Alzheimer disease (AD) is a devastating neurodegenerative disorder. In the United States, approximately 6.5 million people aged 65 years and older are living with AD and nearly two-thirds of them are women.1 It can have particularly devastating ripple effects on caregivers; in 2021, more than 11 million unpaid caregivers provided nearly 16 billion hours of care valued at $271.6 billion to individuals with AD.1
With no known cure for AD, many studies are examining preventative measures, such as the use of estrogen hormone therapy (EHT). Because estrogen facilitates cognitive function and declines during menopause,2 researchers have investigated a possible causal relationship between estrogen deficiency and the onset of AD. Natural menopause is defined as 12 consecutive months of unintentional amenorrhea and has an average age of onset of 51 years.2 Perimenopause describes the time leading up to menopause.2 For most other hormone-deficient diseases, such as hypothyroidism, the treatment is hormone replacement.
When administered during menopause, EHT could improve cognitive function and potentially prevent the development of AD. This timing is important. The risks and benefits of postmenopausal EHT have been a controversial topic since the Women’s Health Initiative (WHI) study was stopped prematurely due to the incidence of breast cancer and cardiovascular disease.3 Unfortunately, because the publication was based on incomplete statistics, many of the findings of this study were presented as more substantial than the actual data support.4
Many of the risks associated with EHT reported in the Women’s Health Initiative (WHI) study are not seen if therapy is started early in menopause. In addition, the WHI study only evaluated synthetic conjugated equine estrogens,3 and participants were up to 15 years postmenopausal, therefore they were without pre-menopausal levels of estrogen and progesterone for a long enough period of time to develop cardiovascular disease and osteoporosis, for example.4 In recent studies, EHT started near the onset of menopause and/or at age 60 years or younger was safe and decreased all-cause mortality.5 This timeframe presents an opportunity to possibly prevent age-related cognitive decline in women.6
Alzheimer Disease
Epidemiology
As noted, AD disproportionately affects women. Because AD pathology precedes clinical manifestations by decades, this higher risk cannot be accounted for by the longer lifespan of women compared with men.6 Early-onset AD, which occurs before age 65, is rare and has been associated with an autosomal dominant inheritance pattern. In people aged 65 years and older, AD is the fifth-leading cause of death.1 From 2000 to 2019, the mortality rate for AD increased by more than 145%, while the number of deaths from heart disease and stroke decreased.1
Pathophysiology
The exact etiology of AD is unknown. Certain risk factors have been identified, such as advancing age, female sex, and a first-degree relative who has had AD.1 The presence of the e4 form of the apolipoprotein E (APOE-e4) gene has been associated with an increased risk for AD.1 Recent studies have also suggested an inflammatory pathway in AD, which might be triggered by chronic fungal, bacterial, or viral infections.7
Physiologic changes in the brain that occur with AD include atrophy and abnormal deposition of beta-amyloid and tau proteins.1 Beta-amyloid protein forms clumps outside the neurons (plaques), and tau protein forms clumps inside the neurons (neurofibrillary tangles).1 These changes cause devastating neuronal dysfunction that manifests clinically as memory loss, progressive cognitive decline, and ultimately, death.1
Diagnosis
The diagnosis of AD is made via a detailed clinical assessment of the patient, including cognitive function, after alternative diagnoses have been excluded. Abnormal levels of beta-amyloid and tau proteins can be identified in cerebrospinal fluid and by positron emission tomography imaging,1 however, these studies are not routinely done due to their invasiveness and cost. A definitive diagnosis of AD can be made post-mortem at autopsy by identifying the hallmark brain changes of plaques and neurofibrillary tangles.
Estrogen
Role in Cognitive Function
The vast estrogen receptor network in the brain controls brain energy metabolism and many other systems.6 Estradiol, the most physiologically important type of estrogen,2 enhances brain function in several ways such as by improving neuronal growth and protecting neurons from injury.8 Several brain areas that are essential for memory and learning, such as the prefrontal cortex and amygdala, have a significant number of estrogen receptors and rely on estrogen availability for proper functioning.6
Deficiency
During perimenopause, estrogen levels fluctuate unpredictably; in menopause, they decline steadily. When estradiol levels decrease, fundamental cellular changes occur in the brain. These include reductions in dendritic spines, synaptic density, and the number of synapses present.2 The regulation of brain glucose metabolism by estrogen dissipates, creating a hypometabolic state.6 These physiologic changes result in “brain fog” characterized by poor concentration and memory problems.9 Although these transformations typically reverse with menopause,9 they illustrate the undesirable effects of estrogen deficiency on cognition. The duration of time without estrogen also matters. Studies have shown that a woman who enters surgical menopause at a younger age has a higher rate of cognitive decline and AD-related pathology.2
Estrogen Hormone Therapy
Cognitive Benefits
The beneficial effects of EHT on the brain have been well documented. Boyle et al described increased gray and white matter volume in women who had a history of oral estrogen use, including synthetic conjugated equine estrogens, as measured using structural magnetic resonance imaging.10 The Cache County Study found that women using EHT had a decreased incidence of AD compared with those who did not use EHT, and the longest use of EHT (>10 years) reduced the risk for AD the most.11
In contrast, other studies have shown that EHT does not decrease the risk for AD. For example, no cognitive benefits were observed in patients taking EHT despite neuroimaging results showing reductions in both biomarkers for brain aging and the deposition of the beta-amyloid protein.9 In addition, although patients with the APOE-e4 gene are at increased risk for AD, one study suggests that this population has the fastest cognitive decline when taking EHT.9
Timing
Many pathologic changes that occur with AD begin years before the patient develops clinical symptoms.2 Therefore, if EHT is considered, it should be initiated well before the onset of cognitive decline. Studies have suggested that the most beneficial time to start EHT is at or near the onset of menopause.6 EHT also has protective effects against cardiovascular disease when started during this timeframe.12
Considerations
Despite the relationship between estrogen and cognitive function, data for the role of EHT in neuroprotection are inconclusive.9 Currently, the American College of Obstetricians and Gynecologists and the North American Menopause Society do not support its use as primary prevention of cognitive dysfunction,13,14 and the International Menopause Society guidelines cite a lack of evidence to support this use.15 One of the limitations of previous studies, such as the landmark WHI Memory Study,16 is that they included postmenopausal women older than 65 years of age. The studies also did not consider the window of opportunity to begin estrogen replacement at or near the onset of menopause. Further research is needed to explore the potential benefits of administering estrogen during this time frame.
Risks
The decision to start EHT should be individualized for each patient. Hormone therapy should be avoided in those with contraindications, such as a history of estrogen-dependent cancer, thromboembolic events, or a blood clotting disorder. A progestin or progesterone should be given with estrogen if the patient has not had a hysterectomy, as unopposed estrogen can cause endometrial hyperplasia and potentially endometrial cancer.14
Conclusion
Alzheimer disease has a greater incidence in women; therefore, research studies have focused on the beneficial role of estrogen in cognition and the potential of EHT to prevent AD. Some evidence suggests that a window of opportunity exists for EHT initiation at or near the onset of menopause when this therapy is safe and could have neuroprotective effects. Further research is needed to determine factors such as efficacy, dosing, route of administration, and duration of treatment.
This article originally appeared on Clinical Advisor
References:
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