Tau-neurodegeneration mismatch reveals vulnerability and resilience to comorbidities in Alzheimer's continuum.

INTRODUCTION: Variability in relationship of tau-based neurofibrillary tangles (T) and neurodegeneration (N) in Alzheimer's disease (AD) arises from non-specific nature of N, modulated by non-AD co-pathologies, age-related changes, and resilience factors. METHODS: We used regional T-N residual patterns to partition 184 patients within the Alzheimer's continuum into data-driven groups. These were compared with groups from 159 non-AD (amyloid "negative") patients partitioned using cortical thickness, and groups in 98 patients with ante mortem MRI and post mortem tissue for measuring N and T, respectively. We applied the initial T-N residual model to classify 71 patients in an independent cohort into predefined groups. RESULTS: AD groups displayed spatial T-N mismatch patterns resembling neurodegeneration patterns in non-AD groups, similarly associated with non-AD factors and diverging cognitive outcomes. In the autopsy cohort, limbic T-N mismatch correlated with TDP-43 co-pathology. DISCUSSION: T-N mismatch may provide a personalized approach for determining non-AD factors associated with resilience/vulnerability in AD.

Aging and Alzheimer's disease have dissociable effects on local and regional medial temporal lobe connectivity.

Functional disruption of the medial temporal lobe-dependent networks is thought to underlie episodic memory deficits in aging and Alzheimer's disease. Previous studies revealed that the anterior medial temporal lobe is more vulnerable to pathological and neurodegenerative processes in Alzheimer's disease. In contrast, cognitive and structural imaging literature indicates posterior, as opposed to anterior, medial temporal lobe vulnerability in normal aging. However, the extent to which Alzheimer's and aging-related pathological processes relate to functional disruption of the medial temporal lobe-dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity alterations in the medial temporal lobe and its immediate functional neighbourhood-the Anterior-Temporal and Posterior-Medial brain networks-in normal agers, individuals with preclinical Alzheimer's disease and patients with Mild Cognitive Impairment or mild dementia due to Alzheimer's disease. In the Anterior-Temporal network and in the perirhinal cortex, in particular, we observed an inverted 'U-shaped' relationship between functional connectivity and Alzheimer's stage. According to our results, the preclinical phase of Alzheimer's disease is characterized by increased functional connectivity between the perirhinal cortex and other regions of the medial temporal lobe, as well as between the anterior medial temporal lobe and its one-hop neighbours in the Anterior-Temporal system. This effect is no longer present in symptomatic Alzheimer's disease. Instead, patients with symptomatic Alzheimer's disease displayed reduced hippocampal connectivity within the medial temporal lobe as well as hypoconnectivity within the Posterior-Medial system. For normal aging, our results led to three main conclusions: (i) intra-network connectivity of both the Anterior-Temporal and Posterior-Medial networks declines with age; (ii) the anterior and posterior segments of the medial temporal lobe become increasingly decoupled from each other with advancing age; and (iii) the posterior subregions of the medial temporal lobe, especially the parahippocampal cortex, are more vulnerable to age-associated loss of function than their anterior counterparts. Together, the current results highlight evolving medial temporal lobe dysfunction in Alzheimer's disease and indicate different neurobiological mechanisms of the medial temporal lobe network disruption in aging versus Alzheimer's disease.

Tau-Neurodegeneration mismatch reveals vulnerability and resilience to comorbidities in Alzheimer's continuum.

Variability in the relationship of tau-based neurofibrillary tangles (T) and degree of neurodegeneration (N) in Alzheimer's Disease (AD) is likely attributable to the non-specific nature of N, which is also modulated by such factors as other co-pathologies, age-related changes, and developmental differences. We studied this variability by partitioning patients within the Alzheimer's continuum into data-driven groups based on their regional T-N dissociation, which reflects the residuals after the effect of tau pathology is "removed". We found six groups displaying distinct spatial T-N mismatch and thickness patterns despite similar tau burden. Their T-N patterns resembled the neurodegeneration patterns of non-AD groups partitioned on the basis of z-scores of cortical thickness alone and were similarly associated with surrogates of non-AD factors. In an additional sample of individuals with antemortem imaging and autopsy, T-N mismatch was associated with TDP-43 co-pathology. Finally, T-N mismatch training was then applied to a separate cohort to determine the ability to classify individual patients within these groups. These findings suggest that T-N mismatch may provide a personalized approach for determining non-AD factors associated with resilience/vulnerability to Alzheimer's disease.

Aging and Alzheimer's Disease Have Dissociable Effects on Medial Temporal Lobe Connectivity.

Functional disruption of the medial temporal lobe-dependent networks is thought to underlie episodic memory deficits in aging and Alzheimer's disease. Previous studies revealed that the anterior medial temporal lobe is more vulnerable to pathological and neurodegenerative processes in Alzheimer's disease. In contrast, cognitive and structural imaging literature indicates posterior, as opposed to anterior, medial temporal lobe vulnerability in normal aging. However, the extent to which Alzheimer's and aging-related pathological processes relate to functional disruption of the medial temporal lobe-dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity alterations in the medial temporal lobe and its immediate functional neighborhood - the Anterior-Temporal and Posterior-Medial brain networks - in normal agers, individuals with preclinical Alzheimer's disease, and patients with Mild Cognitive Impairment or mild dementia due to Alzheimer's disease. In the Anterior-Temporal network and in the perirhinal cortex, in particular, we observed an inverted 'U-shaped' relationship between functional connectivity and Alzheimer's stage. According to our results, the preclinical phase of Alzheimer's disease is characterized by increased functional connectivity between the perirhinal cortex and other regions of the medial temporal lobe, as well as between the anterior medial temporal lobe and its one-hop neighbors in the Anterior-Temporal system. This effect is no longer present in symptomatic Alzheimer's disease. Instead, patients with symptomatic Alzheimer's disease displayed reduced hippocampal connectivity within the medial temporal lobe as well as hypoconnectivity within the Posterior-Medial system. For normal aging, our results led to three main conclusions: (1) intra-network connectivity of both the Anterior-Temporal and Posterior-Medial networks declines with age; (2) the anterior and posterior segments of the medial temporal lobe become increasingly decoupled from each other with advancing age; and, (3) the posterior subregions of the medial temporal lobe, especially the parahippocampal cortex, are more vulnerable to age-associated loss of function than their anterior counterparts. Together, the current results highlight evolving medial temporal lobe dysfunction in Alzheimer's disease and indicate different neurobiological mechanisms of the medial temporal lobe network disruption in aging vs. Alzheimer's disease.

Tau-Atrophy Variability Reveals Phenotypic Heterogeneity in Alzheimer's Disease.

OBJECTIVE: 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 relationship - manifested 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. ANN NEUROL 2021;90:751-762.