The Genetics Of Dementia
“Genetics loads the gun, our lifestyle pulls the trigger.”
-Multiple attributions
I’m doing something a little different with this article.
Since genetics is a very complex and nuanced field I’m going to start with a short crash course on genetics to help you apply the information here. If you already feel pretty confident about your genetics knowledge, feel free to skip the first section.
The second section of the article will be written as a series of FAQs derived from the questions I often get from my clients and readers. Feel free to scroll through, looking for answers to your own questions.
A Quick Crash Course On Genetics
You have about 25,000 genes in your personal genome. You can think of your genome as a very large city broken into 23 city blocks called chromosomes. Each gene is an address on a certain city block. Every address (gene) does something unique to their location. Some genes are very unique because they do something that only a few other genes do.
For example you have two main genes (addresses) on your 15th chromosome (city block), that determine your eye color. These are the genes OCA2 and HERC2. While these two genes are the main ones associated with eye color there are about 10 other genes that support them.
As you can see, even in the case of eye color which is controlled mostly by two genes, there are many other influences from other helper genes that assist the main genes to do their job.
This is one of the reasons that genetics is so complicated.
It’s extremely rare for there to be one single gene that’s solely responsible for a certain function or disease.
Let’s look at a few more examples to really solidify how this works.
You can think of each gene as being a small factory that works within your cells to produce very specific proteins. These proteins are used by your body for certain functions.
For example, the genes (addresses) that code for bone growth turn on cells in your bones called osteoblasts to produce more bone cells. When you do strength training or when you fracture a bone, those genes will be more active than usual and produce more bone cells to repair or reinforce the structure of your skeletal system.
This is called an epigenetic effect where an external influence or environmental factor turns some genes on and some genes off based on the needs of your body.
Another example is what happens when you eat. Genes that code for the proteins that help with digestion, called enzymes, are activated by the thought, smell, sight and taste of food, and your body produces these enzymes to help you digest your food and extract all the good nutrients from them.
The redundancy of having many genes doing the same vital functions is critical because if one gene (address) is faulty or less productive, the others can pick up the slack and keep your body functioning.
Things get very interesting and more complex when we start thinking about the genetic differences between people, known as genetic variability.
All humans for the most part have the same genome (city), the same number of chromosomes (city blocks), and even the same genes (addresses). There are some exceptions like Trisomy 21, also known as Down’s Syndrome which you can read about in the Notes and Resources section at the end of the article.
What makes people different are the unique variations of gene structure at a specific location in your genome.
For example, let’s pretend we have a gene called “shirt.” This gene produces something used to cover the top of your body. Each person can have a variation of the shirt gene that codes for shirts of different colors or styles.
The function of the shirt gene is the same from one person to the next. Small variations in the structure of the gene determine what color or style of the shirt is produced. This is called your phenotype.
These differences are called gene variants. It’s these variants that geneticists are interested in when looking for traits associated with health and longevity, or traits that predispose someone to disease.
Now that you have the basics of DNA, chromosomes, genes, and gene variants, let’s discuss how all this works together to make you who you are with all your genetic strengths and challenges.
Genetic Diseases
Your genome (city) is actually two cities that are mirror images of one another. You get one city from your father and one city from your mother. The chromosomes and genes all match up perfectly to create this one mirror city (double helix DNA).
At each gene location you will have a variant from each parent. In some cases the variants from each parent are the same (homozygous). In many cases the variants will be different (heterozygous).
The difference, or heterozygosity, of variants is what’s responsible for evolution through natural selection.
Heterozygosity gives us genetic resilience through adaptation.
Sometimes though a gene variant from one parent can be so strong that it overpowers or dominates the activity at that gene location. This is called an autosomal dominant gene variant.
Other times a trait or phenotype won’t happen unless you have the same two gene variants from each parent. This is called an autosomal recessive gene variant.
In the case of recessive genes, a potential disease can be hiding for many generations until matched to someone who has the same gene variant. If that variant is responsible for a certain disease, the parents can be free from the disease while their children could be affected by it. These are called recessive diseases.
Other genetic-associated diseases can be autosomal dominant also known as monogenic or Mendelian diseases. In this case a child only needs one copy of the gene variant from one parent to have the disease.
Mendelian diseases are usually obvious because one of their parents often has a history of the disease themselves and it can be tracked back for multiple consecutive generations in a family tree.
Ok, so why is all this important for understanding the genetics of dementia?
Many diseases of dementia do have genetic factors that influence
Your risk of getting it.
How early you get it.
How severe it can be.
What you could do to prevent, avoid, or treat it.
Some people who get Alzheimer’s Disease and Frontotemporal Dementia (the two most common causes of dementia) can inherit it directly from one of their parents through a Mendelian (dominant) gene pathway.
But, this is the vast minority of people who get dementia and is associated with earlier onset and more severe forms of the disease.
Other people who get those diseases can have complex interactions of many different recessive genes. They could also get two copies of the same dysfunctional variant from each of their parents.
This is by far the vast majority of people who get dementia and is also the most responsive to prevention efforts.
To put it in perspective, out of the 35 million people who have been diagnosed with Alzheimer’s disease, only 500 families have been identified as being carriers of the autosomal dominant form of the disease.
The rest of those diagnosed with Alzheimer’s fall into the autosomal recessive category where they need two copies of the same variant from each parent (still pretty rare).
Or there are multiple epigenetic (external) factors at play turning on genes that create disease and turning off genes that offer protection from the disease.
This is by far the largest category of people who get dementia.
What this means is that even if you have a genetic variant that puts you at a higher risk for getting dementia, you actually have a lot of control over
your risk for getting it,
how early you get it
how severe it could be
This interaction between our genes, our behaviors, and our environment is present in almost all chronic diseases including
Heart disease
Type 2 diabetes
Autoimmune disease
Most forms of cancer
Knowing how to align your behaviors and environment with your genetic needs is the most important factor for living a long and healthy life.
This is the essence of longevity and healthspan.
Now, onto your questions!
How Do I Know If I Have A Genetically Dominant Form Of Dementia?
The key factor for predicting heritable diseases like an autosomal dominant (monogenic) form of Alzheimer’s Disease is your family history.
In fact, most experts believe this is more important than genetic testing because:
There are only three monogenic variants that cause dementia that we know of so far, but there could be others.
A family history will always be more predictive than just genetic screening alone for monogenic disease.
What you’ll need to calculate your risk is a health history of three generations of first-degree relatives.
A first degree relative in this case would be:
Full sibling
Biological parent
Biological grandparent
Biological great grandparent
You would also need to know the age when they started having symptoms or were diagnosed with dementia.
Here is a way to calculate your risk of carrying a monogenic (dominant) variant and developing the disease earlier than average (84 years)
At least one affected member in three consecutive generations = 86% chance
Two or more first degree relatives who were diagnosed younger than 61 = 68%
Two or more first degree relatives who were diagnosed younger than 65 = 15%
Two or more first degree relatives who were diagnosed at 65 or older = 1%
For example, if your mother was diagnosed with dementia in her early 70’s and your grandfather was diagnosed in his late 60’s your chance of having a dominant variant in your genome is about 1%
Hopefully you can see how rare it is to have one of these dominant forms of dementia.
If you’ve done this assessment and have a higher risk for a dominant form of dementia, or you’re just curious, these are the three known monogenic disease variants you and your doctor can look for:
Specific Monogenic Dementia Genes:
PSEN1 (most common )
APP (less common )
PSEN2 (least common)
How Do I Know If I Have A Genetically Recessive Form Of Alzheimer’s Disease?
The biggest risk factor for all forms of dementia is age. In fact, the average age for diagnosis of all forms of dementia is 84 years old.
There are some genetic factors however that can put you at a higher risk for developing dementia at an early age, even if you don’t have a dominant (monogenic) disease.
Most recessive diseases happen when:
Both parents give their child the same recessive variant (homozygous).
Multiple recessive variants interact in a way that causes a disease (polygenic).
Your behaviors and environment interact with your genes to cause a disease (epigenetic).
If you remember, a recessive genetic disease can skip one or many generations. So while a family history is useful, the only real way to see if you have a recessive gene that increases your or your children’s risk for dementia is by doing a genetic screening.
By far the most common and currently the most important recessive gene variant is called APOE4.
You may have even watched the documentary Limitless where Dr. Peter Attia, a longevity expert, informs actor Chris Hemsworth that he has two copies of this variant which puts him at a higher risk for Alzheimer’s disease.
We’ll dive more into APOE4 in the next question, but first I’d like to give you an excerpt from an MIT article on newly discovered gene variants you and your doctor could screen for.
As gene research goes on, researchers are finding links between late-onset Alzheimer's and a number of other genes.
Examples include:
ABCA7. This gene seems to be linked to a greater risk of Alzheimer's disease. Researchers suspect that it may have something to do with the gene's role in how the body uses cholesterol.
CLU. This gene helps the brain clear the protein called amyloid-beta. Research suggests that an imbalance in the making and clearing of amyloid-beta is key to getting Alzheimer's disease.
CR1. Not enough of the protein this gene makes might cause chronic swelling and irritation, called inflammation, in the brain. Inflammation is another possible factor in getting Alzheimer's disease.
PICALM. This gene is linked to how brain nerve cells, called neurons, talk to each other. How they talk to each other is important for them to work well and to form memories.
PLD3. Scientists don't know much about the role of PLD3 in the brain. But it's recently been linked to a significantly increased risk of Alzheimer's disease.
TREM2. This gene affects how the brain responds to swelling and irritation, called inflammation. Rare changes in this gene are linked to an increased risk of Alzheimer's disease.
SORL1. Some forms of SORL1 on chromosome 11 appear to be linked to Alzheimer's disease.
Credit to The Mayo Clinic for providing this information about late-onset Alzheimer’s research.
What Is APOE4 And Why Is It Important To Brain Health?
If you’ve seen the documentary on Disney+ called Limitless, you may have seen the episode where longevity specialist, Peter Attia, tells actor Chris Hemsworth that he has two copies of the APOE4 gene variant.
Since Chris has two copies, one from each parent, he’s at much higher than average risk for developing Alzheimer’s disease, possibly at a younger age than average.
Here’s the thing. It’s not that uncommon to have one copy of the APOE4 gene. In fact, about 25% of the general population has one copy. Statistically, this increases their risk for developing Alzheimer’s sometime in their life by double compared to the person who doesn’t have that variant.
It’s worth noting that people who have one copy of APOE4 and who develop dementia, usually get it in their late 70s or 80s.
The problem is that for people like Chris who have two copies, their risk increases to about 12x and it often comes on earlier in life.
This means that Chris’s statistical risk for getting early onset dementia is 12 times that of the average person.
Fortunately, only 2-3% of the general population have two copies.
What’s even better is that APOE4 is one of the most researched gene variants, and brain scientists have a good idea of what it does and why it increases the risk for dementia.
If we know why a disease happens then we can often prevent, delay or more effectively treat it.
So for all your science nerds out there, here’s what we know so far about what APOE4 is and how it could contribute to Alzheimer’s disease.
The APOE gene produces a particle called a lipoprotein that shuttles fatty acids like cholesterol and triglycerides around the brain.
Most people (~70%) have the APOE3 variant that offers no extra protection but also no additional risk.
Some people (< 5%) have a variant called APOE2 which actually provides added protection against Alzhemier’s.
The problem with APOE4 is the lipoproteins it makes have issues safely and effectively carrying cholesterol and triglycerides around in the brain.
This can cause an unhealthy buildup of fatty acids in areas they shouldn’t be at and prevent those fatty acids from being delivered to places they should.
The brain cells most affected by this dysfunctional carrier molecule are the astrocytes and glial cells.
Astrocytes do a lot of things for the brain including:
Providing structure (a physical matrix) for the rest of the neurons to organize upon.
Generate fuel and energy for the rest of the brain cells (neurons) to use.
Clear waste products, toxins and inflammation out of the brain.
When astrocytes aren’t working properly bad things will happen.
Structural tangles in the brain cells can develop.
Waste products and inflammation build up, damaging brain cells.
Plaques form within and between brain cells.
There isn’t enough fuel and energy for the brain to retrieve memories, learn new things and repair itself.
The vast network of neurons has problems connecting and communicating with other parts of the brain.
As an example, imagine living in a house where the roof is caving in, there is garbage everywhere, there’s a weird slime on the floors, and worst of all the internet sucks.
This is metaphorically what a brain with Alzheimer’ diseases is like.
It’s important to note that just having one or even two copies doesn’t guarantee you’ll get early onset Alzheimer’s Disease. In the next article I’ll introduce some specific strategies to prevent or delay dementia, even for those who are at a higher genetic risk.
Hint - The goals for the prevention strategies are to:
Safeguard the structure of the brain.
Clear toxins and metabolic waste.
Prevent and reduce inflammation.
Improve brain energy and metabolism
Safeguard and build new brain cell connections.
Do You Suggest General Genetic Screening?
I’d like to make it clear that I’m not a professional geneticist or genetics counselor but I have learned a lot about functional and clinical genetics over the years. That said, I actually do disagree with the recommendations against screening for genetic variants associated with Alzheimer’s disease and other forms of dementia.
The experts’ opinions assume:
The general population is not psychologically resilient enough to receive some potentially bad news, and they are afraid it could trigger anxiety and depression.
That since there are no current pharmaceutical or surgical interventions to treat dementia, the genetic information is not all that useful.
I whole-heartedly disagree! It’s my opinion that screening for dominant and recessive gene variants can help patients and their doctors to craft a useful prevention strategy.
There’s an unfortunate idea underlying the field of genetics called genetic determinism which means that our genetics, like fate, are unalterable.
While we may not be able to actually change our genome, we can influence how our genome behaves.
A new and promising field of medicine called preventative neurology is emerging. Here, doctors help their patients develop personalized strategies to prevent or delay many forms of neurodegenerative diseases like dementia, Parkinson’s, Disease and Multiple Sclerosis.
Unless we know what potential genetic challenges we have, it’s impossible to proactively address them.
The old assumption there’s nothing we can do to prevent or delay neurodegenerative disease is not only outdated, it’s just wrong, even in the case of genetically dominant diseases.
If we know the prevalent underlying physiological causes of dysfunction or disease then we can take steps to prevent or treat it.
This is why I’m a proponent of general genetic screening in conjunction with a thorough personal and family health history.
As health care providers we also need to have the communication skills to deliver hard information in a way that’s constructive and provides a road to prevention and recovery, even if that road includes hard work and requires some serious change.
…unfortunately they don’t teach communication skills in medical school.
But, if you’re interested in genetic screening I don’t recommend you try it on your own.
The health evaluations that come with many commercially available genetic tests can be misleading and in some cases incorrect.
It’s important to have a trusted and knowledgeable health provider or advisor who knows how to interpret the information and provide recommendations based on that information.
What Can I Do If I Have A Higher Genetic Risk For Dementia?
If you feel you have a higher genetic risk for dementia based on your family history I’d suggest working with a preventative neurologist, genetic counselor or health consultant to help you understand your risk and help you develop a strategy to prevent or delay it.
You could start by first talking with your primary care doctor. Sometimes you’d be surprised at what resources they have, and in some cases insurance will actually pay for a genetic test and referral to a genetics specialist.
That said, most conventional medical providers operate under the assumption that not much can be done for people who are predisposed to Alzheimer’s Disease or other forms of dementia.
As you’ll see in the next article, this assumption may be completely wrong and could be preventing many people from living longer and fuller lives.
For an article index for this series click this link.
Become a Subscriber!
Click this link to subscribe to my newsletter where I share articles, videos and subscriber discounts to help you on your path toward optimal health, performance and longevity.
Notes and References:
There are some conditions like Trisomy 21 (Down’s Syndrome) where they have one extra chromosome at the 21st location (city block) in their DNA. Having this extra chromosome creates the trait or phenotype that we see in people with Down’s Syndrome.
MIT article on APOE4, Alzheimer’s Disease and Lipid Dysregulation