Plasma amyloid β 42/40 ratios as biomarkers for amyloid β cerebral deposition in cognitively normal individuals

Abstract

IntroductionPlasma amyloid β (Aβ) peptides have been previously studied as candidate biomarkers to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease.MethodsFree and total Aβ42/40 plasma ratios (FP42/40 and TP42/40, respectively) were determined using ABtest assays in cognitively normal subjects from the Australian Imaging, Biomarker and Lifestyle Flagship Study. This population was followed-up for 72 months and their cortical Aβ burden was assessed with positron emission tomography.ResultsCross-sectional and longitudinal analyses showed an inverse association of Aβ42/40 plasma ratios and cortical Aβ burden. Optimized as a screening tool, TP42/40 reached 81% positive predictive value of high cortical Aβ burden, which represents 110% increase over the population prevalence of cortical Aβ positivity.DiscussionThese findings support the use of plasma Aβ42/40 ratios as surrogate biomarkers of cortical Aβ deposition and enrichment tools, reducing the number of subjects submitted to invasive tests and, consequently, recruitment costs in clinical trials targeting cognitively normal individuals.

Plasma amyloid beta levels are associated with cerebral amyloid and tau deposition

“…We observed significantly lower levels of plasma Aβ T42:T40 in patients with AD than in CN older adults, as has been previously reported [2–18]. In addition, a trend for lower plasma Aβ F42:F40 in patients with AD was also observed.…”

“…In addition, all samples were processed blinded to the diagnostic group or amyloid status. We analyzed two ratios, free plasma Aβ42 to free Aβ40 (Aβ F42:F40) and total plasma Aβ42 to total Aβ40 (Aβ T42:T40), as they had been previously shown to correlate with amyloid positivity [5,13,16,36].…”

“…Specifically, previous studies have suggested that plasma levels of Ab, tau, and other target proteins, such as neurofilament light, amyloid precursor protein, and others, are altered in patients with AD and those in the prodromal stage of AD, mild cognitive impairment (MCI). A number of studies have suggested that plasma Ab42 and Ab40 measures, as well as the ratio of Ab42/ Ab40 are reduced in patients with AD and MCI and that these plasma biomarkers can predict the presence of AD and MCI and progression from normal to impaired cognition [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. However, other studies have shown that higher plasma Ab measures are associated with AD and conversion to AD [19][20][21][22][23][24].…”

Current state of Alzheimer’s fluid biomarkers

“…In a separate study, plasma Aβ40 did not correlate with Aβ-positive PET in cognitively normal elderly individuals [83]. However, as with CSF, the ratio of Aβ42/Aβ40 in plasma may be more useful than Aβ40 alone; plasma Aβ42/Aβ40 appears to be associated with an increased risk of progression to AD dementia [373, 377], and has shown promise in detecting Aβ-positivity [87, 261, 273, 274, 371, 377] and supporting the diagnosis of AD [31, 179, 383]. …”

Aβ and tau structure‐based biomarkers for a blood‐ and CSF‐based two‐step recruitment strategy to identify patients with dementia due to Alzheimer's disease

“…Thus, there is a general agreement that a minimal-invasive, reliable, and cost-effective blood test is requested as a first screening funnel to identify individuals with high risk for AD [11][12][13][14][15]. To date, only few blood tests present the potential to detect AD [16][17][18][19].…”