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@INPROCEEDINGS{Ruiz:283113,
      author       = {Ruiz, Agustin and García-González, Pablo and Puerta,
                      Raquel and Cano, Amanda and Olivé, Clàudia and Marquié,
                      Marta and Valero, Sergi and Rosende-Roca, Maitee and Sanz,
                      Pilar and Alegret, Montserrat and Brosseron, Frederic and
                      Martino-Adami, Pamela and de Rojas, Itziar and Heneka,
                      Michael T. and Ramirez, Alfredo and Navarro, Arcadi and
                      Sáez, María Eugenia and Tárraga, Lluís and Cavazos,
                      José E. and Boada, Mercè and Fernández, Victoria and
                      Socorro, Alfredo Cabrera},
      title        = {{L}ong‐{R}ead {S}equencing {R}eveals {A}ncestral
                      intragenic {APOE} {H}aplotypes with {D}istinct {R}oles in
                      {A}lzheimer’s {D}isease},
      journal      = {Alzheimer's and dementia},
      volume       = {21},
      number       = {S7},
      issn         = {1552-5260},
      reportid     = {DZNE-2026-00009},
      pages        = {e108005},
      year         = {2025},
      abstract     = {Background:The apolipoprotein E (APOE) ε4 allele remains
                      the strongest genetic risk factor for late-onset
                      Alzheimer’s disease (AD), yet the marked variability in
                      its pathogenicity suggests underlying genetic complexity.
                      Historically, efforts to resolve the intragenic architecture
                      of APOE have been hampered by the limitations of
                      conventional genotyping and short-read sequencing, as well
                      as the presence of homoplasy in common intragenic
                      markers—misleading similarities arising from convergent
                      variants.Objective:We leveraged Oxford Nanopore Technology
                      (ONT) to phase intragenic APOE variants, resolve homoplasy,
                      and examine the impact of phased haplotypes on cerebrospinal
                      fluid (CSF) APOE protein levels and AD
                      progression.Methods:Using long-read sequencing in a Spanish
                      memory clinic cohort (n = 1,267), we reconstructed
                      full-length 4 kb APOE haplotypes, identifying 59 unique
                      configurations grouped into five major haplogroups. Common
                      intragenic variants defined ancestral ε4 (4A, 4B) and ε3
                      (3A, 3B) haplogroups. These were analyzed for associations
                      with CSF APOE levels (Olink platform) and progression from
                      mild cognitive impairment (MCI) to dementia using adjusted
                      Cox regression models.Results:ONT sequencing successfully
                      resolved homoplasy between the APOE promoter
                      region—particularly at rs405509—and the canonical
                      protein isoforms, uncovering common but functionally
                      distinct ε3A/B and ε4A/B intragenic sub-haplotypes with
                      independent biological effects. Carriers of the ε4A
                      haplotype exhibited significantly lower CSF APOE protein
                      levels (p = 0.004), whereas the ε3B haplotype was
                      associated with elevated CSF APOE protein levels (p =
                      0.025). Notably, both haplotypes were linked to a slower
                      progression from MCI to AD, independent of APOE genotype,
                      age, sex and core CSF biomarkers.Conclusion:This study
                      redefines the human APOE ε3 and ε4 alleles as genetically
                      heterogeneous entities. Using ONT long-read sequencing, we
                      achieved high-resolution mapping of intragenic haplotypic
                      structure and regulatory variation previously obscured by
                      conventional approaches. This enabled the identification of
                      ancestral haplotypes with distinct functional profiles and
                      potential relevance to Alzheimer’s disease pathogenesis.
                      These findings highlight the importance of incorporating
                      haplotype-level resolution into Alzheimer’s risk
                      assessment, therapeutic targeting, and precision medicine
                      strategies.},
      month         = {Jul},
      date          = {2025-07-27},
      organization  = {Alzheimer’s Association
                       International Conference, Toronto
                       (Canada), 27 Jul 2025 - 31 Jul 2025},
      cin          = {AG Heneka},
      ddc          = {610},
      cid          = {I:(DE-2719)1011303},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)1 / PUB:(DE-HGF)16},
      doi          = {10.1002/alz70861_108005},
      url          = {https://pub.dzne.de/record/283113},
}