Genetic and physiological basis of Alzheimer’s disease: A review

Emerging diagnostic biomarkers and therapeutic targets in Alzheimer's disease

Alzheimer’s Disease and Cognitive Disorders: From Molecular Drivers to Multilevel Clinical Solutions

Abstract Alzheimer’s disease (AD) represents the leading cause of dementia worldwide, accounting for approximately 70% of all dementia cases, and is characterized by progressive cognitive decline arising from complex interactions among molecular, genetic, environmental, and systemic factors. This review integrates current mechanistic insights with evolving diagnostic and therapeutic approaches. Central pathogenic processes include amyloid-β (Aβ) aggregation, tau hyperphosphorylation and propagation, neuroimmune dysregulation, synaptic failure, and network-level circuit disruption. Genetic and epigenetic contributors such as APOE genotype, aging-related inflammatory signaling, oxidative stress, and lifestyle-associated risk factors further modify susceptibility and disease trajectory. Recent advances in fluid biomarkers, amyloid and tau molecular imaging, and digital phenotyping—such as AI-driven cognitive assessments, gait analysis, voice analytics, and passive activity monitoring—have improved early detection and patient stratification. Emerging therapeutic strategies include disease-modifying agents, neuroprotective interventions, neurotrophin mimetics, and hormesis-based lifestyle approaches such as structured exercise, caloric modulation, and intermittent fasting. Precision-medicine trial designs and biomarker-guided therapeutic selection are transforming clinical research. At the clinical and public health level, caregiver-centered care models, community-based support systems, and multidomain prevention strategies emphasize the need for equitable, culturally informed dementia care. Future progress will depend on large-scale, diverse cohort studies, multi-omics integration, single-cell brain atlases, and AI-supported neuropathology pipelines to enable prevention and intervention during the preclinical window. This review highlights the importance of bridging mechanistic research with real-world clinical practice to generate impactful diagnostic, therapeutic, and policy outcomes. Keywords: Alzheimer’s disease, amyloid-β and tau pathology, neurodegeneration, biomarkers and digital phenotyping, precision medicine.  

Alzheimer’s Disease in the Era of Geroscience: Mechanisms, Biomarkers, and Therapeutic Prospects

Alzheimer’s disease (AD) is the leading cause of dementia and a heterogeneous neurodegenerative disorder characterized by amyloid-β (Aβ) and tau pathology, impaired proteostasis, neurovascular dysfunction, maladaptive glial and immune responses, and synaptic dysfunction. Human genetic evidence supports an upstream role for Aβ. Anti-Aβ monoclonal antibodies substantially reduce amyloid burden and modestly slow clinical decline in early symptomatic AD. Continued decline despite plaque removal is consistent with ongoing downstream tau pathology, glial responses, and neuronal injury. This narrative review examines AD mechanisms, biomarkers, and therapeutic prospects from a geroscience perspective and applies the eight hallmarks of neurodegenerative diseases as an analytical framework. Advances in blood-based biomarkers, particularly plasma phosphorylated tau 217, may improve biological detection, but their clinical value depends on assay performance, intended use, and patient context. Gut dysbiosis and gut–brain communication are considered separately as candidate systemic modifiers because causal evidence in humans remains insufficient. The hallmarks are overlapping analytical categories, not independent primary causes, and their therapeutic relevance depends on disease stage and pathway activity. Future studies should establish which preventive strategies and biomarker-guided, stage-matched combination therapies improve clinically meaningful outcomes and identify the patients most likely to benefit.

Decoding the Genetic Basis of Alzheimer's Disease: A Comprehensive Review of Key Causal and Risk Genes, Pathological Mechanisms, Convergent Pathways, and Emerging Therapeutic Targets

Progress in multi-omics technologies, disease models using induced pluripotent stem cells (iPSC), gene editing with CRISPR-Cas9, and artificial intelligence (AI) analysis are likely to speed up the implementation of precision medicine for early diagnosis, risk prediction, and treatment of Alzheimer's disease.

Exploring the Multiple Pathogenic Mechanisms, Clinical Manifestations, Diagnostic and Therapeutic Dilemmas, and Research Frontiers of Alzheimer's Disease

With the rapid growth of the global aging population, the incidence of Alzheimer's disease (AD) has been increasing year by year. This progressive, irreversible and insidious neurodegenerative disease will lead to progressive cognitive deterioration, posing a major public health threat to seniors and bringing heavy burdens to families and society. However, its complex and multi-dimensional pathogenesis has not been fully clarified, and major bottlenecks still exist in early screening, accurate diagnosis, and radical treatment. This paper systematically reviews the progression of AD, categorizing it into three stages: the subjective cognitive decline, mild cognitive impairment and AD dementia and describes its progression from early latent symptoms to severe functional impairment in middle and late stages. Based on this, this article deeply analyzes the multiple and interrelated pathogenic mechanisms of AD from four dimensions: canonical amyloid-tau proteinopathy, cerebral metabolic dysfunction, cerebral white matter structural impairment and systemic inducing factors. The study summarizes current mainstream interventions, pointing out key dilemmas including delayed diagnosis, single-target therapeutic limitations, and comorbidity interference, and lack of curative drugs. Additionally, this paper reviews cutting-edge research fields: diabetes-associated pathological pathways, DTI imaging, AI-assisted diagnosis, gut-brain axis regulation, and new targeted treatments. The study shows that AD is a complex disease driven by multiple factors, systems and mechanisms, and a single intervention is difficult to overcome the current predicament. This paper offers a comprehensive theoretical reference for AD early warning, pathological mechanism research, precision diagnosis and treatment, and translational medical development.

Multimodal mechanistic pathways in Alzheimer’s disease: toward an integrated model of pathogenesis

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by β-amyloid plaques, tau tangles, synaptic dysfunction, and large-scale network failure. While the amyloid cascade hypothesis has dominated, emerging evidence suggests distinct yet interacting amyloid and tau trajectories influenced by genetic, vascular, metabolic, and inflammatory factors. Understanding this multimodal convergence is key to redefining AD pathogenesis. Following PRISMA 2020 guidelines, mechanistic studies published from January 2016 to August 2025 were reviewed from pubmed and the cochrane library. Eligible studies provided original data on molecular, cellular, or systems-level mechanisms of AD. Findings were synthesized across seven domains: amyloid, tau, neuroinflammation, synaptic dysfunction, mitochondrial stress, metabolic dysregulation, and genetics. Across 22 studies, evidence supports a shift from a linear amyloid model to a multidimensional framework. Amyloid and tau initiate independently but later interact to accelerate degeneration. APOE ε4 carriers show amyloid-driven disease, while non-carriers exhibit tau-dominant progression, with females showing higher vulnerability. fMRI and DTI reveal early Default Mode Network and white matter disruption. Biomarkers (Aβ42, tau, NfL, neurogranin, SNAP25) detect early changes, while mitochondrial and glial dysfunction and vascular-metabolic stress further modulate progression. AD emerges from converging genetic, molecular, and network-level abnormalities. A multimodal approach integrating imaging, fluid biomarkers, and genetics offers promise for early detection, risk stratification, and personalized multi-target therapies.