Open research questions in Alzheimer's disease research and treatments

What the literature leaves open

• The study identifies the challenge of integrating pathway information into polygenic risk scores. The challenge of selecting the most informative pathways for risk prediction is also identified. The study highlights the need for a unified approach to pathway definition and integration.

  Comparing pathway-informed polygenic risk score strategies on a multi-cohort evaluation of amyloid-β positivity · 2026 · DOI

• Demographic heterogeneity between cohorts, - Age differences between Aβ-negative individuals in AIBL and ADNI, - Limited generalizability due to cohort compositions

  Comparing pathway-informed polygenic risk score strategies on a multi-cohort evaluation of amyloid-β positivity · 2026 · DOI

• important limitations remain in anti-amyloid immunotherapies, - the amyloid cascade theory's ability to fully explain AD is debated

  Targeting amyloid-β pathology by chimeric antigen receptor astrocyte (CAR-A) therapy · 2026 · DOI

• further studies are needed to fully understand the potential of CAR-A therapy, - investigation of the long-term effects of CAR-A therapy

  Targeting amyloid-β pathology by chimeric antigen receptor astrocyte (CAR-A) therapy · 2026 · DOI

• Investigate the underlying mechanisms of the association between NLR and cognitive decline - Examine the association between NLR and cognitive decline in other populations - Explore the use of NLR as a biomarker for cognitive decline

  Neutrophil-to-lymphocyte ratio predicts early cognitive decline associated with tau pathology in Alzheimer’s disease: a longitudinal study of the ADNI cohort · 2026 · DOI

• One challenge is the limited understanding of the precise mechanism by which Aβ contributes to vascular injury and neurodegeneration. Another challenge is the complexity of the Aβ–senescence–microglia axis. A technical challenge is the difficulty in directly examining the processes involved in BAM subsets.

  Border-Associated Macrophage Migrasomes in Alzheimer’s Disease: An Emerging Aβ–Senescence–Microglia Axis? · 2026 · DOI

• Most causal steps remain derived from cell and mouse experiments, - Direct evidence for BAM-derived migrasomes in human AD brain tissue is not yet available, - The review focuses on a pathological axis in which persistent vascular Aβ40 and aging-related stress shift clearance-competent BAMs toward oxidative-stress and senescent-like states, - Human evidence is currently strongest for CAA rather than parenchymal AD

  Border-Associated Macrophage Migrasomes in Alzheimer’s Disease: An Emerging Aβ–Senescence–Microglia Axis? · 2026 · DOI

• Suboptimal pharmacokinetics and off-target actions of current REV-ERB agonists. Limited understanding of the intrinsic rhythmicity of REV-ERB signaling and how to exploit it therapeutically. Need for brain-penetrant ligands and rational combinations to optimize the translational potential of REV-ERB-targeted therapies.

  REV-ERBs as regulators of circadian rhythm, neuroinflammation, and glial lipid homeostasis in Alzheimer’s disease. A narrative review · 2026 · DOI

• Current compounds are limited by suboptimal pharmacokinetics and off-target actions, - SR9009 and SR9011 display relatively short plasma half-lives, - Modest receptor affinity constrains their translational potential

  REV-ERBs as regulators of circadian rhythm, neuroinflammation, and glial lipid homeostasis in Alzheimer’s disease. A narrative review · 2026 · DOI

• The role of Icariside II in regulating mitochondrial dysfunction-related neuronal injury is not fully clarified. The mechanisms by which Icariside II exerts its neuroprotective effects are not well understood.

  Icariside II protects against neuronal injury by modulating PI3K/AKT-dependent mitochondrial dynamics and apoptosis in Alzheimer’s disease models · 2026 · DOI

• , Mfn2 knockdown or enforced Drp1 activation) are warranted to determine whether restoration of mitochondrial dynamics is indispensable for the neuroprotective effects of ICS II.

  Icariside II protects against neuronal injury by modulating PI3K/AKT-dependent mitochondrial dynamics and apoptosis in Alzheimer’s disease models · 2026 · DOI

• Investigate the role of other oral pathogens in AD pathogenesis - Explore the mechanisms by which gut dysbiosis contributes to AD development and progression - Study the long-term effects of SARS-CoV-2 on neuroinflammation and cognitive function

  Exploring the role of infectious pathogens in Alzheimer’s disease neuroinflammation · 2026 · DOI

• The development of more accurate, effective, and human-relevant models to combat AD

  Beyond Transgenic Mice: Emerging Models and Translational Strategies in Alzheimer’s Disease · 2025 · DOI

• current experimental models have limitations in fully replicating the complexity of human AD - the majority of murine models are based on familial AD mutations, which represent only a small fraction of human cases - significant anatomical and physiological differences exist between murine and human brains

  Beyond Transgenic Mice: Emerging Models and Translational Strategies in Alzheimer’s Disease · 2025 · DOI

• clarify the role of LLPS in tau aggregation, - unveil the structural features of soluble tau aggregates, - understand the involvement of 'fuzzy coat' regions in oligomer and fibril formation

  The Enigma of Tau Protein Aggregation: Mechanistic Insights and Future Challenges · 2024 · DOI

• Identifying potential candidate SNPs as risk factors for disease etiology is challenging due to the difficulty in meeting the significance threshold (p-value < 0.05). Understanding the causal genetic variants and genes influencing AD risk at susceptible loci remains limited. Attributing heritability to the identified loci is still ambiguous.

  Comprehensive Overview of Alzheimer’s Disease: Etiological Insights and Degradation Strategies · 2024 · DOI

• attributing heritability to genetic loci is still ambiguous, - understanding the causal genetic variants and genes influencing AD risk remains limited, - only a few genes have been extensively studied in AD patients, - the significance threshold for single nucleotide polymorphisms was difficult to meet

  Comprehensive Overview of Alzheimer’s Disease: Etiological Insights and Degradation Strategies · 2024 · DOI

• The paper identifies a gap in the understanding of the etiopathogenesis of Alzheimer's disease and the role of tunneling nanotubes in the spread of pathological proteins. It highlights the need for further research on TNTs and their potential as a target for therapy. The paper also notes that current AD treatments focus on alleviating symptoms, and that intensifying research on TNTs could bring scientists closer to a better understanding of AD and the development of effective therapies.

  Potential Mechanisms of Tunneling Nanotube Formation and Their Role in Pathology Spread in Alzheimer’s Disease and Other Proteinopathies · 2024 · DOI

• The high economic cost of AD diagnosis and treatment. The lack of effective diagnosis and treatment methods for AD. The need to understand the molecular mechanisms of RET's effects on AD.

  Resistance Exercise Training as a New Trend in Alzheimer’s Disease Research: From Molecular Mechanisms to Prevention · 2024 · DOI

• the lack of an effective method to diagnose patients, - the high costs of diagnosis and treatment, - the high impact of this pathology on the quality of life of patients and their caregivers

  Resistance Exercise Training as a New Trend in Alzheimer’s Disease Research: From Molecular Mechanisms to Prevention · 2024 · DOI

• The frequent coexistence of -synuclein (-syn) and amyloid-{beta} (A{beta}) aggregates in neurodegenerative diseases suggests that heterotypic interactions between these amyloidogenic proteins may influence disease progression, yet their molecular consequences remain poorly understood.

  Aβ42-Driven α-synuclein Fibril Polymorphism and Distinct Intracellular Aggregation · 2026 · DOI

• The findings motivate further study of mitochondrial antioxidant defense in tau-associated astrocyte dysfunction.

  Soluble pathogenic tau transmission to astrocytes drives acute oxidative damage, cellular senescence, and neurovascular uncoupling in a model of Alzheimers tauopathy · 2026 · DOI

• Alzheimer's disease (AD) is characterized by the deposition of amyloid-beta (A{beta}) and microtubule-associated protein tau (MAPT) neurofibrillary tangles in the brain; however, the molecular mechanisms underlying associated synaptic dysfunction remain unclear.

  Autonomous AI-Driven Nanoscale Spatial Mapping Reveals Novel Targets and Ternary Architectures in 5xFAD Alzheimer's Disease Model · 2026 · DOI

• However, the role of the membrane-rich neuronal environment on the assembly and mechanics of full-length tau remains unclear.

  Neuronal lipid composition regulates distinct states of full-length tau assembly, mechanics and membrane interactions · 2026 · DOI

• Background The genetic architecture of Alzheimer disease remains incompletely understood.

  Heritability and rare variant contributions to Alzheimer disease in the Midwestern Amish · 2026 · 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
• 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
• Tyrosinase-induced neuromelanin accumulation triggers rapid dysregulation and degeneration of the mouse locus coeruleus · bioRxiv · 2026
• Head-to-head comparison of brain-derived pTau217 and total pTau217 for brain amyloid and tau pathology classification · Proceedings of the National Academy of Sciences · 2026
• Human microglial transitions at the Aβ–tau inflection point associate with divergent pathways to dementia and resilience · Nature Medicine · 2026
• Metal nanocomposites for biosensing amyloid beta peptides: Advancing point-of-care diagnostics in Alzheimer's disease · Coordination Chemistry Reviews · 2026
• Association of [ 18 F]Flortaucipir–PET and Plasma p-Tau217 With Tau Neuropathology in Alzheimer Disease and Other Neurodegenerative Disorders · Neurology · 2026
• Arc mediates intercellular tau transmission via extracellular vesicles · Cell · 2026

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