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This increasing body of literature indicates that menopause hormonal replacement therapy (MHT) may substantially mitigate the risk of developing late-life cognitive decline due to progressive Alzheimer's disease (AD) pathophysiology. For the first time, we investigated the question whether MHT impacts AD biomarker-informed pathophysiological dynamics in de-novo diagnosed menopausal women.We analyzed baseline and longitudinal differences between MHT-taking and -not women in terms of concentrations of core pathophysiological AD plasma biomarkers, validated in symptomatic and cognitively healthy individuals, including biomarkers of (1) the amyloid-β (Aβ) pathway, (2) tau pathophysiology, (3) neuronal loss, and (4) axonal damage and neurodegeneration.We report a prominent and significant treatment response at the Aβ pathway biomarker level. Women at genetic risk for AD (APOE e4 allele carriers) have particularly shown favorable results from treatment.To our knowledge, we present first prospective clinical evidence on effects of MHT on AD pathophysiology during menopause.

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 are key to unleashing Aβ effects in pathological tau phosphorylation. In a large study (n=1,016) across three cohorts, we tested whether astrocyte reactivity modulates the association of Aβ with plasma tau phosphorylation in CU people. We found that Aβ pathology was associated with increased plasma phosphorylated tau levels only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau-PET analysis revealed that tau tangles accumulated as a function of Aβ burden only in CU Ast+ individuals with a topographic distribution compatible with early AD. Our findings suggest that increased astrocyte reactivity is an important upstream event linking Aβ burden with initial tau pathology which might have implications for the biological definition of preclinical AD and for selecting individuals for early preventive clinical trials.

The mechanisms by which the apolipoprotein E ε4 (APOEε4) allele influences Alzheimer’s disease (AD) pathophysiological progression are poorly understood. Here, we tested the association of APOEε4 carriership and amyloid-β (Aβ) burden with longitudinal tau pathology progression. We studied 104 individuals across the aging and AD spectrum who underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aβ ([18F]AZD4694) and tau ([18F]MK-6240) at baseline, as well as a follow-up tau-PET scan (mean follow-up, 2.4 years). We further assessed longitudinal changes in tau phosphorylation (plasma phosphorylated tau at threonine 217 [p-tau217+]), brain atrophy (gray matter density), and clinical function (clinical dementia rating scale sum of boxes). We found that APOEε4 carriership potentiates Aβ effects on longitudinal tau tangle accumulation over two years. The APOEε4-potentiated Aβ effects on tangles were mediated by longitudinal plasma p-tau217+ increase. This longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline. Our results support a model in which the APOEε4 allele plays a key role in Aβ downstream effects on the aggregation of phosphorylated tau in the form of neurofibrillary tangles in the living human brain.

Tau-PET provides valuable prognostic information in Alzheimer’s disease but using blood-based biomarkers as a first-line screening tool could reduce costs. In this study, plasma Aβ42/Aβ40, pTau181, pTau217, pTau231, NfL, and GFAP were measured along with tau-PET in 550 memory clinic patients who had subjective cognitive decline, mild cognitive impairment, or any form of dementia from the Swedish BioFINDER-2 study. For each biomarker, cutoffs were established to achieve 90% sensitivity for detecting tau-PET positivity. The percentage of participants who fell below the cutoff was calculated along with the tau-PET positive rate among participants with abnormal biomarker values. Results showed that between 18–51% of tau-PET scans could be saved with plasma screening, with P-tau217 performing best. Performance of GFAP, P-tau181, and P-tau231 was in a second tier. The PET positive rate among those who would receive a tau-PET scan was ~ 75% with plasma screening compared to 37% in the entire study population.

IntroductionIn Alzheimer’s disease clinical research, glial fibrillary acidic protein (GFAP) released into the cerebrospinal fluid and blood is widely measured and perceived as a biomarker of reactive astrogliosis. However, it was demonstrated that GFAP levels differ in individuals presenting with amyloid-β (Aβ) or tau pathology. The molecular underpinnings behind this specificity are unexplored. Here we investigated biomarker and transcriptomic associations of GFAP-positive astrocytes with Aβ and tau pathologies in humans and mouse models.MethodsWe studied 90 individuals with plasma GFAP, Aβ- and Tau-PET to investigate the association between biomarkers. Then, transcriptomic analysis in hippocampal GFAP-positive astrocytes isolated from mouse models presenting Aβ (PS2APP) or tau (P301S) pathologies was applied to explore differentially expressed genes (DEGs), Gene Ontology processes, and protein-protein interaction networks associated with each phenotype.ResultsIn humans, we found that plasma GFAP associates with Aβ but not tau pathology. Unveiling the unique nature of GFAP-positive astrocytic responses to Aβ or tau pathology, mouse transcriptomics showed scarce overlap of DEGs between the Aβ and tau mouse models, While Aβ GFAP-positive astrocytes were overrepresented with genes associated with proteostasis and exocytosis-related processes, tau hippocampal GFAP-positive astrocytes presented greater abnormalities in functions related to DNA/RNA processing and cytoskeleton dynamics.ConclusionOur results offer insights into Aβ- and tau-driven specific signatures in GFAP-positive astrocytes. Characterizing how different underlying pathologies distinctly influence astrocyte responses is critical for the biological interpretation of astrocyte-related biomarker and suggests the need to develop context-specific astrocyte targets to study AD.FundingThis study was supported by Instituto Serrapilheira, Alzheimer’s Association, CAPES, CNPq and FAPERGS.

Understanding whether vascular risk factors synergistically potentiate Alzheimer’s disease progression is important in the context of emerging treatments for preclinical Alzheimer’s disease. The existence of a synergistic relationship could suggest that the combination of therapies targeting Alzheimer’s disease pathophysiology and vascular risk factors might potentiate treatment outcomes. In the present retrospective cohort study, we tested whether vascular risk factor burden interacts with Alzheimer’s disease pathophysiology to accelerate neurodegeneration and cognitive decline in cognitively unimpaired subjects. We evaluated 503 cognitively unimpaired participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Baseline vascular risk factor burden was calculated considering the history of cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, stroke or transient ischemic attack, smoking, atrial fibrillation, and left ventricular hypertrophy. Alzheimer’s disease pathophysiology was evaluated using cerebrospinal fluid (CSF) amyloid-β1-42 (Aβ1-42) reflecting brain amyloidosis (A) and tau phosphorylated at threonine 181 (p-tau181) reflecting brain tau pathology (T). Individuals were dichotomized as having an elevated vascular risk factor burden (V+ if having two or more vascular risk factors) and as presenting preclinical Alzheimer’s disease [(AT)+ if having abnormal CSF p-tau181 and Aβ1-42 levels]. Neurodegeneration was assessed with plasma neurofilament light (NfL) and global cognition with the modified version of the Preclinical Alzheimer’s Cognitive Composite. Linear mixed-effects models revealed that an elevated vascular risk factor burden synergistically interacted with Alzheimer’s disease pathophysiology to drive longitudinal increases in plasma NfL levels (β = 5.08, P = 0.016) and cognitive decline (β = −0.43, P = 0.020). Additionally, we observed that vascular risk factor burden was not associated with CSF Aβ1-42 or p-tau181 changes over time. Survival analysis demonstrated that individuals with preclinical Alzheimer’s disease and elevated vascular risk factor burden [(AT)+V+] had a significantly greater risk of clinical progression to cognitive impairment (adjusted Hazard Ratio = 3.5, P < 0.001). Our results support the notion that vascular risk factor burden and Alzheimer’s disease pathophysiology are independent processes; however, they synergistically lead to neurodegeneration and cognitive decline. These findings can help in providing the blueprints for the combination of vascular risk factor management and Alzheimer’s disease pathophysiology treatment in preclinical stages. Moreover, we observed plasma NfL as a robust marker of disease progression that may be used to track therapeutic response in future trials.

COVID-19 has been associated with many neurological complications including stroke, delirium and encephalitis. Furthermore, many individuals experience a protracted post-viral syndrome which is dominated by neuropsychiatric symptoms, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of severe COVID-19 more broadly.We sought to investigate the dynamics of, and relationship between, serum markers of brain injury (neurofilament light [NfL], Glial Fibrillary Acidic Protein [GFAP] and total Tau) and markers of dysregulated host response including measures of autoinflammation (proinflammatory cytokines) and autoimmunity. Brain injury biomarkers were measured using the Quanterix Simoa HDx platform, cytokine profiling by Luminex (R&D) and autoantibodies by a custom protein microarray.During hospitalisation, patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependant manner, and there was evidence of ongoing active brain injury at follow-up 4 months later. Raised NfL and GFAP were associated with both elevations of pro-inflammatory cytokines and the presence of autoantibodies; autoantibodies were commonly seen against lung surfactant proteins as well as brain proteins such as myelin associated glycoprotein, but reactivity was seen to a large number of different antigens.Furthermore, a distinct process characterised by elevation of serum total Tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses in the same manner as NfL and GFAP.

Background: Alzheimer’s disease (AD) was biologically defined by the 2018 NIA-AA Research Framework (RF), which recommends dichotomously defining biomarker status as normal or abnormal with single cutpoints. However, a three-range approach remains unexplored in AD fluid biomarkers. Objective: To assess the prognostic utility of a three-range approach for CSF biomarkers in AD. Methods: We included 1278 non-demented individuals (CU: n=575; MCI: n=703) from the ADNI with baseline CSF Elecsys® biomarkers. Within it, we defined three-range cutpoints with two-graph receiver operating characteristics (TGROC) for each CSF biomarker (Aβ1-42, p-tau, p-tau/Aβ1-42), based on amyloid PET positivity. Then, linear mixed-effects and Cox proportional hazards models were used to estimate longitudinal cognitive trajectories and risk of clinical progression based on CSF biomarker status. Hereby derived three-range cutpoints were compared to previously described binary thresholds for the same biomarkers. Power analyses for simulated trials were also carried. Results: We observed dynamic amyloid-PET changes for participants in the intermediate range, while a static profile for clearly normal and abnormal groups. Longitudinally, our approach revealed a divergent intermediate cognitive trajectory undetected by dichotomization, with power analyses demonstrating potential applications for trial enrichment. Conclusion: The proposed approach can improve CSF-based diagnosis, refine prognostic assessment and enhance clinical trial recruitment.

International audience; The establishment of the Acheulean in Europe occurred after MIS 17, but it was after the harsh glaciation of MIS 12 and during the long interglacial of MIS 11 that human occupation of western Europe became more sustained, with an increased number of sites. Menez-Dregan I (Brittany, France) is one of the key sites in western Europe that dates from this threshold, with an alternating sequence of 16 occupation levels and four marine deposits, from MIS 12 to 8. The large lithic assemblages of over 154,000 artifacts from knapping (cores, flakes) and shaping (macro-tools and shaping flakes) show the varying use of raw materials and activities at the site through the sequence. This work focuses on the study of the handaxes and cleavers using technological and metrical methods with multivariate analysis, in combination with geometric morphometrics, and places these analyses within the context of other technological changes at the site. Collectively, results show the persistent use through the sequence of the same lithic raw materials and technologies, including fire-use and the import of glossy sandstone from 20 km away, but with variation in activities at the site. These findings suggest that Menez-Dregan I shows the development of a specific material culture that reflects the local resources and environment. Results further indicate that the site shows the sustained hominin occupation of the area, despite varying climate and environment, with strong traditions of social learning that were maintained through flexibility of site-use, deep understanding of the local territory and the innovation of new technologies, such as the use of fire. Evidence from the site is placed within the wider context of Europe, and contrasted with areas to the north, such as Britain, where hominin occupation was more sporadic and driven by cyclical climate change.

The period between 600 and 400 ka is a critical phase for human evolution in Europe. The south and northwest saw a dramatic increase in sites, the spread of handaxe technology alongside bone and wooden tool manufacture, efficient hunting techniques, and the use of fire. Lithic assemblages show considerable variation, including the presence/absence of handaxes and tool morphology. To explain this variation, we propose the Cultural Mosaic Model, which suggests that there is a range of expressions of the Acheulean, with local resources being instrumental in creating distinct material cultures with or without handaxes. We argue that if typologically and technologically distinct assemblage types are regionally distributed, chronologically separated, and persistent over time, then they are unlikely to be caused purely by raw material constraints or functional variation but rather reflect populations with different material cultures. We initially assess the model using British data. Britain was a northwestern peninsula of Europe, and oscillations in climate led to episodic occupation. The terraces of the pre-MIS 12 Bytham River provide a framework for dating occupation to MIS 13 and 15, while during MIS 11, archaeological sites with rich environmental records can be dated to substage level. We suggest there are six chronologically and typologically distinct assemblage types that reflect a series of population incursions into Britain. We review the broader European lithic record, which is consistent with the Cultural Mosaic Model. In developing the model, we suggest that during stable climate, localized cultures developed, while climatic change led to shifts in population, with increased knowledge exchange and gene flow. We suggest that group expression through material culture was an important stage in social development by promoting group cohesion, larger group size, better cooperation, improved knowledge transfer, and enabling populations to survive in larger foraging territories in northern Europe.

Introduction: Sleep is beneficial and necessary for nearly every tissue in and function of the human body. A lack of sleep can lead to many health hazards including depression, heart disease, obesity, hypertension, and diabetes. Utilizing an appropriate pillow can promote optimal spinal alignment, thus improving sleep quality and duration. The purpose of this study was to analyze available literature and determine the level of evidence of different pillow parameters (material, height, shape, and thermal properties) to promote and enhance sleep quality, spinal alignment, and to decrease waking symptoms. Methods: Following detailed and systematic search in major ergonomics-related data bases (PubMed, CINAHL, Science Direct, & Google Scholar) by independent searchers applying systematized search processes, eleven articles qualified for inclusion in this review (309 participants). The methodological qualities of included articles were assessed by two independent raters utilizing the PEDro scale and the Modified PEDro Scale for Ergonomics Research (MPSER). Similarly, the authors utilized the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to evaluate the quality of evidence that these articles established. Results: There is moderate evidence that some of the following pillow parameters could improve sleep quality/spinal alignment, and decrease sleep-related neck pain. The parameters are; a latex pillow material, a contoured pillow design (higher sides to accommodate side sleepers and a lower, flattened middle to accommodate back sleepers), a seven to eleven centimeters height of the unloaded central part of the pillow, and a cooling surface. Conclusion: Patients/clients are encouraged to consider as many of the above mentioned parameters as possible when choosing a new pillow that fits their individual needs of promoting sleep comfort.

Introduction Subjectively experienced cognitive decline in older adults is an indicator of increased risk for dementia and is also associated with increased levels of anxiety symptoms. As anxiety is itself emerging as a risk factor for cognitive decline and dementia, the primary question of the present study is whether an 8-week mindfulness-based intervention can significantly reduce anxiety symptoms in patients with subjective cognitive decline (SCD). The secondary questions pertain to whether such changes extend to other domains of psychological, social, and biological functioning (including cognition, self-regulation, lifestyle, well-being and quality of life, sleep, and selected blood-based biomarkers) associated with mental health, older age, and risk for dementia. Methods SCD-Well is a multicenter, observer-blinded, randomized, controlled, superiority trial, which is part of the Horizon 2020 European Union-funded “Medit-Ageing” project. SCD-Well compares an 8-week mindfulness- and compassion-based intervention specifically adapted for older adults with SCD with a validated 8-week health education program. Participants were recruited from memory clinics in four European sites (Cologne, Germany; London, United Kingdom; Barcelona, Spain; and Lyon, France) and randomized with a 1:1 allocation, stratified by site. Results The primary outcome, change in anxiety symptoms, and secondary outcomes reflecting psychological, cognitive, social, and biological functioning are assessed at baseline, postintervention, and 4 months after the end of the intervention. Discussion The study will provide evidence on whether a mindfulness-based intervention can effect changes in anxiety and other risk factors for cognitive decline and dementia in older adults with SCD and will inform the establishment of intervention strategies targeted at improving mental health in older adults., Highlights • Mindfulness may benefit older adults with subjective cognitive decline (SCD). • SCD-Well compares an 8-week mindfulness intervention to a health education course. • Patients with SCD were recruited from memory clinics in four countries. • Outcomes include anxiety symptoms, psychosocial, cognitive, and biological function. • Results will inform future prevention studies and strategies in SCD.