WHETHER WE ARE STRESSED OR depressed, foggy from sleep deprivation, or bouncing back and forth between feeling exhausted and wired, our brains not functioning at their best can certainly be unsettling. Ultimately, when we struggle with these issues, we can find ourselves second-guessing our decisions or worrying unduly about the future. Though not everyone will experience all of these challenges at once, many women will hit “speed bumps” over the course of their lifetimes, confronted by a combination of these symptoms to a degree that is disruptive enough to give them pause. This can be due to the fact that, over time, our bodies and brains are going through various shifts and changes. It’s up to us to make sure such transitions are attended to properly, and to gain access to the right strategies to address each symptom.
I cannot stress this enough: No two women are alike. What works for you may not work for your friend, your colleague, or even your own daughter—and vice versa. It is high time to abandon the one-size-fits-all approach that has dominated the field of women’s health for centuries, in favor of a more dynamic model that focuses on women as individuals instead.
This concept is at the heart of precision medicine, an emerging approach for disease treatment and prevention that takes our personal, individualized variability into account. Precision medicine embraces a paradigm that allows us to break free from the algorithmic treatments bound by hit-or-miss, average-person practices. It offers a customized approach based on our own personal set of data: our genetics, our medical status, the specific environment in which we live, and the lifestyle choices we make. All these factors become equally informative, especially when it comes to prevention.
The idea is simple: we can maximize patients’ chances of better health outcomes if we tailor treatments to what we know about their particular set of health and lifestyle “signatures,” which not only determine their various strengths and vulnerabilities but can also cue their responses to a variety of interventions. All these factors have predictive values that help identify those risks specific to each person. This means they also allow for the development of a more effective personalized prevention plan, which can assist us in sidestepping what may have otherwise become future pitfalls.
So let’s find out which risks and concerns you need to address to optimize cognitive health and protect your brain for a lifetime of use. First, we will focus on genetic risks. Then we will look at a variety of clinical conditions that can be addressed and are often completely reversible. Finally, in part 3, we will review a host of strategies proven to offset and minimize any impact of the identified risks.
In the era of DNA testing, many people want to know their genetic future, as well as that of their children and entire families. While this is perfectly legitimate, there are different ways to go about it. One way is deeply rooted in science and carried out by certified clinical labs (CLIA labs); another way involves direct-to-consumer (DTC) genetic-testing companies and can range from reasonable to downright predatory.
Due to the price collapse of genetic testing and the FDA’s gradual ease of the regulatory environment, DTC genetic-testing companies such as 23andMe, Family Tree DNA, MyHeritage, and ancestry.com are booming. According to industry estimates, the number of people who have had their genes analyzed with DTC tests currently exceeds 12 million.
The problem isn’t the DTC tests that tell you about your lineage or whether you’re likely to have blue eyes (which, incidentally, you already know). Those are based on measurable data. The problem is that many of the other tests run the risk of being only slightly more accurate than horoscopes, while others still are irresponsible at best. One that springs immediately to mind is the test that promises to improve your child’s soccer ability with a personalized DNA-based program. Or another test that claims to predict your kid’s ability to learn languages. Or yet another that will guess (because it’s literally guessing) a person’s chance of a high or low IQ.
As a scientist, I feel that the information provided by genetic testing could be of value—but that’s assuming said information is accurate and reliable. Instead, even the largest and more reputable companies have been objects of criticism. For example, in 2008, the FDA cracked down on 23andMe, ordering the company to cease providing analyses of people’s risk factors until the tests’ accuracy could be validated. Basically, nobody actually knows just how reliable the reports are.
No matter what DTC companies try to sell you, aside from ancestry details and limited information about specific health risks, you really mustn’t base your decisions on those findings. I say this because most DTC companies share limited information with users but let them download more of their raw data for informational purposes, in spite of the fact that the accuracy of the raw data is “not guaranteed.” This is code for “the data may be wrong.” Many users miss this vital point and go on to enlist the help of third-party services such as Promethease.com or codegen.eu to obtain user-friendly readouts of additional pieces of information, including genetic markers for diseases like cancer, Alzheimer’s, and Parkinson’s.
There are two major problems with this approach: first, the actual data is potentially incorrect. Second, the promised interpretation of the data is also potentially incorrect. That’s because several of these third-party companies operate by leveraging content from free public archives for genetic variations, in spite of evidence that much of the available information may be inaccurate.
Just recently, an eye-opening study revealed that 23andMe misdiagnosed genetic markers of cancer risk, such as the BRCA gene (aka the “Angelina Jolie gene”), in a whopping 40 percent of cases—which makes the test only slightly more accurate than tossing a coin. Obviously, this sort of misinformation is disturbing on a number of levels. In the Alzheimer’s field, genetic testing through DTC channels is not recommended, but many people use it to find out their APOE genotype. More on this below, in “Genetic Testing for Alzheimer’s.” For the time being, the bottom line is this: only genetic testing carried out by CLIA-certified labs meets quality standards and is worth your trust and money.
DNA testing has been used for decades for certain types of familial cancers and for brain diseases like Alzheimer’s, multiple sclerosis, Parkinson’s disease, Huntington’s disease, and epilepsy. The result of a genetic test can confirm or rule out a suspected genetic condition, or help determine a person’s chance of developing or passing on one.
Specifically for cognitive health, many people who are experiencing forgetfulness, memory loss, or difficulties with attention and language are concerned about their risk of Alzheimer’s. Does having a parent affected by Alzheimer’s imply that their children are eventually destined to suffer the same fate? If your mother or father has Alzheimer’s, will you get it, too? How common is it to have the bad Alzheimer’s genes?
These are very valid concerns. Alzheimer’s is a complex disease, and its ins and outs can be confusing, which can be especially dismaying to patients and families trying to wend their way through the experience of developing the disease or caring for someone who has it.
As referenced at the beginning of this book, we now know that very few people develop Alzheimer’s because of a rare genetic mutation in their DNA. These mutations are called “autosomal dominant,” which means that a single copy of the mutation, inherited from one parent, is enough to cause the disease. So far, scientists have identified such Alzheimer’s mutations in three genes: the amyloid precursor protein (APP) gene and the presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes. All three cause an overproduction of amyloid plaques, which in turn causes a particularly aggressive early-onset form of the disease that develops when people are in their thirties, forties, or fifties. This early-onset familial form is the only genetically determined form of Alzheimer’s that is passed on from one generation to the next. A child whose biological mother or father carries a genetic mutation for early-onset Alzheimer’s has a fifty-fifty 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, too.
Again, these mutations are less common than many people fear. In the majority of people, any genetic risk of developing Alzheimer’s is linked not to rare genetic mutations but to susceptibility genes, in particular the APOE gene mentioned in chapter 3. It is very important to understand the difference between testing for a genetic mutation and testing for genetic risk factors, which we will do shortly. If Alzheimer’s runs in your family and you are concerned about possibly being at risk, below you will find practical guidelines that will help you determine whether genetic testing is a viable option for you.
Before proceeding, take whatever time is necessary to fully understand the repercussions of having this test. If today you are a perfectly healthy forty-year-old who has seen a parent claimed by this disease, would you want to know if you face the same destiny? How will this knowledge change your life? Will knowing this help you or harm you?
Answers to these questions vary greatly. Many people, health-care providers included, argue that the test’s value hinges entirely on having access to a cure. Since therapeutic options are scarce, the risks of any psychological harm in knowing you are at risk may very well outweigh any benefit gained. On the other hand, some people decide on the test hoping that effective treatment may be developed for them in time, while others are interested in clinical trial opportunities. Some people look at it as an opportunity to plan ahead, since long-term care and disability insurance, retirement, advance directives, and even a will can be major motivators to learning more about one’s health risks. For others, simply knowing what the future has in store is reason enough to find out. Particularly as those with a family history of Alzheimer’s approach the age at which their relatives began to suffer, it is understandable for them to feel anxious about their own potential risk. Some may believe they already have the disease, which can lead them to doubt their mental capacities prematurely, questioning every instance of forgetfulness or brain fog.
Whatever the motivation, it’s true that knowing one’s genetic status does have implications for the entire family. The decision is intensely personal and is ideally made after a period of research and self-reflection. It’s also important to realize that while genetic testing can help you address some of these concerns, you don’t actually need that information to put your finances in order, nor to help contribute to research. It is just as important to know that you don’t always need DNA testing to rule out a genetic mutation with reasonable certainty. How? Keep reading.
Over the years I’ve noticed that defining Alzheimer’s as “early” or “late” onset can be confusing to patients. Countless people have told me that their mother, father, or grandparent had “early-onset Alzheimer’s,” only for me to later find out that more times than not, their relatives did not exhibit symptoms of the disease until well after the age of sixty. From a diagnostic perspective, patients who develop Alzheimer’s after age sixty are not early-onset, but rather late-onset patients. This is an important distinction because patients with a later onset of the disease are unlikely to carry the genetic mutations that cause it. As a result, Alzheimer’s developed after age sixty is usually not caused by genetic mutations, and is therefore less likely to be transmitted from the parents to their children.
This is not universally the case, though, so a great first step in determining whether you or a loved one may be carrying a genetic mutation is to have an Alzheimer’s doctor do a thorough family history evaluation. (If you are looking for an Alzheimer’s doctor, see appendix A for guidance.) This evaluation is typically based on a family history questionnaire like the one included below, which is broken down into first- and second-degree family members. Use it as a guide to gather all the necessary information. The key facts you need to find are at what age symptoms began to occur and which types of symptoms were present (e.g., memory loss, confusion, depression, tremors, hallucinations). While collecting this information might be difficult and emotionally painful, it really is a crucial step. I find that families often have an uncanny ability to remember details about unexpected or peculiar behaviors when it comes to their relatives. Did any of your relatives routinely lose their keys or misplace objects like reading glasses? Did they tend to forget names or fail to recognize familiar faces or places? Did they repeat the same sentences over and over again, get confused about the time or day, or perhaps even forget what familiar objects were for?
Other things to find out include current age, age at the time of first symptoms, age at diagnosis, age at death, and the cause of death of relatives both affected and unaffected. Additionally, your doctor needs to know if any of your relatives suffered from conditions that can mimic the symptoms of dementia (e.g., ALS, epilepsy, brain cancer) or that may suggest different genetic links (e.g., Down syndrome). Write in the name and clinical information for all your family members, or as many as you can. Add as many columns as you need and go back in time as far as possible. For example, if one of your great-grandparents had dementia, by all means include this information in the forms.
If dementia runs in your family, this comprehensive information will help your doctor determine if the disease is more likely genetically driven or influenced by medical issues like cardiovascular disease or diabetes.
FIRST-DEGREE FAMILY HISTORY FORM
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PARENTS |
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Myself |
Mother |
Father |
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Alzheimer’s disease |
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Parkinson’s disease |
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Huntington’s disease |
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Frontotemporal dementia |
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Lewy body disease |
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Pick’s disease |
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Vascular dementia |
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Stroke |
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Amyotrophic lateral sclerosis (ALS) |
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Down syndrome |
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Epilepsy |
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Cancer (specify type/location) |
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Heart disease (bypass, angina, etc.) |
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High cholesterol |
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Hypertension |
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Diabetes (specify type 1 or 2) |
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CHILDREN |
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Son 1 |
Son 2 |
Daughter 1 |
Daughter 2 |
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Alzheimer’s disease |
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Parkinson’s disease |
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Huntington’s disease |
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Frontotemporal dementia |
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Lewy body disease |
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Pick’s disease |
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Vascular dementia |
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Stroke |
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Amyotrophic lateral sclerosis (ALS) |
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Down syndrome |
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Epilepsy |
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Cancer (specify type/location) |
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Heart disease (bypass, angina, etc.) |
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High cholesterol |
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Hypertension |
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Diabetes (specify type 1 or 2) |
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SIBLINGS |
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Brother 1 |
Brother 2 |
Sister 1 |
Sister 2 |
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Alzheimer’s disease |
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Parkinson’s disease |
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Huntington’s disease |
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Frontotemporal dementia |
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Lewy body disease |
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Pick’s disease |
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Vascular dementia |
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Stroke |
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Amyotrophic lateral sclerosis (ALS) |
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Down syndrome |
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Epilepsy |
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Cancer (specify type/location) |
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Heart disease (bypass, angina, etc.) |
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High cholesterol |
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Hypertension |
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Diabetes (specify type 1 or 2) |
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SECOND-DEGREE FAMILY HISTORY FORM
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GRANDPARENTS |
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Maternal grandmother |
Maternal grandfather |
Paternal grandfather |
Paternal grandmother |
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Alzheimer’s disease |
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Parkinson’s disease |
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Huntington’s disease |
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Frontotemporal dementia |
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Lewy body disease |
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Pick’s disease |
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Vascular dementia |
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Stroke |
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Amyotrophic lateral sclerosis (ALS) |
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Down syndrome |
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Epilepsy |
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Cancer (specify type/location) |
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Heart disease (bypass, angina, etc.) |
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High cholesterol |
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Hypertension |
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Diabetes (specify type 1 or 2) |
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RELATIVES |
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Maternal uncle |
Maternal aunt |
Paternal uncle |
Paternal aunt |
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Alzheimer’s disease |
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Parkinson’s disease |
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Huntington’s disease |
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Frontotemporal dementia |
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Lewy body disease |
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Pick’s disease |
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Vascular dementia |
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Stroke |
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Amyotrophic lateral sclerosis (ALS) |
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Down syndrome |
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Epilepsy |
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Cancer (specify type/location) |
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Heart disease (bypass, angina, etc.) |
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High cholesterol |
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Hypertension |
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Diabetes (specify type 1 or 2) |
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Once you’re ready, the guide below will help you to interpret the information:
Genetic diseases are typically “multigenerational,” which means that any genetic mutation would have affected at least one of your great-grandparents, grandparents, parents, and/or their siblings. If two or more of your closest relatives have or had Alzheimer’s, and particularly if they developed symptoms at a young age (generally speaking, before age sixty, but especially if it was in their forties or fifties), a gene mutation, while not a certainty, is a possibility. In this case, ask your doctor whether genetic testing is advised.
If only one of your parents and no other relatives have ever had dementia, and especially if the affected parent developed symptoms well after age sixty, you are unlikely to be carrying a gene mutation. In any case, it is always wise to discuss your family history with your doctor.
If your doctor determines that genetic testing is advisable, here is what you need to know. Genetic testing can be used in two ways: to confirm the presence of an Alzheimer’s mutation in patients who are already showing symptoms, and as a means by which to assess risk in people without any symptoms at all.
When a young or middle-aged person has symptoms of Alzheimer’s and there is a family history of Alzheimer’s before age sixty, doctors may suggest diagnostic DNA testing. Typically, this is done only if there is a previously known case of early-onset Alzheimer’s in the family.
Diagnostic DNA testing is done most commonly on the PSEN1 gene, since mutations in this gene are the most frequent. Testing can be done through a commercial company called Athena Diagnostics (www.athenadiagnostics.com), or through some CLIA-certified labs affiliated with academic medical centers (wwwn.cdc.gov/clia). Sometimes DNA testing is done on the APP or PSEN2 genes, too. No commercial test is available for them, but testing can be done at some academic centers or as part of a clinical trial. If you enroll in a research study or clinical trial, the costs of genetic testing are typically covered by the sponsor.
As for the procedure, it is relatively simple. You will go for a blood draw, which is then sent out for testing, just like any standard blood test. If the test comes back positive, the doctor will then be able to identify the mutation that causes Alzheimer’s in the family, which may prompt additional family members to test as well. If the test comes back negative, you don’t have the mutation.
I cannot stress enough that genetic counseling, both before and after the test, is of paramount importance. Receiving genetic information without appropriate counseling can have an adverse and often unexpected psychological impact on some people, especially those with a predisposition to anxiety or depression. Thanks to the field having worked out a careful and conservative approach to genetic testing from the outset, such extreme outcomes have remained very rare. Nonetheless, even though the rate of catastrophic consequences is not high, they do occur. It is important to know yourself and to make sure you get all the help available to you before and after testing. It is particularly important to avoid rash decisions, so do consult with your spouse, your partner, or a trusted friend before going forward with the decision as to whether or not to test. If you decide to take the test, you can find a genetic counselor in two ways:
Contact your nearest Alzheimer’s support community, as described in appendix A.
Search the online directory of the National Society of Genetic Counselors: www.nsgc.org.
When a family member is found to be carrying a specific mutation, at-risk siblings, adult children, or other relatives can also find out whether they have inherited the mutation. About 10 percent of eligible relatives choose to get tested.
However, predictive testing is complicated because it deals with predicting the future of a currently healthy, symptom-free person, rather than testing someone who is presently ill. Guidelines are therefore even more strict. Specifically, if you are worried about your own risk due to a family member who has or had Alzheimer’s, but this specific relative has not been tested for genetic mutations, predictive testing is not available to you. This is due to the relative in question needing to be tested first. If it turns out that they indeed have a genetic mutation, then you will be able to get tested, too. However, there are many instances where the relative with Alzheimer’s has died, so they can no longer be checked for genetic mutations. Another possibility is that the affected relatives are living but refuse to have the test. In either of these cases, your doctor won’t be able to request the test for you.
If you are eligible, take the test and learn whether you are indeed at genetic risk for Alzheimer’s. If you are, what are the next steps? First off, counseling is a must. Secondly, support and advocacy groups exist to help you connect with other patients and families, as well as with the research, resources, and services in place to assist you (see appendix A for more information). Many organizations have experts who serve as medical advisers or provide lists of doctors and clinics that can help. Equally important is the option to enroll in clinical trials that focus on genetic heritability. Currently, two large clinical trials, the Dominantly Inherited Alzheimer Network (DIAN) and the Alzheimer’s Prevention Initiative’s (API) Autosomal Dominant Alzheimer’s Disease (ADAD) trial, are testing the effectiveness of amyloid-clearing drugs in volunteers carrying genetic mutations for Alzheimer’s (see appendix A). These studies are open to enrollment, and more trials will hopefully become available soon.
If you remember from chapter 3, the APOE gene is the only established genetic risk factor for late-onset Alzheimer’s. Let me reiterate that APOE is not a bad genetic mutation, but it does influence Alzheimer’s risk. Currently, APOE testing is used in research settings to identify study participants who may have an increased risk of developing Alzheimer’s. This knowledge helps us look for early brain changes and compare the effectiveness of treatments for people with different APOE profiles. However, this test is not effective in determining any one person’s risk, and is therefore not recommended for clinical use. Here’s why.
There are three APOE varieties, or alleles: E2, E3, and E4. Everyone has two alleles, so there are six possible combinations: E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, or E4/E4. People with the E2/E2 combo have the lowest risk of Alzheimer’s, while those with E4/E4 have the highest risk. E4/E4 carriers are also more likely to develop symptoms at an earlier age, though still typically after age sixty. A study of 17,000 dementia-free people estimated that if you are sixty to seventy-five years old and have two copies of the APOE-4 gene (i.e., E4/E4), then you have a 30 to 55 percent risk of developing mild cognitive impairment or Alzheimer’s by age eighty-five. If you have only one copy of the APOE-4 gene, you have a 20 to 25 percent risk of developing either condition by age eighty-five. If you don’t have the gene, however, your risk is still 10 to 15 percent.
You can see why information about APOE status doesn’t help much in terms of predicting future dementia. Also, in the case of genetically determined Alzheimer’s, the impact of genetic mutations outweighs that of APOE-4, so testing doesn’t add much information for those patients either.
Nonetheless, from a precision medicine perspective, knowing your APOE status can be helpful—but only if your doctor knows what to do with this information. There are many, often contradictory approaches to counteracting the effects of APOE. There is increasing evidence that APOE-4 carriers respond to some treatments differently, and sometimes better than non-carriers, as you’ll see in part 3. Participating in clinical trials focused on APOE also deserves a thought. For example, the ongoing API Generation study also aims to test two experimental drugs for the prevention or delay of dementia specifically in people with two copies of the APOE-4 gene (see appendix A for more information).
So for those of you who do want to find out, there are three ways to learn your APOE status:
Ask your doctor to run the APOE test. The plus is that you will be tested by a certified lab, which limits the chance of any errors in testing. Results are received directly from your physician, who will either address your concerns or refer you to a specialist to do so.
Enroll in a research study or clinical trial that focuses on APOE status. The advantages are that you will be tested by a certified lab, and the costs of genetic testing will be covered by the sponsor. Clinical trials also provide novel medications that may counteract the effects of APOE-4.
Order a DTC test such as those offered by 23andMe. By ordering the test yourself, you keep this information private, but will not receive guidance from a specialist. Another downside is that there’s a higher chance of testing errors. If you already used DTC channels to find out your APOE profile, I would recommend getting a second opinion via a CLIA lab (www.cdc.gov/clia).
If you are interested in finding out your APOE status, keep in mind that genetic counseling is important in this case as well. For some people, learning that they are APOE-4 carriers becomes a strong motivator to take better care of themselves, with no or minor short-term psychological risks. For others, it can be a very frightening and disconcerting experience instead. You are the only one who knows how you will react to the news, although even you may not know for sure how the information will ultimately impact you. This is why I encourage you to take your time to do the appropriate soul-searching prior to deciding to be tested, and to enlist the help of a trusted counselor or doctor for any questions that come up.