Lewy bodies and neurofibrillary tangles, composed of α-synuclein (α-syn) and tau, respectively, often are found together in the same brain and correlate with worsening cognition. Human postmortem studies show colocalization of α-syn and tau occurs in Lewy bodies, but with limited effort to quantify colocalization. In this study, postmortem middle temporal gyrus tissue from decedents (n = 9) without temporal lobe disease (control) or with Lewy body disease (LBD) was immunofluorescently labeled with antibodies to phosphorylated α-syn (p-α-syn), tau phosphorylated at Ser202/Thr205 (p-tau), or exposure of tau’s phosphatase-activating domain (PAD-tau) as a marker of early tau aggregates. Immunofluorescence for major-histocompatibility complex class 2 (MHCII) and ionized calcium binding adaptor molecule 1 (Iba1) also was performed because inflammation is an additional pathological hallmark of LBDs, and they were a positive control for two markers known to colocalize. The abundance of p-α-syn, p-tau, and MHCII was significantly associated with diagnosis of LBD. Quantification of colocalization showed that MHCII and Iba1 colocalized, demonstrating activated immune cells are mostly microglia. However, p-α-syn rarely colocalized with p-tau or PAD-tau, although the overlap of p-α-syn with PAD-tau was significantly associated with LBD. In the rare cases pathologic α-syn and pathologic tau were found in the same Lewy body or Lewy neurite, tau appeared to surround α-syn but did not colocalize within the same structure. The relationship between tau and α-syn copathology is important for explaining clinical symptoms, severity, and progression, but there is no evidence for frequent, direct protein-protein interactions in the middle temporal gyrus.

BackgroundDisease-modifying therapies targeting the diverse pathophysiology of Alzheimer’s disease (AD), including neuroinflammation, represent potentially important and novel approaches. The glucagon-like peptide-1 receptor agonist semaglutide is approved for the treatment of type 2 diabetes and obesity and has an established safety profile. Semaglutide may have a disease-modifying, neuroprotective effect in AD through multimodal mechanisms including neuroinflammatory, vascular, and other AD-related processes. Large randomized controlled trials are needed to assess the efficacy and safety of semaglutide in early-stage symptomatic AD.Methodsevoke and evoke+ are randomized, double-blind, placebo-controlled phase 3 trials investigating the efficacy, safety, and tolerability of once-daily oral semaglutide versus placebo in early-stage symptomatic AD. Eligible participants were men or women aged 55–85 years with mild cognitive impairment or mild dementia due to AD with confirmed amyloid abnormalities (assessed by positron emission tomography or cerebrospinal fluid [CSF] analysis). After a maximum 12-week screening phase, an anticipated 1840 patients in each trial are randomized (1:1) to semaglutide or placebo for 156 weeks (104-week main treatment phase and 52-week extension). Randomized participants follow an 8-week dose escalation regimen (3 mg [weeks 0–4], 7 mg [weeks 4–8], and 14 mg [weeks 8–156]). The primary endpoint is the semaglutide–placebo difference on change from baseline to week 104 in the Clinical Dementia Rating – Sum of Boxes score. Analyses of plasma biomarkers, collected from all participants, and a CSF sub-study (planned n = 210) will explore semaglutide effects on AD biomarkers and neuroinflammation.ResultsEnrollment was undertaken between May 18, 2021, and September 8, 2023. Completion of the trials’ main phase is expected in September 2025, and the 52-week extension (in which participants and investigators remain blinded to treatment assignment) will continue to October 2026.Conclusionevoke and evoke+ are the first large-scale trials to investigate the disease-modifying potential of semaglutide in participants with early-stage symptomatic AD, including exploration of effects on AD biomarkers and neuroinflammation. The trials will provide data on the potential disease-modifying effects of semaglutide and will be important in evaluating its utility in the treatment of early-stage symptomatic AD.Trial registrationClinicaltrials.gov, NCT04777396 and NCT04777409. Date: 02/03/2021

Alzheimer's disease (AD), Dementia with Lewy bodies (DLB), and Parkinson's disease (PD) represent a spectrum of neurodegenerative disorders (NDDs). Here, we performed the first direct comparison of their transcriptomic landscapes. We profiled the whole transcriptomes of NDD cortical tissue by snRNA-seq. We used computational analyses to identify common and distinct differentially expressed genes (DEGs), biological pathways, vulnerable and disease-driver cell subtypes, and alteration in cell-to-cell interactions. The same vulnerable inhibitory neuron subtype was depleted in both AD and DLB. Potentially disease-driving neuronal cell subtypes were present in both PD and DLB. Cell-cell communication was predicted to be increased in AD but decreased in DLB and PD. DEGs were most commonly shared across NDDs within inhibitory neuron subtypes. Overall, we observed the greatest transcriptomic divergence between AD and PD, while DLB exhibited an intermediate transcriptomic signature. These results help explain the clinicopathological spectrum of this group of NDDs and provide unique insights into the shared and distinct molecular mechanisms underlying the pathogenesis of NDDs.

AbstractBackgroundInflammation is crucial in Alzheimer’s Disease (AD), where oxidized lipid derivatives of polyunsaturated fatty acids (PUFAs), i.e., oxylipins, are potent modulators. Soluble epoxide hydrolase (sEH), known for converting pro‐resolving epoxy‐fatty acids to pro‐inflammatory dihydroxy‐fatty acids (diols), is upregulated in the AD brain. Recent studies identify AD as a systemic disorder, but peripheral organs are understudied. Given the liver’s pivotal role in metabolizing lipids and circulating lipid mediators’ production, we tested the hypothesis that the inflammatory lipid mediator networks altered in the brain are also perturbed in the liver.MethodAD diagnosis was based on the NIA‐AA guidelines. We analyzed lipid mediators in paired postmortem brain and liver tissues from 16 cognitive normal and 63 AD participants with short postmortem intervals (≤3 hours). Both alkali‐releasable and free oxylipins were measured using LC‐MS/MS‐based methods. Aberrant metabolites associated with AD were identified using analysis of covariance, adjusting for sex, age, BMI, and postmortem interval. Sex differences were explored.ResultIn both the brain and liver of AD participants, we found altered levels of alkali‐releasable ethanolamides, recognized for their neuroprotective and anti‐inflammatory properties. The most significant changes were observed in sEH activities within the AD liver, where pro‐inflammatory diols decreased in alkali‐releasable fractions. This reversely confirms the published results of increased free diols in AD plasma, as the esterified oxylipin pool serves as a reservoir for free oxylipins. These findings suggest that circulating metabolites of sEH and ethanolamides may predict AD pathogenesis. We also found that the decreased level of pro‐inflammatory 20‐HETE in the AD liver, which did not align with our expectations. Moreover, observations hinted at male proneness to inflammation.ConclusionOur data show significant alterations in lipid mediators in both the AD brain and liver, with liver exhibiting the most pronounced changes. This supports AD being a systemic disorder with the potential for liver to regulate brain function via lipid mediators and emphasizes the complexity of lipid metabolism in AD. Sex distinctions underscore the importance of considering it as a variable in future research. Additionally, it highlights the need to explore the biological implications of alkali‐releasable mediators.

ContextOlfactory dysfunction (OD) is a common early symptom of Parkinson’s disease (PD). However, OD is not specific to PD, as approximatively 20% of the general population exhibit different forms of OD. To use olfactory measures for early Parkinson screening, it is crucial to distinguish PD-related OD from Non-Parkinsonian OD (NPOD).Objectives and hypothesisThis study aimed to compare the structural changes associated with PD-related OD (n = 15) with NPOD (n = 15), focusing on gray matter volumes and white matter fiber integrity in chemosensory regions. We hypothesized that PD-related OD presents specific structural alterations in these regions.MethodsParticipants underwent a 3 T MRI scan, which included anatomical T1 and diffusion-weighted imaging. Gray and white matter integrity were assessed using both whole-brain analyses (voxel-based morphometry—VBM and tract-based spatial statistics—TBSS, respectively) and localized approaches, including regions of interest and tractography.ResultsPD patients exhibited significantly higher gray matter volume in the left insula using restricted regions-of-interest analyses, while no other significant gray or white matter differences were found between groups.ConclusionStructural imaging of the gray matter, particularly the insula, but not of white matter, differentiates PD-related OD from NPOD.

Disease-specific fluid biomarkers are in demand for parkinsonian syndromes (PS). Corticotropin-releasing hormone (CRH) was proposed as a biomarker for Lewy body disease. As such, this project aimed to confirm CRH as a potential biomarker for different PS. CRH and misfolded α-synuclein (αSyn) were measured in CSF. The primary cohort included Lewy body disease patients (i.e. Parkinson's disease or dementia with Lewy bodies, n = 77), atypical PS (n = 37) and non-parkinsonian neurodegenerative diseases (n = 164), as well as controls (n = 354). A replication cohort included Lewy body disease (n = 27), atypical PS (n = 58) and controls (n = 58). CRH was downregulated in αSyn positive Lewy body disease, αSyn positive controls and in all atypical PS compared with αSyn negative controls (P = 3.3e-05, P = 3.1e-10, P = 2.9e-03). CRH was also decreased in αSyn positive Lewy body disease compared with αSyn negative non-PS (P = 2e-03) and correlated with cognitive impairment and inflammation in αSyn positive Lewy body disease. We show that CRH is a promising biomarker for Lewy body disease and atypical PS and its association with inflammation and cognitive decline. Reductions in CRH in Lewy body disease and other PS suggest this decrease may relate to dopaminergic degeneration instead of αSyn pathology.