Open research questions in Alzheimer's disease research and treatments
1,688 gap statements mined from Alzheimer's disease research and treatments papers in our 7.9M-paper local library, which holds 6,534 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.
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What the literature leaves open
The relationship between amyloid removal and clinical benefit remains debated. The review does not resolve the question of whether successful amyloid clearance from the brain translates into clinically meaningful effects.
Amyloid-beta-targeting monoclonal antibodies in early Alzheimer’s disease: a cochrane review summary and appraisal for the neurological community · 2026 · DOIThe molecular events that translate systemic metabolic dysfunction into selective interneuron vulnerability in Alzheimer's disease remain incompletely defined. The study aims to fill this gap by investigating cuproptosis effector genes in the human Alzheimer's disease cortex.
A Lipoylation–PDH–TCA Transcriptional Deficit in the Alzheimer’s Disease Cortex — Donor-level Multi-cohort Evidence with Neuronal-composition, Disease-specificity and Matched-null Controls · 2026 · DOIThere is a need to characterize the key components of the exposome associated with the onset of major neurodegenerative diseases. The current state of knowledge on the relationship between neurodegenerative diseases and environmental risk factors is not fully understood.
Neurodegenerative diseases and environmental risk factors: an overview of the available scientific evidence · 2026 · DOIThe specific mechanisms linking dietary salt to neurological pathology remain incompletely understood. The relationship between mitochondrial dysfunction and neurodegeneration is not fully elucidated. The effects of a high-salt diet on cognitive function and amyloid-β accumulation are not well understood.
Dietary high salt drives cognitive impairment and Aβ accumulation via an insufficient compensatory mitophagy response · 2026 · DOIThe delivery of brain peptides across the blood-brain barrier is a major challenge. The rapid proteolytic degradation and short plasma half-life of peptides constrain chronic dosing regimens. The study identifies the need for specialized delivery systems to achieve therapeutic concentrations of brain peptides in relevant brain regions.
The effects of Ishige foliacea extracts on pathological tau phosphorylation remain poorly characterized. There is a need to investigate the neuroprotective and cognition-modulating effects of KDC22-01.
Ishige foliacea Water Extract (KDC22-01) Attenuates Tau Hyperphosphorylation and Ameliorates Scopolamine-Induced Memory Impairment in Mice · 2026 · DOIThe lack of standardization in the literature makes it difficult to compare results across different studies. The need for state-resolved evaluation standards and prioritized hypotheses for the effects of polyphenols poses a significant challenge.
Conformation- and Timing-Resolved Effects of Natural Polyphenols on Amyloid-β: An Evidence-Graded Synthesis and Design Considerations · 2026 · DOIThe effects of natural polyphenols on amyloid-β aggregation are not fully understood. The literature lacks a comprehensive integration of cell-free, cellular, animal, and simulation studies. There is a need for state-resolved evaluation standards and prioritized hypotheses for the effects of polyphenols.
Conformation- and Timing-Resolved Effects of Natural Polyphenols on Amyloid-β: An Evidence-Graded Synthesis and Design Considerations · 2026 · DOIThe formation of amyloid proteins is highly dependent on many factors, such as pH, temperature, concentration, and ionic strength. The blood-brain barrier poses a challenge for the delivery of therapeutic agents to the brain. The development of effective photothermal and photodynamic strategies for AD diagnosis and therapy requires further research.
Photothermal and Photodynamic Strategies for Diagnosis and Therapy of Alzheimer’s Disease by Modulating Amyloid-β Aggregation · 2025 · DOIConventional diagnostic methods are expensive and complex. There is a need for point-of-care biosensing technology for early detection of Alzheimer's Disease biomarkers. Existing two-dimensional graphene-based electrochemical biosensors have limitations in antibody immobilisation efficiency.
Electrochemical Detection of Aβ42 and Aβ40 at Attomolar Scale via Optimised Antibody Loading on Pyr-NHS-Functionalised 3D Graphene Foam Electrodes · 2025 · DOIFurther research to explore the potential of intrathecal pseudodelivery in treating Alzheimer's disease.
Targeting Soluble Amyloid Oligomers in Alzheimer’s Disease: A Hypothetical Model Study Comparing Intrathecal Pseudodelivery of mAbs Against Intravenous Administration · 2025 · DOILimited brain penetration of traditional intravenous monoclonal antibodies. Risks associated with intravenous monoclonal antibodies such as amyloid-related imaging abnormalities. Need for a novel method to target soluble amyloid-β oligomers in Alzheimer's disease.
Targeting Soluble Amyloid Oligomers in Alzheimer’s Disease: A Hypothetical Model Study Comparing Intrathecal Pseudodelivery of mAbs Against Intravenous Administration · 2025 · DOIThe limited efficacy of existing therapeutic strategies for Alzheimer's disease. The need to improve blood-brain barrier permeability and optimize drug delivery systems. The lack of understanding of the potential of marine natural products in treating Alzheimer's disease.
The Advancements of Marine Natural Products in the Treatment of Alzheimer’s Disease: A Study Based on Cell and Animal Experiments · 2025 · DOIThe paper identifies the limited regenerative capacity of the central nervous system as a challenge. It notes the complexity of neurodegenerative diseases, which have genetic, environmental, and multifactorial origins. The challenge is in developing therapeutic approaches that can address the complex molecular processes underlying neurodegenerative diseases.
Further research is required to overcome challenges related to the low oral bioavailability of phlorotannins and their limited ability to cross the BBB. Further studies based on both basic research and systems pharmacology are essential to clarify the underlying molecular mechanisms and support clinical translation. Further research is necessary to confirm the clinical utility of GTS-21 in AD.
Neurodegenerative disorders are complex and multifactorial, making it challenging to develop effective therapeutic options. The progression of neurodegenerative disorders is often slow, making it difficult to assess the efficacy of treatments. The paper highlights the need for further research into the role of neuroinflammation in neurodegenerative disorders.
Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications · 2024 · DOIExperimental follow-up on the perturbational connectivity score is suggested - Further research on the molecular events that translate systemic metabolic dysfunction into selective interneuron vulnerability…
A Lipoylation–PDH–TCA Transcriptional Deficit in the Alzheimer’s Disease Cortex — Donor-level Multi-cohort Evidence with Neuronal-composition, Disease-specificity and Matched-null Controls · 2026 · DOIThe focus on the hippocampus means that other brain regions affected by AD were not examined - The sample size was limited due to the high intensity of manual analysis required for sub-regional analyses - Background noise could still have affected the results - The study did not differentiate between diffuse amyloid and amyloid lakes - The image analysis pipeline did not include markers or morphological criteria…
Advanced quantitative mapping of Alzheimer’s disease neuropathology and microglial activation in post-mortem hippocampal tissue · 2026 · DOIInvestigation of downstream mechanisms, - Development of more effective and safe amyloid-targeting therapies, - Research on the durability of benefit beyond 18…
The evolving landscape of amyloid-targeting therapies in Alzheimer’s disease: progress and challenges · 2026 · DOIThe complexity of ligand binding to amyloid fibrils - The need to account for ligand size and cooperativity - The challenge of determining the lattice binding site concentration in binding…
Three Distinct Binding Modes Govern High-Affinity Ligand Interactions with Amyloid Fibrils · 2026 · DOIThe poor understanding of how ligands bind to amyloid fibrils - The lack of a practical framework for determining the binding mode of ligands to amyloid fibrils - The need for improved binding affinities and characteristic fluorescence…
Three Distinct Binding Modes Govern High-Affinity Ligand Interactions with Amyloid Fibrils · 2026 · DOIRapid proteolytic degradation, short plasma half-life, and poor oral bioavailability constrain chronic dosing regimens, - The blood-brain barrier remains a major bottleneck, - Many neuropeptide systems are pleiotropic and widely…
Further investigation of KDC22-01 as a candidate functional-food ingredient for cognitive health. Studies on the long-term effects and potential side effects of KDC22-01. Investigation of the effects of KDC22-01 on other neurodegenerative diseases.
Ishige foliacea Water Extract (KDC22-01) Attenuates Tau Hyperphosphorylation and Ameliorates Scopolamine-Induced Memory Impairment in Mice · 2026 · DOIThe paper identifies the gap in understanding the behavioural impairments in the 5xFAD mouse model, - The gap in translating research findings into a deeper understanding of AD human conditions due to conflicting reports from different laboratories, - The need to assess the affinity between physiological/sensory malfunctions and behavioural impairments…
Development of new compounds capable of impeding the progression of the disease, - Exploration of novel areas such as glymphatic and lymphatic pathways, - Investigation of the potential molecular targets arising from various…
From Fundamentals to Innovation in Alzheimer’s Disease: Molecular Findings and Revolutionary Therapies · 2024 · DOI
Most-cited papers in Alzheimer's disease research and treatments
- The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics · Science · 2002 · 11,708 citations
- Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer's Disease in Late Onset Families · Science · 1993 · 7,530 citations
- Lecanemab in Early Alzheimer’s Disease · New England Journal of Medicine · 2022 · 4,739 citations
- Alzheimer's Disease Is a Synaptic Failure · Science · 2002 · 3,725 citations
- The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor · Nature · 1987 · 3,718 citations
- Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo · Nature · 2002 · 3,642 citations
- Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease · Nature · 1991 · 3,598 citations
- Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis · Science · 2003 · 3,569 citations
- Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice · Science · 1996 · 3,535 citations
- β-Secretase Cleavage of Alzheimer's Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE · Science · 1999 · 3,253 citations
Most recent work
- CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis · Cell · 2026
- Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer’s disease · Cochrane Database of Systematic Reviews · 2026
- Efficient amyloid-β degradation in Alzheimer’s disease using SPYTACs · Cell · 2026
- Targeting amyloid-β pathology by chimeric antigen receptor astrocyte (CAR-A) therapy · Science · 2026
- Molecular features of human pathological tau distinguish tauopathy-associated dementias · Cell · 2026
- A systems approach uncovers drivers of the multifocal emergence of an astrocyte state contributing to cognitive decline in Alzheimer's disease · bioRxiv · 2026
- Oxidative Stress and Lysosomal Dysfunction in Neurodegenerative Diseases: Underlying Mechanisms and Nanotherapeutic Targeting Strategies · Antioxidants · 2026
- Immunity in Alzheimer’s disease: From mechanisms to therapies · Immunity · 2026
- The liver as a metabolic and immune hub in Alzheimer’s disease: From mechanisms to therapeutic opportunities · The Journal of Prevention of Alzheimer s Disease · 2026
- Tyrosinase-induced neuromelanin accumulation triggers rapid dysregulation and degeneration of the mouse locus coeruleus · bioRxiv · 2026
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