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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, Aβ 1–43  is more prone to aggregation and has higher toxic properties than the long-known Aβ 1–42 . However, a direct effect on Aβ 1–43  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, Aβ 1–43  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 Aβ 1–42  and Aβ 1–40  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 Aβ 1–43  levels compared to controls ( p  = 0.037; < 0.001). CSF Aβ 1–43  levels positively correlated with CSF Aβ 1–42  in both pathogenic and unclear carriers and controls (all  p  < 0.001). The p.E318G carriers showed reduced Aβ 1–43  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 Aβ 1–43  and Aβ 1–42  levels, we could re-classify as “likely pathogenic” 3 of the unclear mutations.    Conclusion  This is the first time that Aβ 1–43  levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of Aβ 1–43  in  APP  and  PSENs  carriers highlights the pathogenic role of longer Aβ peptides in AD pathogenesis. Alterations in Aβ 1–43  could prove useful in understanding the pathogenicity of unclear  APP  and  PSENs  variants, a critical step towards a more efficient genetic counselling.

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