Endocrine Dyscrasia in the Etiology and Therapy of Alzheimer's Disease.

Some of the most compelling data demonstrating the importance of hormone balance within the HPG axis for maintaining cognitive health comes from human clinical trials. The suppression of gonadotropins is one therapeutic strategy that could prevent and halt the progression of AD. Fortunately, agents to suppress gonadotropin secretion and signaling already exist in the form of GnRH analogues. 112 These analogues lower circulating LH and FSH concentrations. In this respect, a Phase II clinical trial premised on much of the above evidence showed that the GnRH analogue leuprolide acetate (Lupron Depot; 22.5 mg) when taken together with an acetylcholinesterase inhibitor, stabilized cognitive performance in post-menopausal women with mild to moderate AD over a one year period. 34 A similar result using GnRH analogues was reported for men being treated for prostate cancer. 113 GnRH agonists have a well-defined safety profile and no differences in adverse events were found between treatment and placebo arms in the Lupron Depot clinical trial. 34 For treatment long-term such as in AD, leuprolide in the form of Lupron Depot (i.m.) or Eligard (s.c.) are convenient options and the 22.5 mg dose was found more efficacious than the 11.25 mg dose. The use of these analogues in hypogonadal post-menopause women obviates the need for add-back sex steroid therapy. GnRH analogues have been used for decades to treat conditions such as prostate cancer in men, endometriosis and uterine leiomyoma in women, precocious puberty in children, the suppression of spontaneous ovulation as part of controlled ovarian hyperstimulation during in vitro fertilization and many off-label uses. 114 The many GnRH analogues in the form of GnRH agonists and GnRH antagonists are well-reviewed for structure and function by Millar and Newton. 115 Clinically, GnRH analogues come in multiple forms that can be administered via depot implants, pellets, nasal spray, and infusion pump, for varying dosages that span from 1 day up to 12-months. A follow-up trial – the LUCINDA Trial (LeUprolide+Cholinergic Inhibition to reduce Neurologic Decline in Alzheimer’s; ClinicalTrials.gov Identifier: NCT03649724 ) using Eligard ® is currently ongoing 116 and is expected to be complete in 2026. FDA-approved GnRH analogues represent a quick and safe option for a disease modifying treatment to reach the burgeoning AD population. Rebalancing of the HPG axis with 17β-estradiol replacement therapies (which results in the lowering of circulating gonadotropins) have shown mostly modest, or no, cognitive benefits in post-menopausal women with and without AD. 117 – 126 Similar results have been reported with the use of testosterone in men. 127 , 128 In studies of 17β-estradiol treatment in women with AD where circulating LH and/or FSH have been measured, 122 , 126 17β-estradiol treatment (50 μg transdermal daily) for 3 months or 48 months was shown to decrease circulating LH by ~45%, 122 and LH and FSH by 25 and 30%, 126 respectively. However, only the Wharton study, 122 demonstrated favorable cognitive effects, which were found across multiple cognitive domains, including visual memory and semantic memory in post-menopausal women with AD. While the Wharton study 122 reduced LH to reproductive adult levels, the Kling study 126 did not reduce LH or FSH to reproductive adult levels. These data suggest that sufficient 17β-estradiol and testosterone dosages and long-term attenuation of signaling may be required in order to elicit sufficient negative feedback on the HP to suppress circulating gonadotropins and improve cognitive performance. 122 , 126 Interestingly, women who underwent a bilateral oophorectomy and were treated with 17β-estradiol maintained cognitive abilities and brain structure compared to untreated women. 70 , 75

A significant body of basic, epidemiological and clinical data supports hypothalamic-pituitary-gonadal (HPG) hormones as regulating embryonic, fetal and neonatal brain development and the maintenance of cognitive function during the reproductive phase of adult life. 3 – 5 It is perhaps not surprising then that the dysregulation of the HPG axis (endocrine dyscrasia) with menopause and andropause prevents the maintenance of brain structure and function, and leads to neurodegeneration and cognitive dysfunction associated with AD and Parkinson’s disease (PD) later in life. 6 – 9 Endocrine dyscrasia is associated with a significant decrease in circulating sex steroids and other gonadal protein sex hormones like inhibin B and AMH, but significant increases in elevated luteinizing hormone (LH), follicle-stimulating hormone (FSH), and gonadotropin-releasing hormone (GnRH) secretion and signaling. 10 Evidence is accumulating that the elevations in circulating gonadotropin hormones post-menopause, and with andropause, as a result of the loss of negative feedback by gonadal-produced hormones on the hypothalamus and pituitary, leads to altered neuronal signaling, the aberrant re-entry of neurons into the cell cycle and subsequent neurodegeneration. 7 , 11 In particular, in vitro , animal, epidemiological and human studies link increases in pituitary gonadotropins to the biochemical, neuropathological (amyloid-β deposition, neurofibrillary tangles, endoreduplication) and cognitive changes associated with AD and cerebrovascular diseases. This review collates these data, together with emerging data that indicates rebalancing the HPG axis can provide treatment options for this disease. It should be noted that while epidemiological and biological data also links endocrine dyscrasia to PD and vascular changes, biochemical and epidemiological data linking other mixed AD histopathologies such as those involving synucleinopathies and age-related TDP-43 encephalopathy have yet to be reported.

Over the last two decades considerable evidence has been published indicating that the endocrine dyscrasia associated with menopause and andropause is key to the development of cognitive decline and AD. Irrespective of the underlying mechanisms by which endocrine dyscrasia promotes cognitive impairment, strategies to rebalance the HPG axis offer the most promise for finding treatments for these conditions. The pre-clinical, epidemiological, and clinical evidence supporting GnRH analogues and the dual suppression of both LH and FSH, as a treatment for AD cannot be overlooked. Repurposing GnRH analogues to treat AD, as in the LUCINDA Trial, 116 comes with the advantage that these drugs can reach the public more quickly, safely and at lower cost than entirely new drugs.

Dementia accounts for ~3% of deaths in the USA, of which 46.4% of dementia deaths are attributed to Alzheimer’s disease (AD); 38.9% of dementia deaths are attributed to unspecified dementia; 8.5% to other degenerative diseases of nervous system, not elsewhere classified; and 6.2% to vascular dementia. 1 The majority of these dementia cases are age-related, as illustrated by the fact that 33.3% of people aged 85 and older have AD. 2 An estimated 6.7 million individuals in the USA live with AD, which is the fifth-leading cause of death among Americans aged 65 and older.

Numerous in vitro and preclinical animal studies demonstrate that elevated LH induces amyloid-β production, AD neuropathology and cognitive decline 12 – 24 while lowering LH by a variety of methods including GnRH analogue treatment reverses and prevents AD protein deposition, hippocampal dysfunction and cognitive decline in animals. 7 , 13 , 15 , 17 , 18 , 20 , 22 , 23 , 25 – 31 The role of elevated gonadotropins in inducing the biochemical and pathological changes associated with AD is further supported by recent animal studies demonstrating that elevations in FSH correlate with AD neuropathology and cognitive decline in an AD mouse model, 32 while the blockade of FSH signaling prevented these age-related neuropathological changes and cognitive decline. Contrary to these findings, a previous study using FSH receptor knockout (FORKO) chimeric mice carrying two transgenes expressing the amyloid-β precursor protein (AβPPsw, Swedish mutation) and presenilin-1 lacking exon 9 (PS1Δ9), demonstrated larger and more diffuse plaques than the double transgenic (AβPPsw/PS1Δ9) model, in addition to significant hypertrophy and activation of microglia and astrocytes. 33 Interestingly, FORKO females exhibit hypergonadotropic-hypogonadism with high levels of circulating FSH and LH, placing the culpability for the observed AD neuropathology on the shoulders of LH (and perhaps GnRH). Confirmation of the role of FSH in more appropriate models of cognitive decline, such as non-transgenic aged animals, would go a long way to clarifying the importance of FSH in AD pathogenesis. Nonetheless, these papers are important additions to an already significant body of evidence accumulated over the last two decades indicating that the age-related elevation in circulating gonadotropins is strongly associated with the etiology of AD. 34 Although reproductive endocrine dyscrasia results from the loss of gonadal sex steroid and sex protein hormone production at menopause and with andropause in men, evidence supports the elevation in gonadotropins rather than the loss of gonadal sex steroids as the primary driver of AD pathology and cognitive decline and includes: 1) the lowering of brain amyloid-β with a GnRH-agonist in intact mice; 13 2) prevention of ovariectomy-induced AD neuropathology and cognitive decline in rodents treated with agents that lower both gonadotropins and sex steroids; 15 , 17 , 20 , 25 , 30 , 31 , 35 , 36 and 3) the 50% decrease in AD in men with prostate cancer 37 treated with gonadotrophin-lowering agents. 38 Supporting a role for LH signaling in AD, an LHCGR intronic variant has been shown to be significantly associated with decreased risk of AD in males carrying an apolipoprotein E ε 4 ( APOE ε 4) allele. 39 Endocrine dyscrasia also is associated with cerebrovascular changes associated with AD, vascular hemorrhage, and encephalitis. 40 , 41 Castration of rodents induces changes in the selective permeability of the blood-brain barrier, 42 changes that are likely due to elevation in the gonadotropin:sex steroid ratio as: 1) an increase in connexin-43 expression in the mouse brain following ovariectomy was suppressed in ovariectomized animals treated with leuprolide acetate, 42 2) human chorionic gonadotropin (hCG), the fetal equivalent of LH, regulates angiogenesis-vessel maturation by stimulating perivascular cell recruitment, migration, and proliferation, and by inference must be involved in vascular compliance, 43 and 3) hCG regulates tissue remodeling by increasing matrix metalloproteinase-9 production. 44 , 45 The changes in vascular structure induced by age-related endocrine dyscrasia are likely to promote amyloidosis, since amyloid-β has barrier functions. 46 – 48 Thus, the endocrine dyscrasia associated with aging likely plays a pivotal role in the alterations in vascular structure and function observed in the aging brain, stroke, vascular dementia, and AD. A number of mechanistic pathways have been proposed for gonadotropin-induced neurodegeneration, including direct effects of LH on hippocampus 22 that lead to upregulation of γ-secretase 13 and C/EBPβ–δ-secretase 32 , 49 pathways, amyloid-β deposition, tau phosphorylation 50 and the stimulation of terminally differentiated neurons to re-enter the cell cycle resulting in cell cycle arrest and apoptosis (reviewed in Atwood and Bowen 7 ). In addition, administration of GnRH analogues has been shown to reduce neurodegeneration by compensating for inflammation-induced loss of hypothalamic GnRH neurons. 51 Endocrine dyscrasia provides a very plausible explanation for the development of late-onset AD in post-menopausal and andropausal individuals via dysregulated hormonal signaling that leads to aberrant cell cycle re-entry of neurons. But what about the 1–2% of individuals that develop early-onset AD? In this regard, the currently identified EOAD genes (AβPP, PS1 and PS2) also have been shown to drive aberrant cell cycle re-entry of neurons. 52 A detailed mechanistic explanation of how gene mutations in these developmental genes (AβPP, PS1, and PS2) induce early onset-AD has previously been outlined. 53

A large number of epidemiological studies support the association (timing and magnitude) of endocrine dyscrasia (elevated pituitary gonadotropins, low gonadal sex steroids and protein sex hormones) with the development of cognitive decline and AD. These data are highlighted in the 73 studies referenced below and include: 1) the increased prevalence of cognitive disease in women compared with men, which correlates with the abrupt earlier loss of gonadal function; 2 , 54 – 58 ; 2) the increased risk of dementia, mild cognitive impairment (MCI), and brain structural abnormalities in men, and in premenopausal women who undergo a bilateral gonadectomy, 59 – 76 but not in women who underwent a bilateral oophorectomy after the commencement of natural menopause (i.e., gonadotropins already high, steroids already low; 69 , 77 with the exception of one study). 76 Among women undergoing surgical menopause, a younger age at surgery is associated with faster decline in global cognition, semantic and episodic memory, worse performance in verbal fluency and executive function, and accumulation of Alzheimer’s neuropathology; 69 3) the increased risk of dementia in premenopausal women with spontaneous premature menopause (premature ovarian failure before age 40 60 , 65 , 76 or earlier menopause (<47 years 60 , 73 , 76 , 78 )); 4) the decreased incidence of cognitive changes and dementia in women with later menopause; 73 , 76 , 79 – 81 5) the protection against cognitive changes with older age at menarche; 81 6) the abrupt cognitive deficits observed in premenopausal women and men following chemical castration (with GnRH agonists), deficits that are reversible with simultaneous administration of 17β-estradiol in women; 82 – 90 7) a decrease in the incidence of dementia in women with a history of oral contraceptive use; 73 , 81 , 91 , 92 8) a decreased risk of AD in post-menopausal women with chronic kidney disease related cognitive dysfunction who were taking hormone replacement therapy; 93 9) the negative correlation between serum 17β-estradiol in women 94 and testosterone in men 11 , 95 – 98 with AD, but positive correlation between serum gonadotropins in men and women with AD 11 , 95 , 97 – 105 and men and women with cognitive impairment with PD; 8 , 9 and 10) the 50% decrease in the prevalence of AD in men following treatment with GnRH agonists, 13 , 37 , 38 although other studies have shown either no change 71 , 106 – 108 and one study has shown an increase in AD risk with GnRH agonists. 109 Studies that have correlated gonadotropins with biomarkers of AD and PD include: 1) the association of increased serum LH concentration, rather than lower serum free testosterone, with the accumulation of Aβ in plasma of elderly men; 103 2) in subjective memory complainers, LH is positively correlated with plasma A levels, while an increased frequency of the APOE ε 4 allele and increasing serum LH levels have a significant impact on Pittsburgh compound B retention; 110 3) FSH and LH are correlated with Aβ 42/40 ratio in men and women with cognitive impairment with PD; 8 , 9 4) studies in women have suggested that elevations in FSH are associated with the development of AD neuropathology and cognitive changes. 111 In women with earlier menopause, higher circulating FSH concentrations were associated with significant subcortical volumetric loss in the left amygdala and right amygdala, more recognizable climacteric and depressive symptoms, decreased quality of sleep, and decreased working memory and executive functions. FSH levels also were correlated to lower working memory accuracy and longer working memory reaction time. 111 While numerous studies indicate that elevated gonadotropin concentrations confer an increased risk for developing dementia (see above), contrasting effects of LH and FSH have been reported in older post-menopausal women, 102 where high plasma concentrations of FSH, but not LH, were associated with improved Cambridge Cognition Examination (CAMCOG) scores, with the impact of FSH-associated improvement in CAMCOG being greater in older women. Taken together, these data strongly support an earlier induction of endocrine dyscrasia in women and men as leading to an earlier onset and increased risk of cognitive decline, MCI and AD. Conversely, maintenance of hormone balance within the HPG axis delays cognitive decline and decreases the risk of MCI and AD. From a therapeutic perspective, these data provide logical pathways to treat cognitive decline, MCI, and AD.