Alzheimer’s Disease–Down Syndrome Link Is Not All about APP

Down syndrome is caused by an extra copy of chromosome 21 (trisomy 21) and represents the single most common risk factor for early-onset Alzheimer’s disease. Estimates suggest that about two-thirds of people with Down’s syndrome will have developed clinical dementia by the time they reach their 60s.

Animal studies have already shown that an extra copy of the amyloid precursor protein (APP) gene —which is sited on chromosome 21—is enough to cause early-onset Alzheimer’s disease, even in the absence of Down syndrome. Studies in mice models by a team of researchers in the U.K., Europe, and the U.S. now suggest that three copies of chromosome 21 genes other than APP may influence Alzheimer’s disease pathogenesis in Down syndrome patients Their results showed that extra copies of non-APP genes are associated with increased amyloid-β (Aβ) aggregation and Aβ plaque deposition, and with worsening cognitive deficits.

The researchers hope that their findings could ultimately help lead to new treatments for Alzheimer’s disease in people with Down syndrome, but could also throw new light on the pathogenesis of Alzheimer’s disease in individuals who don’t have Down syndrome.

“We’ve shown for the first time that genes other than APP are playing a role in early-onset Alzheimer’s disease in our model of Down syndrome,” comments Frances Wiseman, Ph.D., senior research fellow at University College London (UCL), and first author of the team’s paper, which is published today in the journal Brain. “Identifying what these genes are, and what pathways are involved in the earliest stages of neurodegeneration, could help us to one day intervene with these pathways to prevent the disease in people with Down syndrome.”

“Although we’re looking at Alzheimer’s disease through the lens of Down syndrome, this international collaboration provides insight into the earliest stages of disease progression, which may be applicable to modulating Alzheimer’s disease in the general population,” adds Elizabeth Fisher, Ph.D., professor of neurogenetics at UCL, who is co-senior author of the paper, which is entitled “Trisomy of Human Chromosome 21 Enhances Amyloid-β  Independently of an Extra Copy of APP.”

Approximately 6 million people worldwide have Down syndrome. A proportion of affected individuals will start to accumulate Aβ in their brains during childhood, and the vast majority will have Aβ accumulation by the time they are in their mid-20s. By the age of 40 years all individuals with Down syndrome will have developed neurofibrillary tangles that are similar to those developed by patients with Alzheimer’s disease in the general population, the authors explain.

While extra copies of the APP gene, even without trisomy 21, are enough to cause early-onset Alzheimer’s disease, scientists haven’t understood whether any of other 600 or more protein-coding and noncoding genetic elements on chromosome 21 might also influence disease pathogenesis in people with Down syndrome.

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