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

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 both 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 APPin the clinical, biochemical and neuropathological findings of AD in DS.

Down syndrome, Alzheimer disease, and cerebral amyloid angiopathy: The complex triangle of brain amyloidosis

“…Doran et al reported the case of a patient with a partial trisomy 21 lacking APP triplication, who died at the age of 72 without dementia and without evidence of AD in multidisciplinary studies, including neuropathology. Authors suggest that those findings confirm the obligatory role of APP in the clinical, biochemical and neuropathological findings of AD in DS (Doran et al, ). However, the role of the APP gene as the sole factor triggering Aβ deposition in DS has been questioned.…”

“…Because of still not well understood mechanisms that are probably not only related to Aβ load, mutation site contributes to the phenotypic and pathological heterogeneity, particularly in cases of PSEN1 mutations beyond codon 200, in which a more severe CAA has been consistently found (Ryan, Biessels, et al, ). In contrast, in rare autopsy cases of DS with partial trisomy 21, where APP is not overexpressed, AD neuropathology and CAA was absent even at 72 or 78 years of age at autopsy (Doran et al, ; Prasher et al, ). Altogether, CAA in DS may be a critical vascular pathology associated with aging, in which higher levels are most likely due to APP overexpression and consequent increased Aβ accumulation, but the participation of other coexistent mechanisms can not be completely ruled out (Drachman, Smith, Alkamachi, & Kane, ; Wiseman et al, ).…”

“…Strikingly, there is a small subset of subjects who do not develop cognitive impairment at any age. The exact reasons for this are currently unknown, but the underlying genetic type of DS (complete or partial‐ including or not APP region‐ trisomy, traslocation, or mosaicism), a possible protective role of other genes on chromosome 21, concurring pathophysiological processes, or lifestyle factors could play a role (Doran et al, ; Wilcock et al, ).…”

Plasma amyloid and tau as dementia biomarkers in Down syndrome: Systematic review and meta‐analyses

“…The assumption that triplication of the APP gene causes AD pathology in DS is in line with rare case studies of individuals with partial trisomy of chromosome 21 who have only two copies of the APP gene, where post‐mortem neuropathological examinations revealed normal age‐related changes but no evidence of AD neuropathology (Doran et al, ; Prasher et al, ). However, the triplication of other genes on chromosome 21 aside from APP could also play a role in AD pathogenesis, as is suggested by findings of (a) differing amyloid deposition in animal model studies depending on the extent of the triplication (Wiseman et al, ), and (b) the apparent clinical and neuropathological differences between individuals with AD due to full trisomy 21 and those with the rare copy number variant resulting in APP duplication (Zis & Strydom, ).…”

Plasma metabolites related to cellular energy metabolism are altered in adults with Down syndrome and Alzheimer's disease

“…It is generally accepted that the increased risk of susceptibility to AD seen in individuals with DS is highly penetrant genetically and frequently preserved in the case of segmental trisomies (although see Doran et al, ). It remains an open question, however, as to whether this is exclusively an effect of the copy number expansion of chromosome 21 genes.…”