Breast cancer survivors demonstrated an 8% lower risk of Alzheimer disease compared with cancer-free controls in a large, nationwide Korean cohort study that followed more than 70,000 patients for a median of 7.3 years. The risk reduction was based on subdistribution hazard ratios (SHRs) that accounted for death as a competing event.
The retrospective analysis included 70,701 breast cancer survivors who underwent surgery between 2010 and 2016, matched 1:3 with 180,360 cancer-free controls. Among survivors, 1229 cases of Alzheimer disease (AD)were identified, with an incidence rate of 2.45 per 1000 person-years, compared with 3430 cases and an incidence rate of 2.63 per 1000 person-years among controls.
"Survivors exhibited a slightly lower risk of AD compared with cancer-free controls (SHR =0.92; 95% confidence interval [CI], 0.86-0.98), especially among individuals 65 years or older (SHR = 0.92; 95% CI, 0.85-0.99)," the authors reported. Landmark analyses showed that this protective association did not persist with longer survival. At 5 years postdiagnosis, the risk reduction was no longer statistically significant (SHR = 0.98; 95% CI, 0.89-1.08), suggesting the association diminished over time.
Treatment-Specific Risk Patterns
Among treatment modalities, radiation therapy was the only intervention significantly associated with reduced AD risk. "Cancer treatment with radiation therapy (adjusted hazard ratio [AHR] = 0.77; 95% CI, 0.68-0.87) was associated with reduced risk of AD among survivors," the researchers reported. A total of 50,681 patients (71.7%) underwent radiotherapy.
Other treatments showed no statistically significant associations with AD risk. Anthracycline chemotherapy, used in 50.1% of survivors, was associated with a numerically lower—but not statistically significant—risk (AHR, 0.86; 95% CI, 0.73-1.01). Endocrine therapies, including tamoxifen (47.0% of survivors) and aromatase inhibitors (30.0% of survivors), demonstrated no significant associations with AD risk (AHR = 0.92; 95% CI, 0.78-1.09 and AHR = 1.04; 95% CI, 0.90-1.20, respectively). Trastuzumab and taxane-based chemotherapy also showed no association (AHR = 1.00; 95% CI, 0.82-1.23 and AHR = 1.08; 95% CI, 0.90-1.30, respectively).
Methodological Rigor and Risk Modeling
The study addressed limitations of prior research by incorporating competing risk analysis and adjusting for numerous potential confounders. “Previous studies are limited by several methodologic issues. To our knowledge, no study has considered important risk factors, such as smoking, alcohol, physical activity, and body mass index,” the researchers wrote.
Covariates included sociodemographic variables, comorbidities (diabetes, hypertension, dyslipidemia, chronic kidney disease), and health-related behaviors. Among these, current smoking was most strongly associated with increased AD risk (AHR = 2.04; 95% CI, 1.53-2.72). Diabetes mellitus was associated with a 58% increased AD risk (AHR = 1.58; 95% CI, 1.36-1.82), and chronic kidney disease showed the strongest association (AHR = 3.11; 95% CI, 1.98-4.88). Lower income status also conferred greater risk (AHR = 1.24; 95% CI, 1.08-1.43).
Proposed Mechanisms
The researchers proposed several biological explanations for the observed associations. "In vitro, anthracyclines can inhibit and dissolve tau aggregation," they explained. "An in vivo study reported that anthracycline significantly reduced the formation of amyloid deposits, suggesting its beneficial effects through the inhibition of fibril growth and facilitation of amyloid deposit clearance."
For radiation therapy, the researchers noted, “The mean unintended dose to the brain from breast cancer radiotherapy was estimated to be approximately 0.2 Gy using a 50-Gy tumor dose.” A pilot study found that patients with AD treated with low-dose whole-brain radiotherapy (3 Gy) experienced temporary cognitive improvements, potentially mediated by neuroprotective effects on microglia.
The authors distinguished chemotherapy-related cognitive changes—often termed "chemobrain"—from AD. “In contrast to AD, chemotherapy-induced cognitive impairment is subtle, typically remains within normal cognitive function range, and does not affect the retrieval of remote memories,” they wrote. “Chemotherapy-induced cognitive impairment does not always lead to the development of AD due to different mechanistic origins and should be distinguished from AD.”
Study Population and Diagnostic Criteria
The cohort included women with a mean age of 53.1 years (standard deviation [SD], 8.5) who underwent breast cancer surgery and had a national health screening within 2 years before diagnosis. Exclusion criteria included age younger than 40 years, history of other cancers, and pre-existing dementia.
AD diagnosis required both clinical coding (International Classification of Diseases, Tenth Revision [ICD-10]: F00 or G30) and at least one prescription of an approved antidementia medication (donepezil, rivastigmine, galantamine, or memantine), along with a Mini-Mental State Examination score ≤26 and either Clinical Dementia Rating ≥1 or Global Deterioration Scale ≥3.
Limitations and Interpretation
The authors acknowledged that their analysis lacked detailed clinical data on cancer stage and radiation dose/fraction. Because the cohort was limited to women with operable breast cancer, the findings may not apply to those with more advanced disease or significant comorbidities.
They also noted the potential for selection bias in longer landmark analyses: “As survival period increased, the SHR approached 1.00,” suggesting that long-term survivors may differ in unmeasured ways from the broader survivor population. The maximum follow-up was 11 years.
Clinical Implications
The findings provide reassurance about the cognitive safety of breast cancer treatment in relation to AD. “Concerns about chemobrain and the long-term adverse effects of breast cancer treatment on cognition are common, but our findings suggest that this treatment does not directly lead to AD,” the researchers concluded.
“Appropriate management of modifiable risk factors for AD, such as smoking and diabetes, along with standard cancer treatment is a feasible and effective option to lower AD risk among breast cancer survivors,” they wrote.
This investigation, based on the Korean National Health Insurance Service database, represents the largest to date examining AD risk among breast cancer survivors and benefits from robust statistical design, including competing risk regression and comprehensive covariate adjustment.
The authors declared no competing interests.
Source: JAMA Network Open
