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News translated from sources National Association for Public Health and The Royal House of Norway (both in Norwegian)

Greetings from the Fang lab members and alumni Video (edited by Karl Stavem), song by Prof. Jon Storm-Mathisen, and playing the Chinese music instrument Gu-zheng by Dr. Shu-qin Cao.

On April 18 2023, researcher Evandro Fei Fang at the University of Oslo and Akershus University Hospital is the winner of the National Association for Public Health’s Dementia Research Prize for 2023.

His work in the search for effective drugs against Alzheimer’s disease is described as “groundbreaking”.

At the same time, Fang reminds that all good forces must make a joint effort to fight the disease that affects many of us.

Network for knowledge exchange
Over the past five years, Evandro Fei Fang has contributed to establishing networks for knowledge exchange between dementia researchers, held lectures about the research and his findings at prestigious universities worldwide and put the fight against dementia on the map and agenda in a number of ways.

The main reason for the award is also a concrete solution proposal Fang and his research team have put forward regarding a mechanism for removing damaged mitochondria in the brain. This track is referred to by several as “groundbreaking” in the search for effective medication against Alzheimer’s disease.

Garbage in the brain
– We believe that a main reason why we experience memory loss and other cognitive impairments when we get older is that a lot of “rubbish” accumulates in our brains over time. There is a “garbage truck” (termed “autophagy” in biology) in the brain that normally clears this away when we are younger, he says.

– When we age, however, this “garbage truck” becomes less efficient. The question is, why does this function lose effectiveness? There are several reasons, but an important element is that the garbage truck’s “engine” (termed “mitochondria” in biology) begins to wear out after many years of work. And if the engine goes on strike, the garbage truck doesn’t work well.

From theory to dementia drugs?
His hypothesis about what goes wrong when the form of dementia develops is also far more than an exciting theory. The mechanism has been replicated in studies carried out by several other research teams in a number of countries, which strengthens the belief in the potential medicinal value.

This understanding of Alzheimer’s has also led to Fang and his research team identifying two promising components which they hope can be further developed into effective medicines against the disease.

Evandro Fei Fang emphasizes the belief that this track can eventually lead to a better everyday life for those of us affected by Alzheimer’s.

– We should concentrate on repairing the garbage truck’s engine. The reason why we have different forms of plaque in the brain, and thus defining features of the disease picture in an Alzheimer’s diagnosis, is because this rubbish is created, but not removed. We need to add energy that restarts the engine and gets this cleaning process in the brain going again, says the award winner.

Cure requires community-wide dedication
At the same time, for Evandro Fei Fang, the fight against dementia is something that cannot be won on one’s own. He wants a joint boost against the disease, and believes we all play a key role on the road to a better future for people with dementia and their relatives.

– Our understanding of dementia and how we find the way to an effective drug against Alzheimer’s does not rest only on one lab or one research team. The whole society must work towards the same goal, not least in terms of funding. Our financial contributors, the ability to collaborate, the infrastructure around research and support from politicians and decision-makers are all very important elements. We must all play as a team if we are to manage this, he emphasizes.

The researcher is also clear about how much it means that ordinary Norwegians are on the team.

– Every kroner we receive in support moves us a small step towards the big goal. The support from private individuals through the National Association for Public Health is therefore very important to those of us who work with this every day. I hope and believe that what we are working on will be able to give a great deal of value back to society in the form of better prevention and better treatment of Alzheimer’s disease. My big thanks go to everyone who donates to the cause, says Evandro Fei Fang emphatically.

The jury’s reasoning
Since 2 October 2017, Evandro Fei Fang has been employed as a researcher at UiO, where he has established a very active group and conducts research on ageing and dementia at an internationally high level.

Fang and his colleagues have put forward a new etiological hypothesis for Alzheimer’s disease – defective mitophagy, the mechanism for removing damaged mitochondria (damaged engine of the garbage truck), the cells’ energy supply.

This hypothesis has been very well received in the competitive Alzheimer’s field with 676 citations to his 2017 article in Nature Neuroscience as of April this year.

The proposed mechanism is supported by trials in many species and welcomed in the international trade press (among others Kingwell 2019 Nat Rev Drug Discov) and international media. An editorial in Nat Rev Drug Discov points out that increasing mitophagy is a new and promising strategy for the treatment and prevention of Alzheimer’s disease.

The studies provide immediate clinical translation, since Fang has characterized several mitophagy-induced substances, e.g. the NAD+ precursor nicotinamide riboside (NR), and the naturally occurring urolithin (UA), as potential drugs against Alzheimer’s, and is now participating in clinical testing of NR in Alzheimer patients.

Very recently, the Fang laboratory has made an important new discovery: they used artificial intelligence with wet-lab validation in AD animals, and have identified two mitophagy-inducing ‘lead compounds’ as robust anti-AD drug candidates.

Since 2003, over 250 drugs have been in clinical testing for Alzheimer’s, but almost all have failed. The substances have mostly only been aimed at eliminating Aβ plaques and Tau tangles. It therefore seems necessary to focus on other mechanisms.

Fang and colleagues have proposed that impaired function of the NAD+-mitophagy axis is a ‘new’ etiological mechanism for AD. Fang has shown that NAD+ treatment increases mitophagy and counteracts memory loss in 4 animal models of Alzheimer’s. This has high clinical relevance, in the short and long term: Nicotinamide riboside (NA), which is converted to NAD+ in the body, is absorbed easily after oral administration without known toxicity. Clinical trials of NR on AD patients are in progress.

In Chinese
挪威国王哈拉尔五世（Harald V av Norge）向方飞（Evandro Fei Fang）副教授颁发挪威国家公共卫生协会痴呆症研究奖

2023 年 4 月 18 日，奥斯陆大学和阿克斯胡斯大学医院的副教授方飞（ Evandro Fei Fang） 获得了挪威国家公共卫生协会 2023 年痴呆症研究奖。

他在寻找有效治疗阿尔茨海默病药物方面的工作被描述为“开创性的”。

知识交流网络

在过去的五年中，方飞为建立痴呆症研究人员之间的知识交流网络做出了贡献，在全球知名大学举办了关于该研究和他的发现的讲座，并以多种方式将抗击痴呆症提上日程。

获奖的主要原因也是方和他的研究团队提出了关于大脑中受损线粒体清除机制的具体解决方案。在寻找有效治疗阿尔茨海默病的药物方面，这条路线被一些人称为“开创性”。

脑袋垃圾堆积

– 我们认为，随着年龄的增长，我们会出现记忆力减退和其他认知障碍的一个主要原因是，随着时间的推移，我们的大脑中会积累大量的“垃圾” （例如错误折叠或者缠积蛋白）。他说，大脑中有一辆“垃圾车”（生物学上称为“自噬”），通常会在我们年轻时将“垃圾”有效清除。

– 然而，当我们变老时，这种“垃圾车”的效率就会降低。问题是，为什么这个功能会失效呢？原因有几个，但一个重要因素是垃圾车的“发动机”（生物学上称为“线粒体”）在工作多年后开始磨损。如果发动机罢工，垃圾车就不能正常工作。

从理论到痴呆药物？

他关于痴呆症发展时出了什么问题的假设也远不止是一个令人兴奋的理论。该机制已在许多国家的其他几个研究小组进行的研究中得到重复，这加强了人们对潜在药用价值的信心。

对阿尔茨海默氏症的这种理解也促使 方飞和他的研究团队确定了两个有前途的成分，他们希望可以将它们进一步开发成治疗该疾病的有效药物。

方飞强调相信这条赛道最终可以为我们这些受阿尔茨海默氏症影响的人带来更好的日常生活。

– 我们应该集中精力修理垃圾车的引擎。我们大脑中有不同形式的斑块，并因此在阿尔茨海默氏症诊断中定义疾病图片的特征，是因为这些垃圾是产生的，但没有被清除。获奖者说，我们需要补充能量来重新启动引擎，让大脑中的清洁过程再次进行。

痴呆药物研发需要全社会的奉献

同时，对于方飞来说，与痴呆症的斗争是靠一己之力无法取胜的。他希望联合起来抗击这种疾病，并相信我们都在为痴呆症患者及其亲属创造更美好未来的道路上发挥着关键作用。

– 我们对痴呆症的理解以及我们如何找到一种有效的抗阿尔茨海默氏症药物的方法不仅仅取决于一个实验室或一个研究团队。整个社会必须朝着同一个目标努力，尤其是在资金方面。我们的财务贡献者、合作能力、围绕研究的基础设施以及政治家和决策者的支持都是非常重要的因素。他强调说，如果我们要做到这一点，我们就必须团结一致。

研究人员也很清楚普通挪威人在团队中的意义。

– 我们收到的每一克朗支持都会让我们朝着大目标迈出一小步。因此，个人通过全国公共卫生协会提供的支持对于我们这些每天都在与此打交道的人来说非常重要。我希望并相信，我们正在开展的工作能够以更好地预防和治疗阿尔茨海默病的形式为社会回馈大量价值。我非常感谢所有为这项事业捐款的人，方飞强调说。

陪审团的推理

自 2017 年 10 月 2 日起，方飞被聘为 UiO 和AHUS研究员，在那里他建立了一个非常活跃的团队，并在国际高水平的衰老和痴呆方面进行研究。

方和他的同事们提出了阿尔茨海默病的新病因假说——有缺陷的线粒体自噬，即清除受损线粒体（垃圾车发动机受损）、细胞能量供应的机制。截至今年 4 月，他在《自然神经科学》(Nature Neuroscience) 发表的 2017 年文章被引用了 676 次，这一假设在竞争激烈的阿尔茨海默氏症领域广受好评。

拟议的机制得到许多物种试验的支持，并受到国际媒体和国际媒体的欢迎。 例如，权威药物研发的科学杂志自然综述药物研发（Kingwell 2019 Nat Rev Drug Discov）的一篇社论指出，增加线粒体自噬是治疗和预防阿尔茨海默病的一种新的、有前途的策略。

方实验室基础研究推动直接的临床转化研发，因为 该实验室已经筛选出几种线粒体自噬诱导剂，例如NAD+ 前体烟酰胺核苷和天然存在的尿石素 作为潜在的抗阿尔茨海默氏症药物。NAD+ 前体正用于阿尔茨海默氏症患者的临床试验。

Some pictures (photographers He-Ling Wang, Yuan Fang, Evandro F. Fang, and from the Fang lab)