Dickerson, Bradford C

Abstract The standard approach to quantify amyloid (Aβ) PET averages uptake within a single cortical mask that assumes no clinically relevant spatial heterogeneity in uptake patterns. Here, in a sample of 12,379 clinically impaired participants taken from four phenotypically diverse cohorts we use data-driven approaches to discover heterogeneous patterns of Aβ-PET binding, uncovering a reproducible and clinically relevant pattern of posterior predominant Aβ-PET binding. In particular, Aβ-PET positive participants who have posterior predominant binding are less likely to be APOE -ε4 carriers, more severely impaired, have thinner cortex in posterior regions, and greater posterior tau PET burden. Furthermore, in a subsample of participants with neuropathological assessment, participants with posterior predominant Aβ binding have a higher likelihood of having cerebral amyloid angiopathy at autopsy. These findings suggest that Aβ-PET accumulates along two orthogonal axes with biological and clinical relevance, indicating that the standard approach to assess Aβ-PET is insufficient to capture meaningful signal from Aβ-PET imaging. This work has implications for the diagnosis and treatment of Alzheimer’s disease and extends our understanding of the mechanisms governing variable Aβ-PET distribution and its downstream effects.

Abstract Patients with atypical variants of Alzheimer's disease (AD) often present at a younger age with predominantly non‐amnestic impairments and a more aggressive disease course. Historically, individuals with atypical presentations have not been included in large‐scale clinical trials, which typically focus on late‐onset, sporadic amnestic‐predominant AD. Consequently, treatment options and research efforts specific to atypical AD remain limited. The emergence of amyloid‐targeting therapies that slow disease progression underscores these challenges, as evidence supporting their efficacy in early‐onset amnestic and non‐amnestic AD variants is scarce. This perspective article argues that atypical AD represents an excellent disease model for clinical trials and proposes strategies to address critical gaps in clinical trial design for this population. Key considerations include optimizing participant selection approaches, establishing syndrome‐specific or surrogate biological and clinical endpoints, and fostering advocacy to enhance early and accurate diagnosis, equitable representation, and outcomes for these populations.