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Hormones are the Answer to Alzheimer’s Disease
A. Edward Friedman
Abstract: Hormones are known to be able to counteract the biochemical properties associated with
Alzheimer’s as shown by in vitro and animal studies. Studies have also demonstrated a correlation
between low free testosterone levels and Alzheimer’s in men. A study using transgenic male mice showed
incredibly positive results by using genetic manipulation to produce superphysiological high levels of
testosterone with none of the testosterone being converted to estradiol. Although animal studies and
human epidemiological studies all point to the fact that hormones are the answer to Alzheimer’s, to date,
no clinical studies, or even case studies, have been done on humans using the levels of hormones which,
in theory, should be effective.
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Introduction
Currently, an estimated 5.7 million Americans have Alzheimer’s disease (AD) and by
2050 it is projected that 13.8 million Americans will have it. AD is the sixth leading cause of
death in the United States. It is estimated that the total cost for everyone alive today in the United
States who will eventually develop AD is $47.1 trillion. The six drugs currently approved by the
FDA for the treatment of AD temporarily improve symptoms for some people, but do nothing to
slow or stop the progression of the disease. Approximately 484,000 new cases of AD and
dementia are expected in 2018 for people aged 65 or older [1].
There are a number of biochemical properties associated with AD. Two major properties
involve the formation of extracellular 𝛽-amyloid (A𝛽) plaques between neurons in the brain and
the formation within neurons of neurofibrillary tangles composed mostly of hyperphosphorylated
tau protein. AD patients have alterations in their brain chemistry that favor the formation of these
plaques and tangles. In the study of cancer, bacteria, or viruses, it is a matter of course that
natural selection will result in mutations advantageous to the invading organism. However, in the
case of AD, there is no cell division, therefore natural selection is not a factor. Logically, there
must be some other explanation for the biochemical properties attributed to AD, which all favor
the progression of AD. Falling hormone levels are the logical explanation for this, since all of the
biochemical properties attributed to AD are observed as hormone levels decrease. This also
explains why AD increases with age, since hormone levels drop with age.
Extracellular Plaque Deposits
The extracellular plaque deposits associated with AD are composed primarily of Aβ [2].
There are two main forms of Aβ - those with 40 amino acids and those with 42. Normally,
around 90% of the Aβ secreted is composed of 40 amino acids (Aβ40) and 5-10% is Aβ42 [3].
Aβ42 is the major, and sometimes only, form of Aβ found in AD plaques [4].
Aβ is created by the cleavage of the amyloid precursor protein (APP) first by β-secretase
and then by γ-secretase. Another enzyme, α-secretase, cleaves APP at a spot within the Aβ
sequence and thus prevents the formation of Aβ [5]. Although excess levels of Aβ are involved
in the development of AD, there is a range of Aβ which is necessary to maintain the proper
functioning of the synapses within the brain [6]. In patients with AD, there is a large decrease in
α-secretase activity and a large increase in β-secretase activity [7].
Both testosterone (T) [8] and estradiol (E2) [9] have been shown to reduce the neuronal
generation of A𝛽. A study on mice showed that a cyclic administration of progesterone (P4) in
which high levels of P4 were achieved 10 days in a row every 30 days decreased A𝛽 levels and
enhanced the decrease that E2 alone produced [10].
The fact that T reduces total Aβ can be explained by the fact that T downregulates β-
secretase activity [11], upregulates α-secretase activity [12], and upregulates neprilysin activity
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[13]. Neprilysin is an enzyme which breaks down both Aβ monomers and Aβ oligomers [14]. E2
also downregulates β-secretase activity [15], upregulates neprilysin activity [16], and upregulates
α-secretase activity [12], which explains how E2 reduces total Aβ. More research is needed to
determine the exact mechanism of how P4 interacts with Aβ production. In fact, to add to the
complexity regarding P4, continual high levels of P4 actually negates the downregulation of Aβ
production caused by E2 [10].
In preventing Alzheimer’s, it may be important to reduce the Aβ42/Aβ40 ratio. T reduces the
Aβ42/Aβ40 ratio [11] as does E2 [17]. More research is needed to understand the relationship
between P4 and the Aβ42/Aβ40 ratio.
Neurofibrillary Tangles
Hyperphosphorylation of the tau protein plays a central role in the formation of the
neurofibrillary tangles associated with AD [18]. T prevents the hyperphosphorylation of the tau
protein [19]. E2 has no effect on this hyperphosphorylation [20], but P4 downregulates tau
hyperphosphorylation, whether given continually or for 10 days in a row every 30 days [10].
Brain Blood Flow and Metabolism
Glucose metabolism is impaired in the brains of those with AD [21]. T enhances brain
glucose metabolism [22] as does E2 [23]. More research is needed to determine the effect of P4
on brain glucose metabolism.
Cerebral blood flow is impaired in those with AD [24]. T improves cerebral blood flow
[25] as does E2 [26]. P4 does not have any effect on cerebral blood flow [27].
Correlating factors
It was reported that men who undergo androgen deprivation therapy (ADT) for at least
one year more than doubled their risk of developing Alzheimer’s within 2.7 years [28]. However,
a subsequent study that had a mean of 4.3 years claimed that there was no increased risk of
dementia for men undergoing ADT [29]. A study of over 100,000 women showed that those
women who had hysterectomies without any hormone replacement had twice the rate of
dementia as women who had not undergone hysterectomies [30].
A 19-year study on men showed that while there was no correlation between total T and
AD, every 10 unit increase in the free T index resulted in a 26% decreased chance of developing
AD [31]. T bound to sex hormone binding globulin cannot pass through the blood-brain barrier
[32]. This explains why there is no correlation between total T and Alzheimer’s.
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Researchers showed that people who followed the Mediterranean-DASH Intervention for
Neurogenerative Delay (MIND) diet for an average of 4.5 years reduced their risk of developing
AD. The subjects were divided into tertiles depending on how closely they followed the diet. The
tertile that was most compliant had 47 % of the risk of developing AD as compared to those in
the most non-compliant tertile. Even the middle tertile had 65% of the risk [33].
People who smoked more than two packs of cigarettes per day more than doubled their
risk of developing AD [34]. AD is correlated with air pollution. People living in cities with the
highest tertile of air pollution increase their risk of developing AD more than 4-fold as compared
to those living in cities with the lowest tertile [35]. Autopsy studies showed that people living in
heavily polluted cities accumulated over 4 times as much Aβ42 in their brains as people living in
cities with low levels of air pollution [36]. Long term exposure to both coarse and fine
particulate matter air pollution leads to significantly faster cognitive decline in older women
[37]. Mice that were exposed to a nickel nanoparticle-enhanced atmosphere for 3 hours more
than doubled the Aβ42 levels in their brains 24 hours later [38].
Possession of the apolipoproteinE4 (apoE4) allele is a very strong risk factor for AD. The
presence of apoE4 results in reduced transport of Aβ out of the brain across the blood-brain
barrier [39]. Vitamin D3 increases the transport of Aβ out of the brain across the blood-brain
barrier [40].
A 24-week double blind study on men with mild Alzheimer’s disease found that raising
their free T levels from 5.1 ng/dL to 9.4 ng/dL resulted in no objective improvement in cognitive
scores. However, subjectively, the caregivers reported quality of life improvement [41].
Women who have mutations of their estrogen receptor-β (ER-β) have an increased risk of
developing Alzheimer’s [42]. A study showed that early intervention with a phytoestrogen
formulation that binds 83 times more strongly to ER-β than to ER-α resulted in prolonged
survival, improved spatial recognition memory, and slower progression of amyloid pathology in
triple transgenic female mice [43].
Discussion
There are four factors that are correlated with the development of Alzheimer’s – hormone
levels, air pollution, diet, and genetics. It is not currently possible to implement genetic
engineering in humans, so nothing can be done directly to counteract genes that contribute to the
risk of Alzheimer’s. In the case of ApoE4, research is needed to determine whether increased
levels of vitamin D3 may offset the reduced transport of Aβ caused by that mutation. It is
possible to reduce air pollution, modify diet, and alter hormone levels.
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Air pollution increases brain inflammation [35]. Brain inflammation is correlated with
AD, whereas the long-term use of anti-inflammatory drugs is correlated with a reduction in the
risk of developing AD [44]. It is possible that pollution has other detrimental effects on the brain
which increases the risk of developing AD instead of just inflammation. More research is needed
to identify the comparative risk of all of the components of air pollution. Also, research is needed
to determine whether pollutants in our food and water may increase the risk of AD. In an ideal
world, the components which contribute to Alzheimer’s would be identified and then be
eliminated. Individuals can alter their exposure to air pollution by choosing where they live.
However, this is not a practical solution to the overall problem of Alzheimer’s disease.
It is not clear exactly what the role of diet is in the development of AD. There is no
question that the MIND diet reduced the incidence of Alzheimer’s. However, more research is
needed to determine if this diet simply delays the onset of Alzheimer’s or completely eliminates
its risk. Also, other dietary factors and nutritional supplements should be tested with regards to
Alzheimer’s in order to see what else should be added to, or eliminated from, one’s diet in order
to minimize the risk of developing Alzheimer’s.
The conflicting results with regards to ADT and Alzheimer’s are somewhat disturbing
[28,29]. However, both studies lasted for less than 5 years. The most likely explanation for these
contradictory results is that the time frame was too short to produce any meaningful results. The
19-year study of free T levels and Alzheimer’s showed that higher free T levels are protective
and that low free T levels allowed researchers to predict the development of AD up to 10 years in
advance of any symptoms [31]. This implies that it may take up to 10 years from the time that
free T drops below a critical level before the symptoms of AD appear. Multiple studies show that
T reverses the biochemical processes associated with AD [8,11,12,13,19,22,25]. Therefore, it is
extremely likely that if studies are done with longer time frames, it will be shown that ADT
increases the risk of Alzheimer’s.
Both improved diet and increased hormone levels should help prevent Alzheimer’s. No
study has shown that diet has any major positive effect in transgenic mice. However, the most
promising study to date involved adding an aromatase knockout mutation to male transgenic
mice [11]. The effect of this mutation was to produce superphysiological high levels of T with
none of the T being converted to E2. None of these transgenic mice ever exhibited any
Alzheimer’s-like symptoms, all of them had better memories than wild-type mice, and none of
them showed any decline in memory as they aged. Although it is not possible to induce such a
mutation in humans, it is possible to achieve the same effects of this mutation by using T
supplementation along with an aromatase inhibitor. Ideally, studies should be done on male
transgenic mice to determine what the effect is of bringing their T to superphysiological high
levels with and without an aromatase inhibitor and how that compares with those transgenic male
mice which had an aromatase knockout mutation. Also, studies should be done to examine what
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the effect of adding T plus an aromatase inhibitor would be on male transgenic mice at the point
that they start to exhibit Alzheimer’s-like symptoms. A study done using transgenic mice with a
conditional knockout for the β-secretase gene showed that after these mice reached adulthood,
knocking out the β-secretase gene resulted in the elimination of all of the Aβ plaques as well as
improved cognitive function [45].
It is impossible to resurrect dead brain cells, so there is no hope of curing advanced AD.
However, the above experiment raises the strong possibility that if early stage AD were to be
stopped and the Aβ plaques eliminated, then people may be able to experience improved
cognitive ability, just as was shown for the mice. This would enable people to relearn what was
lost due to the early stage AD. The fact that knocking out the β-secretase gene in transgenic mice
had such good results suggests that a drug that blocked β-secretase activity might be useful in
treating AD in humans. However, some Aβ appears to be necessary for proper brain function [6].
Since T downregulates β-secretase activity, a sufficiently high level of free T may result in the
removal of Aβ plaques while still retaining enough Aβ for proper brain function. More research
is needed in this area.
There can be no doubt that a sufficiently high level of T will prevent AD in men [25].
However, is it safe for men to maintain the long-term high levels of T necessary to prevent AD?
It is known that the risks of administering T to men are potentially causing too much E2 and too
many red blood cells [46]. Both of these conditions can be easily monitored and treated. There
has been a claim that T increases the risks of heart attacks and strokes in men [47], but the
methodology used in this study has been refuted by researchers from Harvard, with 29
professional societies demanding that this article be retracted [48]. In fact, the latest evidence
shows that T is extremely effective in preventing heart attacks and strokes in men whose starting
T is 350 ng/dL or less [49]. T is also very useful in treating men after they have suffered a heart
attack [50]. Also, the risk of further strokes for hypogonadal men who have suffered an ischemic
stroke has been shown to be greatly reduced by T [51].
While some doctors may have some concern that T may cause prostate cancer (PCa) in
men, T is only the secondary cause of PCa. The primary cause is high local levels of E2 within
the epithelial cells of the prostate [52]. In fact, T seems to be beneficial against early stage PCa.
A 12-year study of hypogonadal men showed that those men who received T had a 2.7% rate of
PCa vs. 8.9% for those men who did not receive T, with none of the treated men being diagnosed
with PCa after the first 18 months [53]. The percentage of men with occult PCa tumors should
have been roughly the same in both groups. This means that for the men treated with T who did
not develop PCa, at best, T killed all of the PCa present and at worst, T slowed down the growth
rate of the occult PCa tumors to such an extent that they never grew large enough to be detected.
This finding in no way disputes the fact that the absence of T is capable of killing most PCa. The
absence of T and the presence of high T kill PCa using different mechanisms [54].
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It remains to be determined what is the maximum level of T that can safely be used in
men. Because it is known that too high a level of E2 or too high a hematocrit level is dangerous
[46], experiments must be done with increasing levels of T while monitoring and controlling E2
and hematocrit levels in order to determine how dangerous T itself is. For example, it is known
that T worsens sleep apnea in some men [55], but it is not known whether this is due to the
increased level of T or the increased level of E2. In this study both the T and E2 levels increased
2 to 3-fold. The authors assumed that T was the sole cause for the results they observed, but they
did nothing to rule out E2 in spite of the fact that for severely obese men, the severity of
obstructive sleep apnea is inversely proportional to their free T level [56].
Once it is proven that superphysiological high levels of T can be safely administered to
men, then it may be possible to stop early stage AD in men. Assuming the effect of T on men is
similar to its effect on transgenic male mice, then their cognitive ability may even be improved
after the progression of AD is halted. If it turns out to be necessary to incorporate an aromatase
inhibitor to maximize the effect of high T, then this would have the added benefit of preventing
the formation of PCa in any men who do not already have any PCa cells within them. This is
because initiation of PCa requires high E2 local levels [52], not normal E2 local levels, so it is
not necessary to totally inhibit aromatase in order to prevent PCa. It remains to be seen how
beneficial this combination of T accompanied by an aromatase inhibitor would be on other health
issues, such as metabolic syndrome, heart attacks, and strokes. The effects of different amounts
of aromatase inhibitor would have to be tested if that combination is in fact very effective.
Ideally, it should be possible to maintain a level of E2 that is still above the clinically low level
of E2 which is less than 20 pg/mL [57].
While it is clear that high enough levels of T should prevent and possibly halt the
progression of AD in men, using such high levels long term in women is not feasible due to the
masculinizing effects of T. However, it is possible AD may be prevented in women by using a
combination of T, estrogen, and P4. High enough levels may even stop the progression of early
stage AD.
It has been demonstrated that T serum levels as high as 299 ng/dL can be safely used in
women. This level even significantly reduced the risk of breast cancer [58]. A study involving
lean elderly women showed that the free androgenization index (FAI) was 0.377 for those
women with AD as opposed to 1.163 for those women without AD [59]. Clearly low free T
levels increase women’s risk of developing AD. The more than 3-fold difference in the FAI is
especially striking.
The fact that ER-β is protective against AD for females [42,43] raises the question about
what effect ER-α has on AD. Since E2 binds equally well to ER-α and ER-β [60], all of the AD
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experiments involving E2 should be redone with estriol (E3) used as well. E3 binds to ER-α ~9
times more weakly than E2 does and binds to ER-β ~3 times more weakly than E2 does [60].
However, in spite of the weaker binding of E3 to both estrogen receptors, E3 was shown to be
more effective than E2 in preventing Aβ aggregation, which is a critical event in the formation of
AD [61]. This article offers a valuable inference. Since E3 is more effective than E2, it must be
because of the ER-β: ER-α binding strength ratio. In the case of E2, the ratio is 1:1, whereas in
the case of E3 the ratio is 3.2:1 [60]. Since ER-β has been shown to be effective in combating
AD [43], the reason that E3 is more effective than E2 must be because ER-α counteracts the
beneficial effects of ER- β to some extent. Therefore, if exogenous estrogen is to be used in
preventing or treating AD, it makes sense to use E3 instead of E2.
The case for using P4 in a cyclic manner is very compelling [10]. The 10 high days in a
row of P4 every 30 days roughly approximates the behavior of P4 in women’s menstrual cycle
[62]. Would maintaining young adult levels of T, estrogen, and P4 result in women never
developing AD? Long term studies would have to be done to answer this question. However, it is
possible that as women age, they would need higher levels of T than they had as young adults in
order to maximize its effect in preventing AD. “In addition to testosterone, the androgen
precursors dehydroepiandrosterone sulfate (DHEAS) and androstenedione, found in much
greater concentrations (up to 103-fold) than testosterone, also decline with age. We have found
that higher serum levels of testosterone (supplied by the implant) are necessary to provide
adequate amounts of testosterone to the AR, replacing not only testosterone but also the
significant contributions of DHEAS and androstenedione to bioavailable testosterone [63].”
All of the evidence indicates that hormones counteract the biological processes associated
with AD, however, for the most part, researchers are not pursuing this avenue of treatment. In
men, this may be due to unwarranted fears that T will increases the risk of prostate cancer, heart
attack, and stroke. There are also unwarranted fears that hormones are too dangerous to
administer to women. One example of this is an article by the Women’s Health Initiative (WHI)
published in 2002 which showed that administering conjugated equine estrogens plus progestin
to 8506 postmenopausal women for 5.2 years increased their risk of chronic heart disease by
29%, of breast cancer by 26%, of stroke by 41%, and of pulmonary embolism by 113% [64].
Another article by the WHI published in 2003 showed that administering conjugated equine
estrogens plus progestin to 4532 healthy women aged 65 years of age or older for 5.6 years
resulted in increasing their rate of probable dementia by 105% with AD being the most common
classification [65]. Most doctors and medical researchers took these findings to mean that
hormone replacement was too dangerous to give to women and especially dangerous for women
over 65 because of more than doubling their risk of AD. However, a different study found that
postmenopausal women who took bioidentical estrogen and P4 for 8.1 years had the same rate of
breast cancer as those women who took no hormones [66]. In order to understand these findings,
it is important to look at the biochemistry of the hormones involved. The WHI study used
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medroxyprogesterone acetate (MPA) instead of P4. At the doses that MPA was used in the WHI
study, MPA would block the intracellular androgen receptor by 80-95% [67]. The authors stated
“We propose that the observed excess of breast malignancies associated with combined HRT
may be explained, in part, by synthetic progestins such as MPA acting as endocrine disruptors to
negate the protective effects of androgen signaling in the breast.” Since androgen signaling also
helps prevent the biological processes associated with AD, this also explains why combined
HRT with MPA increased the rate of dementia by 105% for women 65 years of age or older
[65]. Since T levels in women drop as they age [63], blocking the intracellular androgen receptor
by 80-95% will be more likely to produce an artificial state of T deficiency the older the woman
is. It should also be noted that conjugated equine estrogen contains no estriol [68], which makes
it less likely to be helpful in preventing AD.
Conclusion
There is no question that diet can help prevent AD. However, there is no evidence that
diet alone is sufficient to totally prevent AD in transgenic mice. The case for using hormones to
prevent AD is much more convincing, but there is no reason not to utilize the MIND diet in
addition to administering hormones, especially in individuals with genetic mutations that make
them more prone to develop AD. It also makes sense to minimize exposure to air pollution.
In men, the role of T in preventing AD is extremely convincing. The direct correlation
between low free T levels and the increased risk of developing AD is very striking [25]. The
research in male transgenic mice was remarkable since when the transgenic mice were treated in
such a way as to have superphysiological high levels of T, not only did they have no symptoms
of AD, but their memories were better than those of normal mice [11]. If the results of the mouse
study can be carried over to men, then not only would superphysiological high levels of T along
with an aromatase inhibitor be a protocol for preventing AD, but it quite possibly could halt the
progression of AD for those men who already have it.
In women, since it is not feasible to use just high levels of T to prevent AD, estrogen and
P4 must also be incorporated. Because of the powerful effect of ER-β in preventing the
symptoms of AD [43], until such time as there is an FDA approved drug that binds specifically
to ER-β, E3 is the most likely form of estrogen to help prevent AD. Therefore, the most likely
protocol for preventing AD in women and possibly halting the progression of early stage AD is
superphysiological high levels of T accompanied by an aromatase inhibitor, superphysiological
high levels of E3, and cyclic use of P4 in which high, or even superphysiological high, levels are
achieved 10 days in a row every 30 days.
More research is needed in order to optimize the protocols for using hormones to prevent
and treat AD in men and women. It is unfortunate that claims of great harm attributed to
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hormone use in both men and women were made and widely propagated by the mainstream
media. The recent articles proving that the proper use of hormones is not just safe, but in fact
beneficial has been ignored by the mainstream media. As a result, too many doctors, researchers,
and even the general public have an unwarranted fear of hormones which is interfering with the
research necessary to discover the dosages needed to put an end to AD.
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