The data reported here support the hypothesis that KIBRA genotype, in combination with APOE ε4 and Aβ-amyloid, affects rates of memory decline and hippocampal atrophy in cognitively normal adults. In those CN adults with high Aβ-amyloid burden at baseline, KIBRA non-T carriers showed significantly faster decline in the statistically driven global composite, and verbal episodic memory when compared to T carriers with low Aβ-amyloid burden. Within the subset of CN adults with high Aβ-amyloid burden, we showed that those who are APOE ε4 + ve and KIBRA non-T carriers had significantly faster rates of decline in verbal episodic memory over 6 years, compared to APOE ε4 + ve/KIBRA T carrier and both APOE ε4-ve groups. Importantly, minimal decline was also observed in the APOE ε4 + ve/KIBRA T carrier group, suggesting that carriage of the KIBRA T allele imparts a level of resilience to negative effects of APOE ε4 and Aβ-amyloid on memory performance. Further, between group comparisons of the rates of clinical conversion (CN > MCI/AD) over the course of the study revealed no significant differences, suggesting that the faster rates of decline were not due to a higher rate of clinical conversion.

This is further supported by the observations that rates of hippocampal atrophy in this study also differ based on KIBRA genotype. In CN adults Aβ-amyloid has been previously reported to be associated with increased hippocampal atrophy2,35,36, however in this study this was only observed in those individuals who did not possess the KIBRA T-allele, whilst in contrast KIBRA T-carriers’ rate of atrophy did not significantly differ from the Αβlow groups. In a meta-analysis of APOE neuroimaging studies, hippocampal atrophy has been shown to be increased in APOE ε4 carriers5. Here we report that this association, in a group of Αβhigh CN individuals, was again only observed in those individuals who did not possess the KIBRA T-allele, whilst in contrast APOE ε4 + ve/KIBRA T-carriers’ rate of atrophy did not differ from the APOE ε4-ve groups. Taken together, we propose that the KIBRA T allele affords carriers a level of resilience to the detrimental effects of Aβ-amyloid and APOE ε4 allele on neurodegeneration, specifically hippocampal atrophy.

The findings presented herein are in line with the original study12 and subsequent reports linking the KIBRA T allele with resilience in episodic memory performance18,19,20,21,24. The absence of replication by other studies27,28,29,31,32,33 may be in part due to the lack of consistency in the measures of memory decline, whereby varying single neuropsychological tests, aiming to measure a certain feature of memory or cognition, were used. The use in this current study of a combination of global and episodic memory composite scores, which encompass several different tests best associated with a cognitive construct, could also have contributed to the ability to detect associations with the KIBRA genotype. However, the lack of inclusion of an assessment of underlying Aβ-amyloid burden in the previous studies may in fact be the more telling contributor to the lack of consensus on the association of KIBRA with cognitive performance. The level of neocortical Aβ-amyloid is associated with differential rates of cognitive decline1,37, and this is further altered by genetic factors, in particular APOE10,11 and BDNF6,7. Accounting for the underlying Aβ-amyloid burden in the current study may have further contributed to the detection of differences in rates of cognitive decline and hippocampal atrophy reported with APOE ε4 and KIBRA.

Whilst the incorporation of cognitive composites and accounting for underlying Aβ-amyloid burden is considered a strength of this study, the following limitations of the study are acknowledged. Firstly, the use of different cognitive tests individually or in combination for the calculation of domain composites, then those specifically described in this study and using the methodology described herein, may yield different results. Second, this study included 6-years of longitudinal follow-up and validation in other longitudinal cohorts, not undertaken herein, over longer durations of follow-up, may result in different findings. Third, the cognitively normal participants in this study were volunteers and not selected at random from the community, they were generally well educated and performed well on cognitive assessments and as such the findings presented herein may be applicable only to similar cohorts. Fourth, there is an overlap between those who are Aβhigh and those who are APOE ε4 + ve, which could confound the results when looking at their interaction. Finally, the KIBRA T-allele’s previously reported association with altered brain activation using fMRI12,19 could not be tested due to the lack of fMRI data, under a non-resting state, in the AIBL Study.

Studies have previously demonstrated the main areas of KIBRA expression in the brain are those also that are implicated in memory function, the hippocampus and temporal cortex12,38. Furthermore, increased KIBRA gene expression in the temporal cortex39 and hippocampus22 has been associated with late onset AD. However, in a recent post-mortem brain transcriptomic study in neuropathogically normal individuals by Piras and colleagues a trend towards increased KIBRA gene expression was observed in KIBRA T homozygotes40. Further quantitative PCR analysis reported an over-expression in T-homozygotes compared to C-homozygotes in the hippocampus40. Further, the transcriptomic analysis revealed differential activation of the MAPK pathway40, a pathway important in learning and memory processes, suggesting a potential mechanism underpinning a decline in memory performance reported in this study. It has also been shown that there is increased hippocampal activity in episodic memory performance tasks in KIBRA T carriers when compared with non-T carriers19, consistent with the notion of protection from memory decline. KIBRA T allele carriers have also been shown to have a decreased levels of brain activation compared to non-T allele carriers in several hippocampal regions activated during memory retrieval12. The authors hypothesised that individuals who do not carry the T allele require a greater level of hippocampal activation for memory retrieval12.

In addition to the association studies described above, recent in vivo evidence provides molecular insights into mechanisms by which KIBRA is involved in memory performance. Synaptic plasticity, which is altered in AD, is modulated by dendrin, which in turn binds to the protein that KIBRA encodes (KIBRA; see review41). Further, KIBRA protein contains a protein kinase C (isoform ζ; PKCζ) binding domain42 and has been reported to co-localise with protein kinase M (isoform ζ; PKMζ)43, a brain specific variant of PKCζ, which plays important roles in memory formation and long-term potentiation. Johannsen et al. have shown the function of the KIBRA protein to be regulated by its C2 domain38, which is required for Ca2+ binding and is therefore involved in signal transduction in the neurons. This regulation is hypothesised to mediate the effect of the KIBRA protein on memory formation38. In a recent study, Tracy and colleagues have proposed a novel mechanism by which acetylated tau associated memory loss and disruption of synaptic plasticity is mediated by a reduction in postsynaptic KIBRA protein14. This finding links the previous reports of reduced KIBRA gene expression in AD with a biological mechanism mediated by acetylated tau. Whether the KIBRA T allele affords a level of resilience to this loss of synaptic plasticity remains to be determined.

Our findings indicate that KIBRA rs17070145 genotype, when combined with high brain Aβ-amyloid burden and APOE ε4 carriage, modifies longitudinal rates of decline in verbal episodic memory, a global cognitive composite and hippocampal volume. We propose that early in the disease process of AD, carriers of the KIBRA T-allele are conferred a level of resilience to Aβ-amyloid and APOE ε4 driven decline. The potential mechanisms by which KIBRA contributes to synaptic plasticity, and AD progression warrant further investigation, including the potential impact on Aβ-amyloid accumulation, and may reveal novel pathways contributing to neuroprotection/neurodegeneration. Our results also highlight the potential application of genetics for risk stratification when designing clinical trials, particularly those that employ Aβ-amyloid imaging for screening. The nature of the effects of genetic variations, specifically assessing the combined effect(s) of additional genes affecting cognitive performance would have merit in such settings and requires further investigation.