Tau accumulation within the default mode network as a predictor of longitudinal clinical decline in atypical Alzheimer’s disease

Abstract

AbstractBackgroundIdentifying individuals with symptomatic Alzheimer’s disease (AD) at greater risk of steeper cognitive decline would allow professionals and loved‐ones to make better‐informed medical, support, and life‐planning decisions. In typical AD, the magnitude of cerebral tau accumulation in vivo predicts clinical deterioration. Despite its promise, the utility of tau PET in predicting cognitive decline in individuals with atypical clinical presentations of AD remains unclear. We examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline across atypical AD syndromes.MethodFifty‐seven A/T/N‐positive patients (mean age = 64.13 ± 7.72; 24M/33F) with atypical syndromes of AD (19 Posterior Cortical Atrophy, 16 logopenic variant of Primary Progressive Aphasia, 16 dysexecutive AD, five early‐onset AD with single‐domain impairment, and one Corticobasal Syndrome) and 24 amyloid‐negative control participants were included in this study. All participants underwent 18F‐Flortaucipir (FTP) PET, amyloid PET, and structural MRI scans at baseline. The rate of clinical decline was quantified as the annualized change in Clinical Dementia Rating Sum‐of‐Boxes scores (CDR‐SB) at baseline and follow‐up visits (mean time interval = 1.24 ± 0.34 years). General linear model analyses were performed to examine the pattern of baseline cortical tau deposition in atypical AD patients and its relationship with the rate of clinical decline.ResultCompared with amyloid‐negative controls, atypical AD patients showed prominent FTP uptake in posterior cortical regions at baseline, including bilateral posterior cingulate cortex/precuneus and lateral temporo‐parietal cortices, which canonically constitute the posterior default mode network (DMN). A brain‐behavior regression analysis revealed widespread regions within the DMN where the magnitude of baseline FTP uptake predicted the rate of change in CDR‐SB, with anterior DMN regions (medial prefrontal and anterior temporal cortices) most strongly predicting clinical decline.ConclusionGreater baseline tau accumulation in the anterior DMN, possibly suggesting more extensive tau spread in this network, predicts faster clinical decline in atypical AD. This may serve as an imaging biomarker to guide prognostication for patients with atypical AD and their families and to inform the design of clinical trials, including potentially recruiting multiple clinical phenotypes of AD into a single trial.