Hormone-modulating therapy used to treat patients with breast cancer may be associated with a 7% lower risk of developing Alzheimer’s disease and related dementias later in life, according to a recent study published by Cai et al in JAMA Network Open.
Background
About 67% of patients with breast cancer have tumors that are hormone receptor–positive and grow in response to estrogen or progesterone. In these patients, hormone-modulating therapy can impede tumor growth by blocking hormones from attaching to these receptors. The three main types of hormone-modulating therapy include selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders.
Although the use of hormone-modulating therapy has been linked to increased survival, there is conflicting evidence about whether the treatment may increase or decrease the risk of developing Alzheimer’s disease and related dementias—debilitating conditions that are characterized by memory loss; changes in mood or behavior; and difficulty thinking, problem-solving, and reasoning.
Study Methods and Results
In the recent study, investigators used a federal database of patients aged 65 years and older to identify 18,808 female patients diagnosed with breast cancer between 2007 and 2009 who didn’t have a previous Alzheimer’s disease and related dementias diagnosis or a history of using hormone-modulating therapy prior to their breast cancer diagnosis. They sought to better understand the risk of Alzheimer’s disease and related dementias following hormone-modulating therapy.
Among the patients involved in the study, 66% of them had received hormone-modulating therapy within 3 years of their diagnosis and 34% of them hadn’t received the treatment. After an average follow-up of 12 years, the investigators found that 24% of the patients who received hormone-modulating therapy and 28% of those who didn’t receive the treatment developed Alzheimer’s disease and related dementias.
To calculate the risk of developing Alzheimer’s disease and related dementias, the investigators accounted for the risk of mortality associated with increased age and the duration of exposure to hormone-modulating therapy. They found that although receipt of hormone-modulating therapy was associated with an overall decrease in the relative risk of developing Alzheimer’s disease and related dementias, the protective effects of the treatment were most pronounced in patients aged 65 to 69 years, diminished with age, and varied by race. Notably, in patients aged over 80 years, there was an increased risk of Alzheimer’s disease and related dementias among the patients who received hormone-modulating therapy.
“Our study [reveals] that younger women may benefit more from [hormone-modulating therapy] in terms of reduced risk of developing Alzheimer’s disease and other types of dementias,” explained lead study author Chao Cai, PhD, Assistant Professor at the University of South Carolina College of Pharmacy. “The benefits of [hormone-modulating therapy] decreased for women aged 75 and older, particularly in those who identified as White. This suggests that the timing of [hormone-modulating therapy] initiation is crucial and treatment plans should be tailored to a patient’s age,” she continued.
Additionally, Black female patients aged 65 to 74 years who received hormone-modulating therapy had a 24% reduction in the relative risk of developing Alzheimer’s disease and related dementias—which dropped to 19% in those aged 75 years and older. White women aged 65 to 74 years had an 11% reduction in the risk of Alzheimer’s disease and related dementias following hormone-modulating therapy, but this beneficial association disappeared after age the age of 75.
Further, the risk of developing Alzheimer’s disease and related dementias varied by the type of hormone-modulating therapy the patients received. The investigators proposed that because estrogen has neuroprotective effects, these therapies could influence the risk of Alzheimer’s disease and related dementias by mimicking estrogen, influencing estrogen production, or modulating estrogen receptor levels. Hormone-modulating therapy may also affect clearance of a protein called beta-amyloid, stability of tau protein, and vascular health—all of which are closely linked to brain health and Alzehimer’s disease and related dementias risk.
Conclusions
“Black women have higher rates of breast cancer and tend to have higher lifetime stress due to structural racism and other societal factors, which are associated with worse outcomes,” said Modugno. “We don’t know the mechanisms behind the racial disparities we saw with [hormone-modulating therapy] and risk of [Alzheimer’s disease and related dementias], but it’s possible that these factors could contribute. It deserves further investigation,” underscored senior study author Francesmary Modugno, MS, PhD, MPH, Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of Pittsburgh and a member of the Magee-Womens Research Institute at the University of UPMC Hillman Cancer Center. “Our findings emphasize the importance of being cognizant of individual patient factors when we prescribe medications or develop treatment plans for breast cancer. It’s not one-size-fits-all. We need to think about each individual patient to optimize outcomes and minimize risks,” she stressed.
The investigators noted that a limitation of the study was that it only included patients over 65 years of age. In the future, they hope to include younger female patients who haven’t reached menopause yet to further understand the link between hormone-modulating therapy] and the risk of dementia.
“The relationship between [hormone-modulating therapy] for breast cancer and dementia risk is complex and influenced by multiple factors. Ongoing research is needed to further understand the mechanisms behind this association and provide clearer guidance on the use of [hormone-modulating therapy],” she concluded.
Disclosure: The research in this study was supported by the National Institutes of Health, the Carolina Center on Alzheimer's Disease and Minority Research, and the University of Pittsburgh Dean’s Faculty Advancement Fund. For full disclosures of the study authors, visit jamanetwork.com.
