Abstract
A single nucleotide polymorphism, rs17070145, in the KIdney and BRAin expressed protein (KIBRA) gene has been associated with cognition and hippocampal volume in cognitively normal (CN) individuals. However, the impact of rs17070145 on longitudinal cognitive decline and hippocampal atrophy in CN adults at greatest risk of developing Alzheimer’s disease is unknown. We investigated the impact rs17070145 has on the rate of cognitive decline and hippocampal atrophy over six years in 602 CN adults, with known brain Aβ-amyloid levels and whether there is an interactive effect with APOE genotype. We reveal that whilst limited independent effects of KIBRA genotype were observed, there was an interaction with APOE in CN adults who presented with high Aβ-amyloid levels across study duration. In comparison to APOE ε4-ve individuals carrying the rs17070145-T allele, significantly faster rates of cognitive decline (global, p = 0.006; verbal episodic memory, p = 0.004), and hippocampal atrophy (p = 0.04) were observed in individuals who were APOE ε4 + ve and did not carry the rs17070145-T allele. The observation of APOE effects in only non-carriers of the rs17070145-T allele, in the presence of high Aβ-amyloid suggest that carriers of the rs17070145-T allele are conferred a level of resilience to the detrimental effects of high Aβ-amyloid and APOE ε4.
Highlights
In cognitively normal older individuals, high levels of neocortical amyloid-β (Aβ-amyloid) are associated with subtle but detectable cognitive decline[1] and hippocampal atrophy[2]
Co-varied for apolipoprotein E (APOE) ε4 carrier and Aβ-amyloid status (classified by being above (Αβhigh) or below (Αβlow) Positron Emission Tomography (PET) Aβ-amyloid tracer-specific thresholds) there were no significant differences in the trajectories between T carriers and non-carriers for measures of global cognition or episodic memory amongst cognitively normal (CN) adults (Supplementary Figure 1, Supplementary Table 1)
Within the subset of CN adults with high Aβ-amyloid burden, we showed that those who are APOE ε4 + ve and KIdney and BRAin expressed protein (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
Summary
In cognitively normal older individuals, high levels of neocortical amyloid-β (Aβ-amyloid) are associated with subtle but detectable cognitive decline[1] and hippocampal atrophy[2]. Decline in measures of episodic memory, modified by genetic variation, have been reported in both the healthy elderly[10] and those predicted to be in the early stages of AD based on neocortical Aβ-amyloid imaging[6,7,11] These findings raise the potential that other genetic factors may moderate the toxic effects of Aβ-amyloid early in AD and contribute to altered rates of cognitive decline and hippocampal atrophy. KIBRA is a cytoplasmic, signal transducer protein expressed mainly in the kidney and brain[13] and in vitro experiments suggest that, through reduction in postsynaptic levels, it mediates tau induced memory loss and disruption of synaptic plasticity[14] This in vitro data is supported through genetic studies that report the association of allelic variation in the KIBRA gene with memory performance, hippocampal atrophy and measurable differences in brain activation. Common to all these studies is the lack of inclusion of Aβ-amyloid imaging, which may contribute to the lack of consensus due to the impact of underlying Aβ-amyloid burden on cognition not being considered[1,6,7,11]
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