Sharpening our diagnostic toolkit for Alzheimer’s

Currently, more than 57 million people worldwide are living with Alzheimer’s disease or other forms of dementia, and that number is expected to triple to 152 million by 2050, with substantially higher rates in women and Black adults.

“Having new treatments for dementias like Alzheimer’s is incredibly important, but just as important is ensuring we can get those treatments to patients in time to make a difference,” says Joachim Reischl, VP of External Innovation, Diagnostics. “Treatments typically work best when they’re delivered as early as possible, which means we need to identify those patients before they exhibit full-blown symptoms of disease.” 

However, only 8% of patients with expected mild cognitive impairment (MCI) are diagnosed in primary care, leaving a whopping 92% undiagnosed. The potential impact of a blood test that could be effective at the pre-symptomatic stage of disease is enormous. 

To get ahead of this impending crisis, Danaher partnered with researchers at Washington University School of Medicine in St. Louis on a Beacon project on the next generation of plasma biomarkers for Alzheimer’s disease to address this challenge in two ways: identifying and validating new diagnostic markers for Alzheimer’s disease to enable the next generation of precision therapies as well as sharpening insights on how patients progress from mild cognitive impairment to later-stage dementias.

Beyond plaques and tangles biomarkers

The current gold standard of Alzheimer’s disease detection is to look for signs of the hallmarks of Alzheimer's in the brain, namely “plaques” of amyloid-beta (Aβ) proteins and “tangles” of tau proteins. Measuring these levels requires looking directly at cerebral spinal fluid through a spinal tap – an invasive and uncomfortable procedure that is often only offered in specialized facilities. Some recent assays also measure these same proteins (Aβ and tau) in blood.

But Alzheimer’s is a complex disease with numerous other biomarkers, including some that could potentially be used to diagnose the disease with a blood test before symptoms even emerge. To identify those potential biomarkers, the Beacon research team is leveraging the massive sample collection from the lab of primary investigator Carlos Cruchaga, PhD, including more than 3,000 plasma samples and 7,000 proteins from Alzheimer’s patients and cognitively normal individuals. These participants, part of the Knight Alzheimer’s Disease Research Center, are extremely well characterized with longitudinal clinical, cognitive and imaging data, allowing the identification of early disease biomarkers as well as those for disease progression. 

This large-scale approach enables them to identify and analyze the top additional biomarkers of Alzheimer’s that are present in both cerebral spinal fluid and plasma, which can be isolated in a much simpler-to-perform blood test. The promise and potential of large-scale plasma proteomic profiling for early detection and monitoring of Alzheimer’s was recently published in Nature Aging. 

“There is a need to identify new Alzheimer’s disease biomarkers and develop new clinical assays for early diagnosis and prognosis,” said Carlos Cruchaga, PhD, a professor of Psychiatry and director of the NeuroGenomics and Informatics Center at WashU Medicine. “Now that therapies targeting Aβ are approved and those for tau are being developed, there is a need to develop new predictive models that go beyond those proteins to capture Alzheimer’s disease neurodegeneration and not just Aβ and tau brain deposits.”

These additional biomarkers are important not just to develop more precise diagnostic tests for new treatment modalities in development, but also to lay the foundation for how to monitor patients under treatment and to decipher how aspects of the disease are being impacted by treatments – all in the service of enabling precision therapy specific to the disease mechanisms active in a given patient.

Predicting disease progression

Blood-based biomarkers can also shed light on how and when patients progress from MCI to full-blown Alzheimer’s disease. For some patients, this transition can take years, making it especially challenging to track and predict.

“An MCI-to-Alzheimer's progression monitoring test is important not just for patient management, but also for identifying which patients are likely to progress, how quickly that progression will take place, and identifying the disease mechanisms in a given patient,” says Reischl.

This is especially true with the advent of new, diverse disease-modifying treatments that extend beyond targeting amyloid-beta and tau proteins.

“Alzheimer’s is an incredibly complex disease that presents with a wide range of comorbidities,” says Reischl. “With the advent of amyloid beta targeting treatments, patients may be cleared from amyloid-beta and pTau but some may still exhibit cognitive symptoms. Having a fuller understanding of how different proteins manifest at different stages of disease will give us the kind of comprehensive understanding of the biology we need in order to develop even better, more effective therapies for patients at all stages of disease.”

The future of Alzheimer’s diagnostics

With the need for innovative approaches to dementias like Alzheimer’s only increasing, Danaher is making continued investments in Beacon partnerships to spur academic investigations. These include projects that will focus on understanding the diversity of Alzheimer’s biomarkers on a global scale and sharpening our ability to identify early risk factors for patients in primary care settings. 

While much of the work on blood tests for Alzheimer’s has been focused on honing diagnosis at the symptomatic stage of disease, collaborations like this Beacon are a prime example of the cutting-edge academic work that can ultimately benefit patients. 

“We are deeply invested in creating academic partnerships because they are the kind of long-range, forward-thinking projects that will lead to the next great breakthrough diagnostics and treatments,” says Reischl.