DNA determines a large part of the risk for Alzheimer’s disease, but it remained unclear how many genetic risk factors contribute to disease.
A team led by Prof. Bart De Strooper (VIB-KU Leuven) and Dr. Mark Fiers now show that many of those risk factors affect brain maintenance cells called microglia, and more particularly their response to amyloid-beta, one of the proteins aggregating in the brains of Alzheimer patients.
The individual effects of small genetic variations are likely small, but the combination of hundreds of such subtle alterations might tip the balance and cause disease.
Why do some people get Alzheimer’s disease while others do not, even when growing very old?
Despite decades of research, researchers still don’t know the full answer to this question. Epidemiological studies show that about two-thirds of a person’s risk for Alzheimer’s disease is genetically determined.
A few dozen risk genes have been identified, but recent evidence shows that there could be hundreds of additional genetic variants that each contribute in a small but significant way to disease risk.
From risk gene to disease mechanism
Bart De Strooper (VIB-KU Leuven) has been studying the mechanisms of Alzheimer’s disease for decades.
His team tries to find out what this combined genetic risk can teach us about how the disease develops in our brain: “Two crucial questions arise from the myriad of genetic studies.
First, what is the link between these Alzheimer risk genes and the amyloid-beta plaques or tau tangles we find in Alzheimer brains; and second, are they all involved in one central cellular or molecular pathway, or do they define many parallel pathways that all lead to Alzheimer’s?”
The researchers set out to understand when these genes are expressed and in particular, whether they respond to tau or amyloid‐beta pathology.
“When it comes to risk, you always need to take the context into account,” explain Mark Fiers, co-lead author of the study.
“If you don’t wear your seatbelt in the car, there is no problem as long as you don’t have an accident.”
With this in mind, the researchers aimed to understand under which circumstances genetic risk for Alzheimer’s comes into play. Fiers: “Almost every person develops some degree of Alzheimer pathology in the brain, i.e. amyloid-beta plaques and tau tangles.
However, some people remain cognitively healthy despite a high pathology load, while others develop Alzheimer symptoms quite rapidly.”
“To gain more insight we checked gene expression in two different mouse models of Alzheimer’s, one displaying amyloid-beta and the other tau pathology, at different ages,” says Annerieke Sierksma, a postdoctoral researcher in De Strooper’s lab.
“We identified that many of the genes linked to Alzheimer’s risk are particularly responsive to amyloid-beta but not to tau pathology.”
Microglia activation
The team identified 11 new risk genes that are significantly upregulated when facing increased amyloid-beta levels. All these genes are expressed in microglia, cells that play a key role in brain maintenance.
Ashley Lu, a Ph.D. student closely involved in the analysis: “We could confirm that microglia exposed to amyloid-beta drastically switch to an activated status, something that occurs to a much lesser extent in the tau mice.
These new insights indicate that a large part of the genetic risk of Alzheimer’s disease involves the microglial response to amyloid-beta.”
Understanding genetic risk
Should we rethink the classical gene‐based view, where certain mutations or genetic variants lead to disease?
De Strooper thinks so: “One single genetic variant within a functional network will not lead to disease. However, multiple variants within the same network may tip the balance to a disease‐causing disturbance.
Such a hypothesis could also explain the conundrum that some /individuals with a lot of amyloid-beta in their brain do not develop clinical symptoms.”
“While amyloid-beta might be the trigger of the disease, it is the genetic make‐up of the microglia, and possibly other cell types, which determines whether a pathological response is induced,” adds Fiers.
“Identifying which genetic variants are crucial to such network disturbances and how they lead to altered gene expression will be the next big challenge.”
Do Genes Cause Diseases?
Genetic mutations (permanent change in one or more specific genes) can cause diseases. If a person inherits a genetic mutation that causes a certain disease, then he or she will usually get the disease. Sickle cell anemia, cystic
fibrosis, and some cases of early-onset Alzheimer’s disease are examples of inherited genetic disorders.
Other changes or differences in genes, called genetic variants, may increase or decrease a person’s risk of developing a particular disease. When a genetic variant increases disease risk but does not directly cause a disease, it is called a genetic risk factor.
Identifying genetic variants may help researchers find the most effective ways to treat or prevent diseases such as Alzheimer’s in an individual.
This approach, called precision medicine, takes into account individual variability in genes, environment, and lifestyle for each person.
The expression of genes—when they are “switched” on or off—can be affected, positively and negatively, by environmental and lifestyle factors, such as exercise, diet, chemicals, or smoking.
The field of epigenetics is studying how such factors can alter a cell’s DNA in ways that affect gene activity.
Genes and Alzheimer’s Disease
There are two types of Alzheimer’s – early-onset and late-onset. Both types have a genetic component.
Late-Onset Alzheimer’s Disease
Most people with Alzheimer’s have the late-onset form of the disease, in which symptoms become apparent in their mid-60s and later.
Researchers have not found a specific gene that directly causes late-onset Alzheimer’s disease. However, having a genetic variant of the apolipoprotein E (APOE) gene on chromosome 19 does increase a person’s risk. The APOE gene is involved in making a protein that helps carry cholesterol and other types of fat in the bloodstream.
APOE comes in several different forms, or alleles. Each person inherits two APOE alleles, one from each biological parent.
- APOE ε2 is relatively rare and may provide some protection against the disease. If Alzheimer’s disease occurs in a person with this allele, it usually develops later in life than it would in someone with the APOE ε4 gene.
- APOE ε3, the most common allele, is believed to play a neutral role in the disease—neither decreasing nor increasing risk.
- APOE ε4 increases risk for Alzheimer’s disease and is also associated with an earlier age of disease onset. Having one or two APOE ε4 alleles increases the risk of developing Alzheimer’s. About 25 percent of people carry one copy of APOE ɛ4, and 2 to 3 percent carry two copies.
APOE ε4 is called a risk-factor gene because it increases a person’s risk of developing the disease. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer’s. Some people with an APOE ε4 allele never get the disease, and others who develop Alzheimer’s do not have any APOE ε4 alleles.
Recent research indicates that rare forms of the APOE allele may provide protection against Alzheimer’s disease. More studies are needed to determine how these variations might delay disease onset or lower a person’s risk.
Early-Onset Alzheimer’s Disease
Early-onset Alzheimer’s disease is rare, representing less than 10 percent of all people with Alzheimer’s. It typically occurs between a person’s 30s and mid-60s. Some cases are caused by an inherited change in one of three genes.
The three single-gene mutations associated with early-onset Alzheimer’s disease are:
- Amyloid precursor protein (APP) on chromosome 21
- Presenilin 1 (PSEN1) on chromosome 14
- Presenilin 2 (PSEN2) on chromosome 1
Mutations in these genes result in the production of abnormal proteins that are associated with the disease. Each of these mutations plays a role in the breakdown of APP, a protein whose precise function is not yet fully understood. This breakdown is part of a process that generates harmful forms of amyloid plaques, a hallmark of Alzheimer’s disease.
A child whose biological mother or father carries a genetic mutation for one of these three genes has a 50/50 chance of inheriting that mutation. If the mutation is in fact inherited, the child has a very strong probability of developing early-onset Alzheimer’s disease.
For other cases of early-onset Alzheimer’s, research has shown that other genetic components are involved. Studies are ongoing to identify additional genetic risk variants.
Having Down syndrome increases the risk of developing early-onset Alzheimer’s disease. Many people with Down syndrome develop Alzheimer’s as they get older, with symptoms appearing in their 50s or 60s. Researchers believe this is because people with Down syndrome are born with an extra copy of chromosome 21, which carries the APP gene.
For more information, see NIA’s Early-Onset Alzheimer’s Disease: A Resource List.
Genetic Testing for Alzheimer’s Disease
A blood test can identify which APOE alleles a person has, but results cannot predict who will or will not develop Alzheimer’s disease. Currently, APOE testing is used primarily in research settings to identify study participants who may have an increased risk of developing Alzheimer’s. This knowledge helps scientists look for early brain changes in participants and compare the effectiveness of possible treatments for people with different APOE profiles.
Genetic testing is also used by physicians to help diagnose early-onset Alzheimer’s disease and to test people with a strong family history of Alzheimer’s or a related brain disease.
Genetic testing for APOE or other genetic variants cannot determine an individual’s likelihood of developing Alzheimer’s disease—just which risk factor genes a person has. It is unlikely that genetic testing will ever be able to predict the disease with 100 percent accuracy, researchers believe, because too many other factors may influence its development and progression.
Some people learn their APOE status through consumer genetic testing or think about getting this kind of test. They may wish to consult a doctor or genetic counselor to better understand this type of test and their test results.
Alzheimer’s Genetics Research
Discovering all that we can about the role of Alzheimer’s disease genetic risk and protective factors is an important area of research. NIA supports several major genetics research programs.
Understanding more about the genetic basis of the disease will help researchers to:
- Answer a number of basic questions – What makes the disease process begin? Why do some people with memory and other thinking problems develop Alzheimer’s while others do not?
- Determine how genetic risk and protective factors may interact with other genes and lifestyle or environmental factors to affect Alzheimer’s risk in any one person.
- Identify people who are at high risk for developing Alzheimer’s so they can benefit from new interventions and treatments as soon as possible.
- Explain differences in Alzheimer’s disease risk and protection among racial groups and sexes.
- Focus on new prevention and treatment approaches
More information: Annerieke Sierksma et al. Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology, EMBO Molecular Medicine (2020). DOI: 10.15252/emmm.201910606
