The behavioral variant of Alzheimer's disease: a clinical, neuroimaging and neuropathological perspective

The general aim of this thesis was to explore the clinical, neuroimaging and neuropathological features of bvAD, and to provide the first-ever set of research criteria for this rare and understudied atypical variant of AD. First, we explored alternative neurobiological processes other than frontal atrophy, by investigating patterns of hypometabolism, metabolic connectivity, subcortical atrophy and white matter hyperintensities in bvAD. Then, we examined patterns of tau pathology in bvAD using tau PET and postmortem investigations. Next, we explored whether specialized neurons for social cognition and behavior, Von Economo and phylogenetically related neurons, show a selective loss in bvAD. Subsequently, we explored social cognition and its biometric signature in bvAD. Finally, we established research criteria for bvAD, aimed at improving reliability and consistency of scientific reporting on this phenotype and potentially aiding the clinical diagnosis of bvAD in the future. The key findings of this thesis include: 1. bvAD is characterized by subtle frontoinsular hypometabolism in addition to temporoparietal hypometabolism, increased anterior default mode involvement and reduced connectivity of the posterior cingulate cortex to the right prefrontal cortex compared to typical AD. In addition, our results suggest that subcortical atrophy and white matter hyperintensities do not play a major role in the clinical phenotype of bvAD. 2. bvAD is characterized by a heterogeneous distribution of tau pathology across individual cases, ranging from pronounced anterior involvement to a more temporoparietal pattern based on tau PET. This heterogeneity was confirmed by group-level immunohistochemistry in an independent postmortem sample of bvAD, which showed no differences in regional tau burden in bvAD compared to typical AD. Since frontal regions were not consistently and disproportionally affected by tau pathology in bvAD, tau pathology may not be the main or sole driver of the clinical phenotype in bvAD. 3. No selective loss of VENs and phylogenetically related neurons was found in bvAD compared to tAD and controls. These data suggest that, unlike in bvFTD, behavioral alterations in bvAD may not be related to a loss of VENs and phylogenetically related neurons in the anterior cingulate cortex. 4. bvAD is characterized by deficits across specific aspects of all levels of social cognition, including emotion recognition, empathy, and knowledge of social norms compared to controls, showing a similar but milder social cognition profile compared to bvFTD and a more impaired profile compared to typical AD. In addition, bvAD and bvFTD showed distinct eyetracking signatures compared to typical AD and controls, suggesting less attention for salient features of the face, such as the mouth, while perceiving facial expressions, potentially underlying their emotion recognition deficits. 5. In a systematic review and meta-analysis, we found that bvAD is clinically most reminiscent of bvFTD, while it shares most pathophysiological features with typical AD. We found that bvAD is a combined cognitive and behavioral clinical syndrome and it does not differ from typical AD in terms of neuroimaging and neuropathological characteristics at group-level. Based on these insights, we provided research criteria for bvAD. The first level of diagnostic certainty (“clinical bvAD”) can be established solely based on clinical information, while level II and III (“possible bvAD” and “probable bvAD”) add biomarker confirmation of amyloid-β and tau pathology. Level IV (“definite bvAD”) is assigned through histopathological or genetic (i.e., presence of pathogenic APP, PSEN1 or PSEN2 mutations) confirmation of AD in conjunction with a bvAD clinical syndrome. These criteria may improve the consistency and reliability of future research and may aid future clinical assessments.