Alzheimer's Reading Room
Alzheimer’s Genome Project and the population based studies of the International Genomics of Alzheimer's Project are getting us closer and closer to someday being able to eradicate Alzheimer’s disease using a strategy of early prediction and early intervention.
-- Dr. Rudolph Tanzi
By Rudolph E. Tanzi, Ph.D.
The Four Known Alzheimer’s Genes
Over the past several decades, it has become increasingly clear that inheritance plays a major role in Alzheimer’s disease.
The roughly 25,000 genes in the human genome are comprised of deoxyribonucleic acid (DNA) packaged into 24 different chromosomes, 1-22, X and Y.
A gene’s job is to either make proteins or control the activity of other genes. Over many generations, the DNA of a gene can mutate to create a “variant”. A very rare DNA variant is called a “mutation”, while a variant that is common in the population is called a “polymorphism”.
DNA variants allow for all of us to be a little different from each other.
There are about 3 million variants that differ between any two individuals. Variants in certain genes can directly cause a disease like Alzheimer’s, can increase susceptibility to disease, or can even confer protection against disease.
One’s risk for most age-related diseases such as cancer, diabetes, heart disease, stroke, and Alzheimer’s is strongly influenced by our genes.
For all of these age-related diseases, we know of mutations that guarantee onset of these diseases with no need for input from any other genes or environmental factors. And, we know of polymorphisms that can increase (or decrease) one’s susceptibility to the disease, but without guaranteeing onset of the disease.
In this latter case, other genes and environmental factors usually conspire together to determine when and whether one will get disease. Any gene which can contain a variant(s) that significantly influence one’s susceptibility to Alzheimer’s, whether it be to guarantee the disease or serve to increase (or decrease) risk, is called an “Alzheimer’s gene”.
It is important to remember that all genes are “good”; it is only the variants in the DNA of these genes that can influence one’s lifetime risk for a disorder such as Alzheimer’s disease.
In the 1980’s and 90’s, my laboratory co-discovered the three known genes that can carry mutations causing early-onset (<60 yrs) familial Alzheimer’s disease. These three genes, known as APP, PSEN1 and PSEN2, can harbor any of over 200 different gene mutations that guarantee onset of Alzheimer’s at a relatively early age with no need for additional input from other genes or environmental factors.
These mutations are rare, accounting for only 1-2% of Alzheimer’s cases.
Inheritance of one of these mutations from just one parent virtually guarantees onset of Alzheimer’s, usually by 60 years old. If a parent carries such a mutation, each child has a 50% chance of inheriting the same mutation and getting early-onset Alzheimer’s disease with virtual certainty before 60 years old. Genetic testing is available for the early-onset Alzheimer’s gene mutations, but is usually reserved for those who have a family history of early-onset Alzheimer’s disease.
The fourth known Alzheimer’s gene is APOE. In the early 1990’s, investigators at Duke University found that a common gene variant (polymorphism) of APOE, called epsilon 4, can increase risk for late-onset (>60 yrs) Alzheimer’s disease.
This variant is present in about 20% of the general population but this increases to >50% in Alzheimer’s patients. Unlike the early-onset AD gene mutations, this variant does not guarantee Alzheimer’s, but only serves to increase risk. Inheriting one copy of the variant (from one parent) increases risk by 4-fold (versus the general population) and two copies (from both parents), >10-fold. Importantly, a person can inherit the APOE epsilon 4 gene variant from one or both parents and never get Alzheimer’s in the span of a normal lifetime.
With regard to genetic testing for the common late-onset form of Alzheimer’s, we are not yet able to do so reliably. This is because the APOE epsilon 4 gene variant is not sufficient on it’s own to predict one’s risk for Alzheimer’s reliably. Other genes and environmental factors need to combine with the APOE epsilon 4 gene variant to cause Alzheimer’s.
Some gene variants can exacerbate while others mitigate the risk for Alzheimer’s conferred by the APOE epsilon 4 gene variant. And, we do not yet know the full set of gene variants that can increase or decrease risk for Alzheimer’s when inherited together with the APOE epsilon 4 gene variant.
Thus, APOE gene testing is not recommended as a sole means for predicting Alzheimer’s risk. The other late-onset Alzheimer’s genes must first be identified in order to reliably test for risk for late-onset Alzheimer’s disease.
So how many other Alzheimer’s genes are there?
We know that the four known Alzheimer’s genes, APP, PSEN1, PSEN2, and APOE account for roughly 30% of the inheritance of Alzheimer’s. Thus, 70% of the genetics of Alzheimer’s remains undefined.
We as well as others have been engaged in comprehensive projects to find the other Alzheimer’s genes.
Once we have all of the Alzheimer’s genes in hand, we will be able to more reliably predict one’s lifetime risk for the common late-onset form of Alzheimer’s disease. However, one might ask,
“Why bother to test if there is nothing we can currently do to prevent, stop, or reverse it?”This is certainly a fair question since we still do not have drugs that stop the disease process in Alzheimer’s. We only have drugs like Aricept and Namenda that modestly and temporarily alleviate the symptoms of cognitive decline, but without affecting the progress of the disease.
We need to do better more effective therapies for Alzheimer’s, but how do we get there?
First, we need to identify all of the genes and variants involved in influencing risk for Alzheimer’s disease. Studies of the known Alzheimer’s disease genes (the four previously mentioned) have provided the vast majority of information being used to guide novel drug discovery aimed at preventing, stopping, and maybe even reversing Alzheimer’s disease.
Every new Alzheimer’s gene defect we find provides new clues regarding the cause of the disease what we need to do to stop the disease. Thus far, all four genes have pointed to a small protein called “Abeta” as the cause. Abeta is normally made in the brain, but is found in excessive amounts in the brains of Alzheimer’s patients, e.g. in senile plaques that litter the Alzheimer’s brain around nerve cells.
Small clumps of Abeta can gum up the connections between nerve cells known as synapses. Billions of nerve cells in the brain form trillions of synapses making up our neural network.
The neural network, in all its complexity, is needed for all brain function, including memory and learning. Excessive Abeta disrupts synaptic communication between nerve cells leading to loss of memory and learning and eventually dementia.
Dementia is defined as global and catastrophic cognitive failure; Alzheimer’s disease is the most common form of dementia in the elderly.
End Part One. Next up, Beyond the Original Four Alzheimer’s Genes
Rudolph E. Tanzi, Ph.D.
Joseph P. and Rose F. Kennedy Professor of Neurology
Harvard Medical School
Director, Genetics and Aging Research Unit
Massachusetts General Hospital
Chairperson, Research Consortium, Cure Alzheimer’s Fund
Want to Make a Difference. Click the red button to go to the Cure Alzheimer's Fund and to help support the Alzheimer’s Genome Project
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Original content Bob DeMarco, the Alzheimer's Reading Room