rs2306402 — CTNNA3

Intronic variant in the alpha-T-catenin gene associated with modestly increased late-onset Alzheimer's disease risk, with the strongest female-specific signal in intron 9 of CTNNA3

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CTNNA3 — A Synaptic Adhesion Gene at the Heart of Alzheimer's Chromosome 10 Linkage

The gene CTNNA3 encodes alpha-T-catenin11 alpha-T-catenin
a member of the vinculin/alpha-catenin protein family that anchors cell-cell adhesion complexes to the actin cytoskeleton. While its better-known relative alpha-E-catenin is ubiquitous in epithelial tissue, alpha-T-catenin is enriched in heart and brain, where it stabilizes adherens junctions and supports synaptic integrity. The rs2306402 variant sits within an intron of CTNNA3 on chromosome 10q21.3 — a region that has shown repeated linkage to late-onset Alzheimer's disease (LOAD) in family-based studies — and carries a modest but noteworthy association with AD risk.

The Mechanism

The CTNNA3 protein connects the cadherin–beta-catenin adhesion complex22 cadherin–beta-catenin adhesion complex
the cellular "glue" that holds neighbouring neurons together at their contact points to the intracellular actin cytoskeleton. In doing so, it influences synaptic stability, dendritic spine morphology, and the suppression of Wnt/beta-catenin signalling — a pathway critically involved in neuronal survival and synaptic plasticity. Disruption of this anchoring function could render synapses more vulnerable to the tau and amyloid-beta pathology that accumulates in Alzheimer's disease.

The rs2306402 T allele is an intronic variant; it does not change the CTNNA3 protein sequence. Its biological effect is likely regulatory — influencing splicing efficiency, transcript expression levels, or the use of one of CTNNA3's multiple alternative promoters. Crucially, CTNNA3 contains a nested gene, LRRTM333 LRRTM3
leucine-rich repeat transmembrane neuronal 3, a synaptogenic protein transcribed in the opposite direction within CTNNA3's introns, which independently interacts with APP and BACE1 — the key players in amyloid precursor protein processing. Intronic variants like rs2306402 may therefore affect either or both genes simultaneously.

The Evidence

The most direct evidence for rs2306402 comes from Morgan et al. (2008), who analysed 528 intra-genic SNPs across 67 genes in a chromosome 10 linkage region in 1,160 LOAD cases and 1,389 controls44 Morgan et al. (2008), who analysed 528 intra-genic SNPs across 67 genes in a chromosome 10 linkage region in 1,160 LOAD cases and 1,389 controls
rs2306402 in CTNNA3 reached nominal significance at P=0.024 with OR=1.18. The authors explicitly noted these results would not survive correction for multiple testing and warranted replication — placing this squarely in the emerging evidence tier.

A broader picture of CTNNA3's role in AD comes from Miyashita et al. (2007), who conducted a two-stage SNP association study in 2,762 Japanese subjects (1,313 LOAD cases, 1,449 controls)55 Miyashita et al. (2007), who conducted a two-stage SNP association study in 2,762 Japanese subjects (1,313 LOAD cases, 1,449 controls)
seven SNPs spanning ~38 kb in intron 9 of CTNNA3 showed significant female-specific association with LOAD, independent of APOE-ε4. Multiple logistic regression confirmed direct interaction with female sex as a modifier, with p-values ranging from 5.9×10⁻⁶ to 7.7×10⁻⁴. This female-specificity may relate to oestrogen-dependent regulation of CTNNA3 expression or differential synaptic vulnerability.

Earlier work by Martin et al. (2005) found APOE-ε4-dependent association of several CTNNA3 SNPs66 Martin et al. (2005) found APOE-ε4-dependent association of several CTNNA3 SNPs
effects concentrated in APOE-ε4 carriers in both family-based and case-control analyses, while Ertekin-Taner et al. (2003) linked two CTNNA3 intronic SNPs to elevated plasma Aβ42 levels in LOAD pedigrees77 Ertekin-Taner et al. (2003) linked two CTNNA3 intronic SNPs to elevated plasma Aβ42 levels in LOAD pedigrees
conditional lod score analysis showed these SNPs partially explained the chromosome 10 linkage signal. Importantly, not all studies have replicated these findings: Blomqvist et al. (2004) and Busby et al. (2004) found no association in Swedish/Scottish and European cohorts88 Blomqvist et al. (2004) and Busby et al. (2004) found no association in Swedish/Scottish and European cohorts
CTNNA3 was described as "unlikely to account for the AD susceptibility locus on chromosome 10" alone.

Overall, the evidence paints CTNNA3/rs2306402 as a real but modest, population-heterogeneous, and possibly sex- and APOE-modulated risk factor for LOAD.

Practical Implications

The OR of 1.18 for rs2306402 T-allele carriers translates to roughly 18% increased odds of LOAD per copy of the T allele — a modest effect that is most meaningful when considered alongside other genetic risk factors (particularly APOE ε4) and modifiable risk factors. For TT homozygotes (~5% of Europeans), the combined additive risk from two T alleles may reach approximately 30–40% increased odds, though direct empirical data on TT homozygotes are limited given their rarity.

Because the CTNNA3–LRRTM3 locus is involved in synaptic adhesion and amyloid precursor protein processing, interventions that reduce amyloid burden or support synaptic integrity may be particularly relevant. Monitoring for early cognitive changes and cardiovascular risk factor control represent the most evidence-supported actions available for genetic Alzheimer's risk variants of this magnitude.

Interactions

The most clinically important interaction is with APOE genotype (rs429358 and rs7412). Martin et al. (2005) showed that CTNNA3 association was strongest in APOE-ε4 carriers, suggesting these variants may have synergistic effects on AD risk. Carriers of both a CTNNA3 risk allele and APOE ε4 may warrant particularly proactive risk factor management.

The female-specific intron 9 signal identified by Miyashita et al. suggests sex is an important modulator: women carrying the T allele may face a different risk trajectory than men. LRRTM3 — the gene nested within CTNNA3 — shows its own independent association with LOAD risk through interaction with the APP–BACE1 amyloid pathway, and rs2306402 may tag combined regulatory variation across both genes.

BIN1 rs744373, another major tau-pathway risk SNP on chromosome 2, independently influences tau pathology; individuals carrying risk alleles at both loci should consider a comprehensive Alzheimer's prevention approach.

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal

Typical Alzheimer's risk from CTNNA3; no T-allele burden

You carry two copies of the C allele at rs2306402, the most common genotype in European populations (~61% of Europeans). This means you do not carry the T allele that showed nominal association with late-onset Alzheimer's disease in chromosome 10 linkage studies. Your Alzheimer's risk from this locus is at the population baseline. Other genetic factors — particularly APOE status — remain the dominant inherited determinants of AD risk.

CT Intermediate

One copy of the CTNNA3 Alzheimer's risk allele; modestly increased LOAD risk

The T allele is intronic and likely exerts a regulatory effect on CTNNA3 expression or splicing rather than altering the protein. CTNNA3 encodes alpha-T-catenin, a synaptic adhesion molecule that anchors the cadherin–beta-catenin complex to actin and suppresses Wnt signalling. The gene also hosts LRRTM3, a nested synaptogenic gene that interacts with APP and BACE1. Whether rs2306402 acts through CTNNA3, LRRTM3, or both is not yet established.

If you carry APOE ε4 (rs429358 or rs7412), the combined risk may be meaningfully higher than either variant alone, based on the gene-gene interaction data from Martin et al. (2005).

TT High Risk

Two copies of the CTNNA3 Alzheimer's risk allele; highest CTNNA3-related risk

CTNNA3 encodes alpha-T-catenin, a synaptic cell-adhesion protein expressed in brain and heart. Its intron harbours LRRTM3, a synaptogenic protein that physically interacts with APP and BACE1 at the site of amyloid precursor protein cleavage. Intronic risk variants like rs2306402 T are thought to act through altered gene expression or splicing rather than protein-sequence changes. A TT genotype means both chromosomes carry the risk-associated regulatory variant.

Independent lines of evidence suggest CTNNA3 influences: (1) synaptic stability through cadherin–actin anchoring, (2) Wnt pathway regulation, (3) plasma Aβ42 levels via the LRRTM3–APP interaction. Collectively these pathways are relevant to the earliest stages of Alzheimer's pathology, before clinical symptoms appear.