Cerebrospinal Fluid Levels of Amyloid Beta 1–43 in Patients with Amnestic Mild Cognitive Impairment or Early Alzheimer’s Disease: A 2-Year Follow-Up Study

Abstract

Introduction: Biomarkers that will reliably predict the onset of Alzheimer’s disease (AD) are urgently needed. Although cerebrospinal fluid (CSF) amyloid beta 1–42 (Aβ42), total tau, and phosphorylated tau can be used to complement the clinical diagnosis of AD, amnestic mild cognitive impairment (aMCI), the prodromal phase of AD, is heterogeneous. Biomarkers should be able to determine which patients with aMCI are at greatest risk of AD. Histological studies and animal models indicate that amyloid beta 1–43 (Aβ43) aggregates early, and may play a role in the pathological process of AD. We have examined levels of CSF Aβ43 in a 2-year longitudinal study of aMCI and early AD.Materials and Methods: Cerebrospinal fluid was collected at baseline, and after one and 2 years from patients with AD (n = 19), and patients with aMCI (n = 42). Of these, 21 progressed to AD during the 2 years of study, whereas 21 did not. Controls (n = 32) were lumbar punctured at baseline only. CSF analyses of Aβ43, Aβ42, and total tau were carried out with ELISA.Results: At baseline, CSF Aβ43, CSF Aβ42 and ratios with total tau could be used to separate controls from all three patient groups. CSF Aβ43, but not Aβ42, could separate patients with aMCI who progressed to AD during the 2 years of follow-up, from those that did not. The CSF total tau/Aβ43 ratio had a slightly but significantly larger area under the receiver operating characteristic curve when compared to the CSF total tau/Aβ42 ratio. CSF Aβ43 levels, but not Aβ42 levels, decreased from baseline to 2 years in the AD group.Discussion and Conclusion: CSF Aβ43 was demonstrated to be significantly reduced in patients already by the time that aMCI or AD was diagnosed, compared to controls, and this change must have occurred during the preclinical period. Since our results suggested that CSF Aβ43 distinguishes between subgroups of patients with aMCI better than CSF Aβ42, it may prove to be a useful additional biomarker for identifying aMCI patients at greatest risk of AD.

Cerebrospinal Fluid Levels of Amyloid Beta 1-43 Mirror 1-42 in Relation to Imaging Biomarkers of Alzheimer’s Disease

“…Enhancement of this diagnostic performance would obviously be an advantage. Lauridsen et al (2016) found that when used in a ratio with t-tau, substituting Aβ42 with Aβ43 gave a slight, but significant improvement of the diagnostic accuracy for this distinction, a finding that warrants further exploration. The use of CSF biomarkers in clinical routine is impeded by the invasiveness of lumbar puncture and by the high between-center variability particularly in the measurement of Aβ42.…”

“…Information is sparse regarding CSF Aβ43 as a potential clinical biomarker, especially in early stages of cognitive impairment. Previously, it has been shown that CSF Aβ43 levels are decreased in MCI and AD dementia as compared to controls, with a strong correlation between CSF levels of Aβ43 and Aβ42 ( Kakuda et al, 2012 ; Lauridsen et al, 2016 ). At the late stage of dementia, CSF Aβ43 and Aβ42 appear to have equal diagnostic accuracy for discriminating AD dementia from non-demented controls ( Bruggink et al, 2013 ).…”

“…Treatment of this devastating disease will depend on biomarkers that can reliably identify individuals who will develop dementia due to AD in the future. A previous study following patients with mild cognitive impairment (MCI) for 2 years, found that the baseline cerebrospinal fluid (CSF) levels of amyloid-beta 1-43 (Aβ43) could distinguish patients that converted to AD dementia from those that did not, suggesting that CSF Aβ43 could be a useful addition to the more well-studied CSF biomarkers amyloid beta 1-42 (Aβ42), total tau (t-tau), and tau phosphorylated on position 181 (p-tau) ( Kandimalla et al, 2011 , 2013 ; Lauridsen et al, 2016 ). Aβ43 differs from Aβ42 by one C-terminal threonine residue, and is the product of an alternative γ-secretase cleavage pathway from the amyloid precursor protein (APP) ( Takami et al, 2009 ).…”

The Amyloid, Tau, and Neurodegeneration (A/T/N) Classification Applied to a Clinical Research Cohort with Long-Term Follow-Up

“…Study participants were initially monitored over a period of two years. During this time, almost half of the patients with amnestic MCI at baseline progressed to AD dementia, as described elsewhere [14]. It was subsequently possible to carry out an extended follow-up of the cohort, with a median time of 9 years (range 6-10 years).…”

“…Biomarkers central to the A/T/N classification (A␤ 42 , t-tau, and p-tau) were analyzed by ELISA (Fujirebio Innogenetics) as described previously [19]. Coefficients of variation for the amyloid and tau markers have been given elsewhere [14,20].…”