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 (A beta)42 to detect amyloid pathology, the A beta(42)/A beta(40) ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer's disease (AD). However, whether A beta(42) and amyR have different meanings and whether A beta(40) represents more than an A beta(42)-corrective factor remain to be clarified. Our study aimed to compare the ability of A beta(42) and amyR to detect AD pathology in terms of p-tau/A beta(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 A beta(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 (CSFA beta(42) + /amyR - = 46) and pathological amyR (CSFA beta(42) + /amyR + = 52). We used two distinct cut-offs to determine pathological values of p-tau/A beta(42): (1) & GE; 0.086 and (2) & GE; 0.122. FDG-PET patterns were evaluated in a subsample of patients (n = 46) and compared to 24 controls. Results CSF A beta(40) levels were the lowest in A - T - and in CSFA beta(42) + /amyR - , higher in CSFA beta(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 A beta(40) and p-tau in A - T - (beta = 0.58; p < 0.001), CSFA beta(42) + /amyR - (beta = 0.47; p < 0.001), and CSFA beta(42) + /amyR + patients (beta = 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 A beta 40 (+ 0.8 z-scores) in the normal amyR range, becoming steeper over the pathological threshold of amyR (p-tau: + 5 z-scores, A beta(40): + 4.5 z-score). CSFA beta(42) + /amyR + patients showed a significantly higher probability of having pathological p-tau/A beta(42) than CSFA beta(42) + /amyR - (cut-off & GE; 0.086: OR 23.3; cut-off & GE; 0.122: OR 8.8), which however still showed pathological values of p-tau/A beta(42) in some cases (cut-off & GE; 0.086: 35.7%; cut-off & GE; 0.122: 17.3%) unlike A - T - . Accordingly, we found reduced FDG metabolism in the temporoparietal regions of CSFA beta(42) + /amyR - compared to controls, and further reduction in frontal areas in CSFA beta 42 + /amyR + , like in A + T + . Conclusions Pathological p-tau/A beta(42) and FDG hypometabolism typical of AD can be found in patients with decreased CSF A beta(42) levels alone. AmyR positivity, associated with higher A beta(40) levels, is accompanied by higher CSF p-tau and widespread FDG hypometabolism.