Blood Biomarkers from Research Use to Clinical Practice: What Must Be Done? A Report from the EU/US CTAD Task Force

Abstract

Timely and accurate diagnosis of Alzheimer’s disease (AD) in clinical practice remains challenging. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present limitations for clinical practice (i.e., cost, accessibility). Emerging blood-based markers have the potential to be accurate, cost-effective, and easily accessible for widespread clinical use, and could facilitate timely diagnosis. The EU/US CTAD Task Force met in May 2022 in a virtual meeting to discuss pathways to implementation of blood-based markers in clinical practice. Specifically, the CTAD Task Force assessed: the state-of-art for blood-based markers, the current use of blood-based markers in clinical trials, the potential use of blood-based markers in clinical practice, the current challenges with blood-based markers, and the next steps needed for broader adoption in clinical practice.

Independent study demonstrates amyloid probability score accurately indicates amyloid pathology

“…11 In addition, recent recommendations by the EU/US CTAD Task Force on the topic of what must be done to progress blood biomarkers from research use to clinical practice for the purpose of timely and accurate AD diagnosis, further support the use of combined biomarkers and risk factors in prediction models to limit misdiagnoses by healthcare providers. 24 In the present study, an exploratory analysis in healthy individuals indicated APS CLIA cutoff values established in cognitively impaired individuals continue to perform with high diagnostic accuracy in other populations including those who are cognitively unimpaired. Further studies in healthy individuals are currently underway to establish and expand the PrecivityAD test's diagnostic performance.…”

“…Similar improvements to amyloid prediction by the addition of ApoE proteotype status and age were observed in the CLIA validation studies of the PrecivityAD test and APS model used in current clinical care 11 . In addition, recent recommendations by the EU/US CTAD Task Force on the topic of what must be done to progress blood biomarkers from research use to clinical practice for the purpose of timely and accurate AD diagnosis, further support the use of combined biomarkers and risk factors in prediction models to limit misdiagnoses by healthcare providers 24 …”

“…Instead, appropriate context of use in this population applies to the clinical research setting where blood biomarkers are proving their utility as (i) prescreening tools to rule-out unnecessary CSF or PET evaluations in individuals who are likely to be amyloid negative, thereby lowering screening costs, accelerating trial enrollment timelines, and reducing inconvenience for otherwise willing study participants 25,26 ; (ii) an inclusion criterion (diagnostic tool) without the need for confirmatory CSF or PET testing; and (iii) as theragnostic markers to show biological target engagement and/or disease-modifying effects of investigational therapies. 9,10,24 Sixty-nine percent of individuals from the current AIBL analysis had at least two amyloid PET scans, which enabled an exploratory evaluation of PrecivityAD test results in the context of each individual's longitudinal amyloid accumulation trajectory. In this preliminary analysis, a single APS measurement discriminated between the presence or absence of amyloid plaques, and it also helped identify cognitively impaired and healthy control individuals on an amyloid accumulation trajectory versus those with stable, low amyloid levels.…”

“…Until further clinical validity is established, it is premature to use blood biomarkers for predictive evaluation of cognitively unimpaired individuals in the clinic as part of their routine clinical care or wellness visits. Instead, appropriate context of use in this population applies to the clinical research setting where blood biomarkers are proving their utility as (i) prescreening tools to rule‐out unnecessary CSF or PET evaluations in individuals who are likely to be amyloid negative, thereby lowering screening costs, accelerating trial enrollment timelines, and reducing inconvenience for otherwise willing study participants 25,26 ; (ii) an inclusion criterion (diagnostic tool) without the need for confirmatory CSF or PET testing; and (iii) as theragnostic markers to show biological target engagement and/or disease‐modifying effects of investigational therapies 9,10,24 …”

On gaps of clinical diagnosis of dementia subtypes: A study of Alzheimer’s disease and Lewy body disease

“…Seed amplification assays for alpha synuclein in cerebrospinal fluid (CSF), skin, and other biofluids and mucosa offer promising avenues to overcome these disparities by relying on biological evidence over clinical assessment, especially through routes that are less invasive ( Bellomo et al, 2022 ). Similarly, more widespread use of PET and CSF measures of amyloid and tau, and, even more importantly, plasma measures of amyloid, tau, and other markers (e.g., NfL, GFAP) ( Angioni et al, 2022 ) will offer more accurate assessment of AD co-pathology. At the same, more studies need to be done to assess how clinical syndromes may differ across demographic variables and how these variables impact LBD and AD biomarkers assessments, specifically with an examination of social determinants of health ( Majoka and Schimming, 2021 ; Gleason et al, 2022 ).…”