Interpreting blood‐based biomarker results in heterogeneous populations with multiple co‐morbidities
Authors: Mielke Michelle M. 
Published: December 2022

AbstractBackgroundA major benefit of the use of blood‐based biomarkers in screening for Alzheimer’s disease (AD) pathology, or diagnosing AD dementia, is that the collection of blood is less invasive and costly than cerebrospinal fluid or neuroimaging markers. Blood biomarkers are also more feasible and available at the primary care levels, where most individuals will present with cognitive symptoms. However, most studies examining blood‐based biomarkers of amyloid, phosphorylated tau, or neurodegeneration for screening or diagnosis have been conducted in neurology or memory clinics. Patients that reach these clinics often have less comorbidities and are younger than those seen and followed in primary care. Thus, there is a need to assess the utility of these blood‐biomarkers in diverse, community‐based cohorts of older ages, with multiple comorbidities, and with brain co‐pathologies (i.e., cerebrovascular disease).MethodUsing examples from the Mayo Clinic Study on Aging and other community‐based studies, we will synthesize the impact of demographics, comorbidities, and co‐pathologies on blood measures of amyloid‐beta, phosphorylated tau, neurofilament light chain (NfL), total tau, and glial fibrillary acid protein (GFAP). Additional discussion will focus on how these factors may impact cut‐points and the interpretation of the blood biomarkers across the AD clinical spectrum, as well as potential methods to better elucidate the biomarker results for clinical care.ResultBlood measures of amyloid‐beta, phosphorylated tau, NfL, total tau, and GFAP are differentially affected by age and sex and some comorbidities (e.g., chronic kidney disease, stroke, myocardial infarction, diabetes, body mass index). Although adjusting for covariates has been a method used in some research studies, adjustment will not work on an individualized level for patients seen in primary care. Different cutpoints may be needed based on age and the presence or absence of specific comorbidities. In addition, when interpreting the results for diagnosis and prognosis, co‐occurring co‐pathologies (e.g., cerebrovascular disease) must be considered.ConclusionSeveral studies have shown the promise of blood‐based biomarkers for screening and diagnosing AD in memory clinics. However, several considerations and steps are needed before these blood biomarkers can be implemented for use at the population level and in primary care.BackgroundWhen and how to communicate effectively the results of genetic and biomarker based prediction, detection, and quantification of the brain substrates of dementia involve important ethical and legal issues critical for precision medicine. AGREEDementia is an open working group that focuses on informed discussions and development of educational material to support communication and use of this information.MethodMembers attend two meetings monthly via videoteleconference. One meeting is a targeted working group that focuses on the following: 1. People with Symptoms, 2. People without Symptoms, 3. Research, 4. Ethics/Healthcare Law, 5. Diversity. Members also attend a monthly “all hands” meeting where they receive updates from other groups, partner organizations, and hear presentations on emerging research and resources.ResultOver the past few years AGREEDementia has produced several collaborative papers, webinars, and decision tools for people considering undergoing biomarker testing that will be discussed. Membership continues to grow to over 120 though level of involvement varies. The group is largely comprised of academic researchers (76%) including neurologists, neuropsychologists, clinical trial coordinators, ethicists, and healthcare lawyers. The second largest subgroup was from advocacy groups and stakeholders (18%) and 6% are students. Collaborations with other organizations including the NIA, Alzheimer’s Association/ISTAART, the Lewy Body Dementia Association, Association for Frontotemporal Dementia, and Cohen Veterans Bioscience greatly enrich the group by publicizing conferences and collaborating on papers and products. The Alzheimer’s & Dementia Outreach, Recruitment & Engagement at NIA also disseminates decision tools and other materials. Over time, the stakeholder group developed from an audience providing consultation to a creative force that pioneered a program to support people with cognitive dysfunction attending AAIC and other scientific conferences. The Diversity workgroup was added in order to mentor and teach research staff in sensitive outreach to diverse cohorts. The ongoing, monthly, lecture series and links to all these materials are hosted at a website, AGREEDementia.com.ConclusionWith controversies around how best to integrate biomarker and genetic information into clinical care, when to share research data with the public, and implement novel biomarker‐based therapies, AGREEDementia has provided an open forum for all to visit and consult.