1. Review
Involvement of Luteinizing Hormone
in Alzheimer Disease Development
in Elderly Women
C. V. Rao, PhD1,2,3
Abstract
Alzheimer disease (AD) is a slow progressive neurodegenerative disease that affects more elderly women than elderly men. It
impairs memory, typically progresses into multidomain cognitive decline that destroys the quality of life, and ultimately leads to
death. About 5.3 million older Americans are now living with this disease, and this number is projected to rise to 14 million by
2050. Annual health-care costs in the United States alone are projected to increase to about US$1.1 trillion by 2050. The initial
theory that decreasing estrogen levels leads to AD development in postmenopausal women has been proven inconclusive. For
example, Women’s Health Research Initiative Memory Study and the population-based nested case–control study have failed to
demonstrate that estrogen/progesterone (hormone replacement therapy [HRT]) or estrogen replacement therapy could prevent
the cognitive decline or reduce the risk of AD. This led to the realization that AD development could be due to a progressive
increase in luteinizing hormone (LH) levels in postmenopausal women. Accordingly, a large number of studies have demonstrated
that an increase in LH levels is positively correlated with neuropathological, behavioral, and cognitive changes in AD. In addition,
LH has been shown to promote amyloidogenic pathway of precursor protein metabolism and deposition of amyloid b plaques in
the hippocampus, a region involved in AD. Cognate receptors that mediate LH effects are abundantly expressed in the hippo-
campus. Reducing the LH levels by treatment with gonadotropin-releasing hormone agonists could provide therapeutic benefits.
Despite these advances, many questions remain and require further research.
Keywords
Alzheimer disease, luteinizing hormone, estrogens, androgens, LH/hCG receptors, Ab plaques, neurofibrillary tangles
Introduction
Alzheimer disease (AD) is a neurodegenerative disease that
primarily affects elderly women.1-3
The disease progression
is exceedingly slow and can take decades before the symptoms
appear and a clinical diagnosis can be made.1-3
Dementia,
which is a decline in cognitive ability and memory loss, is the
hallmark feature of AD.1-3
It accounts for more dementias than
from any other illnesses, including vascular etiologies. The
distinction between them often made by an expert neurolo-
gist.1-3
Since some of the AD symptoms overlap with those
due to other neurodegenerative diseases and even from taking
certain medications, careful clinical history and neurological
examination are important for AD diagnosis.1,3
The risk factors, which can influence each person differ-
ently, include family history, genetics, heart disease, stroke,
high blood pressure, dyslipidemia, low levels of vitamin folate,
and so on.1-3,4
Obesity and type 2 diabetes increase the risk 3.0-
and 1.5-fold, respectively.1-3,5,6
Only 1% of all cases with AD
are inherited.1-3
There are risk (apolipoprotein E4) and deter-
ministic (amyloid precursor protein [APP], presenilin 1 and 2)
AD genes.7,8
The mutations in deterministic genes cause a rare
form of the disease.7,8
Healthy weight maintenance, prevention of type 2 diabetes,
exercise, and drinking coffee and red wine in moderation
appear to reduce the risks of AD.1-3
Being physically and men-
tally active and engaging in social activities can delay the onset
and slow the progression of AD.1-3
There are no simple diag-
nostic tests.1-3
Position emission tomography (PET), spinal
taps to determine brain amyloid b (Ab) levels, and brain
1
Department of Cellular Biology and Pharmacology, Reproduction and
Development Program, Herbert Wertheim College of Medicine, Florida
International University, Miami, FL, USA
2
Department of Molecular and Human Genetics, Reproduction and
Development Program, Herbert Wertheim College of Medicine, Florida
International University, Miami, FL, USA
3
Department of Obstetrics and Gynecology, Reproduction and Development
Program, Herbert Wertheim College of Medicine, Florida International
University, Miami, FL, USA
Corresponding Author:
C. V. Rao, Departments of Cellular Biology and Pharmacology, Molecular
and Human Genetics, and Obstetrics and Gynecology, Reproduction and
Development Program, Herbert Wertheim College of Medicine, Florida
International University, Miami, FL 33199, USA.
Email: crao@fiu.edu
Reproductive Sciences
1-14
ª The Author(s) 2016
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DOI: 10.1177/1933719116658705
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2. imaging can be helpful in the diagnosis of AD.1-3
These tests
are expensive and not widely available. Therefore, blood
biomarker-based tests, which detect Ab, are being developed.
However, unequivocal diagnosis can only be made at
autopsy.1-3,9
The incidence of AD is higher among older African and
Hispanic than Caucasian Americans.10
The total number of
cases with AD is increasing each year in the United States, due
to an increase in life expectancy from better health care and the
number of people surviving into their 80s, 90s, and beyond.
There are mild, moderate, and severe forms of the disease.1-3
Although individuals with mild AD can live up to 25 years, the
ones with severe AD typically live for only 5 years.1-3
In severe
form of AD, most of the cortex is severely damaged and brain
dramatically shrinks due to widespread cell death.1-3
Alzhei-
mer disease is one of the top 10 leading causes of death in the
United States, sixth leading cause of death among adults, and
fifth leading cause of death among 65- to 85-year-old people.1-3
Alzheimer disease is a very expensive disease. For exam-
ple, US$226 billion is estimated to cost for AD care in the
United States in 2015.11
These costs do not include unpaid
care given by family members and friends, which is roughly
estimated to be 18 billion hours or about US$218 billion.3
Living with AD is extremely difficult because of pain, suffer-
ing, loss of individuals’ dignity, financial setbacks, disruption
of families, among others.1-3
Amyloid Plaques and Neurofibrillary Tangles
The deposition of Ab protein plaques and formation of neuro-
fibrillary tangles of hyperphosphorylated tau proteins in the
hippocampus and frontal cortex are hallmark features of
AD.12-15
The plaques are formed due to an imbalance between
the production and the clearance of Ab from the brain.12,13
The
plaques are rather inert and its Ab aggregates promote synaptic
dysfunction, disrupt mitochondrial activity, induce cascades of
generation of free radicals, cause oxidative damage, increase
tau phosphorylation, impair receptor signaling, Ca2þ
homeos-
tasis, induce membrane depolarization, proinflammatory
changes, and so on.12,13
The neurofibrillary tangles consist of
intraneuronal paired helical filaments of hyperphosphorylated
tau protein. These tau proteins contain more phosphorylation
sites and have a higher molecular weight than the normal tau
protein.14,16
The tangles interfere with protein and nutrient
traffic in neurons.1-3,16,17
Plaques and tangles can also cause
an immune response and work synergistically to promote neu-
rodegeneration in the brain.12-16
Amyloid bs are formed from APP, a single-pass transmem-
brane protein, with a large extracellular domain and a small
cytoplasmic tail.17
Amyloid bs are formed by the sequential
cleavage at the N-terminal domain by b-secretase, resulting in
shedding of APP ectodomain.18
Then, g secretase cleaves
membrane-associated APP C-terminus domain, releasing Ab
molecules.18
There are 2 forms of Ab molecules, Ab1-40 and
Ab1-42.18
They are sticky, but Ab1-42 is more neurotoxic
because it aggregates much more rapidly, which facilitate
further deposition of Ab molecules.18
The Ab plaques can be
cleared from the brain by efflux, phagocytosis, and enzyme
degradation by neprilysin and insulin-degrading enzyme (pre-
ferential toward insulin).12,13
Neurofibrillary tangles, on the
other hand, can disappear due to dissolution.16
Neuroprotective agents, such as estrogens and androgens,
promote nonamyloidgenic pathway of APP metabolism in
which a-secretase cleaves within Ab domain of APP, prevent-
ing the formation of Ab molecules and releasing neuroprotec-
tive a-APP fragments.18-20
The neurotoxic agents, such as
luteinizing hormone (LH)/human chorionic gonadotropin
(hCG), promote amyloidogenic pathway of APP metabolism
in which Abs are formed.21,22
The mutations in deterministic
genes result in the overproduction and deposition of Ab
molecules.7,8
Paradigm Shift on the Actions of LH/hCG
Luteinizing hormone and hCG are structural and functional
homologs that are secreted by anterior pituitary gland and
human placenta, respectively.23
They belong to glycoprotein
and cystine-knot growth factor families.23,24
The latter super-
family includes nerve growth factor (NGF).24
Luteinizing hor-
mone and hCG bind to the same cell surface G-protein-coupled
receptors, which are different from the NGF receptors.25,26
According to the old paradigm, LH/hCG receptors are only
present in gonads and LH/hCG can only regulate gonadal
functions. The paradigm shift has changed this dogma.27
It
has revealed that functional LH/hCG receptors are also pres-
ent in central and peripheral (spinal cord and adrenal pheo-
chromocytoma cells, which have an embryological origin
with neural crest) nervous systems among the other nongona-
dal tissues.28-30
The LH/hCG receptors have been demonstrated in fetal rat
brain and in adult rat, mouse, bovine, and human brains.28,31,32
In fetal rat brains, receptors have been found in diencephalon,
mesencephalon, rhombencephalon, and telencephalon.31
The
receptors are present in neurons as well as in the glial cells.33,34
The neuronal receptors are involved in neurite outgrowth and
their survival.33
The glial cell receptors are involved in the
regulation of prostaglandins (PGs) synthesis, which influence
cell proliferation.34
The sum of all the LH actions can contrib-
ute to growth, development, and differentiation of fetal brains.
Adult brain receptors have been well characterized. The
receptors were found in hippocampus; dentate gyrus; cerebel-
lum; cerebral cortex; hypothalamus; preoptic area; anterior
pituitary; choroid plexus; ependymal cells of third, fourth, and
lateral ventricles; pineal gland; and brain stem, with the highest
levels in rat hippocampus.28,30,32,35
Unlike adults, fetal hippo-
campus does not contain higher receptor levels than the other
brain areas.31
The receptors were also detected in primary as well as in
immortalized cells, such as hypothalamic GT1-7 neurons, a-T3
anterior pituitary gonadotropins, HN33p hippocampal neurons,
and so on.36-40
The receptor promoter usage appears to be the
same among these cells.41
However, the transacting protein
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3. levels are different, which may explain the receptor level dif-
ferences among the cells.41
The functional relevance of adult brain LH/hCG receptors
has been investigated by primary GnRH and hippocampal neu-
rons as well as by GT1-7, a-T3, and human M17 neuroblas-
toma cells. In primary and in GT1-7 cells, hCG inhibited the
release of gonadotropin-releasing hormone (GnRH).36,38
This
inhibition was due to a decrease in the transcription of GnRH
gene in GT1-7 neurons.36
The mechanisms involved downre-
gulation of GnRH receptor gene by decreasing the stability of
the transcripts and induction of a 95-kDa transacting protein,
which binds to AT-rich sequence (À91 to À81 base pair) in the
50
-flanking region of GnRH gene promoter.36,39,42
The induc-
tion preceded by an activation of cyclic AMP (cyclic AMP
[cAMP])/protein kinase A (PKA) signaling and increase in
protein synthesis, phosphor-CREB, c-Fos, and c-Jun lev-
els.38,43
Dimer conformation of the hormone and the receptor
presence are required for the LH/hCG actions.36
These findings
support the presence of short-loop negative feedback mechan-
ism in which some of the LH released from anterior pituitary
gets back into portal circulation to reach hypothalamus to inhi-
bit GnRH release.44-47
The LH/hCG treatment of a-T3 cells resulted in a dose- and
time-dependent and hormone-specific increase in gonadotropin
a-subunit levels.37,48
As expected, GnRH treatment also
increased the gonadotropin-a subunit levels.48
Both LH and
GnRH are synergistic, however, they differed in their mechan-
ism of action. Thus, while LH acted to increase the stability of
gonadotropin-a subunit transcripts, GnRH increased not only
the stability of transcripts but also the transcription of the
gene.48
The LH actions in a-T3 cells suggest that LH promotes
its own synthesis by an ultra-short-loop positive feedback
mechanism, and several previous studies have shown its exis-
tence.44-47
A similar mechanism has been found for hCG synth-
esis in human placenta.49
The neuronal receptors are colocalized with cytochrome
P450 side-chain cleavage enzyme (P450scc).32
The LH/hCG
receptor activation results in a 2-fold increase in pregneno-
lone secretion and an increase in steroidogenic acute regula-
tory protein expression in rat primary hippocampal neurons
and in human M17 neuroblastoma cells.50,51
These findings
suggest that LH and hCG are capable of increasing mitochon-
drial cholesterol transport and its subsequent cleavage by
P450 scc. Thus, LH/hCG can induce steroid production just
as in the gonads.
As peripheral macrophages,52-54
central nervous system
(CNS) macrophages, that is, glial cells, also contain LH/hCG
receptors.34,55
Their activation results in an increase in induci-
ble nitric oxide synthesis, mediated by tumor necrosis factor
a.55
Glial cells can also synthesize PGs and neurosteroids.34,50
Luteinizing hormone/hCG can stimulate glial cell synthesis of
PGs, and whether they can also regulate the synthesis of neu-
rosteroids is unknown.34
The hippocampal receptors are involved in behavioral reg-
ulation.56-61
Thus, central and peripheral injection of hCG
resulted in several behavioral changes, which include:
a. decrease in taste neophobia,61
b. increase in non-rapid eye movement sleep (NREM),
with no effect on rem (REM) sleep,61
c. decrease in exploratory and increase in resting beha-
viors,60,61
and
d. decrease in active awake phase, walking, sniffing, and
chewing.60
The behavioral changes are similar regardless of the route of
injection.61
About 1% of peripherally injected hCG can cross
blood barrier and reach cerebrospinal fluid and hippocampus in
an intact form.61
Some of the above behavioral changes were
considered typical of human pregnancy. Thus, pregnancy-
specific behaviors are likely mediated by the increasing hCG
levels during the first half of pregnancy.
The behavioral hCG effects are blocked by coadministration of
indomethacin.60
Moreover, hCG treatment increased prostaglandin
D2 (PGD2) and decreased prostaglandin E2 (PGE2) synthesis.60
Treatment of hippocampal HN33p cells resulted in a modest dose-
and time-dependent and hormone-specific increase in 5-
lipoxygenase levels.40
These findings support that the products of
arachidonic acid metabolism mediate the behavioral effects of hCG.
Neural retina, which is an extension of CNS, also contains
LH/hCG receptors.62,63
The receptor transcript levels are sim-
ilar between retina and cerebral cortex.62
Photoreceptor cells
contained the highest receptor levels, followed by a gradual
decline through inner retinal layers.62
The findings support the
previously suspected LH/hCG role in visual processing and in
pathological eye conditions.64,65
Different cells in gray and white matter of spinal cord con-
tain LH/hCG receptors.29
The receptors seem to mediate the
neurotropic effects of hCG.66
Thus, hCG-treated rats showed a
possible functional recovery and physiological communication
across the spinal cord injured site.67
It is possible that not only the hippocampal LH/hCG recep-
tors but also those in the other brain areas could somehow be
involved in the complex pathogenesis of AD. Further research
is required to verify and extend this possibility.
Evidence Implicating LH in AD Development
in Elderly Women
Estrogens are neuroprotective.68-70
This protection comes from a
host of different mechanisms such as reducing the neuronal loss
andcerebral ischemia,stimulatingaxonal sprouting,dendrite spine
formation,andpromotingnonamyloidgenicpathwayofAPPmeta-
bolism.19,68-73
In addition, estrogens levels are positively corre-
lated with cognitive performance. Their replacement in women
with cognitive impairment results in an improvement.74-100
Spatial
memory decreases in ovariectomized rats, but estrogen treatment
reversesit.101,102
These findingssuggest that HRT and ERT should
preventcognitivedeclineinwomenwhohadanovarianfailure ora
natural age-dependent decline in ovarian activity. However,
the results of clinical testing were inconclusive.74-100
This could
be due to a number of different reasons, and one of them could
be the recipient’s age when the treatment began.
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4. The Women’s Health Research Initiative Memory Study
(WHIMS) is ancillary to Women’s Health Initiative (WHI)
on hormone therapy trials. From 39 of 40 WHI clinical centers,
the WHIMS recruited 4894 eligible women (aged 65 years or
older) free of dementia.103,104
They were either placed on HRT
(n ¼ 2229) or on placebo (n ¼ 2303). Global cognitive function
was measured annually.103,104
The results revealed that HRT
did not improve cognitive function when compared with pla-
cebo group.103,104
Moreover, a subset of women showed a
small increased risk of cognitive decline.103
Another study,
population-based nested control, revealed that ERT did not
reduce AD risk in 112 481 women as compared with a similar
number of cohorts who did not use the therapy.105
The studies
of this size can be expected to have some uncontrolled vari-
ables, which could possibly undermine their conclusions. Nev-
ertheless, the bottom line of the studies is that neither HRT nor
ERT could prevent cognitive decline or AD development in
older women.103-105
The results led to a critical period hypoth-
esis as well as initiated a search for other hormonal causes for
AD development.
According to the critical period hypothesis, while HRT
started immediately after menopause could have worked, it
becomes detrimental with time delay.106,107
In fact, HRT was
administered more than 5 years after the menopause onset in
about 36% of women.103,104
The time delay effect can perhaps
be explained by neurological damage, which increases with an
advancing age of patients with AD.
Concerning the other hormonal basis for AD develop-
ment, it is well known that ovarian function declines with
age, which results in a decrease in estrogen levels and an
increase in LH levels, due to a loss of negative feedback
mechanism by estrogens.108,109
Therefore, the consequence
of estrogens decrease is an increase in LH and/or follicle-
stimulating hormone (FSH) levels. However, this possibil-
ity received almost no attention until the discovery of hip-
pocampal LH/hCG receptors, greater elevation in LH
levels in women with AD, and direct LH effects on cogni-
tion and biochemical changes typical of AD. The role of
FSH is unknown even though its synthesis and receptors
have been demonstrated in rat hippocampus.110
Further
studies are now required to test the possibility of FSH invol-
vement in AD.
There were a now many reports demonstrating the role of
LH in AD development. These are:
– Epidemiological studies have shown that higher LH lev-
els parallel an increase in AD risk.4,111
– Circulating LH levels are more than doubled in postme-
nopausal women who have developed AD than the
cohorts who did not develop the disease or in non-AD
patients with cognitive deficits.112,113
– Ovariectomy causes an elevation in Ab levels in cere-
brospinal fluid and hippocampus.114
– The reduction in LH levels improves cognition,
decreases Ab levels in mouse brain, and prevents mem-
ory loss in neurotoxin-induced AD model.21,115-118
– Similar reduction in LH levels in AD models results in a
decrease in cognitive deficits.114-116,119
– Blocking LH synthesis improves cognition in an intact
AD Tg 2516 mice.116
– Overexpression of LH impairs memory in a mouse AD
model.120
– Elevated LH levels correlate with an increased AD risk
and progression, cognitive decline, and increased Ab
levels.112,113,120-124
– Alzheimer disease brains have a strong immunoreactive
LH than the control brains. Moreover, LH accumulates
in pyramidal neurons of AD brains compared with the
age-matched normal brains.121
– Direct exposure of guinea pig brain to LH results in
altered Ab levels.125
– Luteinizing hormone promotes amyloidogenic pathway
of APP metabolism, Ab secretion, and its deposition in
the aging brain.21
– Human chorionic gonadotropin increases b-secretase
activity in a dose-dependent manner.22
The hCG admin-
istration leads to an increase in Ab40 accumulation and
cognitive deficits in a mouse model of AD.22,126,127
– The same hCG treatment applied even to ovariecto-
mized rats results in the disruption of spatial mem-
ory and increase in soluble Ab1-40 and Ab1-42
levels.126
– Treatment of AD transgenic mice with gonadotropin
releasing hormone analog (GnRHA) decreases Ab
deposition and improves working memory.120
– The GnRH analogs (GnRHa) treatment results in a 3.5-
fold reduction in Ab1-42 and 1.5-fold reduction in Ab1-
40 levels and improved cognition in the absence of any
changes in estrogen receptors (ERs) a and b, cyto-
chrome P450 119, and StAR levels.21,115
– The GnRHa treatment, but not HRT, improved hippo-
campal spatial memory in 3xTg AD female mice in an
advanced stages of the disease.119,120
– The GnRHa treatment upregulates the pathways associ-
ated with a cognition improvement such as Ca2+
/calmo-
dulin-dependent protein kinase 1 (CAMK 1), glutamate
receptor 1 serine residue831 (GluR1Ser831). Estrogens,
on the other hand, had no effect.115,119
– Ablation of LH actions through inactivation of LH/hCG
receptor gene resulted in a reduced Ab accumulation,
plaque formation, and improvement in neuropathologic
features in mouse model of APPSWþ
/LHrÀ
.128
– Infants from Down syndrome pregnancies, who had an
in utero exposure to high hCG levels, have an increased
prevalence and an early onset of AD.129-131
Luteinizing Hormone Actions in the Peripheral Organs
That Can Potentially Contribute to the AD Development
Ovaries, adrenal glands, adipose tissue, and pancreas also
contain functional LH/hCG receptors.132-136
The LH
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5. actions in them could potentially contribute to AD devel-
opment in postmenopausal women through further eleva-
tion in LH levels. The LH elevation comes from the
estrogen formation from the androgen precursors, which
then positively feedback on hypothalamic–pituitary axis to
release even more LH (Figure 1).
The involvement of ovaries is related to the LH stimulation
of stromal cell luteinization and their secretion of andro-
gens.137,138
The adrenal involvement is related to the LH sti-
mulation of zona fasciculate to secrete androgens.139-141
Adipose tissue involvement is related to an aromatization of
ovarian and adrenal-derived androgens.142-144
As obesity is one of the risk factors for the AD devel-
opment, it is possible that LH-induced risk involves its fat
deposition property.134
For example, LH can stimulate cell
proliferation, differentiation, and leptin secretion from pre-
adipocytes.134
These actions are mediated by cAMP-/PKA-
independent mitogen-activated protein kinase (MAPK)/
c-Fos signaling.134
Obesity decreases sex steroid–binding
globulin, which results in an increase in circulating free
estradiol levels.145
The free estradiol is a powerful stimu-
lus for bioactive LH release from the anterior pituitary.146
The involvement of the pancreas is related to the LH stimu-
lation of pancreatic b-cells to release more insulin.135
The
increased insulin levels can stimulate proliferation and luteini-
zation of ovarian stromal cells, their secretion of androgens,
and aromatization in adipose tissue.145,147
The impact of per-
ipheral insulin on CNS actions is not known.
The sum of all the LH actions in peripheral organs can result
in further elevation in LH levels in postmenopausal women
who develop AD as compared with cohorts who do not develop
the disease. It is not just the elevation in LH levels alone that
can cause AD development, as not all postmenopausal women
will develop the disease. The subset of women who develop
AD must have other predisposing genetic, epigenetic, environ-
mental, lifestyle risk factors, and so on. This reasoning should
not be surprising as AD, like most other diseases, has multi-
factorial etiology.
Can the Other Conditions of Elevated LH/hCG Lead
to AD Development in Women?
Short-term LH elevations, such as preovulatory surges, are not
likely to lead to AD development, not only because of its
Brain
Ovaries AdrenalsPancreas
Adipose
Ɵssue
LH
LH
Androgens AndrogensInilusn
Estrogens
LH
Figure 1. The proposed model of luteinizing hormone (LH) involvement in the development of Alzheimer disease (AD) in elderly women. In
this model, LH released from anterior pituitary gland gets back to hippocampus to promote amyloidogenic pathway of amyloid precursor
protein (APP) metabolism (line thickness denotes the primary action). Secondarily, LH can also act on peripheral tissues either to increase
androgens secretion or insulin release. The androgens are then aromatized into estrogens in adipose tissue, which positively feedback to release
more LH. Endogenously produced brain LH may also have a role in the disease process, but this remains to be further investigated.
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6. shorter duration of elevation but also due to concomitant
increase in estrogen levels, which are neuroprotective.19,68-70
Similarly, pregnancy may also not lead to the AD development,
even though hCG levels are elevated for a longer duration,
because estrogen levels are also elevated to a greater degree
at the same time. These predictions should be further ver-
ified by epidemiological studies on AD incidence in women
who have incessantly ovulated, like nuns, as compared with
those who had interrupted cycles due to pregnancy. Similar
information can come from comparing women who had
multiple pregnancies with those who had fewer pregnancies
during their lifetime.
The AD incidence in other elevated LH/hCG states, such as
polycystic ovarian syndrome (PCOS) and pituitary and placental
(gestational trophoblastic neoplasms) tumors that secrete exces-
sive amounts of LH and hCG, respectively, in the absence of
concomitant increase in estrogen levels, is unknown. However,
there are leads for women with PCOS. There are reports on
women with PCOS having long-term health consequences
including cognitive decline and altered brain microstruc-
ture.148-150
Furtheraffirmationcancome fromretrospectivechart
reviews of the patients. The possibility of AD incidence in rare
cases,suchasinactivating andactivating LH/hCGreceptormuta-
tions, can also be obtained by the reviews of patient charts.
Infants born from Down syndrome pregnancies seem to
develop AD at younger ages.129-131
This is presumably due
to intrauterine exposure to high maternal hCG levels. However,
whether the same high hCG levels can influence AD develop-
ment in the mother is not known. But it is not likely because of
a concomitant elevation in estrogen levels in the mother.
Potential Mechanisms of LH Actions in AD
The following scenarios can be envisioned from what is already
known about the LH/hCG actions in neurons, glial cells, and in
the other somatic cells.27,30,33,34,36-40,42,48,50,51,55
The LH actions can be nongenomic and genomic. In both
cases, initial cell surface receptor binding is required. The
binding results in an activation of second messenger signaling
systems such as cAMP/PKA, protein kinase C (PKC), MAPK,
and so on.
The second messengers can then mediate the nongenomic
actions such as alterations in protein phosphorylation and ion
flux changes. The phosphorylation may include secretases,
other enzymes, proteins associated with APP metabolism
toward the amyloidogenic pathway, hyperphosphorylation of
abnormal tau proteins, and so on.
The chronic actions may require genomic changes, where
activated kinases, directly and indirectly, affect the transacting
factors, which could either increase or decrease the transcrip-
tion of genes. However, the identity of these genes is unknown
for the most part.
The LH actions may also include influencing the stability of
preexisting transcripts, their translation efficiency, and post-
translational modifications of proteins. These changes could
involve both nongenomic and/or genomic mechanisms.
In the above scenarios, the molecular details are not known.
Obviously, a great deal of further research is required to fill the
knowledge gaps to better understand how LH/hCG acts, which
could reveal new therapeutic targets.
Further Research to Answer Some
Important Questions on AD in Elderly
Women
The AD development in elderly women is due to physiological
hormonal changes that are associated with aging. Since not all
women going through these changes will develop AD, others
such as genetic, epigenetic, environmental, lifestyle factors,
and so on, must also be required. The identity of them remains
elusive, and only further research can reveal them. Even though
AD is a terrible disease and deaths from it are increasing rela-
tive to cancer and heart disease, AD research funding (US$660
millions) pales by comparison with cancer (US$5.4 billion) and
heart disease (US$1.2 billion).151
This disparity must somehow
be reconciled in order to make the necessary scientific
advances to conquer AD.
Part of the further research should focus on answering the
following fundamental questions.
a. Does age alter brain’s response to estrogens and LH?
b. What role, if any, FSH plays in AD development?
c. The brain can also make estrogens and LH.152-160
The
question then are:
1. What role do the brain-derived hormones play in
AD development in contrast to those that come
from periphery?
2. Is there a relationship between peripheral and brain
levels of estrogens and LH?
3. Do high estrogens suppress brain LH signaling dur-
ing premenopausal period and that this suppression
somehow is lost in an age-dependent manner dur-
ing postmenopausal years? If so, why and how the
suppression mechanisms are lost during aging.
d. What molecular mechanisms are involved in the neuro-
protective role of estrogens?
e. Luteinizing hormone/hCG do not seem to be neurotoxic
when estrogen levels are high. How does the falling
estrogen levels trigger/enhance the development of neu-
rotoxicity of LH?
f. What are the critical genetic and nongenetic factors that
work in concert with LH in AD development?
g. Does LH regulate brain’s insulin synthesis as it does in
the pancreas?
Role of Testosterone (T) and LH in AD
Development in Elderly Men
Elderly men account for about one-third of total cases with
AD.1,2
This gender difference could partly be due to a higher
mortality from atherosclerosis, cardiovascular disease, and so
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7. on, among them, as compared with elderly women. The other
reason could be hormonal changes. For example, age-
dependent hormonal changes are different in elderly men as
compared with elderly women. Thus, elderly men have gradual
increase and lower peak LH levels as compared with elderly
women.161-167
Moreover, the decrease in serum T levels is
gradual as compared with faster and greater decrease in estro-
gens in elderly women.161,163,164,166-168
It is also possible that
the brain sensitivity to androgens is maintained in elderly men,
whereas the estrogen sensitivity dramatically decreases in
elderly women. Elderly men also have an increased androgen
resistance and what role this might play is unknown.18
Inter-
estingly, the gender difference is even seen in APP transgenic
mice. Thus, male mice have a lower brain Ab deposition than
female mice.169
It is possible that both decreasing T levels and increasing
LH levels are involved in AD development in elderly men.18
However, it is not clear whether T is secondary to LH and vice
versa or both work in concert in reciprocal manner.18,170-178
In
support of the LH involvement, increase in its levels results in
neuropathological and cognitive changes characteristic of AD,
reducing its levels in male gonadectomized mice, causing cog-
nitive benefits, and LH/hCG receptor variant reduces AD risk
in men.18,171,175-179
The risk of death in men with AD decreases
when they are placed on GnRHa therapy for prostate cancer.180
The GnRHa treatment works in elderly men, with variable
results just as in elderly women with AD.18
Multiple lines of evidence suggest that T is neuroprotective
and decrease in its levels leads to neuropathological and beha-
vioral changes that are the hallmark of AD.20,181-183
The evi-
dence includes:
– Testosterone levels are positively associated with cogni-
tion in elderly men.184
– The AD development increases as the T levels decline
during aging.170
– The men with AD have a lower T levels, low T levels are
an independent risk factor for AD, and T deprivation
increases the future AD risk.99,112,184
– Testosterone levels are negatively associated and LH
levels are positively associated with the brain Ab
deposition during early stages (mild cognitive impair-
ment) and presymptomatic phase of AD (subjective
memory complemers).177
– The T therapy works in hypogonadal men with AD.185
– Men who have undergone chemical castration have
increased Ab levels.171,186,187
– Men with AD have reduced brain T levels.188
– Declining T levels is a risk factor for AD.183,188,189
– Testosterone levels are inversely correlated with Ab
levels.171,176,187
– Testosterone has distinct effects on plasma and cere-
brospinal fluid levels of Ab protein.189,190
– Testosterone decreases neuronal Ab secretion.20,174
– Testosterone decreases Ab toxicity in cultured hippo-
campal cells.18,191
– Testosterone improves neuronal viability, synaptic
plasticity, cognition, and reduce AD pathology
treatment.173,184,192,193
– Gonadectomy increases Ab levels, and reducing LH
levels improves cognition.176,178
– Androgen depletion in transgenic mice increases brain
Ab deposition and impairs hippocampal-dependent
behavioral performance.175
– Testosterone regulates the development of AD neuro-
pathology in mice model of AD.194,195
– T lowers Ab levels in a 3x Tg-D male mice.18
The studies on whether T conversion to E is necessary in AD
are inconclusive.18,196
Regardless, the findings suggest that T
replacement should work for the treatment of elderly men with
AD. However, the results are contradictory, which is eerily
similar to the results of HRT or ERT in women with AD.18
If
both T decline and LH rise are independently involved in AD
development, perhaps a better approach will be to combine T
replacement with GnRHa in the treatment of elderly men. This
possibility requires clinical verification. Since T replacement
therapy may increase prostate cancer and cardiovascular
risks, it can be replaced with selective androgen receptor
modulators.18,197
Currently Approved Treatments for AD
There are 6 Food and Drug Administration (FDA)-approved
prescription drugs for the treatment of AD symptoms.198
Four
are acetylcholinesterase inhibitors and they are sold under
brand names of Aricept, Razadyne, Exelon, and Cognex.198
The first 3 are commonly prescribed, and Cognex is rarely
prescribed because of the side effects, including liver dam-
age.198
They all work by increasing acetylcholine, a neuro-
transmitter required for memory, judgment, and thought
processes.198
The fifth is Namenda (brand name), which blocks
N-methyl-D-aspartate (NMDA) receptors, thus protect neurons
from an excess glutamate.198
The sixth one Namzaric, a com-
bination of Aricept and Namenda (brand name Namzaric), is
indicated for patients with moderate to severe disease.198
Acet-
ylcholinesterase inhibitors are indicated either for all stages
(Aricept) or only for those with mild to moderate disease
(Razadyne and Exelon). All the drugs are rather well tolerated.
They cannot, however, reverse the disease or stop further
destruction of the nerve cells. Thus, their effectiveness
decreases as the nerve cell damage increases.198
Finally, there is an antiepileptic drug, Levetiracetam, which
has been tested in patients with dementia at 12 times the lower
dose than that used in epileptics.199
It works by decreasing the
hippocampal neuronal overactivity.199,200
The FDA has
recently approved it for phase III clinical trials.199
There are several new drugs in pipeline that decrease the Ab
production, inhibit its aggregation, or increase its clearance.201
They are MK-8931, which block the b-secretase activity,198
and Solanezumab, a monoclonal antibody, which binds Ab,
Rao 7
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8. prevent the formation of new plaques and carry excess Ab
away from the brain.198
Abnormal form of tau protein can collapse and twist into
tangles, which destroy microtubules and ultimately neu-
rons.14,16
AADvac1 is a vaccine that stimulates the body’s
immune system to attack an abnormal tau protein.198
Microglia
act as a first line of immune defense in the brain and it helps
clear Ab from the brain. CSP-1103, a microglial modulator, is
being evaluated for AD therapy.
Insulin is required for brain health.6,202,203
Part of the brain
insulin is locally synthesized, and the rest comes from periph-
eral circulation.203-206
Insulin activates its brain receptors to
regulate hippocampal metabolism, memory formation, and so
on.203,207
In type 2 diabetes, hippocampal Ab accumulation
increases, and this increase prevents insulin binding to its
receptors, resulting in insulin resistance and exacerbation of
neurodegeneration.202,203,205
Therefore, nasal insulin adminis-
tration is being evaluated to increase brain insulin signaling.198
Future Therapeutic Possibilities
The involvement of LH in AD development in postmenopausal
women offers an obvious therapeutic approach of reducing its
levels by treatment with GnRHa. There are several studies
demonstrating the therapeutic benefit of GnRHa treatment.208
However, a recent phase 2 48-week, double-blind, and placebo-
controlled clinical study on 109 women aged 65 years or older,
with mild to moderate AD, with low- or high-dose GnRHa
(Lupron), showed no benefit especially with a low dose.209
The
high dose, on the other hand, showed statistically nonsignifi-
cant trend of benefit.209
The individuals in the high-dose group,
who are already taking acetylcholinesterase inhibitor, showed a
statistically significant improvement.209
This is likely to be due
to the differences in their mechanism of action. More such
combination therapies and with varying doses need to be tested
to determine whether therapeutic efficiency can be further
improved.
The failure of Lupron treatment alone is not the last verdict,
because most of the other previous clinical trials of AD drugs
on people with dementia diagnosis have failed, presumably due
to prior irreversible brain damage, small sample size, and host
of other factors such as dose, route, duration of treatment, and
so on. Since the treatment failures are common, one should
consider starting the therapies on individuals who have a strong
family history and/or at high risk, as determined by PET, spinal
taps, or brain scans, or even at the onset of early warning signs
such as memory loss, confusion, frequent falling, disorienta-
tion, inability to comprehend, and complete the simple tasks.
The other therapeutic possibilities include developing even
more potent GnRHa, LH/hCG receptor inhibitors, and LH/hCG
receptor gene silencers that can be selectively directed to hip-
pocampus and frontal cortex. Multipronged therapeutic
approaches that prevent further destruction of nerve cells and
also reverse pathological biochemical changes will be optimal
to combat AD. It is estimated that any therapy that can delay
AD progression even by 5 years could reduce the disease
prevalence by 40% and saves over US$300 billion for the
US economy.199
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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