A Novel PSEN1 Mutation (I238M) associated with Early-Onset Alzheimer's Disease in an African-American Woman

Article type: Short Communication

Authors: Ting, Simon Kang Seng^a | Benzinger, Tammie^b | Kepe, Vladimir^c | Fagan, Anne^d | Coppola, Giovanni^{e; f} | Porter, Verna^e | Hecimovic, Silva^g | Chakraverty, Suma^h | Alvarez-Retuerto, Ana Isabel^{e; f} | Goate, Alison^h | Ringman, John M.^{e; f; *}

Affiliations: [a] Department of Neurology, Singapore General Hospital, Singapore | [b] Departments of Radiology and Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA | [c] Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA | [d] Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA | [e] Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA | [f] Easton Center for Alzheimer's Disease Research at UCLA, Los Angeles, CA, USA | [g] Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia | [h] Department of Psychiatry, Washington University, St. Louis, MO, USA

Correspondence: [*] Correspondence to: John M. Ringman, M.D., M.S., Clinical Professor, UCLA Department of Neurology, Easton Center for Alzheimer's Disease Research, 10911 Weyburn Ave., #200, Los Angeles, CA 90095-7226, USA. Tel.: +1 310 794 3231; Fax: +1 310 794 3148; E-mail: jringman@mednet.ucla.edu.

Abstract: Mutations in PSEN1 are the most common cause of autosomal dominant familial Alzheimer's disease (FAD). We describe an African-American woman with a family history consistent with FAD who began to experience cognitive decline at age 50. Her clinical presentation, MRI, FDG-PET, and PIB-PET scan findings were consistent with AD and she was found to have a novel I238M substitution in PSEN1. As this mutation caused increased production of Aβ42 in an in vitro assay, was not present in two population databases, and is conserved across species, it is likely to be pathogenic for FAD.

Keywords: African, Alzheimer's disease, amyloid-β₄₂, autosomal dominant, familial, gamma-secretase, in vitro, PIB-PET, presenilin-1, PSEN1

DOI: 10.3233/JAD-131844

Journal: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 271-275, 2014