Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting millions of individuals globally. Every day, researchers, clinicians, and dementia professionals from around the world work towards discoveries that will lead to advancements in the prevention, diagnosis, and treatment for dementia and AD. Last month, over 10,000 of these researchers, clinicians and dementia professionals gathered at the 2023 Alzheimer’s Association International Conference (AAIC) in Amsterdam, Netherlands to share their latest research breakthroughs to achieve this aim. The AAIC is the world’s largest meeting dedicated to advancing dementia science.

Blood-Based Biomarkers in Alzheimer’s Disease

Among the many topics covered in the scientific presentations this year, the role of blood-based biomarkers in AD was prominently featured; several using Simoa® technology and Simoa® assays to support their findings. Notably, the National Institute on Aging and the Alzheimer’s Association Identification presented a proposal for new Alzheimer’s disease diagnostic criteria that incorporates the use of blood-based biomarkers¹. In line with this new proposal, the identification and validation of blood-based biomarkers associated with AD is crucial to improving research, drug development, diagnostics, and patient care. Quanterix’s ultrasensitive biomarker detection continues to make an impactful presence at AAIC, powering over 160 abstracts this year. Highlights from AAIC 2023 include the following:

The Power of p-Tau 217 in AD Research and Pathology Detection

One promising blood-based biomarker that garnered significant attention at AAIC 2023 is p-Tau 217, a specific isoform of tau protein phosphorylated at the threonine 217 residue. Tau is a microtubule-associated protein important for neuronal stability. One of the major neuropathological hallmarks of AD is hyperphosphorylation of the tau protein which is thought to lead to tau pathology and neuronal death. Previous research studies have demonstrated that plasma levels of p-Tau 217 are elevated in AD and are correlated with amyloid-PET positivity.

Presentations from the University of Gothenburg used the new and commercially available ALZpath p-Tau 217 Simoa® immunoassay in multiple studies to demonstrate the utility of p-Tau 217 as a highly specific and predictive indicator of AD pathology. One study found that the novel immunoassay demonstrated high accuracy in detecting amyloid and tau pathology across all stages of AD continuum². While another study showed that p-Tau 217 was the earliest plasma biomarker of dementia of the Alzheimer’s type in older primary care patients when compared to plasma p-Tau 181, amyloid beta 42/40 (Aβ42/Aβ40), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)³.

Multiple presentations using a p217+ tau Simoa® immunoassay further supported the potential use of p-Tau 217 as blood-based biomarker associated with AD. One study out of the University of Pittsburg demonstrated that plasma p-Tau 217 was a biomarker of Aß deposition in preclinical AD and appeared to be linked to both amyloid and tau pathology in symptomatic AD⁴. Additionally, researchers from the University of Melbourne showed that using p-Tau 217 alone to select cognitive impaired participants for a clinical trial could significantly reduce costs, compared to selection by PET⁵.

Finger Prick as a Collection Method for Detecting AD Associated Blood-Based Biomarkers

While plasma biomarkers have proven capable of detecting AD pathologies, one limitation is that they require on-site sampling with time-limited and temperature dependent processing protocols. A notable presentation led by Nicholas Ashton and his team at the University of Gothenburg aimed to further facilitate the usefulness of blood-based biomarkers by investigating a novel method of measuring NfL, GFAP, p-Tau 181, and p-Tau 217 from capillary dry blood spots obtained by finger pricks and venous dry blood spots⁶.  During this pilot study (DROP-AD), a total of 77 capillary and venous dried blood spot samples from memory clinic participants from ACE Alzheimer Center Barcelona were collected and biomarker levels were measured using the NfL, GFAP, p-Tau 181, and p-Tau 217 Simoa® immunoassays.  Their data showed that capillary NfL, GFAP and p-Tau 217 measurements from dry blood spots correlated highly with their counterparts in EDTA plasma⁷. Additionally, capillary dry blood spot GFAP correlated with Mini-Mental State Examination, a screening tool for cognitive impairment, Clinical Dementia Rating, and amyloid status⁷. This study underscores the potential quantification of GFAP, NfL, p-tau217 from a finger prick collection which may be able to facilitate remote monitoring of patients with suspected neurologic disorders.

The Mastermind of the Alzheimer’s Blood Test

The use of blood-based biomarkers for the detection AD pathology are beginning to be used in clinical practice. However, there is a growing opinion that multiple biomarkers are needed to help sort out the complexities of AD, co-pathologies, and non-AD dementias. NfL, GFAP, Aβ40, Aβ 2, and p-Tau are the blood-based biomarkers that currently show the most potential. Mike Miller (Quanterix) and Inge Verberk, PhD (Amsterdam UMC, VUmc) gave a Product Theater Presentation where they discussed work aimed at optimizing a multi-biomarker approach to aid in differential diagnosis of AD from other dementias with a blood test.

Novel fluid biomarkers of Alzheimer’s Disease

Individuals with Down Syndrome (DS) have a high risk of developing AD later in life and it is important to understand the biological link between these conditions to advance progress in diagnostics and treatment. It has been observed that p-Tau 212 is significantly increased in AD-DS male brains, suggesting a possible involvement of p-Tau 212 in progression to AD in individuals with DS. Researchers from the University of Gothenburg and their collaborators presented a study where they tested an in-house developed p-tau212 immunoassay using the HD-X™ Automated Immunoassay Analyzer. They showed that plasma p-Tau 212 started increasing around 20 years before people were diagnosed as prodromal AD-DS, CSF p-Tau 212 started increasing approximately 27 years before diagnosis, and that both plasma and CSF p-Tau 212 were strongly correlated⁸. Additionally, plasma p-Tau 217 was able to effectively differentiate asymptomatic DS from dementia-DS and cognitively normal from mild cognitive impairment, suggesting that plasma p-Tau 212 could be useful for early DS and AD differentiation⁸.

References

1. Proposed New Diagnostic Criteria for Alzheimer’s Disease Unveiled at AAIC 2023. AAIC. July 16, 2023. https://aaic.alz.org/releases_2023/new-alzheimers-diagnostic-criteria-unveiled.asp
2. Ashton NJ, Molfetta GD, Brum WS, et al. Plasma ALZpath p-tau217 for the identification of amyloid and tau positivity. Presented at: Alzheimer’s Association International Conference; July 16-20, 2023; Amsterdam, Netherlands.
3. Kleineidam L, Oezdemir S, Martino-Adami P, et al. P-tau217 is the earliest plasma marker of dementia of the Alzheimer’s type in older primary care patients. Presented at: Alzheimer’s Association International Conference; July 16-20, 2023; Amsterdam, Netherlands.
4. Ferreira PCL, Bellaver B, Povala G, et al. Plasma p-tau231 and p-tau217 provides information on tau tangle deposition in symptomatic Alzheimer’s disease individuals. Presented at: Alzheimer’s Association International Conference; July 16-20, 2023; Amsterdam, Netherlands.
5. Feizpour A, Dore V, Doecke JD, et al. Prognostic utility of plasma p217+tau vs amyloid and tau PET in the Alzheimer’s continuum. Presented at: Alzheimer’s Association International Conference; July 16-20, 2023; Amsterdam, Netherlands.
6. Simple Finger Prick Test Exemplifies Advances in Alzheimer’s Disease Blood Tests. AAIC. July 19, 2023. https://aaic.alz.org/releases_2023/finger-prick-blood-test-alzheimers-disease.asp
7. Huber H, Montoliu-Gaya L, Blennow K, et al. A finger prick collection method for detecting blood biomarkers of neurodegeneration – a pilot study (DROP-AD). Presented at: Alzheimer’s Association International Conference; July 16-20, 2023; Amsterdam, Netherlands.
8. Kac PR, Alcolea D, Montoliu-Gaya L, et al. Plasma p-tau212 is an early biomarker to identify Alzheimer’s Disease pathology in Down Syndrome. Presented at: Alzheimer’s Association International Conference; July 16-20, 2023; Amsterdam, Netherlands.