Pathogenicity: Alzheimer's Disease : Pathogenic, Corticobasal Syndrome : Not Classified
Clinical Phenotype: Alzheimer's Disease, Corticobasal Syndrome, Myoclonus, Parkinsonism, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73637671 T>C
dbSNP ID: rs63750599
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTC to CCC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4


This missense mutation in exon 4 was first identified in a young Japanese man living in the United States. While a college student in his early 20s, the proband developed early onset dementia with spastic paraparesis. Sequence analysis revealed a PSEN1 mutation; no other mutations in the coding regions of PSEN1, PSEN2, or APP were detected. The patient’s parents and two siblings did not carry the L85P mutation or any other mutation in PSEN1, PSEN2, or APP. The fact that neither parent was a mutation carrier suggests that it may be a rare de novo mutation. In addition to progressive impairment of intelligence and memory, neuropsychological evaluation of the patient revealed a complex visual problem not attributable to abnormalities of optic fundi, visual acuity, visual field, or color identification. Thus, the patient was thought to have a visual variant of AD (see Levine et al., 1993) rather than typical AD (Ataka et al., 2004).

The mutation was also identified in a 29-year-old woman of Romanian descent presenting with possible corticobasal syndrome (López-García et al., 2019). She suffered from asymmetric limb apraxia, parkinsonian signs, and myoclonus. The first symptoms included depressed mood and impairment of short-term memory. The patient also carried a variant in the SPAST gene, P45Q, which was reported as of uncertain pathogenicity. Of note, more than 240 mutations in SPAST, which encodes a microtubule regulator, cause spastic paraplegia type 4.


Neuropathological examination was not available. In the Japanese patient, single-photon emission computed tomography (SPECT) and PET showed bilateral hypoperfusion and hypometabolism in the occipital and temporal lobes (Ataka et al., 2004). In the Romanian patient, brain MRI showed symmetric, mild diffuse cortical and subcortical atrophy with subtle parietal predominance (López-García et al., 2019). In addition, a decrease in dopaminergic presynaptic transporters was observed in the putamen and right caudate nucleus, and FDG-PET revealed severe temporoparietal hypometabolism, with increased metabolic activity in the occipital cortex. Lastly, diffuse amyloid accumulation was observed in the cortex and basal ganglia, as assessed by PiB-PET, and in cerebrospinal fluid, Aβ42 was reduced, while total tau levels were increased and phosphorylated tau levels were unaffected.

Biological Effect

In transfected cells, the mutation was associated with a marked increase in Aβ42 production and in the Aβ42/Aβ40 ratio (Ataka et al., 2004). However, in an in vitro assay with isolated proteins, the mutant produced less Aβ42 than wild-type PSEN1, and Aβ40 production was undetectable (Sun et al., 2017). L85 closely contacts APP as revealed by a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment (Zhou et al., 2019; Jan 2019 news). Interestingly, the residue contributes to APP but not Notch binding (Yang et al., 2019).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021)

Last Updated: 13 Sep 2021


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News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . The visual variant of Alzheimer's disease: a clinicopathologic case study. Neurology. 1993 Feb;43(2):305-13. PubMed.
  2. . A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease with spastic paraparesis. Arch Neurol. 2004 Nov;61(11):1773-6. PubMed.
  3. . A Rare PSEN1 (Leu85Pro) Mutation Causing Alzheimer's Disease in a 29-Year-Old Woman Presenting as Corticobasal Syndrome. J Alzheimers Dis. 2019;70(3):655-658. PubMed.
  4. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
  5. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  6. . Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 PubMed.
  7. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease with spastic paraparesis. Arch Neurol. 2004 Nov;61(11):1773-6. PubMed.


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