Does Hormone Therapy Increase or Decrease Alzheimer’s Dementia Risk?

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The data regarding the risk of Alzheimer’s dementia for women taking hormones is nuanced and sometimes contradictory. Fortunately, there are emerging, useful data and important considerations to help guide clinicians when working with menopausal patients.

In 2023, there were several studies published in prestigious medical journals describing a potential increased risk of developing dementia and Alzheimer’s disease (AD) in women who received menopausal hormone therapy (MHT). This included a Danish nested case-control study in BMJ and a cross-sectional study from Wisconsin published in JAMA Neurology.

Also published in 2023 in the journal Frontiers of Aging Neuroscience was a review of six randomized clinical trials (RCTs) and 45 observational reports. That analysis found that the RCTs involving postmenopausal women aged 65 and older showed an increased risk of dementia with hormone therapy compared to placebo; however, the observational studies featuring women on hormone therapy younger than age 60 indicated a 32 percent reduced risk of all-cause dementia.

Another 2023 study published in Alzheimer’s Research & Therapy used data from participants in the European Prevention of Alzheimer’s Dementia cohort and found that early use of hormone therapy improved brain function and volume in high-risk women who were APOE4 carriers. This is consistent with a 2015 randomized controlled trial published in Neurology featuring women aged 42 to 56 who utilized hormone therapy within five to 36 months of their last menstrual period that found an increase in brain volume and white matter hypersensitivity compared to placebo.

Hormone therapy’s beneficial cognitive role makes sense from a mechanistic standpoint. According to a 2022 review in Frontiers in Aging Neuroscience, estrogen plays a significant role in regulating hippocampal learning and memory, and its decline in menopausal women can increase the risk of memory loss and neurodegenerative diseases. In addition to cognition, estrogen influences mood and sleep via its interactions with the cholinergic and dopaminergic systems, as well as its influence on brain mitochondrial function. However, it appears that the timing of estrogen replacement is critical if hormone therapy is to be beneficial versus detrimental.

Therapeutic Window of Opportunity

Over the past decade, research looking at the critical window hypothesis of hormone therapy and cognition has grown considerably. These latest 2023 studies seem to confirm that the positive cognitive benefits of hormone therapy are dependent on the timing and occur if treatment is initiated within the first five years of menopause.

What’s the clinical conclusion? The most important aspect of the research to date is that it identifies a therapeutic window in which initiation of hormone therapy can benefit cognition. 

The 2022 position statement from the North American Menopause Society (NAMS) is a key resource when it comes to hormone therapy, which states that hormone therapy may be harmful to memory and cognition when initiated in women aged 65 or older and beneficial to women if initiated within five years of the last menstrual period. According to NAMS, women experience menopause between age 40 and 58, with the average being 51.

The Women’s Health Initiative Memory Study found that when hormone therapy was initiated in women aged 65 or older, there was a doubling of all-cause dementia, which confirms that timing is everything. According to NAMS, two nested case-control studies showed no increased risk overall but did suggest an increased risk of AD with the use of estrogen-progesterone therapy for more than five years.

NAMS goes on to state that when hormonal therapy is initiated immediately after hysterectomy with bilateral oophorectomy versus during the natural postmenopausal period, it can have beneficial cognitive effects. While hormone therapy is presently not indicated to prevent or treat cognitive decline, it may play an important role in women who have a first-degree relative who has had or has AD if the therapy is started within that five-year window. Hormone therapy should not be used if the patient already has dementia.

In addition to NAMS, all international organizations support the use of MHT for short periods, usually three to five years, at the lowest possible estrogen dose to accomplish the desired goals, whether that is symptom relief or osteoporosis risk reduction.

NAMS does state that continuing hormone therapy for longer than five years may be needed in select populations, such as a woman under the age of 52 who has had a bilateral oophorectomy or history of premature ovarian insufficiency. Women using hormone therapy as a treatment for osteoporosis or those who find it to be the only solution to their symptom management may also need to use the therapy for a longer period.

An Integrative Approach

It’s important to start with a comprehensive history and medical evaluation, including a deep dive into the patient’s general health, symptom severity/duration, family health history, individual medical history, and risk of specific health conditions, including dementia. The patient’s priorities, values, fears, and other factors can also be considered to help create an individualized treatment plan.

Integrative practitioners have many tools and strategies to help patients feel better and be more comfortable as they go through menopause, in addition to disease prevention and risk reduction, including:

  • Diet, exercise, and stress management advice
  • Nutritional supplements
  • Botanical extracts
  • Hormones from natural substances
  • Compounded bio-identical hormones
  • Pharmaceutical bio-identical hormones
  • Synthetic, conventional hormones
  • Other prescription and over-the-counter medications

Before considering MHT, practitioners should rule out any potential contraindications and cautions, as well as evaluate cardiovascular, AD, osteoporosis, and breast cancer risk in particular.

If systemic MHT is indicated and if the uterus is present, estrogen, along with the appropriate dose of progesterone, is typically prescribed. If there is no uterus, then estrogen alone is sufficient for most women.

If the patient is within the therapeutic window and hormone therapy is an option, practitioners should consider these factors:

  • Dose and type of estrogen
  • Type of progestogen 
  • Estrogen alone or with progestogen
  • Route of administration
  • Duration of hormone therapy

Regarding progestogens, transdermal absorption of progesterone is erratic, and progesterone cream is insufficient for endometrial protection. Most organizations, including NAMS, recommend micronized progesterone.

The clinical bottom line is to evaluate the benefits versus the risks for each patient. Menopause symptoms can be very uncomfortable for some women and can significantly and negatively impact the patient’s quality of life. That’s why it’s important to utilize a comprehensive, integrative approach that explores all options, which may include systemic MHT if initiated during that therapeutic window.

About the Expert

Tori Hudson, ND, graduated from the National University of Naturopathic Medicine (NUNM) in 1984 and has served the college in several capacities. She is currently a clinical professor at NUNM, Southwest College of Naturopathic Medicine, and Bastyr University. Hudson is the medical director of A Woman’s Time in Portland, Oregon, and director of product research and education for VITANICA. She is the founder and co-director of the Naturopathic Education and Research Consortium (NERC), a nonprofit organization for accredited naturopathic residencies. Hudson is a faculty member of the Fellowship in Integrative Health & Medicine, Academy of Integrative Health & Medicine. Dr. Hudson is a nationally recognized author, and her latest book is The Menopause Companion (2023).