Motor dysfunction, which includes changes in gait, balance, and/or functional mobility, is a lesser-known feature of Alzheimer\'s Disease (AD), especially as it relates to the development of neuropsychiatric symptoms (NPS). This study (1) compared rates of NPS between autopsy-confirmed AD patients with and without early-onset motor dysfunction and (2) compared rates of non-AD dementia autopsy pathology (Lewy Body disease, Frontotemporal Lobar degeneration) between these groups. This retrospective longitudinal cohort study utilized National Alzheimer\'s Coordinating Center (NACC) data. Participants (N = 856) were required to have moderate-to-severe autopsy-confirmed AD, Clinical Dementia Rating-Global scores of ≤1 at their index visit, and NPS and clinician-rated motor data. Early motor dysfunction was associated with significantly higher NPI-Q total scores (T = 4.48, p < .001) and higher odds of delusions (OR [95%CI]: 1.73 [1.02-2.96]), hallucinations (2.45 [1.35-4.56]), depression (1.51 [1.11-2.06]), irritability (1.50 [1.09-2.08]), apathy (1.70 [1.24-2.36]), anxiety (1.38 [1.01-1.90]), nighttime behaviors (1.98 [1.40-2.81]), and appetite/eating problems (1.56 [1.09-2.25]). Early motor dysfunction was also associated with higher Lewy Body disease pathology (1.41 [1.03-1.93]), but not Frontotemporal Lobar degeneration (1.10 [0.71-1.69]), on autopsy. Our results suggest that motor symptoms in early AD are associated with a higher number and severity of NPS, which may be partially explained by comorbid non-AD neuropathology.

Alzheimer\'s disease (AD) presents a significant challenge to global health. It is characterized by progressive cognitive deterioration and increased rates of morbidity and mortality among older adults. Among the various pathophysiologies of AD, mitochondrial dysfunction, encompassing conditions such as increased reactive oxygen production, dysregulated calcium homeostasis, and impaired mitochondrial dynamics, plays a pivotal role. This review comprehensively investigates the mechanisms of mitochondrial dysfunction in AD, focusing on aspects such as glucose metabolism impairment, mitochondrial bioenergetics, calcium signaling, protein tau and amyloid-beta-associated synapse dysfunction, mitophagy, aging, inflammation, mitochondrial DNA, mitochondria-localized microRNAs, genetics, hormones, and the electron transport chain and Krebs cycle. While lecanemab is the only FDA-approved medication to treat AD, we explore various therapeutic modalities for mitigating mitochondrial dysfunction in AD, including antioxidant drugs, antidiabetic agents, acetylcholinesterase inhibitors (FDA-approved to manage symptoms), nutritional supplements, natural products, phenylpropanoids, vaccines, exercise, and other potential treatments.

Objectives: Positive adaptation, like higher control beliefs, following a disability diagnosis is important to buffer against excess disability; however, no study has examined how the recent diagnosis of Alzheimer\'s disease and related dementias (ADRD) impacts control beliefs. The current study addresses this gap in the literature. Method: We use data from the 2012-2016 waves of the Health and Retirement Study. Propensity score weighting was used to address the systematic selection of an ADRD diagnosis to understand how control beliefs (perceived constraints and mastery) are impacted two years following a diagnosis. Results: A new diagnosis of ADRD was associated with a lower mastery score two years later, regardless of baseline functional ability (b = -0.652, p < .001). No associations were noted between a new ADRD diagnosis and perceived constraints. Conclusions: Our results suggest that a recent diagnosis of ADRD has negative implications for mastery, which may facilitate excess disability.

Ferroptosis, a form of cell death characterized by lipid peroxidation, is involved in neurodegenerative diseases such as Alzheimer´s disease (AD). Recent studies have shown that a first-line antimalarial drug artemisinin is effective to counteract AD pathology. In this study, we investigated the protective effect of artemisinin against neuronal ferroptosis and the underlying mechanisms. In hippocampal HT22 cells, pretreatment with artemisinin dose-dependently protected against Erastin-induced cell death with an EC50 value of 5.032 µM, comparable to the ferroptosis inhibitor ferrostatin-1 (EC50 = 4.39 µM). We demonstrated that artemisinin (10 μM) significantly increased the nuclear translocation of Nrf2 and upregulated SLC7A11 and GPX4 in HT22 cells. Knockdown of Nrf2, SLC7A11 or GPX4 prevented the protective action of artemisinin, indicating that its anti-ferroptosis effect is mediated by the Nrf2-SLC7A11-GPX4 pathway. Molecular docking and Co-Immunoprecipitation (Co-IP) analysis revealed that artemisinin competitively binds with KEAP1, promoting the dissociation of KEAP1-Nrf2 complex and inhibiting the ubiquitination of Nrf2. Intrahippocampal injection of imidazole-ketone-Erastin (IKE) induced ferroptosis in mice accompanied by cognitive deficits evidenced by lower preference for exploration of new objects and new object locations in the NOR and NOL tests. Artemisinin (5, 10 mg/kg, i.p.) dose-dependently inhibited IKE-induced ferroptosis in hippocampal CA1 region and ameliorated learning and memory impairments. Moreover, we demonstrated that artemisinin reversed Aβ1-42-induced ferroptosis, lipid peroxidation and glutathione depletion in HT22 cells, primary hippocampal neurons, and 3×Tg mice via the KEAP1-Nrf2 pathway. Our results demonstrate that artemisinin is a novel neuronal ferroptosis inhibitor that targets KEAP1 to activate the Nrf2-SLC7A11-GPX4 pathway.

Alzheimer\'s disease (AD) is the most common cause of dementia, characterized by memory loss, cognitive decline, personality changes, and various neurological symptoms. The role of blood-brain barrier (BBB) injury, extracellular matrix (ECM) abnormalities, and oligodendrocytes (ODCs) dysfunction in AD has gained increasing attention, yet the detailed pathogenesis remains elusive. This study integrates single-cell sequencing of AD patients\' cerebrovascular system with a genome-wide association analysis. It aims to elucidate the associations and potential mechanisms behind pericytes injury, ECM disorder, and ODCs dysfunction in AD pathogenesis. Finally, we identified that abnormalities in the pericyte PI3K-AKT-FOXO signaling pathway may be involved in the pathogenic process of AD. This comprehensive approach sheds new light on the complex etiology of AD and opens avenues for advanced research into its pathogenesis and therapeutic strategies.

Apolipoprotein E (apoE) has a pivotal role in Alzheimer\'s Disease (AD) pathophysiology. APOE4 has been recognized as a risk factor for developing late-onset AD. Recently, APOE4 homozygosity was regarded as a new familial genetic trait of AD. In this opinion paper, we summarized the potential pleiotropic antagonism role of APOE4 in children living under early life adversity and afflicted with enteric infection/malnutrition-related pathogenic exposome. APOE4 was found to be neuroprotective early in life despite its increasing risk for AD with aging. We call for awareness of the potential burden this can bring to the public health system when APOE4 carriers, raised under adverse environmental conditions in early life and then aging with unhealthy lifestyles in later life may be at special risk for cognitive impairments and acquired AD. We postulate the importance of anti-senescence therapies to protect these individuals and remediate aging-related chronic illnesses.

Neurodegenerative diseases are group of debilitating and progressive disorders that primarily affect the structure and functions of nervous system, leading to gradual loss of neurons and subsequent decline in cognitive, and behavioral activities. The two frequent diseases affecting the world\'s significant population falling in the above category are Alzheimer\'s disease (AD) and Parkinson\'s disease (PD). These disorders substantially impact the quality of life and burden healthcare systems and society. The demographic characteristics, and machine learning approaches have now been employed to diagnose these illnesses; however, they possess accuracy limitations. Therefore, the authors have developed ranking-based ensemble approach based on the weighted strategy of deep learning classifiers. The whole modeling procedure of the proposed approach incorporates three phases. In phase I, preprocessing techniques are applied to clean the noise in datasets to make it standardized according to deep learning models as it significantly impacts their performance. In phase II, five deep learning models are selected for classification and calculation of prediction results. In phase III, a ranking-based ensemble approach is proposed to ensemble the results of the five models after calculating the ranks and weights of them. In addition, the Magnetic Resonance Imaging (MRI) datasets named Alzheimer\'s Disease Neuroimaging Initiative (ADNI) for AD classification and Parkinson\'s Progressive Marker Initiative (PPMI) for PD classification are selected to validate the proposed approach. Furthermore, the proposed method achieved the classification accuracy on AD- Cognitive Normals (CN) at 97.89%, AD- Mild Cognitive Impairment (MCI) at 99.33% and CN-MCI at 99.44% and on PD-CN at 99.22%, PD- Scans Without Evidence of Dopaminergic Effect (SWEDD) at 97.56% and CN-SWEDD at 98.22% respectively. Also, the multi-class classification shows the promising accuracy of 97.18% for AD and 97.85% for PD for the proposed framework. The findings of the study show that the proposed deep learning-based ensemble technique is competitive for AD and PD prediction in both multiclass and binary class classification. Furthermore, the proposed approach enhances generalization performance in diagnosing neurodegenerative diseases and performs better than existing approaches.

UNASSIGNED: Decline in renal function impairs systemic clearance of amyloid-β which characterizes Alzheimer\'s disease while albuminuria is associated with blood-brain barrier disruption due to endothelial damage. Arterial stiffness adversely affects the brain with high pulsatile flow damaging cerebral micro-vessels.
UNASSIGNED: To examine association between a novel kidney disease index (KDI), which is a composite index of estimated glomerular filtration (eGFR) and urinary albumin-to-creatinine ratio (uACR), and cognitive function with potential mediation by arterial stiffness.
UNASSIGNED: This was a longitudinal multi-center study of participants with type 2 diabetes (T2D) aged 45 years and above. We assessed cognitive function with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Pulse wave velocity (PWV), an index of arterial stiffness, was measured using applanation tonometry method. KDI was calculated as geometric mean of 1/eGFR and natural logarithmically-transformed (ln)(ACR*100).
UNASSIGNED: There were 1,303 participants with mean age 61.3±8.0 years. LnKDI was associated with lower baseline RBANS total score with adjusted coefficient -2.83 (95% CI -4.30 to -1.35; p < 0.001). 590 participants were followed over up to 8.6 years. LnKDI was associated with lower follow-up RBANS score in total, immediate memory, visuo-spatial/construction and attention domains with corresponding adjusted coefficients -2.35 (95% CI -4.50 to -0.20; p = 0.032), -2.93 (95% CI -5.84 to -0.02; p = 0.049), -3.26 (95% CI -6.25 to -0.27; p = 0.033) and -4.88 (95% CI -7.95 to -1.82; p = 0.002). PWV accounted for 19.5% of association between and follow-up RBANS total score.
UNASSIGNED: KDI was associated with lower cognitive function globally, and in immediate memory, visuo-spatial/construction and attention domains. Arterial stiffness mediated the association between KDI and cognitive decline in patients with T2D.

UNASSIGNED: 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is valuable in Alzheimer\'s disease (AD) workup.
UNASSIGNED: To explore the effectiveness of 18F-FDG PET in differentiating and staging AD and associations between brain glucose metabolism and cognitive functions and vascular risk factors.
UNASSIGNED: 107 participates including 19 mild cognitive impairment (MCI), 38 mild AD, 24 moderate AD, 15 moderate-severe AD, and 11 frontotemporal dementia (FTD) were enrolled. Visual and voxel-based analysis procedures were utilized. Cognitive conditions, including 6 cognitive function scores and 7 single-domain cognitive performances, and vascular risk factors linked to hypertension, hyperlipidemia, diabetes, and obesity were correlated with glucose metabolism in AD dementia using age as a covariate.
UNASSIGNED: 18F-FDG PET effectively differentiated AD from FTD and also differentiated MCI from AD subtypes with significantly different hypometabolism (except for mild AD) (height threshold p < 0.001, all puncorr < 0.05, the same below). The cognitive function scores, notably Mini-Mental State Examination and Montreal Cognitive Assessment, correlated significantly with regional glucose metabolism in AD participants (all p < 0.05), whereas the single-domain cognitive performance and vascular risk factors were significantly associated with regional glucose metabolism in MCI patients (all p < 0.05).
UNASSIGNED: This study underlines the vital role of 18F-FDG PET in identifying and staging AD. Brain glucose metabolism is associated with cognitive status in AD dementia and vascular risk factors in MCI, indicating that 18F-FDG PET might be promising for predicting cognitive decline and serve as a visual framework for investigating underlying mechanism of vascular risk factors influencing the conversion from MCI to AD.

UNASSIGNED: Alzheimer\'s disease (AD) is related to one or more chronic illnesses, which may develop cognitive decline and dementia. Cognitive impairment is increasing, and public health officials must address risk factors for AD to improve the health of rural West Texas communities.
UNASSIGNED: The purpose of this study was to explore the sociodemographic and chronic disease risk factors related to cognitive impairment among elderly adults living in Cochran, Parmer, and Bailey counties in rural West Texas.
UNASSIGNED: Statistical methods such as Pearson\'s chi-squared, proportion tests, univariate binary logistic regression, and a multivariable logistic regression were utilized to analyze data. SPSS software was used to detect the significant relationship between cognitive impairment and risk factors.
UNASSIGNED: Summary statistics were obtained for sociodemographic and chronic diseases by using cross-tabulation analysis and comparing the county respondents with proportion tests. A univariate binary logistic regression method was utilized and found that age group 60-69, anxiety, depression, diabetes, hypertension, and cardiovascular disease were significantly associated with cognitive impairment. Using a multivariable logistic regression approach, it was found that Bailey County (age group 60-69) had a higher likelihood (p = 0.002) of cognitive impairment than Parmer (p = 0.067) and Cochran counties (p = 0.064). The risk of females (p = 0.033) in Parmer County was 78.3% lower compared to males in developing AD.
UNASSIGNED: Identifying significant risk factors for cognitive impairment are important in addressing issues of geographic variations and integrating such factors may guide relevant policy interventions to reduce cognitive impairment incidence in rural communities within West Texas.