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Alzheimer disease (AD) predominantly affects individuals above 60 years of age. Autosomal dominant mutations in 3 genes—amyloid precursor protein (APP), presenilin1 (PSEN1), and presenilin2 (PSEN2)—account for a small proportion of AD cases. These cases are usually associated with an early age at onset (as early as the third decade, but have been shown to have onset as late as 70 years).1 Mutations in PSEN1 are more common (over 170 different mutations reported) than APP or PSEN2 mutations (http://www.molgen.ua.ac.be/ADMutations/default.cfm?MT=0&ML=0&Page=Home). We have identified a family of Irish/English ancestry with a 2-generation history of autosomal dominant early onset AD (EOAD, onset in the late 40s). Affected individuals in this family carry a novel PSEN1 mutation, G217R. We describe the clinical features, autopsy findings, and biologic significance of this mutation.
The proband was identified after referral to a clinical trial at age 54 years with symptom onset in her early 40s. She was unable to complete the clinical trial and was lost to follow-up. The pedigree was later referred to our center due to the strong family history of EOAD and a mutation identified in the proband (IV-4) by Athena Diagnostics. Eight people were reported by family history (figure, A) or medical records to have EOAD. The mean age at onset in this family is 45.5 years (range 43–47 years). The mean age at death is 55.5 years (range 49–65 years). The son of IV-10 contacted us at the time of his father’s death. By history and medical records, IV-10 had probable AD. At age 44 years, he was having anxiety attacks and depression. By age 46 years, he was unable to perform a delivery job due to problems with memory and orientation. He was treated with donepezil. By age 47 years, he had chemical burns from a work-related accident; afterwards, his memory worsened. A CT of the brain (figure, B) revealed cortical atrophy. At age 51 years, he entered a nursing home due to incontinence and nighttime confusion. He had several hospitalizations for agitation and aggressive behavior and died at age 52 years of dehydration and aspiration pneumonia.
At autopsy, the fresh brain weighed 1,144 g (normal range: 1,250–1,400 g). There was mild generalized atrophy. Coronal slicing revealed a moderately dilated lateral ventricle and hippocampal atrophy (figure, C). Microscopic evaluation revealed abundant Aβ-diffuse and neuritic plaques and neurofibrillary tangles (figure, D–F) meeting neuropathologic criteria for AD.2 An unusual feature of this case was the large number of cotton wool plaques (CWP), a morphologic subtype of diffuse Aβ plaques (arrows in the figure, D and E), which have been reported previously in cases of AD with some PSEN1 mutations.3,4
Primers were designed to target each exon and at least 50 bp of 3′ and 5′ flanking intronic sequence of PSEN1. Sequencing was performed using ABI Big Dye version 3.1 (Applied Biosystems, Foster City, CA). Sequence analysis was performed using Sequencher software (Gene Codes, Ann Arbor, MI). A transversion from G to C, resulting in a change from glycine (GGT) to arginine (CGT) at codon 217 (G217R), was found in individual IV-10 (figure, G). This was the same mutation found by Athena Diagnostics in the first cousin (IV-4) of this subject.
To test the biologic consequences of G217R, we introduced the mutation into PSEN1 cDNA by QuickChange II site-directed mutagenesis (Stratagene, Cedar Creek, TX) and examined the effect of this mutation on Aβ production in vitro. HEK293 cells were transiently cotransfected with a human APP cDNA and a PSEN1 cDNA construct carrying either the wild-type sequence or the G217R mutation. Conditioned media was collected and secreted Aβ40 and Aβ42 were analyzed using an ELISA assay.5 The Aβ42/40 ratio was significantly higher in G217R-transfected cells compared to wild-type PSEN1-transfected cells (figure, H), confirming that the mutation is likely to be pathogenic.
CWPs are large rounded plaques, containing both Aβ40 and Aβ42, and are relatively free of dystrophic neurites; they have been observed in a subset of families with PSEN1 mutations.3,4 The unusual morphology of the Aβ plaques in these cases may result from the mutation altering APP trafficking and metabolism.
Although most families with CWP clinically have spastic paraparesis,6 we found no evidence for this in the medical record for individual IV-10. Interestingly, one of the few EOAD families reported with CWP but no spastic paraparesis also carries a mutation at codon 217 (G217D).4,7
We report a novel PSEN1 mutation, G217R, that is associated with typical AD clinical presentation in an EOAD family but is pathologically associated with large numbers of CWPs.
The authors thank the family for participation in this study.
Supported by grant P50-AG05681 from the NIH/National Institute on Aging, Bethesda, MD (Washington University Alzheimer’s Disease Research Center, St. Louis, MO), by The Barnes Jewish Foundation, and by The Charles and Joanne Knight Alzheimer’s Research Initiative of the Washington University Alzheimer’s Disease Research Center.
Disclosure: The authors report no disclosures.
Received December 17, 2008. Accepted in final form March 17, 2009.
Address correspondence and reprint requests to Dr. Alison Goate, Department of Psychiatry, B8134, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110; goate/at/wustl.edu