What is the role of the APP gene in the pathophysiology of Alzheimer disease (AD) in Down syndrome (DS)?

Updated: Nov 13, 2019
  • Author: Norberto Alvarez, MD; Chief Editor: Jasvinder Chawla, MD, MBA  more...
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The over expression of the APP gene might be related to the overproduction of the major protein observed in the senile plaque, the Abeta (1-42) peptide, which is considered to be one of the important factors leading to the development of the pathology of DS with AD. Abeta peptide is generated by the cleavage of the APP by beta and gamma secretase enzymes.

In addition, and supporting the role of APP triplication, a normal extra copy of APP, in the absence of trisomy 21, is associated with a rare, early form of familial AD (the dup-APP). In this condition, the triplication present varies in size but the presence of only one APP triplication is enough for the development of the syndrome, which is very similar in terms of clinical presentation and pathology, barring a few differences, to AD in DS. [31]

Duplication of APP, but not the prion protein (PRNP) gene, is a significant cause of early-onset dementia according to a large UK series. [32]

APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. [33] APP may be active early in life since there are reports of increased deposits of Abeta 42 amyloid in the brain of fetuses with trisomy 21, [34] but the significant accumulation does not occur until the second or third decade, suggesting that maybe there is a more efficient clearance mechanism in early life. Certainly, further studies on the role of APP as well as other factors that modulate APP expression would enhance our understanding of AD in DS and non-DS populations. [35]

Beta site APP-cleaving enzyme 1 (BACE1), the most important beta secretase in vivo, is elevated in persons with DS and may also play a role in the accumulation of beta-amyloid. [36]  

Another important factor cold be the apolipoprotein E (APOE) epsilon 4 allele, which is also associated with a higher deposition of beta-amyloid as well as higher risk and early onset of AD in DS. However, the APOE epsilon 2 allele may play a protective role since it is associated with a decrease in amyloid deposition.

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