Chances are, you already know someone with Alzheimer’s disease (AD); currently, an estimated 5 million Americans have the disease.1 If you don’t already know someone, chances are you eventually will as our population ages; nearly 20% of people ages 75-84, and nearly half of people older than 85 years of age, have AD.2 Indeed, the scope of the problem is so large, with future projections so dire, that President Obama recently announced a National Plan to fight AD, with the ambitious goal of developing effective prevention and treatment approaches for AD and related dementias by 2025.3
This leads to some natural questions: What is Alzheimer’s disease? What causes Alzheimer’s disease? What can genetics—the study of genes, which are the modules by which instructions for specific traits are transmitted from parents to offspring—tell us about Alzheimer’s disease, both at the level of understanding the disease and at the level of understanding our individual risk factors?
Alzheimer’s Disease: History and Definitions
Alzheimer’s disease is named after the German doctor, Alois Alzheimer, who first identified the disease in a 51-year old patient, Auguste Deter. Ms. Deter came to Dr. Alzheimer in 1901 with an array of symptoms including problems with memory, comprehension, and language.4 The symptoms progressed over the next five years until she died in 1906, at which time Alzheimer studied her brain to characterize the neuropathological features that may have contributed to her symptoms.5 As Dr. Alzheimer viewed Auguste’s brain under a microscope, he noticed many abnormal features including plaques outside of cells and neurofibrillary tangles in neurons (the core cell type found in the brain). He called the disease “presenile dementia” and reported his findings at lectures and conferences throughout Europe. The influential German psychiatrist Emil Kraepelin (often thought to be the founder of modern scientific psychology) popularized the eponym “Alzheimer’s disease” by using the phrase in the 8th edition of his Handbook of Psychiatry published in 1910.6 While modern medicine and science are continually changing what we know about the disease, the name “Alzheimer’s disease” has remained constant.
Defining Alzheimer’s Disease: Seeing is Believing
Figure 1: Amyloid beta plaques and neurofibrillary tangles are features commonly observed in the brains of patients with AD.
We now understand AD as a progressive neurodegenerative disorder with distinct neuropathological and clinical features—many of which Dr. Alzheimer described in his original work. We define AD, like many diseases, based on features we can observe (using a microscope) in the brains of people who die of AD. These pathological characteristics include:
Amyloid beta (or Aβ) plaques: Plaques made up of a protein called amyloid beta are found as extracellular deposits in the brains of AD patients. Scientists believe that molecules of Aβ are initially soluble when produced but, over the course of the disease, gradually clump into aggregates called “oligomers” and eventually deposit as insoluble plaques in the brain tissue. While it is unclear exactly how Aβ is linked to degeneration of neurons, most scientists believe that the build-up of some forms of Aβ is harmful to the brain.
Neurofibrillary tangles: In later stages of AD, another protein called tau also aggregates to form tangles within neurons, disrupting the normal structure of microtubules, which form a sort of scaffold. In healthy neurons, microtubules assemble in structures resembling railroad tracks, guiding essential molecules from the cell bodies of neurons down to the ends of these long, branched cells. This process, however, does not work as well in the neurons of AD patients. In AD and several other neurodegenerative disorders, the tau protein becomes hyperphosphorylated (accumulating excessive phosphate at many sites in its structure), which is believed to interfere with the functioning of microtubules.
Neurodegeneration: In AD, the accumulation of harmful forms of amyloid beta and tau is believed to lead to the death of neurons, or neurodegeneration. Brains of AD patients examined after death often reveal severe tissue shrinkage compared to brains of non-AD patients of the same age.
Clinical Symptoms of AD: A Pathological Case of Location
The most common problem described by AD patients early in their disease is memory loss. This clinical symptom is a consequence of where the most severe neurodegeneration is taking place in the brain. For brain diseases, the “where” often determines what the disease will look like, because different parts of the brain are responsible for governing different functions and capacities. In the case of AD, several areas that are hit early and hard include the entorhinal cortex and the hippocampus, two brain regions that are particularly important for forming new memories. It then comes as no surprise that one of the areas in which people with AD have the most trouble is memory tasks, including making new memories.7 AD also eventually affects many areas of the cortex—or outer layer—of the brain, damaging areas responsible for planning, judgment, and thinking.
As the preceding section illustrates, we are often defining AD by what it looks like, either in brain samples observed under a microscope or when a living patient is examined by a neurologist, but not by what causes it. This may have ramifications when it comes to how we think about research and treatment targets for AD.
Alzheimer’s Disease: Genetics
Part of the reason we don’t define Alzheimer’s disease by what causes it is that we don’t completely understand why people get the disease. We know a few things that can cause AD in a few people, and also a few risk factors that affect a lot of people, but there remain many potential cases of AD that, to our present understanding, lack direct causation. Much of what we do currently know about the causes of AD has been gained through recent genetic studies.
To fully understand a discussion of the genetics behind AD, it is useful to have a basic understanding of some key terms:
Gene: a unit of heredity by which instructions for specific traits are transmitted from parents to offspring. A gene can have different alleles, which represent the alternative variants of that gene. These alleles instruct a person’s cells to make different versions of a protein, which then results in different physical traits, called phenotypes.
Penetrance: refers to the proportion of individuals with a specific variant of a gene that express a certain trait or phenotype. In the case of AD, gene variants that are highly penetrant are those that cause AD in most or all of the people who have them. Usually, highly penetrant disease- causing variants are rare, so they are called mutations.
Risk factor: a risk factor is anything shown to increase the risk or susceptibility to a disease. Risk factors can include lifestyle, personal behaviors, environmental conditions, and genes. What is crucial to understand is that risk factors are not deterministic, but rather probabilistic. This means that if you have a risk factor for Alzheimer’s, it doesn’t mean you will develop AD for certain. In fact, many who have risk factors for AD never experience any symptoms of the disease. Having a risk factor simply means you have a greater chance of developing the disease when compared to someone without that risk factor.
Mendelian inheritance: describes the pattern by which genes and traits are passed to offspring according to Mendel’s law of segregation (each parent randomly passes one allele to his or her offspring) and law of independent assortment (separate genes for separate traits are passed down independently). Common modes of Mendelian inheritance include autosomal dominant traits, where having one mutated allele will lead to the disease, and autosomal recessive traits, where both alleles of the mutated gene are required for the disease phenotype to be present. In Alzheimer’s disease, we know of at least 3 important Mendelian causes of AD: mutations in the genes for presenilin 1 (PS1), presenilin 2 (PS2), and amyloid precursor protein (APP). In addition, there is at least one very important risk factor for AD: a particular variant of the gene for apolipoprotein E (APOE). Efforts to identify additional risk factors for AD are ongoing, but even if other genes are proven to be genetic risk factors, they are unlikely to be as important as APOE.
Early-onset AD and the Role of PS1, PS2, and APP
Early-onset AD is often defined as cases where patients experience AD symptoms before the age of 65. Although the original patient of Dr. Alzheimer’s was an early-onset patient, early-onset AD is, in fact, rare and represents less than 5% of all AD cases.8
PS1, PS2, and APP mutations primarily cause early-onset AD. AD caused by mutations in PS1, PS2 and APP is often referred to as familial AD. In these cases, AD is inherited in an autosomal dominant manner, meaning that having just one copy of mutation associated with the disease will lead to the development of AD with virtually 100% certainty. As a consequence, each child of an affected parent has a 50% chance of inheriting the disease-causing mutation as well, so the disease appears to strongly “run in the family.”
Shared pathways between PS1, PS2, and APP give us insight into what may be causing the neurodegeneration seen in AD. APP encodes amyloid precursor protein, which is then cut up into fragments. These fragments include amyloid beta (Aβ), the protein that makes up the plaques found in AD. PS1 and PS2 encode parts of gamma secretase, a group of proteins that plays a crucial role in cutting up amyloid precursor protein to make Aβ. Since PS1, PS2, and APP all converge in the generation of Aβ, and mutations in any of these genes can cause AD, this strongly suggests that the irregular processing of amyloid precursor protein, with abnormal production of Aβ, leads to the neurodegeneration seen in AD. This hypothesis is known as the amyloid hypothesis and illustrates how knowledge of the genes involved in a disease can give us insight into what goes wrong in a disease.
As an historical note, many years after Dr. Alzheimer described her case, Auguste Deter’s brain tissue was examined. She was found to have a mutation in one of the copies of her PS1 gene, which may explain her early and severe form of AD.
Late-onset AD: APOE as a Risk Factor and Other Implicated Genes
Mutation in the gene that encodes apolipoprotein E (APOE) is the major risk factor for late-onset AD, or cases where AD symptoms emerge after age 65. Late-onset AD represents over 95% of cases of AD.
Apolipoprotein E, a class of apolipoprotein, exists in three common forms (or alleles), which are called APOE-ε4, APOE-ε3 and APOE-ε2. Everyone inherits one of these alleles from each parent, which gives the instructions for which forms of the APOE protein their cells will make. People who inherit the APOE-ε4 allele, causing them to make the APOE-ε4 version of the protein, have an increased risk of developing Alzheimer’s disease. Those who inherit two copies (one from each parent) have an even greater risk, estimated at 10 to 30 times that of an individual who doesn’t possess the APOE-ε4 variant.9 Scientists believe that approximately that 20-25% of all AD cases can be linked to the APOE-ε4 allele in some fashion.
Figure 2: Alzheimer’s disease is predicted by both probabilistic factors, which signify a greater chance of developing the disease, and deterministic factors, which indicate a significantly increased change of developing the disease due to genetic, or inherited, factors.
Other late-onset genes implicated in AD include but are not limited to clustering (CLU), sortilin-related receptor, L (DLR class) A repeats containing (SORL1), complement receptor type 1 (CR1), phosphatidylinositol binding clathrin assembly protein (PICALM), and triggering receptor expressed on myeloid cells 2 (TREM2). All of these genes, like APOE, are risk factors for AD and many ongoing studies are seeking to better characterize their roles in the pathogenesis of AD.
Issues Raised by Our Understanding of Alzheimer’s Disease Genetics
1. Is it knowledge you want to have?
Genetic testing is available for many of the genetic markers of AD we’ve discussed. Testing positive for mutations that cause autosomal-dominant Alzheimer’s disease—such as PS1, PS2, and APP mutations—means an almost 100% chance of developing AD. Individuals with these mutations often come from families with a history of early-onset AD cases across multiple generations. In contrast, genetic testing for risk factors such as APOE only gives a probabilistic sense of developing AD. Due to the lack of robust preventative treatments for Alzheimer’s disease, patients, physicians, and genetic counselors must carefully weigh the potential benefits of the knowledge gained from genetic testing against the costs.
On one hand, patients may want to undergo genetic testing for Alzheimer’s in order to have the comfort of knowing their risk. This information can empower patients with the ability to plan for the future, relieving some of the psychological anxieties related to not knowing. On the other hand, some patients will avoid genetic testing because it may give rise to negative psychosocial effects such as anxiety or depression, alter relationships with family members, and potentially lead to social restrictions or discrimination.
A common ethical problem that arises from genetic testing is whether patients or their doctors have an obligation to tell family members if the patient gets a positive result for a disease. Because family members often share similar genetic profiles, genetic testing can potentially affect all family members. Before individuals undergo genetic testing, it is important they understand all the potential consequences of knowing this information so they can make an informed decision.
2. So who’s getting tested?
Another brain disease that has been studied extensively is Huntington’s disease (HD), which, like AD, is also progressive, fatal, and incurable. Because HD is entirely caused by mutations in one gene—the gene that encodes huntingtin (HTT)—we can know exactly whether someone is likely to develop HD by sequencing this gene. The ability to conduct this genetic test has been available for nearly 10 years, yet fewer than 15% of people at risk for the disease choose to undergo genetic testing, despite knowing they have a 50% chance of inheriting it from an affected parent.10 The other ~85% choose not to know, despite evidence suggesting that one’s psychological health may not suffer from this genetic knowledge.11 For familial AD, even fewer people undergo genetic testing.12
The decision to test for autosomal dominant genetic conditions, such as familial AD or Huntington’s, typically takes place after conversations with a physician and a genetic counselor. Research studies are now investigating potentially preventative AD treatments in people confirmed as carrying an autosomal dominant AD mutation. It is possible to participate in these types of studies without you or your family learning of your mutation status, if you decide that you do not wish to know this information. Individuals with early-onset Alzheimer’s disease in their family who interested in learning more about these studies can visit the Dominantly Inherited Alzheimer’s Network (DIAN) Expanded Registry at http://dianexr.org for more information.
Unlike genetic testing for HD or familial AD, where having the marker means almost certain development of the disease, genetic testing for the majority of AD cases will only give a probabilistic sense of developing the disease. For many, this uncertainty can cause additional stress and anxiety. One of the most well known examples of an individual choosing not to have this genetic knowledge is that of James Watson, who, along with Francis Crick, ushered in the modern era of molecular biology by solving the double helix structure of DNA. Watson was one of the first individuals to have his entire genome sequenced, but he chose to be blinded to data on his APOE genotype.13
The thought of developing Alzheimer’s disease is an understandably scary thought for many. However, researchers and doctors around the world are leveraging advancements in biomedical research in order to better understand the causes of AD. Much progress has been made since Dr. Alzheimer first identified the disease, but we must continue to investigate the underlying causes of AD so that we can develop better treatment and preventative therapies for our aging populations.
Summary and Conclusions
Alzheimer’s disease is a progressive brain disease with no cure that currently affects 5 million Americans. The number of people with Alzheimer’s disease will increase as our population ages.
We know some of the Mendelian genetic causes of Alzheimer’s disease. In other words, we know of specific genes that, when mutated, can cause AD in specific families, with onset usually before the age of 65. These genes are the ones that encode presenilin 1 (PS1), presenilin 2 (PS2), and amyloid precursor protein (APP).
We also know of an important genetic risk factor that is relatively common—present in >25% of people—that substantially increases your risk of developing late-onset AD. This risk factor is APOE genotype, where the APOE-ε4 allele gives you a significantly increased risk of developing AD.
The study of genes may give us important insights into what causes a disease, and this is certainly the case for AD, where all three of the Mendelian genetic causes of AD may point to one pathway that goes wrong in disease. However, there are important issues raised for individual patients, their families, and society by the possibility of genetic testing. Chief among these is the question of whether you would want to know your genetic status if you could not do anything to cure or halt progression of the disease.