Prevention of Alzheimer Dementia and Cognitive Decline

描述（由申请人提供）：阿尔茨海默病（AD）的痴呆是在症状前神经变性多年之后发生的。因此，理想的AD干预将通过在症状前阶段减缓或停止疾病过程来减少痴呆症的发生。实验室研究结果表明，阿糖胞苷依赖性炎症或信号传导机制在AD发病机制中可能很重要，流行病学证据表明，抑制前列腺素通路的考克斯-1或考克斯-2激活的常规NSAID可降低AD痴呆的发病率。因此，设盲、安慰剂对照的阿尔茨海默氏病抗炎预防试验（ADAPT）旨在测试双重抑制剂NSAID纳洛芬或考克斯-2选择性药物塞来昔布是否可以降低AD痴呆的发生率并减轻与年龄相关的认知能力下降。在平均21个月的治疗分配后停止治疗时，对ADAPT提供信息性结果的期望降低。事实上，最近发表的ADAPT结果显示，NSAID暴露没有任何益处，而是表明治疗后痴呆症的发病率早期增加。然而，在过去的22个月里，萘普生分配的组显示出AD痴呆的发病率降低，并且萘普生的早期和晚期作用方向之间的对比是惊人的。不幸的是，资金的中断使数据收集工作不得不结束，并在ADAPT的预期治疗效果似乎正在显现之际揭开其面纱。因此，本申请建议在30个月的时间间隔内对ADAPT队列进行随访，使用电话筛查认知困难，然后评估筛查阳性个体的新痴呆结局。然后，我们将在一年后重复这一过程，并将新的结果与ADAPT的结果相结合，以累积大约180个AD痴呆“事件”以及一系列广泛的纵向认知测试分数。因此，我们的具体目标1是扩展与治疗分配相关的AD痴呆和年龄相关认知下降的ADAPT结局的观察。我们特别寻求发现萘普生是否可以导致AD痴呆症发病率的长期降低。此外（在数据允许的情况下），我们试图描述老年人对萘普生（或塞来昔布，如果有的话）的“双向”或“双相”反应，其发生率在短暂的增加间隔后出现更大的风险降低时期。具体目的2是确定ADAPT中两种NSAID治疗中的任何一种的有限暴露是否会导致年龄相关认知下降的长期变化，这可能是AD病理学的早期表现。尽管安全性问题可能会否定当前一代NSAID预防AD痴呆的效用，但阐明其对人类疾病的影响作为AD发病机制和未来预防策略的指标非常重要。

DESCRIPTION (provided by applicant): The dementia of Alzheimer's disease (AD) follows years of pre-symptomatic neurodegeneration. An ideal AD intervention would therefore reduce the occurrence of dementia by slowing or stopping the disease process in its pre-symptomatic stages. Laboratory results suggest that prostaglandin-dependent inflammatory or signaling mechanisms may be important in AD pathogenesis, and epidemiologic evidence suggests that conventional NSAIDs that inhibit COX-1 or COX-2 activation of the prostaglandin pathway can reduce AD dementia incidence. The masked, placebo-controlled Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was therefore designed to test whether the dual-inhibitor NSAID naproxen or the COX-2 selective agent celecoxib can reduce the incidence of AD dementia and mitigate age-related cognitive decline. Expectations for informative results from ADAPT were diminished when its treatments were stopped after an average 21 months of treatment assignment. Indeed, recently published results from ADAPT showed no benefit from NSAID exposure, but instead suggested an early increase in the incidence of dementia with treatment. Over the past 22 months, however, the naproxen-assigned group has shown reduced AD dementia incidence, and the contrast between the earlier and later direction of effects with naproxen is striking. Unfortunately, interruption of funding has necessitated an end of data gathering and the unmasking of ADAPT just when its predicted treatment effects seem to be emerging. This application therefore proposes to follow up the ADAPT cohort over an interval of 30 months, using the telephone to screen for cognitive difficulty and then evaluating screen-positive individuals for new dementia outcomes. We will then repeat this process a year later and combine the new results with those of ADAPT to accrue some 180 total AD dementia "events" as well as an extensive array of longitudinal cognitive test scores. Our Specific Aim 1 is thus to extend observations on the ADAPT outcomes of incident AD dementia and age-related cognitive decline in relation to treatment assignment. We seek in particular to discover whether naproxen can cause a long-term reduction in the incidence of AD dementia. Also (as permitted by the data) we seek to characterize a "bi-directional" or "bi-phasic" response of elderly people to naproxen (or, if any, to celecoxib) with a brief interval of increased incidence followed by a more substantial epoch of diminished risk. Specific Aim 2 is to determine whether the limited exposures in ADAPT to either of the two NSAID treatments produced long-term change in age-related cognitive decline as a possible early manifestation of AD pathology. Although safety concerns will probably negate the utility of current generation NSAIDs for prevention of AD dementia, the elucidation of their effects on the disease in humans is of great importance as an indicator of AD pathogenetic mechanisms and future prevention strategies.