Plasma β-amyloid in Alzheimer’s disease and vascular disease

Abstract

Implementation of amyloid biomarkers in clinical practice would be accelerated if such biomarkers could be measured in blood. We analyzed plasma levels of Aβ42 and Aβ40 in a cohort of 719 individuals (the Swedish BioFINDER study), including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer’s disease (AD) dementia and cognitively healthy elderly, using a ultrasensitive immunoassay (Simoa platform). There were weak positive correlations between plasma and cerebrospinal fluid (CSF) levels for both Aβ42 and Aβ40, and negative correlations between plasma Aβ42 and neocortical amyloid deposition (measured with PET). Plasma levels of Aβ42 and Aβ40 were reduced in AD dementia compared with all other diagnostic groups. However, during the preclinical or prodromal AD stages (i.e. in amyloid positive controls, SCD and MCI) plasma concentration of Aβ42 was just moderately decreased whereas Aβ40 levels were unchanged. Higher plasma (but not CSF) levels of Aβ were associated with white matter lesions, cerebral microbleeds, hypertension, diabetes and ischemic heart disease. In summary, plasma Aβ is overtly decreased during the dementia stage of AD indicating that prominent changes in Aβ metabolism occur later in the periphery compared to the brain. Further, increased levels of Aβ in plasma are associated with vascular disease.

Blood Biomarkers for Alzheimer’s Disease: Much Promise, Cautious Progress

“…This study compared AD with MCI and control subjects from a Swedish cohort, showing that while plasma t-tau differentiates AD from control, there is no significant effect for MCI versus control. The former finding has been replicated in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort and the Swedish BioFINDER study [ 40 ] and the latter finding has been independently replicated in a larger cohort from the Mayo Clinic Study of Aging [ 41 ], using the same platform. While the difference in plasma t-tau levels between MCI and control did not reach statistical significance, there was a significant inverse correlation between plasma tau and cognitive performance (in the global, memory and attention/executive function domains), as well as between plasma t-tau and cortical thickness in an AD region of interest defined on MRI.…”

Aβ Amyloid Pathology Affects the Hearts of Patients With Alzheimer’s Disease

“…The latter is also regarded as the reverse link between myocardial functional decline in AD and aging (38,41). Furthermore circulating Aβ 40 was shown to worsen vascular atherosclerosis, and to predict disease progression and cardiovascular mortality in patients with established CAD (42,43). Here, we tested whether other mechanisms link cardiac dysfunction to the brain disorder in the absence of any known causes of compromised cardiovascular function.…”

A digital enzyme-linked immunosorbent assay for ultrasensitive measurement of amyloid-β 1–42 peptide in human plasma with utility for studies of Alzheimer’s disease therapeutics

“…Measurement of Aβ 1–42 levels in cerebrospinal fluid (CSF) has proved useful as an aid in early detection of AD, particularly when combined with other CSF AD biomarkers such as tau and phosphorylated tau proteins [8–15]. In contrast, plasma Aβ 1–42 has been found to be of limited value as a diagnostic marker of AD, with contradictory reports from a variety of studies and investigators [13–18], although a recent study [19] demonstrates that Aβ 1–42 is significantly decreased in subjects with AD. Nevertheless, plasma Aβ 1–42 continues to be of great interest as a pharmacodynamic marker of γ-secretase (GS) and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) drug target engagement in studies of candidate therapeutics [20, 21].…”