Silibinin-loaded PEGylated niosomal nanoparticles restore hippocampus histological changes, memory and learning, and downregulate the inflammasome pathway in Alzheimer's disease animal models.

High-throughput simultaneous quantification of glycopeptides and phosphopeptides enabled by 12-plex DiLeu isobaric tags and dual-functional Titanium(IV)-IMAC material.

Increasing evidence indicates a potential role of white matter (WM) damage in the onset and progression of Alzheimer disease (AD). However, the biological processes underlying in vivo WM imaging biomarkers remain unclear. We sought to determine the molecular signatures associated with WM integrity in cognitively normal individuals with and without amyloid pathology. We selected older individuals without dementia (Clinical Dementia Rating <1) from the Alzheimer Centrum Amsterdam when they had diffusion tensor imaging (DTI) and CSF proteomic (untargeted tandem mass-mass spec) data available. Fractional anisotropy (FA) and mean diffusivity (MD) values were computed for the total WM and for 12 tracts of interest. We tested associations between protein levels (predictors) and both global and regional FA and MD values (outcomes) with linear models. Models further included an interaction between protein levels and amyloid status to evaluate specificity to disease. Gene-set and cell-type enrichment analyses were performed on proteins showing significant associations to characterize the underlying biological and cellular processes. A total of 96 participants were included in this study (mean age 67.82 ± 6.93 years; 45% male participants). A total of 234 protein levels (17.1%) were significantly associated with global DTI measures. Of these, 29.9% was unique for FA, and 29.9% for MD, while levels of the remaining proteins were associated with both measures (WM-generic proteins). WM-generic proteins were mostly enriched for pathways related to lipid metabolism and in endothelial cells, whereas proteins specific to FA were mostly related to blood coagulation and enriched in astrocytes and those specific to MD were mainly associated with processes related to actin filaments and enriched in oligodendrocytes. When looking at the interaction with amyloid status, both global FA and MD alterations in A+ participants were associated with biological processes of axonogenesis and synaptic plasticity. Regional analysis revealed distinct proteomic profiles associated with variations in regional FA and MD, with processes linked to synaptic plasticity specifically related to integrity of limbic fibers. Loss of WM integrity in the very early stages of AD seems to be related to alterations in biological processes associated with neuronal plasticity and oligodendrocyte integrity. Our findings provide new insights into the distinct biological mechanisms regulating WM integrity and its relationship with AD pathology.

Approximately 450,000 Veterans are living with Alzheimer disease and related dementias (ADRD), and the high prevalence of ADRD represents a major public health challenge for the Veterans Health Administration. While advancing age and genetic predisposition are well-established ADRD risk factors, growing evidence suggests that additional modifiable factors may also play an important role. This study leveraged data from the VA Million Veteran Program (MVP) to (1) estimate 10-year incidence of ADRD and (2) evaluate associations between a broad range of individual-level risk and resilience factors and incident ADRD in a large, nationally representative sample of Veterans. This retrospective cohort study included Veterans aged ≥65 years at MVP enrollment who completed the MVP Baseline Survey and had VA electronic health record (EHR) data available. Individual-level variables including sociodemographic factors, military-specific characteristics, military environmental exposures (MEEs), health conditions, and health behaviors were characterized using MVP Baseline Survey data and supplemented with EHR data as available. The primary outcome was ADRD, which was determined using a validated algorithm based on International Classification of Diseases diagnosis codes extracted from the EHR. Associations between each risk/resilience factor and incident ADRD were examined using separate Cox regression models adjusted for age, sex, and education. The sample included 245,949 Veterans (age: mean 73.16, SD 6.84 years; 2.59% female). Approximately 4.56% (n = 11,216) of the sample developed ADRD over 10 years. History of traumatic brain injury (TBI; hazard ratio [HR] 2.96, 95% CI 2.76-3.17), depression (HR 2.93, 95% CI 2.82-3.04), and alcohol use disorder (AUD; HR 2.35, 95% CI 2.19-2.53) were the health factors most strongly associated with ADRD. ADRD risk was also elevated among Veterans with a history of exposure to Agent Orange (HR 1.09, 95% CI 1.03-1.14), chemical/biological warfare agents (HR 1.31, 95% CI 1.23-1.39), and pyridostigmine bromide tablets (HR 1.67, 95% CI 1.44-1.93). Findings identified TBI, depression, AUD, and MEEs as key variables associated with ADRD in Veterans. These factors may represent important targets for prevention and intervention efforts aimed at improving the long-term health of aging Veterans. Additional work is needed to clarify the mechanisms through which these factors influence ADRD risk and to establish whether observed associations are causal.

This review explores Alzheimer's disease (AD) in individuals with Down syndrome (DS), a genetically defined population with near-universal development of AD neuropathology by age 40. We examine the genetic basis of DS-AD, epidemiology, biomarker trajectories, and clinical trial innovations, highlighting how insights from DS research inform broader AD pathogenesis, early detection, and therapeutic strategies. Advances in biomarker research, including longitudinal studies such as ABC-DS, have mapped predictable trajectories of amyloid, tau, and neurodegeneration in DS-AD, aligning closely with clinical staging. Plasma and CSF biomarkers (Aβ42, p-tau, NfL, GFAP) and neuroimaging modalities (amyloid/tau PET, MRI) demonstrate early and sequential changes decades before dementia onset. Revised AD diagnostic criteria now classify DS individuals as Stage 0 from birth, acknowledging genetic determinism and enabling earlier intervention. Comparative analyses between DS-AD, autosomal-dominant AD, and sporadic AD reveal shared pathological features but distinct timing and distribution of amyloid and tau. Clinical trials targeting amyloid and APP pathways in DS are underway, leveraging predictable disease progression to accelerate therapeutic development. Studying AD in DS provides a unique lens into the natural history of Alzheimer's disease, offering critical insights into genetic drivers, biomarker evolution, and therapeutic opportunities. The genetically defined and biologically concordant nature of DS-AD enables precise staging and early intervention strategies that can be translated to sporadic and familial AD. Continued investment in DS research will advance biomarker validation, refine clinical trial design, and inform personalized treatment approaches for the broader AD population.

Bletilla striata polysaccharide alleviates Alzheimer's disease in Caenorhabditis elegans by modulating autophagy via the insulin/AMPK pathway.

Alzheimer's disease (AD) is commonly defined by its hallmark brain pathologies, yet mounting evidence shows that metabolic impairment particularly linked to mitochondrial dysfunction, is a central and systemic feature of the disease. This review highlights consistent abnormalities in mitochondrial function, and turnover (mitophagy) across multiple AD-derived peripheral cells, including skin fibroblasts, lymphocytes, platelets, and peripheral blood mononuclear cells. We also report on potential peripheral AD biomarkers linked to mitochondria dysfunction in AD. Mitochondrial abnormalities in peripheral cells from individuals with AD robustly correlate with disease development. These mitochondrial dysfunctions mostly include reduced respiratory chain activity, increased accumulation of reactive oxygen species (ROS), altered mitochondrial membrane potential, and consequently decreased ATP production. Studies have also identified a complex pattern of mitochondrial hyperactivity and hypoactivity in peripheral cells of AD patients that appears to depend on the stage of AD and whether the disease is sporadic or familial. Furthermore, multiple steps of the mitophagy pathway are disrupted in peripheral cells as AD progresses. Finally, biochemical and proteomic analyses of peripheral fluids further support the loss of mitochondrial homeostasis in AD patients. Collectively, the reviewed findings support mitochondrial homeostasis disruption as a core pathophysiological component of AD and a promising target for biomarker development and therapeutic intervention.

A growing population of people living with Alzheimer's Disease requires improved supports for aging in place. Assistive technologies (ATs) can delay institutionalization, reduce care partner strain, and improve quality of life for this population. The abilities and needs of this population change during disease progression, but it remains unclear which ATs are best suited for specific stages. The purpose of this scoping review was to provide a snapshot in time by mapping currently available ATs assessed in peer-reviewed research, across the seven stages of Alzheimer's Disease progression. The review followed the Arksey and O'Malley framework to identify and harvest information from Medline, Scopus, CINAHL, and Embase databases. Inclusion criteria were Alzheimer's Disease, technology interventions of any type and duration, English language, and the period between 2000 and 2023. Data was extracted and analyzed using six predetermined domains of ATs for dementia: safety devices, clinical devices, memory aids, ATs for preventing social isolation, ATs for leisure activities, and ATs for supporting everyday tasks. A total of 87 ATs, reported in 47 articles, were mapped along seven stages of the disease. A variety of ATs are available, with high technology (e.g., tracking devices) targeting initial stages, and low technology (e.g., weighted blanket) targeting later stages. Music therapies were present across all disease stages. The map has the potential to inform people with Alzheimer's Disease, care partners, technology companies, policy makers and service providers on current AT availability and need for further development.

A timeline of structural and functional consequences to ipRGCs in a mouse model of Alzheimer's disease.

ELAVL1 interacts with APP and promotes Aβ-induced apoptosis in Alzheimer's disease by activating Bcl-2/Bax signaling.

Longitudinal subcortical volume changes and their correlations with multiple PET and fluid biomarkers in dominantly inherited Alzheimer's disease.

Access to novel potent pleiotropic prodrugs, targeting both butyrylcholinesterase and serotonin reuptake, with anti-amnesic activities in Alzheimer's disease model.

Variations in Mental Distress Among Caregivers of Individuals With Chronic Illnesses and Comorbid Cognitive Impairment.

Targeting the Nrf2/HO-1 aixs: A therapeutic strategy against regulated cell death in Alzheimer's disease.

Impaired awareness is common among people with Alzheimer's disease (AD) and the related disorders Huntington's disease (HD), and Korsakoff's syndrome (KS). Individuals with impaired awareness have an altered perception of their situation or functioning, which may pose challenges for care staff in nursing home settings. Yet, little is known about their experiences with impaired awareness. We conducted five focus groups with professional caregivers (N = 28) of nursing home residents with AD, HD and KS about their experiences with impaired awareness (two AD, one HD, one KS and one mixed focus group). Participants were certified nursing assistants, vocationally trained nurses and social workers. Conversations were audio-taped and transcribed verbatim. Data were analyzed using thematic analysis. We identified three main themes: (1) Manifestations of impaired awareness, including observed expressions of impaired awareness and impact on resident interactions. These manifestations were consistent across all three disease groups. (2) Reflections and emotions on these manifestations (characterized by compassion, astonishment and uncertainty). Impaired awareness increased the overall emotional burden for professional caregivers. Additionally, they sometimes felt uncertain about whether impaired awareness was intentional or disease-related. (3) Dealing with impaired awareness, by balancing between moving along and setting boundaries. Caregivers had difficulties determining the most effective approach to deal with impaired awareness. Impaired awareness impacts the work of caregivers of residents with AD, HD and KS. Gaining a better understanding of how impaired awareness affects residents' emotions and behavior can contribute to the development of effective care approaches for caregivers.

Da-Bu-Yin-Wan rescues cognitive deficits in aging and Alzheimer's disease models by Wnt/β-catenin-dependent restoration of lysosomal acidification.

Single-vesicle profiling of multiple biomarkers on serum EVs via EV-CATCH and nano-flow cytometry for clinical stratification of Alzheimer's disease.

Alzheimer disease (AD) and epilepsy are major causes of neurologic disability and are reciprocally related: epileptiform discharges, subclinical seizures, and epilepsy are more prevalent in patients with AD compared with controls; progressive cognitive impairment commonly afflicts epilepsy patients; and late-onset epilepsy patients have higher rates of new-onset dementia. Epidemiologic studies support shared risk factors (e.g., genetic variants, vascular disease, sleep disorders, microbiome) with notable divergences. AD and epilepsy have some overlapping anatomic (e.g., hippocampus, entorhinal, and association cortex), clinical (e.g., memory, attentional, and executive) impairments, and neuropathologic (e.g., amyloid, tau, neurofibrillary tangles) features. Shared clinical and translational challenges include underlying mechanisms (e.g., genetic variants, neuroinflammation, metabolic and mitochondrial dysfunction, excitatory/inhibitory imbalance, microbiome, and sociodemographic factors) and identifying valid and reliable biomarkers (e.g., total tau and phosphorylated tau (p-tau), amyloid deposition, Aβ42/Aβ40 ratio) to assess disease progression, predict outcomes, and assess potentially disease-modifying interventions. Identifying convergences and divergences between epilepsy and AD may inform our understanding. The clinical, neurophysiologic, neuropathologic, and molecular pathologic changes in AD and epilepsy may reveal pathophysiologic insights and therapeutic opportunities.

Rare mutations in the ATP binding cassette subfamily A member 7 (ABCA7) gene are known risk factors for Alzheimer's disease (AD). Genetic sequencing in 1372 Belgian patients previously revealed rare ABCA7 mutations in 102 carriers, 58 with a premature termination codon mutation (PTC) and 44 with a missense mutation. Among carriers, 14 received post-mortem examination. Here, we reviewed and report the demographics, clinicopathological phenotypes, and diagnoses of identified ABCA7 mutation carriers. Carriers mostly developed late-onset AD (71 ± 9 years) and had a high familial load (67 % with positive family history). Patients presented with classic amnestic AD based on neuropsychological assessment, imaging and CSF biomarkers. However, vascular involvement was observed in a considerable part of patients, leading to diagnosis of vascular dementia (9 %) and cerebral amyloid angiopathy (CAA) (6 %). In line with this, neuropathology of the 14 examined carriers uncovered extensive levels of CAA and AD hallmarks. Carriers of an ABCA7 missense mutations displayed a less aggressive phenotype, with comparable onset but longer disease duration compared to carriers of a PTC mutation. Furthermore, non-amnestic features including language, dysexecutive and behavioural symptoms, were more frequently seen in PTC patients (18 % vs 9 %), as was the case for concomitant vascular disease (22 % vs 10 %). Taken together, the clinical phenotype of rare ABCA7 mutation carriers spans the AD-CAA spectrum. Patients present with a classical AD phenotype although clinical heterogeneity is observed among carriers. The presence of a cerebrovascular component (CAA) may, in part, explain this heterogeneity.

A novel enzyme-activated tandem fluorescent probe for dual detection of BChE and A β plaques in Alzheimer's disease.