Accelerating Alzheimer’s Detection
How precision medicine, biomarkers, and data science are changing the face of Alzheimer’s disease research, diagnosis, and treatment
Kolb C Hartmuth | | 5 min read | Opinion
The precision medicine revolution is here and a sea of change is coming for Alzheimer’s disease (AD) research, screening, diagnosis, and treatment. At the Alzheimer’s Association International Conference (AAIC) in Amsterdam in July 2023, neurodegeneration researchers gathered to share new evidence about the biological underpinnings of the disease – and how their findings could improve treatment.
The tremendous progress in the biological understanding of the disease and the development of sensitive assays for measuring neuropathological changes led the National Institute on Aging and the Alzheimer’s Association (NIA-AA) to revise and refine the 2018 research framework that offers guidelines for the diagnosis of AD. The NIA-AA framework defines AD biologically – rather than based on clinical symptoms – which has allowed the development of disease modifying therapies. This step, along with the collective insights presented at AAIC, propel us forward in our quest to bring innovative treatments to AD patients.
The science of Alzheimer’s disease is ever-evolving
Over the past 20 years, the primary focus of my research has been on developing diagnostic tools for precision medicine studies based on novel imaging and fluid biomarkers. Guided by the principles of Click Chemistry, my team developed the PET imaging agent 18F-T807/AV1451/Flortaucipir for detecting and quantifying neurofibrillary tangles (NFT), which are aggregates of hyperphosphorylated tau, in AD (“tau pathology”) (2). Later, we added a highly sensitive blood test for quantifying phospho-tau 217 (p217+tau) to our diagnostic tool kit (3). Phospho-tau 217 is associated with amyloid and tau pathology.
Biomarkers have not only helped our understanding of AD, but also led to multiple breakthroughs in treatment. Sensitive diagnostic tools can now detect disease pathology in AD years before the onset of clinical symptoms, so they have the potential to preserve the most critical and rapidly diminishing variable when it comes to AD: time. My team’s AD research program is grounded in the latest advancements in precision medicine, data science, and digital health. The primary focus in our company’s therapeutic strategy is on the tau protein, where we use biomarkers for early diagnosis, disease staging, and monitoring to support drug development – with the ultimate goal of slowing or even halting disease progression.
Alzheimer’s symptoms can span 10–20 years of a person’s life. Marked by memory loss, cognitive decline, and the eventual inability to independently perform daily functions of living, this symptomatic period defines life with AD. It is not often appreciated that the disease starts decades before the onset of symptoms, beginning with the abnormal biochemistry of two proteins – amyloid beta (Aβ) and phosphorylated tau. With a biology-based research framework, we have made considerable progress in developing tools that are capable of early and accurate detection of AD pathologies before the onset of cognitive impairment caused by irreversible damage to the brain. We can now identify “pre-symptomatic” patients who may benefit the most from intervention.
Evaluating emerging plasma-based biomarkers
Wide-ranging access to these precision medicine tools is an important consideration, which means we have to develop tests that are non-invasive, affordable, and timely – all while maintaining the precision that is needed for decision-making. We believe the “research use only” blood p217+tau test could be valuable, if it was converted into an automated, scalable, validated in vitro diagnostics assay to support routine screening of larger populations – which is the foundation for broad-based disease interception. Alongside our collaborators, we presented more than a dozen abstracts at AAIC 2023 on this blood assay and its relationship with disease pathology.
First, my team evaluated the association of plasma p217+tau against two established biomarker measures: Aβ and tau accumulation PET (positron emission tomography) imaging (2). Our findings were consistent with our hypothesis that highly sensitive detection of p217+tau present in blood can offer accurate predictions of amyloid and tau status. The percentage of true results (positive or negative) for predicting amyloid status was over 85 percent, which allows for a highly efficient screening flow. Additionally, higher levels of plasma p217+tau were associated with increased amounts of NFT pathology, as measured by tau PET, allowing us to identify individuals with too much NFT pathology. The test has the potential to predict progression from mild cognitive impairment to AD dementia.
We estimate that the plasma p217+tau pre-screen reduces the number of tau PET scans by 65 percent. This way, unnecessary scans can be avoided, thereby reducing patient burden, allowing faster, more efficient trials to be conducted. This pre-screening approach allowed us to identify patients with NFT burden associated with early disease for our phase 2 autonomy trial with a tau PET success rate as high as 85 percent. We have employed the plasma p217+tau assay to screen out individuals with too little NFT pathology and with too much pathology for the purposes of our trial.
What does the future hold?
As disease-modifying treatments become a reality, tools capable of precise screening and early diagnosis will need to keep up. We envision a future where blood tests will be the gold standard for diagnosing AD. A preview of what the future holds for precision neuroscience includes:
- Early development of precision approaches based on known mechanisms of disease: blood and imaging tests for patient selection, staging, and progression monitoring.
- More precision medicine trials with the appropriate biomarkers (genetic, biochemical, behavioral, digital): scalable p217+tau blood-based diagnosis for phase 2 and phase 3 trials.
- Development and use of (reasonably likely) surrogate endpoints for clinical trials, such as amyloid or tau PET.
- Drug development shifts from treatment to biomarker/diagnostics-driven prevention/interception; therapy may be enabled by pre-symptomatic biomarker-based diagnosis.
- Commercial diagnostics will become a common public health tool that allows individualized therapy selection; automated, scalable, validated in vitro diagnostics will support routine screening of larger populations everywhere.
My pursuit of breakthrough science is motivated by a vision to identify patients with AD before daily functioning is impacted – to preserve time, independence, and connection for people affected by AD and those around them.
Credit: Images sourced from Unsplash.com
- C Groot et al., Alzheimers Res Ther, 14 (2022). PMID: 35568889
- DT Chien et al., J Alzheimers Dis, 34, 457 (2013). PMID: 23234879
- G Triana-Baltzer et al., Alzheimers Dement, 13 (2021). PMID: 34095436