Characterizing the spatiotemporal variability of Alzheimer’s disease pathology

Abstract

Alzheimer's disease (AD) is characterized by the progressive spread of tau pathology throughout the cerebral cortex. The pattern of spread is thought to be fairly consistent across individuals, though more recent work has demonstrated substantial variability in the AD population that is often associated with distinct clinical phenotypes. Still, a systematic, unbiased, whole-brain characterization of spatiotemporal variation in tau deposition in AD is lacking. We analyzed 1612 tau-PET scans and applied to this sample a disease progression modeling framework designed to identify spatiotemporal trajectories of pathological progression. We identified four distinct trajectories of tau progression, ranging in prevalence from 18-33\%, with no one progession predominating. We replicated previously described limbic-predominant and medial temporal lobe-sparing variants, while also discovering posterior and lateral temporal subtypes resembling atypical clinical variants of AD. These "subtypes" were stable during longitudinal follow-up, and could be replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes, however, no "typical" variant predominated. Across all subtypes, younger age was related to worse cognition and more rapid tau accumulation. Additionally, network diffusion models implicated that pathology originates and spreads through distinct corticolimbic in the different subtypes. Together, our results suggest variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of "typical AD", and a revisiting of tau pathological staging.

DNA Methylation in Genetic and Sporadic Forms of Neurodegeneration: Lessons From Alzheimers, Related Tauopathies and Genetic Tauopathies

“…While this certainly holds true on a population basis, advances in PETimaging improved longitudinal clinical studies, and artificial intelligence (AI)based data interpretation have very recently allowed to better correlate the clinical symptoms in AD with structural and TAU-based brain abnormalities. These new data have revealed four different subtypes of AD, that can now be described not only clinically, but in close correlation also using TAU-based PET-imaging [18]. While Aβ deposition may be a far-reaching upstream trigger or indicator of disease onset, it is now fairly clear from a clinical, anatomical and imaging-based perspective that aberrant deposition and other changes in TAU are the main driver of AD pathology and consequent CI.…”

At a Glance: An Update on Neuroimaging and Retinal Imaging in Alzheimer’s Disease and Related Research

“…The spread of tau pathology was until recently believed to cascade throughout the brain in a predictable or stereotypical pattern outlined by the Braak's tau staging system. However, this has been questioned recently, with four distinct tau trajectory phenotypes proposed (39). Using from the first-generation tau ligand 18F-flortaucipir, the following spatiotemporal subtypes were proposed (a) limbic, (b) medial temporal load (MTL)-sparing, (c) posterior, and (d) lateral temporal.…”

DNA Methylation in Genetic and Sporadic Forms of Neurodegeneration: Lessons from Alzheimer’s, Related Tauopathies and Genetic Tauopathies

“…However, advances in PET-imaging have improved output from longitudinal clinical studies. Artificial intelligence (AI)-based data interpretation has very recently allowed to better correlate the clinical symptoms in AD with structural and TAU-based brain abnormalities, revealing four different subtypes of AD, which can now be described clinically and in close correlation using TAU-based PET-imaging [36]. In sum, Aβ deposition may be an upstream trigger or indicator of disease, but from a clinical, anatomical and imaging-based perspective aberrant deposition and other changes of TAU must be the main driver of AD pathology and consequent CI.…”