Sequential amyloid-β and tau accumulation foreshadows cognitive decline

Abstract

Nature reviews | Neurology The preclinical phase of Alzheimer disease (AD) is marked by the sequential accrual of amyloid-β (Aβ) and tau pathology in the brain, according to the results of a new longitudinal PET imaging study. The findings, which were published in JAMA Neurology, support a model whereby Aβ pathology increases the susceptibility to tau deposition, which in turn predicts cognitive decline. Plaques containing Aβ and neurofibrillary tangles composed of hyperphosphorylated tau are the main pathological hallmarks of AD. However, the relative contributions of Aβ and tau to the disease process — and, thus, their capacity to serve as therapeutic targets — are still open to debate. To attempt to address these issues, researchers are now turning their attention to the earliest stages of AD. “Both autopsy and cross-sectional PET studies have demonstrated that Aβ and tau pathologies are present in healthy older adults, but the temporal trajectories of these pathologies have not previously been investigated in a longitudinal study,” explains corresponding author Keith Johnson, who is based at Massachusetts General Hospital, Boston, MA, USA. “Studying these trajectories is important to better understand the impact that anti-Aβ and anti-tau therapies could have at different stages of AD.” Johnson and his colleagues analysed data from 60 cognitively healthy individuals aged 65–85 years who were enrolled in the Harvard Aging Brain Study. Over a follow-up period of 7 years, the participants underwent serial brain PET scans, using the tracers 11C-Pittsburgh compound B (11C-PiB) and 18F-flortaucipir (18F-FTP) to detect Aβ and tau pathology, respectively. In addition, the participants underwent annual cognitive assessments. Of the 60 participants, 17 had high 11C-PiB signals at the beginning of the study and a further 3 progressed to the high 11C-PiB group within the first 3 years. Of note, the 18F-FTP–PET scans were only introduced 3 years into the study, as the 18F-FTP tracer had been unavailable up to that point. The researchers found that a fast rate of Aβ accumulation was predictive of subsequent deposition of tau in the inferior temporal cortex, and the rate of tau accumulation in this region correlated with the rate of cognitive decline. By the end of the study, six participants, all of whom exhibited high 11C-PiB signals and fast rates of tau accumulation, had progressed to mild cognitive impairment (MCI) — a pre-dementia condition that is thought to be a precursor to AD. “The results are in agreement with the view hypothesized from autopsy and cross-sectional PET data that AD is an Aβ-facilitated tauopathy leading to cognitive decline, MCI and dementia,” concludes Johnson. “They highlight the close relationship between tau pathology and cognition and the potential of tau PET imaging to serve as an outcome measure in preventive and therapeutic clinical trials.” The findings suggest a role for 11C-PiB–PET in the detection of early AD-associated pathological changes in the brain, whereas 18F-FTP–PET is likely to be more useful for tracking disease progression. The study also showcases the advantages of longitudinal monitoring over crosssectional assessments. However, the authors acknowledge several limitations to the study, including the small sample size and the fact that 18F-FTP was not available from the outset. “Larger samples will help us to more thoroughly investigate the spatiotemporal relationships between Aβ, tau and brain structure and function, and the variations that exist between individuals,” comments Johnson. “Studying younger participants will also be crucial to our understanding of the origins of these pathologies, and longer follow-up times are needed to track the entire sequence from early Aβ accumulation to dementia.” Heather Wood A L Z H E I M E R D I S E A S E