Different associations between amyloid-βeta 42, amyloid-βeta 40, and amyloid-βeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer’s disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study

Background Despite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aβ) 42 to detect amyloid pathology, the Aβ 42 /Aβ 40 ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer’s disease (AD). However, whether Aβ 42 and amyR have different meanings and whether Aβ 40 represents more than an Aβ 42 -corrective factor remain to be clarified. Our study aimed to compare the ability of Aβ 42 and amyR to detect AD pathology in terms of p-tau/Aβ 42 ratio and brain glucose metabolic patterns using fluorodeoxyglucose-positron emission tomography (FDG-PET). Methods CSF biomarkers were analyzed with EUROIMMUN ELISA. We included 163 patients showing pathological CSF Aβ 42 and normal p-tau (A + T − = 98) or pathological p-tau levels (A + T + = 65) and 36 control subjects (A − T −). A + T − patients were further stratified into those with normal (CSFAβ 42 + /amyR − = 46) and pathological amyR (CSFAβ 42 + /amyR + = 52). We used two distinct cut-offs to determine pathological values of p-tau/Aβ 42 : (1) ≥ 0.086 and (2) ≥ 0.122. FDG-PET patterns were evaluated in a subsample of patients ( n = 46) and compared to 24 controls. Results CSF Aβ 40 levels were the lowest in A − T − and in CSFAβ 42 + /amyR − , higher in CSFAβ 42 + /amyR + and highest in A + T + ( F = 50.75; p < 0.001), resembling CSF levels of p-tau ( F = 192; p < 0.001). We found a positive association between Aβ 40 and p-tau in A − T − ( β = 0.58; p < 0.001), CSFAβ 42 + /amyR − ( β = 0.47; p < 0.001), and CSFAβ 42 + /amyR + patients ( β = 0.48; p < 0.001) but not in A + T + . Investigating biomarker changes as a function of amyR, we observed a weak variation in CSF p-tau (+ 2 z -scores) and Aβ 40 (+ 0.8 z -scores) in the normal amyR range, becoming steeper over the pathological threshold of amyR (p-tau: + 5 z -scores, Aβ 40 : + 4.5 z -score). CSFAβ 42 + /amyR + patients showed a significantly higher probability of having pathological p-tau/Aβ 42 than CSFAβ 42 + /amyR − (cut-off ≥ 0.086: OR 23.3; cut-off ≥ 0.122: OR 8.8), which however still showed pathological values of p-tau/Aβ 42 in some cases (cut-off ≥ 0.086: 35.7%; cut-off ≥ 0.122: 17.3%) unlike A − T − . Accordingly, we found reduced FDG metabolism in the temporoparietal regions of CSFAβ 42 + /amyR − compared to controls, and further reduction in frontal areas in CSFAβ 42 + /amyR + , like in A + T + . Conclusions Pathological p-tau/Aβ 42 and FDG hypometabolism typical of AD can be found in patients with decreased CSF Aβ 42 levels alone. AmyR positivity, associated with higher Aβ 40 levels, is accompanied by higher CSF p-tau and widespread FDG hypometabolism.