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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-023-01291-w.