Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

The biological definition of Alzheimer’s disease using CSF biomarkers requires both abnormal amyloid (A) and p-tau (T) levels. However, biomarkers and corresponding cutoffs may not always reflect the presence or absence of pathology. Previous studies suggest that up to 32% of autopsy-confirmed Alzheimer’s disease individuals show normal CSF p-tau levels in vivo, but these studies are sparse and had small sample sizes. Therefore, we studied in three independent autopsy cohorts whether CSF A+T– excluded Alzheimer’s disease based on autopsy or not. We included 215 individuals with ante-mortem CSF collection and autopsy performed from three cohorts: the Amsterdam Dementia Cohort (n = 80, 37 (46%) Alzheimer’s disease at autopsy, time between CSF collection and death 4.5±2.9 years); from the Antwerp Dementia Cohort (n = 92, 84 (91%) Alzheimer’s disease at autopsy, time CSF collection to death 1.7±2.3 years); and from the Alzheimer’s Disease Neuroimaging Initiative (n = 43, 31 (72%) Alzheimer’s disease at autopsy, time CSF collection to death 5.1±2.5 years). Biomarker profiles were based on dichotomized CSF Aβ1-42 and p-tau levels. Accuracy of CSF AT profiles to detect autopsy-confirmed Alzheimer’s disease was assessed. Lastly, we investigated whether the concordance of AT profiles with autopsy diagnosis improved when CSF was collected closer to death in 9 (10%) Antwerp Dementia Cohort and 30 (70%) Alzheimer’s Disease Neuroimaging Initiative individuals with repeated CSF measurements available. In total, 50-73% of A+T– individuals and 100% of A+T+ individuals had Alzheimer’s disease at autopsy. Amyloid status showed the highest accuracy to detect autopsy-confirmed Alzheimer’s disease (accuracy, sensitivity and specificity in Amsterdam Dementia Cohort: 88%, 92% and 84%; in Antwerp Dementia Cohort: 87%, 94% and 12%; and in Alzheimer’s Disease Neuroimaging Initiative: 86%, 90% and 75% respectively). The addition of CSF p-tau did not further improve these estimates. We observed no differences in demographics or on degree of Alzheimer’s disease neuropathology between A+T– and A+T+ individuals with autopsy-confirmed Alzheimer’s disease. All individuals with repeated CSF measurements remained stable in Aβ1-42 status during follow-up. None of the Alzheimer’s disease individuals with a normal p-tau status changed to abnormal, however four (44%) Antwerp Dementia Cohort individuals and two (7%) Alzheimer’s Disease Neuroimaging Initiative individuals changed from abnormal to normal p-tau status over time, and all had Alzheimer’s disease at autopsy. In summary, we found that up to 73% of A+T– individuals did have Alzheimer’s disease at autopsy. This should be taken into account in both research and clinical settings.