ABSTRACT
Blood‐based markers (BBMs) have recently shown promise to revolutionize the diagnostic and prognostic work‐up of Alzheimer’s disease (AD), as well as to improve the design of interventional trials. Here we discuss in detail further research needed to be performed before widespread use of BBMs. We already now recommend use of BBMs as (pre‐)screeners to identify individuals likely to have AD pathological changes for inclusion in trials evaluating disease‐modifying therapies, provided the AD status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. We also encourage studying longitudinal BBM changes in ongoing as well as future interventional trials. However, BBMs should not yet be used as primary endpoints in pivotal trials. Further, we recommend to cautiously start using BBMs in specialized memory clinics as part of the diagnostic work‐up of patients with cognitive symptoms and the results should be confirmed whenever possible with CSF or PET. Additional data are needed before use of BBMs as stand‐alone diagnostic AD markers, or before considering use in primary care.
INTRODUCTION
Blood‐based markers (BBMs) have recently shown promise to revolutionize the diagnostic and prognostic work‐up of Alzheimer’s disease (AD), as well as to improve the design of interventional trials. We here aim to provide appropriate use recommendations for use of these BBMs in clinical practice and trials. To this aim, we discuss the current need for biomarkers; we briefly summarize the state‐of‐the‐art of results for the most promising BBMs; and, more importantly, we define research priorities needed to fill significant knowledge gaps. Finally, we describe the consensus appropriate use recommendations defined by this expert group for use of BBMs in the clinic as well in trials.
THE CURRENT NEEDS FOR BLOOD‐BASED AD BIOMARKERS
Clinical practice
Approximately 25% to 30% of patients with a clinical diagnosis of AD dementia are misdiagnosed when assessed at specialized dementia clinics, and the accuracy of clinical diagnosis is similar or even lower for other dementias, including frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and vascular dementia. 1 , 2 , 3 However, most patients with cognitive or behavioral symptoms are managed in primary care where the misdiagnosis is even higher. Fifty percent to 70% of symptomatic patients with AD are not recognized or correctly diagnosed in primary care today, because routine cognitive screening is not performed and there is a lack of easily accessible, time‐ and cost‐effective, and accurate diagnostic tools. 4 The problem is even worse in early stages of the disease, that is, in patients without dementia who have either subjective cognitive decline (SCD) or mild cognitive impairment (MCI). Further, clinicopathological studies highlight that the match between clinical phenotype and biology/neuropathology in neurodegenerative dementias is imperfect. 4 Such studies also note that the diseases have a preclinical prodrome during which symptoms may be absent or very mild and non‐specific despite active neuropathological processes. 4
Methods for individualized prognosis of progression from SCD and MCI to AD dementia are also largely lacking. Timely and accurate diagnosis of AD goes beyond providing patients with diagnostic and prognostic information. It extends to optimization of treatment strategies (e.g., with symptomatic cholinesterase inhibitors or possibly novel anti–amyloid beta [Aβ] therapies) and providing appropriate care. Misdiagnosis leads to unnecessary care‐seeking and costly investigations due to diagnostic uncertainty. The established cerebrospinal fluid (CSF) and positron emission tomography (PET) measures have excellent diagnostic properties, but they are less useful outside very specialized clinics due to limited accessibility, invasiveness (e.g., CSF measures require a lumbar puncture, and PET requires infusion of stable isotopes and exposure to radiation), contraindications (e.g., anticoagulant medication might prohibit lumbar puncture) and high costs (PET is expensive and not universally covered by health insurance). 4 This precludes use of CSF and PET biomarkers in most primary and secondary care settings worldwide. Thus, a major benefit of the use of BBMs in screening for AD pathology, or diagnosis, is that the collection of blood is less invasive and likely less costly than CSF or neuroimaging markers, and more feasible at the primary care levels where most individuals will present with cognitive symptoms. 4 , 5 Although the development of BBMs has been previously hindered by insufficient analytical sensitivities, recent studies suggest promising results using easily accessible and potentially scalable BBM tests. 4 , 5 For example, primarily in specialized memory clinics, blood‐based AD biomarkers have been shown to differentiate AD dementia from dementia caused by other neurodegenerative disorders with accuracies non‐inferior to CSF and PET biomarkers, and to predict future development of AD dementia in non‐demented patients with cognitive complaints. 4
Clinical trials
When targeting upstream pathologies, such as Aβ pathology, therapies will likely be more effective during the early preclinical (“pre‐symptomatic”) stages before manifest and irreversible neurodegeneration has already occurred. It is also possible that certain pathologies (e.g., Aβ pathology) might trigger downstream events (e.g., spread of neocortical tau aggregates and synaptic degeneration), in which the latter eventually becomes independent from the initiating event. 6 Therefore, diagnostic biomarkers identifying AD pathology before the onset of overt clinical symptoms are needed to recruit suitable individuals with early disease to clinical trials. 4 , 5 Today, clinical trials typically use Aβ‐PET or CSF to screen for preclinical AD in cognitively normal individuals. However, the very high costs and low accessibility (especially in more diverse socioeconomic settings), and high number of screen failures (i.e., individuals who turn out to have normal PET or CSF results) make this approach very challenging. Consequently, clinical trials in this early stage of the disease have been hampered by the difficulty to recruit large numbers of participants across diverse settings. For example, it took the A4 (Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s) trial, which was the first phase 3 trial in preclinical AD, 3.5 years and > 4000 amyloid PET scans to identify and randomize 1169 participants with elevated brain amyloid. Therefore, it is very likely that blood‐based AD biomarkers will be increasingly used to identify those more likely to have pre‐symptomatic AD, who then can undergo PET or CSF measurements to confirm preclinical AD before entering the trial. 4 , 5 Even for clinical trials involving prodromal or dementia due to AD, blood biomarkers may substantially reduce the cost of screening and time to fully enroll the trial. Further, there is a need for BBMs to study drug target engagement or pharmacodynamic drug effects on downstream disease processes like neurodegeneration or neuroinflammation. 4 As an example, in other neurological diseases, like multiple sclerosis (MS), spinal muscular atrophy, and human immunodeficiency virus (HIV)‐associated neurocognitive dysfunction, plasma neurofilament light (NfL) concentration decreases in response to disease‐modifying treatment as a sign of reduced neurodegeneration. 7 , 8 , 9