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Abstract Details

Clinical and Imaging Features of Early Onset Alzheimer’s Disease with a SORL1 Nonsense Variant
Aging, Dementia, Cognitive, and Behavioral Neurology
P5 - Poster Session 5 (11:45 AM-12:45 PM)
7-005
The SORL1 gene encodes a sortilin-related receptor involved in beta amyloid lysosomal degradation and clearance. SORL1 genetic variants are associated with increased AD risk or more highly penetrant disease in selected pedigrees. In the setting of a family history of dementia, this gene may play an important role in causing AD.
To describe a case of early onset Alzheimer's disease (AD) in a carrier of a SORL1 nonsense variant with family history of dementia, slow clinical progression, and very subtle findings noted on FDG-PET.

A 56-year-old male was evaluated for a 13-year history of progressive cognitive and memory decline. He had difficulties with complex IADLs (managing finances, transportation, medications) though preserved performance with basic ADLs. There was a family history of dementia in his father, with onset around age 65 years, and cognitive decline in his brother, with symptom onset in his early 50s.

Neuropsychological testing demonstrated impairment in verbal learning and memory, visual memory and relative weakness in category fluency, though otherwise high performance in multiple other domains. FDG-PET showed bilateral medial temporal hypometabolism and posterior cingulate hypometabolism. MRI brain showed only subtle temporal atrophy. Genetic testing revealed a pathogenic nonsense mutation in the SORL1 gene, c.862del (p.Glu288Lysfs*5).  This variant is absent from population databases and is predicted to result in absent or disrupted protein.

This SORL1 variant is suspected to cause AD in this patient with slowly progressive Early-Onset AD and unusually subtle imaging findings. Studies suggest that frameshift and nonsense variants leading to loss of protein function are highly penetrant, lead to an earlier age of onset, and may confer a twelve-fold increased risk of AD. Further research is needed to determine the risk of AD, the rate of progression, and the typical imaging features in patients with SORL1 variants.

Authors/Disclosures
Conor T. Flavin, MD (University of Utah Health)
PRESENTER
Dr. Flavin has nothing to disclose.
Christine Cliatt Brown, MD (University of Utah) Dr. Cliatt Brown has nothing to disclose.
Jared Bartell, MD (University of Utah) Dr. Bartell has nothing to disclose.
Emily Spoth, Other (University of Utah) Ms. Spoth has stock in Applied Genetic Technologies Corporation. Ms. Spoth has stock in MeiraGTx Holdings. Ms. Spoth has stock in Ocugen. Ms. Spoth has stock in PTC Therapeutics.
Satoshi Minoshima Satoshi Minoshima has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Hamamatsu Photonics. The institution of Satoshi Minoshima has received research support from Nihon Medi-physics. The institution of Satoshi Minoshima has received research support from Fujifilm.
Paolo M. Moretti, MD (University of Utah) The institution of Dr. Moretti has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie, Inc. The institution of an immediate family member of Dr. Moretti has received research support from NIH. The institution of an immediate family member of Dr. Moretti has received research support from VHA. The institution of an immediate family member of Dr. Moretti has received research support from DOD.