Curr Alzheimer Res [JOURNAL]
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200 papers
Advances in Nose-to-Brain Delivery Systems for Effective Alzheimer's Disease Management.
Sahu A, Khileshwari, Patle K … +2 more , Jain P, Ajazuddin
Curr Alzheimer Res · 2026 Jan · PMID 41588888 · Publisher ↗
Neurodegenerative diseases comprise a heterogeneous group of disorders characterized by the progressive structural and functional deterioration of neurons in the central nervous system. Among them, Alzheimer's disease is...
Neurodegenerative diseases comprise a heterogeneous group of disorders characterized by the progressive structural and functional deterioration of neurons in the central nervous system. Among them, Alzheimer's disease is the most prevalent worldwide. Despite their distinct clinical manifestations, many neurodegenerative disorders share convergent pathophysiological mechanisms such as protein misfolding and aggregation, oxidative stress, mitochondrial dysfunction, and neuroinflammation, which ultimately drive neuronal loss. These processes lead to profound impairments in cognitive performance, motor coordination, and overall functional capacity, making such diseases exceptionally difficult to diagnose early and manage effectively. Traditional treatment approaches administered orally or parenterally face limitations, including high hepatic metabolism, poor penetration across the blood-brain barrier (BBB), and systemic side effects. This review highlights the potential of the nose-to-brain (N2B) delivery system as an emerging and promising therapeutic strategy. N2B delivery utilizes the olfactory and trigeminal nerve pathways in the nasal cavity to rapidly and precisely deliver drugs to the central nervous system without crossing the blood-brain barrier. Because the system is non-invasive, it offers high bioavailability, reduced systemic exposure, and improved patient compliance. The use of lipid nanocarriers, nanoparticles, dendrimers, and nanogels to enhance the stability of drugs, facilitating efficient targeting and controlled release, is a crucial factor in optimizing N2B drug delivery systems. Various attributes influence drug transport, which are physiological, physicochemical and formulation-dependent characteristics. The main challenges faced by the N2B delivery system are enzymatic degradation and mucociliary clearance. Emerging technologies, such as AI, 3D Printing, and personalized medicine, all hold promise for future inventions in this area. Preclinical and clinical trials demonstrate the efficacy of delivering N2B in treating neurodegenerative diseases; however, its full potential remains to be seen due to regulatory, safety, and scalability concerns. Hence, this review emphasizes the research required to pursue interdisciplinary collaboration and unlock the full potential of N2B delivery, as well as a new approach to transforming neurodegenerative conditions.
Vagus Nerve Stimulation in the Management of Neurodegenerative Diseases: A Systematic Review of Advances in Animal Research and Clinical Applications.
Edelbach B, Huang L, Boling W
Curr Alzheimer Res · 2026 Jan · PMID 41588887 · Publisher ↗
INTRODUCTION: Vagus Nerve Stimulation (VNS) has been approved by the FDA as a treatment for epilepsy, depression, post-ischemic stroke rehabilitation, and migraine in patients. It is emerging as a potential treatment for...
INTRODUCTION: Vagus Nerve Stimulation (VNS) has been approved by the FDA as a treatment for epilepsy, depression, post-ischemic stroke rehabilitation, and migraine in patients. It is emerging as a potential treatment for neurodegenerative diseases. Herein, we summarize the research on VNS and its application in common neurodegenerative diseases. METHODS: A literature search was completed in PubMed, ScienceDirect, and Google Scholar using the terms: "neurodegeneration," "neuromodulation," "Vagus Nerve Stimulation," "Parkinson's Disease (PD)," "Alzheimer's Disease (AD)," "dementia," "neuroinflammation," and "cognitive dysfunction." Animal and clinical studies using VNS as a primary intervention in neurodegenerative diseases were included. RESULTS: The studies of VNS application in Parkinson's and Alzheimer's models were reviewed. In animal studies, VNS was associated with increased locomotion and balance, as well as reduced cognitive impairments. The underlying neuroprotective mechanisms included: increased dopaminergic neurons, reduced α-synuclein concentration in the brain, preservation of the nigrostriatal dopaminergic pathway, increased α7nAChR expression, reduced apoptotic markers, reduced neuroinflammation, and significant reductions in microglial and astrocytic densities. In clinical studies with small patient populations of PD or AD/mild cognitive impairment, VNS was associated with improved gait parameters and enhanced performance in memory-based tasks. DISCUSSION: Vagus Nerve Stimulation (VNS) shows neuroprotective and anti-inflammatory effects in animal models of Alzheimer's and Parkinson's disease, but clinical results remain inconsistent due to variability in treatment duration, outcome measures, and reliance on subjective assessments. Emerging physiologic biomarkers such as VSEP, EEG, and magnetoencephalography may provide more objective measures of therapeutic response. CONCLUSIONS: The systematic review highlights the potential of VNS as a therapeutic approach for managing neurodegenerative diseases. The efficacy of VNS in animal models of Parkinson's and Alzheimer's diseases involves both neuroprotection and anti-neuroinflammation, while additional protective mechanisms require further exploration.
Causal Effects Between Neurodegenerative Diseases, Metabolites, and Brain Volume.
Liu H, Hescham S, Clusmann H … +2 more , Temel Y, van der Meer D
Curr Alzheimer Res · 2026 Jan · PMID 41588886 · Publisher ↗
INTRODUCTION/OBJECTIVE: Neurodegenerative diseases such as Alzheimer's disease (AD), Lewy dody dementia (LBD), and Parkinson's disease (PD) are linked to changes in brain volume. However, causal evidence on how these dis...
INTRODUCTION/OBJECTIVE: Neurodegenerative diseases such as Alzheimer's disease (AD), Lewy dody dementia (LBD), and Parkinson's disease (PD) are linked to changes in brain volume. However, causal evidence on how these diseases affect brain volume and whether metabolites mediate these causal effects remains limited. METHODS: We applied mediation Mendelian randomization analysis using GWAS summary statistics. The inverse variance-weighted method was used to assess causal effects and identify potential metabolite mediators. RESULTS: The MR analyses indicated that bilateral thalamus and putamen volumes (FDR < 0.05) had causal effects on PD. AD and LBD showed causal effects on bilateral thalamus and hippocampus (FDR < 0.01), with LBD specifically showing a causal effect on bilateral putamen (FDR < 0.05). Mediation analyses revealed that AD had a genetically predicted association with Nervonoy- L-carnitine and 1-linoleoyl-2-arachidonoyl-GPC (p-value = 0.04 and 0.01, respectively). Moreover, Nervonoy-L-carnitine was suggestively negatively associated with hippocampus volume (p-value = 0.03 and 0.02, respectively). 1-linoleoyl-2-arachidonoyl-GPC exhibited a negative genetically predicted association with hippocampus volume (p-value < 0.05). Additionally, LBD showed a negative genetically predicted association on the ratio of retinol to linoleoyl-arachidonoyl- glycerol (p-value = 0.02), and a positive genetically predicted association on Nervonoy-L-- carnitine (p-value < 0.05) and 1-linoleoyl-2-arachidonoyl-GPC (p-value = 0.03). DISCUSSION: These results suggest that AD and LBD affect brain regions through causal pathways. The involvement of specific metabolites highlights potential mechanisms linking neurodegeneration to brain volume. CONCLUSION: Nervonoylcarnitine and 1-linoleoyl-2-arachidonoyl-GPC may mediate the predicted effects of AD and LBD on hippocampal volumes, while the ratio of retinol to linoleoyl-arachidonoyl- glycerol mediates only LBD.
MicroRNA Signatures in Alzheimer's Disease and Normal-Tension Glaucoma: A Comparative Expression Analysis of miR-128 and miR-455-3p.
Arish M, Hashemzehi Z, Baghaei V … +4 more , Maleki A, Salari AM, Rasouli S, Dakkali MS
Curr Alzheimer Res · 2026 Jan · PMID 41508961 · Publisher ↗
INTRODUCTION: The relationship between Alzheimer's disease (AD) and normal-tension glaucoma (NTG) is an emerging area of interest owing to shared neurodegenerative features. Nevertheless, few studies have ascertained cir...
INTRODUCTION: The relationship between Alzheimer's disease (AD) and normal-tension glaucoma (NTG) is an emerging area of interest owing to shared neurodegenerative features. Nevertheless, few studies have ascertained circulating microRNAs (miR) across both conditions. This study aimed to compare the expression of miR-128 and miR-455-3p in patients with NTG and AD and in controls, and to explore their potential as circulating biomarker candidates. MATERIALS AND METHODS: In this cross-sectional study, serum miRNAs were extracted using a column- based kit and quantified by SYBR Green qRT-PCR (normalized to U6). Each reaction was run in triplicate. Data were analyzed via ANCOVA adjusted for age and sex, followed by Bonferroni post-hoc tests. RESULTS: Both miR-128 and miR-455-3p were significantly upregulated in the AD and NTG groups compared with controls (p < 0.001 for both). Adjusted mean expression for miR-128 was approximately 2.1 in AD, 2.6 in NTG, and 0.3 in controls, while the corresponding miR-455-3p values were 2.9, 3.1, and 0.8, respectively. Post-hoc comparisons confirmed higher expression in both disease groups compared with controls, but not between AD and NTG. Power analysis revealed >0.99 power for group comparisons with controls, consistent with robust group-level differences. DISCUSSION: miR-128 and miR-455-3p are implicated in neuronal stress responses, mitochondrial regulation, and amyloid-beta processing. Their parallel upregulation in AD and NTG suggests overlapping molecular signatures and may reflect systemic responses to neurodegenerative stress. These findings are also consistent with growing evidence that the eye and brain share vulnerability to similar cellular processes in neurodegeneration. CONCLUSION: Elevated serum miR-128 and miR-455-3p in both AD and NTG indicate overlapping expression profiles across conditions. These miRNAs may serve as promising circulating biomarker candidates and support the concept of a molecular interplay between ocular and cerebral pathologies. However, their diagnostic and mechanistic potential warrants validation in largescale, longitudinal studies.
The Cause-and-Consequence Relationships between Domestic Abuse and Alzheimer's Disease: Identification of Five Subtypes.
Twiss E, McPherson C, Weaver DF
Curr Alzheimer Res · 2026 Jan · PMID 41503902 · Publisher ↗
Domestic abuse (DA) and Alzheimer's disease (AD) and related dementias) are two of humankind's most significant societal healthcare issues. DA is widespread, with one in three women and one in four men experiencing physi...
Domestic abuse (DA) and Alzheimer's disease (AD) and related dementias) are two of humankind's most significant societal healthcare issues. DA is widespread, with one in three women and one in four men experiencing physical, psychological, emotional, sexual, and financial abuse in their lifetime. AD is the most common form of dementia and is expected to affect more than 152 million people worldwide by 2050. Given the incidence and prevalence of these two problems, any causal relationship between them carries profound societal consequences. Herein, we describe five types of overlapping relationships between DA and AD: 1. intimate partner violence (IPV) as a risk factor for AD; 2. AD as a risk factor for worsening ongoing DA; 3. abuse of caregivers by people with AD; 4. abuse of people with AD by caregivers; and 5. reactivation of previous DA behavior in a person with AD. Chronologically, these five types cover the spectrum from occurring decades before the onset of AD symptoms to emerging only after AD symptoms have manifested. Mechanistically, these five subtypes reflect the paradoxical fact that DA and AD may be causes or consequences of each other. Phenomenologically, they encompass the full spectrum of DA, including physical, psychological, emotional, sexual, and financial abuse. Given the challenges in recognizing, managing, and treating both DA and AD, society's need to recognize the DA/AD Problem and to identify and prevent the five subtypes of DA and AD overlap is an emerging healthcare priority.
Unlocking Neuroprotection: Potassium Channel Openers in Alzheimer's Disease.
Kumar S, Sharma A, Mehra G … +2 more , Kazmi TZ, Sharma N
Curr Alzheimer Res · 2026 Jan · PMID 41503901 · Publisher ↗
Alzheimer's disease is a neurodegenerative disorder characterized by impairments in cognitive functions such as thinking, behavior, and memory. The major pathological abnormalities associated with the disease include the...
Alzheimer's disease is a neurodegenerative disorder characterized by impairments in cognitive functions such as thinking, behavior, and memory. The major pathological abnormalities associated with the disease include the formation of neurofibrillary tangles and amyloid plaques, which further cause neuroinflammation and nerve cell death. Currently, treatments for the disease focus on symptomatic management rather than addressing the root cause of neurological changes. Therefore, the current status of therapy highlights the need for more effective therapeutic substances that can either prevent abnormal deposition or slow neurodegeneration to preserve nerve cells. In this respect, ATP-sensitive potassium channel openers may have a potential role in prevention and protection. The present article focuses on several cellular mechanisms of this class, including the limitation of neuronal excitability, modulation of neurotransmitter release, prevention of aberrant protein buildup, reduction of excessive calcium influx, reduction of reactive oxygen species levels, and reduction of microglial activation.
Current Perspectives on Oxytocin and Alzheimer's Disease-Related Symptoms.
Modaffari A, Dixon S, Alshehri MSA … +1 more , Castejon AM
Curr Alzheimer Res · 2026 Jan · PMID 41503900 · Publisher ↗
Alzheimer's Disease (AD) is a neurodegenerative disorder accounting for 60-80% of dementia cases globally. Several risk factors are associated with increased AD onset, including genetics, physical activity, and varying l...
Alzheimer's Disease (AD) is a neurodegenerative disorder accounting for 60-80% of dementia cases globally. Several risk factors are associated with increased AD onset, including genetics, physical activity, and varying levels of social interaction. Extensive research has explored potential treatments for AD, among which oxytocin (OX) has shown beneficial effects on memory-related neurological processes. OX has been suggested to modulate neuroplasticity within the hippocampus in rat and mouse AD models. Further studies indicate that intranasal administration of OX may lead to significant improvements in memory and cognition. In addition, a non-peptide agonistic analogue, LIT-001, has been investigated. This review aims to provide insight into the potential of OX as a therapeutic target for AD and to explore alternatives that activate similar cellular signaling pathways.
Improving Quality of Life in Dementia through Tailored Interventions: A Systematic Review from Saudi Arabia.
Khallaf R, Alokely A, Hli N … +4 more , Khan H, Kiyani MM, Al-Hussain F, Bashir S
Curr Alzheimer Res · 2026 Jan · PMID 41503899 · Publisher ↗
INTRODUCTION: Quality of life (QoL) in dementia care can be enhanced through nonpharmacological interventions. This systematic review and meta-analysis aimed to evaluate the effectiveness of such interventions across dem...
INTRODUCTION: Quality of life (QoL) in dementia care can be enhanced through nonpharmacological interventions. This systematic review and meta-analysis aimed to evaluate the effectiveness of such interventions across demographic groups in Saudi Arabia. METHODS: A systematic search identified 11 studies assessing sensory stimulation, mindful walking, functional independence, caregiver support, and public awareness interventions. Data were extracted on study design, population, and outcome measures. Three outcome studies were narratively synthesized. RESULTS: Sensory stimulation interventions (n = 62) showed the strongest behavioral improvements, with a large effect size (Hedges' g = -2.03). Data from other studies were insufficient for quantitative pooling, and no formal meta-regression or heterogeneity analyses were conducted. DISCUSSION: Findings suggest that behavioral and psychological interventions tailored to older adults yield the most significant QoL benefits. Caregiver support and awareness programs offer important supplementary benefits, although limited data restrict broader generalizations. CONCLUSION: Non-pharmacological interventions, particularly those targeting behavioral and psychological outcomes, improve QoL in dementia care. However, further high-quality studies with comprehensive outcome reporting are needed to strengthen the evidence base and guide populationspecific strategies.
Effect of Ascorbic Acid on the Transgenic Drosophila Expressing Human Aβ-42 in the Neurons.
Siddique YH, Ara G, Naz F … +5 more , Varshney H, Gaur K, Subhan I, Fatima J, Jyoti S
Curr Alzheimer Res · 2026 Jan · PMID 41503898 · Publisher ↗
INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-beta (Aβ) peptides, especially the toxic Aβ42 isoform, which induces excessive reactive oxygen spec...
INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-beta (Aβ) peptides, especially the toxic Aβ42 isoform, which induces excessive reactive oxygen species (ROS) production leading to oxidative damage, lipid peroxidation, and neuronal loss. Given the critical role of oxidative stress in AD pathogenesis, antioxidants such as ascorbic acid (AA) are being explored for their therapeutic potential. OBJECTIVE: This study aimed to investigate the neuroprotective efficacy of ascorbic acid in a transgenic Drosophila melanogaster model expressing human Aβ42 in neuronal tissues. METHODS: Transgenic and wild-type flies were maintained on diets supplemented with optimized, non-toxic concentrations of AA. Biochemical assays were performed to evaluate oxidative stress and antioxidant defense, including glutathione (GSH) levels, glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), thiobarbituric acid-reactive substances (TBARS), and protein carbonyl content (PCC). Acetylcholinesterase (AChE) activity and locomotor performance were also assessed. RESULTS: Ascorbic acid supplementation significantly enhanced GSH levels, normalized GST, SOD, and CAT activities, and reduced TBARS and PCC levels, indicating restoration of redox balance. Partial recovery of AChE activity suggested protection of cholinergic neurotransmission. Functionally, AA-fed AD flies exhibited improved locomotor performance, delayed onset of memory impairment, and extended lifespan compared to untreated AD flies. CONCLUSION: The findings demonstrate that ascorbic acid provides multifaceted neuroprotection by mitigating oxidative stress, stabilizing cholinergic function, improving behavioural outcomes, and enhancing longevity. AA emerges as a promising, low-cost natural antioxidant for potential use in Alzheimer's disease management.
Relation between Cerebrospinal Fluid Catecholamines and Vascular Risk Factors, Thyroid Function and Vitamins in Healthy Individuals and Patients with Neurodegenerative Diseases.
Moreira IP, Serrao P, Sequeira L … +3 more , Sa MJ, Vieira-Coelho MA, Guimaraes J
Curr Alzheimer Res · 2026 · PMID 41486994 · Publisher ↗
INTRODUCTION: The locus coeruleus is the primary site of norepinephrine (NE) synthesis in the brain. Its dysfunction has been implicated in the pathogenesis of Alzheimer's disease. Vascular risk factors, thyroid dysfunct...
INTRODUCTION: The locus coeruleus is the primary site of norepinephrine (NE) synthesis in the brain. Its dysfunction has been implicated in the pathogenesis of Alzheimer's disease. Vascular risk factors, thyroid dysfunction, and vitamin deficiencies have also been associated with an increased risk of dementia. This study aimed to evaluate the relationship between the catecholaminergic system-by measuring cerebrospinal fluid (CSF) levels of L-3,4-dihydroxyphenylalanine (L-DOPA), dopamine (DA), and NE-and vascular risk factors, thyroid dysfunction, and vitamin deficiencies. METHODS: We conducted a cross-sectional observational study in which CSF levels of L-DOPA, DA and NE were measured in 117 participants. Data on Blood Pressure (BP), heart rate, glycaemic and lipid profiles, smoking history, thyroid function and vitamin B12 and folic acid levels were collected for each participant. RESULTS: We found significant correlations between NE and CSF glucose levels (r = 0.308, p = 0.003) in participants without diabetes mellitus, between L-DOPA and orthostatic variation of diastolic BP (r = -0.288, p = 0.014) and high-density lipoprotein (r = 0.404, p = 0.001) and between NE and triglycerides (r = 0.271, p = 0.030) and folic acid (r = 0.298, p = 0.009). DISCUSSION: This is the first study to demonstrate correlations between CSF NE levels and CSF glucose, probably due to the effect of NE on astrocytes, and between CSF NE levels and folic acid, possibly related to its role in catecholamine synthesis. CSF L-DOPA levels were correlated with cardiovascular risk factors such as the orthostatic regulation of diastolic BP. CONCLUSION: These findings may contribute to a better understanding of the pathophysiology of neurodegenerative diseases.
miRNAs: Promising Biomarkers for Alzheimer's Diagnosis and Treatment.
Cai M, Yan S, Sun Y … +2 more , Huo Q, Dai X
Curr Alzheimer Res · 2026 Jan · PMID 41486993 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, and chronic neuroinflammation, leadin...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, and chronic neuroinflammation, leading to synaptic dysfunction and cognitive decline. Current diagnostic methods rely on clinical symptoms and limited biomarkers, while available treatments only provide symptomatic relief without halting disease progression. MicroRNAs (miRNAs), small non-coding RNAs of 19-22 nucleotides, have emerged as crucial regulators of gene expression through post-transcriptional mechanisms and show distinct dysregulation patterns in AD patients' blood, cerebrospinal fluid (CSF), and brain tissues. Key miRNAs such as miR-132, miR-146a, miR-34a, and miR-125b demonstrate consistent alterations in expression levels, correlating with disease progression and offering potential as non-invasive diagnostic tools. This review comprehensively examines the dual role of miRNAs as diagnostic biomarkers and therapeutic targets for AD. We also provide an analysis of specific miRNA signatures in different biofluids (plasma, serum, CSF) and brain regions that correlate with disease stages, highlighting their potential for early and non-invasive diagnosis. Therapeutically, miRNAs modulate multiple AD-related pathways, including neuroinflammation via NF-κB signaling, Aβ production through BACE1 inhibition, and tau phosphorylation via GSK3β regulation. miRNAs also influence synaptic plasticity, mitochondrial function, and autophagy, presenting multifaceted opportunities for intervention. However, challenges, including miRNA heterogeneity, stability, and targeted delivery, remain critical impediments. Advances in nanocarriers, exosomal miRNAs, and viral vectors show promise in overcoming these obstacles, enabling precise miRNA modulation. In addition, we underscore the need for standardized protocols, further validation in clinical cohorts, and the development of cost-effective detection methods to translate miRNA-based approaches into practical diagnostics and therapies. By integrating miRNA biomarkers with existing diagnostic tools and exploring combinatorial therapeutic strategies, researchers can harness the potential of miRNAs to revolutionize AD intervention, paving the way for early detection and effective treatment of this devastating disease.
Cognitive Status of People with Dementia and its Relation to the Performance in Touch and Tangible Tasks.
Esquer-Rochin M, Rodriguez LF, Gutierrez-Garcia JO
Curr Alzheimer Res · 2026 · PMID 41486992 · Publisher ↗
BACKGROUND: Previous research explores the relationship between the cognitive status of people with dementia (PwD) and their performance in complex, domain-specific interaction tasks. However, these activities and their...
BACKGROUND: Previous research explores the relationship between the cognitive status of people with dementia (PwD) and their performance in complex, domain-specific interaction tasks. However, these activities and their sophisticated instructions are challenging for PwD, potentially biasing performance metrics. This study aims to answer whether the cognitive status of PwD is related to their performance in simple touch and tangible tasks disassociated from a domain. METHODS: This study involved 7 formal caregivers and data from 21 PwD corresponding to completion times of interaction tasks. Relationships between completion times and the cognitive status of PwD were explored using Spearman's rank correlation, mutual information, gini importance, permutation importance, and a principal component analysis (PCA) visualization. RESULTS: Completion times of drag & drop, grasp, and tap interaction tasks have a strong negative monotonic association with the MMSE score (Bonferroni-corrected p-value < 0.05). The most relevant gestures were drag & drop, tap, and grasp. The PCA visualization allowed formal caregivers to detect relationships between patients' performance and their MMSE scores (p-value < 0.05). DISCUSSION: The cognitive status of PwD is related to their performance in simple interaction tasks disassociated from a domain. As the MMSE score decreases, task completion times increase. In addition, the PCA visualization was considered useful to inform decision-making. CONCLUSION: This work provides the foundation for technology-enhanced cognitive activities supported by touch and tangible gestures that can be used to determine the cognitive status of PwD.
The Role of Microglial Cells and Cytokine Modulation in Alzheimer's Disease: A Neuroinflammatory Perspective.
Chaudhary V, Singh AP, Sharma H … +1 more , Taumar D
Curr Alzheimer Res · 2026 Jan · PMID 41486991 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by abnormalities in protein metabolism leading to the accumulation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibr...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by abnormalities in protein metabolism leading to the accumulation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (hyperphosphorylated tau protein). While these pathological constructs have held significant attention for decades, emerging evidence highlights the understanding of neuroinflammation (notably involving microglia, and cytokine signaling) as a critical initial event with respect to the inception and progression of AD. This review discusses the dynamic and dualistic effects of immune response in AD based on the relationship between neuroinflammatory processes and classical neuropathological characteristics. Microglia are ubiquitous immune cells in the central nervous system responsible for maintaining homeostasis as the brain's "housekeepers" by removing cellular debris, pruning synapses, and monitoring cell interactions. However, microglia in AD function produce a chronically activated phenotype that elicits neurotoxicity, impairs synaptic functioning, and is are protracted source of neuroinflammation. The appearance of disease-associated microglia (DAM) may illustrate complexities of TREM2 signaling for the anabolism of Aβ clearance and the modulation of inflammatory systems. Cytokine imbalance - higher expression of pro-inflammatory (e.g., IL-1β, TNF-α) and lower expression of antiinflammatory (e.g., IL-10, TGF-β) - adds to a self-perpetuating inflammatory loop that exacerbates Aβ and tau pathology, brain-blood barrier permeability, and peripheral-CNS immune communications. The mechanisms of an inflammatory event may drive brain tau hyperphosphorylation, tau propagation, along with other pathophysiological neurodegenerative features of traumatic brain injury and Alzheimer's disease. While examples of therapies targeting microglia and their cytokine activity are actively being explored, clinical efforts have been mixed. Neuroimaging development (e.g., TSPO-PET), cytokine collection and compositional approaches, and application of single-cell transcriptomics are providing new ways of thinking about complex neuroimmunology. Exploring, informing, and defining the timing, context, and variations of neuroinflammatory responses will be ultimately needed to create effective, targeted therapies for Alzheimer's disease (AD).
Hypertension is the Main Vascular Risk Factor for Cognitive Impairment, Microvascular Pathology and Brain Atrophy in Alzheimer's Disease.
Tripathi SM, Shiells H, Waymont J … +5 more , Staff R, Schelter B, Bentham P, Wischik CM, Murray AD
Curr Alzheimer Res · 2026 · PMID 41486990 · Publisher ↗
INTRODUCTION: Alzheimer's Disease (AD) is the commonest pathology underlying dementia, but it frequently coexists with cerebrovascular disease (CVD). Existing literature supports a possible role for vascular risk factors...
INTRODUCTION: Alzheimer's Disease (AD) is the commonest pathology underlying dementia, but it frequently coexists with cerebrovascular disease (CVD). Existing literature supports a possible role for vascular risk factors (VRFs), including hypertension, diabetes and dyslipidaemia in AD pathogenesis. This study aims to determine whether VRFs contribute to typical AD pathogenesis or co-morbid CVD in mixed AD. METHODS: Well-characterised probable AD subjects participating in two large clinical trials of Hydromethylthionine were classified into "typical AD" and "mixed" patterns based on FDG-PET images. VRFs, including hypertension, diabetes and dyslipidaemia, and MRI-derived White Matter Hyperintensities (WMHs) and brain fraction (as a measure of brain atrophy) were analysed to investigate the relationship between VRFs and AD subtypes. RESULTS: Of 794 participants, 533 (67.1%) were classified as typical AD and 261 (32.8%) were classified as mixed. Among VRFs, cardiovascular risks were significantly more frequent in typical AD (59%) than in mixed subtype (47%) (p = 0.002). DISCUSSION: We found that it was mainly hypertension that differed according to subtypes. Although brain atrophy is the main driver of cognitive impairment in patients with AD subtype, the microvascular pathology in the form of WMHs was significantly higher in patients with hypertension, irrespective of subtype. CONCLUSION: Although hypertension is the main risk factor for cerebrovascular disease, contrary to our expectation, hypertension is common in typical AD than the mixed subtype, and this association is driven by the hitherto unsuspected contribution of microvascular pathology to cognitive impairment in typical AD.
Spectral Biomarkers of Functional Brain Network Alteration in Alzheimer's Disease.
Behrouzinia S, Afshar M, Khanteymoori A
Curr Alzheimer Res · 2025 · PMID 41140215 · Publisher ↗
INTRODUCTION: The primary objective of this study was to examine changes in brain network architecture across multiple frequency bands using spectral analysis of both weighted and binarized functional connectivity networ...
INTRODUCTION: The primary objective of this study was to examine changes in brain network architecture across multiple frequency bands using spectral analysis of both weighted and binarized functional connectivity networks. This cross-sectional observational study, conducted as a secondary analysis of a publicly available EEG dataset, analyzed spectral coherence measurements from 25 patients with Alzheimer's disease (AD) and 25 age- and sex-matched healthy controls (HC). Nevertheless, the modest sample size and cultural homogeneity of the dataset may limit the statistical power and generalizability of the results. A data-driven thresholding approach was employed to generate binary networks, allowing a robust comparison of connectivity disruptions associated with AD. METHOD: Brain network features derived from the graph Laplacian, including weighted Fiedler value, spectral range, and Middle Eigenvalue, were analyzed across seven frequency layers: delta, theta, alpha1, alpha2, beta1, beta2, and gamma. For binary networks, the Fiedler value was calculated after thresholding. Statistical group comparisons between AD and HC were performed using t-tests (p < 0.05), and each feature was assessed based on the number of frequency bands showing significant differences. RESULTS: Among all features, the weighted Fiedler value was the most discriminative, showing significant reductions in AD patients within the alpha2 and beta1 bands. In binary networks, the Fiedler value remained significantly lower in AD within the alpha2 band, confirming topological degradation even without edge weight information. Other spectral features showed similar trends, but did not reach statistical significance in the binary networks. DISCUSSION: The consistent decline in Fiedler value across both weighted and binary networks indicates a global reduction in connectivity characteristic of AD. These spectral markers offer a quantitative and interpretable framework for understanding the progressive disconnection syndrome in AD. CONCLUSION: This study demonstrates significant alterations in Laplacian spectral features of brain networks between the AD and HC groups across specific frequency bands. These exploratory findings indicate that the spectral features, particularly the Fiedler value, consistently differentiate AD patients from healthy controls across frequency bands, suggesting its potential as a biomarker. However, larger and longitudinal studies are needed to confirm its diagnostic and prognostic utility. The combined use of weighted and binarized connectivity matrices enhances analytical sensitivity and facilitates the application of spectral graph theory for the early detection and monitoring of AD.
Low-Dimensional Nanomaterials in Alzheimer's Disease: Current Applications.
Shi Y, Luo W, Hu Y … +1 more , Chen W
Curr Alzheimer Res · 2026 · PMID 41140214 · Publisher ↗
INTRODUCTION: Alzheimer's Disease (AD) is a common neurodegenerative disorder (NDD) driven by multifaceted pathologies, including β-amyloid (Aβ) aggregation, tau protein hyperphosphorylation, oxidative stress, metal ion...
INTRODUCTION: Alzheimer's Disease (AD) is a common neurodegenerative disorder (NDD) driven by multifaceted pathologies, including β-amyloid (Aβ) aggregation, tau protein hyperphosphorylation, oxidative stress, metal ion dyshomeostasis, and neuroinflammation. Current therapeutic strategies remain limited by insufficient Blood-Brain Barrier (BBB) penetration, singletarget approaches, and inefficacy against nanoscale pathological aggregates. This review highlights the emerging potential of low-dimensional nanomaterials (LDNMs) as multi-target therapeutic platforms for AD. METHODS: We systematically evaluate zero-dimensional (0D), one-dimensional (1D), and twodimensional (2D) nanostructures and establish a "nano-nano" interaction paradigm that demonstrates how LDNMs interact with AD core pathological factors. Supporting tables summarize experimental data quantifying the effects of LDNMs on Aβ and tau pathologies, oxidative stress, metal ion homeostasis, neuroinflammation, and the delivery of BBB-penetrant drugs. RESULTS: LDNMs exhibit significant potential in mitigating core AD pathologies. They effectively inhibit Aβ aggregation and tau hyperphosphorylation, attenuate oxidative damage, restore metal ion homeostasis, reduce neuroinflammatory activity, and enable targeted drug delivery to the brain. DISCUSSION: The multi-target functionality of LDNMs overcomes major limitations of single-target therapies. Their nanoscale dimensions and modifiable surfaces enable synergistic interactions with pathological factors, offering a holistic intervention strategy. Limitations and translational challenges are discussed for future research directions for clinical application. CONCLUSION: This review links the structure and drug loading of LDNMs to multi-targeted efficacy against core AD pathology. It establishes a mechanistic connection between nanomaterial size and multi-pathway efficacy that transcends the limitations of single-target strategies. Moreover, it also provides a comprehensive framework for designing LDNMs-based nanotherapeutics, highlighting their potential as multi-target platforms for AD therapy.
The Role of Lipoprotein and Gut Microbiome in Alzheimer's Disease: A Review of Novel Findings and Potential Applications.
Zhao R, Che M, Cui Y … +2 more , Peng J, Chen M
Curr Alzheimer Res · 2025 Oct · PMID 41140213 · Publisher ↗
Alzheimer's disease (AD), a progressive neurodegenerative disorder, is inadequately comprehended, with hypotheses implicating amyloid-β, tau pathology, mitochondrial dysfunction, and epigenetic factors. Recent research u...
Alzheimer's disease (AD), a progressive neurodegenerative disorder, is inadequately comprehended, with hypotheses implicating amyloid-β, tau pathology, mitochondrial dysfunction, and epigenetic factors. Recent research underscores the significance of lipoproteins and the gut microbiota in the etiology of AD. Apolipoprotein E (ApoE), particularly the E4 subtype, emerges as a key genetic risk factor, influencing oxidative stress, synaptic defects, glucose metabolism, and amyloid-β clearance. Lipoprotein receptors, such as LRP-1, also influence the integrity of the blood-brain barrier, indicating potential for therapeutic applications. Novel therapies targeting lipoproteins, such as ALZ-801 and IDOL inhibitors, show promise in preclinical and clinical trials. Concurrently, the gut microbiome's impact on AD is increasingly recognized. Dysbiosis correlates with inflammation, mitochondrial oxidative stress, impaired autophagy, and neurotransmitter imbalances. Gut-derived metabolites, including phenylalanine and isoleucine, promote Th1 cell activation and microglial dysfunction, exacerbating AD pathology. Interventions, like probiotics, GV-971, and polyphenols, demonstrate efficacy in restoring microbial balance and mitigating cognitive decline. Crucially, bidirectional interactions between lipoproteins and the gut microbiome are implicated in AD. ApoE genotypes influence gut microbial composition, while microbiota- derived short-chain fatty acids and endotoxins modulate lipid metabolism and neuroinflammation. These interactions, mediated via the gut-brain axis, highlight novel therapeutic avenues. Current FDA-approved AD drugs face limitations in efficacy and side effects, underscoring the need for innovative strategies targeting lipoprotein-gut microbiome crosstalk. Integrating insights into lipoprotein biology and gut microbiota dynamics may offer transformative potential for AD treatment, emphasizing combinatorial approaches to modulate these interconnected pathways. Further research is warranted to elucidate mechanistic links and translate preclinical findings into clinical applications.
Innovative Approaches in Molecular Docking for the Discovery of Novel Inhibitors Against Alzheimer's Disease.
Singh B, Singh K, Gupta JK … +3 more , Semwal BC, Jain D, Sharma MC
Curr Alzheimer Res · 2025 · PMID 41133842 · Publisher ↗
INTRODUCTION: Alzheimer's disease (AD) is a debilitating neurodegenerative condition marked by progressive cognitive decline and memory impairment, affecting millions worldwide. Despite extensive research, no definitive...
INTRODUCTION: Alzheimer's disease (AD) is a debilitating neurodegenerative condition marked by progressive cognitive decline and memory impairment, affecting millions worldwide. Despite extensive research, no definitive cure exists, underscoring the need for innovative approaches to drug discovery and development. METHODS: This review focuses on the application of molecular docking techniques in the context of AD drug discovery. The methodology involves the use of computational modeling tools to predict and analyze the interactions between small drug-like molecules and key protein targets implicated in AD pathogenesis, particularly amyloid-beta (Aβ) and tau proteins. RESULTS: Molecular docking has enabled the virtual screening of large chemical libraries to identify potential inhibitors of Aβ aggregation and tau hyperphosphorylation. Numerous studies have validated docking-predicted interactions with and experiments, resulting in the discovery of novel compounds with promising pharmacological profiles. Docking has also aided in the optimization of ligand binding affinity and selectivity toward AD-relevant targets. DISCUSSION: The integration of molecular docking with experimental techniques enhances the reliability and efficiency of the drug discovery process. Docking allows for the early identification of bioactive molecules, reducing time and cost compared to traditional methods. However, limitations such as rigid receptor assumptions and scoring function inaccuracies require further refinement. CONCLUSION: Molecular docking stands out as a powerful computational tool in the quest for effective AD therapies. Simulating protein-ligand interactions accelerates the identification of potential drug candidates and supports the rational design of targeted interventions, paving the way for future clinical applications in combating Alzheimer's disease.
Recent Advances in the Application of Artificial Intelligence in Alzheimer's Disease.
Yao L, Ni J, Wei M … +6 more , Li T, Li F, Wang T, Xiao W, Shi J, Tian J
Curr Alzheimer Res · 2025 · PMID 41133841 · Publisher ↗
Artificial intelligence (AI) refers to a system that can simulate and execute the processes of human thinking and learning, and make informed decisions. Fueled by the development of AI, the quality and effectiveness of m...
Artificial intelligence (AI) refers to a system that can simulate and execute the processes of human thinking and learning, and make informed decisions. Fueled by the development of AI, the quality and effectiveness of medical work have gained momentum. AI technology plays an increasingly important role in healthcare, exhibiting substantial potential in clinical practice and decision-making processes. In Alzheimer's disease (AD), where early diagnosis and treatment remain challenging due to clinical heterogeneity and insidious progression, AI could offer excellent solutions. AI models can integrate multi-modal data to identify pre-symptomatic biomarkers and stratify high-risk cohorts, improving diagnostic accuracy, assisting with personalizing treatment and care. Furthermore, AI can accelerate drug discovery and development through drug-target identification and predictive modeling of compound efficacy. However, data quality, supervision, transparency, privacy, and ethical concerns need to be addressed. By identifying and retrieving studies for the systematic review, this article provides a comprehensive overview of current progress and related AI applications in AD.
Assessing Alzheimer's Disease Risk Among Latina/o/x Older Adults: A CART Analysis.
Moon SS, Boyas JF, Lee J
Curr Alzheimer Res · 2025 Oct · PMID 41126413 · Full text
INTRODUCTION/OBJECTIVE: Alzheimer's Disease (AD) presents a significant public health challenge in the U.S., with Latina/o/x elders being disproportionately affected. This study examines the key risk factors associated w...
INTRODUCTION/OBJECTIVE: Alzheimer's Disease (AD) presents a significant public health challenge in the U.S., with Latina/o/x elders being disproportionately affected. This study examines the key risk factors associated with AD in this population. METHODS: We analyzed data from the National Alzheimer's Coordinating Center (2017), focusing on 9,801 Latina/o/x older adults (32.7% males and 67.3% females). Statistical analyses conducted included Chi-square tests, t-tests, and Classification and Regression Tree (CART) analysis, which was used as the main statistical tool. RESULTS: The CART model, trained on 70% of the sample and tested on the remaining 30% (N = 9,801), identified seven terminal nodes and selected seven key predictors from 16 candidate variables. The model demonstrated modest discriminative ability (AUC = 0.68 for both training and test sets; misclassification error ≈ 36%). Sensitivity was 75%, while specificity was 55% in the test set. The most important predictors included age, education, smoking history, BMI, hypertension, and use of antidepressant or antipsychotic medications. A critical threshold emerged at < 5.5 years of education, which, in interaction with age and smoking, was associated with notably increased AD risk. CONCLUSION: This study emphasizes the crucial role of sociodemographic factors-particularly gender, age, and education-in determining AD risk among Latina/o/x elders. CART analysis identified key thresholds for age and education levels impacting AD risk. The findings suggest the need for targeted interventions and policies, with a focus on education and lifestyle factors, to mitigate AD risk in this vulnerable population.
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