If you’d asked me at age sixteen what my life’s dream was, I’d say it was to discover the Alzheimer’s gene. Statements like that one would make any geneticist cringe, or chuckle, or both. It’s a common misconception that one “bad” gene causes Alzheimer’s disease, and that discovering this gene would lead to a cure. The fact of the matter is that Alzheimer’s disease, and most other diseases, are so much more complicated than a single gene. There are a multitude of genes involved, as well as an entire spectrum of non-genetic influences. To try and make sense of this confusing topic, I’ve written this article as a brief overview of the genetics of Alzheimer’s disease.
Note: If you’re not familiar with the science of Alzheimer’s, you may want to look at Alzheimer’s Disease: A general overview to provide a bit of background.
The Amyloid-Beta Protein
Genes encode proteins, and so to understand the role of genetics in Alzheimer’s, we need to first look at the proteins involved. Senile plaques are considered one of the main hallmarks of Alzheimer’s disease. These toxic protein clumps accumulate in the brain over many years and eventually lead to the death of neurons, causing the brain to physically shrink. They form when a protein called amyloid-beta becomes “sticky” and begins to adhere to itself, forming large star-shaped clumps.
Amyloid-beta begins as a longer protein called amyloid precursor protein (APP). APP is usually cut by enzymes called secretases to form a non-sticky version of amyloid-beta that is 40 amino acids long. However, if APP is cut by a different set of secretases, a longer version of amyloid-beta with 42 amino acids is formed. This longer form is what sticks together to form senile plaques in Alzheimer’s disease .
Familial Alzheimer’s Disease
Alzheimer’s disease is divided into two forms. Approximately 5% of cases are of the familial, early-onset form. This type of Alzheimer’s typically affects individuals in their mid-forties and fifties. There are three genes known to be involved with familial Alzheimer’s disease: APP, PSEN1, and PSEN2. APP, as I described above, is the precursor to amyloid-beta, and so certain mutations can make it prone to the cleavage pathway that results in the sticky 42-length protein. Similarly, PSEN1 and PSEN2 are believed to affect the gamma-secretase complex that cleaves APP into amyloid-beta.
Mutations in these three genes are autosomal dominant. This means that only one copy of the mutation is needed to cause the disease, and that carriers have a fifty-percent chance of passing on the gene to each of their children. The mutations also tend to have high penetrance, meaning that their effects cannot be readily altered by environmental factors–i.e., having the mutation nearly always leads to the disease , .
Sporadic Alzheimer’s Disease
In contrast to the relatively simple genetics of familial Alzheimer’s, late-onset sporadic Alzheimer’s disease (which makes up 95% of cases) is far more complex. The only gene that has been conclusively identified as a risk factor is apolipoprotein E, abbreviated as apoE. We still aren’t sure exactly how apoE affects the brain, but the main hypothesis is that it’s involved with clearing away amyloid-beta before it can accumulate to toxic levels. There are three major versions of this gene: apoE2, apoE3, and apoE4. Having one copy of the apoE4 allele increases the risk of Alzheimer’s by 3 times, while having two copies increases the risk by nearly 15 times. Conversely, having at least one copy of the apoE2 allele reduces the risk of Alzheimer’s , .
It is important to note that unlike the genes involved with familial Alzheimer’s, the apoE alleles are not highly penetrant. Approximately 1 in 5 people have at least one copy of apoE4, yet the majority of them never develop Alzheimer’s. Additionally, there are many people who develop Alzheimer’s without possessing apoE4. The allele increases the risk of developing the disease but is far from a guarantee , . Overall, it’s estimated that apoE accounts for less than 20% of the genetic risk for sporadic Alzheimer’s , .
So where does the other 80% come from? The answer gets even more complicated here. There are dozens of genes that are weakly correlated with overall risk, age of onset, rate of progression, or other disease variables. Individually, each of these genetic variants has only a tiny effect, but when combined, each person’s unique combination of variants creates a genetic profile that influences his or her risk of developing the disease (see A New Approach to Predicting Risk of Alzheimer’s Disease). The majority of these weakly-associated genetic variants have yet to be identified .
In familial Alzheimer’s, there is little that a person can do to prevent the disease if he or she has inherited the gene. However, only 24-33% of a person’s risk for sporadic Alzheimer’s disease is attributable to genetics alone , . The remaining risk is modulated by non-genetic factors, including medical conditions, diet, and lifestyle choices. A recent meta-analysis identified 13 non-genetic factors that significantly increase the risk for Alzheimer’s disease, including smoking, being overweight in midlife, cardiovascular disease, low education, and depression. In addition, they identified 23 factors that reduce the risk of Alzheimer’s, including a healthy diet, physical activity, mental stimulation, and certain medical conditions .
It was once thought that we couldn’t change our brains after birth, but the discovery of neuroplasticity revolutionized the field by showing us that our daily actions can have enormous impacts on the structure and function of our brains. Similarly, the growing study of epigenetics (meaning “above genetics”) proves that we are not at the mercy of our genes. Though we are born with a set DNA sequence, the choices we make throughout our lives determine which genes are turned on or off, a process that can significantly influence our risk of disease. We may not be able to change the genetic risk coded into our DNA, but we can all help protect our brains from Alzheimer’s disease through simple lifestyle choices.