Plasma amyloid β 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease

Abstract

INTRODUCTION: Blood-based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. METHODS: We investigated whether plasma concentrations of the Aβ1-40/Aβ1-42 ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain Aβ positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-a-priori hypothesis study using machine learning. RESULTS:The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma Aβ1-40/Aβ1-42 ratio. The accuracy is not affected by the apolipoprotein E (APOE) ε4 allele, sex, or age. DISCUSSION: Our results encourage an independent validation cohort study to confirm the indication that the plasma Aβ1-40/Aβ1-42 ratio, assessed via Simoa, may improve future standard of care and clinical trial design.

Reply to “Usefulness of Plasma Amyloid as Prescreener of the Earliest Alzheimer Pathological Changes Depends on the Study Population”

“…We acknowledge that cross‐validation in external cohorts is essential. Of note, our results do not stand alone; multiple recent studies using highly sensitive immunoassays for blood‐based amyloid beta quantification showed capability to discriminate between amyloid‐positive and amyloid‐negative cognitively normal individuals, with or without subjective cognitive complaints, providing independent support for our findings. Moreover, in our article we not only investigated the association of plasma amyloid and CSF amyloid, but showed that low plasma amyloid levels are related to a higher risk of subsequent clinical disease progression to mild cognitive impairment or dementia.…”

Salivary Biomarkers for Alzheimer’s Disease and Related Disorders

“…The assessment of Ab by PET or CSF immunoassays is now included in research criteria for AD [46] as well as in the biological definition of the disease [47]. Ab peptides can be readily measured in plasma utilising ultra-sensitive immunoassays [5,6] or targeted mass spectrometry (MS) [3] and emerging evidence suggests that a decreased Ab peptide ratio can identify cerebral Ab-positive individuals with high sensitivity and specificity ( Table 2).…”

“…One of the many challenges that the dementia community face is the detection of the pre-symptomatic phase of the AD using non-invasive, widely accessible and disease relevant biomarkers. In recent times, blood biomarkers have taken centre stage, with measurements of Ab species [3][4][5][6], the axonal injury marker neurofilament light (NfL) [7,8] and phosphorylated tau on threonine 181 (P-tau181) [9] showing much promise. There are now international efforts underway to progress these biomarkers to be applicable for clinical use [10].…”

Plasma neurofilament light associates with Alzheimer's disease metabolic decline in amyloid‐positive individuals

“…Recent advancements in proteomic assays have demonstrated the potential use of plasma Aβ to identify brain Aβ‐positive individuals with moderate‐to‐high accuracy [4–8]. The measurement of T‐tau in plasma has limited diagnostic value, albeit being slightly but significantly increased in patients with AD [9] but promising data are emerging on P‐tau [10].…”

“…Recent advancements in proteomic assays have demonstrated the potential use of plasma Ab to identify brain Abpositive individuals with moderate-to-high accuracy [4][5][6][7][8].…”