▎藥明康德

編者按：抗擊阿爾茨海默病（AD）的戰役已進入新紀元，而阿爾茨海默病藥物發現基金會（ADDF）始終活躍在這一領域的前沿，致力于以明確的轉化醫學目標加速診斷技術與療法的研發。通過其獨特的公益創投模式，該基金會已資助超過150家生物科技企業，持續推動早期藥物開發。其最具雄心的項目之一"診斷加速器計劃"（DxA）作為一項獲得1億美元支持的全球倡議，正致力于開發可負擔、可及的生物標志物與診斷工具，用于阿爾茨海默病及相關癡呆癥的早期檢測。作為全球醫藥創新的賦能者，藥明康德長期以來也在為包括阿爾茨海默病在內的神經系統疾病創新療法研發提供各種服務，助力合作伙伴加速這些創新療法獲批上市。今年5月，FDA批準了首款輔助診斷阿爾茨海默病的血液檢測，值此契機，我們與ADDF聯合創始人兼首席科學官Howard Fillit博士展開對話，探討該領域的發展演進，并勾勒未來十年將阿爾茨海默病疾病負擔減半的關鍵戰略路徑。

Howard Fillit博士是國際知名的老年醫學專家、神經科學家及阿爾茨海默病研究領域的資深學者。作為ADDF的聯合創始人兼首席科學官，他長期致力于推動神經退行性疾病的創新療法研發，在老年醫學與認知障礙領域具有深遠影響力。Fillit博士擁有逾40年的學術與臨床經驗，發表了300余篇學術論著，其學術貢獻獲得業界廣泛認可。

您好，感謝您接受我們的訪談。您親歷了阿爾茨海默病研究領域從數十年躑躅不前到如今重煥生機的完整歷程。在您看來，當前我們應對該疾病的策略發生了哪些根本性轉變？

Howard Fillit博士：我們現在所看到的正是藥物研發的標準路徑——始于基礎科學發現，最終轉化為臨床效益。就阿爾茨海默病而言，這個過程始于一個多世紀前：1906年Alois Alzheimer醫生在對早老性癡呆患者進行尸檢時首次描述了斑塊和神經原纖維纏結。但直到1970年代，阿爾茨海默病才被認為是老年癡呆癥最常見的病因，而真正有意義的研究直到1980年代才起步，可以說我們完全是從零開始。這正是早期研究舉步維艱的主要原因之一。

直至1984年，β-淀粉樣蛋白才被確認為腦內斑塊的核心成分之一，這一發現不僅為我們提供了首個AD分子靶點，更掀起了全球范圍內的研究熱潮。自1985年起，整個研究領域幾乎將全部精力都聚焦于淀粉樣蛋白，斥資數十億美元用于闡明其致病機制、開發檢測方法并最終實現靶向干預。

近二十年來，我們首次迎來FDA批準的疾病修飾療法——Leqembi和Kisunla，這標志著AD治療領域的歷史性突破。這些進展得益于生物標志物和診斷工具開發領域的顯著進步，堪稱一場真正的醫學革命。那么，究竟是什么發生了根本性改變？我們終于將人類病理學發現、靶點驗證、診斷技術和臨床干預連成了一個完整的閉環。

ADDF采取了哪些獨特策略來降低研發風險和催化重大突破？其他生物科技公司或醫藥企業可以從貴機構的模式中獲得哪些啟示？

Howard Fillit博士：我們建立ADDF的使命只有一個：加速阿爾茨海默病藥物研發。這包含三大支柱——加速生物標志物開發、投資并開展早期治療手段研發、推動預防醫學研究。作為一家公益創投機構，我們不資助基礎研究，也不參與倡導工作，而是將所有資源集中于轉化醫學研究，這正是我們區別于多數基金會的核心特征。

我們通過可轉換債券、股權認證及風險投資式優先股權等方式，已完成對150余家早期生物科技企業的投資。關鍵在于，我們的資金嚴格綁定具體科研項目而非企業日常運營開支。企業必須向我們提交清晰的工作計劃、詳細預算及明確的里程碑節點。

此外，我們還提供真正的專業支持。ADDF擁有十余位專職神經科學家——其中多數具備深厚的產業界經驗。當我們投資一家企業時，我們不僅會評估他們的提案，還會幫助他們改進提案。許多阿爾茨海默病初創團隊都來自學術界，他們往往缺乏中樞神經系統（CNS）藥物開發的實戰經驗，無論是在臨床還是臨床前階段。例如，他們未必總是清楚特定研發項目中如何選擇最適用的動物模型。我們的專家團隊會全程指導——從選擇最佳動物模型到考慮監管策略——確保項目以最優配置向前推進。

另一個關鍵要素在于，作為公益創投機構，我們專注于長期投入。一般風投基金的投資期限可能只有10年，而我們能陪伴項目走得更遠。有一家生物科技企業與我們持續合作近二十年，在我們的幫助下，如今他們正努力為一個3期臨床項目籌集資金——這家企業的發展歷程尤其令我們振奮。

我們此前討論過CNS藥物研發史上居高不下的失敗率。根據您的經驗，這個領域至今仍存在哪些重大認知誤區？我們該如何破除這些誤區以提振行業信心與投資熱情？

Howard Fillit博士：其中一個重大問題在于歷史積淀不足——我們缺乏像腫瘤學領域數十年積累的臨床試驗體系。從1980年代到21世紀初，我們幾乎是從零開始學習有關阿爾茨海默病的一切。

2010年前后有一個典型案例：多家企業都在測試抗β-淀粉樣蛋白單抗藥物。某大型3期試驗中，一家公司使用正電子發射斷層掃描（PET）示蹤劑檢測大腦中的β-淀粉樣蛋白并進行了亞組分析，結果令人震驚——約30%受試者的淀粉樣蛋白掃描呈陰性。這意味著他們腦內根本沒有該藥物的靶點蛋白。更有可能的是，這些被領域專家納入試驗的癡呆患者很可能根本未患上阿爾茨海默病。

這給我們敲響了警鐘。它表明主觀診斷不夠準確，也指明了試驗失敗的一個關鍵原因。解決方案是采用基于生物標志物入組標準，使臨床試驗篩選變得更加客觀。ADDF支持了淀粉樣蛋白PET成像技術的早期開發，該技術應用后，臨床試驗的嚴謹性和效率顯著提升。

如今，血液生物標志物正推動新一輪變革，這將使試驗設計更加精準和可擴展。結合認知評估與tau蛋白成像技術的進步，我們已掌握開展嚴謹、可靠且高效的阿爾茨海默病臨床試驗的方法論。無論藥物最終成敗，至少我們能確保試驗本身科學可靠——這與十年前相比已是天壤之別。

圖片來源：123RF

隨著基于血液的生物標志物和神經影像學的進步，我們離實現阿爾茨海默病的實時精準醫療還有多遠？

Howard Fillit博士：我認為我們已處于一個重要的拐點。阿爾茨海默病的血液檢測首次成為現實，而且已有多種檢測方法進入市場。它們采用不同的生物標志物和技術。最具前景的靶點是p-tau217，其與β-淀粉樣蛋白斑塊密切相關；其他方法還包括Aβ42/40比值檢測、磷酸化tau/非磷酸化蛋白比例分析等。現有的檢測方法五花八門，新技術仍在不斷涌現。

阿爾茨海默病的診療進展始于創新，成于協作。通過"診斷加速器"計劃——一項由Leonard Lauder、Bill Gates、Jeff Bezos等慈善家共同出資1億美元發起的全球生物標志物倡議——我們已在全球支持70余個生物標志物項目。這些項目不僅涵蓋體液標志物，還包括用于改善和簡化認知評估的數字生物標記物，它們為AD的早期干預、更具包容性的臨床試驗以及未來個體化的預防性AD護理鋪平了道路。我們正邁入阿爾茨海默病診斷的變革時代，這著實是一個激動人心的里程碑。

預防醫學研究是ADDF的三大支柱之一。在預防AD方面，您認為哪個方向最有前景？

Howard Fillit博士：最令人振奮的工作之一當屬里程碑式的FINGER研究——這是首個評估生活方式干預能否預防阿爾茨海默病的隨機臨床試驗。其研究結果令人信服：約40%的AD病例或可預防。該研究采用五大干預方案：積極的社會互動、持續的職業活動、嚴格管控糖尿病與高血壓、規律運動及地中海飲食。簡言之，它將行之有效的心血管疾病預防策略應用于腦健康領域，同時強調認知刺激——本質上，這是一種"用進廢退"的腦力維持模式。

現在我們正推進ADDF資助的FINGER 2.0研究。正如心臟病學從單純生活方式干預發展到聯合他汀類藥物，我們正在干預方案中增加藥物成分。這項研究選用二甲雙胍，一種具有多重神經保護潛力的抗衰老候選藥物。目標是通過生活方式、共病管理與藥物三聯方案，驗證其能否更有效延緩早期阿爾茨海默病（包括輕度認知障礙）的進展。這標志著預防醫學的新疆界，我們對研究前景充滿期待。

圖片來源：123RF

感謝您的真知灼見！最后，您認為阿爾茨海默病領域研發的未來會如何？

Howard Fillit博士：我相信在不久的將來，我們將擁有血液檢測等實用工具，來識別處于疾病極早期階段的患者。在此基礎上，我們將向精準醫療模式邁進——利用生物標記物，以衰老生物學為基礎，根據患者獨特的神經退行性病變通路對其進行表型分析。這將催生個體化、多模式的治療方案：針對每位患者的生物學特征定制聯合療法。

我認為，未來五年內，我們有望見證首批超越現有治療標準的聯合療法的誕生。屆時，認知功能衰退的延緩率可能從當前的30%提升至50%甚至60%。同樣重要的是，我們將獲得"阿爾茨海默病可預防"的概念驗證證據。其影響將極為深遠：如果我們能將AD的發病時間或病程進展推遲五年，患者數量便可減半。這一目標不僅切實可行，更令人無比振奮。

Renewed Optimism on Alzheimer’s Disease: A Conversation with Dr. Howard Fillit, Co-Founder and Chief Science Officer, Alzheimer’s Drug Discovery Foundation

Editor’s Note:As the fight against Alzheimer’s disease enters a new era, the Alzheimer’s Drug Discovery Foundation (ADDF) remains at the forefront, accelerating the development of diagnostics and therapies with a clear focus on translational impact. Through its unique venture philanthropy model, the ADDF has funded over 150 biotech companies and continues to play a pivotal role in advancing early-stage drug development. One of its most ambitious efforts is the Diagnostics Accelerator (DxA)—a $100 million global initiative aimed at developing affordable, accessible biomarkers and diagnostic tools for the early detection of Alzheimer’s and related dementias. As the FDA authorized the first blood test to aid in the diagnosis of Alzheimer’s this May, we had a conversation with Dr. Howard Fillit, ADDF Co-Founder and Chief Science Officer, on the field’s evolution and outlines the critical strategies needed to halve the burden of Alzheimer’s in the years ahead.

Thanks for joining us, Howard. You’ve seen the Alzheimer’s field evolves—from decades of frustration to a moment of renewed optimism. What do you think has fundamentally shifted in our approach to the disease?

Howard Fillit:That’s a great question. What we’re seeing now is the usual course of drug development—starting with foundational science and ultimately translating into clinical impact. In Alzheimer’s, that arc began more than a century ago, when Alois Alzheimer first described plaques and tangles during the autopsy of a patient with presenile dementia in 1906. But it wasn’t until the 1970s that Alzheimer’s was even recognized as the most common cause of dementia in old age, and meaningful research didn’t begin until the 1980s. So, we started from scratch—literally zero. That’s a key reason for the frustration.

It wasn’t until 1984 that beta-amyloid was identified as a core component of the plaques, which gave us our first molecular target and catalyzed a massive research effort. From around 1985 onward, we’ve had an intense, nearly singular focus on amyloid, with billions of dollars invested in understanding it, detecting it, and ultimately targeting it.

For the first time in nearly two decades, we have disease-modifying therapies approved by the FDA— Leqembi and Kisunla — marking a historic breakthrough in Alzheimer’s treatment. These advances are possible because of remarkable progress in biomarkers and diagnostic tools. It's really a revolution.So, what’s fundamentally changed? We’ve finally connected the dots between human pathology, target engagement, diagnostics, and clinical intervention.

At the ADDF, how do you uniquely reduce risk and catalyze breakthroughs? And what lessons can others in biotech or pharma take from your approach?

Howard Fillit:We built the ADDF with a single mission: to accelerate drug development for Alzheimer’s. That included three pillars—acceleration of the development of biomarkers, developing and investing in early-stage treatments, and prevention. As a venture philanthropy, we don’t fund basic research, we don’t do advocacy—we put all our resources into translational science. That's one thing that makes our model different from many other foundations.

We’ve made over 150 investments in early-stage biotech companies, using convertible notes and warrants and we also use VC-style Preferred Equity.The difference is that our funds are tied strictly to a specific scientific project, not general expenses. Companies have to come to us with a clear work plan, a detailed budget, and defined milestones.

We also bring real expertise. We have more than 10 neuroscientists on staff—most with deep industry expertise.When we fund a company, we don’t just evaluate their proposal—we help improve it.A lot of early-stage Alzheimer’s startups come from academia and don’t have experience navigating the nuances of CNS drug development, either clinically or preclinically. For example, they don’t always know which animal models are the best ones to employ in that particular drug development program.Our team helps guide them—whether it’s choosing the right animal model or thinking through regulatory strategy—so the programs are in the best position to move forward.

Another key is that, as a venture philanthropy, we're in it for the long run.Whereas a venture capital fund might be limited to 10 years, we can stay in programs much longer. There is one biotech that we've been working with for almost 20 years. And we've helped them to get to the point where they're trying to raise funding now for a phase III program. And we're very excited about that particular company.

We’ve talked about the historically high failure rate in CNS drug development. From your experience, what are some of the biggest misconceptions that still haunt the field—and how can we overcome them to build more confidence and investment?

Howard Fillit:One big issue has been the lack of history—no decades of trial infrastructure like we’ve had in oncology. In the 1980s through the 2000s, we learned everything from scratch about Alzheimer’s.

An example came around 2010, when companies were testing monoclonal antibodies against beta-amyloid. In one major Phase III trial, a company used a PET tracer for beta-amyloid in the brain and did a sub-study. What they found was striking: about 30% of trial participants had negative amyloid scans. So, they didn't have amyloids in the brain, which was the target of the drug they were testing. And more than likely, they didn't have Alzheimer's disease, even though they had dementia and were enrolled by experts in the field.

That was a major wake-up call.It showed that subjective diagnoses weren’t good enough, and it highlighted a key reason why trials were failing.The solution came with biomarker-based enrollment, so the criteria for clinical trials became more objective.At the ADDF, we helped support the early development of amyloid PET imaging, and once that was implemented, the rigor and the efficiency of clinical trials improved dramatically.

Today, we’re seeing the next leap forward with blood-based biomarkers, which will make trials even more precise and scalable. Combined with advances in cognitive assessments and tau imaging, we now know how to run rigorous, robust, and efficient Alzheimer’s trials. Whether a drug succeeds or not, at least we know the trial was done right—and that’s a huge shift from where we were even a decade ago.

圖片來源：123RF

With the advances in blood-based biomarkers and neuroimaging, how close are we to achieving real-time precision medicine in Alzheimer’s?

Howard Fillit:That’s a great question.I think we’re already at a major inflection point.For the first time, we now have blood tests for Alzheimer’s disease—and several are on the market. They use different biomarkers and technologies. One of the most promising is p-tau217, which correlates strongly with beta-amyloid plaques. Others include the Aβ42/40 ratio, or the percentage of phosphorylated vs. unphosphorylated tau. So, there are different methods, and new ones are emerging.

Progress in Alzheimer’s starts with innovation and is made possible through collaboration. With the Diagnostics Accelerator (DxA), a $100 million global biomarker initiative—funded by leading philanthropists like Leonard Lauder, Bill Gates, Jeff Bezos and more—the DxA has supported more than 70 different biomarker programs worldwide.These include not only fluid-based markers but also digital biomarkers to improve and simplify cognitive assessment that pave the way for earlier intervention, more inclusive clinical trials, and a future of personalized, preventive Alzheimer’s care. We're entering a transformative era for Alzheimer’s diagnostics, which is an exciting milestone.

Prevention is one of the three pillars of the ADDF. In terms of prevention of Alzheimer’s, which direction do you find most promising?

Howard Fillit:One of the most exciting efforts is the landmark FINGER trial—the first randomized clinical trial to evaluate whether Alzheimer’s can be prevented through lifestyle interventions. The findings are compelling, suggesting that up to 40% of cases may be preventable. It uses a five-pronged approach: social engagement, continued occupational activity, rigorous management of diabetes and hypertension, regular exercise, and a Mediterranean-style diet.In short, it applies proven heart disease prevention strategies to brain health, with the added emphasis on cognitive stimulation—essentially, a “use it or lose it” model for maintaining mental vitality.

Now we’re moving into what we call FINGER 2.0, an ADDF-funded study. Just as cardiology evolved from lifestyle changes alone to combining them with drugs like statins, we’re adding pharmacological interventions to the mix. In this case, we’re testing metformin—one of the leading anti-aging candidates with multiple potential neuroprotective effects.The idea is to combine lifestyle and comorbidity management with a drug to see if we can better slow progression in early-stage Alzheimer’s, including those with mild cognitive impairment.It’s a new frontier in prevention, and we're hopeful about where it’s headed.

圖片來源：123RF

Thank you for your insights! To conclude, if you could make one bold prediction, what do you see as the future of Alzheimer’s research and development?

Howard Fillit:I believe we’ll soon have practical tools—like blood tests—to identify patients very early in the disease. From there, we’ll move toward a precision medicine model:using biomarkers to phenotype patients based on their unique neurodegenerative pathways, grounded in the biology of aging. This will enable a personalized, multimodal approach to treatment—combining therapies tailored to each individual’s biology.

Within the next five years, I think we’ll see the first examples of combination therapies that move beyond our current standard. Instead of a 30% slowing in cognitive decline, we could be looking at 50% or even 60%. Just as important, I believe we’ll have proof of concept showing prevention is possible. And here’s the impact:if we can delay the onset or slow the progression of Alzheimer’s by just five years, we could cut the number of cases in half.That’s achievable and incredibly exciting.

參考資料：

[1] HOWARD FILLIT, MD. Retrieved June 20, 2025, from https://www.alzdiscovery.org/about-addf/people/howard-fillit

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