PITTSBURGH - Hormone modulating therapy(HMT)usedfor the treatment of breast cancer was associated with a 7% lower risk of developing Alzheimer's disease and related dementiaslater in life, according to a new study published todayin JAMA Network Open.

The study, which is one of the largest of its kind,found thatalthoughHMT was linked with protection against the development of dementiaoverall, the association decreased with age and varied by race.

About two-thirds of breast cancerpatients have tumors that are hormone receptor positive, meaning that they grow in response to estrogen or progesterone. For these patients, HMT can impede tumor growthby blocking hormones from attaching to these receptors. While use ofHMT is linked with increased survival,there is conflicting evidence about whether it increases or decreases the risk of developingAlzheimer's disease and related dementias (ADRD), debilitating conditions that are characterized bymemoryloss, changes in mood or behavior,and difficultieswith thinking, problem-solving andreasoning.

To improve understanding aboutthe risk of ADRD following HMT in breast cancer patients, Modugno teamed up with lead author Chao Cai, Ph.D., assistant professor at the University of South Carolina College of Pharmacy. They used a federal database of peopleaged 65 and older to identifywomen who were diagnosed withbreast cancerbetween 2007 and 2009andwhodid not have a previousADRD diagnosisor history of using HMT beforetheirbreast cancer diagnosis.

Of 18,808 patientswho fit the criteria,66%had received HMT within three years of their diagnosis and 34%hadnot. During an average of 12 years of follow-up, 24% of HMT users and 28% of non-HMT users developed ADRD.

To calculate the risk of developing ADRD, the researchers accounted for the risk of death associated with increased age and duration of exposure to HMT.They found that while HMT use was associated with an overall decrease in the relative risk of developing ADRD, the protective effect of HMT was most pronounced in patients aged 65through 69 and diminished with age. Notably, when patients aged over80, there was an increased risk of ADRD in HMT users. [Link]

"Our study suggests that younger women may benefit more from HMT in terms of reduced risk of developingAlzheimer's disease and other types of dementia," said Cai. "The benefits of HMT decreasedfor women aged 75 and older, particularly in those who identified as white. This suggests that the timing of HMT initiation is crucialand treatment plans should be tailored to a patient's age."

Black women aged 65through 74 who used HMT had a 24% reduction in relative risk of developing ADRD, which droppedto19% after age 75. White women aged 65through 74 had an 11% reduction in risk of ADRD with HMT use, but thisbeneficialassociation disappeared after age 75.

"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'tknow the mechanisms behind the racial disparities we saw with HMT and risk of ADRD, but it'spossible that these factors could contribute. It deserves further investigation."

Thereare three main types of HMT: selective estrogen receptor modulators, aromatase inhibitors and selective estrogen receptor degraders. The analysis found that the riskof developing ADRD varied by HMT type.

According to Cai, estrogen has neuroprotective effects, so thesetherapies could influence ADRD risk by mimicking estrogen, influencingestrogen productionor modulating estrogen receptorlevels. HMT might alsoaffect clearance of a protein called beta-amyloid, stability of tau protein and vascular health, all of which are closely linkedto brain health and ADRD risk.

"The relationship between HMT for breast cancer and dementiarisk is complex and influenced by multiple factors," explainedCai. "Ongoing research is needed to further understand the mechanisms behind this association and provide clearer guidance on the use of HMT."

A limitation of the study was that it only included patients over 65. In the future, Caiand Modugno will include younger women who haven't reached menopause yet to further understand the link between HMT and dementia risk.

Other authors onthe study were KaowaoStrickland, M.P.H., Sophia Knudsen, Sarah Beth Tucker, and Chandana Sai Chidrala, M.S., all ofthe University of South Carolina.

Photos (click image for high-res version)

First Photo

Caption: Francesmary Modugno, Ph.D. M.P.H., professor of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and member of Magee-Womens Research Institute and UPMC Hillman Cancer Center

Credit: Francesmary Modugno

Second Photo

Caption: Chao Cai, Ph.D., assistant professor at the University of South Carolina College of Pharmacy

Credit: University of South Carolina

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