Amidst an amygdala renaissance in Alzheimer’s disease

Abstract

Laura E. M. Wisse and David Berron contributed equally to this work. Accepted manuscripts: Accepted manuscripts are PDF versions of the author’s final manuscript, as accepted for publication by the journal but prior to copyediting or typesetting. They can be cited using the author(s), article title, journal title, year of online publication, and DOI. They will be replaced by the final typeset articles, which may therefore contain changes. The DOI will remain the same throughout.Supplementary material: Supplementary material is available at Brain online at: https://doi.org/10.1093/brain/awad411 .Copyright © The Author(s) 2023. The amygdala was highlighted as an early site for neurofibrillary tau tangle pathology in Alzheimer’s disease in the seminal Braak & Braak article (1991). This knowledge has, however, only received traction recently with advances in imaging and image analysis techniques. Here, we provide a cross-disciplinary overview of pathology and neuroimaging studies on the amygdala. These studies provide strong support for an early role of the amygdala in Alzheimer’s disease and the utility of imaging biomarkers of the amygdala in detecting early changes and predicting decline in cognitive functions and neuropsychiatric symptoms in early stages. We summarize the animal literature on connectivity of the amygdala, demonstrating that amygdala nuclei that show the earliest and strongest accumulation of neurofibrillary tangle pathology are those that are connected to brain regions that also show early neurofibrillary tangle accumulation. Additionally, we propose an alternative pathway of neurofibrillary tangle spreading within the medial temporal lobe between the amygdala and the anterior hippocampus. The proposed existence of this pathway is strengthened by novel experimental data on human functional connectivity. Finally, we summarize the functional roles of the amygdala, highlighting the correspondence between neurofibrillary tangle accumulation and symptomatic profiles in Alzheimer’s disease. In summary, these findings provide a new impetus for studying the amygdala in Alzheimer’s disease and a unique perspective to guide further study on neurofibrillary tangle spreading and the occurrence of neuropsychiatric symptoms in Alzheimer’s disease.This work is supported by grants from the Swedish Research Council (2022-00900) and the Crafoord Foundation (LW). This study is supported by MultiPark - A Strategic Research Area at Lund University (LW). This work is supported by the National Institutes of Health: U19-AG033655, P30-AG066507, P41-EB031771, R01-EB020062, T32-GM13677, U19-MH114821, R01-NS074980-10S1, RF1MH126732, RF1MH128875, F30AG077736 (MM and KS) and the Kavli Neuroscience Discovery Institute (MM and KS) as well as the Kavli Foundation and the KG. Jebsen Foundation (MPW). This work is further supported by the Elly Bergren Foundation and regional research support by the Division of Psychiatry, Habilitation and Medical aid, Region Skåne (MJ). This work was partly supported by the National Institute for Health and Care Research 23 Exeter Biomedical Research Centre