Expressive

rs10153124 (LUC7L): Alzheimer's Age at Onset

Key takeaways

  • rs10153124 near the LUC7L gene shows a suggestive link to the age when Alzheimer's dementia begins in people who carry the PSEN1 E280A hereditary mutation
  • The discovery comes from the world's largest hereditary Alzheimer's kindred, a Colombian founder population of 340 genotyped PSEN1 E280A mutation carriers
  • Evidence is preliminary: the variant met suggestive significance thresholds with replication hints across multiple independent cohorts, but per-variant effect sizes were not available in the study text
  • Gene expression data show the alternative allele changes activity levels of four nearby genes across skeletal muscle, gut, blood vessels, and skin

Key takeaways

  • rs10153124, near the LUC7L gene, shows a suggestive link to the age when Alzheimer's dementia begins in people who carry the PSEN1 E280A hereditary Alzheimer's mutation
  • The discovery comes from the world's largest hereditary Alzheimer's kindred, a Colombian founder population of 340 genotyped PSEN1 E280A mutation carriers
  • Evidence is preliminary: the variant met suggestive significance thresholds with replication hints across multiple independent cohorts, but specific per-variant effect sizes were not available in the study text
  • Gene expression data show the alternative allele changes activity levels of four nearby genes across skeletal muscle, digestive tissues, blood vessels, and skin

What the research says rs10153124 was identified as a suggestive modifier of age at dementia onset in a genome-wide association study of 340 Colombian individuals carrying the PSEN1 E280A mutation - a hereditary variant that typically causes mild cognitive impairment (MCI; a stage of memory and thinking decline that precedes full dementia) at a median age of 44 years and dementia at a median age of 49 years. The study used TOPMed array imputation (a computational method for inferring ungenotyped variants using a 97,256-sample reference panel) and sought replication across seven independent cohorts, including 116 mutation carriers from the Dominantly Inherited Alzheimer's Network (DIAN). The alternative allele at this locus is associated with altered expression of four nearby genes across skeletal muscle, gastrointestinal, vascular, and skin tissues GTEx Portal.

Reported associations

  • Age at dementia onset (autosomal dominant Alzheimer's disease): Identified as a suggestive modifier of dementia onset age in 340 PSEN1 E280A mutation carriers; the parent study found 13 variants meeting p<1×10^-7 or p<1×10^-5 with replication evidence across seven independent cohorts, with discovery n=340 and primary replication n=116 (DIAN)
  • FAM234A expression (skeletal muscle): The alternative allele is associated with increased FAM234A expression in skeletal muscle GTEx Portal
  • ENSG00000268836 expression (gastrointestinal and subcutaneous adipose tissues): The alternative allele is associated with reduced expression of this uncharacterized gene transcript in colon sigmoid, esophagus mucosa, esophagus muscularis, and subcutaneous adipose (fat under the skin) tissue GTEx Portal
  • NME4 expression (tibial artery): The alternative allele is associated with increased expression in tibial artery (a major blood vessel of the lower leg) GTEx Portal
  • MRPL28 expression (skin): The alternative allele is associated with increased expression in both sun-exposed (lower leg) and sun-protected (suprapubic) skin GTEx Portal

Evidence quality Evidence for rs10153124 as an age-at-onset modifier in autosomal dominant Alzheimer's disease is preliminary. The discovery cohort of 340 individuals is the largest PSEN1 E280A sample assembled to date, but small by genome-wide association study standards; the parent study identified 13 variants reaching p<1×10^-7 or p<1×10^-5 with replication evidence spanning seven cohorts - including sporadic early-onset and multiple late-onset Alzheimer's studies alongside DIAN (n=116 mutation carriers) - reinforcing the biological plausibility of the broader set of findings. However, the study text available did not specify which individual variants replicated, at what threshold, or with what effect size, so the strength of replication for rs10153124 specifically cannot be assessed from the provided material. The unique study design - all participants share the same causative mutation, removing aging-related confounding - sharpens the phenotype but limits generalizability to sporadic Alzheimer's disease. The source study was published in Alzheimer's & Dementia (2023); no PMID was included in the provided metadata. GTEx eQTL evidence for the four expression associations (n=953 donors, FDR<0.05, cis-window) is technically robust, though the functional connection between altered peripheral tissue gene expression and Alzheimer's disease onset timing is not explained by any of the provided sources.

Tissue-specific expression effects

  • FAM234A: Increased expression in skeletal muscle associated with the alternative allele GTEx Portal
  • ENSG00000268836: Reduced expression in colon sigmoid, esophagus mucosa, esophagus muscularis, and subcutaneous adipose tissue GTEx Portal
  • NME4: Increased expression in tibial artery GTEx Portal
  • MRPL28: Increased expression in both sun-exposed and sun-protected skin GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is the LUC7L gene?

LUC7L stands for Luc7-like RNA binding protein. The provided study did not characterize its specific biological function in the context of Alzheimer's disease, and its role in brain aging or dementia timing is not yet established.

Is rs10153124 a cause of Alzheimer's disease?

No. rs10153124 was studied as a potential modifier of when dementia begins in people who already carry the PSEN1 E280A hereditary Alzheimer's mutation, not as a cause of the disease itself. It may influence timing, not susceptibility.

What is the PSEN1 E280A mutation?

PSEN1 E280A is a mutation in the presenilin-1 gene that causes autosomal dominant Alzheimer's disease. Carriers typically develop mild cognitive impairment around age 44 and dementia around age 49. The Colombian kindred studied here is the world's largest known hereditary Alzheimer's disease family.

How strong is the evidence linking rs10153124 to Alzheimer's age at onset?

The evidence is preliminary. The discovery was made in 340 individuals and had replication hints across seven independent cohorts, but the specific effect size and replication threshold for this variant were not reported in the available study text. Larger confirmation studies are needed.

Which genes does rs10153124 affect?

GTEx expression data show the alternative allele is linked to changed expression of four nearby genes: FAM234A in skeletal muscle, NME4 in tibial artery tissue, MRPL28 in skin, and an uncharacterized gene transcript in digestive and fat tissues. Whether these expression changes relate to Alzheimer's biology is not known.