Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Thymoquinone (TQ) is the active component of black seeds with many health benefits. Intermittent fasting (IF) is a dietary pattern with antioxidant and neuro-regenerative effects. This study explored the neuroprotective potential of TQ, IF or their combination on hippocampus of AD-like rat model with emphasis on the underlying mechanisms as neurogenesis and autophagy. Eighty adult male rats were divided into 7 groups: control, TQ given TQ (50 mg/kg/day orally), IF underwent IF for 14 h/day, AL given Aluminum chloride (AlCl) (300 mg/kg/day orally) to induce AD-like pathology, AL + TQ, AL + IF and AL + TQ+ IF for 4 weeks. AD-like pathology was evaluated by behavioral tests, histopathology, immunostaining for apoptosis (Bax), microglia (CD68) and neurogenesis (nestin). Expressions of p-Tau, oxidative stress & autophagy markers (P62 and LC3B II) were assessed by western blot. AL group showed histological and ultrastructural AD-like features as apoptotic neurons, amyloid β deposition, significant elevation in MDA, p-Tau and P62, reduction in SOD and LC3B II, upregulation of Bax immune-expression and number of CD68 + activated microglia and diminished nestin positive cell number. TQ and IF mitigated these changes particularly when used in combination. In conclusion, TQ and IF protect against AlClinduced hippocampal AD-like pathology through reduction of oxidative stress, apoptosis, amyloid deposits, p-Tau expression and their modulatroy effects on microglia activation, neurogenesis and autophagy. The neuroprotective potential of IF is superior to TQ, while the optimal neuroprotection is achieved by the combination of both.

This study examined the associations between 24-h movement behaviors and cognitive function in cognitively unimpaired older adults, and whether Alzheimer's disease brain signatures, including gray matter mean diffusivity (GMMD) and thickness/volume signatures, moderated these associations. A total of 91 participants were enrolled in the AGUEDA trial (NCT05186090), with 89 included in this cross-sectional analysis (mean age = 71.61 ± 3.85 years; 56.2% females). Moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), sedentary behavior (SB), and sleep were objectively assessed using 9-day wrist-worn accelerometry. Cognitive function was assessed across attention/inhibitory control, episodic memory, processing speed, visuospatial processing, and working memory. Thickness/volume and GMMD signatures were derived from cortical and hippocampal regions. Compositional linear regression models (CoDA) examined associations, adjusting for age, sex, and education, and tested interactions between movement behaviors and Alzheimer's disease brain signatures. No direct associations were observed between 24-h movement behaviors and cognitive domains (all p > 0.05). However, GMMD signature, but not thickness/volume signature, moderated several movement behavior-cognition associations. Moderation was most evident for episodic memory, with significant interactions for MVPA, LPA, and sleep, while LPA exhibited the broadest pattern of moderation across cognitive domains, interacting with attention/inhibitory control, episodic memory, processing speed, and working memory (all p for interaction ≤ 0.04). In conclusion, the associations between 24-h movement behaviors and cognitive function may depend on microstructural brain integrity (i.e., GMMD). These findings highlight the importance of considering Alzheimer's disease-related brain signatures when investigating lifestyle-cognition associations and support a more personalized approach to promoting cognitive health in older adults. Future prospective longitudinal studies and CoDA interventional trials are needed to establish temporal precedence and evaluate whether targeted time reallocations can actively attenuate cognitive trajectories across distinct microstructural vulnerability profiles. Trial Registration: NCT05186090.

BACKGROUND: Although the epidemiology of Creutzfeldt-Jakob disease (CJD) in Israel has been studied extensively, it is unknown whether its incidence is mainly a result of vertical transmission due to the high penetrance of the E200K mutation in patients with familial CJD (f-CJD) compared to sporadic CJD (s-CJD), or whether there are other yet undiscovered contributing factors. OBJECTIVES: To conduct an age-period-cohort (APC) analysis of Creutzfeldt-Jakob disease in Israel. METHODS: In this APC analysis, we used a web-based statistical tool to identify whether patient age, period of birth, and cohort had any effect on incidence trends of s-CJD and f-CJD. RESULTS: APC analysis demonstrated no significant shifts in net drift, indicating the absence of any overall trend of changes over time. Cohort analysis revealed that individuals affected by either s-CJD or f-CJD who were mostly born in Israel in the second half of the 20th century exhibited the same risk as those born mainly in Libya at the beginning of 20th century. There were no changes in risk of s-CJD and f-CJD between 1985 and 2019. CONCLUSIONS: The incidence rates of s-CJD and f-CJD in Israel have remained unchanged, indicating that the probability of a future increase in the incidence is negligible.

Understanding the molecular mechanisms of aging guides the development of prevention, intervention, and treatment strategies to reduce the incidence of common age-associated diseases. Over the past decades, the proposed key features (hallmarks) of aging cells have directly or indirectly provided us clues, furthering our understanding of the causes of disease and assisting with the development of therapeutic strategies for diseases such as rare premature aging diseases like Werner syndrome and ataxia telangiectasia (A-T), as well as the common age-related diseases like dementia and sarcopenia. In this editorial, we take a closer look at three of these hallmarks including genomic instability, defective macroautophagy, and mitochondrial dysfunction, and the applications of these concepts in understanding the progress of complex diseases. Mounting studies from the laboratory, supported by emerging clinical evidence, point to the reduction of the oxidized form of nicotinamide adenine dinucleotide (NAD) as a commonality between many of these hallmarks of aging. Intriguingly, stimulating mitochondrial autophagy (mitophagy) via improvement of NAD availability appears to be a promising and effective therapeutic strategy for many diseases relating to aging. Future studies on the hallmarks of aging should address their internal linkages and clinical interventions.

In humans, hypersecretion of amyloidogenic amylin (islet amyloid polypeptide, IAPP) in the setting of insulin resistance and type 2 diabetes (T2D) promotes systemic oligomerization and tissue deposition, with deposits identified in failing human hearts and the cerebrovasculature of patients with Alzheimer's Disease. In the renal vasculature, amylin aggregation disrupts microvascular integrity, activating hypoxia signaling pathways and contributing to maladaptive erythropoietic responses, including excess erythrocytosis. We hypothesized that amyloid-forming amylin would activate hypoxia-inducible factor (HIF) signaling, leading to metabolic alterations in liver and heart during T2D pathogenesis. To investigate this, we used the HIP rat, which expresses human amylin specifically in pancreatic β-cells, comparing tissues from 14 to 16-month-old rats with those from age-matched wild-type, hyperglycemic UCD and amylin-knockout (AKO) rats. We found greater accumulation of HIF-1α and HIF-2α in HIP rat livers compared with those in other groups, alongside increased expression of HIF-1 target genes. Mitochondrial ETS capacity was elevated in HIP rat livers, in conjunction with the formation of mitochondrial supercomplexes. Amylin aggregates formed in the hearts of HIP rats, alongside HIF-1α and HIF-2α accumulation. This was associated with suppression of ETS capacity, and increased p-AMPK/AMPK, indicating possible cardiac energetic impairment. Pancreatic secretion of amyloidogenic amylin is thus associated with HIF activation in key metabolic organs beyond the renal vasculature, and occurs alongside mitochondrial alterations in liver and heart that are consistent with sustained hypoxic stress. Our results, alongside previous work, suggest that amylin dysregulation is an overlooked, human-relevant aspect of diabetes pathogenesis, and as such, a potential therapeutic target.

Curcumin, a polyphenolic natural product, binds to Aβ42, a protein involved in Alzheimer's Disease, to inhibit self-aggregation in vitro. Molecular understanding of the binding is important in designing new molecules to inhibit Aβ42 aggregation. We performed OH radical footprinting of Aβ42 in the presence and absence of curcumin by using fast photochemical oxidation of proteins (FPOP), followed by mass spectral analysis, to monitor changes in Aβ42 protein dynamics in the presence of curcumin. The results reveal that curcumin binding reduces oxidative footprinting at the N-terminus and middle region, indicating binding at these sites. Kinetic modeling of the percentage modification shows a significant change in the aggregation of Aβ42 in the presence of curcumin, whereby one aggregate population nearly disappears. The [Aβ42:curcumin] binding complexes were also explored using density functional theory (DFT), optimizating the starting structures at the B3LYP/6-31G(d) level for both the N-terminal/middle and C-terminal/middle regions. The structure of the lowest-energy complex has curcumin binding at the N-terminal plus middle regions, and this was validated by reoptimization using 6-311G(d,p) and applying Grimme's dispersion function (GD3). This structure was further confirmed by reoptimization in aqueous media using the Conductor-like Polarizable Continuum Model (CPCM). The new structure not only accounts for the observed changes in •OH footprinting of the N-terminal, middle, and C-terminal regions but also forecasts how this approach can provide insight into protein aggregation. A molecular-level understanding of the binding site of curcumin with Aβ42 should be helpful in the design of new aggregation modulators.

There is currently no consensus on the most important treatment outcomes in patients with mild cognitive impairment (MCI). As part of developing a core outcome set for MCI, we conducted a pragmatic scoping umbrella review to summarize outcomes reported in previous studies. Six electronic databases were searched from inception to August 2023. Systematic and scoping reviews in English with ≥70% of studies describing at least one quantitative outcome of interventions involving adults with MCI were eligible. Verbatim outcomes were extracted from eligible papers within selected reviews. From 170 papers covering 153 studies from 42 reviews, 143 unique outcomes were identified. Global cognition was the only outcome reported by more than 50% of studies. Two-thirds of outcomes were reported by no more than three studies. Heterogeneous outcome reporting limits evidence synthesis and treatment evaluation. A core outcome set for MCI is warranted to standardize outcome reporting and offer stronger evidence for decision-making.

BACKGROUND: Dementia places substantial physical, psychological, and social demands on informal caregivers, and caregiving needs may change across the dementia trajectory as cognitive, behavioral, and functional changes alter day-to-day care demands. Digital interventions may not fully address caregivers' evolving and heterogeneous needs and preferences. This study aimed to develop a user-centered mobile application informed by caregiver-identified needs and preferences across the dementia trajectory and to evaluate its effectiveness. METHODS: A randomized controlled trial was conducted following a qualitative intervention-development phase. The intervention was developed in accordance with the Medical Research Council framework for complex interventions and informed by principles of person-centered dementia care and qualitative interviews with informal caregivers. The application provided dementia education; communication and daily-care guidance organized to reflect changing caregiving needs; guidance for behavioral and psychological symptoms; caregiver self-care and stress-management resources; information on formal and informal support services; and customizable reminders. Caregivers were randomized to receive usual care with access to the mobile application for 8 weeks or usual care alone. Outcomes included caregiver burden (Zarit Burden Interview), quality of life (WHOQOL-BREF), neuropsychiatric symptoms (Neuropsychiatric Inventory), and caregiver distress related to these symptoms. System usability was assessed post-intervention in the intervention group. Outcomes were assessed at baseline and week 8 using repeated-measures analysis of variance. RESULTS: A total of 86 caregivers were randomized, of whom 75 were included in the analysis (intervention, n = 37; control, n = 38). Significant group-by-time interactions were observed for overall quality of life (p < 0.001) and the psychological domain (p < 0.001), with greater improvements in the intervention group than in the control group. No significant group-by-time interactions were observed for caregiver burden, neuropsychiatric symptom severity, or caregiver distress. The application demonstrated good usability at week 8. CONCLUSIONS: The user-centered mobile application was associated with improvements in overall and psychological quality of life among participants included in the 8-week analysis, while no significant intervention effects were observed for caregiver burden, neuropsychiatric symptoms, or caregiver distress. Larger studies with longer follow-up and more detailed assessment of application engagement are needed to evaluate the durability and broader effects of the intervention. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov (Registration number: NCT06179667 , Date of registration: 27 November 2023).

BACKGROUND: The scope of medical conditions addressed in Emergency Departments (ED) increases with growing numbers of older patients among the ED patient population. More information on their chief complaints and related treatment outcomes is essential to ensure high-quality ED care. The objective of this study was to describe the pattern of chief complaints of older ED patients and evaluate the associations between these complaints and outcomes such as mortality and hospital admission. METHODS: This secondary analysis is based on the observational 'Epidemiology of Geriatric patients in Europe' (EGERS) study. This prospective, routine data cross-sectional study was conducted in 36 EDs across 9 European countries. Data collection from routine clinical records of all patients aged 65 and older over a 7-day period from October 19 to November 30, 2020 during the Covid-19 pandemic. Patients with one documented non-traumatic chief complaint were analyzed. Descriptive statistics, logistic regression, and general linear mixed models were used to assess factors associated with hospital admission and in-hospital mortality. Odds ratios (OR) and 95% confidence intervals (CI) were reported. RESULTS: The study population consisted of 2,794 patients with one specified chief complaint. The mean age was 77.4 (± 8.2) years. The most frequent chief complaints were shortness of breath, abdominal pain, chest pain, weakness and fatigue, and extremity pain and numbness, representing 59% of the cohort. Highest age (≥ 85), geriatric risks (i.e. presence of dementia/Alzheimer's disease (AD), home help service or previous falls), polypharmacy, and shortness of breath increased the odds of being admitted to hospital (OR 1.4 [1.2-1.9]; OR 1.6 [1.3-1.9]; OR 1.3 [1.1-1.6]; OR 3.0 [2.4-3.8]), while female sex was negatively associated with admission (OR 0.7 [0.6-0.8]). Shortness of breath was positively associated with in-hospital mortality (OR 2.2 [1.4-4.3]). CONCLUSION: Older patients frequently require hospital admission. As chief complaints do not reflect underlying condition or severity, structured evaluation, staff training and geriatric specific care pathways may improve care and reduce adverse clinical outcomes.

Neurodegenerative diseases such as Alzheimer's disease (AD) and Lewy body disease (LBD) are frequently associated with spatial navigation impairments. However, these impairments are less pronounced in frontotemporal dementia and limbic-predominant age-related TDP-43 encephalopathy. While basal forebrain degeneration occurs in all of these diseases, disruption of cholinergic pathways and related cholinergic deficits has been primarily observed in AD and LBD, and in both of these conditions, basal forebrain degeneration appears to be associated with spatial navigation deficits. In this review, we discuss current understanding of spatial navigation impairments in neurodegenerative diseases, with a particular focus on disease-related changes in the basal forebrain and their associations with impaired spatial navigation abilities in humans.

Neurological disorders, including ischaemic and haemorrhagic stroke, traumatic brain injury, and chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, represent a major global health burden. Despite diverse etiologies, these conditions share common pathological mechanisms driven by oxidative stress, neuroinflammation, mitochondrial dysfunction, iron dysregulation, and secondary neuronal injury. The nuclear factor erythroid 2-related factor 2 (Nrf2) signalling cascade and its downstream target heme oxygenase-1 (HO-1) are master regulators of cellular redox homeostasis. HO-1 plays a pivotal yet dichotomous role: its products biliverdin/bilirubin and carbon monoxide exert antioxidant, anti-inflammatory, and anti-apoptotic effects, whereas excessive HO-1 induction can exacerbate iron-mediated oxidative injury and ferroptosis through the release of redox-active ferrous iron. Rather than cataloguing protective studies, this review builds a contextual framework that specifies when HO-1 activation is protective versus detrimental, organised around three converging determinants: cell-type specificity, iron-handling capacity, and disease stage. We extend this framework to the often-overlooked dimensions of sex, age, and model heterogeneity, and use it to interrogate conflicting findings across the literature. We further dissect how Nrf2/HO-1 regulates ferroptosis through the GPX4-ACSL4-SLC7A11 axis, critically appraise the largely unexamined relationship between Nrf2 and the parallel FSP1/CoQ10, GCH1/BH4, and DHODH defence systems, and distil lessons from clinical trials of Nrf2 activators. The goal is an analytical account that identifies where the evidence is robust, where it is contradictory, and where the principal research gaps lie.

BACKGROUND: Alzheimer's disease (AD) is an age-dependent neurodegenerative syndrome in which microglial senescence bridges biological ageing and Aβ-tau pathology. Senescent microglia undergo permanent cell-cycle arrest, upregulate p16 and SA-β-gal, and secrete a pro-inflammatory senescence-associated secretory phenotype (SASP) that sustains chronic neuroinflammation. Mitochondria-endoplasmic reticulum contact sites (MERCS) are dynamic physical junctions between the endoplasmic reticulum (ER) and mitochondria, whereas mitochondria-associated membranes (MAM) are biochemically enriched ER subdomains located at MERCS. MERCS coordinate calcium shuttling, mitochondrial dynamics, lipid trafficking and the unfolded protein response (UPR); however, whether their dysfunction drives microglial senescence in vivo remains largely untested. MAIN TEXT: This review critically integrates five MERCS-linked signalling axes that are hypothesised to drive microglial senescence, namely calcium overload, mitochondrial fission-fusion imbalance, inflammatory amplification, lipid dysregulation and unresolved ER stress. We apply a standardized four-tier evidence-grading framework to stratify causal evidence, systematically distinguish dystrophic, disease-associated (DAM) and bona-fide senescent microglia on the basis of transcriptomic and proteomic data from AD models and human tissues, and address underexplored dimensions including APOE/TREM2 crosstalk, mitophagy, epigenetic regulation, peripheral inflammation and senolytic combinations. We stress that inflammatory activation, oxidative stress and mitochondrial dysfunction represent common cellular stress responses that cannot independently define bona-fide microglial senescence. Because more than 90% of current mechanistic evidence is derived from non-microglial models, MERCS dysfunction in microglia remains a compelling hypothesis that requires rigorous in-vivo validation. Notably, MERCS dysfunction and AD-relevant APOE/TREM2 signalling engage in mutually modulatory crosstalk rather than a simple linear upstream-downstream hierarchy. CONCLUSION: Translational development faces several barriers, including poor blood-brain barrier (BBB) penetration, off-target neurotoxicity, uncharacterised long-term safety and limited generalisability from APP/PS1 models lacking tauopathy. All MERCS-targeted and senolytic combinatorial strategies discussed herein represent prospective pre-clinical research directions rather than mature clinical therapeutic approaches. We propose an experimental roadmap based on conditional knockouts, intravital imaging and bidirectional interventions. Overall, MERCS dysfunction is proposed as a candidate multimodal upstream hub for calcium, mitochondrial, inflammatory, lipid and ER-stress signalling, and rigorous in-vivo validation together with microglia-selective delivery platforms is essential for therapeutic translation.

Alzheimer's disease (AD) is a prevalent, chronic, and progressive neurodegenerative disorder that predominantly affects the elderly population, and no effective pharmacological treatments are currently available. Histone deacetylase 6 (HDAC6) is overexpressed in the hippocampus of AD patients, and its inhibition has been shown to clear amyloid-β (Aβ) deposits, promote tau protein degradation, ameliorate mitochondrial transport deficits, and restore α-tubulin acetylation. Thus, selective HDAC6 inhibition represents a promising therapeutic strategy for AD, yet the underlying mechanisms by which HDAC6 inhibitors ameliorate cognitive impairment in AD remain elusive. In our previous study, a series of novel imidazo[1,2-a]pyridine-based HDAC6 inhibitors were developed, among which compound a17 exhibited potent HDAC6 inhibitory activity with an IC value of 7.51 nM, warranting further investigation into its anti-AD effects. Herein, we demonstrated that a17 exerted robust neuroprotective effects against L-Glutamate (L-Glu-)/Aβ-induced HT22 cell injury. Additionally, a17 displayed favorable blood-brain barrier (BBB) permeability in vitro and drug-likeness properties. In vivo studies revealed that a17 significantly attenuated AD-like phenotypes in an Aluminium chloride (AlCl)-induced zebrafish AD model, a mechanism potentially associated with the differential regulation of ODC1, Serpine1, and PAG-1. Furthermore, a17 markedly improved scopolamine-induced memory deficits in mice. Collectively, these findings indicate that an HDAC6 inhibitor, a17, was found to attenuate AD-associated pathological and behavioral markers by regulating the expression of ODC1, Serpine1, or PAG-1. Accordingly, a17 merit consideration for a pharmacological treatment of choice for AD.

Learning and memory are fundamental cognitive processes that rely on activity-dependent epigenetic mechanisms to shape synaptic and neuronal plasticity. Among these, DNA methylation and demethylation have emerged as pivotal regulators that convert transient neural activity into enduring transcriptional programs. In mammals, DNA methylation marks include 5-methylcytosine (5mC) as well as the less well-established N6-methyladenine (6mA) and the more enigmatic N4-methylcytosine (4mC). Compared with 5mC, the abundance, genomic distribution, and regulatory role of 6mA and 4mC remain incompletely defined, partly due to low abundance and technical challenges, yet these non-canonical marks may provide an additional regulatory layer in specific biological contexts. Accordingly, this review focuses on the best-characterized pathway in the nervous system, 5mC and its activity-regulated oxidative turnover. This system comprises a dynamic spectrum of cytosine modifications, including 5mC, 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), orchestrated by distinct enzyme families such as DNMTs, TETs, and TDG. We review current insights about how these regulators shape activity-induced gene expression programs underlying learning and memory, and we discuss how dysregulated DNA (de) methylation contributes to impaired transcriptional control and cognitive decline in neurodegenerative diseases, particularly Alzheimer's disease. Finally, we highlight recent advances in high-resolution mapping technologies for DNA modifications, which are expanding our ability to resolve cell type- and locus-specific epigenetic dynamics in the brain. A deeper understanding of these pathways may inform targeted strategies to preserve or restore cognitive function in neurological disorders.

The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is an established driver of inflammation in diseases such as diabetes, Alzheimer's disease, and gout. Previously, we screened 875 FDA-approved drugs for NLRP3 inhibitors and identified ponatinib as one of the five candidates that reduced NLRP3 inflammasome activation without causing cytotoxic effects in bone marrow-derived macrophages (BMDMs). Therefore, we hypothesize that ponatinib may be an effective NLRP3 inflammasome inhibitor. We performed dose curves and cytotoxicity assays to determine an effective in vitro concentration of ponatinib in BMDMs (1 μM) and primary microglia (0.5 μM) that reduced IL-1β secretion without inducing cytotoxicity. In BMDMs, ponatinib inhibited Nlrp3- and Caspase-1-dependent IL-1β and IL-18 secretion and significantly reduced caspase-1 processing. Ponatinib also reduced IL-1β secretion by microglia, indicating possible NLRP3 inflammasome inhibition in this cell type, but further testing is required. Although ponatinib has previously been demonstrated to drive cardiotoxicity-mediated inflammation, these data suggest that at specific doses, in vitro ponatinib can be non-cytotoxic and effective in attenuating NLRP3 inflammasome activation in macrophages and microglia.

BACKGROUND: The impact of cognitive impairment (CI) on perioperative quality of life (QoL) in older surgical patients remains under-explored. We compared longitudinal QoL trajectories by CI status and examined associations between preoperative QoL and postoperative outcomes. METHODS: Patients aged ≥65 years undergoing elective non-cardiac surgery at two academic hospitals were assessed for preoperative CI using the Ascertain Dementia 8-Item Questionnaire (AD8), Montreal Cognitive Assessment (MoCA), and Mini-Cog. QoL was measured preoperatively and at 30 and 90 days postoperatively using a 0-100 visual analogue scale (VAS). QoL trajectories were analyzed using linear mixed-effects models, with time and cognitive status as covariates. RESULTS: Among 370 participants (median age 73 years [IQR: 69-77]; 58% female), 292 and 289 participants completed 30- and 90-day follow-up, respectively. Compared to those without AD8-defined CI (CI), participants with CI reported significantly lower QoL preoperatively (67 ± 3 vs. 78 ± 1, P < 0.001) and postoperatively at 30 days (59 ± 3 vs. 75 ± 1, P < 0.001) and 90 days (60 ± 3 vs. 77 ± 1, P < 0.001). Lower preoperative QoL was associated with greater all-cause complications, non-home discharge, and composite adverse outcomes within 30 days, as well as composite adverse outcomes at 90 days. Higher pain, frailty, anxiety/depression, and CI remained independently associated with lower perioperative QoL. CONCLUSION: Older patients with CI experienced persistently lower QoL throughout the perioperative period, compared to those without CI. Although QoL transiently declined within the CI group at 30 days, longitudinal QoL trajectories did not differ significantly between participants with and without CI. Brief preoperative screening of CI and QoL may nevertheless help identify patients at risk of poor QoL and adverse postoperative outcomes.

Self-defining future projections (SDFPs) are vivid, emotionally salient projections of personally meaningful events that anchor identity and guide motivation. While past self-defining memories ground the self in remembered experiences, SDFPs extend this function into the future, offering a forward-looking perspective on identity and well-being. In Alzheimer's disease (AD), cognitive decline threatens autonomy, memory, and self-continuity, yet little is known about how SDFPs are affected. The present study examined SDFPs in 37 individuals with mild AD and 40 cognitively healthy older adults. Participants generated SDFPs, which were evaluated for specificity, integrative meaning, importance, and emotional valence. Compared to controls, patients with AD produced less specific, less integrated, and less important future events, while emotional intensity remained comparable across groups. In AD patients, better cognitive functioning predicted greater specificity, whereas higher depression and anxiety were associated with reduced specificity, integration, and importance, as well as higher negative emotions. These findings highlight that AD compromises the structural and identity-related features of future self-projections, but preserves emotional engagement, suggesting a potential pathway for interventions to support motivation, self-continuity, and well-being.

Sleep disordered breathing (SDB) commonly co-presents with other ventilatory impairments in patients with Alzheimer's disease (AD). Typically reported as either obstructive (OSA) or complex sleep apnoea in AD patients, SDB results in repeated bouts of hypoxia and hypercapnia from insufficient ventilation. It is thought not only that these repeated hypoxic events result in an exacerbation of AD but also that SDB and other ventilatory impairments may be a precursor to neurodegenerative diseases. Although the cause of SDB in AD patients is unclear, chemosensory drive malfunction, a response critical to maintaining homeostatic oxygen and carbon dioxide balance, may play a role. We examined basal ventilation, SDB and chemosensory function in 5XFAD mice, a beta amyloidosis model of AD which displays progressive amyloid beta (Aβ) plaque deposition by 8 months of age. We found that both male and female 5XFAD mice had nearly twice as many spontaneous apnoeas per hour compared to WT mice. Basal ventilation (V̇) and air convection requirement (ACR) while awake were unchanged, but both hypoxic and hypercapnic ventilatory responses were impaired in 5XFAD mice. While WT mice responded to acute hypoxia with the expected increase in V̇ of ∼150%, 5XFAD mice showed a blunted increase of ∼70% with a similarly blunted hypercapnic response (∼100% increase in 5XFAD mice/∼200% increase in WT mice). Further, we found substantial Aβ deposition in the ventral lateral medulla, an important site for rhythm generation and chemosensing. Taken together, these data suggest a correlation between SDB, Aβ deposition and chemosensory deficits in 5XFAD mice. KEY POINTS: Respiratory dysfunction is common among Alzheimer's disease (AD) patients, but the nature of this dysfunction is not well understood Sleep disordered breathing (SDB) is prevalent in AD patients and is thought to contribute to disease progression 5XFAD mice, a model of beta amyloidosis, display similar respiratory deficits to humans with AD, including SDB and chemosensory changes We show that amyloid beta plaque deposition in the brainstem of 5XFAD mice localizes to regions of respiratory control Our data suggest that amyloid beta plaque deposition in brainstem respiratory control regions contributes to chemosensory dysfunction in 5XFAD mice, a pathology that could worsen SDB occurrence and potentially Aβ-dependent neuropathologies such as AD.

BACKGROUND: Stroke is a major risk factor for dementia, and fatigue is common among stroke survivors. Whether self-reported fatigue is associated with dementia risk among individuals with prevalent stroke remains unclear. METHODS: We conducted a prospective cohort study of 484,749 UK Biobank participants without dementia at baseline. Participants were classified into four groups according to prevalent stroke and self-reported fatigue: neither exposure, fatigue only, prevalent stroke only, and prevalent stroke with fatigue. The primary outcome was incident all-cause dementia. Secondary outcomes were Alzheimer disease and vascular dementia. Cox proportional hazards models used age as the time scale and adjusted for demographic, socioeconomic, lifestyle, and cardiometabolic factors. Sensitivity analyses included landmark, competing-risk, extended-adjustment, stroke-subtype, and time-updated stroke analyses. RESULTS: Of 484,749 participants, 60,379 had fatigue only, 5,706 had prevalent stroke only, and 1,697 had both prevalent stroke and fatigue. Compared with participants with neither exposure, adjusted hazard ratios for all-cause dementia were 1.51 (95% CI, 1.42-1.60) for fatigue only, 1.94 (95% CI, 1.74-2.17) for prevalent stroke only, and 2.79 (95% CI, 2.32-3.35) for prevalent stroke with fatigue. For participants with both prevalent stroke and fatigue, hazard ratios were 1.86 (95% CI, 1.32-2.62) for Alzheimer disease and 4.33 (95% CI, 3.24-5.80) for vascular dementia. Among participants with prevalent stroke, fatigue was associated with all-cause dementia after adjustment for time from recorded stroke occurrence to baseline assessment (HR, 1.36; 95% CI, 1.10-1.70), whereas the associations with Alzheimer disease and vascular dementia were not statistically significant. CONCLUSIONS: Prevalent stroke with self-reported fatigue was associated with the highest risk of incident dementia compared with neither exposure. Among participants with prevalent stroke, fatigue was associated with all-cause dementia but not clearly with Alzheimer disease or vascular dementia.

Alzheimer disease (AD) pathology affects the transentorhinal/entorhinal region early but whether entorhinal cortex (EC) astrocytes are causal drivers or therapeutic targets remains unresolved. This narrative review evaluates EC astrocytes through an explicit evidence hierarchy. We distinguish: (1) human EC-specific neuropathology, imaging, and transcriptomic findings, (2) human AD astrocyte data lacking EC-cell resolution, (3) mechanistic evidence from animal and cellular models, and (4) translational hypotheses. Human data support early EC vulnerability and region- and stage-dependent astrocyte remodeling, whereas the most direct functional evidence comes from rodent medial EC layer II and should be interpreted as circuit plausibility rather than anatomical equivalence to the human EC. We therefore prioritize candidate astrocyte modules according to astrocyte specificity, relevance to EC or medial temporal pathology, mechanistic links to circuit dysfunction, and the availability of measurable target-engagement readouts. These modules include inflammatory-complement signaling, EAAT2/GLT-1-mediated glutamate clearance, MAO-B/GABA metabolism, AQP4-related gliovascular regulation, astrocytic calcium signaling, and APOE-related lipid handling. Cell transplantation, glial reprogramming, and engineered extracellular vesicles remain experimental platforms. EC astrocytes should therefore be viewed as candidate circuit-glial vulnerability nodes requiring human validation, not as established clinical targets.

Neurodegenerative disorders are characterized by progressive neuronal loss and remain a major global health concern, largely due to their complex and multifactorial nature. These conditions, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, involve overlapping mechanisms such as oxidative stress, chronic inflammation, mitochondrial dysfunction, and impaired neurotransmission. In recent years, natural bioactive compounds have gained attention as potential therapeutic candidates. Among them, apigenin, a dietary flavonoid widely found in fruits and vegetables, exerts neuroprotective effects through multiple cellular pathways. This review highlights the potential role of apigenin in modulating key pathological processes in the central nervous system. Apigenin reduces oxidative stress by scavenging reactive oxygen species and activating endogenous antioxidant systems, particularly through Nrf2 signaling. It also exhibits anti-inflammatory effects by inhibiting pathways such as NF-κB and MAPK, thereby lowering pro-inflammatory cytokine production and regulating microglial activation. In addition, apigenin supports mitochondrial function and inhibits apoptosis by modulating Bcl-2 family proteins and caspase activity. Its role extends beyond maintaining blood-brain barrier integrity to regulating autophagy and mitophagy and enhancing neurotrophin signaling, especially through the BDNF/TrkB pathways. Moreover, apigenin influences neurotransmission by balancing excitatory and inhibitory signaling and modulating cholinergic and monoaminergic systems. Despite promising preclinical findings, its clinical application remains limited due to bioavailability challenges and insufficient human studies.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by persistent neuroinflammation, oxidative imbalance, cognitive decline, Aβ buildup, tau phosphorylation, and synaptic dysfunction. Despite progress in understanding AD's development, effective treatments are still limited. Isorhapontigenin (ISO), a methoxylated stilbenoid similar to resveratrol, shows neuroprotective, anti-inflammatory, and antioxidative effects. In this study, we explored ISO's therapeutic potential in a mouse model of AD-like pathology induced by LPS, focusing on TLR4/RAGE-triggered NF-κB signaling pathway and related neuroinflammatory responses, oxidative stress, GSK3β signaling, tau pathology, Aβ accumulation, glial activation, and synaptic health. Western blot and immunofluorescence techniques were used to measure the levels of TLR4/RAGE signaling components, glial markers (GFAP and Iba-1), p-NF-κB signaling pathway activation, proinflammatory cytokines ( TNF-α, COX-2, and IL-1β), oxidative stress indicators (Nrf2 and HO-1), neurodegeneration markers (p-GSK3β, p-tau, and Aβ), and synaptic proteins (PSD-95, SNAP-23, and SYP). Nissl staining helped assess neuronal density and structure. BV2 microglial cells were treated similarly in vitro, followed by viability tests and Apotox-Glo™ triplex assays, along with protein expression analysis. The levels of TLR4, RAGE, GFAP, and Iba-1 increased in the LPS-treated group, along with proinflammatory mediators, ROS, LPO, and neurodegenerative markers. Yet, ISO treatment significantly reduced their expression. Moreover, LPS lowered Nrf2 and HO-1 levels, reduced p-GSK3β, and decreased synaptic proteins, indicating oxidative damage and synaptic failure. ISO reversed these changes by restoring p-GSK3β, activating Nrf2/HO-1, and boosting synaptic protein levels, followed by behavioral improvement as evidenced by reduced escape latency and increased spontaneous alternations in the Morris water maze (MWM) and Y-maze tests. Additionally, ISO preserved neuronal and synaptic integrity and provided consistent neuroprotection in BV2 cells. Overall, these results demonstrate that ISO reduces LPS-induced AD-like pathology by activating TLR4/RAGE-driven p-NF-κB, decreasing neuroinflammation, enhancing Nrf2/HO-1 activity, inhibiting GSK3β, lowering Aβ and p-Tau accumulation, preserving synaptic health, and prominent improvement in spatial memory, emphasizing its potential as an AD treatment.

Diabetes is an established driver of microvascular disease, causing complications such as retinopathy, nephropathy, and neuropathy. However, the mechanisms whereby diabetes disrupts brain microvascular function remain poorly understood. Diabetes is strongly associated with cognitive impairments, including Alzheimer's Disease (AD), in which pericyte pathology is implicated in cerebrovascular dysfunction. Pericytes are critical regulators of blood-brain barrier integrity and capillary blood flow, yet their behavior during early diabetes remains uncharacterized. Using a 14-day streptozotocin (STZ) mouse model of early hyperglycemia, we demonstrate two distinct phenotypic changes in the brain prior to pericyte loss. First, tissue clearing and 3D imaging reveal significantly increased pericyte-vessel bridging across multiple brain regions, including the entorhinal cortex and hippocampus, regions among the earliest and most affected in AD. Second, longitudinal two-photon microscopy demonstrates that brain pericytes constrict capillaries in a manner correlated with blood-glucose levels. Capillary constriction occurs at pericyte soma and is associated with significantly reduced red blood cell velocity. Pericytes exhibiting early constriction predominantly maintain this phenotype rather than transitioning to a bridging state, suggesting these represent distinct disease-associated behaviors. These findings indicate that early pericyte pathology may contribute to cerebrovascular dysfunction in diabetes, with implications for understanding microvascular mechanisms linking diabetes and AD.

Although ageing is naturally associated with cognitive decline, some lifestyle factors, such as formal education and occupational complexity, were shown to promote the preservation of cognitive functions such as memory. Genetic factors, such as the Complement Receptor 1 (CR1) gene, were also identified to have an impact on cognition. This cross-sectional study aimed to assess the associations of education, occupational complexity, and CR1 polymorphisms (rs6656401) with cognitive functions in a sample of autonomous, healthy older adults. A final sample of 102 participants was tested for executive functions, episodic memory, non-verbal memory, and reaction speed, while the final sample for the genetic assessment was 48. The mPACC scores were calculated in order to classify the participants into standard or High-Performing Older Adults. The lifelong occupations were classified according to the International Standard Classification of Occupations-08 criteria. The results revealed that education was more strongly associated with cognitive performance than occupational complexity. However, occupational complexity was independently associated with mental state among the highest education group. Furthermore, normative scores for older adults over 75 are provided. The CR1 AG/AA genotypes were associated with poorer memory performance among older participants, although these exploratory findings should be interpreted with caution due to the limited genetic sample size. The findings are consistent with the hypothesis that both education and occupation are associated with higher cognitive performance in older adults. The findings also suggest distinct cognitive effects of CR1 polymorphisms regarding ageing, although these results should be considered hypothesis-generating rather than confirmatory.