Journal of Alzheimer's Disease最新文献

BackgroundDementia disorders are affecting millions of people globally, characterized by memory loss, communication difficulties, and motor function decline. Accurate and early dementia detection is crucial for effective management and treatment. Gait analysis offers a non-invasive method for dementia detection by identifying subtle changes in walking patterns that often precede cognitive symptoms.ObjectiveThis study aims to evaluate the clinical utility of video-based gait analysis using the Timed Up and Go (TUG) test under single and dual-task conditions (TUGdt) for distinguishing individuals with dementia disorders from healthy controls (HCs).MethodThe study implemented three machine learning models: Support Vector Machine (SVM), Logistic Regression (LR), and Random Forest (RF), to discriminate between persons with dementia and HCs. The dataset consists of a cohort of 64 people with dementia (47 with Alzheimer's disease) and 67 HCs. The participants performed the TUG test as a single and dual-task (TUGdt). In the TUGdt, participants performed the TUG test while simultaneously completing an additional cognitive task (i.e., animal naming (TUGdt-NA) or reciting months in reverse order (TUGdt-MB)).ResultsThe results showed that dual-task classification outperformed the single-task. The SVM algorithm achieved the highest accuracy in the TUGdt-NA task (accuracy of 87% ± 5.1 and recall of 86.6% ± 3.2) using 5-fold cross-validation and accuracy of 85.5% and recall of 89.5% using Leave-One-Out Cross-Validation (LOOCV) in the TUGdt-MB task.ConclusionsIn summary, video-based gait features effectively distinguish people with dementia from HCs, particularly under dual-tasking, offering cost-effective, automated, and non-invasive pre-screening to complement clinical assessments.

BackgroundWhile transcranial alternating current stimulation (tACS) shows therapeutic promise for neurological and psychiatric disorders when applied repeatedly, its potential is constrained by multiple laboratory visits.ObjectiveTraining caregivers to administer tACS at home could make therapy more practical, especially for vulnerable populations such as individuals with mild cognitive impairment (MCI). This study aimed to evaluate caregivers' perceptions and experiences of administering home-based tACS to MCI patients under remote clinical supervision.MethodsTwenty family caregivers (M age: 70 ± 12 years, 11 female) were trained to operate a six-electrode tACS device and administered 20 home-based sessions to MCI patients under real-time remote supervision. Quantitative ratings assessed caregivers' confidence, burden, and perceived benefits.ResultsCaregivers demonstrated high confidence in technical procedures (85-100% across tasks) and rated training as very satisfactory. The majority (85%) would feel comfortable administering tACS independently without remote support. Although most caregivers (70%) experienced daily life interference, nearly all (90%) would reuse the system. Clinically, 45% of caregivers observed patient benefits, and 57% of MCI patients believed sessions were beneficial. Effects on quality of life and memory were mixed, with some reporting mild deterioration, possibly reflecting natural disease progression or the double-blind design.ConclusionsCaregiver-administered home-based tACS proved feasible and acceptable among older caregivers (average age 70), despite daily life interference and mixed clinical perceptions. These findings support the expansion of caregiver-delivered protocols while emphasizing the importance of enhanced training and ongoing remote support to reduce the burden and optimize outcomes.Clinical trial registryhttps://clinicaltrials.gov/study/NCT05708001.

BackgroundThe selection of novel chemical entities that have a reasonable chance of showing clinical efficacy in AD patients is challenging.ObjectiveThe aim of this article is to outline the steps involved in a selection process that can result in the identification of potential preclinical candidates.MethodsWe used a cellular model of injured hippocampal neurons, for the validation of the association of the targets considered (acetylcholinesterase and 5-HT₄ receptor) and for the selection of multi-target ligands active in cellulo. The mechanism of the plural action of the best compound, we called neocopride, was deciphered using several in cellulo approaches. Finally, the protective effect of neocopride against short-term memory impairment was investigated in mice intoxicated with amyloid- β peptide.ResultsOur results show that neocopride displays strong protective effects against short-term memory disorders after oral administration at a dose of 3 mg/kg.ConclusionsThe findings suggest that neocopride is a promising drug candidate It is currently undergoing preclinical regulatory trials for AD.

Phosphodiesterase-5 (PDE-5) inhibitors may be beneficial in Alzheimer's disease (AD). We assessed the PDE-5 inhibitor tadalafil effect on plasma biomarkers of neurodegeneration in 15 individuals with type 2 diabetes post-hoc in a randomized placebo-controlled trial (ClinicalTrials.gov: NCT02601989) at Sahlgrenska University Hospital. Tadalafil reduced plasma amyloid-β 40 and 42 but not the 42/40 ratio over a 6-week treatment period. Glial fibrillary acidic protein was reduced, but not phosphorylated tau217, neurofilament light protein or growth/differentiation factor 15. Tadalafil reduced plasma levels of biomarkers for amyloid metabolism and astroglial activation in patients with diabetes. Designated clinical trials are warranted to validate these results.

BackgroundHabitual daytime napping is a significant aspect of many older adults' sleep-wake cycle. Growing evidence links napping and cognition in the context of Alzheimer's disease (AD), yet little is known about how genetic risk influences this relationship.ObjectiveThis study investigates interactions between genetic risk for AD and napping on cognition in 1655 cognitively healthy middle-aged to older adults.MethodsCognition was assessed using a self-administered online battery and reduced to three variables: memory, visuospatial abilities and executive functions. Genetic risk was assessed with the presence of APOE ɛ4 allele and polygenic risk scores for AD (PRS; excluding APOE). ANCOVA assessed interactions.ResultsThere was a significant interaction between APOE ɛ4 and napping duration on the memory component (F(2,1645) = 3.84, p = 0.022, ηp² = 0.005). APOE ɛ4 carriers reporting long naps demonstrated better memory than non-carriers also reporting long naps. Among APOE ɛ4 carriers, those who napped for ≥ 1 h performed better than those reporting shorter naps. In a separate analysis, there was a significant interaction between PRS and napping (F(2653) = 3.44, p = 0.033, ηp² = 0.010). Low PRS was related to better memory than high PRS among those who did not nap. Within the low PRS group, participants who did not nap outperformed those reporting short naps. Results remained significant after accounting for overnight sleep efficiency.ConclusionsFindings suggest that the relationship between napping and memory may vary as a function of genetic risk for AD. Results could inform studies looking into personalized preventative treatment based on genetic profiles.

BackgroundCognitive decline in Alzheimer's disease (AD) is increasingly linked to cerebrovascular dysfunction, including small vessel disease (SVD). Conventional SVD MRI markers primarily detect late-stage structural damage. Neurovascular coupling (NVC) has emerged as an early indicator of cerebrovascular function and is cross-sectionally associated with cognition, but its association with longitudinal decline remains unclear.ObjectiveTo investigate whether baseline NVC is associated with cognitive decline over 3.5 years in individuals ranging from no cognitive complaints to memory clinic patients with subjective cognitive impairment (SCI) or mild cognitive impairment (MCI).MethodsSeventy-five participants underwent cognitive assessment and MRI, including BOLD fMRI during visual stimulation to assess NVC. Cognitive decline was analyzed as dichotomous outcome (stable versus decline; n = 75) using logistic regression and as continuous outcome for domain-specific change (z-score change; n = 69) using linear regression.ResultsLower baseline NVC was associated with global cognitive decline, both dichotomously (OR = 42.29, p = 0.017) and continuously (B = 0.45, p = 0.012). Baseline NVC was also associated with a decline in executive function (B = 0.47, p = 0.043), but not with other domain-specific decline. Among conventional SVD MRI markers, only lacunar infarcts were associated with decline (OR = 4.12, p = 0.037).ConclusionsBaseline NVC appears to be a predictor of global cognitive decline, outperforming most conventional SVD MRI markers. These findings support the potential utility of NVC as a prognostic marker of cognitive decline in early-stage AD, highlighting its promise for early intervention strategies targeting cerebrovascular dysfunction.

BackgroundAlzheimer's disease (AD) is the most common form of dementia, marked by progressive cognitive decline. Low-density lipoprotein cholesterol (LDL-C) has been implicated in AD pathology, but findings remain inconsistent. Apolipoprotein E4 (APOE4) status and sex may contribute to this variability.ObjectiveTo examine how LDL-C association with neurodegeneration in AD patients, differ according to APOE4 status and gender.MethodsWe stratified 106 AD patients by APOE4 status and sex into four subgroups: male APOE4+, female APOE4+, male APOE4-, and female APOE4-. Longitudinal cortical thickness changes were assessed using magnetic resonance imaging (MRI). We examined the association between LDL-C levels and cortical thinning within each subgroup.ResultsIn APOE4-positive females, higher LDL-C levels were significantly associated with accelerated cortical thinning in several regions, including the parahippocampal (β = -0.0075, p = 0.017), medial orbitofrontal (β = -0.0025, p = 0.028), fusiform (β = -0.0047, p = 0.034), posterior cingulate (β = -0.0097, p = 0.006), and inferior temporal cortices (β = -0.0085, p = 0.019). This subgroup also showed a significant association between LDL-C and MMSE decline (β = -1.409, p = 0.014) as well as longitudinal increases in cerebrospinal fluid phosphorylated tau181 (β = 0.014, p = 0.039). These effects were not observed in other subgroups.ConclusionsElevated LDL-C is associated with increased neurodegeneration and cognitive decline in female AD patients carrying the APOE4 allele. These exploratory findings highlight a subgroup-specific vulnerability to lipid-related neurodegeneration in AD and underscore the importance of considering both sex and genetic background in future studies.

BackgroundEpigenetic dysregulation is increasingly recognized as a key mechanism in the development and progression of Alzheimer's disease (AD). Herpes simplex virus type 1 (HSV-1) infection has been proposed as a potential biological trigger that may accelerate neurodegeneration through epigenetic modifications. Among HSV-1 structural proteins, glycoprotein B (HSV-gB) may influence host-virus interactions affecting neuronal gene regulation.ObjectiveThis study aimed to investigate the contribution of HSV-gB to AD-related epigenetic alterations and to determine whether HSV-gB exposure exacerbates epigenetic dysregulation in two in vitro neuronal AD models.MethodsHuman SH-SY5Y neuroblastoma cells were used to establish two AD models: a differentiation-based aging model induced by retinoic acid and brain-derived neurotrophic factor (RA + BDNF), and an amyloid aggregation model induced by amyloid-β 1-42 (Aβ_1-42). Cells were treated with HSV-gB (190.5 pg/ml) alone or in combination with each model. Global DNA methylation, histone H3 and H4 acetylation, histone multiplex modifications, and HDAC3 and HDAC8 levels were analyzed using ELISA-based assays.ResultsHSV-gB exposure and RA + BDNF treatment induced global DNA hypomethylation and histone hypoacetylation, accompanied by significant increases in HDAC3 and HDAC8 levels. In contrast, the Aβ_1-42 model showed DNA hypermethylation and histone hyperacetylation, indicating distinct epigenetic profiles between differentiation-associated aging and amyloid-driven pathology.ConclusionsHSV-gB contributes to AD-related epigenetic dysregulation and may amplify neurodegenerative mechanisms through HDAC-mediated chromatin remodeling. The findings highlight divergent epigenetic signatures in different AD models and support a potential role for viral factors in modulating AD-associated epigenetic pathways.

BackgroundProteostasis dysfunction plays a central role in Alzheimer's disease (AD), where aberrant accumulation of amyloid precursor protein (APP)-derived peptides, including APP-C99 and amyloid-β (Aβ), contributes to neurotoxicity. Previous work with an APP-C99 neuronal cell model revealed impaired proteasome activity, lysosomal dysfunction, and increased autophagic markers LC3 and p62.ObjectiveTo identify small molecule modulators of proteostasis that reduce Aβ-mediated toxicity and to evaluate their mechanism of action in both cellular and C. elegans models of AD.MethodsWe screened a library of small molecule proteostasis modulators in the APP-C99 cell model to identify compounds that reduce Aβ-mediated cell death. Hits were further analyzed for their effects on APP-C99/Aβ clearance, autophagy, and proteasomal function. Neuroprotective effects were validated in an AD C. elegans model.ResultsThe USP14 deubiquitinase inhibitor IU1 increased cell survival by 40%, reduced APP-C99 and Aβ accumulation, restored proteasomal activity, LC3 and p62 levels to control. IU1 also decreased neuronal loss and improved survival and behavior in AD worms. Notably, autophagy activators, including mTOR inhibitors rapamycin, everolimus, and temsirolimus, worsened Aβ toxicity. Conversely, autophagy inhibitors such as Bafilomycin A and chloroquine reduced APP-C99/Aβ accumulation, enhanced proteasomal activity, decreased cell death, and improved neurodegeneration and behavior in the worm model.ConclusionsThis study reveals that, under Aβ-mediated proteostasis dysfunction, autophagy activation exacerbates toxicity, whereas proteasome activation via allosteric inhibition of USP14 using IU1 was neuroprotective. These findings provide evidence to suggest that targeting proteasome stimulation via pharmacological inhibition of USP14 offers a promising therapeutic strategy for AD.

Internet-based recruitment holds promise for Alzheimer's disease (AD) research, but its effectiveness for engaging rural older adults with cognitive concerns remains unclear. This review synthesized existing literature on internet-based recruitment for AD research targeting rural-dwelling older adults. After searching PubMed, CINAHL, Embase, and Web of Science, 670 non-duplicate records were screened, and only one eligible study was identified. The top two reasons for exclusion were internet-based recruitment was not used or rural recruitment outcomes were not measured. Despite the expansion of digital recruitment in AD research, rural populations remain overlooked, a critical gap given their disproportionate barriers to research participation.