Task: gap002 | Last Updated: 2026-03-15 | Kind: gap-analysis | Total Gaps Identified: 25
This page connects to the broader neurodegenerative disease knowledge graph:
Task: gap002 | Last Updated: 2026-03-15 | Kind: gap-analysis | Total Gaps Identified: 25
This page connects to the broader neurodegenerative disease knowledge graph:
This page identifies and prioritizes the top unanswered questions in [Alzheimer's disease](/diseases/alzheimers-disease) (AD) research. Gaps are ranked by their significance for understanding disease mechanisms, identifying therapeutic targets, and enabling clinical translation. Each gap is scored across four dimensions to guide research funding and focus.
Each knowledge gap is evaluated on four dimensions:
| Dimension | Score Range | What It Measures |
|-----------|-------------|------------------|
| Impact if Solved | 0-10 | Would solving this gap fundamentally change how we treat or prevent AD? |
| Tractability | 0-10 | Is this answerable with current technology, or does it require breakthroughs? |
| Current Effort | 0-10 | Inverted: High score = underexplored (few researchers working on this). Low score = crowded field. |
| Data Availability | 0-10 | Do we have the datasets, biobanks, models, or tools to study this now? |
Max score: 40 — Higher scores indicate gaps that are high-impact, understudied, and ready for investigation.
Impact: 10/10 | Tractability: 8/10 | Current Effort: 6/10 | Data Availability: 9/10
Why It Matters: CLARITY-AD showed lecanemab removes plaques but leaves substantial neurodegeneration unimproved[@van2023]. What else drives progression?
Hypothesis: Amyloid removal is insufficient because:
Impact: 10/10 | Tractability: 5/10 | Current Effort: 8/10 | Data Availability: 7/10
Why It Matters: Identifying the trigger point could enable prevention rather than treatment.[@jack2010]
Evidence: The amyloid cascade hypothesis posits that amyloid accumulation begins 15-20 years before clinical symptoms appear, with a critical threshold needed for downstream tau pathology and neurodegeneration[@bateman2012].
Key hypotheses to test:
Impact: 10/10 | Tractability: 6/10 | Current Effort: 7/10 | Data Availability: 8/10
Why It Matters: Resilience factors could reveal protective mechanisms and new therapeutic targets[@ritchie2024].
Related Pages: Cognitive reserve, Resilient neurons in AD, APOE variants
Impact: 10/10 | Tractability: 7/10 | Current Effort: 7/10 | Data Availability: 8/10
Why It Matters: Critical for validating tau as a therapeutic target.[@hansson2019]
Evidence: Tau PET imaging shows that tau burden correlates more strongly with cognitive decline than amyloid burden, supporting a causal role[@mallach2023].
Related Pages: Tau pathology pathway, Braak staging, Tau immunotherapy
Impact: 9/10 | Tractability: 7/10 | Current Effort: 8/10 | Data Availability: 7/10
Why It Matters: Microglial dysfunction appears early; understanding timing could enable immunomodulation[@ulland2017].
Related Pages: [TREM2](/genes/trem2) [microglia](/cell-types/microglia) pathway, Disease-associated [microglia](/cell-types/microglia), Innate immune signaling
Impact: 9/10 | Tractability: 6/10 | Current Effort: 8/10 | Data Availability: 6/10
Why It Matters: Entorhinal cortex and hippocampus are why could reveal susceptibility first affected; understanding factors.
Related Pages: Selective neuronal vulnerability, Entorhinal cortex neurons, Hippocampal CA1 neurons
Impact: 9/10 | Tractability: 6/10 | Current Effort: 7/10 | Data Availability: 7/10
Why It Matters: Precision medicine requires disease subtyping; could explain variable treatment responses.
Related Pages: [Alzheimer's disease](/diseases/alzheimers-disease) pathogenesis, Biomarkers, Early-onset AD
Impact: 8/10 | Tractability: 7/10 | Current Effort: 9/10 | Data Availability: 6/10
Why It Matters: Gut-brain signaling may modulate [neuroinflammation](/mechanisms/neuroinflammation); manipulable through diet/probiotics[@kowalski2024].
Related Pages: Gut-brain axis, Neuroinflammation, Microbiome
Impact: 9/10 | Tractability: 6/10 | Current Effort: 8/10 | Data Availability: 5/10
Why It Matters: Sex-specific factors (menopause, immune responses) may reveal protective strategies[@decourt2023].
Related Pages: Estrogen signaling, Modifiable risk factors
Impact: 8/10 | Tractability: 7/10 | Current Effort: 7/10 | Data Availability: 7/10
Why It Matters: Herpesviruses found in AD brains; could represent treatable infection component.
Related Pages: Infectious causes hypotheses, Neuroinflammation
Impact: 9/10 | Tractability: 8/10 | Current Effort: 5/10 | Data Availability: 8/10
Why It Matters: Temporal ordering (Aβ → tau → inflammation → neurodegeneration) guides intervention timing.
Related Pages: Amyloid cascade pathway, Biomarker temporal sequence, APP amyloid pathway
Impact: 9/10 | Tractability: 7/10 | Current Effort: 6/10 | Data Availability: 7/10
Why It Matters: CAA, white matter lesions, and CBF reduction interact with amyloid; underappreciated.
Related Pages: Vascular cognitive impairment, Neurovascular unit, Vascular risk factors
Impact: 8/10 | Tractability: 8/10 | Current Effort: 6/10 | Data Availability: 8/10
Why It Matters: [TREM2](/genes/trem2) R47H increases risk 3x; understanding could validate [microglia](/cell-types/microglia)l target[@ulland2017].
Related Pages: [TREM2](/genes/trem2) [microglia](/cell-types/microglia) pathway, [TREM2](/genes/trem2) agonist therapies, Microglia in AD
Impact: 9/10 | Tractability: 7/10 | Current Effort: 6/10 | Data Availability: 7/10
Why It Matters: Synapses lost early; whether this is cause or consequence determines therapeutic focus.
Related Pages: Synaptic plasticity deficits, Neuronal network dysfunction
Impact: 7/10 | Tractability: 6/10 | Current Effort: 7/10 | Data Availability: 6/10
Why It Matters: Iron, copper, zinc accumulate in plaques; may be cause or effect.
Related Pages: Metal ion homeostasis, Oxidative stress
Impact: 7/10 | Tractability: 6/10 | Current Effort: 5/10 | Data Availability: 7/10
Related Pages: Metal homeostasis, Protein aggregation
Impact: 8/10 | Tractability: 7/10 | Current Effort: 4/10 | Data Availability: 8/10
APOE4 carriers have increased risk for late-onset AD through effects on amyloid clearance, tau pathology, and [neuroinflammation](/mechanisms/neuroinflammation)[@yamazaki2024].
Related Pages: APOE4 and AD, APOE lipid metabolism
Impact: 7/10 | Tractability: 6/10 | Current Effort: 6/10 | Data Availability: 6/10
Related Pages: Chronic traumatic encephalopathy, Traumatic brain injury
Impact: 8/10 | Tractability: 9/10 | Current Effort: 3/10 | Data Availability: 8/10
Related Pages: Modifiable risk factors, Cognitive reserve
Impact: 10/10 | Tractability: 6/10 | Current Effort: 5/10 | Data Availability: 7/10
Related Pages: Preclinical AD, Disease-modifying therapies, Biomarkers
Impact: 8/10 | Tractability: 7/10 | Current Effort: 7/10 | Data Availability: 5/10
Why It Matters: Emerging evidence suggests LLPS drives [protein aggregation](/mechanisms/protein-aggregation); could reveal new therapeutic targets.
Related Pages: Liquid-liquid phase separation, Protein aggregation
Impact: 7/10 | Tractability: 6/10 | Current Effort: 6/10 | Data Availability: 6/10
Why It Matters: Astrocytes are increasingly recognized as key players in neurodegeneration.
Related Pages: Neuroinflammation, Cellular senescence
Impact: 8/10 | Tractability: 5/10 | Current Effort: 5/10 | Data Availability: 6/10
Why It Matters: Mitochondrial dysfunction is an early event in AD; therapeutic potential.
Related Pages: Mitochondrial dysfunction, ER-mitochondria contact sites
Impact: 7/10 | Tractability: 8/10 | Current Effort: 4/10 | Data Availability: 7/10
Why It Matters: Sleep disturbances precede cognitive decline; potential for early intervention.
Related Pages: Sleep and neurodegeneration, Circadian disruption
Impact: 7/10 | Tractability: 5/10 | Current Effort: 6/10 | Data Availability: 6/10
Why It Matters: Peripheral immune infiltration may contribute to [neuroinflammation](/mechanisms/neuroinflammation).
Related Pages: Peripheral immune infiltration, Adaptive immunity, Blood-brain barrier
| Gap # | Topic | Related Mechanisms | Related Cell Types | Related Treatments |
|-------|-------|-------------------|-------------------|-------------------|
| 1 | Amyloid removal efficacy | Amyloid cascade, Tau pathology | Cortical neurons | Anti-amyloid antibodies |
| 2 | Aging to AD switch | Vascular dysfunction, Microbiome | Multiple | Prevention strategies |
| 3 | Resilience | Cognitive reserve, APOE | Resilient neurons | N/A |
| 4 | Tau causality | Tau pathology, Prion-like spreading | Vulnerable neurons | Tau immunotherapy |
| 5 | Immune system timing | [TREM2](/genes/trem2), DAM, Neuroinflammation | Microglia | [TREM2](/genes/trem2) agonists |
| 6 | Selective vulnerability | Neuronal metabolism, Connectivity | Entorhinal, Hippocampal | N/A |
| 7 | Disease heterogeneity | Biomarkers, Genetics | Multiple | Precision medicine |
| 8 | Microbiome-gut-brain | Gut-brain axis, Inflammation | Enteric neurons | Probiotics, Diet |
| 9 | Sex differences | Estrogen, Immune response | Multiple | Hormonal therapy |
| 10 | Viral involvement | Neuroinflammation, Immunity | Multiple | Antivirals |
| 11 | Pathogenesis sequence | Biomarker cascade, APP | Multiple | Timing interventions |
| 12 | Vascular factors | NVU, CBF, CAA | Endothelial cells | Vascular therapies |
| 13 | [TREM2](/genes/trem2) variants | Microglial signaling | Microglia | [TREM2](/genes/trem2) modulators |
| 14 | Synaptic loss | Network dysfunction, Excitotoxicity | Synapses | Synaptic protectors |
| 15-25 | (Various) | Multiple | Multiple | Various |
This section tracks recent publications and advances addressing the knowledge gaps listed above.
Recent findings from 2025 conferences and publications:
The following diagram shows the key molecular relationships involving alzheimers-disease discovered through SciDEX knowledge graph analysis: