Despite these data, there have been limited and conflicting investigations examining the association of ADT with neurocognitive function 10 and no known studies examining the association of ADT with risk of Alzheimer’s disease. In the current study we use a novel informatics approach, using electronic medical record data from more than 5 million patients, to examine the association of ADT with the subsequent development of Alzheimer’s disease among men with prostate cancer.

The use of ADT in the treatment of prostate cancer has also been associated with a number of cognitive deficits. 10 , 11 Concerningly, ADT has been linked to impairments in visuomotor and executive functioning, which are cardinal features of Alzheimer’s disease. 11 Additionally, men diagnosed with Alzheimer’s disease have demonstrated lower levels of circulating and brain testosterone, with low testosterone levels preceding disease onset. 12 - 15 Among men with Alzheimer’s disease, testosterone supplementation has been shown to improve spatial and verbal memory. 16 Finally, although the majority of cancers have an inverse association with Alzheimer’s disease risk, prostate cancer is associated with a significantly increased risk of Alzheimer’s disease. 17

The goal of ADT is to profoundly lower male androgens, specifically testosterone, secondary to the androgen dependence of prostate cancer. Although most individuals return to normal testosterone levels post treatment, 20% to 30% have prolonged androgen suppression. 5 , 6 Importantly, low testosterone levels have been linked to a number of adverse health effects, including cardiometabolic disease. 7 Additionally, evidence supports an association between ADT and negative health consequences, including diabetes and cardiovascular disease. 8 , 9

Androgen deprivation therapy (ADT) has been a mainstay of treatment of prostate cancer since the 1940s. Although its use has historically been limited to metastatic disease, randomized evidence supports the use of ADT in combination with external-beam radiation therapy for locoregional disease with high-risk features. 1 , 2 Overall the use of ADT has increased dramatically over recent decades, 3 with an estimated 500,000 men currently receiving ADT for prostate cancer in the United States. 4

Results were compared between Stanford and Mt. Sinai. Kaplan-Meier curves were constructed to examine the cumulative probability of remaining Alzheimer’s disease–free in the full cohort and in the propensity score–matched cohort. Kaplan-Meier curves were compared in the full and propensity score–matched cohorts using log-rank and Cox regression–based tests for equality, respectively. The duration of ADT use was also tested for association with Alzheimer’s disease risk using Cox regression models. Specifically, we examined Alzheimer’s disease risk among those with less than 12 months ADT use and greater than or equal to 12 months ADT use compared with non-ADT users. We additionally conducted a test for trend of the risk of Alzheimer’s disease with increasing duration of ADT use across categories (ie, no ADT, < 12 months, ≥ 12 months). Finally, we evaluated whether an association between ADT and Alzheimer’s disease might be secondary to unmeasured physician or patient characteristics by using falsification analysis. 31 Specifically, we selected five outcomes to test for association with ADT with no known or hypothesized association: anaphylaxis, rhabdomyolysis, tuberculosis, allergic rhinitis, and abdominal aortic aneurysm.

Propensity score–matched analyses and traditional multivariable-adjusted Cox regression analyses were adjusted for age at prostate cancer diagnosis; race; smoking status; use of antiplatelet, anticoagulant, antihypertensive, and statin medications; and a history of cardiovascular disease, diabetes, or malignancy. We adjusted for cardiometabolic disease–associated variables and age, as they have been shown to increase Alzheimer’s disease risk 27 , 28 and, along with prior malignancy, contribute to patients’ likelihood of receiving radiation therapy and therefore ADT, if, for example, they are poor surgical candidates. We additionally accounted for race given known racial disparities in stage at diagnosis and access to definitive cancer treatment. 29 , 30 Further sensitivity analyses were conducted including individuals receiving chemotherapy, among only those with at least 5 years of follow-up, and using shared-frailty models to account for the matched nature of the data.

Hazard ratios were calculated using propensity score–matched and traditional multivariable-adjusted Cox proportional hazards models to test the effect of ADT on risk of Alzheimer’s disease. Specifically, we used 1:5 nearest-neighbor propensity score matching with replacement. We then analyzed the propensity score–matched data set using weighted Cox proportional hazards models as previously described. 26

For all analyses, the start of the follow-up period was defined as either the initiation of ADT for ADT users or, for non-ADT users, the time of prostate cancer diagnosis plus the median time to ADT use in our study. The end of the follow-up period was that of the last available record, either inpatient or outpatient, or the time of Alzheimer’s disease diagnosis. Baseline patient characteristics were compared for ADT and non-ADT users using a t test or χ 2 test. All included variables were binary except age.

All individuals with prostate cancer and data on all defined covariates who had follow-up data for at least 180 days after prostate cancer diagnosis were eligible for study inclusion ( Fig 1 ). Patients with exposure to ADT were only included if they had follow-up after initiation of ADT. Men who received chemotherapy were excluded, given evidence for chemotherapy-associated cognitive dysfunction and an expected high correlation between receipt of chemotherapy and ADT use. 25 Those with a history of dementia, including Alzheimer’s disease, frontotemporal dementia, and Lewy body dementia, as well as stroke, were also excluded, given concern for misclassification of Alzheimer’s disease (see Appendix Table A2 for variable definition). A history of dementia was determined using data from 365 days before through 180 days after prostate cancer diagnosis to limit misclassification of prevalent disease. A history of stroke was determined using only data before prostate cancer diagnosis. Individuals who received ADT but developed Alzheimer’s disease before starting ADT were also excluded.

Adjustment covariates included were age at prostate cancer diagnosis; race; smoking status; use of antiplatelet, anticoagulant, antihypertensive, and statin medications; and a history of cardiovascular disease, diabetes, or malignancy. Gleason score was included as a covariate in sensitivity analysis in those patients with available data (n = 4,373). We used ICD-9 diagnostic codes, clinical text data, medication lists, and pharmacy records to define each covariate with further details outlined in Appendix Table A2 . Medication use and a history of diabetes or malignancy were determined using data from 365 days before through 180 days after prostate cancer diagnosis. A history of cardiovascular disease was determined using data from 365 days before through 180 days after prostate cancer diagnosis with the exception of myocardial infarction, which used data only before prostate cancer diagnosis.

New-onset Alzheimer’s disease was defined using terms from clinical notes (Appendix Table A1 ) and ICD-9 diagnostic code 331.0. Among ADT users, incident Alzheimer’s disease was ascertained after initiation of ADT and at least 180 days after prostate cancer diagnosis to limit inclusion of prevalent disease. Among non-ADT users, incident Alzheimer’s disease was ascertained starting 180 days after the time of prostate cancer diagnosis and after the median time to ADT use in our study.

The use of ADT was defined using data from clinical notes and medication lists including pharmacy orders. Specific medication names are detailed in the Appendix. Duration of ADT was calculated using time-stamp data at each determined instance of ADT use.

Prostate cancer was defined as (1) ICD-9 code (185), (2) billing code for radical prostatectomy (ICD-9 60.5 or CPT code 55810-55815, 55840-55845) plus either ADT use (in medication lists or clinical text) or clinical text evidence of prostate cancer diagnosis (Appendix Table A1 ), or (3) clinical text evidence of prostate cancer diagnosis and ADT use (in medication lists or clinical text). In essence, in the absence of an ICD-9 code for prostate cancer, two data points specific for prostate cancer were required. This approach was used to identify prostate cancer diagnoses not reflected in billing codes (eg, only clinical notes were available or data were from visits not resulting in billing for prostate cancer) while limiting misclassification.

These methods have been compared against advanced natural language–processing methods in a functional evaluation, which showed little impact on the accuracy of association detection in large data sets. 22 As further validation, in drug safety studies, the sensitivity and specificity in detecting 25 different conditions via methods used in this study were 0.74 and 0.96, respectively. 18

We used a previously validated 18 and implemented 19 - 21 text-processing pipeline 22 to analyze clinical data. We extracted International Classification of Diseases-9th revision (ICD-9) diagnosis and Current Procedural Terminology codes, medication lists, and positive-present mentions of drug and disease concepts from all clinical notes. We removed uninformative phrases based on term frequency analysis of more than 50 million clinical documents 23 and suppressed terms having fewer than four characters because the majority of these are ambiguous abbreviations. We used NegEx regular expressions to flag negative mentions (eg, “ruled out prostate cancer”) and to determine if a term was mentioned in the history or family history section of the note. 24 The result is a list of present, positive mentions of biomedical concepts, which are converted into a patient-feature matrix for analysis (Appendix Fig A1 , online only).

We used data from Stanford University (1994 to 2013) and Mt. Sinai (2000 to 2013) health systems. There were 1.8 million patients at Stanford and 3.7 million patients at Mt. Sinai, representing 40 million patient encounters with transcriptions of all inpatient and outpatient clinical notes as well as pathology and radiology reports and structured medication lists. Both data sources were accessed under approved institutional review board protocols. Access to Mt. Sinai data was obtained via an institutional research agreement.

Results were similar in propensity score–matched analyses that included individuals who received chemotherapy (HR, 1.96; 95% CI, 1.13 to 3.40; P = .016) and when accounting for within–propensity score–matched group correlation (HR, 1.73; 95% CI, 1.09 to 2.75; P = .019). Among those with at least 5 years of follow-up we observed a consistent proportion of ADT use (15.6%) and a similar risk of Alzheimer’s disease among ADT users (HR, 1.89; 95% CI, 1.11 to 3.21; P = .018). Subgroup analysis adjusted for Gleason score demonstrated a similar magnitude of effect (HR, 1.84; 95% CI, 0.78 to 4.32; P = .161) but had significantly decreased power secondary to few patients with Alzheimer’s disease (n = 47).

Propensity score–matched Cox regression analysis ( Table 3 ) supported a statistically significant positive association between ADT use and Alzheimer’s disease risk (hazard ratio [HR], 1.88; 95% CI, 1.10 to 3.20; P = .021), as did traditional multivariable-adjusted Cox regression analysis (HR, 1.66; 95% CI, 1.05 to 2.64; P = .031). This association did not differ by location in the propensity score–matched Cox regression analysis ( P = .700). Analyses stratified by duration of ADT use ( Table 4 ) demonstrated that individuals with at least 12 months of ADT use had the greatest risk of subsequent Alzheimer’s disease (HR, 2.12; 95% CI, 1.11 to 4.03; P = .011). We also showed a statistically significant increased risk of Alzheimer’s disease by category of increasing ADT duration ( P for trend = .016). Schoenfeld residuals tests demonstrated that the proportional hazards assumption was met for all models.

There were 16,888 individuals with prostate cancer meeting all inclusion and exclusion criteria ( Fig 1 ). Of these, 2,397 (14.2%) received ADT, with a median time from prostate cancer diagnosis to ADT use of 35.6 days. Before propensity score matching, individuals receiving ADT were statistically significantly older and more likely to be white, smokers, on antiplatelet, anticoagulant and antihypertensive medications, and have a history of cardiovascular disease and diabetes ( Table 1 ). No statistically significant differences existed among measured baseline covariates in the propensity score–matched cohort. There were 125 new diagnoses of Alzheimer’s disease during a median follow-up period of 2.7 years (interquartile range, 1.0 to 5.4 years). The median time to Alzheimer’s disease diagnosis was 4.0 years (interquartile range, 2.0 to 7.4 years). Gleason score was available for a subset of patients (n = 4,373), of whom 58% had a Gleason score less than 7, 29% had a Gleason score of 7, and 13% had a Gleason score greater than 7 (Appendix Table A3 ).

DISCUSSION Section: Choose Top of page Abstract INTRODUCTION METHODS RESULTS DISCUSSION << REFERENCES

We used a novel informatics approach to demonstrate an association between the use of ADT in the treatment of prostate cancer and an increased future risk of Alzheimer’s disease. We support this association using both propensity score–matched and traditional multivariable regression models adjusted for a wide range of potential confounding factors. We also show an association between greater duration of ADT use and increased risk of Alzheimer’s disease, which is significant given that length of ADT use is associated with a longer period of testosterone suppression.5 Our findings did not differ across two separate electronic medical record data sets in a large patient population consisting of a diverse group of individuals. Additionally, we support the validity of our study by showing no association between ADT and five distinct outcomes as falsification tests31 as well as replicating known associations between age and cardiovascular disease with Alzheimer’s disease. Use of the electronic medical record in this way allows rapid investigation of a rich data source to study a broad range of postmarketing outcomes, including those unlikely to be seen in smaller clinical trials.19

There are a number of plausible mechanisms to explain a neuropathic effect of androgen deficiency in the etiology of Alzheimer’s disease. Androgens have been shown to aid in neuron growth and axonal regeneration.32 Androgens also modulate β-amyloid protein accumulation, the main component of amyloid plaques.32 ADT use in the treatment of prostate cancer has been shown to result in elevated circulating β-amyloid protein levels.33 Additionally, low testosterone levels and ADT have been associated with a number of cardiometabolic derangements, including subsequent diabetes, coronary heart disease, myocardial infarction, and peripheral arterial disease.8,34-36 Interestingly, cardiometabolic diseases have been shown to increase Alzheimer’s disease risk,27,28 which we demonstrate in the current analysis with a positive association between cardiovascular disease and future Alzheimer’s disease. Furthermore, the combination of atherosclerosis and the possession of the Alzheimer’s disease risk genotype, apolipoprotein-E ε4, may interact to further increase Alzheimer’s disease risk.37

Despite these data, limited direct research has been conducted regarding the association of ADT with cognitive impairment, and existing studies have yielded mixed results. Individual analyses have shown that 47% to 69% of men receiving ADT develop deficits in at least one cognitive area characteristic of Alzheimer’s disease, including visuospatial abilities and executive functioning.11 A 2014 meta-analysis examined the literature across seven cognitive domains and found that patients receiving ADT had a statistically significant impairment of visuomotor ability compared with control participants.10 No known studies have specifically examined the association of ADT use in the treatment of prostate cancer with future Alzheimer’s disease risk.

The current study has a number of limitations that warrant discussion. Our criteria for Alzheimer’s disease were limited to billing codes and clinical note documentation. The use of billing records in the diagnosis of Alzheimer’s disease introduces a potential for bias,38 as may the incorporation of clinical text data. Even in a controlled setting, the diagnosis of Alzheimer’s disease remains clinical and susceptible to misclassification. However, data support a high degree of accuracy in the clinical diagnosis of Alzheimer’s disease compared with autopsy results.39,40 Although we cannot exclude the presence of prevalent Alzheimer’s disease in this study, we have no reason to suspect a differential misclassification that would introduce bias into our analysis.

Additionally, individuals may be more likely to receive definitive radiation therapy and ADT if they are poor surgical candidates secondary to a high number of comorbidities, such as cardiovascular disease, which are also risk factors for Alzheimer’s disease.27 We therefore adjusted for a broad range of comorbidities and conducted propensity score–matched analyses. However, given the retrospective nature of this study and the limitations of data available from the electronic medical record, we were unable to account for all possible risk factors, such as laboratory values (eg, lipids), family history, and other biometric data (eg, systolic blood pressure). Similarly, we were only able to extract Gleason score for a minority of patients; despite demonstrating a similar magnitude of effect, the analysis was underpowered, and therefore no conclusion can be drawn about the effect of disease stage based on our data. Future studies may be needed to fully account for stage of disease and to characterize the nature of this association across prostate cancer risk groups.

Finally, we calculated ADT duration from clinical notes as well as medication and pharmacy records. It is probable that some individuals received a different duration of ADT than was documented. We therefore conducted ADT duration analysis using broad categories of ADT duration (ie, greater than or less than 12 months use) to limit the potential influence of any misclassification. Additionally, misclassification of ADT duration would likely bias the significant result we observed toward the null, as compared groups would become more similar.

In conclusion, we provide support for an association between the use of ADT in the treatment of prostate cancer and an increased risk of Alzheimer’s disease in a general population cohort of 16,888 individuals with prostate cancer. Our study further demonstrates the utility of novel methods of analyzing electronic medical record data to generate practice-based evidence.20 Future prospective studies in traditional cohorts are needed to confirm this finding.