INtervention for Cognitive Reserve Enhancement in delaying the onset of Alzheimer’s Symptomatic Expression: The INCREASE study

阿尔茨海默病（AD）是当今社会面临的最重要的公共卫生问题之一。 据估计，美国（US）有500万65岁及以上的人目前患有AD， 到2050年，这一数字可能会增加近两倍。为了解决这一阻碍人口负担的问题，国家阿尔茨海默病项目 2015年国家适应行动方案（NAPA）报告强调，需要确定预防战略， 发病虽然已经非常重视开发和测试有效的疾病修饰剂， 针对AD的这种无症状临床前阶段（pAD）的策略，很少强调 目前可用的针对认知储备的策略，导致（1）延迟症状发作，（2）缩短 症状性疾病的整个过程，和（3）大大减少AD的经济和社会影响。 我们假设，有针对性地减少不适当的药物使用（Beers Criteria 2015）， AD风险受试者的认知储备，延迟临床症状的发作，并降低患病率 和症状性疾病的持续时间。这一战略的影响，如果成功的话，包括大幅度减少 通过延迟疾病的症状阶段， 雅阁国家适应行动方案目标。我们的具体目标是： 具体目标1。进行一项为期12个月的随机安慰剂对照试验，以评估我们的患者的影响- 以药师-医生团队为中心的MTM干预，减少不必要和不适当的药物治疗 在社区居住的老年非痴呆受试者中使用。主要结果指标将包括术前至术后 干预措施：（1）使用不适当的药物，如药物适当性所衡量的 2）认知储备变化评分（CRCS），定义为东莨菪碱- 挑战与未挑战的神经认知评分测量。 具体目标2评价临床前淀粉样蛋白负荷对认知储备缺陷和下降的影响 （测量为CRCS），以评价延缓pAD症状性疾病进展的疗效。 虽然不能消除AD或缩短生物学疾病的持续时间，但症状发作的延迟和 由于减少不适当的药物使用而导致的功能下降的进展可以减轻AD 患病率并显著降低不仅与AD相关的医疗支出，而且可能与所有形式的 包括前驱期无症状的痴呆。研究结果将有助于更大规模地实施 在临床实践中采取类似的药物管理策略， 在老龄化人口中保持认知健康的策略。

Alzheimer's disease (AD) represents one of the most important public health issues our society is facing today. An estimated 5 million people age 65 and older in the United States (US) are currently living with AD, and this number may nearly triple by 2050. To address this impeding population burden, the National Alzheimer's Project Act (NAPA) 2015 report emphasized the need for identifying preventive strategies that can delay symptomatic disease onset. While much emphasis has been placed on developing and testing effective disease-modifying strategies targeting this asymptomatic preclinical phase of AD (pAD), little emphasis has been placed on currently available strategies that target cognitive reserve, resulting in (1) delaying symptom onset, (2) shortening the overall course of symptomatic disease, and (3) substantially reducing the financial and societal impact of AD. We hypothesize that targeted reductions in inappropriate medication use (Beers Criteria 2015), will bolster cognitive reserve in subjects at risk for AD, delaying the onset of clinical symptoms, and reducing the prevalence and duration of symptomatic disease. The impact of this strategy, if successful, includes a dramatic reduction in overall health care expenditures for the millions affected by AD by delaying the symptomatic phase of disease in accord with NAPA aims. Our specific aims are: Specific Aim 1. Conduct a 12-month, randomized, placebo-controlled trial to evaluate the impact of our patient- centered, pharmacist-physician team MTM intervention in reducing unnecessary and inappropriate medication use in community-dwelling, elderly, non-demented subjects. Primary outcome measures will include pre- to post- intervention measures of: (1) use of inappropriate medications as measured by the Medication Appropriateness Index (MAI); 2) Cognitive Reserve Change Score (CRCS) defined as the difference in the scopolamine- challenged vs unchallenged measures on the neurocognitive score. Specific Aim 2 Evaluate the impact of preclinical amyloid burden on cognitive reserve deficits and decline (measured as CRCS) to evaluate efficacy of delaying symptomatic disease progression in pAD. While not eliminating AD or shortening duration of biological disease, the delay in symptom onset and progression to functional decline resulting from reduction in inappropriate medication use could lessen AD prevalence and significantly reduce healthcare expenditures related to not only AD, but potentially all forms of dementia involving a prodromal asymptomatic period. Study results would enable the larger implementation of similar medication management strategies in clinical practice to address the need for multifaceted preventive strategies to maintain cognitive health in the aging population.