Hormone therapy and Alzheimer’s: a complex relationship

Alzheimer’s disease, a debilitating neurodegenerative disorder, is a growing concern worldwide. Women are more likely to develop Alzheimer’s than men, with nearly two-thirds of Americans with Alzheimer’s being women.

This disparity has led scientists to investigate the role of hormones — particularly estrogen — in the development and progression of Alzheimer’s disease. A number of theories have been proposed to try to explain it:

Greater lifetime vascular risk: women tend to live longer than men, which increases their lifetime vascular risk. Vascular risk factors such as hypertension, diabetes, and obesity have been associated with a higher risk of Alzheimer’s. Women are disproportionately at risk for dementia when these conditions are present.
Stress of pregnancy: pregnancy, particularly multiple pregnancies, can lead to long-term changes in the body, including increased stress levels and changes in metabolism, which could potentially increase the risk of Alzheimer’s.
Lower education: lower levels of education have been associated with a higher risk of Alzheimer’s disease. Historically, women have been given less educational opportunities than men, particularly a couple of generations ago. And so, this could be a risk factor which contributes to the higher prevalence of Alzheimer’s in women, especially in older demographics.
Less physical activity: physical activity has been shown to have neuroprotective effects and reduce the risk of Alzheimer’s disease. Studies have shown that, due to a range of socioeconomic reasons, women — particularly older women — are statistically less physically active than men, which could potentially increase their risk of Alzheimer’s disease.
Hormonal changes: women undergo significant hormonal changes throughout their lives, particularly during pregnancy and menopause. These changes — especially the decrease in estrogen levels after menopause — have been suggested to increase the risk of Alzheimer’s disease. The role of estrogen in the brain is complex and multifaceted, and it is thought to have neuroprotective effects.
Genetics: certain genetic factors may also contribute to the higher risk of Alzheimer’s in women. Carrying the Apo-E4 allele, for example, is a well-known genetic risk factor for Alzheimer’s, and women are statistically more likely to be carriers.

Again, it’s important to note that these are — at the time of writing — just theories; further research and scientific method is needed before they can be considered citable reasons for the higher prevalence of Alzheimer’s disease among women.

The relationship between Alzheimer’s disease and hormone replacement therapy

An area of research that’s recently gotten a lot attention is hormone replacement therapy (HRT), a common treatment for menopausal symptoms in women. The findings so far, however, have been surprisingly contradictory.

One study involving postmenopausal women who had undergone a common form of HRT called estrogen-progestin therapy found a significant increase in the risk of developing Alzheimer’s disease, proportional to the duration of HRT use.

Women who had used HRT for a year or less had a 21% increased risk of developing Alzheimer’s, indicated by a hazard ratio of 1.21.
Alarmingly, this risk escalated to a 74% increased risk for women who had used HRT for more than 12 years, marked by a hazard ratio of 1.74.
This study also found that the risk of developing dementia was positively associated with both continuous and cyclic estrogen-progestin therapy, with an increased risk of 31% and 24% respectively.
This increased risk was consistent even in women who had started the treatment at 55 years of age or younger.
When the researchers narrowed down their focus to late-onset dementia and Alzheimer’s disease specifically, the findings remained consistent: a 21% increased risk for late-onset dementia and a 22% increased risk for Alzheimer’s disease.

These findings are particularly notable considering the widespread use of HRT among postmenopausal women.

Contradictions and confounding factors

However, it’s important to note that these results do not necessarily imply a direct causal relationship between HRT and Alzheimer’s disease. Further research is needed, as there could have been confounding factors that influenced the results.

Potential misleading factors (confounds) may include: the age at which women started HRT; the type of hormones used; and the duration of the therapy. For instance, some studies suggest that starting HRT closer to menopause may have protective effects against Alzheimer’s.

So, what’s the contradiction? Findings from other studies suggest that HRT — especially estrogen therapy — may actually have a protective effect against Alzheimer’s. These studies propose that estrogen may help maintain cognitive function and delay the onset of Alzheimer’s symptoms.

Science is an ever-correcting fine-tuning process. As we gather more data and develop better research methodologies, our understanding of complex issues like the relationship between hormone replacement therapies and Alzheimer’s evolves.

Until we have a firmer understanding, it’s recommended that women make informed decisions about HRT in consultation with their healthcare providers. Each woman’s unique situation — including her menopausal symptoms, overall health, and personal and family medical history — should be taken into account when deciding whether to start or continue HRT.

As research and clinical trials continue, we can hope for more definitive answers that will guide healthcare decisions and eventually lead to new strategies for preventing and treating Alzheimer’s disease.

References

Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimer’s Dement. 2021;17(3):327-406.
Imtiaz B, et al. Postmenopausal hormone therapy and Alzheimer disease: A prospective cohort study. Neurology. 2017;88(11):1062-1068.
Savolainen-Peltonen H, et al. Use of postmenopausal hormone therapy and risk of Alzheimer’s disease in Finland: nationwide case-control study. BMJ. 2019;364:l665.
Mikkola TS, Savolainen-Peltonen H. Hormone therapy and Alzheimer’s disease: the estradiol window hypothesis. Maturitas. 2020;136:7-12.
Henderson VW, et al. Postmenopausal hormone therapy and Alzheimer’s disease risk: interaction with age. J Neurol Neurosurg Psychiatry. 2005;76(1):103-105.
Kwakowsky A, et al. Is Hormone Replacement Therapy a Risk Factor or a Therapeutic Option for Alzheimer’s Disease? Neuropsychiatr Dis Treat. 2020;16:1551-1571.
Zárate S, et al. Estrogen in synaptic plasticity and Alzheimer’s disease. Int J Mol Sci. 2018;19(11):3306.
Podcasy, J. L., & Epperson, C. N. (2016). Considering sex and gender in Alzheimer disease and other dementias. Dialogues in clinical neuroscience, 18(4), 437–446.

About The Author

Ayesha Sherzai, MD

Dr. Ayesha Sherzai is a neurologist and co-director of the Alzheimer’s Prevention Program at Loma Linda University, where she leads the Lifestyle Program for the Prevention of Neurological Diseases. She completed a dual training in Preventative Medicine and Neurology at Loma Linda University, and a fellowship in Vascular Neurology and Epidemiology at Columbia University. She is also a trained plant-based culinary artist.