In fact, the elderly lady would have been ill for a long time: forgetful, disoriented, dependent on care 20 years ago, even 30 years ago. She was to share the fate of her family members, who suffer from an early Alzheimer's disease and have passed it on for generations. Because even she carries a pathological change in a gene called presenilin 1. This mutation irreversibly causes an early onset of the disease – in fact.
But this woman was still in her head after her 70th birthday. She easily forgot. It is an absolutely special case that amazes the experts. The researchers wanted to know what was protecting the woman. After analyzing their entire genome by an international team, he discovered an unusual gene change in a Ghana known to Alzheimer's researchers called APOE 3. Results published this week in the journal Nature Medicine.
Families with genetic changes that lead to Alzheimer's are extremely rare, accounting for less than one percent of Alzheimer's.
The elderly lady lives in northwestern Colombia, in the department of Antioquia, and is one of the largest Alzheimer's families in the world with about 5,000 members. An estimated 1800 carry the mutation. That means they get Alzheimer's between 43 and 45, die from 49 to 50, and die about 10 years later. "La Bobera," a madman, called people in the remote Andean region a disease until on-call doctor Francisco Lopera, along with colleagues, discovered that it was Alzheimer's disease. It is likely that the Spanish immigrant brought the disease to the region in the 17th century, according to a team led by Ken Kosik of the University of California, Santa Barbara, USA.
Kosik was also included in the current study. However, along with his group, he found multiple gene changes in the presenilin-1 genes among families. "The reasons why these genetic changes have accumulated in the region of Colombia are unknown," Kosik says.
Families with genetic changes that lead to Alzheimer's are extremely rare, accounting for less than one percent of Alzheimer's. As a rule, brain disease occurs sporadically from the age of 60 years. However, researchers can learn a lot about the disease from affected families.
Colombia, however, is a mystery to her. An image analysis (MRI and PET) of her head showed that large parts of her brain were almost inundated with typical deposits of a protein fragment called beta-amyloid. A common thesis of Alzheimer's disease researchers is that beta-amyloid plays a crucial role in the disease and is the driver of mass nerve death.
APOE determines risk
The new findings contradict that assumption, US researchers write in a comment on the current study. Unless beta-amyloid is nerve harmful only in the presence of unchanged APOE. Conversely, a change in the APOE-3 gene could actively protect a woman from the onset of the disease, according to Christian Haass, Alzheimerexperte of the Munich University Ludwig Maximilian and the German Center for Neurodegenerative Diseases: "APOE binds to beta-amyloid, and changes the way it protein fragments are deposited in the brain or removed. "
The APOE gene occurs in humans in three variants: APOE 2, 3, and 4. It forms proteins that are involved in lipid metabolism. Among other things, they supply nerve cells with cholesterol. Three versions of APOE are known to Alzheimer's researchers because they have an impact on the risk of developing Alzheimer's disease.
The Colombian has a rare change in both copies of the APOE-3 gene (called the Christchurch mutation). How this change could protect against Alzheimer's for years, despite the numerous deposits of amyloid in the brain, will now be investigated by molecular biologists. "We will incorporate Colombian genetic modification into human stem cells and look at how microglial cells respond to it," Haass says. The biologist is currently focusing on microglial cells. These are the cells to remove harmful deposits in the brain, especially at the onset of Alzheimer's disease. Later, however, they appear to be involved in chronic inflammatory processes.
Exceptional as the Colombian case, she is not the only one who is protected against Alzheimer's despite a family gene mutation. The research team around Kosika knows a few other people in Colombia who carry a pathological gene change, but still have no memory or much later memory. In addition to members of the Colombian family, there is an international network of other affected families, called Dian (Dominantly Inherited Alzheimer's Network).
New ideas for therapies
Also known are these lucky family members who did not receive Alzheimer despite gene modification and age. Perhaps researchers, like a Colombian woman, will discover protective genes, clarify their function, and come up with new ideas for future treatment for Alzheimer's.
Created: 08.11.2019, 18:26 hour
Rizcogenic and protective genes in Alzheimer's disease
A rare familial form of Alzheimer's disease:The changes that cause the disease occur mainly in three genes: App gene, Presenilin1 gene (most common), Presenilin2 gene (rareest). All mutations found in the three genes increase the production and deposition of beta-amyloid in the brain of the diseased person.
A common sporadic form of Alzheimer's disease: The APOE 4 gene variant is one of the highest risk factors for Alzheimer's disease if it appears twice, i.e., one copy from the father and one from the mother inherited. More than 40 percent of Alzheimer's patients have two copies of APOE 4.
The second gene, a variant of TREM 2, poses a high risk of Alzheimer's disease as APOE 4. TREM 2 plays an important role in microglial cells, brain phagocytes.
Modifications of protective genes are also known. This includes the Colombian APOE3 / Christchurch mutant. The APOE2 version was also known to protect in duplicate. In the Icelandic population, as well as in Finland, Norway and Sweden, researchers found another rare gene change. This concerns the APP gene. However, due to this change, carriers produce less beta amyloid. (AP)