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Open research questions in Alzheimer's disease research and treatments

113 unresolved questions extracted from the limitations and future-work sections of 627 Alzheimer's disease research and treatments papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • A role for the trafficking receptor SORLA (Sortilin-related receptor containing LDLR class A repeats) in reducing Aβ levels has been well established; however, relatively little is known with respect to whether and how SORLA can potentially affect tau pathology in vivo.

    SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain · 2026 · DOI

  • It has long been established that the flux through the PPP is downregulated in AD; however, the specific enzy- matic determinants underlying this impairment remain incompletely characterized.

    Transaldolase 1 contributes to pentose phosphate pathway disruption and synaptic dysfunction in Alzheimer’s disease · 2026 · DOI

  • Regarding the molecular mechanisms specific to this model, the role of the Nrf2-ARE pathway in mediating zinc's antioxidant action has not been analyzed in the context of combined estrogen deficiency and D-galactose-induced oxidative stress.

    Zinc as a Neuroprotective and Antioxidant Strategy in an Alzheimer-like Rat Model Induced by Ovariectomy and D-Galactose: A Clinicopathological and Therapeutic Review · 2026 · DOI

  • Among these, ap- proximately 25 APP mutations have been identified as pathogenic (27), although their precise pathogenic mecha- nisms remain incompletely understood.

    A Cerebral Organoid Model of Familial Alzheimer’s Disease Using Amyloid Precursor Protein Mutation, Val669Leu ( <i> APP <sup>Seoul</sup> </i> ) · 2026 · DOI

  • A recent study demonstrated that medium flow at approximately 10 μm/s reduces Aβ1-42 neurotoxicity in explant brain cultures containing neurons and beating ependymal cilia; however, the underlying mechanisms remain unclear.

    Cellular basis of medium flow-mediated reduction of Aβ neurotoxicity in cultured neurons · 2026 · DOI

  • Although improving mitochondrial function has been shown to rescue cognitive deficits in AD models, the underlying molecular mechanisms remain elusive.

    CAPNS1 restoration partially alleviates mitochondrial dysfunction and synaptic deficits in Alzheimer’s disease through the Ca2+-CaMKIIβ-MAPK-PGC-1α axis · 2026 · DOI

  • BackgroundLead (Pb) is associated with Alzheimers disease (AD); however, the relationships between Pb and AD hippocampal transcription remains unclear.

    Cell composition, transcriptomic, and functional pathway changes in the hippocampus in Alzheimer's disease and overlap with lead (Pb) exposure signatures · 2026 · DOI

  • ABSTRACT Background It is increasingly recognized that Alzheimer’s disease (AD) co-pathology contributes to dementia in PD, but its role in earlier stages of cognitive impairment remains uncertain.

    Association Between Plasma Phosphorylated Tau‐217 and Cognition in Parkinson's Disease · 2026 · DOI

  • AQP4 modulates water influx and efflux in the interstitial fluid, yet how AQP4 localization impacts cerebral amyloid angiopathy (CAA) remains poorly understood.

    Aquaporin-4 mislocalization from astrocyte endfeet prolongs survival in a prion-cerebral amyloid angiopathy model · 2026 · DOI

  • The amyloid precursor protein (APP), a central pathogenic factor in Alzheimers disease, retains physiological functions independent of amyloid production that remain poorly understood.

    The evolutionarily conserved APP-Spastin cooperation regulates endolysosomal homeostasis and apoptotic cell degradation · 2026 · DOI

  • This reveals a critical non-amyloidogenic function of APP in maintaining tissue homeostasis through efficient efferocytosis, with broad implications for inflammatory and neurodegenerative disorders that warrant further investigation.

    The evolutionarily conserved APP-Spastin cooperation regulates endolysosomal homeostasis and apoptotic cell degradation · 2026 · DOI

  • Urinary incontinence (UI) is a common and debilitating comorbidity in Alzheimers disease (AD), yet its underlying pathophysiology remains poorly defined.

    Amyloid-beta is present in the spinal cord of APP/PS1 mice and may contribute to neuropathology manifesting as lower urinary tract dysfunction · 2026 · DOI

  • Background: Alzheimer's disease (AD) involves complex molecular alterations in the cerebrospinal fluid (CSF) proteome, yet the links between these protein changes and hallmark AD pathology remain incompletely defined.

    Biomarker-informed CSF proteomics reveals ENPP2-LPA lipid signaling associated with Alzheimer's disease · 2026 · DOI

  • HLA-DR-restricted T-cell reactivity to amyloid {beta} (A{beta}) has been associated with Alzheimer's disease (AD), but structural evidence for HLA presentation of A{beta}-derived peptides remains elusive.

    Structural presentation of amyloid β by HLA · 2026 · DOI

  • Throughout the preclinical phase of Alzheimer's disease (AD) {beta}-amyloid (A{beta}) accumulates preferentially within the default mode network (DMN), yet the functional and behavioural consequences of this pathological burden remain poorly understood.

    Dopamine Compensates for Amyloid-Induced Default Mode Network Dysfunction to Support Learning · 2026 · DOI

  • duplicates the human brain environment that cannot be matched by 2D cell cultures (Prasannan et al., 2022; Whitehouse et al., 2025). Human fibroblast-derived 3D-cultured generated brain organoids show strong tau pathology and Aβ aggregation, and APOE ε4-expressing organoids have much higher quantities of Aβ42 protein than their 2D counterparts (Kim et al., 2024). The formation of a brain-like structure in 3D occurs when Matrigel contains its ECM components laminin and collagen, supporting neuronal development and synaptic formation and resulting in improved pathological representation (Massimi et al., 2020; Prasannan et al., 2022). AD-related symptoms are enhanced by 3D architecture because 3D organoids develop Aβ plaque formation and tau hyperphosphorylation at faster rates than control samples. Furthermore, thioflavin T-positive aggregates and phosphorylated tau (p-Tau) deposits exist together with neuronal markers in the same areas of the tissue (Kim et al., 2024; Korde and Humpel, 2024). The physical limits of 3D environments allow the investigation of Aβ plaque behavior by analyzing the geometric shape and the relationships with brain tissue and the spatial arrangement. APP/ PS1 transgenic mouse cerebellum using synchrotron X-ray phase contrast tomography demonstrates that Aβ plaques in 3D organoids develop into elongated shapes that follow the same patterns as human AD brain tissue (Massimi et al., 2020). The structural simplicity of 2D cultures prevents the modeling of plaque-tissue interactions because they do not possess the required spatial organization. Three-dimensional organoids enable the study of plaque formation and the cause of neuritic dystrophy and synaptic degeneration through pre- and post-synaptic marker colocalization and the progressive reduction of synaptic puncta density (Guido et al., 2023; Kim et al., 2024). The 3D system elucidates Aβ aggregation together with cellular stress responses, including oxidative stress and mitochondrial dysfunction, at higher complexity than 2D cultures because 3D cultures need more power to function while their physical boundaries exist (Park et al., 2023; Whitehouse et al., 2025). The 3D organoid system offers new solutions because it allows the use of patient-specific genetic data and enables the study of in different cell types to addresses key restrictions found conventional 2D cell culture models. Aβ accumulation and caspase-induced cell death is shown in 3D brain spheroids derived from iPSCs of AD patients, enabling the conduct of large-scale drug tests for neuroprotective compounds, including curcumin and nordihydroguaiaretic acid (Park et al., 2023).

    Modeling Alzheimer’s disease with brain organoids: mechanisms, applications, and future directions · 2026 · DOI

  • Qing Zhao 1,2, Songtao Li 1,2, Yanxiu Ju 1,2, Xiangyi Kong 2,3* and Xilin Liu 2,4* 1Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China, 2Engineering Laboratory of Memory and Cognitive Impairment Disease of Jilin Province, China-Japan Union Hospital of Jilin University, Changchun, China, 3Department of Vascular Surgery, China-Japan Union Hospital of Jilin University, Changchun, China, 4Department of Hand and Foot Surgery, China- Japan Union Hospital of Jilin University, Changchun, China Human pluripotent stem cell-derived brain organoids have emerged as a transformative platform for modeling Alzheimer’s disease (AD), thus addressing long-standing translational obstacles posed by the disease’s complex etiology and interspecies differences. This review systematically examines methodological advances in brain organoid technology, from basic fabrication and brain-regionspecific organoids to multicellular assembloids that incorporate microglia and vascular components, with an emphasis on strategies for overcoming fetal-like phenotypes. We surveyed literature published between 2018 and April 2026 that focused on human iPSC-derived organoid models that recapitulate core AD pathologies, including Aβ plaques, tau tangles, neuroinflammation, and blood–brain barrier dysfunction. Key findings demonstrate that organoids effectively capture genotype–phenotype relationships for major AD genes (APP, PSEN1, PSEN2, and APOEε4), enable the dissection of signaling pathway dysregulation (Wnt/β-catenin), and when combined with CRISPR editing and single-cell multi-omics, reveal cell-type-specific disease mechanisms. Organoids have also been successfully applied to patient-specific “avatar” models and high-throughput drug screening, thus advancing precision medicine approaches. However, current technological bottlenecks—including a lack of functional vascularization, batch-to-batch variability, and insufficient standardization—limit the full recapitulation of chronic, age-dependent AD pathology. This review critically evaluates these limitations, addresses ethical considerations surrounding neural organoids, and looks forward to future integration with artificial intelligence, spatial omics, and multi-organ systems to accelerate the translation of organoid-based discoveries into clinical applications. KEYWORDS 3D cell culture, Alzheimer’s disease, brain organoids, disease modeling, drug screening, induced pluripotent stem cells, neurodegenerative diseases, precision medicine Frontiers in Cell and Developmental Biology 01 frontiersin.org Zhao et al.

    Modeling Alzheimer’s disease with brain organoids: mechanisms, applications, and future directions · 2026 · DOI

  • This possibility is biologically plausible given the established contribution of complex I and complex III to mitochondrial superoxide production, but remains to be experimentally validated in the LOU hippocampus (Brand, 2016; Murphy, 2009), and with reports of reduced skeletal-muscle mitochondrial H₂O₂ production and oxidative-stress-related adaptations in the LOU strain (Garait et al.

    Proteomic signatures of cognitive resilience in LOU/c/Jall rats converge with inverse hippocampal axes of Alzheimer disease. · 2026 · DOI

  • Proteins frequently occupy multiple subcellular compartments as spatial proteoforms, yet the contribution of aberrant protein localization to AD pathogenesis remains poorly understood.

    Quantitation of Spatial Proteoforms in Alzheimer's Disease · 2026 · DOI

  • Hsp60 and Hsp10 form a mitochondrial chaperonin complex that folds dozens of AD-implicated mitochondrial proteins, but this client network has not been evaluated as an integrated proteostasis axis in AD.

    Mitochondrial Hsp60/10 Client Protein Decline Reveals Braak/Tau- and Cognition-Linked Proteostasis Vulnerabilities in Alzheimer's Disease · 2026 · DOI

  • PKA catalytic activity is regulated by two nonredundant regulatory subunits, Type I (RI/RI{beta}) and Type II (RII/RII{beta}), whose divergent functions are not fully understood.

    Selective knockout of PKA regulatory subunits reveal opposite catalytic and metabolic consequences with implications for Alzheimer's disease · 2026 · DOI

  • While prior studies have implicated LRP1 in tau binding and internalization, the biochemical features of this interaction and its suitability for therapeutic targeting remain incompletely defined.

    High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction · 2026 · DOI

  • Based on accumulating evidence in recent years, the pathogenesis of Alzheimer’s disease (AD) is better conceptualized as a multifactorial, multilevel dynamic framework rather than a linear process driven by a single pathogenic factor [6,38,41]. Key contributors, including neuroinflammation, synaptic dysfunction, mitochondrial metabolic imbalance, and genetic susceptibility, are highly interconnected and mutually regulated, collectively shaping disease progression across different stages [3,16,18,20,21]. A single hypothesis is no longer sufficient to explain the marked heterogeneity observed in AD in terms of clinical manifestations, pathological burden, and treatment responses [1,19,43]. Increasing evidence from the limited efficacy of Aβ-targeting therapies, along with advances in understanding immune and metabolic dysregulation, suggests that AD more closely reflects a state of systemic neuronal network dysfunction [35-39,3,16]. This multifactorial framework also provides important implications for diagnosis and treatment. Emerging approaches, such as blood-based biomarkers, enable clinicians to assess Aβ deposition and tau pathology more precisely [22- 27], while therapeutic strategies should align with disease stage and dominant pathological drivers, favoring multi-target interventions over single-target approaches [40,42,43]. Looking forward, a central objective of future AD research is to further refine this multifactorial framework by integrating diverse lines of evidence and clarifying the interactions and synergistic effects among key pathological processes [27,41]. Such efforts will help establish a more structured, mechanism-based approach to diagnosis and treatment, moving beyond empirical symptom management toward precision intervention. references 1. Blennow K, de Leon MJ, Zetterberg H, et al. Alzheimer’s disease. Lancet. 2006;368:387–403. 2. World Health Organization. Dementia. 2025. Available from: https://www.who.int/zh/news-room/fact-sheets/detail/dementia 3. H e n e k a M T, E l K h o u r y J, Wy s s - C o r a y T, e t a l. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14(4):388–405. 4. Frisoni GB, Hansson O, Nichols E, et al. New landscape of the diagnosis of Alzheimer’s disease. Lancet. 2025;406:1389– 1407. 5. Howard R, McShane R, Lindsay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N Engl J Med. 2012;366:893–903. 6. Kepp KP, Robakis NK, Høilund-Carlsen PF, et al. The amyloid cascade hypothesis: an updated critical review. Brain. 2023;146(10):3969–3990. 7. Povala G, Bellaver B, Bastiani MAD, Ferrari-Souza JP, et al. Amyloid beta and tau are associated with the dual effect of neuroinflammation on neurodegeneration. Alzheimers Dement. 2025 Oct;21(10):e70746. 8.

    Multifactorial Pathogenesis, Diagnosis, and Therapeutic Strategies in Alzheimer’s Disease · 2026 · DOI

  • Clinical research in Alzheimer’s disease (AD) has become increasingly biomarker-driven; however, the biomarker natural history of EOAD-particularly in pedigrees car- rying pathogenic APP variants-remains insufficiently characterized [12].

    Clinical, neuroimaging, and biomarker profiling of four Alzheimer’s disease pedigrees caused by pathogenic APP variants · 2026 · DOI

  • Previous studies linked the non-WT expression of the TACR3 variant rs2765 with cognitive decline and reduced volume of the hippocampus and basal forebrain, but systematic replication and mechanistic validation were lacking.

    TACR3 variant confers resilience to aging and Alzheimer's disease · 2026 · DOI

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113 open questions have been extracted from the limitations and future-work passages of 627 Alzheimer's disease research and treatments papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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