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The effects of fasting-mimicking diet (FMD) cycles in reducing many aging and disease risk factors indicate it could affect Alzheimer's disease (AD). Here, we show that FMD cycles reduce cognitive decline and AD pathology in E4FAD and 3xTg AD mouse models, with effects superior to those caused by protein restriction cycles. In 3xTg mice, long-term FMD cycles reduce hippocampal Aβ load and hyperphosphorylated tau, enhance genesis of neural stem cells, decrease microglia number, and reduce expression of neuroinflammatory genes, including superoxide-generating NADPH oxidase (Nox2). 3xTg mice lacking Nox2 or mice treated with the NADPH oxidase inhibitor apocynin also display improved cognition and reduced microglia activation compared with controls. Clinical data indicate that FMD cycles are feasible and generally safe in a small group of AD patients. These results indicate that FMD cycles delay cognitive decline in AD models in part by reducing neuroinflammation and/or superoxide production in the brain.

In this cross-sectional study, we assessed palliative care (PC) needs in older adults with dementia. Using the NECPAL CCOMS-ICO© 3.1 tool and comprehensive geriatric assessment, 16.25% of the 554 evaluated patients required PC, which had clinical frailty and a moderate stage of dementia. Advanced frailty was associated with the poorest prognosis, according to the PC-based stratification. Our findings support the use of PC assessment in dementia care, which focuses on a person-centered approach while minimizing unnecessary or ineffective treatments and meeting the real-world patient's needs. PC care may fulfill the multidimensional nature of dementia, shifting towards personalized palliative approaches. [ABSTRACT FROM AUTHOR]

Background: As the population ages, the concept of frailty becomes increasingly relevant and may be considered a precursor between aging and the development of dementia in later life. Similarly, the construct of cognitive reserve (CR) is an accepted model of cognitive resilience that may account for individual differences in trajectories of brain aging, mitigating the clinical expression of dementia. Objective: We aim to estimate the role of CR and frailty in moderating the prediction of dementia in the population aged over 80 who are attending an Italian outpatient memory clinic. Methods: Comprehensive Geriatric Assessment, Clinical Frailty Scale (CFS) to screen for frailty, and Cognitive Reserve Index questionnaire (CRIq) to evaluate CR, were used to assess patients systematically. We performed multivariate logistic regression to assess associations with dementia. Model performance and interaction between frailty and cognitive reserve were then evaluated. Results: 166 patients were consecutively enrolled (mean age was 85.7 years old, females composed 68%); 25% had a diagnosis of amnestic mild cognitive impairment, and 75% had a diagnosis of dementia. Multivariate regression analysis showed that CRIq and CFS were the main clinical assessment tools associated with the presence of dementia, even after collinearity adjustment. No significant interaction of CFS*CRIq was found. Conclusions: To our knowledge, this is the first study to investigate the association between CR, frailty, dementia, and their related interacting terms in a real-world population of very old patients. Our findings may suggest that both CR and frailty shape an individual's resilience throughout their lifetime. This may potentially counteract the effects of brain neuropathology, in line with the hypothesis that meaningful associations exist between CR, frailty, and cognition in later life. [ABSTRACT FROM AUTHOR]

Background: Discrepancy between caregiver and patient assessments of apathy in mild cognitive impairment (MCI) is considered an index of apathy unawareness, independently predicting progression to AD dementia. However, its neural underpinning are uninvestigated. Objective: To explore the [18F]FDG PET-based metabolic correlates of apathy unawareness measured through the discrepancy between caregiver and patient self-report, in patients diagnosed with MCI. Methods: We retrospectively studied 28 patients with an intermediate or high likelihood of MCI-AD, progressed to dementia over an average of two years, whose degree of apathy was evaluated by means of the Apathy Evaluation Scale (AES) for both patients (PT-AES) and caregivers (CG-AES). Voxel-based analysis at baseline was used to obtain distinct volumes of interest (VOIs) correlated with PT-AES, CG-AES, or their absolute difference (DISCR-AES). The resulting DISCR-AES VOI count densities were used as covariates in an inter-regional correlation analysis (IRCA) in MCI-AD patients and a group of matched healthy controls (HC). Results: DISCR-AES negatively correlated with metabolism in bilateral parahippocampal gyrus, posterior cingulate cortex, and thalamus, PT-AES score with frontal and anterior cingulate areas, while there was no significant correlation between CG-AES and brain metabolism. IRCA revealed that MCI-AD patients exhibited reduced metabolic/functional correlations of the DISCR-AES VOI with the right cingulate gyrus and its anterior projections compared to HC. Conclusions: Apathy unawareness entails early disruption of the limbic circuitry rather than the classical frontal-subcortical pathways typically associated with apathy. This reaffirms apathy unawareness as an early and independent measure in MCI-AD, marked by distinct pathophysiological alterations. [ABSTRACT FROM AUTHOR]

A recent study by Ding et al. explores the integration of artificial intelligence (AI) in predicting dementia risk over a 10-year period using a multimodal approach. While revealing the potential of machine learning models in identifying high-risk individuals through neuropsychological testing, MRI imaging, and clinical risk factors, the imperative of dynamic frailty assessment emerges for accurate late-life dementia prediction. The commentary highlights challenges associated with AI models, including dimensionality and data standardization, emphasizing the critical need for a dynamic, comprehensive approach to reflect the evolving nature of dementia and improve predictive accuracy. [ABSTRACT FROM AUTHOR]

Background: Apathy is a frequent behavioral symptom of Alzheimer's disease (AD). The Apathy Evaluation Scale (AES) is a tool exploring the perception of apathy by both caregivers (CG-AES) and patients (PT-AES), and the discrepancy in their ratings is a proxy of patients' disease unawareness. Objective: To assess in a cohort study of patients with amnesic mild cognitive impairment (aMCI) whether apathy and awareness of apathy predict progression to dementia and timing. Methods: From the global AES scores of 110 patients with aMCI and their caregivers, we obtained two principal indices for analysis: 1) 'Apathy', the mean of PT-AES and CG-AES, and 2) 'Discrepancy', obtained by subtracting CG-AES from PT-AES. Patients were followed with visits every six months for three years or until dementia. AES indices and the principal demographical/neuropsychological variables were filtered from multicollinearity. The most robust variables entered a logistic regression model and survival analyses (Cox regression, log-rank test of Kaplan-Meier curves) to estimate which predicted the risk and timing of progression, respectively. Results: Sixty patients (54.5%) developed dementia (57 AD) after 6.0–36.0 months, 22 (20%) remained in an MCI stage, and 28 (25.5%) dropped out. 'Discrepancy' was a robust and accurate predictor of the risk of progression (AUC = 0.73) and, after binarization according to a computed cutoff, of timing to dementia. Conclusion: A structured evaluation of apathy, both self-assessed and estimated by caregivers, can provide useful information on the risk and timing of progression from aMCI to dementia. The discrepancy between the two estimates is a fairly reliable index for prediction purposes as a proxy of disease unawareness. [ABSTRACT FROM AUTHOR]

Background: Information on prevalence, pathophysiology, and clinical assessment of paratonia are scarce. In a previous study, we suggested that surface electromyography (EMG) can be used to assess paratonia.Objective: To assess clinical and EMG features of paratonia in both patients with cognitive impairment and healthy subjects.Methods: We examined 18 patients with Alzheimer's disease (AD), 21 patients with mild cognitive impairment (MCI), 30 healthy seniors (seniors), and 30 healthy juniors (juniors). Paratonia was assessed using the "Paratonia Scale". EMG bursts were recorded from biceps and triceps during manually applied passive movements of elbow joint. Continuous (sinusoidal) and discontinuous (linear) movements were applied at 2 different velocities (fast and slow).Results: In comparison to juniors, seniors had higher clinical scores. In comparison to seniors, AD had higher oppositional scores, while MCI had higher facilitatory scores. EMG activity during passive movements correlated with paratonia clinical scores, was velocity-dependent and increased with movement repetition, most effectively for sinusoidal movements. Similar EMG activity was detected in not paratonic muscles.Conclusion: Paratonia increases with normal aging and cognitive decline progression. While facilitatory paratonia is due to involuntary contraction of the shortening muscle, oppositional paratonia is due, at least partially, to involuntary contraction of the lengthening muscle. Most characteristic feature of this muscle contraction is the progressive increase with movement repetition, that helps distinguish oppositional paratonia from spasticity and rigidity. A similar EMG activity is detected in not paratonic muscles, showing that, during tone assessment, the descending motor system is incompletely inactivated also in normotonic muscles. [ABSTRACT FROM AUTHOR]

Background: It 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. Aims: In 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. Methods: This 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. Results: The 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. Conclusions: These data indicate that serum UA is reduced in AD, supporting that UA may have a potential protective role against AD in old age. [ABSTRACT FROM AUTHOR]

Alzheimer's disease may mimic frontotemporal dementia. We describe a case of presenile dementia who presented with peudo-psychotic symptoms carrying a PSEN1 mutation (P355 S), which was not known to be pathogenic. PET-FDG showed bilateral frontotemporal hypometabolism, but at MRI, multiple microbleeds were detected, suggestive of amyloid angiopathy. [ABSTRACT FROM AUTHOR]

Accumulating evidence in mice models of accelerated senescence indicates a rescuing role of ascorbic acid in premature aging. Supplementation of ascorbic acid appeared to halt cell growth, oxidative stress, telomere attrition, disorganization of chromatin, and excessive secretion of inflammatory factors, and extend lifespan. Interestingly, ascorbic acid (AA) was also found to positively modulate inflamm-aging and immunosenescence, two hallmarks of biological aging. Moreover, ascorbic acid has been shown to epigenetically regulate genome integrity and stability, indicating a key role of targeted nutrition in healthy aging. Growing in vivo evidence supports the role of ascorbic acid in ameliorating factors linked to Alzheimer's disease (AD) pathogenesis, although evidence in humans yielded equivocal results. The neuroprotective role of ascorbic acid not only relies on the general free radical trapping, but also on the suppression of pro-inflammatory genes, mitigating neuroinflammation, on the chelation of iron, copper, and zinc, and on the suppression of amyloid-beta peptide (Aβ) fibrillogenesis. Epidemiological evidence linking diet, one of the most important modifiable lifestyle factors, and risk of Alzheimer's disease is rapidly increasing. Thus, dietary interventions, as a way to epigenetically modulate the human genome, may play a role in the prevention of AD. The present review is aimed at providing an up to date overview of the main biological mechanisms that are associated with ascorbic acid supplementation/bioavailability in the process of aging and Alzheimer's disease. In addition, we will address new fields of research and future directions. [ABSTRACT FROM AUTHOR]

In spite of in depth investigations in the field of the amyloid cascade hypothesis, so far, no disease modifying therapy has been developed for Alzheimer's disease (AD). The pathophysiology provides some evidence of the inverse correlation between cancer and AD. Both AD and cancer are characterized by abnormal cellular behaviors; trigger factors along with a meta synchronously action is expected to drive cancer or neurodegeneration, supporting, respectively, progressive neuronal loss or uncontrolled cell proliferation in cancer cells. So far, cancer and AD are seemingly two opposite ends of the same biological spectrum. Basic science increasingly indicates shared molecular mechanisms between cancer and AD and gives weight to key relevant biological theories; according to them, the inverse tuning of clustered gene expression, the sharing of mutual independent pathway or the deregulated unfolded proteins system (UPR) may count for this inverse association. Additionally, the common biological background gave credibility to the recent discovery of a repurposing role for cancer drugs in AD. It refers to the development of new uses for existing pharmaceuticals having the same role as the original mechanism or to the discovery of a new drug action with disease modifying effects. The present review summarizes the most important biological theories that link neurodegeneration and cancer and provides an up-to-date revision of the repurposing cancer agents for AD. The review also addresses the gap of knowledge, since drug cancer repositioning holds an important promise but further investigations are warranted to ascertain the clinical relevance of such attractive clinical candidate compounds for AD. [ABSTRACT FROM AUTHOR]

Autopsy studies have indicated brain accumulation of amyloid-β peptides as a common pathogenetic hallmark of amnestic cognitive impairment (aMCI) and overt Alzheimer's disease (AD). The pathogenesis of AD is still debated but recent reports have even designated AD as type III diabetes. This study aims to assess plasma levels of malondialdehyde, pentosidine, and insulin resistance in a group of aMCI patients, AD subjects, and age- and gender-matched controls, to confirm, beyond the accumulation of amyloid-β, the presence of a metabolic disorder, as a causative/contributive factor for AD. Patients were recruited and diagnosed as aMCI (n = 180), AD (n = 84), and age- and gender-matched controls (n = 62) at three different Italian memory clinics. Plasma insulin and glucose, plasma pentosidine and malondialdehyde (MDA), HOMA-IR and QUICKI score for insulin sensitivities indexes were collected at the basal visit. Plasma MDA levels were higher in the aMCI group who converted to AD compared to controls, stable aMCI subjects, and AD subjects (p < 0.01) respectively, while plasma pentosidine was higher compared to controls. The aMCI group showed a significant correlation between HOMA-IR, QUICKI, insulin, and MDA (p < 0.02). aMCI might be considered the early biochemical active disease stage where glycoxidation, hyperinsulinemia, and pro-amyloidogenic status are at the highest rate while overt AD might indicate the glycoxidative cascade dwindling, ending a process possibly started two decades earlier. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is a life shortening disease, and the lack of disease modifying therapy implies a huge impact on life expectancy as well as an outgrowing financial and socioeconomic burden. Cholinesterase inhibitors (ChEIs) represent the first line symptomatic therapy, whose benefit to harm ratio is still a matter of debate. Acetylcholinesterase enzyme is a core interest for pharmacological and toxicological research to unmask the fine balance between therapeutic drug efficacy, tolerability, safety, and detrimental effects up to adverse drug reaction. So far, a body of evidence advocated that an increased vagal tone was associated to an increased risk of gastrointestinal and cardiac side effects (negative chronotropic, arrhytmogenic, hypotensive effects), able to hamper ChEIs effects on cognition, reducing administration feasibility and compliance, especially in older and comorbid patients. Conversely, a growing body of evidence is indicating a protective role of ChEIs on overall cardiovascular mortality in patients with dementia, through a series of in vitro and in vivo investigations. The present review is aimed to report the up to date literature in the controversial field of ChEIs and cardioprotection in dementia, offering a state of the art, which may constitute the conceptual framework to be enlarged in order to build higher evidence. Chronic vagal nerve stimulation acted upon by donepezil might improve long term survival through pharmacological properties apart from cholinesterase inhibition, able to offer cardioprotection, abating the overall cardiovascular risk, and, thus profiling a new line of therapeutic intervention for ChEI drug class. [ABSTRACT FROM AUTHOR]

The search for markers that are able to predict the conversion of amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) is crucial for early mechanistic therapies. Using artificial neural networks (ANNs), 22 variables that are known risk factors of AD were analyzed in 80 patients with aMCI, for a period spanning at least 2 years. The cases were chosen from 195 aMCI subjects recruited by four Italian Alzheimer's disease units. The parameters of glucose metabolism disorder, female gender, and apolipoprotein E ℇ3/ℇ4 genotype were found to be the biological variables with high relevance for predicting the conversion of aMCI. The scores of attention and short term memory tests also were predictors. Surprisingly, the plasma concentration of amyloid-β _{42} had a low predictive value. The results support the utility of ANN analysis as a new tool in the interpretation of data from heterogeneous and distinct sources. [ABSTRACT FROM AUTHOR]

Vitamin D (VD) and micronutrients, including folic acid, are able to modulate both the innate and the adaptive immune responses. Low VD and folic acid levels appear to promote cognitive decline as in Alzheimer's disease (AD). A machine learning approach was applied to analyze the impact of various compounds, drawn from the blood of AD patients, including VD and folic acid levels, on the Mini-Mental State Exam (MMSE) in a cohort of 108 patients with AD. The first analysis was aimed at predicting the MMSE at recruitment, whereas a second investigation sought to predict the MMSE after a 4 year follow-up. The simultaneous presence of low levels of VD and folic acid allow to predict MMSE, suggestive of poorer cognitive function. Such results suggest that the low levels of VD and folic acid could be associated with more severe cases of cognitive impairment in AD. It could be hypothesized that simultaneous supplementation of VD and folic acid could slow down the progression of cerebral degeneration at least in a subset of AD individuals. [ABSTRACT FROM AUTHOR]

Epidemiological and experimental data suggest that type 2 diabetes (DM2) and sporadic late-onset Alzheimer's disease (AD) share a common mechanism, that is able to produce accumulation of insulin and amyloid β42 (Aβ42), the major pathogenic events respectively of the two conditions. In 71 non diabetic patients with amnestic mild cognitive impairment we found a significant linear correlation between fasting plasma levels of insulin and Aβ42 (R=+0.25, P<0.05). The levels of both peptides were elevated in comparison to 48 age-matched cognitively normal controls. The correlation of insulin and Aβ42 plasma levels suggests a pathogenic link between DM2 and sporadic AD. [ABSTRACT FROM AUTHOR]

Epidemiological and experimental data suggest that type 2 diabetes (DM2) and sporadic late-onset Alzheimer's disease (AD) share a common mechanism, that is able to produce accumulation of insulin and amyloid beta 42 (Abeta42), the major pathogenic events respectively of the two conditions. In 71 non diabetic patients with amnestic mild cognitive impairment we found a significant linear correlation between fasting plasma levels of insulin and Abeta42 (R = +0.25, P < 0.05). The levels of both peptides were elevated in comparison to 48 age-matched cognitively normal controls. The correlation of insulin and Abeta42 plasma levels suggests a pathogenic link between DM2 and sporadic AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease and vascular dementia are estimated to be the most common causes of dementia, although mixed dementia could represent the most prevalent form of dementia in older adults aged more than 80 years. Behavioral disturbances are common in the natural history of dementia. However, so far, there is a paucity of studies that investigated the causal association between behavioral psychological symptoms of dementia and dementia sub-types, due to the high heterogeneity of methodology, study design and type of clinical assessment. To understand the scant evidence on such a relevant clinical issue, it could be hypothesized that a new shifting paradigm could result in a better identification of the relationship between behavioral disturbances and dementia. This narrative review provides an update of evidence on the behavioral patterns associated with different dementia sub-types and offers a potential future perspective as common ground for the development of new translational studies in the field of behavioral disturbances in dementia and the appropriateness of psychoactive treatments. [ABSTRACT FROM AUTHOR]