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Testosterone and Alzheimer's Disease – What's the Connection?

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Testosterone and Alzheimer's disease are more closely linked than previously thought. Growing evidence [6] shows that low plasma testosterone level is significantly associated with increased risk of Alzheimer's disease. According to the latest research, testosterone and estrogen may help prevent chronic inflammation 1,2 and the accumulation of toxic proteins called amyloids3 in the brain. Researchers now understand this to be one of the leading causes of dementia and Alzheimer's disease

  • Acute inflammation in the brain is a well-established defense against infection, toxins, and injury. But, when the equilibrium of anti-inflammatory and pro-inflammatory signaling is interrupted, as seen in AD, it results in chronic inflammation.
  • Low testosterone and estrogen levels can cause an increase in harmful protein levels in the brain. These tau and beta-amyloid proteins collect within the neurons and the pathways causing damage, sometimes resulting in Alzheimer's disease and other types of dementia.
  • Low circulating testosterone and estrogen levels are risk factors for Alzheimer's disease.
  • Decreased circulating testosterone and estrogen are also associated with declining cognitive performance, particularly with memory-related tasks.
  • Conversely, hormone supplementation in hypogonadal men and postmenopausal women improves memory performance.
  • Hormone supplementation may be beneficial for preventing and treating Alzheimer's disease in both men and women.

As men and women age, there is a natural decline in androgen hormone production. Coincidently as testosterone and estrogen levels fall, incidents of age-related diseases such as Alzheimer's, heart disease, stroke, and certain cancers increase. There is growing evidence that by maintaining androgen levels, you can avoid and even reverse many of these diseases, extend life, and vastly improve your quality of life.

How Common Is Alzheimer's?

An estimated 6.2 million Americans aged 65 and older were living with Alzheimer's dementia in 2021. This number could grow to 13.8 million by 2060, barring the development of medical breakthroughs to prevent, slow, or cure AD.

The disease is the sixth-leading cause of death in the United States. Rising to the fifth leading cause of death for those age 65 and older. Sadly, Alzheimer's is also a principal cause of disability and poor health and mortality. Alzheimer's is a progressive disease, with sufferers living through years of poor health as the disease progresses, and they become entirely dependent on family support or the care system.

 Women are more at risk of dementia [4] than men, with women making up 65% of cases. This statistic may not sound overly significant, but that means that only 35% are men. While getting old is the leading risk factor for dementia and women usually live longer, this does not entirely explain the disparity. We now understand that the androgen hormones testosterone and estrogen have protective qualities on the brain. Low testosterone in men and low estrogen in women impacts vulnerability [2] to Alzheimer's disease.

What Causes Alzheimer's Disease?

If we were to try and cover all potential causes of Alzheimer's in one article, you would face a complex thesis that would take days to read, and you would probably come out of it none the wiser. However, scientists now believe the leading causes [3] are chronic inflammation and the build-up of damaging proteins in the brain that cause molecular and cellular changes that begin years before any symptoms appear.

Inflammation Could Be The Main Cause of Alzheimer's

The risk of developing Alzheimer's is linked to several risk factors. Age, cardiovascular change, brain injury, and metabolic disorders such as diabetes. These risk factors are related to immune responses, particularly elevated inflammation and associated inflammatory signals that can directly increase AD risk. 

Type 2 Diabetes Mellitus, Alzheimer's Disease, and Inflammation 

Alzheimer's disease, in many cases, can be characterized by abnormal metabolic changes, particularly those seen in people with T2DM. Decreased glucose metabolism is shown to be a distinct characteristic of AD [242][243][244]. The link between the two is well established, along with other conditions affecting the brain, such as vascular dementia and Parkinson's disease.

One of the key studies, the 1999 Rotterdam Study, found that type-2 diabetes mellitus (T2DM) could double the risk of AD development [248]. Since this study, many others have substantiated that TD2M nearly doubles the chances of developing Alzheimer's disease, so doctors now use it as a predictor for developing AD. [251][252]

Amyloid Plaques

Beta-amyloids are protein fragments in the brain that break off from larger amyloid precursor proteins. In a healthy brain, these proteins are easily broken down and eliminated. Beta-amyloid proteins are chemically "sticky" with the most damaging forming clumps, which the body cannot dissolve. These clumps form between neurons, disrupting cellular function and eventually killing the cells.

Amyloid brain x

Neurofibrillary Tangles

Neurofibrillary tangles are abnormal accumulations of a protein called tau, which collects inside neurons in the brain. In Alzheimer's disease, abnormal chemical changes cause tau to stick to other tau molecules, forming threads that eventually join to form tangles inside your neurons, disrupting communication in the brain.

This combination of a build-up of β-amyloid plaque and the spread of tau neurofibrillary tangles disrupts the neurons and the pathways between them.

Special cells called astrocytes and microglia are supposed to remove this build-up of waste and 'toxic' proteins. However, with Alzheimer's, there seems to be a malfunction in these maintenance cells, meaning they don't do their job, resulting in inflammation of the brain and excess plaque and harmful debris.

Vascular Problems and Alzheimer's

Alzheimer's is rarely only caused by issues with the neurons and pathways in the brain. Vascular problems are also commonplace, restricting blood flow to and around the brain.

Any reduction in blood flow restricts oxygen and glucose supply to the brain. Restricted blood flow also limits the blood's ability to remove toxins. As a result, this causes inflammation of the brain. Long term, the brain starts to deteriorate. This deterioration affects memory, control of certain bodily functions, and even the ability to think for oneself.

Through all these processes, neurons become damaged, and the complex neural highways collapse. As a result, certain areas of the brain begin to shrink. In the final stages of Alzheimer's, this shrinkage becomes widespread, causing significant brain volume loss.

Depression and Alzheimer's Disease

It is well established [6] that there are links between depression and dementia. People with early-life depression (pre 60 years old) or depressive symptoms have twice the risk of dementia and Alzheimer's.

The likely causes linking depression to dementia include vascular disease, stress hormones, brain shrinkage, beta-amyloid plaques, inflammatory changes, and faulty nerve growth.

Can You Prevent Alzheimer's Disease?

Is Alzheimer’s Hereditary?

Your genetic make-up can contribute to your risk of developing Alzheimer's. In reality, the risk is minimal. For the very few, inherited genes can cause Alzheimer's.

Alzheimer's is most common in people in their late 70s and 80s, highlighting the most important risk factor for Alzheimer's disease is age. Having a parent or grandparent with Alzheimer's at this age doesn't increase your risk. But, if a family member gets Alzheimer’s earlier (less than 60 years old), there is a chance it's hereditary.

Late-onset Alzheimer’s is most common, and many of us will have relatives or friends with the disease. Research shows even if you’ve got a close relative with Alzheimer's over 65, your risk hardly increases.

Early-onset Alzheimer's, where people get the disease under 65, is very unusual but can run in families. Again, if you have these genes, it is very rare for you to develop Alzheimer's. In these cases, it often shows in those in their 30s, 40s, and 50s.

If you have a family history of dementia at a young age, you may want to seek more information. There are plenty of charities and groups that can offer advice and support.

Estrogen Offers Protection for The Brain

Testosterone suppression is a treatment for prostate cancer. Research shows that one potential side effect of testosterone suppression is that amyloid levels increase. If reduced testosterone causes high amyloid levels, could increased testosterone counter the problem?

Interestingly, when the levels of testosterone drop, amyloids can reach dangerous levels. Scientists suggest that sex hormones may prevent amyloid deposits from building up in the first place.

Studies are now exploring the role of estrogen as a protective hormone for the brain. In women, most estrogen comes from the ovaries, the corpus luteum, and the placenta. However, the liver and adrenal glands continue to produce small amounts.

The problem arises when the ovaries stop estrogen production after menopause. This almost complete shut down in production means estrogen produced in the liver and adrenal glands becomes the only source. As a result, hormone levels fall dramatically after menopause. Studies [6] now conclude that due to the protection estrogen offers the brain, declining levels contribute to Alzheimer's.

Estrogen is Important for Men Too

In men, testosterone converts to estradiol (a form of estrogen). Although the conversion rate is very low, at about 0.2%, it is the primary source of estradiol in men. Because the testicles never completely stop testosterone production, estrogen levels in older men are often higher than in postmenopausal women. So, men's brains have higher protective levels of estrogen.

If you maintain estrogen using HRT in women, they too can get the protection estrogen offers the brain. Among older women who take estrogen replacement therapy, there are lower death rates from Alzheimer's.

The same theory applies to testosterone therapy for men to prevent Alzheimer's. Estradiol is a by-product of testosterone. As men age, their testosterone levels decline, along with estrogen levels and protection offered to the brain. So, optimizing testosterone can help increase estrogen to brain-protective levels.

Why Not Put Yourself to the Test

If you're worried about Alzheimer's, any other form of dementia, or your long-term health, it's advisable to check your hormone levels to discover if TRT could help. Out at-home blood test comes with a free consultation with one of our expert medical providers, who will look at your symptoms and advise you of your recommended treatment plan. Our simple at-home finger-prick test unlocks valuable information about your hormone health. With a detailed analysis at our CLIA-certified diagnostic labs, we’re here to help you stay healthy and active now and in the years ahead.

 

 

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Disclaimer: The information provided on this page is not a substitute for professional medical advice, diagnosis, or treatment. If you have any questions or concerns about your health, please consult a doctor.

[1] Saint Louis University. (2010, October 5). Low testosterone linked to Alzheimer's disease. ScienceDaily. Retrieved September 7, 2021 from www.sciencedaily.com/releases/2010/10/101005171202.htm

 

[2] 2021 Alzheimer's disease facts and figures. Alzheimers Dement. 2021 Mar;17(3):327-406. doi: 10.1002/alz.12328. Epub 2021 Mar 23. PMID: 33756057.

[3] Viña, Jose and Lloret, Ana. ‘Why Women Have More Alzheimer’s Disease Than Men: Gender and Mitochondrial Toxicity of Amyloid-β Peptide’. 3 June 2010 : S527 – S533.

[4] Ratnakumar A, Zimmerman SE, Jordan BA, Mar JC. Estrogen activates Alzheimer's disease genes. Alzheimers Dement (N Y). 2019;5:906-917. Published 2019 Dec 9. doi:10.1016/j.trci.2019.09.004

[5] Murphy MP, LeVine H 3rd. Alzheimer's disease and the amyloid-beta peptide. J Alzheimers Dis. 2010;19(1):311-323. doi:10.3233/JAD-2010-1221

[6] Byers AL, Yaffe K. Depression and risk of developing dementia. Nat Rev Neurol. 2011;7(6):323-331. Published 2011 May 3. doi:10.1038/nrneurol.2011.60

University of Southern California. (2006, December 20). Testosterone Therapy May Prevent Alzheimer's Disease. ScienceDaily. Retrieved April 26, 2022 from www.sciencedaily.com/releases/2006/12/061219201939.htm

[1] Wahjoepramono EJ, Asih PR, Aniwiyanti V, et al. The Effects of Testosterone Supplementation on Cognitive Functioning in Older Men. CNS Neurol Disord Drug Targets. 2016;15(3):337-343. doi:10.2174/1871527315666151110125704

[2] Uchoa MF, Moser VA, Pike CJ. Interactions between inflammation, sex steroids, and Alzheimer's disease risk factors. Front Neuroendocrinol. 2016 Oct;43:60-82. doi: 10.1016/j.yfrne.2016.09.001. Epub 2016 Sep 17. PMID: 27651175; PMCID: PMC5123957.

[2] Ratnakumar A, Zimmerman SE, Jordan BA, Mar JC. Estrogen activates Alzheimer's disease genes. Alzheimer's Dement (N Y). 2019;5:906-917. Published 2019 Dec 9. doi:10.1016/j.trci.2019.09.004

[3] Murphy MP, LeVine H 3rd. Alzheimer's disease and the amyloid-beta peptide. J Alzheimers Dis. 2010;19(1):311-323. doi:10.3233/JAD-2010-1221

Zárate S, Stevnsner T, Gredilla R. Role of Estrogen and Other Sex Hormones in Brain Aging. Neuroprotection and DNA Repair. Front Aging Neurosci. 2017;9:430. Published 2017 Dec 22. doi:10.3389/fnagi.2017.00430

[5 [ Saint Louis University. (2010, October 5). Low testosterone linked to Alzheimer's disease. ScienceDaily. Retrieved September 7, 2021 from www.sciencedaily.com/releases/2010/10/101005171202.htm

[6] Drummond ES, Harvey AR, Martins RN. Androgens and Alzheimer's disease. Curr Opin Endocrinol Diabetes Obes. 2009 Jun;16(3):254-9. doi: 10.1097/MED.0b013e32832b101f. PMID: 19373081.

[7] Chu LW, Tam S, Wong RL, Yik PY, Song Y, Cheung BM, Morley JE, Lam KS. Bioavailable testosterone predicts a lower risk of Alzheimer's disease in older men. J Alzheimers Dis. 2010;21(4):1335-45. doi: 10.3233/jad-2010-100027. PMID: 21504130.