Tau‐Atrophy Variability Reveals Phenotypic Heterogeneity in Alzheimer's Disease

Abstract

Tau neurofibrillary tangles (T) are the primary driver of downstream neurodegeneration (N) and subsequent cognitive impairment in Alzheimer's disease (AD). However, there is substantial variability in the T-N relationshipmanifested in higher or lower atrophy than expected for level of tau in a given brain region. The goal of this study was to determine if region-based quantitation of this variability allows for identification of underlying modulatory factors, including polypathology. Methods: Cortical thickness (N) and 18 F-Flortaucipir SUVR (T) were computed in 104 gray matter regions from a cohort of cognitively-impaired, amyloid-positive (A+) individuals. Region-specific residuals from a robust linear fit between SUVR and cortical thickness were computed as a surrogate for T-N mismatch. A summary T-N mismatch metric defined using residuals were correlated with demographic and imaging-based modulatory factors, and to partition the cohort into data-driven subgroups. Results: The summary T-N mismatch metric correlated with underlying factors such as age and burden of white matter hyperintensity lesions. Data-driven subgroups based on clustering of residuals appear to represent different biologically relevant phenotypes, with groups showing distinct spatial patterns of higher or lower atrophy than expected. Interpretation: These data support the notion that a measure of deviation from a normative relationship between tau burden and neurodegeneration across brain regions in individuals on the AD continuum captures variability due to multiple underlying factors, and can reveal phenotypes, which if validated, may help identify possible contributors to neurodegeneration in addition to tau, which may ultimately be useful for cohort selection in clinical trials.

Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease

“…Since N S and N M are linked, it is reasonable to predict that T/N S and T/N M relationships are also associated. Indeed, clustering with T/N S approaches yields groups with relative resilience or vulnerability to T 25 . The median regional correlation coefficient between T/N S and T/N M residuals was 0.29, suggesting that while T/N S and T/N M relationships are similar, they may provide some unique information.…”

The neuroimmune axis of Alzheimer’s disease

“…β-amyloid deposition and tauopathy, as assessed by levels of Aβ species and p-Tau (p-Tau 181, 217, 231), respectively, in cerebrospinal fluid (CSF) and plasma as well as directly by positron emission tomography (PET), can be used to detect Aβ- and Tau-related neuropathology prior to the onset of cognitive impairment [ 7 ]. Recent studies have demonstrated that post-translational alterations of Tau also play a role in the rate of clinical AD progression [ 8 ] and variability in tauopathies across brain regions of patients [ 9 ]. Collectively, these studies suggest that AD is a heterogeneous neurodegenerative condition with respect to both clinical presentation and progression of AD pathology.…”

Tau-Neurodegenerationmismatchreveals vulnerability and resilience to comorbidities in Alzheimer’s continuum

“…Age itself is associated with structural changes to regional thickness and volume of grey matter which is at least partially dissociable from structural changes associated with typical AD 31,36 . As such, we previously predicted and found that age was associated with a more global measure of T-N mismatch 21 . In the current analysis, vulnerable groups do tend to be older than resilient ones, with the canonical group around the mean age of the overall cohort.…”

“…There were 184 amyloid positive (A+) and 159 amyloid negative (A-) patients included in this study. Most of the A+ patients were also in our prior study 21 . The summarized clinical characteristics of the cohort are reported in Table S4.…”