Plasma Aβ42 as a Biomarker of Prodromal Alzheimer’s Disease Progression in Patients with Amnestic Mild Cognitive Impairment: Evidence from the PharmaCog/E-ADNI Study

Abstract

It is an open issue whether blood biomarkers serve to diagnose Alzheimer's disease (AD) or monitor its progression over time from prodromal stages. Here, we addressed this question starting from data of the European FP7 IMI-PharmaCog/E-ADNI longitudinal study in amnesic mild cognitive impairment (aMCI) patients including biological, clinical, neuropsychological (e.g., ADAS-Cog13), neuroimaging, and electroencephalographic measures. PharmaCog/E-ADNI patients were classified as "positive" (i.e., "prodromal AD" n = 76) or "negative" (n = 52) based on a diagnostic cut-off of Aβ42/P-tau in cerebrospinal fluid as well as APOE ε 4 genotype. Blood was sampled at baseline and at two follow-ups (12 and 18 months), when plasma amyloid peptide 42 and 40 (Aβ42, Aβ40) and apolipoprotein J (clusterin, CLU) were assessed. Linear Mixed Models found no significant differences in plasma molecules between the "positive" (i.e., prodromal AD) and "negative" groups at baseline. In contrast, plasma Aβ42 showed a greater reduction over time in the prodromal AD than the "negative" aMCI group (p = 0.048), while CLU and Aβ40 increased, but similarly in the two groups. Furthermore, plasma Aβ42 correlated with the ADAS-Cog13 score both in aMCI patients as a whole and the prodromal AD group alone. Finally, CLU correlated with the ADAS-Cog13 only in the whole aMCI group, and no association with ADAS-Cog13 was found for Aβ40. In conclusion, plasma Aβ42 showed disease progression-related features in aMCI patients with prodromal AD.

Diet Influences Peripheral Amyloid Β Metabolism: A Role for Circulating Insulin-Like Growth Factor I

“…A lack of correlation between peripheral and central Aβ clearance agrees with observations that reducing peripheral Aβ does not affect brain Aβ levels, or with the absence of correlation between central and peripheral Aβ levels in AD patients (36)(37)(38)(39). However, increased peripheral Aβ levels after anti-Aβ treatment was reported to parallel a decrease of brain Aβ; reducing peripheral Aβ was sufficient to reduced brain Aβ, and recent studies favor a diagnostic utility of the relationship between plasma and CSF Aβ 1-42 (27,40,41). Thus, the relationship between peripheral and central Aβ is still under debate (42); indeed, a substantial part of brain Aβ clearance in humans takes place in the periphery (43).…”

Assessment of Plasma Amyloid-β42/40and Cognitive Decline Among Community-Dwelling Older Adults

“…Studies exploring cognitive associations with longitudinal cohorts of older adults by using highly reliable techniques are still scarce and present multiple methodological differences that prevented reaching a consensus. [17][18][19][20] Further studies are needed to confirm the use of high-accuracy plasma Aβ in associating Aβ levels with cognitive decline to determine the usefulness of this marker in clinical care and research.…”

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

“…Still, others have found no significant relationship [25,26]. Reduced plasma Ab has also been linked to poorer cognition [6,7,19,21,[27][28][29][30]. In addition, some studies have suggested that plasma levels of Ab42 and Ab40 are associated with the levels of cerebral Ab on positron emission tomography (PET), cerebrospinal fluid levels of Ab and tau, and AD-like brain atrophy [4,7,8,11,16,17,24,[31][32][33][34][35][36][37][38], while others have not seen such an association [25,39,40].…”