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Abstract INTRODUCTIONAlzheimer's disease (AD) initiates years prior to symptoms, underscoring the importance of early detection. While amyloid accumulation starts early, individuals with substantial amyloid burden may remain cognitively normal, implying that amyloid alone is not sufficient for early risk assessment. METHODSGiven the genetic susceptibility of AD, a multi‐factorial pseudotime approach was proposed to integrate amyloid imaging and genotype data for estimating a risk score. Validation involved association with cognitive decline and survival analysis across risk‐stratified groups, focusing on patients with mild cognitive impairment (MCI). RESULTSOur risk score outperformed amyloid composite standardized uptake value ratio in correlation with cognitive scores. MCI subjects with lower pseudotime risk score showed substantial delayed onset of AD and slower cognitive decline. Moreover, pseudotime risk score demonstrated strong capability in risk stratification within traditionally defined subgroups such as early MCI, apolipoprotein E (APOE) ε4+ MCI,APOEε4– MCI, and amyloid+ MCI. DISCUSSIONOur risk score holds great potential to improve the precision of early risk assessment. HighlightsAccurate early risk assessment is critical for the success of clinical trials.A new risk score was built from integrating amyloid imaging and genetic data.Our risk score demonstrated improved capability in early risk stratification.
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This content will become publicly available on April 1, 2026
Synergistic reduction in interfacial flexibility of TREM2 R47H and ApoE4 may underlie AD pathology
Abstract BACKGROUNDThe strongest genetic drivers of late‐onset Alzheimer's disease (AD) are apolipoprotein E4 (ApoE4) and TREM2R47H. Despite their critical roles, the mechanisms underlying their interactions remain poorly understood. METHODSWe conducted microsecond‐long molecular dynamics simulations of TREM2‐ApoE complexes, including TREM2R47H, validating our findings through comparison with published experimental data on TREM2‐ApoE binding interactions. RESULTSOur simulations reveal TREM2WTcan sample an “open” CDR2 conformation, challenging the prevailing notion that this conformation is pathogenic. TREM2WTexhibits greater flexibility, accessing diverse CDR2 conformations, while rigidity in TREM2R47H’s CDR2 may explain its reduced ligand‐binding properties. ApoE2 facilitates dynamic reconfiguration of TREM2‐ApoE2 complexes, which is absent with ApoE4. TREM2R47Hand ApoE4 mutually rigidify each other, suppressing interfacial flexibility. DISCUSSIONOur findings suggest mechanisms underlying ApoE2's neuroprotective functions, ApoE4's pathogenicity, and the synergistic effects of ApoE4 and TREM2R47Hin AD. TREM2WT’s flexibility and reconfiguration with ApoE2 may support microglial activation, while rigidity in TREM2R47H‐ApoE4 interactions may drive pathogenic signaling. HighlightsTREM2WTsamples diverse CDR2 conformations, challenging prior assumptions that an “open” CDR2 state is solely pathogenic.ApoE2 promotes dynamic reconfiguration of TREM2‐ApoE2 complexes, preserving TREM2WT's flexibility.ApoE4's hinge forms a unique binding pocket that enhances TREM2 binding.The TREM2R47H‐ApoE4 complex exhibits mutual rigidity, suppressing CDR2 and hinge flexibility.
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- Award ID(s):
- 2022138
- PAR ID:
- 10630702
- Publisher / Repository:
- Pubmed
- Date Published:
- Journal Name:
- Alzheimer's & Dementia
- Volume:
- 21
- Issue:
- 4
- ISSN:
- 1552-5260
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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