Alzheimer's vs. environmental factors

Is there an environmental factor in Alzheimer's Disease?

"Genes load the gun and environment pulls the trigger." Unfortunately, in the case of Alzheimer's, geneticists are on only just beginning to piece together how the gun is loaded, and they are even less certain where the trigger is. But what they have found out about possible triggers has a familiar enough ring to it -- many of the factors have already been established in other diseases -- that the findings make for a fascinating story. The story matters to me because my mother is battling (late-onset) Alzheimer's -- a disease of great mental anguish and eventual complete mental and physical disability. The questions that matter to me about this story are at the end of the story; I'm hoping that you have answers to offer, or least some questions that might provide clues.

Which main characteristic of Alzheimer's appears most affected by environmental factors?

Some recent studies estimate that it is now the fourth most common cause of death in the developed world [Ewbank 1999]. Alzheimer’s disease (AD) is characterized by plaque formation, neuronal loss, and cognitive decline. Of the two main hallmarks of Alzheimer's -- plaques that gather outside the nerve cells and tangles that gather inside the nerve cell -- it is the plaques that appear most vulnerable to environmental influences. The plaques are made of Amyloid-Beta (or AB, pronounced A-Beta) protein. The creation of the plaques is referred to as amyloidogenesis, a term which will come up in connection to lead in the environment (below).

How can Alzheimer's be affected by the environment?

Alzheimer's is not an issue of 'nature versus nurture': "Many disorders -- like many normal physiological conditions (e.g. blood pressure) and cognitive abilities (e.g. intelligence) -- probably result from the combined action of multiple genes of small effect together with a variety of environment factors." [Tsuang et al 2004]. The question is how the two interact to produce a given illness, such as Alzheimer's. One clue is to approach the interaction between genes and the environment as "genetic control of sensitivity to the environment" [Tsuang et al 2004]. A key gene that appears to be affected by the environment is the APP gene (Amyloid Precursor Protein).

A long-time-missing link between genes and the environment

One factor in this control is epigenetics, a link between nature and nurture, because it deals with factors "on top of" (epi-) or outside of the gene - that can affect whether the gene produces a protein . It is the study of changes in the way a gene functions -- changes that occur without a change of DNA sequence, yet can still be inherited [Wikipedia]. There are intriguing terms that pop out of the Pandora's box of epigenetics -- such as 'bookmarking', 'imprinting', 'position effect', and 'maternal effect', but the term that pops up most for Alzheimer's and the environment is 'methylation' (adding a methyl group), or more often its converse, 'demethylation' (removing a group).

Methylation: a big time effect from 4 tiny atoms

Methylation is the attaching of a single carbon atom and 3 hydrogens to a special part of a gene. The simple attachment or detachment of multiple CH3 groups, has the effect either of increasing the gene's expression -- ie, the gene's ability to "produce" its protein -- or of decreasing its expression. As we shall see later, one environmental factor, lead (Pb), may have a role in pulling CH3's off a gene (APP) that helps produce the amyloid plaques.

How long would it take before an environmental effect would show up?

Many environmental factors engender their disease-creating effect as early as before conception (at the sperm and egg stage), during embryonic stages, or as a newborn. This early-effect appears to be a factor in Alzheimer's as well. Early exposure to Pb has been shown to produce methylation of the APP gene in early development [Wu 2008a]. The gene that is most connected with late-onset Alzheimer's (ie, after age 65) is APOE4, which is actually a variant of a gene; the other variants are harmless. This gene, as we shall see, connects head injury to increased risk for Alzheimer's (remember, an epigenetic factor is one that affects the activity of a gene without changing the gene's sequence).

Lead in early development

There is evidence in baby monkeys that exposure to lead during infancy sets in motion the build up of the amyloid plaques that spell Alzheimer's much later in life. It seems like a long stretch between lead and infancy and amyloid plaques in old age, but here is what some researchers have pieced together [Wu et al 2008a]: Lead creates stress products in the brain by engendering (among other things) the production of 8-hydroxyguanine. These molecules attach themselves to one or more of the many CpG (Cytosine Guanine) groups in the gene that produces amyloid (APP). One of the toxic effects of lead in the brain is the creation of oxidative damage in a way that increases the production of amyloid from the APP gene, and the increase in amyloid increases the odds that amyloid plaques will form. It does this in the same way that 2 "no's" create a "yes". For example, when the APP gene is methylated, it essentially prevents the gene from producing A-B protein, creating a "no" for amyloid production; when the lead removes or prevents that protective methylation, it says "no" to the "no amyloid" and thus increases the risk of amyloid. The exposure in infancy has an effect in old age because methylation of the DNA of a gene during development determines how responsive the gene will be for the rest of the organisms' life -- i.e., will it produce too much protein? [caption id="attachment_378" align="aligncenter" width="420" caption="The proposed pathway for how lead exposure in early life affects risk of Alzheimer\'s"]PbDemethylation.anim[/caption] And, indeed, exposing a species of monkeys whose APP gene is 96% identical to our own, to lead in infancy, resulted in increased levels of amyloid plaques in old age in one of the areas of the brain that are damaged by Alzheimer's -- the frontal association cortex -- a part of the brain necessary for decision-making. As the authors of this finding conclude, "these data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD" [Wu2008b]

Minerals in drinking water -- really ?

Lead is not the only mineral that may have an effect on risk of Alzheimer's; a 7-year study of 7600 women in France in 2004 showed that a low silica (silicone and oxygen) concentration in their drinking water had a significant correlation to their cognitive ability. Furthermore, "women with AD were 27 times as likely to have low daily intake compared to the other women in the study." [Gillette-Guyonnet et al 2005] They tested for, but found no correlation to cognitive function for either calcium or aluminum.

How could the 'Alzheimer's gene' - APOE4 - have a connection to head injury?

Head injury has been shown to be a risk factor for Alzheimer's since at least 1985 [Mortimer et. al. 1985, Whalley et. al. 1981]. In an attempt to quantify this, other researchers have found this: If someone has a head injury but doesn't have the APOE4 gene (the #4 variant of the APOE gene), then their risk is no different from everybody else's -- no different than for the population as a whole [Mayeux 1995]. If they're in the opposite situation -- no head injury, but 'yes' on the APOE4, they they've twice the risk of everybody else.

A five-to-tenfold increase in odds

But if they have both the APOE4 and a history of head injury? Their risk is 10 times that of everybody else. The APOE4 is thought to contribute to the clumping of amyloid protein into plaques in the brain, so the hyothesis is that head injury increases the amount of amyloid available for possible clumping and the APOE4 takes over to help the clumping. In other words, "head injury contributes to the pathogenesis of AD by increasing beta-amyloid precursor protein (APP) in the cerebral cortex, which exacerbates the effect of the APOE-e4 allelle (which is thought to be related to cerebral beta-APP deposition)." [Tsuang et al 2004] And that's just a few of the factors contending for a role in Alzheimer's. This is only a bare introduction to the research, as of August 2008, into the factors that are only pieces of the large and life-threatening puzzle of biological interactions that add up to Alzheimer's.

Unanswered questions

For the greater amount of amyloid that lead exposure is hypothesized to engender: Is there a proven connection between amount of amyloid and the clumping of the amyloid into plaques? What is the physiology and chemistry of plaque formation?

What is the chemistry of lead in the brain?

Do other metals or 'factors' affect methylation of the APP gene?

The connection between low silicates and incidence of Alzheimer's : what are the links in the chain -- what is the molecular mechanism -- that would convert the correlation to a causation?

If the deciding factor for developing Alzheimer's is ones environment, especially ones early environment, then why fuss with keeping the mind and body active to prevent or stave off the disease?

Does physical and mental activity do anything more than bolster the body's immune defenses?



[Basha et al 2005] Basha MR, Murali M, Siddiqi HK, Ghosal K, Siddiqi OK, Lashuel HA, Ge YW, Lahiri DK, Zawia NH, Lead (Pb) exposure and its effect on APP proteolysis and Abeta aggregation.,official publication of the Federation of American Societies for Experimental Biology, FASEB J. 2005 Dec;19(14):2083-4.

[Ewbank 1999] Ewbank DC. Deaths attributable to Alzheimer's disease in the United States. Am J Public Health 89(1):90-2 (1999)

[Gillette-Guyonnet et al 2005] Cognitive impairment and composition of drinking water in women: findings of the EPIDOS Study1–3, Gillette-Guyonnet S, Andrieu S, Nourhashemi F, de La Guéronnière V, Grandjean H, Vellas B, Am J Clin Nutr 2005;81:897–902.

[Mayeux et al 1995] Mayeux R, Ottman R, Maestre G, Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer’s disease. Neurology 1995;45:555-7.

[Mortimer et al 1991] Mortimer JA, French LR, Hutton JT et al. Head injury as a risk factor for Alzheimer’s disease. Neurology 1985;35:264-7. [Tsuang et. al. 2004] Tsuang MT, Bar JL, Stone WS, Faraone SV, Gene-environment interactions in mental disorders, World Psychiatry. 2004 June; 3 (2): 73–83.

[Whalley 1991] Whalley LJ. Risk factors in Alzheimer’s disease. Br Med J 1991; 303:1215-6.

[Wikipedia] Epigenetics

[Wu et. al. 2008a] Wu J, Basha M R, Zawia N, The Environment, Epigenetics and Amyloidogenesis, J Mol Neurosci (2008) 34:7

[Wu et. al. 2008b] Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, Harry J, Rice DC, Maloney B, Chen D, Lahiri DK, Zawia NH, Alzheimer’s Disease (AD)-Like Pathology in Aged Monkeys after Infantile Exposure to Environmental Metal Lead (Pb):Evidence for a Developmental Origin and Environmental Link for AD, The Journal of Neuroscience, January 2, 2008 • 28(1):3–9

Background information

[Ryman 2006] Ryman D, Lamb BT, Genetic and Environmental Modifiers of Alzheimer’s Disease Phenotypes in the Mouse, Current Alzheimer Research, 2006, 3, 465-473

[Edwards 2007] Edwards TM, Myers JP, Environmental Exposures and Gene Regulation in Disease Etiology, Environ Health Perspect. 2007 September; 115(9)
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