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.