**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Binh A. Nguyen, Center for Alzheimer's and Neurodegenerative Diseases, UTSW Medical Center, Dallas, Texas.

**Main Body of the Abstract**
ATTR amyloidosis is caused by the conversion of soluble transthyretin into amyloid fibrils that accumulate in affected organs leading to premature death. This conversion is facilitated by mutations in the ttr gene in variant ATTR (ATTRv) amyloidosis or by unknown aging-related factors in wild-type ATTR (ATTRwt) amyloidosis. While ATTRwt patients typically present with major cardiac involvement later in life, ATTRv patients exhibit considerable symptom variability, often involving neuropathy symptoms and occurring as early as the age of 25. Multiple studies in neurodegenerative diseases suggest that structural differences in the amyloid fibrils found in the brain determine the clinical diagnosis. To explore this hypothesis in ATTR amyloidosis, we use cryogenic electron microscopy to determine and compare the structures of cardiac fibrils extracted from various patients with cardiomyopathy, neuropathy, or a mixed phenotype, and with various genotypes (ATTRwt, ATTRv-P24S, ATTRv-A25S, ATTRv-V30M, ATTRv-T60A, ATTRv-V122I, ATTRv-I84S). We also compare the structures of ATTR fibrils from the heart and the nerves from the same ATTRV30M patient. Remarkably, all neuropathic ATTRI84S patients exhibit fibril structural polymorphism; shown among different individuals and within the same fibrils. In contrast, cardiomyopathic or mixed patients exhibit similar fibril structures across different mutations. The fibril structure extracted from ATTRV30M nerves also resembles that of the cardiomyopathic type. Further studies are warranted to determine the implications of our findings.



**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Binh A. Nguyen, Center for Alzheimer's and Neurodegenerative Diseases, UTSW Medical Center, Dallas, Texas.

**Main Body of the Abstract**
ATTR amyloidosis is caused by the conversion of soluble transthyretin into amyloid fibrils that accumulate in affected organs leading to premature death. This conversion is facilitated by mutations in the _ttr_ gene in variant ATTR (ATTRv) amyloidosis or by unknown aging-related factors in wild-type ATTR (ATTRwt) amyloidosis. While ATTRwt patients typically present with major cardiac involvement later in life, ATTRv patients exhibit considerable symptom variability, often involving neuropathy symptoms and occurring as early as the age of 25. Multiple studies in neurodegenerative diseases suggest that structural differences in the amyloid fibrils found in the brain determine the clinical diagnosis. To explore this hypothesis in ATTR amyloidosis, we use cryogenic electron microscopy to determine and compare the structures of cardiac fibrils extracted from various patients with cardiomyopathy, neuropathy, or a mixed phenotype, and with various genotypes (ATTRwt, ATTRv-P24S, ATTRv-A25S, ATTRv-V30M, ATTRv-T60A, ATTRv-V122I, ATTRv-I84S). We also compare the structures of ATTR fibrils from the heart and the nerves from the same ATTRV30M patient. Remarkably, all neuropathic ATTRI84S patients exhibit fibril structural polymorphism; shown among different individuals and within the same fibrils. In contrast, cardiomyopathic or mixed patients exhibit similar fibril structures across different mutations. The fibril structure extracted from ATTRV30M nerves also resembles that of the cardiomyopathic type. Further studies are warranted to determine the implications of our findings.



Cryo-EM study of fibril polymorphism in ATTR amyloidosis PB9 (#213)

We invite you to attend the XIX International Symposium on Amyloidosis to be held in Rochester, MN.

This symposium is organized as a hybrid meeting (with the focus on in-person) held from Sunday, May 26 through Thursday, May 30, 2024.

Together with the ISA Board and members of Mayo Clinic, a very attractive scientific hybrid program is being planned. The program will cover a variety of types of systemic amyloidosis: ATTR (hereditary and wild-type), AL (light-chain), AA and less frequent forms. There will be key lectures, specific symposia including those company sponsored, oral presentations and poster sessions of accepted abstracts.

COURSE DESCRIPTION
This program will provide a comprehensive review of state-of-the-art education in systemic amyloidosis: basic science, pathophysiology, diagnosis, current and emerging treatments. Scientific presentations will include competitive oral and poster abstracts. The rapid evolution of scientific discovery and expanding treatment options has created tremendous interest in the field and this meeting will fill and important gap in educating scientists and clinicians.