In the book, “Outlive,” Peter Attia refers to neurodegenerative diseases, such as Alzheimer’s and dementia, as one of the “Four Horsemen” of chronic diseases that significantly impacts human longevity and the experience of aging. This blog post explores the Alzheimer's research and treatment landscape, culminating in the recent approval of innovative drugs, and underscores the importance of continued advances for patients and caregivers. 

Alzheimer's disease is a progressive neurodegenerative disorder that affects millions of people worldwide. With the global aging population, the economic burden of AD is expected to grow significantly. By 2050, the total annual cost of care is projected to exceed $1.1 trillion (in 2021 dollars), reflecting a nearly threefold increase from the present day.  

The road to finding effective AD treatments has been challenging, with highs from scientific breakthroughs, crushing lows due to research failures and regulatory hurdles, and the relentless advocacy of patient groups.  

The Journey of Alzheimer's Research 

The path to understanding Alzheimer's disease has been marked by significant milestones in research. Early discoveries focused on the accumulation of amyloid plaques and tau tangles in the brain, which are hallmark features of the disease. These insights led to the development of various therapeutic approaches targeting these proteins. 

Recent research has expanded our understanding of Alzheimer's, incorporating genetic, environmental, and lifestyle factors. Studies have identified several genes associated with increased risk, such as APOE-e4, and have explored the role of inflammation and vascular health in disease progression. Advances in neuroimaging and biomarkers have also improved early diagnosis and tracking of disease progression. 

As of July 2024, there are two approved drugs for the treatment of AD:  

1. Kisunla (donanemab-azbt), manufactured by Lilly, was approved earlier this month on July 2, 2024 and is indicated for adults with early, symptomatic AD (including mild cognitive impairment or mild dementia stage of disease). In the 18-month clinical study, Kinsula reduced amyloid plaques on average by 61% at 6 months, 80% at 12 months, and 84% at 18 months compared to the start of the study.  

1. Leqembi (lecanemab-irmb), a collaboration between Eisai and Biogen, was first approved via the FDA’s Accelerated Approval pathway in January 2023, then granted traditional approval almost exactly a year ago on July 6, 2023. The indication is for the treatment of AD and should be initiated in patients with mild cognitive impairment or mild dementia stage of disease. The traditional approval was based on a large Phase III study showing that Leqembi reduced clinical decline by 27% (per the CDR-SB scale). Notably, the secondary endpoint was based on the ADCS MCI-ADL scale, as measured by people caring for patients with AD, and showed a statistically significant benefit of 37%.  

The drug development process for AD has been fraught with challenges – several drug candidates have shown promise in early phases but ultimately failed to demonstrate efficacy in later stages of clinical trials. Here is an overview of some notable Alzheimer's drugs that have failed in earlier phases: 

• Semagacestat (Eli Lilly), a gamma-secretase inhibitor, aimed to reduce amyloid-beta production by inhibiting the gamma-secretase enzyme. In Phase III trials, semagacestat not only failed to slow cognitive decline but also worsened cognition and increased the risk of skin cancer. The trial was halted in 2010 due to these adverse effects. (link) 

• Bapineuzumab (Pfizer/Johnson & Johnson), an anti-amyloid monoclonal antibody designed to target and clear amyloid plaques in the brain. Phase III trials showed no significant difference in cognitive decline between patients receiving bapineuzumab and those receiving a placebo. The trials were discontinued in 2012. (link) 

• Solanezumab (Eli Lilly), an anti-amyloid monoclonal antibody targeting soluble amyloid-beta. Despite showing some promise in Phase II trials, solanezumab failed to demonstrate a statistically significant benefit in slowing cognitive decline in Phase III trials. The drug was deemed ineffective in 2016. (link) 

• Verubecestat (Merck), a beta-secretase (BACE) inhibitor intended to reduce the production of amyloid-beta. Phase III trials for both mild-to-moderate and prodromal Alzheimer's patients were discontinued in 2017 and 2018, respectively, due to lack of efficacy and potential safety concerns. (link) 

• Crenezumab (Genentech/Roche), an anti-amyloid monoclonal antibody designed to clear amyloid plaques. In 2019, crenezumab failed to meet primary endpoints in Phase III trials for prodromal to mild Alzheimer's disease. The trials were discontinued due to lack of efficacy. (link) 

• Tramiprosate (Alzheon), an amyloid anti-aggregation agent aimed to inhibit amyloid-beta aggregation into plaques. Phase III trials did not show a significant benefit in cognitive outcomes compared to placebo. The drug failed to meet its primary endpoints in 2009. (link) 

• Latrepirdine (Dimebon) (Medivation/Pfizer), a candidate with an unexpected MOA – an antihistamine – that was investigated for its potential neuroprotective effects. Despite positive results in early trials, Phase III trials in 2010 did not demonstrate any cognitive or functional benefits over placebo, leading to the discontinuation of further development. (link) 

• Lanabecestat (AstraZeneca/Eli Lilly), a BACE inhibitor aimed at reducing amyloid-beta production. Phase III trials were halted in 2018 due to an independent data monitoring committee's recommendation that the drug was unlikely to meet its primary endpoint of slowing cognitive decline. (link) 

The repeated failures of Alzheimer's drugs in clinical trials underscore the complexity of the disease and the challenges in developing effective treatments. These setbacks have led to a broader understanding that Alzheimer's may require combination therapies targeting multiple pathways and a more personalized approach to treatment. 

Regulatory Challenges: The Case of Biogen's Aduhelm 

The approval of Biogen's Aduhelm (aducanumab) by the FDA in June 2021 was a watershed moment in Alzheimer's treatment, representing the first new therapy approved in nearly two decades. However, the approval process was filled with controversy and highlighted several regulatory challenges. 

The Aduhelm approval was based on its ability to reduce amyloid plaques, with the expectation that this would translate into clinical benefit. However, the clinical trials produced mixed results, with one study showing a significant reduction in cognitive decline and another failing to demonstrate such benefits. The FDA's decision to grant accelerated approval, despite the advisory committee's recommendation against it, sparked debate within the scientific community and among advocacy groups. 

Less than 3 years after approval, in January 2024, Biogen announced the discontinuation of Aduhelm due to these safety issues and the high cost of treatment. In response to the announcement, the Alzheimer’s Association press release conveyed the importance of Aduhelm in the Alzheimer’s therapeutic landscape story – not only was it the first-ever approved drug for AD that addressed one of the underlying causes of the disease (not just symptoms), but it also brought hope to the millions of people living with AD and their families.  

Beyond the Patient: Impact on Families 

In media, the impact of AD is poignantly depicted in the television series "Grey's Anatomy." As popular as the show was when it first came out, I was never one of those who tuned in weekly to catch the latest episodes. On a whim, I started it a few months ago and have been gradually making my way through it. I was struck with the realization of how much the healthcare landscape has evolved over the years since the show started and the impact of AD is poignantly depicted. Dr. Ellis Grey’s storyline highlights the profound effects of Alzheimer's beyond the patient, showcasing the emotional and psychological toll it takes on family members and caregivers. Meredith's struggle with her mother's condition reflects the real-life challenges many face: the fear of stigma, the burden of caregiving, and the grief of watching a loved one's cognitive decline. This portrayal underscores the importance of addressing not only the medical but also the emotional and social aspects of AD, emphasizing the need for comprehensive support systems for patients and their families. 

Patient advocacy groups play a crucial role in shaping the Alzheimer's research and treatment landscape. Organizations such as the Alzheimer's Association and UsAgainstAlzheimer's have been vocal in their support for new treatments while also emphasizing the need for comprehensive care and support for patients and caregivers. 

Advocacy groups hailed Aduhelm's approval as a step forward, providing hope to millions affected by the disease. However, they also expressed concerns about the high cost of the drug and the need for robust post-approval studies to confirm its efficacy and safety. 

Recent Research Advances 

The landscape of Alzheimer's research continues to evolve with promising developments. Researchers are exploring a variety of therapeutic targets beyond amyloid and tau, including neuroinflammation, synaptic health, and neuroprotection. Innovative approaches such as gene therapy, stem cell therapy, and precision medicine are also being investigated. 

One notable area of advancement is the use of combination therapies, which aim to address the multifaceted nature of Alzheimer's disease. Early-stage clinical trials are evaluating the potential of combining anti-amyloid treatments with drugs targeting other pathways, such as inflammation and oxidative stress. 

The Importance of Advances in Neurodegenerative Conditions 

The significance of advances in Alzheimer's research extends beyond the scientific community. For patients and caregivers, every breakthrough offers hope for improved quality of life and the possibility of a future without the devastating impact of the disease. 

Caregivers, often family members, bear a significant burden, providing round-the-clock care and support. Advances in treatment not only have the potential to slow disease progression but also to alleviate some of the emotional and physical toll on caregivers. As such, continued investment in Alzheimer's research is vital for both patients and those who care for them. 

Conclusion 

The journey to effective Alzheimer's treatment is ongoing, marked by scientific innovation, regulatory challenges, and the unwavering support of advocacy groups. The recent approval of Aduhelm represents both a milestone and a call to action for continued research and validation. As the landscape evolves, the collective efforts of researchers, regulatory bodies, and advocacy groups will be essential in bringing hope and relief to those affected by Alzheimer's disease. 

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