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Open research questions in Dementia and Cognitive Impairment Research

363 unresolved questions extracted from the limitations and future-work sections of 3,284 Dementia and Cognitive Impairment Research papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The brain-predicted age difference (brain-PAD) has emerged as a promising biomarker to quantify these alterations, yet its unique clinical contribution relative to conventional measures of global brain atrophy such as the brain parenchymal fraction (BPF) remains underexplored.

    The value of brain age as a transdiagnostic biomarker of neurodegeneration · 2026 · DOI

  • Magnetic resonance imaging-visible perivascular spaces in the centrum semiovale (CSO-PVS) have emerged as a potential imaging marker, although their relevance in amyloid-positive individuals without CAA-related hemorrhages remains uncertain.

    Enlarged Centrum Semiovale Perivascular Spaces as a Noninvasive Imaging Marker of Vascular Amyloid Deposition in Amyloid-Positive Individuals without Cerebral Amyloid Angiopathy-Related Hemorrhages. · 2026 · DOI

  • Future research should validate these findings in more diverse and rural populations and evaluate the added value of informant reports, which show closer alignment with objective impairment (1) and may reduce false positives17,39. It remains unclear why GPs perform limited dementia-specific diagnostic work despite guideline familiarity (45, 46), with possible explanations including time constraints, reimbursement barriers, diagnostic uncertainty and concern about early labeling49–51. Community detection alone is insufficient without coordinated downstream diagnostic action. Co-managed models linking community providers and GPs may bridge this gap. Longitudinal validation of multimodal clusters and cost-effectiveness analyses will be essential for establishing practical value12. Future adaptations should prioritize simplicity, feedback integration and referral mechanisms that align with primary care workflows. Ultimately, early detection must translate into personally meaningful outcomes for older adults and their families52. This includes supporting informed decision-making, promoting access to timely diagnostic evaluation and care, and enabling individuals to engage in preventive actions while autonomy and daily functioning can still be preserved. Community-based detection can serve as a first step in this process, but only if it is embedded within coordinated pathways that ensure continuity from screening to meaningful clinical follow-up.

    Adaptive pathways for multimodal community-based detection of cognitive impairment: the CogScreen I study · 2026 · DOI

  • Future studies should refine problematic items, expand validation to more diverse samples (including caregivers and the general population), and test the ADKS-P in intervention contexts to evaluate its sensitivity to change. Comparative work with alternative tools such as the DKAS would also clarify the strengths and limitations of the ADKS framework in Persian-speaking settings. Incorporating more advanced statistical approaches, such as parallel analysis or item response theory, would provide deeper insights into the scale’s dimensionality and item functioning.

    Validity and reliability of the Persian version of the Alzheimer’s Disease Knowledge Scale among Iranian healthcare professionals and students · 2026 · DOI

  • clearance in the long term, as the same neuro-immune acti- vation that produces early ARIA risk may also more thor- oughly strip vascular and parenchymal amyloid deposits. Understanding this trade-off between early risk and long- term benefit is essential for optimizing the BVCI-guided dosing algorithm, which must balance ARIA prevention against therapeutic efficacy. Second, the NPKST concept is not restricted to lec- anemab and donanemab. As additional anti-amyloid anti- bodies and other immunotherapy-based disease-modifying therapies for AD and related neurodegenerative conditions enter clinical development, the BVCI framework could provide a generalized pharmacodynamic phenotyping tool applicable across the class. The mechanistic similarities in ARIA pathophysiology across different anti-amyloid agents suggest that velocity signatures identified for lecanemab may be transferable, with agent-specific recalibration of biomarker weights and thresholds. Third, the intersection of the NPKST with advanced neu- roimaging-based BBB permeability quantification—par- ticularly dynamic contrast-enhanced MRI (DCE-MRI) with kinetic modeling of BBB permeability parameters—repre- sents a powerful convergent validation approach (Sun et al. 2025). Patients with High BVCI could undergo DCE-MRI to directly visualize BBB permeability corresponding to their biochemical velocity signature, providing mechanistic confirmation and potentially identifying brain regions most at risk for focal ARIA. Fourth, the glymphatic and perivascular drainage axis should be explored as a modifiable risk factor in the NPKST framework (Bonnar et al. 2025). Evidence that lymphatico- venous anastomosis surgery enhances meningeal lymphatic drainage and reduces amyloid accumulation in mouse mod- els, along with preliminary human data suggesting cognitive improvement following surgical augmentation of cervical lymphatic drainage, raises the possibility that augmenting perivascular drainage capacity before anti-amyloid therapy could attenuate ARIA risk by increasing the system’s toler- ance for rapid amyloid mobilization (Chen et al. 2025). If validated, BVCI-identified High Velocity patients might be candidates for perivascular drainage augmentation strate- gies, pharmacological or procedural, before full therapeutic dose escalation.

    Biomarker Based ARIA Stress Test: A Proposed Conceptual Framework for Dynamic Biomarker-Guided ARIA Risk Stratification in Anti-Amyloid Immunotherapy for Alzheimer’s Disease · 2026 · DOI

  • Careful evaluation of algorithm performance is warranted in different EMR systems, as ICD coding practices vary by institution, as demonstrated by this comparison of VA EMR and CMS data.

    Chart review and genetic validation of electronic medical record dementia diagnoses in VA: The impact of CMS data · 2026 · DOI

  • Magnetic Resonance Imaging (MRI) derived brain age varies substantially between individuals, but it remains unclear whether early deviations from normal brain ageing precede future cognitive decline and whether they provide predictive value beyond conventional MRI measures.

    Elevated BrainAGE precedes cognitive impairment and improves prediction of future cognitive decline · 2026 · DOI

  • MeaningBecause of the differential effects of risk factors on the underlying AD pathophysiology, a one-size-fits-all approach to AD risk prediction and prevention is insufficient.

    Orthogonal Contributions of Genetic, Clinical, and Social Determinants of Health Risk Burdens on Alzheimer's Disease Pathophysiology · 2026 · DOI

  • ImportanceAlzheimers disease (AD) arises from complex interactions among genetic, clinical, and social determinants of health (SDoH) risk factors, yet their independent contributions to underlying AD pathophysiology remain elusive.

    Orthogonal Contributions of Genetic, Clinical, and Social Determinants of Health Risk Burdens on Alzheimer's Disease Pathophysiology · 2026 · DOI

  • Adiponectin (APN), an adipokine with anti-inflammatory and neuroprotective properties, has been implicated in both conditions, yet its role in the comorbid state remains unclear.

    Serum adiponectin and cognitive function in Alzheimer’s disease with comorbid depression · 2026 · DOI

  • Introduction Obesity and low handgrip strength (HGS) have both been associated with cognitive impairment and dementia, but their combined association remains unclear.

    The joint association of obesity and low handgrip strength with cognitive impairment and probable dementia: a cross-sectional study · 2026 · DOI

  • A sensitivity analysis was conducted in the subset with deeper clinical and lifestyle phenotyping [38] to assess whether additional covariate adjustment altered the primary single-SNP findings, but this analysis remained limited by the reduced sample size (n = 434), which lowered the detection threshold from effects explaining at least 1.

    Do common dopaminergic variants modulate processing speed in cognitive aging? A longitudinal candidate gene study · 2026 · DOI

  • These findings provide a roadmap for future research requiring enhanced statistical power, broader genetic coverage, and increased demographic diversity. Future studies must utilize substantially larger samples to detect subtle effects charac- teristic of highly polygenic traits. This is particularly critical for rare outcomes like post-mortem analyses, highlighting the need for larger, deeply phenotyped brain bank resources. Whole-genome sequencing would capture the full spectrum of variation, including rare variants and structural polymorphisms like the functional VNTRs in SLC6A3 and DRD4 unas- sessed here, while resolving inconsistent SNP coverage across genes. Research must move beyond static genetic data through longitudinal methods capturing change over time, including Epigenome-Wide Association Studies to map age-related epigenetic drift and analyses testing gene-environment inter- actions. The field should expand from single-pathway focus to systems-biology approaches, as dopamine is modulated by complex neurobiological networks. Future work should investigate interactions with BDNF [49,50], the glutamatergic system [51], the circadian system [52], and adjacent regulatory loci like the ANKK1 Taq1A polymorphism associated with reduced D2/3 receptor binding [53]. PLOS One | https://doi.org/10.1371/journal.pone.0353790 July 17, 2026 14 / 19 The ideal future study would combine WGS, longitudinal deep phenotyping, and in-vivo brain imaging within large, diverse cohorts, enabling causal inference methods like Mendelian randomization to test pathways from genetic variation through brain biology to cognitive decline.

    Do common dopaminergic variants modulate processing speed in cognitive aging? A longitudinal candidate gene study · 2026 · DOI

  • 5 SD) baseline p-tau217 had 24% (95% CI, 20%-28%) and 38% (95% CI, 33%-43%) absolute risk of progression over 5 years, respectively, and risk was markedly higher over 10 years, although longer-term estimates were constrained by limited data.

    Prognostic Value of Blood-Based P-Tau217 Levels for Progression to Cognitive Impairment · 2026 · DOI

  • The Montreal Cognitive Assessment (MoCA; 10–15 min) and Quick Dementia Rating System (QDRS; 3–5 min) are promising brief alternatives, although it remains unclear which tool performs better in discriminating between cognitive and functional impairment stages.

    A comparison of the Quick Dementia Rating System and Montreal Cognitive Assessment for detecting mild cognitive impairment and dementia assessed by the Clinical Dementia Rating Scale · 2026 · DOI

  • However, studies of the prevalence, incidence, and annual conversion proportions to mild cognitive impairment (MCI) and dementia are based on limited data, and results are heterogeneous.

    Estimates of Incidence and Prevalence of Conversions to Mild Cognitive Impairment and Dementia in Patients With Essential Tremor · 2026 · DOI

  • Although previous studies have demonstrated an increased seizure risk in AD, the neuropathologic substrates underlying seizure susceptibility-particularly across dementia subtypes-remain incompletely understood.

    Neuropathologic Correlates of Seizures in Patients With Alzheimer Disease and Dementia With Lewy Bodies · 2026 · DOI

  • ImportanceApolipoprotein E (APOE) {varepsilon}4 is the strongest genetic risk factor for sporadic dementia, yet whether the benefits of intensive systolic blood pressure (SBP) control differ by APOE {varepsilon}4 carrier status remains unknown.

    Effect of Intensive vs Standard Blood Pressure Control According to APOE ε4 Genotype: A Secondary Analysis of SPRINT · 2026 · DOI

  • The clinical meaningfulness of statistical differences remains debated as minimal clinically important differences may not be achieved within 18-month trial windows.

    Efficacy of Anti-Amyloid Monoclonal Antibody Immunotherapy on Cognitive Progression in Alzheimer's Disease Patients : A Systematic Review of Randomized Controlled Trials and Primary Studies · 2026 · DOI

  • In this study, we proposed a hybrid deep learning framework combining ResNet152V2, CBAM, and Bi-GRU for automated classification of Alzheimer’s disease using MRI data alone. learning The model effectively integrates spatial and temporal mechanisms to capture both fine-grained structural changes and sequential inter-slice dependencies in neuroimaging data.

    A deep residual attention–Recurrent model for early and multi-stage Alzheimer's disease detection · 2026 · DOI

  • 17 This suggests that our exercise interventions did not influence AD-related brain microstructure, but it remains unknown whether longer interventions or other exercise modalities may affect these regions. Few studies have examined how exercise interventions influence AD brain signatures, and existing results are heterogeneous.

    Effects of high-intensity interval training with or without resistance training on Alzheimer's disease brain signatures in individuals with coronary artery disease: the Heart-Brain randomized controlled trial. · 2026 · DOI

  • The observed modulation of longitudinal cognitive decline supports further investigation of inflammatory pathways, including microglial and inflammasome signaling, as therapeutic targets in biomarker-defined AD populations.

    NSAID use is associated with lower dementia and Alzheimer disease prevalence and slower cognitive decline: A retrospective longitudinal analysis of the NACC cohort · 2026 · DOI

  • Background In neurodegenerative diseases, the diagnostic value of -synuclein seed amplification assay (SAA) in routine clinical practice and its relationship with cognitive performance and fluid biomarkers remains incompletely characterized.

    Routine implementation of α-synuclein Seed Amplification Assays reveals high diagnostic performance and the limited value of Alzheimer disease fluid biomarkers for detecting α-synuclein co-pathology · 2026 · DOI

  • Strengths and limitations of this studyO_LIThis study evaluates a digitally enabled remote monitoring model for people living with dementia that integrates passive in-home sensors and algorithm-derived digital biomarkers to detect clinically relevant changes such as infection risk, behavioural disturbance and physiological deterioration.

    MinderCare: protocol for a mixed-methods evaluation of a digitally enabled dementia care service. · 2026 · DOI

  • These findings suggest that A{beta}-PET accumulates along two orthogonal axes with biological and clinical relevance, indicating that the standard approach to assess A{beta}-PET is insufficient to capture meaningful signal from A{beta}-PET imaging.

    Characterisation of Posterior Predominant Amyloid PET Binding Across Multiple Cohorts · 2026 · DOI

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363 open questions have been extracted from the limitations and future-work passages of 3,284 Dementia and Cognitive Impairment Research 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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