The genetic architecture of Alzheimer's disease

Genetic architecture is broadly defined as "the genetic basis of a phenotypic trait", i.e., the function/model that maps genotype to phenotype. Here however I refer to its narrower definition as "the list of known associations between genetic variants and a phenotypic trait".

Therefore, before outlining the genetic architecture of Alzheimer's disease (AD), it is critical to clearly define the disease phenotype. Please refer to this page for a description of the neurological and neuropathological traits that lead to a definitive diagnosis of AD. Presently, a definitive diagnosis of AD is possible only by examining brain tissue after death. Therefore, in most genetic association studies, the disease phenotype is a probable diagnosis of AD that is based on clinical signs and symptoms, the history of the illness and, more recently, biomarkers. To complicate matters even further, AD is traditionally divided based on age of onset (AO) into early-onset AD (EOAD, AO < 60-65y) and late-onset AD (LOAD, AO ≥ 60-65y). In addition, AD is also often divided based on family history into sporadic AD (SAD) and familial AD (FAD).

To avoid confusion when discussing Alzheimer's disease genetics, the two aforementioned classification schemes should not be conflated as they often are. For example, EOAD is often equated to familial AD that is caused by autosomal dominant mutations in the APP, PSEN1 and PSEN2 genes. However, the majority of EOAD cases do not conform to an autosomal dominant pattern of inheritance and can also be sporadic [PMID:21911656]. Therefore, here I will adopt a classification system that is based on the mode of inheritance of AD and distinguishes autosomal dominant AD (ADAD) and other Mendelian or atypical patterns [e.g., autosomal recessive AD (ARAD)] from the most common and complex polygenic/multifactorial pattern (AD). It is however very important to be aware of the fact that Mendelian and Multifactorial inheritance stand at opposite ends of a continuum [PMID:25323865].

Autosomal dominant AD (ADAD)

Autosomal recessive AD (ARAD)

Polygenic/Multifactorial AD (AD)

  • APOE (Apolipoprotein E)
    • ε4
      • common, coding (Arg112, Arg158) SNV
      • high risk, ancestral, disease-causing allele with semi-dominant inheritance and incomplete penetrance [PMID:21556001]
      • risk associated with APOE genotypes:
      • ε4/ε4 >> ε4/ε3 ≈ ε4/ε2 >> ε3/ε3 > ε3/ε2 > ε2/ε2
    • ε3
      • common, coding (Cys112, Arg158) SNV
      • intermediate risk allele
    • ε2
      • common, coding (Cys112, Cys158) SNV
      • low risk allele
  • APP (Amyloid Precursor Protein)
  • ABCA7
    • rs113809142
      • rare, splice donor site SNV
      • splice-disrupting SNV causing intron retention → frameshift → premature stop
    • rs200538373
      • rare, intronic SNV
      • splice-disrupting SNV causing intron retention → frameshift → premature stop
    • rs4147929
      • common, intronic SNV
  • TREM2
  • rs6733839
    • candidate gene(s):
      • BIN1 (Bridging Integrator 1)
  • rs10792832
    • candidate gene(s):
      • PICALM (Phosphatidylinositol Binding Clathrin Assembly Protein)
  • rs9331896
    • common, intronic SNV
    • candidate gene(s):
      • CLU (also known as APOJ or CLI, Complement Lysis Inhibitor)
  • rs6656401
    • common, intronic SNV
    • candidate gene(s):
      • CR1 (Complement Receptor Type 1)
  • rs983392
    • common, intergenic SNV
    • candidate gene(s):
  • rs11218343
    • candidate gene(s):
  • rs28834970
    • candidate gene(s):
  • rs11771145
    • candidate gene(s):
      • EPHA1 (EPH Receptor A1)
  • rs9271192
  • rs10948363
    • common, intronic SNV
    • candidate gene(s):
      • CD2AP (CD2-Associated Protein)
  • rs1476679
  • rs2718058
    • candidate gene(s):
  • rs10498633
  • rs17125944
  • rs10838725
  • rs7274581
    • candidate gene(s):
  • rs35349669
  • rs190982
    • candidate gene(s):
  • rs3865444
    • candidate gene(s):
      • CD33 (Sialic Acid Binding Ig-Like Lectin 3)
  • rs8093731
    • candidate gene(s):
  • rs9381040
  • rs74615166

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