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 variant (ApoE4), as a prominent genetic risk factor for LOAD. About 25% of the population has one copy of ApoE4 and carriers with the the ApoE4 variant are estimated to make up approximately 40%-80% of the Alzheimer’s disease population.(2)

As indicated by the Swedish Twin Study, genetic factors in Alzheimer’s disease (AD) and in many other degenerative diseases may increase your vulnerability to the onset of such disorders as you age. Genetic susceptibility associated with AD and many other diseases are linked to genetic mutations (variants).

A mutation of a single DNA base is referred to as single-nucleotide polymorphism (SNP). SNPs (pronounced snips) 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. Each SNP represents a difference in a single DNA building block, called a nucleotide–the bead in the chain (Cytosine, Guanine, Adenine, Thymine). That difference is a substitution of nucleotide base that produces a variation in the DNA sequence (see Illustration below).

Cell, Chromosome, DNA and gene. Cell Structure. The DNA molecule is a double helix. A gene is a length of DNA that codes for a specific protein. Genome Study

Cell, Chromosome, DNA and gene. The DNA molecule is a double helix. A gene is a length of DNA that codes for a specific protein.

The role of ApoE in late-onset Alzheimer’s disease (LOAD) is a good example of how SNPs could 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 the ApoE gene 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 four-fold increased risk for developing LOAD. Similar research has shown that people who inherit two copies of ApoE4 have as much as a fifteen-fold greater risk of developing this disease.(6,2)  However it is important to note that the ApoE4 variant is one of many risk factors associated with LOAD. Not all people who have inherited the ApoE4 variant will develop Alzheimer’s disease. Nevertheless, SNPs are not to be overlooked in those individuals that want to implement a proactive preventive strategy for Alzheimer’s and other degenerative diseases associated with aging.

Understanding one’s own genetic potential for LOAD and the environmental risk factors that carry significant weight, can provide opportunities for positively exercising preventive measures. LOAD 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. LOAD susceptibility as influenced by genes like ApoE4 are factors to be aware of but perhaps more important are the environmental risk factors. Numerous studies indicate that ApoE4 carriers may be more vulnerable to environmental toxins that fall into the classification of neurotoxins. 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.(7) (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/LOAD overall but more so in those with the ApoE4 gene.(8) Stress patterns and the stress hormones that are a byproduct of that deleterious cycle also may contribute to the brain degeneration characteristic of AD.(9) ApoE4 in susceptible individuals could be a more significant increase risk for LOAD 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, CAHLM1 and more recently the TREM2 gene (see article) as significant risk factors as well.

genes-load

* “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.

References:

1. Role of genes and environments for explaining Alzheimer disease.
Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, Fiske A, Pedersen NL.
Arch Gen Psychiatry. 2006 Feb; 63(2):168-74

2. Neuropsychological and neuroimaging changes in preclinical Alzheimer’s disease
Twamley EW, Ropacki SA, Bondi MW. J
Int Neuropsychol Soc. 2006 September; 12(5): 707-735.

3. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD.
Proc Natl Acad Sci U S A. 1993 Mar 1; 90(5):1977-81.

4. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families.
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA.
Science. 1993 Aug 13; 261(5123):921-3.

5. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease.
Cook KD, Myers AJ, Craig DW et al.
J Clin Psychiatry. 2007 Apr;68(4):613-8

6. The Genetics of Alzheimer Disease
Rudolph E. Tanzi
Cold Spring Harb Perspect Med. 2012 Oct 1;2(10).

7. Mercury and Alzheimer’s disease
Mutter J, Naumann J, Schneider R, Walach H.
Fortschr Neurol Psychiatr. 2007 Sep;75(9):528-38. Epub 2007 Jul 12.

8. Apolipoprotein E epsilon4 Magnifies Lifestyle Risks for Dementia: A Population Based Study.
Kivipelto M, Rovio S, Ngandu T, KÃ¥reholt I, Eskelinen M, Winblad B, Hachinski V, Cedazo-Minguez A, Soininen H, Tuomilehto J, Nissinen A.
Journal of Cellular and Molecular Medicine. 2008 Mar 4.

9. Glucocorticoids Increase Amyloid-beta and Tau Pathology in a Mouse Model of Alzheimer’s Disease.
Kim N. Green, Lauren M. Billings, Benno Roozendaal, James L. McGaugh, and Frank M. LaFerla.
The Journal of Neuroscience, August 30, 2006, 26(35):9047-9056

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