Expressive

rs11023139 (SPON1): Cognitive Decline in Alzheimer's

Key takeaways

  • rs11023139 is a SPON1 variant linked to faster cognitive decline in people already diagnosed with Alzheimer's disease
  • The minor allele reached genome-wide significance for decline rate (P = 7.0 x 10^-11) in a study of 303 patients
  • A nearby SPON1 variant replicated this direction in an independent group of 323 AD patients
  • SPON1 protein binds amyloid precursor protein and blocks a key enzyme in the amyloid-beta production pathway
  • Evidence is preliminary - sample sizes are small and no large-scale independent replication is yet available

Key takeaways

  • rs11023139 is a variant in SPON1 (F-spondin), a gene whose protein interacts with amyloid precursor protein in the Alzheimer's disease pathway
  • Minor alleles at this location were linked to faster cognitive decline in Alzheimer's disease patients in a discovery sample of 303 individuals (P = 7.0 x 10^-11)
  • A nearby SPON1 variant (rs11606345) showed a consistent directional signal in an independent replication group of 323 AD patients
  • All evidence comes from small samples of European descent, making these findings preliminary
  • SPON1 had not been previously associated with AD risk at the time of the study; the research examined rate of decline in patients already diagnosed

What the research says A genome-wide study of cognitive decline in Alzheimer's disease identified rs11023139, located in SPON1 (F-spondin), as significantly associated with rate of decline among AD patients, with the minor allele linked to faster cognitive deterioration (P = 7.0 x 10^-11 in 303 ADNI cases) PMID 24495576. A nearby variant, rs11606345, located 5.5 kb upstream in the same gene, showed association in an independent sample of 323 AD cases from the Religious Orders Study and Rush Memory and Aging Project (P = 0.002) PMID 24495576. The gene product is known to bind amyloid precursor protein (APP) and inhibit its cleavage by beta-secretase, an enzyme involved in producing amyloid-beta peptides implicated in AD pathology, providing a plausible biological rationale for the association PMID 24495576.

Reported associations

  • Rate of cognitive decline in Alzheimer's disease (discovery): Minor alleles at rs11023139 were associated with more rapid decline on the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) in 303 ADNI participants of European descent (P = 7.0 x 10^-11) PMID 24495576
  • Rate of cognitive decline in Alzheimer's disease (replication): Nearby variant rs11606345, 5.5 kb upstream of rs11023139, was associated with cognitive decline in 323 independent AD cases from the Religious Orders Study and Rush Memory and Aging Project (P = 0.002) PMID 24495576

Evidence quality The discovery association at rs11023139 reached genome-wide significance (P = 7.0 x 10^-11) in 303 AD cases from the ADNI cohort, a sample that is small by modern GWAS standards. The replication involved a nearby but distinct SNP (rs11606345) rather than the index variant itself, at a p-value (0.002) that does not meet genome-wide significance thresholds; the combined replication sample of 323 individuals is also modest in size. Both cohorts were restricted to participants of European descent, limiting generalizability to other populations. SPON1 had not been previously associated with AD risk at the time of publication, and no larger-scale independent replication studies are included among the provided sources. Overall, this evidence should be considered preliminary PMID 24495576.

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is the SPON1 gene?

SPON1, also called F-spondin, encodes a protein that binds amyloid precursor protein (APP) and inhibits its processing by beta-secretase, an enzyme involved in producing amyloid-beta peptides. Accumulation of amyloid-beta is a hallmark of Alzheimer's disease pathology.

Is rs11023139 linked to the risk of developing Alzheimer's disease?

The available research examined this variant in relation to how fast cognition declines in people already diagnosed with Alzheimer's disease, not whether someone will develop the disease. At the time of the study, SPON1 had not been associated with overall AD risk.

What does the minor allele of rs11023139 do?

In a study of 303 Alzheimer's disease patients, carriers of the minor allele showed faster cognitive decline on a standard assessment scale (ADAS-cog). A nearby variant in the same gene showed the same direction of effect in a separate group of 323 AD patients.

How strong is the evidence for rs11023139 and cognitive decline?

The discovery finding reached genome-wide statistical significance (P = 7.0 x 10^-11), but both the discovery (303 patients) and replication (323 patients) samples were small. Replication used a nearby variant rather than rs11023139 itself, and the evidence is considered preliminary pending larger independent studies.