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lite.cnn.com - on gopher - inofficial | |
ARTICLE VIEW: | |
Genes known to increase the risk of Alzheimer’s may actually be an | |
inherited form of the disorder, researchers say | |
By Brenda Goodman, CNN | |
Updated: | |
2:23 PM EDT, Mon May 6, 2024 | |
Source: CNN | |
Alzheimer’s disease may be inherited more often than previously | |
known, according to a new study that paints a clearer picture of a gene | |
long known to be linked to the common form of dementia. | |
The authors of the study, published Monday in the journal Nature | |
Medicine, say that this might even be considered a distinct, inherited | |
form of the disease and that different approaches to testing and | |
treatment may be needed. | |
Among people diagnosed with Alzheimer’s, researchers recognize . | |
Most cases are thought to be sporadic, which develop later in life. | |
Familial forms, caused by mutations in any of three genes, tend to | |
strike earlier and are known to be rare, accounting for about 2% of | |
all Alzheimer’s diagnoses, or about 1 in 50 cases. | |
Under the new paradigm, 1 in 6 cases of Alzheimer’s would be | |
considered to be inherited, or familial. | |
This shifting appreciation of inherited risk, researchers say, is due | |
to a better understanding of the role of a fourth gene that carries the | |
blueprints to make a lipid-carrying protein called apolipoprotein E, | |
known as APOE. APOE ferries cholesterol throughout the body and brain | |
and is thought to play a role in depositing or sweeping away sticky | |
beta amyloid plaques, which are one hallmark of Alzheimer’s. | |
There of the APOE gene a person can carry. One called APOE2 is thought | |
to be protective against the development of Alzheimer’s disease. | |
APOE3 is thought to confer a neutral risk of the disease. | |
APOE4, on the other hand, is bad news. It has long been recognized | |
that people with at least one copy of the APOE4 gene have an elevated | |
risk of developing Alzheimer’s disease, while people with two copies | |
. | |
Now, researchers say APOE4 shouldn’t just be recognized as a risk | |
factor, it should be viewed as an inherited form of the disease, | |
virtually assuring that a person who has two copies will get the | |
biological changes associated with Alzheimer’s disease in their | |
brains. | |
Teasing out gene’s role in Alzheimer’s | |
In the new study, researchers from Spain and the United States compared | |
people in clinical studies who had two copies of the APOE4 gene with | |
people who had other forms of the APOE gene. | |
They also compared people with two copies of APOE4 to people with other | |
inherited forms of the disease: early-onset autosomal dominant | |
Alzheimer’s disease (ADAD) and Down syndrome-associated Alzheimer’s | |
disease (DSAD). The study included data from nearly 3,300 brains that | |
are stored at the National Alzheimer’s Coordinating Center and data | |
from another 10,000 people who were participants in five clinical | |
trials. | |
Not only were people with two copies of the APOE4 gene much more likely | |
to develop the biological changes that lead to Alzheimer’s disease, | |
similar to people with the other genetic forms of the disease, they | |
were almost assured the diagnosis: Nearly 95% of the people in the | |
studies with two copies of the APOE4 gene had the biology of | |
Alzheimer’s disease by the time they were 82 years old. | |
The study authors say that while APOE4 reliably causes the biological | |
changes associated with the disease — the creation of beta amyloid | |
plaques in the brain — having one or two copies of this gene | |
doesn’t always lead to cognitive decline. Rarely, people can have | |
APOE4 and have a lot of beta amyloid in their brain but not have | |
symptoms, perhaps because of other genetic or environmental factors | |
that protect their brains at the same time. In the large dataset of | |
nearly 3,300 brains kept by the National Alzheimer’s Coordinating | |
Center, for example, 273 individuals had two copies of the APOE4 gene, | |
and 240, or 88%, had dementia. | |
When people with two copies of APOE4 do have symptoms, they tend to get | |
them earlier than others. On average, they developed Alzheimer’s | |
about 10 years earlier — around age 65 — than people with other | |
forms of the APOE gene. Researchers also found that the buildup of | |
beta amyloid and tau in their brains followed almost the same | |
trajectory as has been noted in people with other inherited forms of | |
the disease. Their disease was more severe earlier in life. | |
In all the inherited forms of the disease, “there are striking, | |
striking similarities in the way the disease progresses and the | |
symptoms it gets,” said lead study author Dr. Juan Fortea, a | |
neurologist and director of the Memory Unit of the Neurology Department | |
at Hospital de la Santa Creu i Sant Pau in Barcelona, in a news | |
briefing. | |
Fortea and his co-authors argue that for these reasons, having two | |
copies of the APOE4 gene should be considered a genetic form of the | |
disease, not merely a risk for it. | |
Dr. Charles Bernick, associate medical director of the Cleveland Clinic | |
Lou Ruvo Center for Brain Health, said the study showed how powerful it | |
is to have two copies of the APOE4 gene. | |
“It really drives a disease process,” said Bernick, who was not | |
involved in the study. | |
Shifting understanding of genetic risks | |
The strength of APOE4’s role in the development of Alzheimer’s | |
wasn’t recognized earlier, the researchers think, because APOE4 also | |
plays an important role in heart health, and they think many people | |
with two copies of the gene probably died from cardiovascular causes | |
before they developed Alzheimer’s. had estimated that 30% to 35% of | |
people with two copies of the APOE4 gene would develop mild cognitive | |
impairment or dementia. | |
Researchers say they also found a gene-dose effect. While having two | |
copies of APOE4 assured that a person would see beta amyloid and tau | |
build up in their brains, having just one copy of the gene also | |
increased a person’s risk – but not as much as two copies of that | |
gene. | |
That would mean the APOE4 gene is semi-dominant, Fortea said. Other | |
diseases in which genes show semi-dominance include sickle cell anemia | |
and hypercholesterolemia. In sickle cell, for example, two copies of | |
the gene cause sickle cell disease, but one copy causes sickle cell | |
trait. People with sickle cell trait don’t usually have symptoms, | |
but to have heat stroke or muscle breakdown during strenuous exercise, | |
and they can experience pain crises under certain conditions. | |
Classifying APOE4 as an inherited form of the disease has some big | |
implications. First, it would mean that a far greater proportion of | |
Alzheimer’s cases are caused by genes than has been previously | |
understood. | |
Before APOE4, the only gene changes recognized to cause Alzheimer’s | |
were associated with early-onset forms of the disease and with Down’s | |
syndrome. They accounted for about 2% of Alzheimer’s cases, about | |
1 in 50. | |
People with two copies of the APOE4 gene make up about 15% of people | |
who are diagnosed with Alzheimer’s, or 1 in 7 cases of the disease. | |
About 2% of the general population carries two copies of the APOE4 | |
gene, which would make it one of the most prevalent inherited diseases. | |
The important takeaway from the study, said Dr. Constantine Lyketsos, | |
director of the memory and Alzheimer’s treatment center at Johns | |
Hopkins, is that Alzheimer’s disease shouldn’t be treated as a | |
monolith. Rather, it shows that there are different forms of the | |
disease that need personalized treatment. | |
“The point is, we need to start doing precision medicine and breaking | |
it down. Start with genetics,” said Lyketsos, who was not involved in | |
the study. | |
Gene testing isn’t recommended | |
It is also likely to change how people who carry the APOE4 gene are | |
diagnosed and treated. | |
There are tests available to determine a person’s APOE4 status, but | |
they’re as a routine part of diagnosis. That may need to change, the | |
study authors said. | |
“The consensus and the guidelines now do not recommend testing for | |
APOE4 and that was because the consensus was that it did not help for | |
the diagnosis,” Fortea said. | |
APOE testing is recommended for patients who are being evaluated to | |
take new amyloid-clearing medications, such as . | |
Because Alzheimer’s patients with two copies of the APOE4 gene are at | |
higher risk of serious side effects like brain swelling from these | |
amyloid-clearing medications, some treatment centers have decided not | |
to offer them the drugs, said study author Dr. Reisa Sperling, director | |
of the center for Alzheimer’s Research and Treatment at Brigham and | |
Women’s Hospital. | |
“I find this very problematic, given these data,” she said, noting | |
that it would be important to do research to see whether it might be | |
possible to find safer dosing or safer treatments for this patient | |
group. | |
“For me, this just means we need to treat them earlier,” Sperling | |
said, “and this research really suggests that we should be treating | |
them quite early, at a younger age, and at an early stage of pathology | |
because we know they are very, very likely to progress to impairment | |
quickly.” | |
Dr. Sterling Johnson, a study author who leads the Wisconsin Registry | |
for Alzheimer’s Prevention at the University of Wisconsin, said it | |
would be very important for clinical trials to start to take | |
participants’ APOE4 status into account. | |
“We may need to start treating these as a separate group in our | |
research papers so that we can really understand the relationship | |
between amyloid and tau and symptoms” in people with two copies of | |
the APOE4 gene, in a way that we kind of have not been able to before, | |
Johnson said in the news briefing. | |
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