Down Syndrome, Partial Trisomy 21, and Absence of Alzheimer’s Disease: The Role of APP

Article type: Research Article

Authors: Doran, Eric^a | Keator, David^b | Head, Elizabeth^c | Phelan, Michael J.^d | Kim, Ron^e | Totoiu, Minodora^a | Barrio, Jorge R.^f | Small, Gary W.^g | Potkin, Steven G.^b | Lott, Ira T.^{a; *}

Affiliations: [a] Department of Pediatrics, University of California, Irvine Medical Center, Orange, CA, USA | [b] Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA | [c] Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA | [d] Department of Statistics, University of California, Irvine, CA, USA | [e] Department of Pathology, University of California, Irvine Medical Center, Orange, CA, USA | [f] Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, CA, USA | [g] Department of Psychiatry and Biobehavioral Sciences and the Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA

Correspondence: [*] Correspondence to: Ira T. Lott, MD, University of California, Irvine Medical Center, 101 The City Drive South, ZC 4482, Orange, CA 92868, USA. Tel.: +1 714 456 5333; Fax: +1 714 456 8466; E-mail: itlott@uci.edu.

Abstract: Overexpression of the amyloid precursor protein (APP) gene on chromosome 21 in Down syndrome (DS) has been linked to increased brain amyloid levels and early-onset Alzheimer’s disease (AD). An elderly man with phenotypic DS and partial trisomy of chromosome 21 (PT21) lacked triplication of APP affording an opportunity to study the role of this gene in the pathogenesis of dementia. Multidisciplinary studies between ages 66–72 years comprised neuropsychological testing, independent neurological exams, amyloid PET imaging with 11C-Pittsburgh compound-B (PiB), plasma amyloid-β (Aβ) measurements, and a brain autopsy examination. The clinical phenotype was typical for DS and his intellectual disability was mild in severity. His serial neuropsychological test scores showed less than a 3% decline as compared to high functioning individuals with DS who developed dementia wherein the scores declined 17–28% per year. No dementia was detected on neurological examinations. On PiB-PET scans, the patient with PT21 had lower PiB standard uptake values than controls with typical DS or sporadic AD. Plasma Aβ42 was lower than values for demented or non-demented adults with DS. Neuropathological findings showed only a single neuritic plaque and neurofibrillary degeneration consistent with normal aging but not AD. Taken together the findings in this rare patient with PT21 confirm the obligatory role of APP in the clinical, biochemical, and neuropathological findings of AD in DS.

Keywords: Alzheimer’s disease, amyloid-β, amyloid β-protein precursor, APP, dementia, down syndrome, partial trisomy 21, PiB-PET, trisomy 21

DOI: 10.3233/JAD-160836

Journal: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 459-470, 2017