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Assistant Professor of Radiology, Weill Cornell Medical College
Dr. Chiang reports no financial relationships relevant to this field of study.
SYNOPSIS: tau PET imaging shows progression of brain Alzheimer’s pathology over time and correlates with cognitive impairment better than amyloid PET. In future clinical trials, tau PET can serve as a biomarker for Alzheimer’s disease progression.
SOURCE: Jack CR Jr, Wiste HJ, Schwarz CG, et al. Longitudinal tau PET in ageing and Alzheimer’s disease. Brain 2018;141:1517-1528.
Alzheimer's disease is widely prevalent and incurable, and numerous clinical trials aimed at halting disease progression in these patients have failed. A new research framework has been suggested to stage Alzheimer’s disease on a continuum, based on the presence or absence of beta-amyloid pathology, tau accumulation, and neurodegeneration.1 Although the amyloid hypothesis of Alzheimer’s pathogenesis remains widely accepted, approximately 20% of cognitively normal older adults have been reported to have positive amyloid PET scans,2 and amyloid correlates weakly with clinical symptoms.3 This suggests that amyloid, although an early marker of Alzheimer’s pathology, may not be sufficient to produce neurodegeneration and subsequent cognitive decline. Rather, the presence of pathological tau marks the crossover from Alzheimer’s pathologic change to true Alzheimer’s disease.
In this study, researchers analyzed tau PET scans obtained longitudinally in 126 older adults, ranging from 52 to 94 years of age, who were recruited through the Mayo Clinic Study of Aging, a population-based cohort, and the Mayo Alzheimer's Disease Research Center. Fifty-nine of these subjects were cognitively normal and had negative amyloid PET scans, 37 subjects were cognitively normal and had positive amyloid PET scans, and 30 subjects were cognitive impaired with positive amyloid PET scans. All subjects had two tau PET scans, obtained 12 to 15 months apart.
The researchers found that subjects who were cognitively normal and had negative amyloid PET scans showed no evidence of tau accumulation. Subjects who were cognitively normal but amyloid-positive had low rates of tau accumulation (0.5% per year), predominantly in the temporal lobes but also in the parietal lobes. The cognitively impaired group had the highest rates of tau accumulation (3% per year) in nearly all regions of the brain, although the rates of tau accumulation in the medial temporal lobe were not significantly different from the cognitively normal, amyloid-positive group. Taken together, tau accumulates at greater rates at later stages of Alzheimer’s disease. Furthermore, tau accumulation loosely follows the Braak staging system, in which tau accumulates first in the temporal regions before spreading to the remainder of the brain.
The researchers then defined “early” and “late” Alzheimer’s meta-regions of interest, based on the brain regions that best separated the three groups. Temporal and whole brain regions of interest also were considered, and all meta-regions were found to correlate highly with each other. The researchers found that the sample size required to detect a 25% therapeutic reduction at 80% power in a clinical trial is significantly smaller using tau PET as an outcome measure instead of cognition. For example, the sample size required for a trial targeting amyloid-positive, cognitively normal individuals would be 1,087 using a tau PET temporal meta-region, compared to 1,360 using cognitive scores. The sample size required for a trial of cognitively impaired individuals would be 282 using the “late Alzheimer’s” meta-region, compared to 623 using cognition. Thus, the authors concluded that longitudinal tau PET scans would provide a useful and efficient outcome measurement for clinical trials.
This is a thoughtfully designed study evaluating longitudinal tau PET across three stages of the Alzheimer’s disease continuum, including those without evidence of Alzheimer’s pathology (cognitively normal, amyloid-
negative), those with early Alzheimer’s pathology (cognitively normal, amyloid-positive), and those with Alzheimer’s disease with cognitive impairment. Although tau PET is not used clinically yet, its role in clinical trials could be substantial. It has been reported that a quarter of people with a clinical diagnosis of Alzheimer’s dementia have no Alzheimer’s pathology on autopsy;4 therefore, the effects of drugs targeting Alzheimer’s pathology could be diluted by subjects without the actual disease. Using imaging markers of underlying Alzheimer’s pathology, such as amyloid and tau PET scans, would classify subjects more accurately for enrollment in clinical trials.
It also is notable that cognitively normal subjects with negative amyloid PET scans showed no observable tau accumulation. This further supports the amyloid hypothesis of Alzheimer’s pathogenesis, in which amyloid is an early event in the disease.
Future studies in larger cohorts with longer follow-up should be performed to validate these findings. As the authors noted, the cognitively impaired group included both subjects with mild cognitive impairment and frank dementia. It would be important to know how the rates of tau accumulation differ with severity of cognitive impairment. The authors also focused on the amnestic form of cognitive impairment, whereas other Alzheimer’s subtypes may present with non-memory deficits. The marked heterogeneity of individual tau accumulation trajectories also would be crucial to understand, since group rates of tau accumulation may not be generalizable to individual patients. Finally, although using tau PET as an outcome measure would decrease the number of subjects needed to show a significant effect in a clinical trial, longitudinal PET imaging would markedly increase the cost of the trial, and tau tracers are not yet widely available.
Financial Disclosure: Neurology Alert’s Editor in Chief Matthew Fink, MD; Peer Reviewer M. Flint Beal, MD; Executive Editor Leslie Coplin; Editor Jonathan Springston; and Editorial Group Manager Terrey L. Hatcher report no financial relationships relevant to this field of study.