Journal of Alzheimer's Disease最新文献

Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. In recent years, two cellular processes have emerged as pivotal drivers of neurodegeneration in AD: mitophagy, the selective autophagic clearance of damaged mitochondria, and ferroptosis, an iron-dependent form of regulated cell death. This review outlines the molecular mechanisms of mitophagy and ferroptosis, with a focus on their interplay in AD. We propose that impaired mitophagy disrupts intracellular redox and iron homeostasis, thereby increasing neuronal susceptibility to ferroptosis. Conversely, ferroptosis-executing events, such as lethal lipid peroxidation, can further exacerbate mitochondrial dysfunction. This establishes a self-amplifying vicious cycle that accelerates disease progression. Furthermore, we summarize potential therapeutic strategies targeting this interactive network (e.g., Urolithin A, ferroptosis inhibitors) and highlight promising directions for future research. In contrast to previous reviews that have focused on each process in isolation, this work synthesizes evidence for a self-amplifying feedback loop between impaired mitophagy and exacerbated ferroptosis in AD. We posit that targeting this self-amplifying loop between mitophagy and ferroptosis may offer a novel and effective therapeutic paradigm for halting Alzheimer's disease progression.

BackgroundIn the last 20 years, cognitive-behavioral units (CBUs) have been opened in various countries to provide care for patients with Alzheimer's disease and related dementias who experience severe behavioral and psychological symptoms of dementia (BPSD).ObjectiveThis study examines the perspectives of relatives and healthcare professionals caring for patients in three CBUs in France and highlights key issues in clinical ethics.MethodsUsing the commitment model (a qualitative methodology in clinical ethics), we conducted 154 semi-structured interviews between March 2019 and March 2020, which were subsequently analyzed thematically. The study focused on three CBUs: one in a public hospital and another in a private hospital in the Paris region, and one in a public hospital in the Hauts-de-France region. We interviewed 62 individuals, including 25 relatives and 37 healthcare professionals. Some of the professionals were interviewed several times about their experience with the 30 patients included in the study (18 men and 12 women, average age 79 years).ResultsThree key themes emerged from the interviews: 1) general appreciation for the relational approach adopted in the CBUs, 2) concerns regarding the limitations of care, and 3) distress regarding restrictions to patients' personal freedom.ConclusionsCBUs are a promising and welcome initiatives but would benefit from a reconsideration of cultural approaches to care for older people with BPSD. End-of-life care, interprofessional collaboration and respect for autonomy need to be more thoroughly discussed. In doing so, CBUs could act as catalysts for public debate on the accommodation of people with BPSD.

BackgroundTAR DNA-binding protein 43 (TDP-43) proteinopathy contributes to Alzheimer's disease progression, but diagnosis remains autopsy-dependent.ObjectiveThis study aimed to develop a predictive model using FDG-PET imaging to identify brain regions associated with TDP-43 pathology in vivo.MethodsPenalized logistic regression analyzed data from 294 participants and a subset of 159 with Braak and Thal ≥4. Features included FDG standard uptake value ratios (SUVRs) from 123 brain regions and age. Participants were split into training (90%) and testing (10%) datasets, with significant predictors identified by non-zero coefficients at optimal lambda.ResultsThe model achieved 68% accuracy (AUC = 0.70) in 294 participants, highlighting the middle temporal gyrus, parahippocampal gyrus, and hippocampus. In the subset (n = 159), accuracy was 65% (AUC = 0.71), with the medial amygdala and precentral gyrus as key predictors of TDP-43 pathology.ConclusionsThis study suggests a moderate predictive accuracy of FDG-PET to identify brain regions associated with Alzheimer's disease-related TDP-43 proteinopathy.

BackgroundEvidence on whether arsenic in groundwater is associated with the risk of Alzheimer's disease (AD) is limited.ObjectiveTo investigate the association between long-term exposure to different levels of arsenic and the risk of AD.MethodsWe conducted a population-based cohort study included individuals born in Sweden during 1932-1950 (n = 1,549,700), with follow-up from 1970 until 2016. We classified study individuals by groundwater arsenic levels reported by the Geological Survey of Sweden and identified AD diagnoses through the Swedish National Patient Register and Cause of Death Register. The association between arsenic exposure and AD risk was evaluated using Cox models.ResultsAmong the 1,549,700 individuals [761,055 female (49.1%); mean (SD) age at baseline: 26.5 (5.2) years], 42,219 (2.7%) individuals were exposed to high (>10 µg/l), 7356 (0.5%) to high-middle (5-10 µg/l), 60,799 (3.9%) to low-middle (2-5 µg/l), and 1,439,326 (92.9%) to low (<2 µg/l) levels of arsenic in groundwater at baseline, respectively. A dose-response association was observed for exposure to arsenic at birth, which individuals born in areas with high, high-middle, and low-middle arsenic levels in groundwater had 156% [2.56 (2.43-2.70)], 98% [1.98 (1.80-2.17)], and 47% [1.47 (1.39-1.56)] higher AD risk than those born in low arsenic exposure areas. Similar dose-response relationship exhibited for arsenic exposure defined by the place of residence at young adulthood (at baseline). The sibling analysis yielded similar results for arsenic exposure evaluated at baseline.ConclusionsExposure to higher arsenic levels in groundwater at birth or young adulthood was associated with an increased risk of AD.

Amyloid-β (Aβ) aggregation is considered a central hallmark in the pathophysiology of Alzheimer's disease (AD). Aβ protein aggregates disrupt synaptic architecture, calcium homeostasis, and mitochondrial function, leading to excitotoxicity and synaptic plasticity deficits. Animal models and human studies reveal that Aβ-induced alterations in synaptic activity and neuronal circuit function appear before irreversible damage and the onset of cognitive impairment. This review examines the multifaceted effects of Aβ on synaptic and neuronal circuits across its distinct aggregation states, including monomeric, oligomeric, protofibrillar, and fibrillar forms. Its novelty lies in providing a comprehensive map of Aβ-induced mechanisms that disrupt neuronal electrical function, based on electrophysiological evidence from neuronal cultures, animal models, and patient studies, with a particular focus on preclinical stages of cognitive decline. We suggest that the Aβ-induced synaptic toxicity could serve, first, as a complementary biomarker of brain deterioration and second, as a readout of current AD therapies. This could potentially lead to better outcomes in AD treatments.

BackgroundThe lipid accumulation product (LAP) index, a sex-specific indicator of abdominal lipid accumulation, has emerged as a predictor for cardiometabolic disease. However, its association with dementia has been rarely explored in population-based studies.ObjectiveWe sought to investigate the associations of LAP index with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) as well as with serum inflammatory cytokines among rural-dwelling older adults in China.MethodsThis cross-sectional study included 5670 participants (age ≥ 60 years), with data available in 1851 individuals on serum inflammatory cytokines (interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1). Dementia and subtypes were diagnosed following the international criteria. The LAP index was calculated as [waist circumference (cm)-65] × triglycerides (mmol/L) for men and [waist circumference (cm)-58] × triglycerides (mmol/L) for women. Data were analyzed using multiple logistic and linear regression models.ResultsOf the 5670 participants, dementia was diagnosed in 305 persons (194 with AD and 100 with VaD). As a continuous variable, the LAP index was associated with multivariable-adjusted odds ratios of 1.28 (95% confidence interval: 1.01-1.61) for all-cause dementia, 1.40 (1.05-1.86) for AD, and 1.12 (0.75-1.66) for VaD. As a categorical variable, the highest (versus lowest) quintile of LAP index was associated with multivariable-adjusted odds ratios of 1.91 (1.17-3.12) for dementia, 2.18 (1.19-3.99) for AD, and 1.88 (0.78-4.53) for VaD. A higher LAP index was significantly correlated with serum inflammatory cytokines (p < 0.05).ConclusionsHigh LAP index is linked with dementia and AD in older adults and chronic systemic inflammation might represent a plausible biological pathway.

BackgroundBlood pressure is a major modifiable risk factor for both cardiovascular disease and dementia, yet its relationship with blood-based biomarkers of Alzheimer's disease (AD) and neurodegeneration remains unclear.ObjectiveTo evaluate associations of systolic blood pressure, diastolic blood pressure (DBP), and pulse pressure with plasma biomarkers of AD and neurodegeneration, and to examine whether these associations differ across Non-Hispanic White, Non-Hispanic Black, and Hispanic participants.MethodsParticipants were 2636 cognitively normal older adults enrolled in the Health and Aging Brain Study-Health Disparities. Participants with hypotension or hypertensive crisis were excluded. The outcomes were plasma biomarkers including phosphorylated Tau181, phosphorylated tau217 (p-Tau217), amyloid-β 42 to 40 ratio, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Adjusted multivariable linear regression models evaluated associations between blood pressure measures and log transformed plasma biomarker concentrations. Additional models examined the American Heart Association blood pressure categories as a predictor.ResultsHigher DBP was associated with lower concentrations of neurodegeneration related plasma biomarkers, including p-Tau217, NfL, and GFAP, after correction for multiple comparisons. Analyses using American Heart Association blood pressure categories demonstrated that stage 1 and stage 2 hypertension were associated with lower GFAP concentrations compared with normal blood pressure, with patterns that were broadly consistent across racial and ethnic subgroups.ConclusionsIn this multi-racial ethnic cohort of cognitively normal older adults without hypotension or hypertensive crisis, higher DBP and clinical blood pressure categories were associated with lower levels of select plasma biomarkers of neurodegeneration (NfL and GFAP).

BackgroundEvidence on the prevalence and nature of hearing impairments among patients with Alzheimer's disease and other types of dementia is limited and inconsistent.ObjectiveThe objective of this study was to compare the proportion of individuals with hearing loss and the severity of hearing impairments in peripheral hearing and speech perception in noise of patients with mild cognitive impairment (MCI) and cognitively intact older adults.MethodsParticipants included 40 patients with MCI recruited from a memory clinic and 60 community-dwelling cognitively intact older adults (Clinical Dementia Rating Score of 0 and Mini-Mental State Examination ≥ 26). All participants were assessed with pure-tone audiometry and a speech-in-noise test, and with cognitive tests tapping memory, processing speed, executive functions, attention, and language.ResultsNo significant difference was found in the proportion of individuals with peripheral hearing loss among patients with MCI and cognitively intact older adults (77.5% and 60%, respectively). Speech-in-noise did not differ between the groups either, not even when accounting for aided hearing in those participants that wore hearing aids in their daily life. About one third of patients with MCI did not perceive hearing problems, despite having objectively measured hearing loss. However, this proportion did not differ significantly from the group of cognitively intact older adults.ConclusionsDespite differences in cognitive status, this study did not show significant differences between the groups on measures of peripheral hearing, speech-in-noise, and subjective complaints of hearing when comparing memory clinic patients with cognitively intact older adults.

BackgroundPredicting cognitive function across dementia stages remains challenging. Plasma biomarkers and electroencephalogram (EEG) features may provide complementary information, but their combined predictive value requires further study.ObjectiveTo evaluate the feasibility of integrating plasma biomarkers and EEG features to predict cognitive function in dementia and examine their correlations.MethodsFrom September 2023 to October 2024, 75 patients from two medical centers with mild cognitive impairment, mild dementia, or moderate dementia were enrolled. Resting-state 19-channel EEG data yielded 2737 time-frequency and connectivity features. Plasma biomarkers included tau, p-Tau181, Aβ_1-42, neurofilament light chain (NfL), brain-derived neurotrophic factor, apolipoprotein E genotype, and glial fibrillary acidic protein. Cognitive function was assessed using Cognitive Abilities Screening Instrument (CASI), Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating Sum of Boxes. Machine learning models were developed using plasma-only, EEG-only, and hybrid approaches.ResultsNfL was negatively correlated with CASI (t = -2.059, p < 0.05). Several EEG features showed moderate correlations with cognitive measures and plasma biomarkers, with delta-band relative power between left frontal and temporal regions (F7-FT7) showing the strongest correlation with MoCA. The hybrid model achieved the best performance, with R² > 0.74 across all cognitive measures, outperforming plasma-only and EEG-only models.ConclusionsIntegrating EEG features with plasma biomarkers improves prediction of cognitive function from mild cognitive impairment to moderate dementia, pending external validation.

Alzheimer's disease (AD) affects not only memory and cognition but also the body's automatic functions, such as heart rate and blood pressure. These changes reflect the early disruption of the central autonomic network, the system that links the brain and the heart to maintain physiological balance. Electroencephalography (EEG) measures the brain's electrical activity and reveals patterns of cortical slowing and desynchronization, while heart-rate variability (HRV) reflects how flexibly the heart responds to internal and external demands. This narrative review brings together evidence published between 2000 and 2025 on the combined use of EEG and HRV as a single, integrated biomarker for AD. Studies consistently show that EEG-HRV coupling, which reflects how well the brain and heart communicate, provides better accuracy in distinguishing mild cognitive impairment and early AD than either measure alone. The findings reveal a shared loss of co-ordination between neural and autonomic systems, which is a hallmark of neurovisceral decline. The review also identifies key methodological gaps, including inconsistent recording conditions and lack of standardized analytic methods, which currently limit reproducibility. To bridge this gap, a translational roadmap is proposed to outline short-, mid-, and long-term goals for clinical validation, wearable integration, and digital health applications. Together, EEG-HRV coupling represents a scalable, non-invasive, and physiologically grounded tool that could support earlier and personalized monitoring of AD, helping to connect laboratory discovery with real-world clinical care.