What is the role of genetics 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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Approximately 95% of individuals with DS have trisomy 21. In around 4%, there is a translocation of critical regions of chromosome 21, which are attached to chromosomes 14, 21, or 22. In a small percentage of cases (< 1%), DS is the result of a mosaic with some but not all cells being trisomic. Even though there is triplication of the whole chromosome, probably only a small portion is critical for the development of the neuropathology and clinical features of DS in a complex phenotype-genotype relationship. [24]

The presence of an extra chromosome, along with the overexpression of the genes located in that chromosome, is considered the main reason for the development of the characteristic signs and symptoms of DS and probably plays an important role in the development of AD in persons with DS. Overexpression of genes with consequent increase in activity leads to increased production of end products, which can be toxic for the individual. However, determining which genes are responsible for the development of AD in DS is not easy due to the nunber of genes in chromosome 21 (233 coding genes, 299 long non-coding genes, and 29 microRNA). [25] Besides, the number of clinical expressions of a gene is dependent on several factors like the number of copies of the gene as well as the environmental context. [26] These variations in the expression of the genes' activities in the development of AD in DS may explain the variations in the development of neuropathology and dementia in DS.

Several genes that might play a role in the development of AD are found in chromosome 21. Among them are the APP and cytoplasmic enzyme superoxide dismutase (SOD-1) genes, both of which are important in the regulation of potential toxic metabolites, the reactive oxygen species (ROSs), which are the result of the normal metabolism of O2. These ROSs include free radicals (superoxide anions, nitric oxide, hydroxyl radical) and other non radical metabolites (eg, hydrogen peroxide), among others. The accumulation of ROSs may result in cell death. [27, 5]

The excess activity of SOD-1 in a variety of cells is not limited to the brain and has also been observed in erythrocytes, B cells, T cells, and fibroblasts. This increased activity results in the accumulation of hydrogen peroxide (H2 O2), which may reach toxic levels and may be related not only to the neuronal death observed in DS but also to carcinogenesis and the impairment of immune functions.

In most instances, trisomy 21, the result of a failure of the pair of chromosomes to separate, is of maternal orgin. Interestingly, there is a 4x higher incidence of AD in younger mothers (< 35 years) who give birth to a child with DS compared with mothers >35 years. This pattern was not seen in the fathers, and it is not seen in parents of children with other intellectual disabilities. [28]

Case studies of adults with DS and atypical karyotypes, including translocations, partial trisomies, and varying degrees of mosaicism, showed an association with improved survival and decreased risk of AD when the atypical karyotype is associated with a reduction of the APP gene dose. [29]


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