Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73637692 G>C
dbSNP ID: rs63751141
Coding/Non-Coding: Coding
Genomic Region: Exon 4
Mutation Type: Point, Missense
Codon Change: TGC to TCC


This mutation was first reported in two Italian families, both of whom had a history of familial dementia. Affected members of both families met NINCDS-ADRDA criteria for probable AD; however, the clinical presentation in one family included atypical features.

The three affected members of the family known as FLO57 are described as having a fairly typical presentation of early onset AD, and began to exhibit memory decline in their early 50s, with a mean age of onset of approximately 53.5 years. In contrast, depression, social isolation, and sporadic mutism were the first symptoms of the proband in the other family, known as “FLO28.” These symptoms, which began at age 49, were followed by memory decline and extrapyramidal signs, with rigidity and bradykinesia. Hallucinations and delusions followed, and the proband became progressively more mute and parkinsonian. The proband’s mother had dementia with aggressive behavior, but symptoms reportedly began considerably later, at age 70. No mutations in MAPT were detected in the proband of FLO28, suggesting that PSEN1 C92S may produce a variable clinical phenotype, presenting as either fairly typical early onset AD or with an atypical presentation characterized by extrapyramidal signs and early psychiatric features (Tedde et al., 2003).



Biological Effect

Increased Aβ42 secretion from mammalian cells (Zhang et al., 2000). A study primarily focused on the R278K mutation in PSEN1 found that fibroblasts derived from a patient carrying the PSEN1 C92S mutation secreted higher levels of Aβ42, but not Aβ40, compared with fibroblasts derived from a control individual. Consequently, the Aβ42/Aβ40 ratio was increased (by 57 percent) (Assini et al., 2003).


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Paper Citations

  1. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.
  2. . Mutation of the conserved N-terminal cysteine (Cys92) of human presenilin 1 causes increased A beta42 secretion in mammalian cells but impaired Notch/lin-12 signalling in C. elegans. Neuroreport. 2000 Sep 28;11(14):3227-30. PubMed.
  3. . Pure spastic paraparesis associated with a novel presenilin 1 R278K mutation. Neurology. 2003 Jan 14;60(1):150. PubMed.

Further Reading


  1. . Novel presenilin 1 and presenilin 2 mutations in early-onset Alzheimer's disease families. Neurobiol Aging. 2002; 23(Suppl 1):S312.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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Primary Papers

  1. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.