Executive Function at Risk: Androgen Deprivation Therapy, Cognitive Decline, and the Question of Fitness to Serve

Prostate cancer is the most prevalent solid tumor among men and remains a leading cause of cancer-related morbidity and mortality worldwide. With increasing longevity and improved early detection, a growing number of men are living longer after diagnosis, prompting greater emphasis on the long-term consequences of treatment. These consequences extend beyond oncologic outcomes, encompassing quality of life, functional independence, and increasingly, cognitive health. The intersection of cancer therapeutics and neurocognitive outcomes has become especially relevant in the context of aging populations, where baseline cognitive reserve may already be compromised [1]. 

Among the various treatment options, Androgen Deprivation Therapy (ADT) plays a central role, particularly for patients with intermediate- to high-risk disease or biochemical recurrence. ADT reduces circulating testosterone to castrate levels, suppressing androgen receptor signaling and halting cancer progression. However, testosterone is not solely a driver of prostate malignancy; it also plays a critical role in maintaining brain structure and function. Its depletion is associated with decreased hippocampal volume, impaired synaptic plasticity, altered cerebral glucose metabolism, and upregulation of proinflammatory cytokines. These pathophysiological changes have been linked to cognitive symptoms ranging from subtle forgetfulness and difficulty concentrating to more pronounced impairments in verbal memory and executive functioning [2]. Recent meta-analyses and longitudinal studies have begun to clarify the scope of this risk, with several showing an increased incidence of mild cognitive impairment and dementia among men undergoing long-term ADT [3,4]. 

Radiation therapy and radical prostatectomy, while less frequently associated with direct cognitive effects, are not without concern. Postoperative cognitive dysfunction has been observed in elderly men following major urologic surgeries, a phenomenon believed to be mediated by perioperative neuroinflammation, anesthetic exposure, and cerebral hypoperfusion [5]. Radiotherapy, particularly when administered over extended durations, may induce systemic inflammatory responses that have downstream effects on neural integrity, although the exact mechanisms remain under investigation [6]. These risks may be compounded in individuals with pre-existing vascular comorbidities or neurodegenerative susceptibility [7]. 

These findings hold particular significance for individuals in cognitively demanding leadership roles. The public disclosure of former President Joe Biden’s diagnosis of prostate cancer has prompted renewed interest in the relationship between prostate cancer treatments and cognitive outcomes. While specific details of his treatment have not been made available, the possibility of cognitive side effects from undisclosed interventions such as ADT or adjunct therapies warrants scrutiny. In an era where the medical privacy of public officials intersects with the public's right to informed leadership, the clinical relevance of treatment-induced cognitive changes takes on added ethical and civic dimensions. 

This paper synthesizes recent scientific literature on the cognitive consequences of prostate cancer treatment, emphasizing contemporary mechanistic understanding, recent clinical guidelines, and long-term outcomes. Specifically, I set out to examine whether existing evidence supports the hypothesis that Androgen Deprivation Therapy (ADT) and other prostate cancer treatments contribute to measurable cognitive decline, particularly in aging individuals, and that these effects have implications for leadership fitness in public figures. By critically evaluating these dimensions, I aim to equip clinicians, patients, and policy stakeholders with an evidence-based framework for balancing oncologic control with cognitive preservation, especially in the context of aging populations and public accountability.

A literature review was conducted using PubMed and Google Scholar to examine the cognitive effects of Androgen Deprivation Therapy (ADT), prostate cancer treatments, neuroinflammatory mechanisms, cerebral metabolic disruptions, and ethical considerations in medical transparency. Priority was given to peer-reviewed articles from the last five years to ensure relevance to current clinical and policy discussions. Inclusion criteria emphasized scientific credibility and multidisciplinary perspectives from oncology and neuropsychology guidelines. This review aimed to determine whether existing evidence supports the hypothesis that prostate cancer treatments, particularly ADT, contribute to measurable cognitive decline and to assess the implications for leadership fitness in aging public figures.

The recent public disclosure of former President Joe Biden’s diagnosis of advanced prostate cancer has brought renewed attention to the cognitive implications of cancer treatments in aging individuals, particularly those in high-profile leadership roles. Importantly, no medical diagnosis or judgment is being made regarding President Biden’s symptoms or cognitive status in this discussion. All health information referenced is based on publicly available sources, including official presidential disclosures and widely distributed reports from reputable news outlets. 

On May 16, 2025, it was reported that Biden, age 82, had been diagnosed with a high-grade prostate adenocarcinoma, characterized by a Gleason score of 9 (Grade Group 5) and metastasis to the bone [8]. This classification denotes one of the most aggressive and clinically significant forms of prostate cancer. The diagnosis reportedly followed the emergence of lower urinary tract symptoms and the identification of a suspicious prostate lesion during clinical evaluation. Notably, his most recent publicly known Prostate-Specific Antigen (PSA) test was from 2014, raising questions among some medical observers about the timeline of disease detection and progression [9]. 

Experts have expressed concern over the advanced nature of the disease at the time of diagnosis, particularly given Biden’s access to high-quality healthcare and regular medical evaluations. Current guidelines from the U.S. Preventive Services Task Force does not recommend routine PSA screening for men over 70, due to the balance of benefits and harms in this age group [10]. However, some clinicians argue that individual risk stratification may justify continued surveillance in certain older adults, especially those with high functional status and extended life expectancy [11]. In this context, the delay in detection has raised broader questions regarding prostate cancer screening practices and physician discretion in older patients. 

From a clinical standpoint, treatment for metastatic, hormone-sensitive prostate cancer typically involves ADT, with or without next-generation antiandrogens, radiotherapy, or chemotherapy depending on disease burden and patient performance status [12]. While ADT is effective in controlling disease progression, it has been associated in numerous studies with neurocognitive effects, including decreased verbal memory, slower processing speed, and impaired executive function [2]. The mechanisms underlying these effects include testosterone withdrawal–mediated changes in hippocampal structure, modulation of neuroinflammatory pathways, and decreased cerebral metabolic activity [13]. These risks are heightened in elderly patients, in whom baseline cognitive reserve may already be reduced due to age-related neurodegenerative processes [3]. 

The case of a former U.S. president undergoing treatment for such an aggressive disease highlights the tension between medical privacy and the public’s interest in cognitive transparency among elected leaders. While Biden’s representatives have emphasized that the diagnosis was recent and treatment is ongoing, the disclosure has generated discussions about the extent to which public figures are obligated to reveal serious health conditions that may impact cognitive performance [14]. This issue intersects with ethical principles of autonomy, confidentiality, and accountability, and also underscores the potential for cognitive monitoring to be incorporated into survivorship care planning for patients receiving therapies known to affect brain function [15]. 

As this case continues to unfold in the public eye, it serves as a timely illustration of the real-world stakes involved in understanding and addressing the cognitive sequelae of prostate cancer treatment. It reinforces the need for robust clinical communication, individualized treatment planning that considers cognitive outcomes, and clear policies on health disclosure for individuals in roles of public trust.

Prostate cancer is a biologically heterogeneous disease with a wide spectrum of clinical behavior ranging from indolent tumors requiring no immediate intervention to highly aggressive forms with metastatic potential. The clinical approach to prostate cancer is largely guided by risk stratification based on a combination of tumor histopathology, serum PSA levels, and staging via the TNM system. The Gleason grading system, now aligned with the International Society of Urological Pathology (ISUP) Grade Group classification, remains a cornerstone in assessing tumor aggressiveness. Grade Group 1 corresponds to Gleason score ≤6, while Grade Group 5 reflects the most poorly differentiated tumors with a Gleason score of 9 or 10 [16]. 

Treatment selection is dictated by a combination of patient-specific factors, including age, life expectancy, performance status, comorbidities, and patient preference, in conjunction with disease-specific variables. Current guidelines from the National Comprehensive Cancer Network (NCCN), American Urological Association (AUA), and European Association of Urology (EAU) advocate for risk-adapted strategies that balance oncologic control with preservation of function and quality of life [17]. For men with very low or low-risk disease, active surveillance is often the preferred approach, particularly for older individuals or those with limited life expectancy. Surveillance includes serial PSA testing, digital rectal examination, and periodic prostate biopsies or Magnetic Resonance Imaging (MRI) to monitor for disease progression. This strategy avoids overtreatment and its associated morbidities while preserving curative options if progression occurs [18]. 

Intermediate-risk disease typically warrants more definitive therapy. Radical prostatectomy remains a standard curative option, particularly for younger patients with localized disease. Surgical techniques have evolved from open prostatectomy to minimally invasive approaches, including robot-assisted laparoscopic prostatectomy, which offers reduced perioperative morbidity and faster recovery while maintaining oncologic efficacy [19]. Common complications include urinary incontinence, erectile dysfunction, and, in some cases, postoperative cognitive dysfunction, particularly in elderly patients exposed to general anesthesia [20]. External Beam Radiation Therapy (EBRT) is another first-line treatment for localized or locally advanced disease. Techniques such as Intensity-Modulated Radiation Therapy (IMRT) and Image-Guided Radiation Therapy (IGRT) have improved dose conformity, reducing damage to surrounding tissues. EBRT may be combined with short- or long-term ADT depending on risk classification and tumor volume. Brachytherapy, involving permanent or temporary placement of radioactive seeds within the prostate, is typically reserved for low- to intermediate-risk patients and can also be used as a boost in combination with EBRT [21]. 

ADT, which reduces circulating testosterone through medical or surgical castration, is the backbone of systemic treatment for advanced or metastatic prostate cancer. Medical castration is commonly achieved using Gonadotropin-Releasing Hormone (GnRH) agonists (e.g., leuprolide, goserelin) or antagonists (e.g., degarelix, relugolix). ADT is also used as neoadjuvant, concomitant, or adjuvant therapy with radiation for high-risk localized disease [22]. Though effective in slowing tumor progression, long-term ADT is associated with adverse metabolic, cardiovascular, musculoskeletal, and cognitive effects, requiring multidisciplinary management. In cases of Metastatic Hormone-Sensitive Prostate Cancer (mHSPC), combination therapy with ADT and novel androgen receptor pathway inhibitors (e.g., abiraterone, enzalutamide, apalutamide) has demonstrated significant survival benefits. Chemotherapy, particularly with docetaxel, is another standard option in this setting, especially for patients with high-volume disease. In Castration-Resistant Prostate Cancer (CRPC), additional systemic therapies include radioligand therapy (e.g., 177Lu-PSMA-617), PARP inhibitors for patients with DNA repair mutations, and immunotherapies in select populations [23]. 

The rapidly evolving treatment landscape for prostate cancer demands careful consideration of treatment-related toxicities, including their potential impact on neurocognitive outcomes. As patients live longer with their disease, survivorship care must increasingly integrate not only oncologic surveillance but also screening for treatment-associated functional and cognitive impairments.

The relationship between prostate cancer treatments and cognitive decline is complex and multifactorial. Among available therapies, ADT has emerged as the most extensively studied intervention linked to neurocognitive consequences. ADT suppresses systemic testosterone levels, thereby halting androgen receptor–driven proliferation of prostate cancer cells. However, testosterone also serves critical neuroprotective functions. It modulates neurotransmission, promotes synaptic plasticity, and supports glucose metabolism in brain regions essential for memory and executive function, particularly the hippocampus and prefrontal cortex [24]. The abrupt or sustained withdrawal of testosterone via ADT has been associated with reduced gray matter volume, hippocampal atrophy, and impaired neuronal glucose uptake, all of which contribute to measurable cognitive deficits [25]. 

Animal models and neuroimaging studies support the hypothesis that androgen deprivation leads to dysregulation of neuroinflammatory pathways. In particular, increased levels of interleukin-6 (IL-6), Tumor Necrosis Factor-Alpha (TNF-α), and reactive oxygen species have been observed in testosterone-deprived conditions, which may promote neuronal damage or interfere with synaptic repair [26]. Human studies using PET and fMRI have identified reduced metabolic activity and decreased connectivity in brain regions related to attention, verbal fluency, and working memory in men receiving ADT [27]. While not all patients experience cognitive symptoms, the cumulative evidence suggests that older adults, particularly those with pre-existing vascular or neurodegenerative risk factors, may be more vulnerable to the effects of androgen suppression [28]. 

Cognitive risks are not confined to hormonal therapies. Radical prostatectomy, although localized in scope, has been associated with Postoperative Cognitive Dysfunction (POCD), a syndrome marked by short-term deficits in attention, memory, and processing speed. While the exact mechanisms are still under investigation, several contributing factors have been proposed. General anesthesia is believed to trigger neuroinflammation, reduce blood-brain barrier integrity, and impair neurogenesis through oxidative stress and mitochondrial dysfunction [29]. Older patients and those with pre-existing cognitive impairment are more susceptible, and although POCD is often transient, some individuals may experience long-lasting or even progressive deficits [30]. Additionally, depression—a known comorbidity in prostate cancer patients—has been identified as an independent risk factor for cognitive decline. The psychological burden of a cancer diagnosis, coupled with treatment-induced hormonal changes, can exacerbate mood disturbances, which in turn may impair memory, executive function, and information processing speed [31]. 

Radiation therapy, including both External Beam Radiation Therapy (EBRT) and brachytherapy, can also play a role in systemic inflammatory responses that affect the central nervous system. Although prostate-targeted radiotherapy does not directly expose brain tissue, studies suggest that peripheral inflammation and vascular injury from ionizing radiation may contribute to low-grade neurotoxicity [32]. Additionally, radiation-induced anemia and fatigue can have downstream effects on mental clarity, energy, and processing capacity, particularly in patients with multimorbidity or advanced disease burden [33]. 

Chemotherapy is rarely used in localized prostate cancer but may be employed in metastatic or castration-resistant settings. Agents such as docetaxel and cabazitaxel, while effective in controlling tumor progression, have been associated with the so-called “chemo brain” phenomenon. Though less severe in prostate cancer than in breast or hematologic malignancies, cognitive complaints such as decreased concentration, forgetfulness, and slowed thinking have been reported. Importantly, cognitive impairment is not unique to prostate cancer patients—similar effects have been observed across various malignancies, particularly in individuals undergoing systemic chemotherapy or endocrine therapy for breast cancer and hematologic cancers [34]. Recognizing this broader pattern helps contextualize prostate cancer-related cognitive changes while mitigating potential stigma surrounding ADT-associated cognitive effects. Proposed mechanisms include direct neurotoxic effects, altered cytokine profiles, and mitochondrial damage [35]. These effects are generally subtle but can be clinically meaningful, particularly when combined with other systemic therapies. 

Taken together, the evidence indicates that prostate cancer therapies exert their cognitive effects through a combination of hormonal, inflammatory, and neurovascular pathways. The degree of impairment varies widely between individuals and is modulated by age, treatment duration, baseline cognitive reserve, and concurrent medications. Understanding these mechanisms is essential for clinicians to weigh the neurocognitive risks and benefits of treatment, tailor interventions for vulnerable populations, and incorporate cognitive monitoring into survivorship care plans.

A growing body of clinical evidence suggests that certain prostate cancer therapies are associated with measurable changes in cognitive function, particularly in older adults. Among these treatments, ADT has been the primary focus of investigation due to its widespread use and systemic hormonal impact. Multiple longitudinal cohort studies and meta-analyses conducted in the past decade have reported statistically significant associations between ADT and impairments in memory, executive function, and processing speed. However, the degree and persistence of cognitive decline vary considerably, with some studies reporting subtle subclinical deficits and others identifying long-term cognitive impairment that resembles early dementia patterns [36]. 

A pivotal 2020 meta-analysis including over 14,000 patients found that ADT was associated with a significantly higher risk of incident dementia (Hazard Ratio [HR] 1.21; 95% CI, 1.09-1.35), independent of age, comorbidities, and baseline cognitive status [37]. Another large population-based study using SEER-Medicare data showed that men receiving ADT had an increased risk of Alzheimer’s disease compared to matched controls, with the risk increasing proportionally to the duration of therapy [38]. These findings were corroborated by neuroimaging studies, which demonstrated ADT-associated reductions in brain volume and cortical thickness in frontal and temporal regions—changes often implicated in early-stage neurodegenerative disease [27]. 

Not all studies, however, have found clear evidence of clinically meaningful decline. Some Randomized Controlled Trials (RCTs) and observational studies using neuropsychological batteries have reported transient or non-significant cognitive changes, suggesting that individual vulnerability may play a role. Factors such as patient age, educational attainment, cardiovascular health, baseline cognitive reserve, and concurrent medications appear to modulate risk [39]. Additionally, some studies have been limited by methodological inconsistencies, including short follow-up durations, lack of pre-treatment cognitive baselines, and reliance on screening tools that may not capture subtle cognitive domains. 

Cognitive changes following radical prostatectomy have been less thoroughly studied, though Postoperative Cognitive Dysfunction (POCD) is a well-documented phenomenon in the elderly surgical population. A prospective cohort study involving older men undergoing urologic surgery found that nearly 30% exhibited cognitive decline at hospital discharge, with persistent deficits in 10-15% at three months postoperatively [40]. These deficits were typically confined to attention and memory and were hypothesized to be related to anesthesia-related neurotoxicity, systemic inflammation, and perioperative cerebral hypoperfusion. Notably, the cognitive impact appeared more pronounced in patients with underlying frailty, diabetes, or cerebrovascular disease [30]. 

Evidence regarding radiation therapy and chemotherapy is more limited in the prostate cancer literature. While EBRT does not directly expose the brain to ionizing radiation, systemic effects such as fatigue, cytokine elevation, and secondary anemia may contribute to nonspecific cognitive symptoms, particularly in patients with advanced disease or polytherapy regimens. “Chemo brain,” a constellation of attention and memory complaints seen in patients receiving systemic chemotherapy, has been occasionally reported in those treated with agents like docetaxel or cabazitaxel. However, these findings are often extrapolated from studies in other malignancies, and the specific contribution of chemotherapy to cognitive decline in prostate cancer remains insufficiently characterized [35]. 

Despite some variability in findings, the overall clinical picture supports the inclusion of cognitive monitoring in the comprehensive care of prostate cancer patients, particularly those receiving systemic hormonal therapy. Several organizations, including the International Society of Geriatric Oncology and the American Society of Clinical Oncology, have recommended periodic cognitive screening in older adults undergoing treatment for cancer, though standardized protocols remain to be fully established [41]. Tools such as the Montreal Cognitive Assessment (MoCA), Trail Making Test, and verbal memory tests are frequently employed in both research and clinical practice to assess baseline function and track changes over time. Emerging digital tools and patient-reported outcome measures may offer more scalable solutions for future implementation in survivorship programs [42].

As prostate cancer survivorship increases, the clinical conversation must advance beyond oncologic control to include the broader societal and ethical implications of treatment-associated cognitive effects. While cognitive decline has historically been underemphasized in oncology, its impact on quality of life, decision-making autonomy, and daily functioning can be profound, particularly for older adults. At the population level, the widespread use of ADT and other systemic treatments introduces cognitive risk into the lives of hundreds of thousands of men annually, necessitating a coordinated public health response [43]. 

One critical issue is the absence of standardized cognitive surveillance protocols within prostate cancer treatment guidelines. Despite a growing body of literature indicating potential cognitive decline, routine neurocognitive screening is not a part of current practice recommendations from major oncology organizations such as the NCCN or AUA. This gap is particularly striking in light of recommendations by the International Society of Geriatric Oncology and American Society of Clinical Oncology, which advocate cognitive screening in older adults receiving systemic cancer therapy [41]. Without consistent assessment, cognitive symptoms may be underreported or misattributed to aging or unrelated comorbidities, leading to delays in diagnosis and support. 

This lack of infrastructure is further complicated by the ethical dimensions of cognitive decline in high-functioning individuals and public figures. In leadership roles where executive function, memory, and judgment are paramount, even subtle impairments may affect decision-making or public trust. The recent disclosure of former President Joe Biden’s advanced prostate cancer diagnosis has reinvigorated public discourse on transparency, privacy, and accountability in health communications. While there is a strong ethical imperative to respect medical confidentiality, this must be weighed against the societal implications of impaired cognition in public office [44]. The ethical tension between individual privacy and the public's right to know reflects enduring debates in professions where functional capacity is routinely assessed, such as medical practice, aviation, and military leadership [45]. 

Policy responses to this challenge have lagged behind clinical evidence. Currently, there are no national mandates for disclosing cognitive status among elected officials, and medical fitness for leadership is rarely subject to external review. Several bioethicists have called for the creation of independent, nonpartisan panels to assess the cognitive fitness of aging leaders, citing the growing prevalence of neurodegenerative disease in individuals over 70 [46]. Proposals have also been made to incorporate cognitive screening into the routine physical examinations required for presidential candidates or high-ranking officials. These policies, while controversial, echo similar debates surrounding mental health parity and neuropsychological testing for pilots and judges. 

At the clinical level, shared decision-making models must include a clear discussion of cognitive risks when presenting treatment options for prostate cancer, especially for patients over 65 or those with existing cognitive vulnerability. Informed consent processes should reflect current evidence and ensure that patients understand not only the physical side effects of treatment but also the potential neurocognitive implications. This is particularly important for therapies like ADT and chemotherapy, which carry risks that may not be immediately evident to patients or their families [47]. 

Public health initiatives can also play a key role in reducing the burden of treatment-related cognitive impairment. Educational campaigns, survivorship clinics, and multidisciplinary care teams that include neuropsychologists and geriatricians can help identify and manage cognitive symptoms early. Additionally, digital cognitive monitoring tools and patient-reported outcome measures could provide scalable approaches for surveillance in real-world settings [48]. The intersection of prostate cancer treatment and cognitive health poses an urgent challenge to medical ethics, public policy, and health system design. Addressing this challenge will require a paradigm shift in clinical practice, regulatory standards, and public expectations. Recognizing cognitive function as a core component of survivorship and leadership capacity is a necessary step toward more transparent, ethical, and patient-centered cancer care.

The treatment of prostate cancer, historically centered on survival and tumor control, must now evolve to reflect a broader understanding of patient well-being. This includes the cognitive consequences of therapy, particularly for older adults and long-term survivors. Among the most implicated interventions is ADT, which has been consistently associated with impairments in memory, executive function, and processing speed. Although significant progress has been made in understanding the underlying biological mechanisms, including hormonal disruption, neuroinflammation, and cerebral metabolic changes, clinical integration of this knowledge remains limited. 

Cognitive side effects carry not only medical relevance but also ethical and societal significance. When individuals undergoing treatment hold high-level decision-making responsibilities, the risk of cognitive decline becomes a matter of public interest. The recent case of former President Joe Biden has underscored the importance of transparency in leadership health disclosures and raised questions about how best to manage cognitive risk in such contexts. The ethical tension between respecting privacy and ensuring public accountability remains unresolved, but the need for clearer communication and proactive cognitive assessment is evident. 

This paper supports the incorporation of cognitive screening into routine prostate cancer care, particularly for patients receiving systemic therapies with known neurologic effects. It also encourages the inclusion of cognitive outcomes in oncology trials and greater attention to cognitive domains during survivorship planning. At a policy level, establishing clearer frameworks for health disclosures in leadership roles may help preserve both institutional trust and patient dignity. As survivorship becomes the norm rather than the exception, the responsibility to protect cognitive function must be embraced as part of comprehensive oncologic practice.

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