However, there are more than 200 genes on chromosome 21. So how can one be sure that it is the tripling of the APP gene that causes people with trisomy 21 to develop Alzheimer’s disease so early and so often? Two other genetic abnormalities shed light on this. “Very isolated patients have been found who look like people with Down syndrome and still do not develop any signs of dementia into old age,” says the neurologist. A research group led by Eric Doran from the University of California in Irvine followed such a patient for six years and published the results in 2017. His memory deteriorated only minimally over the years, and the experts discovered almost no beta amyloid clumps. The solution to the riddle: the third copy of chromosome 21 was incomplete in the man who reached the age of 72. He had only two copies of the gene with the amyloid precursor protein.
Down Syndrome or Trisomy 21?
People often mean the same thing when they talk about “trisomy 21” and “Down syndrome”. But the terms have different meanings. The former stands for the genetic cause, i.e. a triple presence of chromosome 21. Down syndrome, on the other hand, is the result of trisomy 21. One speaks of a syndrome when a certain combination of different characteristics and symptoms is present. According to Etta Wilken, a former professor of general and integrative disability education at the University of Hanover, the distinction is important for several reasons. On the one hand, there are several forms of trisomy. In a mosaic trisomy, for example, only some of the cells contain a third copy of chromosome 21. This can even lead to no diagnosis of Down syndrome at all. This designation would be inappropriate in such a case. However, Wilken argues that Down syndrome is a more appropriate term in most cases. The basic genetic equipment determines our development to a large extent, but other factors also play an important role. For Wilken, the term Down syndrome also means that these people are not only physically and mentally impaired, but also through the way society treats them.
Another case of such an incomplete trisomy 21 is known: a woman from Great Britain who died at the age of 78. The rare genetic change with two instead of three alleles (gene variants) for the amyloid precursor protein was discovered in her, and she also showed almost constant cognitive performance in the last five years of her life. So there is a lot of evidence that the supernumerary APP gene is actually the trigger for Alzheimer’s in people with Down’s syndrome.
The second clue comes from “autosomal dominant” or “familial” Alzheimer’s disease. This is a very early form of dementia that can be inherited. Various gene mutations are responsible for this. In some families, only the APP gene is duplicated on one of the two chromosomes 21. These people therefore have three copies of the gene with an otherwise normal number of chromosomes. “Just the tripling of the APP gene is apparently enough to trigger Alzheimer’s,” summarizes Nübling. “People have a 100 percent chance of developing Alzheimer’s, which also starts relatively early.” According to a study by a team from the University of Manchester in 2018, most of those affected are then between 44 and 55 years old.
Evidence of protective genes
Compared to this group, people with trisomy 21 develop dementia later, some even never. So could it be that there are other genes on chromosome 21 that provide some protection against age-related brain degradation if they are present in three copies? An international team led by Dean Nižetić from Queen Mary University in London investigated this in 2021. The researchers grew mini-brains from donated skin cells from people with Down syndrome in Petri dishes. As expected, they found the typical signs of Alzheimer’s such as plaques and tau deposits in most such brain organoids with trisomy 21. In 30 percent of the tissue samples, however, there was no such evidence.
© Yousun Koh (detail)
How Alzheimer’s Plaques Form | The amyloid precursor protein (APP) is located in the cell membrane (green). The beta-secretase cuts off part of the extracellular, i.e. outside of the cell, area. Gamma secretase cuts the intracellular anchoring. Outside the cell remains an amino acid chain of 40 or 42 units: the beta-amyloid, which assembles to form the Alzheimer’s plaques.
In the cells of these Alzheimer-free organoids, the team cut the third copy of the so-called BACE2-Gens, the deposits typical of Alzheimer’s also formed here. The gene codes for the enzyme beta-secretase-2, which prefers to cut APPs into shorter pieces that are less prone to clumping. The authors also report that the cerebrospinal fluid from people with Down syndrome has more of such shortened peptides than that from healthy people. BACE2 seems to counteract the additional APP copy. However, the influence of beta-secretase-2 decreases with age, which would explain the increase in plaques with age.
Georg Nübling warns that such models should always be evaluated in a clinical context. There are too many unknowns involved: »Do the genes on chromosome 21 perhaps also influence the genetic material on other chromosomes? And what about epigenetic changes? It quickly becomes so complex that it’s not really worth investigating.« He also doubts that people with trisomy 21 will develop Alzheimer’s later than those with a tripled APP gene but a normal chromosome set. “It’s not that easy to identify the symptoms of people with Down syndrome,” he explains. “Especially when the level of performance is very low, it is difficult to say when Alzheimer’s disease will actually start.”