Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653586 C>T
dbSNP ID: rs63751210
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TCA to TTA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6


This mutation was first reported in a patient known as Perth-4, who developed progressive forgetfulness, clumsiness and speech difficulty at the age of 31 (Taddei et al., 1998). She later developed myoclonus and seizures. Her condition progressed to end-stage dementia over several years and she died at the age of 37. Her mother and sister died with dementia at 36 and 42 years old, respectively. The proband had a brother apparently unaffected at the age of 45. Segregation could not be formally assessed, but the pattern of inheritance suggests autosomal-dominant transmission in this family.

A second family, known as family G, has been described carrying this mutation; two affected family members experienced early onset myoclonus, seizures, and dementia. An extensive pedigree was constructed with 73 members over five generations; only the proband and his mother were affected. The proband’s maternal grandparents, who were originally from Eastern Europe, lived beyond the age of 80 and were not reported to have suffered from any neurological disorder. The proband began to experience memory loss, periods of confusion, and disorientation at age 29. Family members noticed bizarre behaviors and personality changes at age 30. He developed arm twitching and seizures and died at the age of 40. His mother also experienced symptom onset, notably forgetfulness and personality changes, at age 29. Seizures developed within one year. At age 33, a neurological examination found myoclonus, dysarthria, hyperreflexia, intention tremor, and gait ataxia. She died at age 38 with a diagnosis of progressive myoclonus epilepsy, Unverricht-Lundborg type. The proband was the only member of the family to be tested genetically, therefore segregation with disease could not be assessed (Takao et al., 2001).

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).


A brain biopsy of one affected mutation carrier at the age of 33 showed abundant neurofibrillary tangles, diffuse and compact plaques, and neuritic changes. Four years later, an autopsy confirmed the presence of typical AD pathology, finding extensive plaques and tangles in the cortex and hippocampus. Marked cortical atrophy was observed, as well as depigmentation of the substantia nigra, but no Lewy bodies. Extensive neuronal loss was noted in the cortex as well as the cerebellum (Taddei et al., 1998).

A detailed neuropathological assessment is also available for an unrelated individual with this mutation, the proband from family G. Not surprisingly, he had severe brain atrophy and characteristic histopathologic lesions of AD, including severe deposition of Aβ in the cortex. Unusual features included diffuse Aβ deposits in the cerebellar cortices and subcortical white matter as well as numerous ectopic neurons, often containing tau-immunopositive neurofibrillary tangles, in the white matter of the frontal and temporal lobes. The origin of the ectopic neurons is unknown, but they have been attributed to errant migration during brain development (Takao et al., 2001).

Biological Effect

Although the biological function of this mutation is unknown, cryo-electron microscopy studies indicate that, in wild-type PSEN1, serine 169 helps anchor the interface between PSEN1 and both APP and Notch fragments; its hydroxyl group forming H-bonds with carbonyl oxygen atoms in each of the two substrates (Zhou et al., 2019; Jan 2019 newsYang et al., 2019).

Last Updated: 28 Jun 2021


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News Citations

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

Paper Citations

  1. . Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease. Neuroreport. 1998 Oct 5;9(14):3335-9. PubMed.
  2. . Ectopic white matter neurons, a developmental abnormality that may be caused by the PSEN1 S169L mutation in a case of familial AD with myoclonus and seizures. J Neuropathol Exp Neurol. 2001 Dec;60(12):1137-52. PubMed.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  4. . Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading


  1. . Genetic mutations associated with presenile dementia. Neurobiol Aging. 2002 Jul-Aug; 23(S1):322.

Protein Diagram

Primary Papers

  1. . Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease. Neuroreport. 1998 Oct 5;9(14):3335-9. PubMed.

Other mutations at this position


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