Learn about the genetic risk factors associated with familial Alzheimer's disease and the potential for future gene therapies.
Introduction: What is Alzheimer's Disease?
Alzheimer's disease (AD) is the most common form of dementia and affects mostly older adults. Currently, more than 5.8 million people in the U.S. have the disease1, and the number of cases is expected to grow exponentially unless a cure or preventative treatments can be identified.
AD is broadly characterized by memory loss, cognitive decline, and changes in behavior. Although symptoms vary between patients, the earliest signs of AD often manifest as difficulty completing everyday tasks or getting lost in familiar places. Patients with early-stage AD may also develop a lack of judgment causing them to act in uncharacteristic ways. It can be difficult to identify early-stage AD because changes in memory and cognition are also a part of the normal aging process. However, AD-associated cognitive impairments are more severe than the effects of normal aging. For example, a person with normal age-related memory loss may have difficulty recognizing an acquaintance while someone with early AD may not even recognize members of their own family.
The Genetics of Alzheimer's Disease
The vast majority (95-99 percent) of AD cases have no identifiable genetic cause and are referred to as "sporadic" or late-onset AD. The remaining cases are caused by inherited mutations and are classified as familial AD (fAD). Sporadic and fAD differ in terms of disease onset, with most sporadic cases appearing after the age of 65 and fAD occurring prior to 65 and as early as age 30. Therefore, fAD can also be referred to as early-onset AD (EOAD).
There are two categories of genes that affect a person's chance of developing AD: risk factor genes and deterministic genes.
Risk Factor Genes
A risk factor gene is a variant of a particular gene that increases the likelihood of the carrier getting AD. However, the mere presence of a risk factor gene does not mean that a person will get the disease. Like any genetic trait, risk factor genes are hereditary, and an individual with a parent that has sporadic AD may be at an increased risk for developing the disease, but it is not guaranteed.
The most widely studied AD risk factor gene is APOE. There are three known variants of the APOE gene: APOEe2, APOEe3, and APOEe4. APOEe3 is the most common variant with no known effect on Alzheimer's risk, while APOEe2 is a protective variant that decreases an individual's odds of getting AD.
In contrast, the APOEe4 variant dramatically increases a person's risk for AD. A patient who inherits a single copy of the APOEe4 variant from either parent has a 20-30 percent chance of developing AD sometime in their life compared to just 7-10 percent 2 for someone who is non-carrier for the APOEe4 variant. This number jumps to 50-60 percent for patients that inherit two copies of APOEe4. Many other risk factor genes besides APOE are continuously being discovered.
Unlike risk factor genes, which only increase one's odds of getting AD, deterministic genes directly cause fAD. In other words, simply inheriting a deterministic gene from either parent will guarantee that an individual will develop fAD. Although these mutations are very rare, someone who has a parent with fAD has a 50 percent chance of developing the disease themselves.
There are three genes in which mutant variants cause fAD: APP, PSEN1, and PSEN2. Although the exact mechanisms in which mutations to these genes cause fAD are unclear, all known disease-causing variants affect a small peptide known as amyloid beta (Ab). Ab is normally produced in the brain throughout a person's lifetime; however, mutations to APP or PSEN1/2 either cause Ab to be overproduced or cause Ab to become more "sticky" leading to the formation of toxic Ab aggregates. These findings suggest that Ab is a central player in AD development. Sadly, Ab-targeting therapeutics have thus far been unsuccessful in clinical trials. These failures have motivated researchers to investigate alternative therapeutic approaches aimed at curbing the relentless progression of AD.
Gene Therapy for Alzheimer's Disease—a New Hope?
The ability to change one's genes has long been the Holy Grail of medical research, and recent breakthroughs have driven this idea towards reality. Gene therapies that target the brain are typically centered around two approaches:
- inserting a new gene sequence into brains cells or
- correcting a faulty gene sequence that is already present.
In the case of the former, the strategy is straightforward. A DNA sequence for a particular gene is synthesized and is then "packaged" into lab-made viruses that are then used to treat the brain. Once in the brain, the "therapeutic viruses" deliver the DNA gene sequence into targeted cells, which then use the sequence to produce the specified therapeutic protein. This approach is currently being used in clinical trials to introduce the protective APOEe2 variant DNA sequence into patients that have two copies of APOEe4.
The second approach involves using molecular tools to change a small portion of a person's DNA, usually to correct or remove a disease-causing mutation. This "gene editing" approach is typically accomplished using CRISPR/Cas9. Although many variations of CRISPR/Cas9 are in development, "classic" CRISPR editing involves a synthetic, lab-designed RNA sequence that targets a specific gene. This targeting RNA is needed to guide an enzyme known as Cas9 to the correct part of the genome. Cas9 can be thought of as a pair of "molecular scissors" which physically cuts DNA at the region specified by the lab-made RNA sequence. The end result of this process is the deletion of the faulty, disease-causing mutation. Although this idea may seem far-fetched, CRISPR/Cas9 editing is already being evaluated in clinical trials for a variety of disorders.
Familial AD is a hereditary disease in which carriers of APP, PSEN1, or PSEN2 mutant gene variants will develop AD in their lifetime, typically before the age of 65. Children who have a parent with fAD have a 50 percent chance of receiving the fAD-causing gene from the affected parent and developing the disease.
In contrast, risk factor gene variants such as APOEe4 increase the odds of getting AD but do not guarantee that an individual will be affected. Both fAD and sporadic AD are candidates for gene-therapy based interventions, and future discoveries may positively change the outlook for individuals with risk factor and fAD-causing genes.