Objective: To perform a systematic review and meta-analysis to determine whether fluid and imaging astrocyte biomarkers are altered in Alzheimer's disease (AD). Methods: PubMed and Web of Science databases were searched for articles reporting fluid or imaging astrocyte biomarkers in AD. Pooled effect sizes were determined with mean differences (SMD) using the Hedge’s G method with random-effects to determine biomarker performance. Adapted questions from QUADAS-2 were applied for quality assessment. A protocol for this study has been previously registered in PROSPERO (registration number: CRD42020192304). Results: The initial search identified 1,425 articles. After exclusion criteria were applied, 33 articles (a total of 3,204 individuals) measuring levels of GFAP, S100B, YKL-40 and AQP4 in the blood and cerebrospinal fluid (CSF), as well as MAO-B, indexed by positron emission tomography 11C-deuterium-L-deprenyl ([11C]-DED), were included. GFAP (SMD = 0.94; 95% CI = 0.71-1.18) and YKL-40 (SMD = 0.76; CI 95% = 0.63-0.89) levels in the CSF, S100B levels in the blood (SMD = 2.91; CI 95% = 1.01-4.8) were found significantly increased in AD patients.  Conclusions: Despite significant progress, applications of astrocyte biomarkers in AD remain in their early days. The meta-analysis demonstrated that astrocyte biomarkers are consistently altered in AD and supports further investigation for their inclusion in the AD clinical research framework for observational and interventional studies.

Objective:  To assess the frequency of biologically-defined Alzheimer’s disease (AD) in relation to age, sex and APOEε4, as well as rates of discordance between clinically- and biologically defined AD. Methods: We assessed cognitively unimpaired (CU) elderly (n=166), amnestic MCI (n=77) and probable AD dementia (n=62) subjects who underwent evaluation by dementia specialists and neuropsychologists in addition to amyloid-PET with [18F]AZD4694 and tau-PET with [18F]MK6240. Individuals were grouped according to their AD biomarker profile. Positive predictive value for biologically-defined AD was assessed in relation to clinical diagnosis. Frequency of AD biomarker profiles were assessed using logistic regressions with odds ratios and 95% CIs. Results: The clinical diagnosis of probable AD dementia demonstrated good agreement with biologically-defined AD (positive predictive value: 85.2%). 7.88% of CU elderly subjects were positive for both amyloid-PET and tau-PET. Frequency of biologically-defined AD increased with age (OR: 1.14; p<0.0001) and frequency of APOEε4 allele carriers (Single ε4: OR: 3.82; p<0.0001; Double ε4: OR: 17.55, p<0.0001). Discussion: While we observed strong, but not complete, agreement between clinically-defined “probable AD” dementia and biomarker positivity for both amyloid-β and tau, we also observed that biologically-defined AD was not rare in CU elderly. Abnormal tau-PET was almost exclusively observed in individuals with abnormal amyloid-PET. Our results highlight that even in tertiary care memory clinics, detailed evaluation by dementia specialists systematically underestimates the frequency of biologically-defined AD and related entities.

Objective: To determine the associations between amyloid-PET, tau-PET and atrophy with the behavioural/dysexecutive presentation of Alzheimer’s disease (AD) and how these differ from amnestic AD. Background: The behavioural/dysexecutive variant of AD is a rare clinical syndrome presenting with behavioural changes, apathy and/or executive dysfunction, similar to frontotemporal dementia. Small autopsy studies provide conflicting reports of frontal pathology and recent studies challenge the notion of frontal involvement in this condition. We tested the hypothesis that patterns of cortical tau pathology differentiate behavioural/dysexecutive AD from amnestic AD and correlate to clinical symptoms. Methods: We assessed 15 cases of behavioural/dysexecutive AD recruited from a tertiary care memory clinic, all of whom had biologically defined AD. They were compared with 25 disease severity- and age-matched amnestic AD patients and a group of 131 cognitively unimpaired (CU) elderly individuals. All subjects were evaluated with amyloid-PET, tau-PET, MRI and neuropsychological testing. Results: Voxelwise contrasts identified patterns of frontal cortical tau aggregation in behavioural/dysexecutive AD, with peaks in medial prefrontal, anterior cingulate and frontal insular cortices. No differences were observed in the distribution of amyloid-PET. Voxelwise area under the ROC curve analyses revealed that tau-PET uptake in the medial prefrontal, anterior cingulate and frontal insular cortices were best able to differentiate between behavioural/dysexecutive and amnestic AD (AUC=0.87). Voxelwise regressions demonstrated relationships between frontal cortical tau load and degree of executive dysfunction. Conclusions: Our results provide evidence of frontal cortical involvement of tau pathology in behavioural/dysexecutive AD and highlight the need for consensus clinical criteria in this syndrome.