Clinical Manipulation of Testosterone and Its Impact on Dementia and Health

患有阿尔茨海默病(阿尔茨海默病)的退伍军人人数正在急剧增加。睾丸素是 假设在男性阿尔茨海默病的风险、发病和进展中起重要作用。睾酮缺乏症 在阿尔茨海默病发作之前，可以在临床前阶段促进阿尔茨海默病的病理生理学，此时干预措施可能 拥有最大的成功。前列腺癌和睾酮的雄激素剥夺治疗(ADT) 直接针对睾酮水平的年龄相关性性腺功能减退症的替代疗法(TRT)提供 研究雄激素对阿尔茨海默病的影响的宝贵机会，阿尔茨海默病的前驱 病情轻度认知障碍(MCI)，以及并存的健康状况。在建议的研究中，我们会 利用百万退伍军人计划(MVP)的遗传和临床数据来确定Low的影响 睾酮、ADT和TRT对MCI和阿尔茨海默病相对风险的影响。我们假设长期影响 低睾酮、ADT和TRT将受到阿尔茨海默病的多基因风险和雄激素变异的调节 受体(AR)基因。这些遗传因素代表了疾病易感性的关键的、预先存在的标记，以及 荷尔蒙敏感性尚未纳入对阿司匹林保护和有益作用的研究 睾丸激素对认知和健康的影响。在我们的研究中，我们将首先确定MCI、阿尔茨海默病和 在MVP队列中，睾丸激素水平较低会增加促进痴呆症的病态内科疾病。 接下来，我们将确定睾丸激素水平的临床操作是否与风险差异有关。 治疗MCI和阿尔茨海默病。我们假设，接受ADT的个体患MCI、阿尔茨海默病的风险会增加 与有前列腺癌病史但没有前列腺癌病史的男性相比，还有共同的健康状况 用ADT治疗。我们进一步假设，接受TRT的男性在这些方面的风险将会降低 与没有接受激素替代治疗的睾丸素水平较低的男性相比，这种情况更容易出现。我们会 下一步测试阿尔茨海默病的现有遗传风险是否会改变以睾丸素为中心的治疗对 MCI和阿尔茨海默病。我们假设观察到的ADT和TRT对认知和健康的影响 阿尔茨海默病遗传风险较高的个体的结果将更大。最后，我们将确定是否 CAG重复长度或配体和DNA结合域引起的雄激素敏感性的基因驱动变化 突变调节ADT和TRT的长期风险和益处。我们假设一个更敏感的 AR基因的变异将增加ADT后MCI和阿尔茨海默病的风险。此外，我们假设 更多对雄激素敏感的人将从TRT中受益更多，因此将显示出降低的风险。 MCI和阿尔茨海默病。凭借其庞大的样本量、广泛的基因数据和精心策划的病历数据，MVP 是探索以睾丸素为中心的治疗对痴呆症影响的理想资源 风险，并提供了遗传信息精准医学的原则证明模型。通过评估长期- 在遗传信息设计的背景下，ADT和TRT对认知健康的术语风险和益处， 这项拟议的研究将为睾酮作为MCI和阿尔茨海默病风险因素的作用提供有价值的见解。 并增加我们对可能对干预做出反应的与阿尔茨海默病相关的关键途径的理解。这个 本研究还将阐明与ADT和TRT相关的长期风险和好处，并澄清 这些治疗在某些情况下是有效的，是启动还是延迟病理生理 导致男性出现阿尔茨海默病症状的过程。最后，我们将确定我们的假设是否 调查潜在遗传风险(即阿尔茨海默病的多基因风险)的驱动、遗传信息研究和 基因决定的治疗敏感性(即AR基因内的变异)可以提高治疗效果 和循证使用TRT，减少ADT的有害后果。我们相信我们的研究非常适合 MVP，并将展示更广泛的生物医学研究和 推进个性化/精准医疗。

The number of veterans with Alzheimer’s disease (AlzD) is dramatically increasing. Testosterone is hypothesized to have an important role in risk, onset, and progression of AlzD in men. Testosterone deficiency prior to AlzD onset can promote AlzD pathophysiology during the preclinical phase when interventions may have the greatest success. Androgen deprivation therapy (ADT) for prostate cancer and testosterone replacement therapy (TRT) for age-related hypogonadism that directly target testosterone levels provide valuable opportunities to examine the impact of this androgen on the risk of developing AlzD, its prodromal condition mild cognitive impairment (MCI), and co-morbid health conditions. In the proposed study, we will utilize genetic and clinical data from the Million Veteran Program (MVP) to determine the impact of low testosterone, ADT, and TRT on the relative risk for MCI and AlzD. We hypothesize that the long-term impact of low testosterone, ADT, and TRT will be regulated by polygenic risk for AlzD and variation in the androgen receptor (AR) gene. These genetic factors represent critical, pre-existing markers of disease vulnerability and hormone sensitivity that have yet to be incorporated into research on protective and beneficial effects of testosterone on cognition and health. In our study, we will first determine if the risks of MCI, AlzD, and co- morbid medical disorders that promote dementia are increased by low testosterone levels in the MVP cohort. Next, we will determine if the clinical manipulation of testosterone levels is associated with differences in risks for MCI and AlzD. We hypothesize that individuals who undergo ADT will be at increased risk for MCI, AlzD and co-morbid health conditions relative to men with a history of prostate cancer but who have not been treated with ADT. We further hypothesize that men who receive TRT will be at decreased risks for these same conditions relative to men with low testosterone who do not receive hormone replacement therapy. We will next test whether pre-existing genetic risk for AlzD modifies the impact of testosterone-centered treatments on MCI and AlzD. We hypothesize that the observed effects of ADT and TRT on the cognitive and health outcomes will be greater in individuals at greater genetic risk for AlzD. Finally, we will determine whether genetically driven changes in androgen sensitivity due to CAG repeat length or ligand and DNA binding domain mutations regulate the long-term risks and benefits of ADT and TRT. We hypothesize that a more sensitive variant of the AR gene will confer greater risk for MCI and AlzD following ADT. Furthermore, we hypothesize that more androgen-sensitive individuals will benefit more from TRT, and will therefore show a reduced risk for MCI and AlzD. With its large sample size, extensive genetic data, and curated medical record data, the MVP represents an ideal resource with which to explore impact of testosterone-centered treatments on dementia risk, and provide a proof-of-principle model of genetically informed precision medicine. By evaluating the long- term risks and benefits of ADT and TRT on cognitive health, in the context of a genetically informative design, the proposed study will provide valuable insights into the role of testosterone as a risk factor for MCI and AlzD, and increase our understanding of a critical AlzD-related pathway that may be responsive to intervention. The present study will also shed light on the long-term risks and benefits associated with ADT and TRT, and clarify whether these treatments, which are efficacious in certain contexts, set in motion or delay pathophysiological processes that result in the emergence of AlzD symptoms in men. Finally, we will determine if our hypothesis driven, genetically informed study investigating underlying genetic risk (i.e., the polygenic risk for AlzD) and genetically determined treatment sensitivity (i.e., variation within the AR gene) can improve treatment efficacy and evidence-based usage of TRT and reduce detrimental outcomes of ADT. We believe our study is ideal for the MVP, and will demonstrate effectiveness of the broader program for biomedical research and the advancement of personalized/precision medicine.