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.
Background: Reported sex distributions differ between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that has resulted in varying demographics. Objective: Our aim was to determine the sex distribution of sporadic and genetic FTD cases and its subtypes in an international cohort. Methods: We included 910 patients with behavioral variant frontotemporal dementia (bvFTD; n = 654), non-fluent variant primary progressive aphasia (nfvPPA; n = 99), semantic variant primary progressive aphasia (svPPA; n = 117), and right temporal variant frontotemporal dementia (rtvFTD; n = 40). We compared sex distribution between genetic and sporadic FTD using χ2-tests. Results: The genetic FTD group consisted of 51.2% males, which did not differ from sporadic FTD (57.8% male, p = 0.08). In the sporadic bvFTD subgroup, males were predominant in contrast to genetic bvFTD (61.6% versus 52.9% males, p = 0.04). In the other clinical FTD subgroups, genetic cases were underrepresented and within the sporadic cases sex distribution was somewhat equal. Conclusion: The higher male prevalence in sporadic bvFTD may provide important clues for its differential pathogenesis and warrants further research.
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