alzheimers-disease

Alzheimer's Disease Knowledge Gaps

Task: gap002 | Last Updated: 2026-03-15 | Kind: gap-analysis | Total Gaps Identified: 25

Cross-Linking Context

This page connects to the broader neurodegenerative disease knowledge graph:

Alzheimer's Disease Knowledge Gaps

Task: gap002 | Last Updated: 2026-03-15 | Kind: gap-analysis | Total Gaps Identified: 25

Cross-Linking Context

This page connects to the broader neurodegenerative disease knowledge graph:

• Diseases: [[Alzheimer's disease](/diseases/alzheimers-disease)](/diseases/alzheimers-disease), [[Parkinson's disease](/diseases/parkinsons-disease)](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), [FTD](/diseases/frontotemporal-dementia), [[Huntington's disease](/diseases/huntingtons-disease)](/diseases/huntingtons-disease), [PSP](/diseases/progressive-supranuclear-palsy), [MSA](/diseases/multiple-system-atrophy)
• Brain regions: [[substantia nigra](/brain-regions/substantia-nigra)](/brain-regions/substantia-nigra), [striatum](/brain-regions/striatum), [motor cortex](/brain-regions/motor-cortex), [hippocampus](/brain-regions/hippocampus), [frontal cortex](/brain-regions/prefrontal-cortex)
• Cell types: [[dopaminergic neurons](/cell-types/mesencephalic-dopaminergic-neurons)](/cell-types/mesencephalic-dopaminergic-neurons), [[astrocytes](/cell-types/astrocytes)](/cell-types/[astrocytes](/cell-types/astrocytes)), [[microglia](/cell-types/microglia)](/cell-types/[microglia](/cell-types/microglia)), [motor neurons](/cell-types/motor-neurons), [oligodendrocytes](/cell-types/oligodendrocytes)
• Proteins/Genes: [tau](/entities/tau-protein), [[alpha-synuclein](/proteins/alpha-synuclein)](/proteins/[alpha-synuclein](/proteins/alpha-synuclein)), [TDP-43](/proteins/tardbp-protein), [SNCA](/genes/snca), [GBA](/genes/gba), [LRRK2](/genes/lrrk2), [C9orf72](/genes/c9orf72), [HTT](/genes/htt)
• Mechanisms: [[neuroinflammation](/mechanisms/neuroinflammation)](/mechanisms/[neuroinflammation](/mechanisms/neuroinflammation)), [[mitochondrial dysfunction](/mechanisms/mitochondrial-dysfunction)](/mechanisms/mitochondrial-dysfunction), [[lysosomal dysfunction](/mechanisms/lysosomal-dysfunction)](/mechanisms/lysosomal-dysfunction), [[protein aggregation](/mechanisms/protein-aggregation)](/mechanisms/protein-aggregation), [[oxidative stress](/mechanisms/oxidative-stress)](/mechanisms/oxidative-stress), [[autophagy](/mechanisms/autophagy)](/mechanisms/[autophagy](/mechanisms/autophagy)), [[synaptic dysfunction](/mechanisms/synaptic-dysfunction) dysfunction](/mechanisms/[synaptic dysfunction](/mechanisms/synaptic-dysfunction)-dysfunction)
• Therapeutics: [[gene therapy](/therapeutics/gene-therapy-neurodegeneration)](/therapeutics/gene-therapy-neurodegeneration), [ASOs](/therapeutics/antisense-oligonucleotides), [CRISPR gene editing](/therapeutics/crispr-gene-editing-neurodegeneration), [deep brain stimulation](/therapeutics/deep-brain-stimulation)
• Pathways: [complement system](/mechanisms/complement-system-pathway), [neurotrophic signaling](/mechanisms/neurotrophic-factor-signaling), [cell death pathways](/mechanisms/cell-death-pathways-neurodegeneration)

Overview

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.

Scoring Methodology

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.

Gap Landscape Visualization

Tier 1: Critical Knowledge Gaps (Score ≥30)

1. Why does amyloid removal only slow decline 27%? — 33 points

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:

• Tau pathology continues unchecked after amyloid removal
• Synaptic loss already occurred before treatment
• Need combination therapy targeting both pathologies

2. What triggers the switch from normal aging to AD? — 30 points

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:

• Critical threshold of amyloid accumulation
• Vascular event triggering cascade
• Microbiome shift
• Viral reactivation

3. Why do some amyloid-positive people never get dementia? — 31 points

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

4. Does tau spread cause neurodegeneration or is it a bystander? — 32 points

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

5. What is the role of the immune system in early vs late AD? — 31 points

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

Tier 2: High-Priority Gaps (Score 25-29)

6. What causes selective vulnerability of specific brain regions? — 29 points

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

7. Is AD one disease or several with shared symptoms? — 29 points

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

8. What is the role of the microbiome-gut-brain axis in AD? — 30 points

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

9. Why do women get AD 2x more than men? — 28 points

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

10. What role do viral infections (HSV-1, HHV-6) play in AD? — 26 points

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

11. What is the sequence of events in AD pathogenesis? — 30 points

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

12. How do vascular factors contribute to AD? — 29 points

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

13. What is the function of [TREM2](/genes/trem2) variants in AD risk? — 30 points

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

14. Does [synaptic dysfunction](/mechanisms/synaptic-dysfunction) loss drive cognitive decline? — 29 points

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

15. What is the role of metal ion dysregulation in AD? — 26 points

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

Tier 3: Important Gaps (Score 20-24)

16. Role of metal ion dysregulation in amyloid aggregation — 25 points

Impact: 7/10 | Tractability: 6/10 | Current Effort: 5/10 | Data Availability: 7/10

Related Pages: Metal homeostasis, Protein aggregation

17. How does ApoE4 confer risk at the cellular level? — 27 points

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

18. What is the relationship between TBI and later AD? — 25 points

Impact: 7/10 | Tractability: 6/10 | Current Effort: 6/10 | Data Availability: 6/10

Related Pages: Chronic traumatic encephalopathy, Traumatic brain injury

19. Can lifestyle interventions modify disease trajectory? — 28 points

Impact: 8/10 | Tractability: 9/10 | Current Effort: 3/10 | Data Availability: 8/10

Related Pages: Modifiable risk factors, Cognitive reserve

20. What is optimal timing for therapeutic intervention? — 28 points

Impact: 10/10 | Tractability: 6/10 | Current Effort: 5/10 | Data Availability: 7/10

Related Pages: Preclinical AD, Disease-modifying therapies, Biomarkers

Tier 4: Emerging Research Questions (2025-2026 additions)

21. How does liquid-liquid phase separation contribute to [protein aggregation](/mechanisms/protein-aggregation) in AD? — 27 points

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

22. What is the role of astrocyte reactivity in AD progression? — 26 points

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

23. Can we target [mitochondrial dysfunction](/mechanisms/mitochondrial-dysfunction) to slow AD progression? — 25 points

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

24. What is the relationship between sleep disruption and AD biomarkers? — 26 points

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

25. How do peripheral immune cells infiltrate the AD brain? — 24 points

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-by-Gap Cross-Reference Matrix

| 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 |

Recent Research

This section tracks recent publications and advances addressing the knowledge gaps listed above.

2025-2026 Research Updates

Recent findings from 2025 conferences and publications:

• p-Tau217 as regulatory endpoint: Plasma p-tau217 has emerged as a validated surrogate marker for amyloid PET, with FDA discussions on using it as a trial endpoint[@ptau2025].
• Lecanemab long-term data: CLARITY-AD 24-month data confirmed sustained cognitive benefits with continued treatment, with amyloid PET showing continued plaque reduction[@clarityad2025].
• Donanemab TRAILBLAZER-ALZ 3: New data on earlier-stage patients showed greater treatment effects when initiated at mild cognitive impairment stage[@donanemab2025].
• Combination therapy approaches: CTAD 2025 highlighted emerging trials combining anti-amyloid with tau or [neuroinflammation](/mechanisms/neuroinflammation) targets, reflecting the multi-target hypothesis[@combination2025].
• Blood-based biomarker adoption: Plasma p-tau217 and p-tau181 now clinically implemented for AD diagnosis and staging in major memory clinics[@bloodbased2025].

External Links

Pathway Diagram

The following diagram shows the key molecular relationships involving alzheimers-disease discovered through SciDEX knowledge graph analysis: