Browsing by Subject "Blood‐based biomarkers"

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    Blood-based gene and co-expression network levels are associated with AD/MCI diagnosis and cognitive phenotypes
    (Wiley, 2025-01-09) Chen, Xuan; Reddy, Joseph S.; Wang, Xue; Quicksall, Zachary; Nguyen, Thuy; Reyes, Denise A.; Graff-Radford, Jonathan; Jack, Clifford R., Jr.; Lowe, Val J.; Knopman, David S.; Petersen, Ronald C.; Kantarci, Kejal; Nho, Kwangsik; Allen, Mariet; Carrasquillo, Minerva M.; Saykin, Andrew J.; Ertekin-Taner, Nilüfer; Radiology and Imaging Sciences, School of Medicine
    Background: Alzheimer’s disease (AD) patients have decline in cognitive domains including memory, language, visuospatial, and/or executive function and brain pathology including amyloid‐β and tau deposition, neurodegeneration, and frequent vascular co‐pathologies detectable by neuroimaging and/or cerebrospinal fluid biomarkers. However, molecular disease mechanisms are complex and heterogeneous. It is necessary to develop cost‐effective blood‐based biomarkers reflecting brain molecular perturbations in AD. We identified blood‐based gene and co‐expression network level changes associated with AD/mild cognitive impairment (MCI) diagnosis and AD‐related phenotypes. Method: We performed differential gene expression and weighted gene co‐expression network analysis, followed by meta‐analysis, using blood transcriptome data of 391 participants from the Mayo Clinic Study of Aging and 654 participants from the Alzheimer's Disease Neuroimaging Initiative. The neuroimaging phenotypes include microhemorrhages, infarcts, amyloid burden, hippocampal volume, and white matter hyperintensities. The cognitive phenotypes include standardized cognitive subtest scores and composite scores for memory, language, visuospatial, and executive function. Result: Five out of 18 modules(M) are significantly associated with diagnosis or cognition (FDR‐adjusted p<0.05). M1 and M15 both positively associates with memory, M1 positively associated with language and M15 with visuospatial function. M1 and M15 are enriched in differentially expressed genes (DEGs) associated with language and executive function, respectively. M2 negatively associates with logical memory delayed recall scores(LMDR), memory, executive, and language functions and is enriched in DEGs for these phenotypes. M8 negatively associates with memory, language and executive functions and is enriched in DEGs for memory and language. M12 positively associates with LMDR. M1 and M15 are down‐regulated while M2 and M8 are up‐regulated in AD/MCI patients. Cell‐type enrichment analysis showed M2 is enriched in monocytes and neutrophils; M8 in monocytes; M15 in B cells (FDR <0.05). Gene ontology terms enriched in these modules indicated broad consistency with their cell types. Conclusion: We identified five modules significantly associated with AD/MCI or cognitive phenotypes using blood transcriptome data. These findings nominate blood transcriptome changes and their enriched biological processes as potential pathomechanisms in cognitive decline and AD/MCI development. We aim to investigate these blood transcripts as potential biomarkers for AD or AD‐related phenotypes and therapeutic targets through additional replication and experimental validation studies.
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    Blood‐Based Biomarkers to Aid in Alzheimer’s Disease Prediction or Diagnosis: Analysis in a Multi‐Ethnic Cohort Study
    (Wiley, 2025-01-03) Bahl, Aanya; Honig, Lawrence S.; Kang, Min Suk; Sanchez, Danurys; Reyes-Dumeyer, Dolly; Manly, Jennifer J.; Lantigua, Rafael A.; Dage, Jeffrey L.; Brickman, Adam M.; Vardarajan, Badri N.; Mayeux, Richard; Gu, Yian; Neurology, School of Medicine
    Background: Blood‐based biomarkers may aid in the diagnosis of Alzheimer’s Disease (AD), but their contribution may be confounded by the presence of multiple chronic conditions and have not been well‐tested in community populations. In the current study, we aimed to determine whether blood‐based biomarkers can aid in refining a multi‐ethnic, urban clinically diagnosed AD community‐based cohort. Method: We included 546 individuals in the Washington Heights, Hamilton Heights, and Inwood Columbia Aging Project (WHICAP) study in this cross‐sectional study. Six biomarkers, including phosphorylated‐tau‐181 (P‐tau181), total (T‐tau), amyloid‐beta 40 and 42 (Aβ40, Aβ42), Glial Fibrillary Acid Protein (GFAP), and Neurofilament Light Chain (NfL) were measured using Quanterix SIMOA HD‐X platforms. The association between the biomarkers and AD or cognitive impairment was tested using logistic regression, adjusted for age, sex, ethnic group, and years of education. Individuals were subsequently characterized as ‘biomarker positive’ or ‘biomarker negative’ based on combined GFAP and P‐tau181/Aβ42 cut scores. Result: The mean age of individuals was 79.3 years (6.56) and 379 (69.4%) were women, 133 (24.48%), were Non‐Hispanic Black, 153 (28.0%) Non‐Hispanic White, and 248 (45.4%) were Hispanic. A clinical diagnosis of AD was made in 129 (25.49%) individuals. Low Aβ42 (OR = 0.18, [95% CI: 0.04 ‐ 0.92]), low Aβ42/Aβ40 (OR = 0.49, [95% CI: 0.228 ‐ 0.872), and high P‐tau181/Ab42 (OR = 5.494, [95% CI: 1.523 – 20.416]) were associated with a clinical diagnosis of AD suggesting a role as predictive biomarkers. However, the best combination, GFAP and P‐tau181/Aβ42 cut scores, yielded a sensitivity of 41% and specificity of 70.5% for clinically diagnosed AD. The concordance was 54.5% and the discordance was present in both directions. Low education, cardiovascular and other comorbidities might contribute to the discrepancy between biomarker positivity and clinical diagnosis. Conclusion: While GFAP and P‐tau181/Aβ42 levels are associated with AD pathology and can aid in the diagnosis of AD, the presence of multiple chronic conditions may lead to either false positives or negatives. Large multi‐ethnic community cohort studies are needed to further examine the utility of these biomarkers in aiding in the clinical diagnosis of AD.
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    Considerations for widespread implementation of blood-based biomarkers of Alzheimer's disease
    (Wiley, 2024) Mielke, Michelle M.; Anderson, Matthew; Ashford, J. Wesson; Jeromin, Andreas; Lin, Pei-Jung; Rosen, Allyson; Tyrone, Jamie; VandeVrede, Lawren; Willis, Deanna; Hansson, Oskar; Khachaturian, Ara S.; Schindler, Suzanne E.; Weiss, Joan; Batrla, Richard; Bozeat, Sasha; Dwyer, John R.; Holzapfel, Drew; Jones, Daryl Rhys; Murray, James F.; Partrick, Katherine A.; Scholler, Emily; Vradenburg, George; Young, Dylan; Braunstein, Joel B.; Burnham, Samantha C.; de Oliveira, Fabricio Ferreira; Hu, Yan Helen; Mattke, Soeren; Merali, Zul; Monane, Mark; Sabbagh, Marwan Noel; Shobin, Eli; Weiner, Michael W.; Udeh-Momoh , Chinedu T.; Medicine, School of Medicine
    Diagnosing Alzheimer's disease (AD) poses significant challenges to health care, often resulting in delayed or inadequate patient care. The clinical integration of blood-based biomarkers (BBMs) for AD holds promise in enabling early detection of pathology and timely intervention. However, several critical considerations, such as the lack of consistent guidelines for assessing cognition, limited understanding of BBM test characteristics, insufficient evidence on BBM performance across diverse populations, and the ethical management of test results, must be addressed for widespread clinical implementation of BBMs in the United States. The Global CEO Initiative on Alzheimer's Disease BBM Workgroup convened to address these challenges and provide recommendations that underscore the importance of evidence-based guidelines, improved training for health-care professionals, patient empowerment through informed decision making, and the necessity of community-based studies to understand BBM performance in real-world populations. Multi-stakeholder engagement is essential to implement these recommendations and ensure credible guidance and education are accessible to all stakeholders.
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    Implementing a biomarker‐enabled care pathway to accelerate identification of early‐stage Alzheimer’s disease in primary care
    (Wiley, 2025-01-09) Borson, Soo; Au, Rhoda; Chodos, Anna H.; Gandy, Sam E.; Jain, Holly; Kerwin, Diana R.; Mintzer, Jacobo; Monroe, Stephanie; Robinson, Delecia; Wilcock, Donna M.; Mielke, Michelle M.; Neurology, School of Medicine
    Background: New blood‐based and digital biomarkers for Alzheimer’s disease (AD) make early detection possible at stages when novel, disease‐specific therapies are likely to be most effective. These approaches may offer less invasive, more cost‐effective alternatives to traditional methods such as cerebrospinal fluid (CSF) collection or positron emission tomography (PET) imaging for diagnosing and staging AD. Building care pathways leveraging blood‐based and digital biomarkers starts with understanding the current biomarker landscape and considering opportunities for widespread implementation in primary care clinical practice. Methods: A multidisciplinary team representing neurology, neuropsychology, geriatrics, primary care, epidemiology, laboratory programs, and patient advocacy was convened to review a summary of current biomarker research findings and discuss barriers and opportunities to implement biomarkers as part of an AD consensus‐driven clinical care pathway. Results: The emergence of biomarkers has shifted diagnosis from primarily clinical to a biological definition of AD. However, there is currently no consensus on where biomarkers fit within an AD care pathway and when they should be utilized in primary care or dementia specialist care settings. We found a relative paucity of published data on biomarker test accuracy in diagnosis outside tightly controlled research settings, limiting guidance around how results should be interpreted and managed in real‐world care settings. Evidence gaps are especially pressing for heterogeneous, diverse populations under‐represented in AD research. New biomedical therapies specific to the pathobiology of AD are driving research on blood and digital biomarkers to inform optimal ways to accelerate identification. As most individuals with AD are not evaluated by specialists, accurate and usable information about the place of biomarkers in the diagnosis and treatment of cognitive impairment must reach primary care Conclusions: With growing interest in the promise of non‐invasive biomarkers to improve detection, differentiation, and diagnosis of AD, new research is needed to generate real‐world evidence about their performance across populations, how to interpret results, and how best to use them in patient management. Effective educational strategies are needed to disseminate high‐quality evidence that engages primary care and healthcare delivery systems in implementing optimal clinical pathways. More detailed learnings for successful care pathway implementation will be shared.
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    Opportunities to encourage adoption of a biomarker-enabled care pathway for Alzheimer's in primary care
    (Wiley, 2025-03-11) Borson, Soo; Au, Rhoda; Chodos, Anna H.; Gandy, Sam; Jain, Holly; Alagor, Amy; Cohn, Kristi; Kerwin, Diana R.; Mintzer, Jacobo; Monroe, Stephanie; Robinson, Delecia; Mielke, Michelle M.; Wilcock, Donna M.; Neurology, School of Medicine
    Identification of early-stage Alzheimer's disease (AD) remains a challenge due to limited specialist availability, diagnostic access, disease awareness, and cultural factors. Blood-based biomarkers (BBBM) could play a critical role in the identification and referral of patients suspected of AD to specialty care. A multidisciplinary AD Biomarker Task Force was convened to evaluate current biomarker use cases, define an optimal biomarker-enabled AD diagnostic care pathway, and understand factors impacting adoption. The Task Force identified opportunities to support biomarker-enabled AD diagnostic care pathway adoption, including streamlining risk assessment and screening by leveraging digital tools, activating primary care providers through education, generating data to expand applicability to diverse populations, and advocating for aligned policies and quality measures. Adoption of BBBMs in the primary care setting will be critical to improve early AD detection. However, challenges to pathway adoption persist and will require action from clinicians, payers, policy makers, and patients to address. Highlights: Blood-based biomarkers can streamline the identification of AD in primary care. Future biomarker-enabled diagnostic care pathways will leverage digital assessments. Education, data generation, and policy advocacy are vital to encourage BBBM use. Implementation of AD care pathways requires the activation of diverse stakeholders.
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    Recommendations for clinical implementation of blood-based biomarkers for Alzheimer's disease
    (Wiley, 2024) Mielke, Michelle M.; Anderson, Matthew; Ashford, J. Wesson; Jeromin, Andreas; Lin, Pei-Jung; Rosen, Allyson; Tyrone, Jamie; Vandevrede, Lawren; Willis, Deanna R.; Hansson, Oskar; Khachaturian, Ara S.; Schindler, Suzanne E.; Weiss, Joan; Batrla, Richard; Bozeat, Sasha; Dwyer, John R.; Holzapfel, Drew; Jones, Daryl Rhys; Murray, James F.; Partrick, Katherine A.; Scholler, Emily; Vradenburg, George; Young, Dylan; Braunstein, Joel B.; Burnham, Samantha C.; de Oliveira, Fabricio Ferreira; Hu, Yan Helen; Mattke, Soeren; Merali, Zul; Monane, Mark; Sabbagh, Marwan Noel; Shobin, Eli; Weiner, Michael; Udeh-Momoh, Chinedu T.; Medicine, School of Medicine
    Blood-based biomarkers (BBM) for Alzheimer's disease (AD) are being increasingly used in clinical practice to support an AD diagnosis. In contrast to traditional diagnostic modalities, such as amyloid positron emission tomography and cerebrospinal fluid biomarkers, BBMs offer a more accessible and lower cost alternative for AD biomarker testing. Their unique scalability addresses the anticipated surge in demand for biomarker testing with the emergence of disease-modifying treatments (DMTs) that require confirmation of amyloid pathology. To facilitate the uptake of BBMs in clinical practice, The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to provide recommendations for two clinical implementational pathways for BBMs: one for current use for triaging and another for future use to confirm amyloid pathology. These pathways provide a standardized diagnostic approach with guidance on interpreting BBM test results. Integrating BBMs into clinical practice will simplify the diagnostic process and facilitate timely access to DMTs for eligible patients.