Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations

Alzheimers Res Ther. 2020 Sep 11;12(1):108. doi: 10.1186/s13195-020-00676-5.


Background: Alzheimer's disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. Amongst these, Aβ1-43 is more prone to aggregation and has higher toxic properties than the long-known Aβ1-42. However, a direct effect on Aβ1-43 in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined.

Methods: N = 1431 AD patients (n = 280 early-onset (EO) and n = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, Aβ1-43 levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with Aβ1-42 and Aβ1-40 CSF levels. The soluble sAPPα and sAPPβ species were also measured for the first time in mutation carriers.

Results: A known pathogenic mutation was identified in 5.7% of EOAD patients (4.6% PSEN1, 1.07% APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF Aβ1-43 levels compared to controls (p = 0.037; < 0.001). CSF Aβ1-43 levels positively correlated with CSF Aβ1-42 in both pathogenic and unclear carriers and controls (all p < 0.001). The p.E318G carriers showed reduced Aβ1-43 levels (p < 0.001), though genetic association with AD was not detected. sAPPα and sAPPβ CSF levels were significantly reduced in the group of unclear (p = 0.006; 0.005) and p.E318G carriers (p = 0.004; 0.039), suggesting their possible involvement in AD. Finally, using Aβ1-43 and Aβ1-42 levels, we could re-classify as "likely pathogenic" 3 of the unclear mutations.

Conclusion: This is the first time that Aβ1-43 levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of Aβ1-43 in APP and PSENs carriers highlights the pathogenic role of longer Aβ peptides in AD pathogenesis. Alterations in Aβ1-43 could prove useful in understanding the pathogenicity of unclear APP and PSENs variants, a critical step towards a more efficient genetic counselling.

Keywords: Alzheimer mutations; Alzheimer’s disease (AD); Amyloid-β 1–43 (Aβ1–43); Cerebrospinal fluid (CSF); Oxford Nanopore Technologies (ONT) long-read sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / genetics
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor* / genetics
  • Heterozygote
  • Humans
  • Mutation / genetics
  • Presenilin-1 / genetics
  • Presenilin-2 / genetics


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • PSEN1 protein, human
  • PSEN2 protein, human
  • Presenilin-1
  • Presenilin-2