Biomarkers and the diagnosis of preclinical dementia

Abstract

SUMMARYAlzheimer's disease pathology accumulates years before the onset of clinical symptoms and has been termed ‘preclinical dementia’. Biomarkers have been developed to detect this pathology – namely, brain amyloid deposition and markers of neurodegeneration. In this article we describe these biomarkers and review the evidence for their clinical use in predicting risk both in the cognitively ‘normal’ and in those who already have established cognitive decline. We also discuss the limitations and ethical considerations of these tests and consider whether we should start incorporating Alzheimer's disease biomarkers into clinical practice. We find that, because many cognitively healthy people will have Alzheimer's pathology, and it is not clear whether this does help predict future risk of Alzheimer's disease, diagnosing preclinical dementia carries numerous ethical implications and is currently not being advocated outside research settings.LEARNING OBJECTIVES•Understand the concepts of preclinical and prodromal Alzheimer's disease and the use of biomarkers in this context•Analyse the supporting evidence for the use of biomarkers in prodromal and preclinical dementia•Apply this information to everyday clinical practiceDECLARATION OF INTERESTJ. C. H. works in the Research Institute for the Care of Older People (RICE), which undertakes clinical drug trials for drug companies. He is a sub-investigator on a number of trials (some of which involve neuroimaging and biomarkers) and principal investigator and chief investigator on two trials (neither of which involves biomarkers). All of these trials concern Alzheimer's disease or dementia. He does not receive any direct personal payment from the trials: the payment goes to RICE, which does, however, fund almost half of his post. RICE is an independent charity and separate from the University of Bristol.

Novel fluid biomarkers to differentiate frontotemporal dementia and dementia with Lewy bodies from Alzheimer's disease: A systematic review

“…SAPPβ is a product of APP amyloidogenic processing, marking a critical step towards Aβ generation (Perneczky 2011). Increased CSF sAPPβ have previously correlated to Aβ peptides in AD (Lewczuk, 2010;Gabelle, 2010). As shown in the meta-analysis, CSF sAPP was significantly higher in AD compared to FTD, and intriguingly, a consequent study by the Perneczky group found sAPP was also higher in AD than FTD in plasma samples (Perneczky, 2013).…”

Ethical aspects of facilitating the recruitment of people with dementia for clinical trials: A call for further debate

“…But investigators can identify pathophysiological findings such as amyloid-β deposition in the brain that are indicative of an increased risk of progression to clinical stages of dementia. 14 Conducting clinical trials on individuals at preclinical stages of dementia is promising as this population, unlike people at clinical stages of dementia, are generally more able to engage with researchers and provide informed consent. 15 Also, such clinical trials create new opportunities for investigating disease-modifying agents at earlier stages of dementia.…”

Diagnostic Accuracy of Blood-Based Biomarker Panels: A Systematic Review

“…Alzheimer’s disease is considered a continuum with three phases: the preclinical stage characterized by normal cognitive ability, the prodromal stage characterized by mild cognitive impairment (MCI), and, ultimately, clinically apparent dementia ( Jack et al, 2018 ; Lilford and Hughes, 2018 ; Vermunt et al, 2019 ). The current dementia diagnosis due to AD requires a combination of clinical, neuropsychology, and biomarker measurements.…”