Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer’s disease

An unresolved question for the understanding of Alzheimer’s disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau–positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast+ individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials

The association of age-related and off-target retention with longitudinal quantification of [18F]MK6240 tau PET in target regions

6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18F] MK6240) tau PET tracer quantifies the brain tau neurofibrillary tangle load in Alzheimer disease. The aims of our study were to test the stability of common reference region estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and offtarget retention on the longitudinal quantification of [18F]MK6240 in target regions. Methods: We assessed reference, target, age-related, and off-target regions in 125 individuals across the aging and Alzheimer disease spectrum with longitudinal [18F]MK6240 SUVs and SUV ratios (SUVRs) (mean 6 SD, 2.25 6 0.40 y of follow-up). We obtained SUVR from meninges, exhibiting frequent off-target retention with [ 18F]MK6240. Additionally, we compared tracer uptake between 37 cognitively unimpaired young (CUY) (mean age, 23.41 6 3.33 y) and 27 cognitively unimpaired older (CU) adults (amyloid-b–negative and tau-negative, 58.50 6 9.01 y) to identify possible nonvisually apparent, age-related signal. Two-tailed t testing and Pearson correlation testing were used to determine the difference between groups and associations between changes in region uptake, respectively. Results: Inferior cerebellar gray matter SUV did not differ on the basis of diagnosis and amyloid-b status, cross-sectionally and over time. [18F]MK6240 uptake significantly differed between CUY and CU adults in the putamen or pallidum (affecting 75% of the region) and in the Braak II region (affecting 35%). Changes in meningeal and putamen or pallidum SUVRs did not significantly differ from zero, nor did they vary across diagnostic groups. We did not observe significant correlations between longitudinal changes in age-related or meningeal off-target retention and changes in target regions, whereas changes in all target regions were strongly correlated. Conclusion: Inferior cerebellar gray matter was similar across diagnostic groups cross-sectionally and stable over time and thus was deemed a suitable reference region for quantification. Despite not being visually perceptible, [18F]MK6240 has age-related retention in subcortical regions, at a much lower magnitude but topographically colocalized with significant off-target signal of the first-generation tau tracers. The lack of correlation between changes in age-related or meningeal and target retention suggests little influence of possible off-target signals on longitudinal tracer quantification. Nevertheless, the age-related retention in the Braak II region needs to be further investigated. Future postmortem studies should elucidate the source of the newly reported age-related [18F]MK6240 signal, and in vivo studies should further explore its impact on tracer quantification

Astrocyte biomarker signatures of amyloid-beta and tau pathologies in Alzheimer’s disease

Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer’s disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-β (Aβ) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for Aβ ([18F]AZD4694) and tau ([18F]MK-6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated Aβ-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not Aβ-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of Aβ and tau, respectively, on hippocampal atrophy, which was further associated with cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain Aβ and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression

APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles

Animal studies suggest that the apolipoprotein E ε4 (APOEε4) allele is a culprit of early microglial activation in Alzheimer’s disease (AD). Here, we tested the association between APOEε4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomography for amyloid-β (Aβ; [18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28). We found that APOEε4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOEε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOEε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOEε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition

Subjective cognitive decline in Brazil : prevalence and association with dementia modifiable risk factors in a population-based study

Introduction: Subjective cognitive decline (SCD) may be an early symptom of Alzheimer’s disease. We aimed to estimate the prevalence of SCD in Brazil and its association with dementia modifiable risk factors. Methods: We used data of 8138 participants from the Brazilian Longitudinal Study of Aging (ELSI-Brazil), a population-based study that included clinical and demographic variables of individuals across the country. We calculated the prevalence of SCD and its association with dementia modifiable risk factors. Results: We found that the prevalence of SCD in Brazil was 29.21% (28.22%–30.21%), varying according to region, sex, and age. SCD was strongly associated with hearing loss, low education, psychological distress, Brown/Pardo and Black races. Discussion: The prevalence of SCD in Brazil is higher than in high-income countries. Brown/Black races and dementia modifiable risk factors were associated with SCD. Public strategies that target SCD may help mitigate the incidence of dementia

Race-related population attributable fraction of preventable risk factors of dementia : a latino population-based study

Background: risk factors for dementia have distinct frequency and impact in relation to race. Our aim was to identify differences in modifiable risk factors of dementia related to races and estimate their population attributable fraction (PAF). Methods: an epidemiological cohort was used to estimate the prevalence of 10 modifiable risk factors for dementia among five races—White, Black, Brown, Asian, and Indigenous. Sample weighting was used to estimate the prevalence and PAF of each risk factor in each race. Results:a total of 9070 individuals were included. Overall adjusted PAF was the lowest in Indigenous (38.9%), and Asian individuals (41.2%). Race-related prevalence of individual risk factors was widely variable in our population, but hearing loss was the most important contributor to the overall PAF in all races. Conclusions Public policies aiming to reduce preventable risk factors for dementia should take into consideration the race of the target populations

18 F-MK-6240 tau-PET in genetic frontotemporal dementia

Tau is one of several proteins associated with frontotemporal dementia. While knowing which protein is causing a patient\u27s disease is crucial, no biomarker currently exists for identifying tau in vivo in frontotemporal dementia. The objective of this study was to investigate the potential for the promising 18F-MK-6240 PET tracer to bind to tau in vivo in genetic frontotemporal dementia. We enrolled subjects with genetic frontotemporal dementia, who constitute an ideal population for testing because their pathology is already known based on their mutation. Ten participants (three with symptomatic P301L and R406W MAPT mutations expected to show tau binding, three with presymptomatic MAPT mutations and four with non-tau mutations who acted as disease controls) underwent clinical characterization, tau-PET scanning with 18F-MK-6240, amyloid-PET imaging with 18F-NAV-4694 to rule out confounding Alzheimer\u27s pathology, and high-resolution structural MRI. Tau-PET scans of all three symptomatic MAPT carriers demonstrated at least mild 18F-MK-6240 binding in expected regions, with particularly strong binding in a subject with an R406W MAPT mutation (known to be associated with Alzheimer\u27s like neurofibrillary tangles). Two asymptomatic MAPT carriers estimated to be 5 years from disease onset both showed modest 18F-MK-6240 binding, while one ∼30 years from disease onset did not exhibit any binding. Additionally, four individuals with symptomatic frontotemporal dementia caused by a non-tau mutation were scanned (two C9orf72; one GRN; one VCP): 18F-MK-6240 scans were negative for three subjects, while one advanced C9orf72 case showed minimal regionally non-specific binding. All 10 amyloid-PET scans were negative. Furthermore, a general linear model contrasting genetic frontotemporal dementia subjects to a set of 83 age-matched controls showed significant binding only in the MAPT carriers in selected frontal, temporal and subcortical regions. In summary, our findings demonstrate mild but significant binding of MK-6240 in amyloid-negative P301L and R406W MAPT mutation subjects, with higher standardized uptake value ratio in the R406W mutation associated with the presence of NFTs, and little non-specific binding. These results highlight that a positive 18F-MK-6240 tau-PET does not necessarily imply a diagnosis of Alzheimer\u27s disease and point towards a potential use for 18F-MK-6240 as a biomarker in certain tauopathies beyond Alzheimer\u27s, although further patient recruitment and autopsy studies will be necessary to determine clinical applicability

Dynamic amyloid and metabolic signatures of delayed recall performance within the clinical spectrum of Alzheimer’s disease

Associations between pathophysiological events and cognitive measures provide insights regarding brain networks affected during the clinical progression of Alzheimer’s disease (AD). In this study, we assessed patients’ scores in two delayed episodic memory tests, and investigated their associations with regional amyloid deposition and brain metabolism across the clinical spectrum of AD. We assessed the clinical, neuropsychological, structural, and positron emission tomography (PET) baseline measures of participants from the Alzheimer’s Disease Neuroimaging Initiative. Subjects were classified as cognitively normal (CN), or with early (EMCI) or late (LMCI) mild cognitive impairment, or AD dementia. The memory outcome measures of interest were logical memory 30 min delayed recall (LM30) and Rey Auditory Verbal Learning Test 30 min delayed recall (RAVLT30). Voxel-based [18F]florbetapir and [18F]FDG uptake-ratio maps were constructed and correlations between PET images and cognitive scores were calculated. We found that EMCI individuals had LM30 scores negatively correlated with [18F]florbetapir uptake on the right parieto-occipital region. LMCI individuals had LM30 scores positively associated with left lateral temporal lobe [18F]FDG uptake, and RAVLT30 scores positively associated with [18F]FDG uptake in the left parietal lobe and in the right enthorhinal cortex. Additionally, LMCI individuals had LM30 scores negatively correlated with [18F]florbetapir uptake in the right frontal lobe. For the AD group, [18F]FDG uptake was positively correlated with LM30 in the left temporal lobe and with RAVLT30 in the right frontal lobe, and [18F]florbetapir uptake was negatively correlated with LM30 scores in the right parietal and left frontal lobes. The results show that the association between regional brain metabolism and the severity of episodic memory deficits is dependent on the clinical disease stage, suggesting a dynamic relationship between verbal episodic memory deficits, AD pathophysiology, and clinical disease stages

Blood phospho-tau in Alzheimer disease: analysis, interpretation, and clinical utility

Well-authenticated biomarkers can provide critical insights into the biological basis of Alzheimer disease (AD) to enable timely and accurate diagnosis, estimate future burden and support therapeutic trials. Current cerebrospinal fluid and molecular neuroimaging biomarkers fulfil these criteria but lack the scalability and simplicity necessary for widespread application. Blood biomarkers of adequate effectiveness have the potential to act as first-line diagnostic and prognostic tools, and offer the possibility of extensive population screening and use that is not limited to specialized centres. Accelerated progress in our understanding of the biochemistry of brain-derived tau protein and advances in ultrasensitive technologies have enabled the development of AD-specific phosphorylated tau (p-tau) biomarkers in blood. In this Review we discuss how new information on the molecular processing of brain p-tau and secretion of specific fragments into biofluids is informing blood biomarker development, enabling the evaluation of preanalytical factors that affect quantification, and informing harmonized protocols for blood handling. We also review the performance of blood p-tau biomarkers in the context of AD and discuss their potential contexts of use for clinical and research purposes. Finally, we highlight outstanding ethical, clinical and analytical challenges, and outline the steps that need to be taken to standardize inter-laboratory and inter-assay measurements

Quantification of SNAP-25 with mass spectrometry and Simoa: a method comparison in Alzheimer's disease

BACKGROUND: Synaptic dysfunction and degeneration are central to Alzheimer's disease (AD) and have been found to correlate strongly with cognitive decline. Thus, studying cerebrospinal fluid (CSF) biomarkers reflecting synaptic degeneration, such as the presynaptic protein synaptosomal-associated protein 25 (SNAP-25), is of importance to better understand the AD pathophysiology. METHODS: We compared a newly developed Single molecule array (Simoa) immunoassay for SNAP-25 with an in-house immunoprecipitation mass spectrometry (IP-MS) method in a well-characterized clinical cohort (n = 70) consisting of cognitively unimpaired (CU) and cognitively impaired (CI) individuals with and without Aβ pathology (Aβ+ and Aβ-). RESULTS: A strong correlation (Spearman's rank correlation coefficient (rs) > 0.88; p < 0.0001) was found between the Simoa and IP-MS methods, and no statistically significant difference was found for their clinical performance to identify AD pathophysiology in the form of Aβ pathology. Increased CSF SNAP-25 levels in CI Aβ+ compared with CU Aβ- (Simoa, p ≤ 0.01; IP-MS, p ≤ 0.05) and CI Aβ- (Simoa, p ≤ 0.01; IP-MS, p ≤ 0.05) were observed. In independent blood samples (n = 32), the Simoa SNAP-25 assay was found to lack analytical sensitivity for quantification of SNAP-25 in plasma. CONCLUSIONS: These results indicate that the Simoa SNAP-25 method can be used interchangeably with the IP-MS method for the quantification of SNAP-25 in CSF. Additionally, these results confirm that CSF SNAP-25 is increased in relation to amyloid pathology in the AD continuum