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Anti-amyloid antibodies achieve only ~0.1% brain penetrance via passive diffusion, limiting efficacy. Receptor-mediated transcytosis approaches (TfR1, LRP1) have shown 10-20x improvements in rodents b
TDP-43 undergoes phase separation into stress granules, and aberrant transitions to solid aggregates drive ALS-FTD pathology. Small molecules (including GRP75 modulators, nuclear export inhibitors, an
APOE4's C112R substitution causes aberrant domain interaction altering lipid binding and cholesterol transport. Small molecules (APOE4 correctors like PU-WS13) can shift APOE4 toward APOE3 structure i
Aged neurons show progressive silencing of stress-response and neuroprotective genes through epigenetic mechanisms (H3K27me3 accumulation, loss of H3K27ac). The NAD+-SIRT1 axis coordinates these chang
GBA mutations impair lysosomal glucocerebrosidase, promoting α-synuclein aggregation, which in turn inhibits GBA. This vicious cycle amplifies pathology. Three candidate intervention points exist: res
Senescent microglia and astrocytes accumulate with age and disease, secreting SASP factors that amplify neuroinflammation. Senolytics have shown efficacy in murine tauopathy models. Key challenges for
Single-cell transcriptomic analyses (SEA-AD, Allen Brain Cell Atlas) identify ACSL4 upregulation in specific microglial subtypes near amyloid plaques. ACSL4 promotes arachidonic acid incorporation int
DAM microglia upregulate TREM2 as a response to pathological protein aggregates, but whether sustaining or dampening this phenotype is beneficial remains contested. Early TREM2 activation appears prot
Impaired autophagy-lysosome function is a convergent mechanism across neurodegenerative diseases, making pathway-level intervention attractive. However, nodes of failure differ: CMA (LAMP2A) declines
Microglia-derived IL-1α, TNF, and C1q activate neurotoxic A1 astrocytes, which in turn secrete complement factors feeding back to microglia. Breaking this loop is a therapeutic strategy, but the domin
Epidemiological and mouse model data implicate gut dysbiosis in AD pathogenesis years before symptom onset. However, distinguishing causal metabolites from bystander biomarkers requires mechanistic ev
Chronic neuroinflammation in neurodegeneration partly reflects a failure of active resolution, not just excessive activation. SPMs (including Resolvin D1, Neuroprotectin D1, Maresin 1) activate recept
Single-cell RNA-seq has revealed >10 distinct reactive astrocyte states in neurodegeneration, collapsing the A1/A2 binary. Mapping these states to disease-stage, regional vulnerability, and functional
Entorhinal cortex layer II neurons are ground-zero for AD tau pathology, yet the molecular explanation for this selective vulnerability remains elusive. Candidate mechanisms include high calcium oscil
Digital health sensors capture behavioral and physiological signals continuously outside clinical settings. Combining speech/language models, wearable gait data, passive cognitive probes, and sleep mo
GBA mutations impair lysosomal function and promote alpha-synuclein aggregation, but alpha-synuclein itself inhibits GBA activity. The therapeutic implications of breaking this loop at different point
Senolytics targeting p16/p21+ senescent astrocytes and microglia may reduce SASP-driven neuroinflammation. Linked to 12 hypotheses and 12 targets.
SPMs (resolvins, protectins, maresins) from omega-3s may promote inflammation resolution. Are resolution failures druggable? Linked to 3 hypotheses and 3 targets.
Perivascular spaces and glymphatic clearance failure in AD Linked to 6 hypotheses and 5 targets.
Beat AUROC=0.816 on the OT-AD Target Ranking benchmark (bench_ot_ad_target_ranking_v1). Baseline uses only STRING/Reactome/MyGene features from the SciDEX Forge tool library. Submissions must produce
Mitochondrial transfer between astrocytes and neurons Linked to 16 hypotheses and 16 targets.
Anti-amyloid antibodies (lecanemab, donanemab) have ~0.1% brain penetrance. Engineering improved BBB transcytosis via transferrin receptor, LRP1, or novel shuttle peptides could dramatically improve e
Synaptic pruning by microglia in early AD Linked to 20 hypotheses and 17 targets.
APOE4 differs from APOE3 by C112R causing domain interaction that alters lipid binding and amyloid clearance. Linked to 17 hypotheses and 13 targets.
Extracellular vesicles (EVs), including exosomes and microvesicles, carry molecular cargo (proteins, miRNAs, lipids) from their cells of origin, including neurons, astrocytes, and microglia. Brain-der
Multiple NDDs converge on autophagy-lysosome dysfunction. Are there universal therapeutic targets? Linked to 9 hypotheses and 9 targets.
Epigenetic clocks and biological aging in neurodegeneration Linked to 8 hypotheses and 8 targets.
Why do entorhinal cortex layer II stellate neurons die first in AD? Their unique electrophysiological properties, grid cell function, and high metabolic demand may contribute, but the molecular basis
RNA binding protein dysregulation across ALS FTD and AD Linked to 9 hypotheses and 9 targets.
Astrocytes adopt A1 (neurotoxic) and A2 (neuroprotective) phenotypes, but recent single-cell data reveals far greater heterogeneity. Mapping reactive subtypes to disease stages and therapeutic targets
Microglia activate astrocytes via IL-1alpha/TNF/C1q, and reactive astrocytes feed back to microglia via complement/chemokines. Linked to 5 hypotheses and 5 targets.
TDP-43 undergoes liquid-liquid phase separation that becomes pathological. Small molecules targeting phase separation properties could be therapeutic but the design principles are undefined. Linked t
Sleep disruption as cause and consequence of neurodegeneration Linked to 10 hypotheses and 10 targets.
PSP and CBD both involve 4R-tau but produce distinct neuropathological patterns (tufted astrocytes vs astrocytic plaques). Whether tau strains or regional cellular environments drive these differences
Can speech, gait, retinal imaging, sleep, and smartphone data detect neurodegeneration 5-10 years before diagnosis? Linked to 1 hypotheses and 1 targets.
Emerging evidence suggests gut microbial metabolites (SCFAs, TMAO, tryptophan metabolites) may influence amyloid-beta aggregation and neuroinflammation years before clinical symptoms, but causal mecha