CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios: better diagnostic markers of Alzheimer disease

Abstract

ObjectiveThe diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) must be improved before widespread clinical use. This study aimed to determine whether CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios are better diagnostic biomarkers of AD during both predementia and dementia stages in comparison to CSF Aβ42 alone.MethodsThe study comprised three different cohorts (n = 1182) in whom CSF levels of Aβ42, Aβ40, and Aβ38 were assessed. CSF Aβs were quantified using three different immunoassays (Euroimmun, Meso Scale Discovery, Quanterix). As reference standard, we used either amyloid (18F‐flutemetamol) positron emission tomography (PET) imaging (n = 215) or clinical diagnosis (n = 967) of well‐characterized patients.ResultsWhen using three different immunoassays in cases with subjective cognitive decline and mild cognitive impairment, the CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios were significantly better predictors of abnormal amyloid PET than CSF Aβ42. Lower Aβ42, Aβ42/Aβ40, and Aβ42/Aβ38 ratios, but not Aβ40 and Aβ38, correlated with smaller hippocampal volumes measured by magnetic resonance imaging. However, lower Aβ38, Aβ40, and Aβ42, but not the ratios, correlated with non‐AD‐specific subcortical changes, that is, larger lateral ventricles and white matter lesions. Further, the Aβ42/Aβ40 and Aβ42/Aβ38 ratios showed increased accuracy compared to Aβ42 when distinguishing AD from dementia with Lewy bodies or Parkinson's disease dementia and subcortical vascular dementia, where all Aβs (including Aβ42) were decreased.InterpretationThe CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios are significantly better than CSF Aβ42 to detect brain amyloid deposition in prodromal AD and to differentiate AD dementia from non‐AD dementias. The ratios reflect AD‐type pathology better, whereas decline in CSF Aβ42 is also associated with non‐AD subcortical pathologies. These findings strongly suggest that the ratios rather than CSF Aβ42 should be used in the clinical work‐up of AD.

Midlife Stress in Relation to Late-Life Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: A 25-Year Follow-Up Study

“…This may increase the risk of having the Aβ aggregation cascade taking off, similar to what has been described in familial AD [28]. The absence of an association between stress and the CSF Aβ42/Aβ40 ratio, the best-validated amyloid plaque pathology marker [19], could potentially suggest that stress may increase the risk of Aβ aggregation taking place (through increased amyloidogenic APP processing, reflected by increased Aβ40), but that this has not translated into factual Aβ pathology yet (no association with Aβ42 or the Aβ42/Aβ40 ratio).…”

“…Aβ40, on the other hand, is the most abundant Aβ peptide [18]. Its biochemical function is unclear, but high levels of Aβ40 are suggested to reflect Aβ overproduction and amyloid precursor protein (APP) dysfunction [19]. The total concentration of tau (t-tau) in CSF is thought to reflect the intensity of neuronal degeneration.…”

Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease

“…This can be expressed as the ratio between sAPPβ and sAPPα (sAPPβ/α) and the ratio between the relative expression of the long Aβ species generated by the amyloidogenic pathway (17-42 aa) in relation to the short Aβ species generated by the non-amyloidogenic pathway (13-16 aa). Furthermore, the ratio between cerebrospinal fluid (CSF) Aβ42 and Aβ40 (Aβ42/40) can be regarded as a marker of the total amyloid load in the brain reflected by amyloid positron emission tomography (PET) [18,19,20]. …”

Amyloid‐beta 1‐40 is associated with alterations in NG2+ pericyte population ex vivo and in vitro

“…Since aggregated Aβ1‐40 has been shown to be toxic (Maia et al., 2007) and monomer is potentially beneficial (as described in our in vitro studies), we speculate that samples from AD patients with lower number of NG2+ pericytes also contain higher portions of toxic aggregated Aβ1‐40 and less of the beneficial monomer Aβ1‐40. This would be in line with previous studies on CSF demonstrating a relationship between lower levels of Aβ1‐40 (indicating increased trapped aggregated Aβ1‐40 in the brain) and increased white matter changes (indicating vascular damage; Janelidze et al., 2016; van Westen et al., 2016). …”