Alzheimer's disease

Overview

Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia in older adults. It is characterized clinically by gradual decline in memory, executive function, language, and other cognitive domains, and pathologically by accumulation of amyloid-β plaques, neurofibrillary tangles composed of hyperphosphorylated tau, synaptic dysfunction, neuroinflammation, mitochondrial impairment, and widespread neuronal loss. Olfactory dysfunction is also recognized as an early feature in many patients, and recent work continues to frame the disease as a clinical-biological continuum rather than a purely symptom-based diagnosis.

Biologically, Alzheimer’s disease is strongly linked to dysregulation of multiple pathways, including amyloid processing, tau homeostasis, microglial activation, astrocyte senescence, oxidative stress, autophagy, mitophagy, calcium signaling, insulin resistance, and lipid/metabolic dysfunction. Genetic and molecular studies have highlighted contributors such as apolipoprotein E4, TREM2, CD33, glycogen synthase kinase 3β, NLRP3 inflammasome signaling, and mitochondrial-associated membrane dysfunction. These mechanisms have made the disease a major target for biomarker development, disease staging frameworks, and multimodal therapeutic strategies, including anti-amyloid antibodies, tau-directed agents, GLP-1 receptor agonists, and repurposed metabolic or anti-inflammatory compounds.

Focus of Latest Publications

Recent publications portray Alzheimer’s disease as a highly active research target across diagnostics, biomarker validation, mechanistic biology, and therapy development. Several studies focused on blood-based biomarkers, including plasma p-tau217, p-tau/Aβ42 ratios, and remote capillary sampling, emphasizing their growing role in diagnosis, prognosis, and clinical stratification. One study reported that blood-based biomarkers are reliable indicators of Alzheimer disease-related pathology in cognitively normal individuals, while another examined their association with MRI-measured neurodegeneration. In very old adults, biomarker utility was explored with attention to clinical usefulness, reflecting ongoing uncertainty about how well biomarker-based frameworks generalize to advanced age. A separate study evaluated the revised biological and clinical staging criteria for Alzheimer disease in China, underscoring the move toward integrated staging across biological and clinical dimensions.

Imaging and digital diagnostics were also prominent. Amyloid PET remained central for diagnosis and treatment eligibility, including work on amyloid PET Z-score quantification, radiomics-enhanced 18F-AV45 PET/MRI, and signal reduction in prior ARIA-E regions after anti-amyloid therapy. Machine-learning approaches were used to improve early diagnosis, including a temporal graph learning model, ADGNET, and an AI-assisted 3D-printed hydrogel microneedle delivery concept. Another study used a combined neuronal extracellular vesicle-haematology panel for clinical stratification, reflecting interest in minimally invasive multimodal diagnostics. Olfactory electrophysiological biomarkers were investigated across cognitive states, consistent with olfactory dysfunction as an early symptom.

Therapeutic research in these studies was broad and largely preclinical, with many projects testing compounds or delivery systems in APP/PS1 mice, 5×FAD mice, 5 × FAD mouse models, HT22 cells, and other experimental systems. Anti-amyloid immunotherapy remained a major theme: aducanumab was examined neuropathologically, donanemab was assessed for clinical meaningfulness in early symptomatic disease, and lecanemab was discussed in relation to early Alzheimer disease and APOE ε4 status. A phase 3 trial of oral semaglutide in early-stage symptomatic Alzheimer’s disease and work on tirzepatide versus semaglutide in type 2 diabetes reflected growing interest in GLP-1 receptor agonists and metabolic modulation. Other repurposed agents included metformin, dexmedetomidine, lamotrigine, olmesartan, raltegravir, lithium, canagliflozin, and brexpiprazole, with studies generally reporting attenuation of pathology, improved cognition, or potential risk modification in experimental or observational settings.

Mechanistic studies repeatedly implicated amyloid-β, tau, neuroinflammation, and mitochondrial dysfunction. Several papers described suppression of microglial inflammation and inflammation-driven amyloidogenesis, inhibition of NF-κB and the NLRP3 inflammasome axis, restoration of autophagic pathways, and enhancement of lysosomal degradation of amyloid precursor protein. Astrocytic senescence, glial crosstalk around amyloid plaques, and microglial immune-metabolic homeostasis were also highlighted. Other studies linked Alzheimer’s disease to cuproptosis, ferroptosis, mitophagy, calcium signaling, mitochondrial dynamics, and blood-brain barrier transport via P-glycoprotein. These findings reinforce the view that Alzheimer’s disease is not driven by a single pathway but by interacting pathological cascades.

Metabolic and systemic associations were another recurring theme. Studies examined central and general adiposity, insulin resistance, homocysteine and methionine metabolism, diabetes comorbidity, and parity in postmenopausal women as modifiers of Alzheimer-related outcomes. The disease was also compared with Parkinson’s disease, postoperative delirium, vascular cognitive impairment, and other neurodegenerative conditions, often using shared biomarkers or cross-disease transcriptional programs. This reflects a broader effort to identify common neurodegenerative mechanisms, including microglial programs, mitochondrial dysfunction, and inflammatory signaling.

A substantial portion of the recent literature explored natural products, traditional formulations, and synthetic small molecules as candidate anti-Alzheimer agents. Examples included lawsone, icariin, oleanolic acid, genistein, parthenolide, diosgenin, ajugol, Ficus deltoidea extract, Schisandra chinensis preparations, Danggui Shaoyao San, Kai-Xin-San, Haikun Shenxi Capsule, and other herbal or phytochemical interventions. These studies commonly reported reductions in amyloid burden, tau hyperphosphorylation, oxidative stress, neuroinflammation, or mitochondrial dysfunction, with improved cognitive performance in animal models. Synthetic chemistry studies similarly focused on cholinesterase inhibitors, BACE1 inhibitors, RIPK1 inhibitors, carbonic anhydrase activators, and multitarget ligands designed to modulate amyloid, tau, metal dyshomeostasis, and oxidative stress simultaneously.

Several studies used Alzheimer’s disease as a proxy for neurodegeneration or as a model for broader therapeutic development. For example, one immuno-proteomic study used Alzheimer disease as a proxy of neurodegeneration, and another examined caspase-6 activation in a murine inflammation model to inform neurodegenerative disease therapies. Cross-disease analyses also linked Alzheimer-related biomarkers to Parkinson’s disease and postoperative delirium, while multi-omics and single-cell approaches were used to define molecular subtypes and identify candidate targets such as SPP1, GLELR-associated microglial programs, and TREM2-linked pathways. Overall, the recent literature emphasizes biomarker-driven staging, multimodal imaging, metabolic and inflammatory mechanisms, and increasingly sophisticated therapeutic strategies.

Key Publications

• NEWJun Noninvasive Electrophysiological Biomarkers of Olfactory Responses Across Cognitive States in Alzheimer Dementia: Cross-Sectional Study. (JMIR mHealth and uHealth, 2026, PMID 42335456): "Alzheimer disease (AD) is characterized by progressive cognitive decline, with olfactory dysfunction emerging among its earliest symptoms."
• Jun Immuno-Proteomic Features Associated to Relapse Risk in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease. (Neurology(R) neuroimmunology & neuroinflammation, 2026, PMID 42335444): "...and from Alzheimer disease (AD) as a proxy of neurodegeneration..."
• Jun Associations of Anthropometry Measures Across 35 Years With Late-Life Plasma P-tau217 and Dementia: The HUNT Study. (Neurology, 2026, PMID 42228892): "Central and general adiposity have been linked to dementia risk, but their relation to blood-based Alzheimer disease (AD) biomarkers is unclear."
• Jun Longitudinal Change in Blood-Based Biomarkers and the Association With MRI-Measured Neurodegeneration in Cognitively Unimpaired Individuals. (Neurology, 2026, PMID 42224636): "Blood-based biomarkers are reliable indicators of Alzheimer disease (AD)-related pathology in cognitively normal individuals."
• Jun Effect of Parity and β-Amyloid on Cognition and Hippocampal Volume in Postmenopausal Women. (Neurology, 2026, PMID 42330435): "Epidemiologic studies exploring the effect of parity on Alzheimer disease (AD) yield mixed results, and little is known about how parity may modify the impact of AD pathology on brain and cognitive aging."
• Jun Clinical Evaluation of the Revised Biological and Clinical Staging Criteria for Alzheimer Disease in China. (Neurology, 2026, PMID 42314105): "The 2024 revised criteria introduced an integrated framework for staging Alzheimer disease (AD) across biological and clinical dimensions."
• Jun Phase 2 Futility Trials in Alzheimer Disease and Mild Cognitive Impairment: A Cohort Analysis of the ADNI Data Set. (Neurology, 2026, PMID 42314102): "The cost and complexity of phase 2 randomized-controlled trials (RCTs) hinder further development of promising treatment candidates for Alzheimer disease (AD)."
• Jun Optimized detection of caspase-6 activation in a murine inflammation model to inform neurodegenerative disease therapies. (PloS one, 2026, PMID 42308231): "Caspase-6 (casp-6), is a member of the apoptotic family of caspases (cysteine aspartic proteases) and has been shown to be involved in several neurodegenerative diseases, including Alzheimer's disease."
• Jun Clinical Impact and Prognostic Value of Alzheimer Disease Biomarkers in the Very Old. (Neurology, 2026, PMID 42308436): "Alzheimer disease (AD) is increasingly viewed as a clinical-biological continuum, but the utility of biomarkers in individuals aged ≥80 years, the so-called 'very old,' remains uncertain, because of concerns about its clinical usefulness."
• Jun Radiomics-enhanced 18F-AV45 PET/MRI for integrative assessment and centiloid estimation of amyloid-β burden in Alzheimer's disease. (European radiology experimental, 2026, PMID 42313223): "Reliable assessment of cerebral amyloid-β (Aβ) deposition is essential for the diagnosis and management of Alzheimer's disease (AD)."