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Alzheimer's disease is the most common cause of dementia in elderly people. Research into Alzheimer's disease therapy has been at least partly successful in terms of developing symptomatic treatments, but has also had several failures in terms of developing disease-modifying therapies. These successes and failures have led to debate about the potential deficiencies in our understanding of the pathogenesis of Alzheimer's disease and potential pitfalls in diagnosis, choice of therapeutic targets, development of drug candidates, and design of clinical trials. Many clinical and experimental studies are ongoing, but we need to acknowledge that a single cure for Alzheimer's disease is unlikely to be found and that the approach to drug development for this disorder needs to be reconsidered. Preclinical research is constantly providing us with new information on pieces of the complex Alzheimer's disease puzzle, and an analysis of this information might reveal patterns of pharmacological interactions instead of single potential drug targets. Several promising randomised controlled trials are ongoing, and the increased collaboration between pharmaceutical companies, basic researchers, and clinical researchers has the potential to bring us closer to developing an optimum pharmaceutical approach for the treatment of Alzheimer's disease.

Neurodegenerative diseases such as Alzheimer’s disease (AD) are closely linked to oxidative stress and advanced glycation end products (AGEs), two interrelated processes that exacerbate neuronal damage through mitochondrial dysfunction, protein aggregation, and chronic inflammation. This narrative review explores the metabolic interplay between reactive oxygen species (ROS) and AGEs, with a focus on the AGE-RAGE (receptor for advanced glycation end products) signaling axis as a driver of neurodegeneration. Evidence from preclinical and clinical studies highlights their combined role in disease progression and underscores potential therapeutic targets. Strategies including mitochondria-targeted antioxidants, AGE inhibitors, RAGE antagonists, and metabolic interventions are discussed, along with future directions for biomarker development and personalized treatments. This review integrates current molecular insights into a unified metabolic–inflammatory model of AD, highlighting translational therapeutic opportunities.

BackgroundVitamin E represents a potent antioxidant and anti-inflammatory system, playing a role in Alzheimer’s disease (AD). Different plasma concentrations of the forms of vitamin E are observed in AD compared to cognitively healthy subjects.AimSince these modifications may modulate the markers of oxidative stress and cellular aging, we aim to explore the relationship between vitamin E forms and leukocyte telomere length (LTL) in AD.Methods53 AD subjects and 40 cognitively healthy controls (CTs) were enrolled. The vitamin E forms (α-, β-, γ- and δ-tocopherol, α-, β-, γ- and δ-tocotrienol), the ratio of α-tocopherylquinone/α-tocopherol and 5-nitro-γ-tocopherol/γ-tocopherol (markers of oxidative/nitrosative damage) and LTL were measured.Results and discussionRegression model was used to explore the associations of vitamin E forms and LTL with AD. The interaction of LTL in the association between vitamin E forms and AD was tested. AD subjects showed significantly lower concentrations of α-, β-, γ- and δ-tocopherol, α- and δ-tocotrienol, total tocopherols, total tocotrienols and total vitamin E compared to CTs. AD subjects showed higher values of nitrosative/oxidative damage. The adjusted analyses confirmed a significant relationship of AD with plasma concentrations of α- and β-tocopherols, δ-tocotrienol, total tocopherols, total tocotrienol, total vitamin E and oxidative/nitrosative damage. However, nitrosative damage was significantly associated with AD only in subjects with higher LTL and not in those expressing marked cellular aging.ConclusionsOur study confirms the role of vitamin E in AD pathology and indicates that nitrosative damage influences the association with AD only in subjects characterized by longer LTL.

Background Both serotonergic signalling disruption and systemic inflammation have been associated with the pathogenesis of Alzheimer’s disease (AD). The common denominator linking the two is the catabolism of the essential amino acid, tryptophan. Metabolism via tryptophan hydroxylase results in serotonin synthesis, whilst metabolism via indoleamine 2,3-dioxygenase (IDO) results in kynurenine and its downstream derivatives. IDO is reported to be activated in times of host systemic inflammation and therefore is thought to influence both pathways. To investigate metabolic alterations in AD, a large-scale metabolic phenotyping study was conducted on both urine and serum samples collected from a multi-centre clinical cohort, consisting of individuals clinically diagnosed with AD, mild cognitive impairment (MCI) and age-matched controls. Methods Metabolic phenotyping was applied to both urine ( n  = 560) and serum ( n  = 354) from the European-wide AddNeuroMed/Dementia Case Register (DCR) biobank repositories. Metabolite data were subsequently interrogated for inter-group differences; influence of gender and age; comparisons between two subgroups of MCI - versus those who remained cognitively stable at follow-up visits (sMCI); and those who underwent further cognitive decline (cMCI); and the impact of selective serotonin reuptake inhibitor (SSRI) medication on metabolite concentrations. Results Results revealed significantly lower metabolite concentrations of tryptophan pathway metabolites in the AD group: serotonin (urine, serum), 5-hydroxyindoleacetic acid (urine), kynurenine (serum), kynurenic acid (urine), tryptophan (urine, serum), xanthurenic acid (urine, serum), and kynurenine/tryptophan ratio (urine). For each listed metabolite, a decreasing trend in concentrations was observed in-line with clinical diagnosis: control > MCI > AD. There were no significant differences in the two MCI subgroups whilst SSRI medication status influenced observations in serum, but not urine. Conclusions Urine and serum serotonin concentrations were found to be significantly lower in AD compared with controls, suggesting the bioavailability of the neurotransmitter may be altered in the disease. A significant increase in the kynurenine/tryptophan ratio suggests that this may be a result of a shift to the kynurenine metabolic route due to increased IDO activity, potentially as a result of systemic inflammation. Modulation of the pathways could help improve serotonin bioavailability and signalling in AD patients.

Purpose Advancing age represents the strongest risk factor for Alzheimer’s disease (AD), and the identification of biomarkers able to define what characterizes physiological aging from AD may represent a potential starting point for novel preventive strategies. Among these biomarkers, telomeres seem to be a promising target. Interestingly, high intake of carotenoid-rich food may play a role in protecting telomeres by oxidative stress reduction. Accordingly, low plasma β-carotene concentrations have been found in AD subjects when compared with cognitively healthy subjects. In this study, we aim at investigating the hypothesis that low β-carotene might be associated with markers of accelerated cellular aging, including leucocyte telomere length (LTL) and peripheral mononuclear cell (PBMC) telomerase activity in a cohort of old age subjects. Methods The study was conducted in 68 old age subjects, 37 AD, and 31 age-matched healthy controls. In all subjects, β-carotene plasma level, LTL and peripheral telomerase activity were measured. Results In all populations, β-carotene significantly and positively ( r  = 0.320, p  = 0.008) correlated with telomerase activity, independent of gender. A model having telomerase activity levels as the dependent variable, and age, gender, smoking habit, and β-carotene as independent variables, confirmed that β-carotene was independently associated with telomerase activity ( β  = 0.319, p  = 0.012). Subjects affected by AD had significantly lower plasmatic levels of β-carotene (448 ± 66 mg/ml vs 497 ± 59 mg/ml, p  = 0.001) and LTL (0.53 ± 0.25 vs 0.69 ± 0.29; p  = 0.009) as compared with healthy controls. Β-carotene plasma level was associated with AD diagnosis (OR 0.988; IC95% 0.978–0.997; p  = 0.013) independently of age, gender, smoking habit, ApoE genotype, and LTL. Conclusion Our data show that β-carotene may modulate telomerase activity in old age. Moreover, lower plasma β-carotene levels, correlating with peripheral telomerase activity, are associated with AD diagnosis independent of multiple covariates.

BackgroundIt has been suggested that oxidative stress may have a role in the pathogenesis of Alzheimer's disease (AD). Serum uric acid (UA) could exert neuroprotective effects via its antioxidant capacities. Many studies investigated serum UA levels in subjects with AD, but to date, results are conflicting and evidence in old age subjects is weak.AimsIn this study, we assess whether serum UA levels would be altered in the AD old age subjects compared to those of initial cognitive impairment and healthy controls.MethodsThis is a retrospective study with data gathered from the ReGAl 2.0 project (Rete Geriatrica Alzheimer-Geriatric Network on Alzheimer’s disease), a large Italian multicentric clinical-based study. A cohort of 232 subjects, including 65 (healthy controls HC), 95 mild cognitive impairment (MCI), and 72 AD, were included in the study. Serum UA was measured in all subjects by routine laboratory method.ResultsThe sample population includes 232 subjects, mostly women with a mean age of 79.16 ± 5.64 (range 66–93) years. No significant difference was found in gender distribution between groups. No significant correlation was found in all populations between age and uric acid levels. AD group had significantly lower UA levels as compared with HC. The association of uric acid with AD presence after adjusting for age, gender, body mass index (BMI) and creatinine levels showed that uric acid level was independently associated with the diagnosis of AD.ConclusionsThese data indicate that serum UA is reduced in AD, supporting that UA may have a potential protective role against AD in old age.

Markers of Alzheimer's disease (AD) are being widely sought with a number of studies suggesting blood measures of inflammatory proteins as putative biomarkers. Here we report findings from a panel of 27 cytokines and related proteins in over 350 subjects with AD, subjects with Mild Cognitive Impairment (MCI) and elderly normal controls where we also have measures of longitudinal change in cognition and baseline neuroimaging measures of atrophy. In this study, we identify five inflammatory proteins associated with evidence of atrophy on MR imaging data particularly in whole brain, ventricular and entorhinal cortex measures. In addition, we observed six analytes that showed significant change (over a period of one year) in people with fast cognitive decline compared to those with intermediate and slow decline. One of these (IL-10) was also associated with brain atrophy in AD. In conclusion, IL-10 was associated with both clinical and imaging evidence of severity of disease and might therefore have potential to act as biomarker of disease progression.

BackgroundAlkaline phosphatase has been found on neuronal membranes and plasma alkaline phosphatase (ALP) activity increases during brain injury and cerebrovascular diseases, suggesting that its levels may reflect the neuronal loss. It is known that ALP is higher in subjects affected by Alzheimer’s dementia and inversely correlated with cognitive functions. No study has investigated the relationship between ALP and cognitive functions in old-age subject with pre-clinical cognitive impairment.MethodsThis is a cross-sectional study with data gathered from the ReGAl 2.0 project (Rete Geriatrica Alzheimer-Geriatric Network on Alzheimer’s disease), a large Italian multicentric clinical-based study. A cohort of 209 old-age subjects healthy controls (HC), Subjective cognitive decline (SCD), and Mild Cognitive Impairment (MCI) was included in the study. Cognitive performances were assessed with a large neuropsychological battery. The same day, serum alkaline phosphatase activity was measured in all subjects.ResultsWe found that the SCD group had significantly higher ALP levels as compared with HC (p = 0.001). Among all neuropsychological tests, in all population ALP levels negatively correlated with scores at attentional matrices (r =  − 0.243, p = 0.002), Digit Span Forward (r =  − 0.241, p = 0.003) and Letter Fluency Test (r =  − 0.196, p = 0.044). Attentional Matrices (r =  − 0.208, p = 0.014) and Letter Fluency Test (r =  − 0.229, p = 0.019) remained significantly correlated with ALP even after controlling for gender. In the SCD group, only the Attentional Matrices significantly and negatively correlated with ALP (r =  − 0.344 p = 0.035), while no significant correlations were found in HC or MCI.ConclusionsResults indicate that serum alkaline phosphatase activity is increased in SCD and inversely correlates with cognitive functions. Further studies are needed to investigate the role of ALP in the progression to AD.

The hippocampus is involved at the onset of the neuropathological pathways leading to Alzheimer's disease (AD). Individuals with mild cognitive impairment (MCI) are at increased risk of AD. Hippocampal volume has been shown to predict which MCI subjects will convert to AD. Our aim in the present study was to produce a fully automated prognostic procedure, scalable to high throughput clinical and research applications, for the prediction of MCI conversion to AD using 3D hippocampal morphology. We used an automated analysis for the extraction and mapping of the hippocampus from structural magnetic resonance scans to extract 3D hippocampal shape morphology, and we then applied machine learning classification to predict conversion from MCI to AD. We investigated the accuracy of prediction in 103 MCI subjects (mean age 74.1 years) from the longitudinal AddNeuroMed study. Our model correctly predicted MCI conversion to dementia within a year at an accuracy of 80% (sensitivity 77%, specificity 80%), a performance which is competitive with previous predictive models dependent on manual measurements. Categorization of MCI subjects based on hippocampal morphology revealed more rapid cognitive deterioration in MMSE scores ( p < 0.01) and CERAD verbal memory ( p < 0.01) in those subjects who were predicted to develop dementia relative to those predicted to remain stable. The pattern of atrophy associated with increased risk of conversion demonstrated initial degeneration in the anterior part of the cornus ammonis 1 (CA1) hippocampal subregion. We conclude that automated shape analysis generates sensitive measurements of early neurodegeneration which predates the onset of dementia and thus provides a prognostic biomarker for conversion of MCI to AD. [Display omitted] ► Automated 3D hippocampal morphometry predicted prognosis in mild cognitive impairment. ► Automated prediction of future dementia was correct for 80% of MCI individuals. ► This performance is competitive with predictions based on manual measurements. ► Atrophy predictive of progression was prominent in hippocampal head and CA1 region.

Background/Objectives: Malnutrition, systemic inflammation, and immune dysfunction are key determinants of adverse outcomes in older adults following acute illness. Composite biomarkers integrating these domains could enhance early risk stratification. This study investigates, for the first time in acute geriatric care, the prognostic value of the C-reactive protein–albumin–lymphocyte (CALLY) index—a composite marker of nutritional, inflammatory, and immune status—in predicting short-term survival. Methods: We retrospectively analyzed 264 patients admitted to the acute geriatrics ward of Santa Maria della Misericordia Hospital in Perugia. The CALLY index was calculated as: (Albumin × Lymphocytes)/(CRP × 104). The optimal prognostic cut-off was determined using receiver operating characteristic (ROC) curve analysis. Three-month survival was assessed by Kaplan–Meier analysis. Results: The cohort included 167 women (63.3%) and 97 men (36.7%), with a mean age of 88.0 ± 6.4 years. At 3-month follow-up, 80 patients (30.3%) had died. The CALLY index showed an area under the ROC curve of 0.647 (95% CI: 0.576–0.718; p < 0.001), with a cut-off of 0.055 (sensitivity: 68.5%, specificity: 46.3%). Among deceased patients, 42.5% had a CALLY index <0.055. After multivariable adjustment, a lower CALLY index remained independently associated with increased mortality (B = −0.805; OR = 0.45; 95% CI: 0.215–0.930; p = 0.031). Kaplan–Meier analysis demonstrated significantly higher survival in patients with a CALLY index ≥ 0.055 (Log-rank test: 13.71; p < 0.001). Conclusions: The CALLY index shows a modest but statistically significant discriminative ability for predicting short-term mortality in acutely ill older adults. As a simple, low-cost marker derived from routine laboratory tests, it holds potential for integration into clinical workflows to guide nutritional, metabolic, and prognostic management strategies in geriatric acute care.