New Insights into Atypical Alzheimer’s Disease: From Clinical Phenotype to Biomarkers

A large proportion of Alzheimer’s disease (AD) patients do not present with early memory loss and hence do not meet the criteria for typical AD, but instead have atypical clinical presentations. These patients often have a younger age of onset and an uncertain clinical course. The two most common atypical variants of AD are the visual variant, most commonly referred to as posterior cortical atrophy, characterized by predominant visuospatial/perceptual deficits, and the language variant, characterized primarily by language impairments. Other atypical variants of AD include the dysexecutive variant, the behavioral variant, and the apraxic variant. Research into clinical and neuropathological features of atypical AD may advance not only a timely and accurate diagnosis but also the detection of atypical features and characterization of disease progression, ultimately informing the understanding of AD heterogeneity and treatment implications.

Through this Research Topic, we hope to shed light on multiple approaches that may improve the diagnosis and understanding of atypical AD phenotypes. New advances in biomarkers, specifically fluid biomarkers (CSF and plasma), brain functional, structural network connectivity (rsfMRI and DTI), hypometabolism profiles (18F FDG-PET), regional iron (QSM), amyloid- and tau-PET studies may help better understand atypical AD phenotypes. Among others, capturing and analyzing brain network connectivity patterns will be beneficial in identifying network abnormalities. Advances in characterizing clinical phenotype include quantification of movement, speech, eye tracking, and behavioral symptoms. A better understanding of symptomatology might inform management strategies and appropriate clinical outcomes in heterogeneous groups. New advances in genetic studies will also help unravel associations between candidate genes and the pathophysiology of atypical AD phenotypes. Moreover, studies investigating the detailed symptomatology and neuropsychological profiles, at the individual or group level, in these atypical AD phenotypes will provide new insights into brain-behavior associations. Lastly, a deeper understanding of individual-level molecular PET, MRI, and fluid findings will be crucial to aid diagnosis and help guide the inclusion of these patients in clinical treatment trials for AD.

The general aim of this Research Topic is to provide an update on atypical AD, using a broad range of fine-grained clinical, neuroimaging, and fluid markers, by focusing on new insights in diagnosis, clinical features, fluid, neuroimaging, and genetic markers. We also hope to inspire new collaborations and research ideas across the atypical AD research community.

We are accepting original research articles, case reports, and perspectives for publication within this Research Topic in Frontiers in Neuroscience.