Hormone Depletion and Risk of Alzheimer’s Disease

Hormone Depletion and Risk of Alzheimer’s Disease

It is estimated that nearly 500,000 cases of Alzheimer’s (AD) will be diagnosed this year, approximately one every 69 seconds. As we all know, AD preferentially attacks older folks. Fourteen percent of all people aged 71 and older have dementia. But 71 is not very old these days. So many people in their 70s and even 80s are active physically and mentally and are enjoying life with family and leisure activities. Yet one in six women and one in ten men aged 55 and older will be demented at some time in their life.

It’s not a coincidence that Alzheimer’s risk increases with age while hormone levels decline with age. Is there a link? The biochemistry behind the development of AD certainly supports a very strong and direct link. Testosterone, estradiol, progesterone, DHEA and melatonin are all hormones that decline with age, yet play a critical part in protecting the brain from the ravages of memory loss, brain cell loss and the pathologic processes of AD itself. I don’t have time to cover all these today but I can start with testosterone and try to cover the others soon.

Testosterone is, of course, designated a male hormone but plays a crucial role in life for women as well. Women have only about 10% as much testosterone as men but that 10% is important for many functions, including brain power! Here are just a few pieces of evidence.

In population studies of normal men, those with higher testosterone levels were shown to have better cognitive function than those with lower levels.^1,2

In clinical trials of testosterone replacement, normal aging men with testosterone levels at the lower end of the normal range experienced improvements in both verbal and spatial memory when the level was raised to the upper normal range.³

But how about men with Alzheimer’s? Well, testosterone replacement was also very effective in improving both verbal and spatial memory in a study of men with either Alzheimer’s or mild cognitive impairment (pre-Alzheimer’s).⁴

One of the two hallmarks of AD is the accumulation of beta amyloid protein, forming plaques in the AD brain.

Testosterone influences brain levels of beta amyloid through two other hormones: dihydrotestosterone (DHT) and estradiol (a female hormone). Some of the testosterone in both men and women is converted by the body into these other two hormones. So the more testosterone we have, the more DHT and estradiol our bodies can make. Both DHT and estradiol influence brain beta amyloid by stimulating the activity of an enzyme called neprilysin.^5,6 Neprilysin cleaves beta amyloid into smaller, more soluble components that can be removed from the brain. Estradiol also eliminates beta amyloid by multiple mechanisms that I can discuss in a later blog.

Beta amyloid (the harmful protein) comes from the cleavage of amyloid precursor protein (APP) by the enzyme beta secretase. When APP is cleaved by an enzyme called alpha secretase, a harmless soluble form of amyloid—alpha amyloid—is made. Testosterone has been shown to increase the production of alpha amyloid at the expense of production of beta amyloid.⁸ To put it simply, testosterone reduces the production of beta amyloid in the brain!

It’s important to realize also, why beta amyloid is associated with AD – because it is directly toxic to brain cells. It suppresses their activity to the point that they eventually just die. In addition to reducing beta amyloid production and enhancing its removal, testosterone has been shown to directly protect brain cells from the toxicity of beta amyloid. It does so by increasing the production of a brain-protective protein called HS Protein 70.¹⁰

The second hallmark of AD is the formation of neurofibrillary tangles (NFTs) from the collapse of a protein in brain cells called tau. Tau supports the brain cell structurally, somewhat like the steel frame inside a commercial building. When the tau collapses, the brain cell dies because it looses it’s important structural integrity. Tau collapses and forms NFTs  because it is cleaved by destructive enzymes. One of these bad enzymes that cleaves the tau protein is called calpain. Testosterone actually blocks the calpain enzyme, inhibiting NFT formation.⁹ In an extension of this finding, the reduction in NFT formation by testosterone was further confirmed to improve brain-cell survival.⁹

I’ve got to get back to my day job, now but I can tell you that the evidence for protecting the brain from deterioration is no less impressive for estradiol, progesterone, DHEA and melatonin. I’ll try to fill you in on these later. The important point is that hormone depletion is related epidemiologically and biochemically to AD. When those two types of evidence are combined the point is very difficult to deny. Hormone replacement (HRT), then, becomes a very promising technique for protecting the brain – something we’ve known at the Leonardi Institute for some time now. And I can tell you our bioidentical HRT patients are thriving physically and mentally, on par with people twenty to thirty years their junior! All this and much more about AD is revealed in my and Dr. Nathan Daley’s upcoming book: Alzheimer’s, Memory Loss, MCI: The Latest Science for Prevention and Treatment, which should be released sometime in May. More soon, I hope and a great day to all!

Dr. Dave Leonardi

References:

1.         1. Yaffe, K., L. Y. Lui, J. Zmuda, and J. Cauley. 2002. Sex hormones and cognitive function in older men. Journal of the American Geriatrics Society 50 (4): 707–12.

2.         2. Barrett-Connor, E., D. Goodman-Gruen, and B. Patay. 1999. Endogenous sex hormones and cognitive function in older men. The Journal of Clinical Endocrinology and Metabolism 84 (10): 3681–5.

3.        3. Cherrier, M. M., A. M. Matsumoto, J. K. Amory, M. Johnson, S. Craft, E. R. Peskind, and M. A. Raskind. 2007. Characterization of verbal and spatial memory changes from moderate to supraphysiological increases in serum testosterone in healthy older men. Psychoneuroendocrinology 32 (1): 72–9.

4.         4. Cherrier, M. M., A. M. Matsumoto, J. K. Amory, S. Asthana, W. Bremner, E. R. Peskind, M. A. Raskind, and S. Craft. 2005. Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology 64 (12): 2063–8.

5.         5. Yao, M., T. V. Nguyen, E. R. Rosario, M. Ramsden, and C. J. Pike. 2008. Androgens regulate neprilysin expression: Role in reducing beta-amyloid levels. Journal of Neurochemistry 105 (6): 2477–88.

6.         6. Yang, H. Q., Z. K. Sun, Q. H. Jiang, Q. Shang, and J. Xu. 2009. [Effect of estrogen-depletion and 17beta-estradiol replacement therapy upon rat hippocampus beta-amyloid generation]. Zhonghua Yi Xue Za Zhi 89 (37): 2658–61. [in Chinese].

7.         7. Gouras, G. K., H. Xu, R. S. Gross, J. P. Greenfield, B. Hai, R. Wang, and P. Greengard. 2000. Testosterone reduces neuronal secretion of Alzheimer’s beta-amyloid peptides. Proceedings of the National Academy of Sciences of the United States of America 97 (3): 1202–5.

8.         8. Park, S. Y., C. Tournell, R. C. Sinjoanu, and A. Ferreira. 2007. Caspase-3- and calpain-mediated tau cleavage are differentially prevented by estrogen and testosterone in beta-amyloid-treated hippocampal neurons. Neuroscience 144 (1): 119–27.

9.         9. Zhang, Y., N. Champagne, L. K. Beitel, C. G. Goodyer, M. Trifiro, and A. LeBlanc. 2004. Estrogen and androgen protection of human neurons against intracellular amyloid beta1-42 toxicity through heat shock protein 70. The Journal of Neuroscience 24 (23): 5315–21.

How Did I Get Alzheimer's?

I can imagine being officially diagnosed with Alzheimer's disease (AD). My first thought would be "No, this can't be!"

My second would be "How did this happen?"

The etiology of AD is multifactorial and a bit complex. But by gaining some understanding of those multiple causes we open up opportunities to prevent and even treat the disease.  

To get AD, one must have the genetic disposition to be susceptible. Then the factors of aging play a role in actually getting the disease to develop. By genetic disposition I don't mean having "the Alzheimer's gene". Very few AD victims have genetically transmitted AD. What I mean by being genetically susceptible is that one does not have the genetics to be particularly protected from the disease. This is true for most of us. So we're all at risk. In fact, AD is now the 6th leading cause of death worldwide.

So given that nearly all of us have the genetic capability to develop AD, what specifically is going on to cause the disease? And, more importantly, is there anything I can do to prevent or treat the disease if I’m already diagnosed?

As I mentioned, AD is multifactorial in its causation. The brain is being attacked along seven different avenues, much like a city under siege by an enemy approaching from seven different directions. Here are the seven avenues of attack:

1.     Oxidative Stress

2.     Glycation

3.     Inflammation

4.     Production of beta amyloid protein

5.     Reduced elimination of beta amyloid protein

6.     Brain cell destruction by beta amyloid protein

7.     Development of abnormal tau protein

Please don’t let the medical terminology discourage you. I can simplify these terms for you, albeit not in this blog alone. It will take a number of sessions to get all this on the table. For now, it’s important to understand that all seven of these “attacks” can be defended. And doing so can be very worthwhile. In fact the first three are related directly to aging itself and to our most destructive age-related diseases. For today, let’s just look at number one: oxidative stress.

If you remember from high school chemistry, an atom has a nucleus called a proton, which is orbited by electrons. Electrons like to travel in pairs. And if an electron is all by itself orbiting the proton, that atom is a free radical. That electron will do anything it can to get a mate, so what it typically does is jump ship to the next atom, knock an electron out of its orbit and take its mate. Then the atom that lost the electron becomes the free radical and it immediately goes to the next atom, knocks an electron out of its orbit and takes its mate and so on. What we end up with is a rapid fire transfer of electrons. This is called oxidative stress because every time there is an electron transfer, there is a potential structure change in a molecule. Most of the time it is of no consequence; it may simply be a skin cell ready to slough off anyway. But when brain cells are exposed to oxidative stress (electron transfers and structural changes) it often results in the death of the brain cell. Oxidative stress is one of the primary mechanisms by which we lose brain cells--as in Alzheimer’s, Parkinson’s and even normal brain ageing.

So, clearly, we would like to control oxidative stress if we could.  And the degree of oxidative stress that we undergo is related to the degree of pollution to which we are exposed. For example, when you’re driving in any degree of traffic, do you remember to use the recirc button in your car? That is the button that circulates cabin air around and around and prevents outside air from entering the car. If outside air is being sucked in from the outside, you’re breathing in carbon monoxide which is colorless, odorless and tasteless, so you can’t detect it, and you are also breathing in diesel particulates and other products of hydrocarbon combustion. These not only damage our lungs, but create a shower of free radicals in our bodies. So use your recirc button constantly until you’re completely out of traffic, and then open your vehicle to fresh air.

And what about your water source? Most drinking water is either carbon filtered or simply direct from the tap. Carbon filtration removes toxins and impurities but leaves the minerals in place. Some minerals (e.g. calcium, potassium and magnesium) are beneficial but many others (e.g. aluminum, mercury and, when in excess – even iron) are strong pro-oxidants. That means they promote free radicals and electron transfers and are toxic to brain cells. Reverse osmosis as well as distillation (another processing technique of boiling the water into vapor and recondensing) take out virtually all the impurities and minerals, both toxic and healthful. These are great systems for eliminating those pro-oxidant metals and protecting our brains but we should then be careful to supplement calcium, magnesium and potassium in some form.

Pesticides found in conventional produce also create free radicals. Pesticides are removed from our blood by the liver in a detoxification process. But in that process, a huge shower of free radicals is produced. Organic produce, containing little or no pesticide, doesn’t require hepatic detoxification, so no free radicals are produced in response to eating it.

 Eating produce itself, however, is important because fruits and non-starch vegetables are the very foods that contain antioxidants.  Antioxidants are molecules that can accept the free radical and neutralize it without creating another one, stopping the chain of electron transfers. They are able to do this just by their chemical structure.  Antioxidants are substances such as beta carotene, Vitamins C and E, selenium, alpha lipoic acid, Co Q10, N-Acetyl Cysteine and others. In addition to organic produce, it’s is good idea to take a broad spectrum of antioxidant supplement. Antioxidants work in different tissues by different mechanisms and they complement each other. Some actually help to regenerate others. For example, Vitamin C regenerates vitamin E in the body.

In summary, reducing oxidative stress is a good way to protect your brain and one of many steps we can take to combat AD. To do so, make your air and water as free as possible from free radical-generating pollutants, eat plenty of organic non-starch vegetables and fruits and take a reasonable broad spectrum antioxidant supplement.

But to have a substantial impact on AD, one must defend the brain against all seven of the avenues of attack. I’ll write more on the other six avenues in future blogs along with something about the two “supply avenues” to keep open: cognitive enhancers and brain plasticity. Sorry this is more complex than taking a pill once a day but until we have such a magic bullet, at least we have an effective means of combating this otherwise invariably fatal disease. If you want all the answers now, our book, “Alzheimer’s, Memory Loss, MCI: The Latest Science for Prevention and Treatment” will be published in early May, 2012. It was written by me and my associate, Nathan Daley, M.D.