Proteomics, Genomics & Microarrays


Reframing Alzheimer’s Disease: How genomics, proteomics and AI are powering precision medicine from bench to bedside


Nicole Selenko-Gebauer, MD, MBA, Group VP and Chief Innovation Offi cer, Diagnostics, Danaher Corporation


With tremendous social and economic costs, dementia is now the seventh leading cause of death globally, affecting 57 million people worldwide1. There are nearly 10 million new cases each year - with 60–70% of cases being Alzheimer’s disease (AD) - and this is expected to rise to more than 150 million cases by 20502. Although age is the greatest known risk factor for AD, it is not an inevitable consequence of aging2. AD can also affect younger people, with young- onset dementia - defi ned as symptoms beginning before the age of 65 - accounting for less than 10% of all cases1. The already high and growing burden of this disease means there is ever increasing need for simpler and more accessible diagnostic testing, especially for early diagnosis and treatment.


Infl ammation, autoimmunity and the metabolic roots of AD


Chronic neuroinfl ammation is now widely recognised as a central driver of AD progression. In the AD brain, activated microglia and astrocytes cluster around amyloid plaques and shift toward a sustained pro-infl ammatory state, secreting cytokines3. These immune mediators not only induce oxidative stress and mitochondrial dysfunction but also disrupt insulin and growth factor signalling, creating a feedback loop that accelerates synaptic damage and cognitive decline4. This persistent infl ammatory environment resembles immune overactivation seen in other chronic conditions and increasingly suggests that neuroinfl ammation is not a byproduct but a core driver of AD5.


There is growing recognition of autoimmune-like mechanisms within the disease. In a pattern reminiscent of type 1 diabetes5, where the immune system erroneously targets pancreatic β-cells, the AD brain shows upregulation of immune response genes, major histocompatibility complex (MHC) molecules, and even infi ltration of peripheral immune cells - hallmarks of an autoimmune reaction3. These fi ndings point to a possible breakdown in the brain’s immunological tolerance, where endogenous neuronal and glial components may become targets of the immune system, further perpetuating infl ammation and tissue injury3.


Layered on top of this immune dysregulation is the well-established connection between type 2 diabetes mellitus (T2DM) and AD6. Extensive clinical and molecular research has linked AD to systemic insulin resistance and metabolic dysfunction characteristic of T2DM. Individuals with T2DM are nearly twice as likely to develop


AD, and brain tissue from AD patients shows marked reductions in insulin receptor expression, impaired glucose and lipid metabolism7. These overlapping pathologies have led to the reframing of AD as ‘type 3 diabetes’ - a brain-specifi c form of insulin resistance that incorporates elements of both autoimmune dysregulation and metabolic dysfunction. This reconceptualisation unifi es previously disparate threads of AD research and opens the door to precision therapeutic approaches targeting infl ammation, immune dysfunction and metabolic signalling at the earliest stages of the disease. Much remains to be understood about the pathophysiology, natural history and progression of AD, which then needs to be parlayed into readily accessible diagnostics and disease-modifying treatments.


Biomarkers: The bedrock of precision diagnostics


At the heart of precision medicine lies the identification and application of biomarkers - molecular signals that indicate normal or pathological processes or pharmacologic responses to a therapeutic intervention. In AD, where early intervention is key to slowing or preventing neurodegeneration, the development of highly sensitive, reliable biomarkers is fundamental to enabling accurate diagnosis and disease monitoring well before symptoms emerge.


A promising advance in this field in terms of research comes from Beckman Coulter Diagnostics, which has recently developed a new panel of research use only high-sensitivity immunoassays specifically targeting four proteins that are known to be involved in the pathobiology of AD. These assays measure phosphorylated tau 217 (p-Tau217), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and apolipoprotein ε4 (APOE ε4) in human blood samples8. These biomarkers are well-established indicators of AD pathology (e.g., p-Tau217 ), and are known to be associated with a risk of developing AD (e.g., APOE ε4) or are markers of neurodegeneration and inflammation (i.e., NfL and GFAP)9,10,11,12,13.


Moreover, as current testing approaches require cerebrospinal fluid (CSF) sampling or advanced neuroimaging such as positron emission tomography (PET), the race is on to develop blood-based assays that offer a minimally invasive, scalable alternative suitable for both research and clinical environments. The first such assay for AD approved by the US Food and Drug Administration (FDA) was announced on 16 May 202514.


This assay was developed by Fujirebio with whom Beckman Coulter Diagnostics is in partnership16. Together with Fujirebio and Biogen, Beckman Coulter Diagnostics is continuing work to advance blood- and CSF-based biomarkers of tau pathology that could potentially predict AD years before clinical onset15-17. The ability to monitor AD biomarkers in blood rather than CSF removes a significant barrier to access, particularly in primary care and underserved settings. Combined with machine learning algorithms and other data integration tools, these biomarkers could help stratify patients, predict disease trajectory and guide therapeutic decisions - fulfilling the promise of precision neurology from the earliest stages of disease.


Figure 1: Development of a new high-throughput, fully automated immunoassay for plasma p-Tau 217, for research use only. A: The assay is able to clearly distinguish between amyloid positive and amyloid negative samples. B: Estimated limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ) of the p-Tau217 assay demonstrates precision and analytical sensitivity capable of detecting and quantifying relatively low p-Tau 217 concentrations in periphal blood. Credit: Beckman Coulter Diagnostics.


As available therapeutics are known to have the most benefit and better tolerability when used early in disease, being able to detect AD before clinical symptoms become too severe is critical. Therapeutically, the ambition evolves towards treating early, even if for a limited period of time, to demonstrate impact on delay of disease onset.


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