The cerebrospinal fluid A‐T+ Alzheimer disease biomarker profile: prevalence and clinical relevance

Abstract

AbstractBackgroundThe cerebrospinal fluid (CSF) amyloid β‐negative and tau‐positive (A‐T+) biomarker profile, as defined by normal amyloid β42/40 ratio (Aβ42/40) and increased phosphorylated tau (p‐tau), is sometimes seen in daily clinical practice. However, knowledge is lacking on its prevalence and whether patients with this profile are at risk for biological disease progression and cognitive decline.MethodIn this study, data from four cohorts were included: UGOT (the clinical laboratory database at Sahlgrenska University Hospital, Gothenburg), Alzheimer’s Disease Neuroimaging Initiative (ADNI; cognitively unimpaired [CU] and mild cognitive impairment [MCI] individuals), Wisconsin Registry for Alzheimer’s Prevention, and Wisconsin ADRC cohorts (latter two analyzed jointly, “WISC”; predominantly CU individuals). Repeated measures of cognitive decline (modified preclinical Alzheimer’s composite [mPACC] in ADNI, and PACC‐3 in the WISC sample), amyloid accumulation (only in ADNI: [18F]‐florbetapir amyloid positron emission tomography [PET]) neurodegeneration (only in ADNI: magnetic resonance imaging [MRI], [18F]‐fluorodeoxyglucose PET [FDG‐PET]), and cross‐sectional tau PET ([F18]‐flortaucipir in ADNI and [F18]‐MK6240 in WISC) were used as exposures.ResultIn the UGOT cohort, a total of 7679 individuals were included (46Conclusions6% women; mean [SD] age, 71.0 [8.3] years). Further, 970 individuals from ADNI (45.8% women, mean [SD] age, 72.8 [7.0]), and n = 519 individuals from WISC (66.7% women, mean [SD] age, 59.7 [7.3]) cohorts were included. The prevalence of the A‐T+ profile in the UGOT cohort was 4.1%, compared with A+T+ that constituted 36%, A‐T‐ 42%, and A+T‐ 17%. In ADNI and UGOT, A‐T+ had higher concentrations of Aβ42 and Aβ40 compared to A‐T‐ individuals. The prognosis of CSF biomarker profiles was determined with linear mixed effects models (ADNI and WISC). The A‐T+ profile, compared with A‐T‐, presented no statistically significant rates of cognitive worsening (ADNI and WISC p>0.05), or in longitudinal changes in Aβ‐PET, FDG‐PET, and hippocampal atrophy (all p>0.05), within the ADNI subsample. Cross‐sectionally, A‐T+ individuals had similar tau‐PET uptake to A‐T‐ individuals (p>0.05).ConclusionThe CSF A‐T+ profile is to be considered clinically benign, as individuals with this profile do not have a higher rate of cognitive decline compared with biomarker‐negative individuals and do not display signs of amyloid accumulation or progressive neurodegeneration.