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Original Investigation
May 2017

Neurofibrillary Tangle Stage and the Rate of Progression of Alzheimer SymptomsModeling Using an Autopsy Cohort and Application to Clinical Trial Design

Author Affiliations
  • 1Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst
  • 2Neurology Service, Massachusetts General Hospital, Charlestown, Massachusetts
  • 3Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
JAMA Neurol. 2017;74(5):540-548. doi:10.1001/jamaneurol.2016.5953
Key Points

Question  Does knowing the relative burden of neurofibrillary tangles help predict the rate of progression in Alzheimer’s disease?

Findings  Using extensive statistical modeling of data from a large national data set of autopsy patients with confirmed Alzheimer disease, we determined relative rates of change on various neuropsychological tests for groups of individuals with various extents of neurofibrillary tangles and showed that knowledge of tangle burden improves the chance of predicting rate of progression during a 2- to 3-year period.

Meaning  Knowledge of tangle burden, such as might be available from tau positron-emission tomographic scans in patients, may improve clinical trial design by decreasing heterogeneity and potentially improve counseling of patients regarding disease progression.

Abstract

Importance  The heterogeneity of rate of clinical progression among patients with Alzheimer disease leads to difficulty in providing clinical counseling and diminishes the power of clinical trials using disease-modifying agents.

Objective  To gain a better understanding of the factors that affect the natural history of progression in Alzheimer disease for the purpose of improving both clinical care and clinical trial design.

Design, Setting, and Participants  A longitudinal cohort study of aging from 2005 to 2014 in the National Alzheimer Coordinating Center. Clinical evaluation of the participants was conducted in 31 National Institute on Aging’s Alzheimer Disease Centers. Nine hundred eighty-four participants in the National Alzheimer Coordinating Center cohort study who died and underwent autopsy and met inclusion and exclusion criteria.

Main Outcomes and Measures  We sought to model the possibility that knowledge of neurofibrillary tangle burden in the presence of moderate or frequent plaques would add to the ability to predict clinical rate of progression during the ensuing 2 to 3 years. We examined the National Alzheimer Coordinating Center autopsy data to evaluate the effect of different neurofibrillary tangle stages on the rates of progression on several standard clinical instruments: the Clinical Dementia Rating Scale sum of boxes, a verbal memory test (logical memory), and a controlled oral word association task (vegetable naming), implementing a reverse-time longitudinal modeling approach in conjunction with latent class estimation to adjust for unmeasured sources of heterogeneity.

Results  Several correlations between clinical variables and neurocognitive performance suggest a basis for heterogeneity: Higher education level was associated with lower Clinical Dementia Rating Scale sum of boxes (β = −0.19; P < .001), and frequent vs moderate neuritic plaques were associated with higher Clinical Dementia Rating Scale sum of boxes (β = 1.64; P < .001) and lower logical memory score (β = −1.07; P = .005). The rate of change of the clinical and cognitive scores varied depending on Braak stage, when adjusting for plaques, age of death, sex, education, and APOE genotype. For example, comparing high vs low Braak stage with other variables fixed, the logical memory score decreased a substantial 0.38 additional units per year (95% CI, −0.70 to −0.06; P = .02). Using these data, we estimate that a 300-participant clinical trial with end point of a 20% improvement in slope in rate of change of Clinical Dementia Rating Scale sum of boxes has 89% power when all participants in the trial are from the high Braak stage, compared with 29% power if Braak stage had not used for eligibility.

Conclusions and Relevance  We found that knowledge of neurofibrillary tangle stage, modeled as the sort of information that could be available from tau positron-emission tomography scans and its use to determine eligibility to a trial, could dramatically improve the power of clinical trials and equivalently reduce the required sample sizes of clinical trials.

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