rs17070145 — WWC1 Intronic C>T

KIBRA — The Memory Gene

The KIBRA¹¹ KIBRA
KIdney and BRAin expressed protein, also known as WWC1 (WW and C2 domain containing 1) gene encodes a postsynaptic scaffolding protein that plays a central role in memory formation. In 2006, a genome-wide association study made KIBRA the first gene linked to normal variation in human memory performance through unbiased genomic scanning. A common C-to-T change in intron 9 (rs17070145) was associated with significantly better episodic memory — the ability to recall specific events and experiences. T allele carriers showed 24% better free recall at 5 minutes and 19% better recall at 24 hours compared to CC homozygotes.

The Mechanism

KIBRA protein is highly expressed in the hippocampus and other memory-related brain regions. It functions as a molecular scaffold at postsynaptic densities²² postsynaptic densities
The protein-rich region at the receiving end of a synapse, where neurotransmitter signals are received and processed, where it anchors the enzyme PKMzeta³³ PKMzeta
Protein kinase M-zeta, an atypical protein kinase C isoform that maintains long-term potentiation — the cellular basis of memory at activated synapses. This KIBRA-PKMzeta complex sustains long-term potentiation (LTP)⁴⁴ long-term potentiation (LTP)
The persistent strengthening of synaptic connections, widely considered the cellular mechanism underlying learning and memory by regulating postsynaptic AMPA receptors⁵⁵ AMPA receptors
Glutamate receptors that mediate fast synaptic transmission; their trafficking to and from the synapse controls synaptic strength, keeping synaptic connections strong after learning.

KIBRA also binds to dendrin⁶⁶ dendrin
A postsynaptic protein enriched in the hippocampus that helps organize the postsynaptic density with nanomolar affinity via its WW domains, and this interaction regulates KIBRA's localization to synapses. Additionally, KIBRA participates in the MAPK signaling pathway⁷⁷ MAPK signaling pathway
Mitogen-activated protein kinase pathway, a chain of proteins that communicates signals from the cell surface to the nucleus, involved in synaptic plasticity, which is differentially activated in the hippocampus depending on rs17070145 genotype.

Although rs17070145 sits in an intron and does not directly change the protein sequence, it is in complete linkage disequilibrium⁸⁸ linkage disequilibrium
When two genetic variants are inherited together more often than expected by chance, meaning one variant can serve as a proxy for the other with two missense variants in exon 15 (M734I and S735A) that alter the KIBRA C2 domain's lipid-binding capacity. These linked coding changes likely represent the functional mechanism through which the intronic SNP influences memory.

The Evidence

The original discovery⁹⁹ original discovery
Papassotiropoulos A et al. Common Kibra alleles are associated with human memory performance. Science, 2006 screened over 500,000 SNPs in 341 young Swiss adults and found rs17070145 to be significantly associated with delayed free recall, then replicated the finding in two additional cohorts from Switzerland (n=424) and the United States (n=256). Gene expression confirmed KIBRA was expressed in memory-related brain structures.

A comprehensive meta-analysis¹⁰¹⁰ comprehensive meta-analysis
Milnik A et al. Association of KIBRA with episodic and working memory: a meta-analysis. Am J Med Genet B, 2012 pooling 17 samples (N=8,909 for episodic memory, N=4,696 for working memory) confirmed the association. The T allele explained 0.5% of variance in episodic memory (r=0.068, P=0.001) and 0.1% of variance in working memory (r=0.035, P=0.018). While these effect sizes are small in absolute terms, they are among the largest for any common variant affecting normal cognitive variation.

Functional neuroimaging¹¹¹¹ Functional neuroimaging
Kauppi K et al. KIBRA polymorphism is related to enhanced memory and elevated hippocampal processing. J Neurosci, 2011 revealed that T carriers show increased right hippocampal activation during memory retrieval compared to CC homozygotes, even after matching for age, sex, and performance level. Structural MRI studies have also found that T carriers have larger hippocampal volumes¹²¹² larger hippocampal volumes
Palombo DJ et al. KIBRA polymorphism is associated with individual differences in hippocampal subregions. J Neurosci, 2013, specifically in the CA fields and dentate gyrus — regions critical for memory encoding.

A meta-analysis of 20 case-control studies¹³¹³ meta-analysis of 20 case-control studies
Ling J et al. Association of KIBRA polymorphism with risk of Alzheimer's disease. Neurosci Lett, 2018 found that CC homozygotes had a modestly increased risk of Alzheimer's disease compared to T carriers (OR=1.23 in the homozygote model, OR=1.14 in the dominant model), particularly among older individuals. Recent research has illuminated why: the KIBRA C-terminal fragment repairs synaptic plasticity¹⁴¹⁴ repairs synaptic plasticity
Bhatt N et al. KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss. J Clin Invest, 2024 disrupted by pathogenic tau protein, suggesting KIBRA-mediated synaptic maintenance may protect against neurodegeneration.

Practical Implications

The effect of rs17070145 on memory is real but modest — this is not a gene that determines whether you have a "good" or "bad" memory. The 0.5% of variance explained means that hundreds of other genetic and environmental factors matter far more for your overall memory ability. Education, sleep, exercise, social engagement, and cognitive activity all have substantially larger effects on memory performance than any single common genetic variant.

That said, understanding your KIBRA genotype can inform your approach to brain health. CC homozygotes may benefit more from proactive cognitive maintenance strategies, while T carriers can take some reassurance that their baseline synaptic plasticity machinery is operating efficiently. For everyone, the same lifestyle factors that support general brain health — aerobic exercise, quality sleep, cognitive challenge, and social connection — also support the synaptic plasticity pathways that KIBRA participates in.

The Alzheimer's association adds a long-term dimension: while the absolute risk increase for CC homozygotes is small, it provides additional motivation for lifelong brain health habits, especially in combination with other risk factors.

Interactions

KIBRA rs17070145 interacts with APOE genotype in the context of Alzheimer's risk. Research in 602 cognitively normal adults followed over six years found that APOE epsilon-4 carriers who were also CC homozygotes at rs17070145 showed significantly faster rates of cognitive decline and hippocampal atrophy when amyloid-beta burden was high, compared to T carriers. The T allele appeared to confer resilience against the detrimental effects of APOE epsilon-4 and amyloid accumulation.

KIBRA also interacts with CLSTN2 (calsyntenin 2, rs6439886). The memory-enhancing effect of the KIBRA T allele is modulated by CLSTN2 genotype, with the two genes showing interactive effects on episodic memory performance. Both proteins are involved in synaptic plasticity pathways in the hippocampus.