Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer's disease. Alzheimer's Disease Collaborative Group

Topic: Amyloid, tau and blood-test diagnosis

Background Mutations in the presenilin-1 (PS-1) gene are associated with early-onset Alzheimer's disease. 40-50% of the risk for late-onset disease has been attributed to alleles at the apolipoprotein E (ApoE) locus. We have looked for an association between PS-1 and late- onset disease. Methods We collected blood samples from 208 white cases of dementia of the Alzheimer type and from 185 age-matched controls (mean ages 76.9 and 76.2 years, respectively; 58% female in each series). Clinical diagnostic accuracy for Alzheimer's disease in our patients is 96%. We also studied 29 African-American patients with dementia of the Alzheimer type and 50 age-matched controls (cases vs controls, 77.2 vs 72.0 years; 72 vs 77% female). We used PCR to test for an association between Alzheimer's disease and a polymorphism within the intron 3' to exon 8 of the PS-1 gene. The ApoE genotype of most of the cases and controls was known from previous investigations. Findings Homozygosity of the 1 allele in the PS-1 gene was associated with a doubling of the risk for late-onset Alzheimer's disease compared with the [12]/[22] genotype (odds ratio 1.97, 95% Cl 1.29-3.00). The proportion of Alzheimer's disease cases in the white population that could be attributed to homozygosity at this locus, as estimated by the attributable fraction, was 0.22. This compares with 0.35 for a single copy of ApoE4 and 0.15 for two copies. The smaller African-American series showed similar distribution of PS-1 genotype between cases and controls. Interpretation In our white series of cases, PS-1 accounted for about half as much of the risk for late-onset Alzheimer's disease as did ApoE4.

Key findings

• Background Mutations in the presenilin-1 (PS-1) gene are associated with early-onset Alzheimer's disease. 40-50% of the risk for late-onset disease has been attributed to alleles at the apolipoprotein E (ApoE) locus.
• Findings Homozygosity of the 1 allele in the PS-1 gene was associated with a doubling of the risk for late-onset Alzheimer's disease compared with the [12]/[22] genotype (odds ratio 1.97, 95% Cl 1.29-3.00).

Why it matters

This genetic study found that homozygosity for one allele in the presenilin-1 gene was associated with a doubling of the risk for late-onset Alzheimer's disease. The proportion of cases attributable to this locus was estimated at 0.22, compared with 0.35 for a single copy of APOE4.

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Study details

• Participants29
• Evidence strengthLow

Read the original

• DOI: 10.1016/s0140-6736(96)91140-x
• PubMed: 8596269
• Original source →

May need a subscription Unpaywall, Europe PMC and OpenAlex found no free copy of the full text (checked 10 Oct 2026), so the publisher may charge for it. The PubMed abstract is free.

@article{wragg1996-8596269,
  author  = {Wragg, M. and Hutton, M. and Talbot, C.},
  title   = {{Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer's disease. Alzheimer's Disease Collaborative Group}},
  journal = {Lancet (London, England)},
  year    = {1996},
  doi     = {10.1016/s0140-6736(96)91140-x},
  pmid    = {8596269},
  url     = {https://doi.org/10.1016/s0140-6736(96)91140-x}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease Nature · 1995-06-01 · usefulness score 64/100 · Genetics
• Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer's Disease in Late Onset Families Science · 1993-08-13 · usefulness score 63/100 · Genetics
• Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease Nature genetics · 1994-06-01 · usefulness score 60/100 · Genetics
• Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease Neurology · 1984-07-01 · usefulness score 58/100 · Getting a diagnosis

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