and Chinese medicine based on pathophysiological mechanism: A review

“…[ 1 ] In 2018, National Institute on Aging (NIA) and the Alzheimer’s Association for Alzheimer’s Disease (AA) proposed a framework for the study of amyloid, Tau, and neurodegeneration (ATN) for the definition and diagnosis of AD, [ 2 ] which enabled AD to move from a clinical-biological diagnosis to a purely biological definition applicable to both asymptomatic and symptomatic stages. However, the purely biological definition of AD itself has limitations, and the NIA-AA standard in 2018 [ 2 , 3 ] has caused a lot of debate regarding the use of biomarkers for the diagnosis of AD and the use of clinical signs, symptoms, and phenotypes. [ 4 , 5 ] Therefore, nearly 4 years after the introduction of the NIA-AA criteria, the academic community began to reassess methods of diagnosing AD based on biomarkers.…”

Hsp multichaperone complex buffers pathologically modified Tau

“…Ample evidence exists that hyperphosphorylated Tau accumulates during the development of Alzheimer's disease 1 . Tau phosphorylated at specific sites is actively investigated as biomarker for characterizing early phases of the disease 16,17 . In addition, Tau acetylation is linked to pathogenic aggregation and neurotoxicity 18 , and the reduction of acetylated Tau is neuroprotective 19 .…”

Hsp multichaperone complex buffers pathologically modified Tau

“…1 Tau phosphorylated at specific sites is actively investigated as biomarker for characterizing early phases of the disease. 16,17 In addition, Tau acetylation is linked to pathogenic aggregation and neurotoxicity, 18 and the reduction of acetylated Tau is neuroprotective. 19 Post-translational modifications of Tau such as phosphorylation and acetylation might further play important roles in determining different Tau aggregate structures (strains) and thus underlie different tauopathies.…”