The Alzheimer’s Gene Puzzle – Genetic Links To Late Onset Alzheimer’s Disease (Part 1)
Posted Jul 17 2008 5:06am
By Ralph Sanchez, L.Ac.,CNS,D.Hom
Genetic risk factors to Late Onset Alzheimer’s Disease (LOAD) are significant. A recent study of nearly 12,000 Swedish twin pairs, age 65 and older, determined that 58% to 79% of Alzheimer’s risk is genetic (1). This study showed that in male identical twins, when one brother had Alzheimer’s disease, the other developed the disease 45% of the time. In female identical twins, when one sister had Alzheimer’s disease, the other developed the disease 60% of the time. While this study did not delve into specific gene influences in LOAD, numerous studies have identified Apolipoprotein E4 (ApoE4), as a prominent genetic risk factor for LOAD. About 25% of the population has one copy of the ApoE4 gene and individuals with the the ApoE4 gene are estimated to make up approximately 40%-80% of the Alzheimer’s disease population. (2)
As indicated by the Swedish Twin Study, gene influences are potent risk factors. In Alzheimer’s disease (AD) and in many other degenerative diseases, certain genes can increase your vulnerability to developing diseases associated with aging. Genes associated with AD and many other diseases, have a “normal” version and a “mutated” version, with the mutation of a single DNA base (called a SNP – pronounced snip) making the person more susceptible to developing a particular disease process. SNPs are not uncommon. Everyone has SNPs. They are what make up a person’s unique genetic blueprint. Think of a SNP like changing the color of one bead in a chain. The role of ApoE in AD is a good example of how SNPs affect disease development. Individuals with the ApoE4 variant, a SNP, have an increased risk of developing late-onset Alzheimer’s (3,4). Of course, some SNPs exert a stronger influence on diseases than others. In the early onset form of AD (EOAD), a rare hereditary form of AD affecting less than 10 percent of Alzheimer’s patients, three different SNPs in genes, beta Amyloid Precursor Protein, Presenilin1, and Presenilin 2 are deemed causative for developing early onset AD. In contrast, the ApoE4 gene, a SNP in the ApoE gene, is considered a susceptibility risk factor, not a determinant for developing LOAD.
Several genes have been linked to LOAD with the ApoE4 gene having the clearest association with amount of risk it concurs in individuals that carry that variant. (5) There are three variants of ApoE–ApoE2, ApoE3, and ApoE4. Everyone has two copies of ApoE genes with six possible combinations-ApoE2/2, ApoE2/3, Apoe2/4, ApoE3/3, ApoE3/4, ApoE4/4. Individuals who inherit at least one copy of the ApoE4 variant have an increased risk of at least double, and up to a 3 to 4 fold increased risk for developing LOAD. Similar research has shown that people who inherit two copies of ApoE4 have as much as a ten fold greater risk of developing this disease. (2) It is important to note however, that not all people with Alzheimer’s disease have the ApoE4 variant and not all people who have inherited the ApoE4 gene will develop Alzheimer disease. Nevertheless, SNPs are not to be overlooked in those individuals that want to implement a proactive preventive strategy for AD and other degenerative diseases associated with aging. Understanding one’s own genetic potential for AD and the enviromental risk factors that carry significant weight, can provide opportunities for positively exercising preventive measures. AD and most other diseases have a biological timeline of 10 to 20 years or more, before a diagnosis is made. Waiting for the first signs of cognitive impairment or until that diagnosis is given may also impair your efforts to take control over the best years of your life.
Most diseases of aging are influenced by gene-environment interactions. AD has both genetic and environmental risk factors. The genetic susceptibility influenced by genes like ApoE4 are factors to be aware of, but perhaps more important are the environmental risk factors. Environmental risk factors can act as triggers in the expression of gene potential.* Numerous studies indicate that ApoE4 carriers may be more vulnerable to environmental factors. Individuals with the ApoE 4 gene are less efficient at clearing mercury from the brain. Mercury exposures in those that are more susceptible to its toxic effects, can lead to the same degenerative processes associated with AD. (6) ( See my mercury toxicity article). Other research has demonstrated that physical inactivity, drinking alcohol, smoking and a high intake of saturated fats increases the risk of dementia/AD overall but more so in those with the ApoE4 gene. (7) Stress patterns and the stress hormones that are a byproduct of that deleterious cycle also may contribute to the brain degeneration characteristic of AD. (8) ApoE4 in susceptible individuals could be a more significant increase risk for AD if there are lifestyle and stress issues that are lifelong patterns.
ApoE is not the only gene factor that raises the ante in LOAD. Emerging evidence indicates that other genes play a role in LOAD. The Mayo Clinic (Jacksonville) reported from a large study on first-degree relatives, that genes other than ApoE4 influence susceptibility to developing LOAD. In their report they noted that the gene for Insulin Degrading Enzyme (IDE) is likely a significant contributor to LOAD. Other research has identified the SORL1, BACE1, GAB2 and more recently, the CAHLM1 genes as significant risk factors as well. More on these genes and how they influence the risk for AD will be available soon in coming articles.
My e-book, The Alzheimer’s Solution, will be made available soon, and will provide you with a resource that will cover all you need to know about preventing Alzheimer’s disease. Please sign up to my email list and be among the first to be notified when it is released.
God Bless! Ralph Sanchez, L.Ac.,CNS,D.Hom.
* “Gene expression” refers to the expression of a gene’s code of information into proteins that manifest as the functional and structural entities of cells.
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8. Kim N. Green, Lauren M. Billings, Benno Roozendaal, James L. McGaugh, and Frank M. LaFerla. Glucocorticoids Increase Amyloid-beta and Tau Pathology in a Mouse Model of Alzheimer’s Disease. The Journal of Neuroscience, August 30, 2006, 26(35):9047-9056