老年性痴呆的临床研究，特别是针对淀粉样斑块相关的药物研究已经消耗巨量研究经费。淀粉样斑块是许多学习记忆障碍相关疾病的共同病理基础，但不幸地是，全部相关药物都没有最终取得成功。导致一些沮丧的科学家觉得应该放弃这一思路。也有科学家认为使用这些药物的时机不对，但神经损伤到了不可逆阶段，什么药物都无济于事。上周NIH宣布的这一研究计划将会进一步检验淀粉样斑块学说的可靠性。

这一新的临床研究计划总预算至少需要1亿美元，NIH只承担其中的1/3，另外2/3将来自药物企业。其中一个比较重要的研究是针对650名携带2拷贝APOE4的人群，这一类人在晚年发生老年性痴呆的几率将是普通人群的10倍。所有受试者都是65-70岁的健康人，没有任何老年性痴呆的症状。

美国政府对老年性痴呆的研究非常重视，根据美国卫生和人类服务部的预测，美国在2050年老年性痴呆的发病人数将达到1千万人，这是一个可怕的数字，将给美国政府带来巨大的经济负担和社会压力，所以必须未雨绸缪。不过对已经步入老年社会的中国和日本，这一疾病也同样是一个巨大的威胁。我们希望美国的这一巨额投资获得预期成果，至少给一大批老年人提供一种可以选择的真正有效预防药物。

前不久美国政府启动的脑图计划，其中也有一个目的是为老年性痴呆等神经疾病的机制研究带来重要基础，目前这一计划说明，不可以单纯依靠脑图计划来画饼充饥，一些可能有效的药物研究必须先行一步，只要有效果，没有无法接受的副作用，暂且不论具体分子机制，先用起来再说，这是药物研究一贯遵循的基本原则。这一计划显然更容易获得企业的支持，因为一旦成功，将给这些投资企业巨额的药物利润回报。想起几年前，匆忙启动的一个几十亿元重大新药研究计划，投资规模比这个还要大。不少研究机构甚至一些药物公司都获得直接的项目投资，那么到底这些研究获得那些成功的新药。

NIH's $33 Million Alzheimer's Gamble

The new trial—estimated to cost at least$100 million overall, with most of the remaining funds provided by partners inthe pharmaceutical industry—will be part of the Alzheimer's PreventionInitiative, a large consortium of researchers attempting to identify biomarkersand treatments that can slow or stop the disease. Lead researchers Eric Reimanand Pierre Tariot of the Banner Alzheimer’s Institute in Phoenix plan to give ayet-to-be identified anti-amyloid drug, or placebo, to 650 people who carry twocopies of the APOE4 gene—a genetic double whammy that confers a 10-foldincreased risk of developing Alzheimer’s late in life. All participants will bebetween the ages of 60 and 75 and healthy, including free of recognizedAlzheimer’s symptoms. Roughly a third will likely not have much amyloid intheir brains yet, allowing the researchers to track whether the drug affectsits accumulation, Reiman says.

The Banner trial “is a very reasonableapproach” to figuring out whether anti-amyloid drugs can effectively preventAlzheimer’s disease, says Gary Landreth, a neurologist who studies the diseaseat Case Western Reserve University in Cleveland, Ohio. He notes, however, thatit is quite unusual that the drug to be used has not yet been identified, giventhe size of the grant. Given that no anti-amyloid/Alzheimer's drugs have yetshown any clinical efficacy, “I think this really reflects the state ofdesperation felt in the scientific community as well as the public at largethat we have no effective therapeutics in the face of an ongoing epidemic ofAD,” he says. “They are taking a gamble.”

The APOE4 trial builds on another trial ofan anti-amyloid drug in 300 members of a Colombian family who carry a genemutation that places them at high risk of developing an early-onset form ofAlzheimer’s disease. Rather than wait for the results of that study, Reimansays that he and his colleagues decided to conduct the two trialssimultaneously to ensure that any positive results from the Colombian study canbe quickly tested into a more representative population—drugs that work forpeople with early-onset Alzheimer’s might not necessarily help those withlate-onset Alzheimer’s, he says.

Maria Carrillo, vice president of medicaland scientific relations at the Alzheimer’s Association, an advocacy group,applauds NIH’s giving the trial a green light: Targeting the APOE4 populationwill “increase the possibility that participants in the trial will becomesymptomatic during the period of the study so that the scientists can assesswhether the drug intervention is having an impact on delaying or preventingAlzheimer’s symptoms, without having to wait 10 or 15 years or more,” she says.

The U.S. government has placed a highpriority on tackling Alzheimer’s disease, which is expected to strike 10million Americans by 2050, according to the U.S. Department of Health and HumanServices (HHS). The 2011 National Alzheimer’s Project Act, for example, hasmandated that HHS establish a national plan to prevent or effectively treatAlzheimer’s disease by 2025. The new APOE study will use up the lion’s share ofthe $45 million that Francis Collins, director of NIH, has set aside forAlzheimer’s research in fiscal year 2013. (The $45 million total includes a $5million contribution from the National Institute on Aging [NIA]). According toNeil Buckholtz, director of the NIA Division of Neuroscience, the investmentreflects a shift toward trying to prevent the disease before it ravages thebrain, rather than reverse its effects, and a commitment to testing the amyloidhypothesis properly. “We believe this hypothesis has not received an adequatetest,” he says. He acknowledges, however, that putting so many research dollarsinto one basket is a “high-risk” strategy.

NIH also announced funding for fiveadditional grants to Alzheimer’s research, with a sixth award pending:

A $1.5 million trial testing three newanti-amyloid beta drug treatments—gantenerumab, solanezumab, and a third,undetermined drug—in volunteers with an inherited form of early-onsetAlzheimer’s. Led by Randall Bateman of Washington University in St. Louis, theinternational trial will have the potential to gain $6 million in funding over4 years.

A $2.4 million, 12-week phase 1 trialtesting the safety and tolerability of the steroid allopregnanolone fortreatment of mild cognitive impairment and Alzheimer’s, led by Roberta Brintonand Lon Schneider of the University of Southern California in Los Angeles.Animal studies have shown that the drug can lower amyloid levels, restorecognitive function, and spur the generation of new neurons.

A $1.7 million drug discovery effort toidentify molecular and genetic risk factors and new therapeutic targets forcognitive decline and Alzheimer’s disease, based on data from the ReligiousOrder Study and the Rush Memory and Aging Project. Led by Philip De Jager ofthe Brigham and Women's Hospital, the Broad Institute, and Harvard University,and David Bennett, of Rush University Medical Center in Chicago, the study willfocus on drugs that have completed phase 1 testing, and could be granted $7.9million over 5 years.

A $1.6 million effort to study the complexmechanisms of the disease and identify existing drugs that might be able to beused for Alzheimer’s treatment or prevention, led by Eric Schadt of IcahnSchool of Medicine at Mount Sinai in New York City. The study has the potentialto be granted $8.2 million over 5 years.

A $1.6 million study of the role of theimmune system and brain inflammation in Alzheimer’s disease, led by Todd Goldeof the University of Florida in Gainesville. The study has the potential to begranted $7.7 million over 5 years.