Investigating the influence of KIBRA and CLSTN2 genetic polymorphisms on cross-sectional and longitudinal measures of memory performance and hippocampal volume in older individuals

Abstract

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe variability of episodic memory decline and hippocampal atrophy observed with increasing age may partly be explained by genetic factors. KIBRA (kidney and brain expressed protein) and CLSTN2 (calsyntenin 2) are two candidate genes previously linked to episodic memory performance and volume of the hippocampus, a key memory structure.However, whether polymorphisms in these two genes also influence age-related longitudinal memory decline and hippocampal atrophy is still unknown. Using data from two independent cohorts, the Sydney Memory and Ageing Study and the Older Australian Twins Study, we investigated whether the KIBRA and CLSTN2 genetic polymorphisms (rs17070145, rs6439886) are associated with episodic memory performance and hippocampal volume in older adults (65-90 years at baseline). We were able to examine these polymorphisms in relation to memory and hippocampal volume using cross-sectional data and, more importantly, also using longitudinal data (2 years between testing occasions). Overall we did not find support for an association of KIBRA either alone or in combination with CLSTN2 with memory performance or hippocampal volume, nor did variation in these genes influence longitudinal memory decline or hippocampal atrophy in two cohorts of older adults.

Age-Modulated Associations between KIBRA, Brain Volume, and Verbal Memory among Healthy Older Adults

“…Other studies have found larger hippocampal volumes for T carriers compared to CC homozygotes ( Palombo et al, 2013 ; Witte et al, 2016 ). A recent longitudinal study of older adults failed to detect differential hippocampal volume decline over a 2-year period in T carriers and CC homozygotes ( Boraxbekk et al, 2015 ). Few studies have examined regional brain volumes other than the hippocampus (for example, Wang D. et al, 2013 examined frontal and posterior cingulate regions associated with the default mode network), but to the best of our knowledge, no studies have examined this issue using voxel-based whole brain methods.…”

“…As an example, Almeida et al (2008) found that KIBRA allele variants have minimal impact once significant cognitive decline is evident among older adults, presumably due to incipient neurodegenerative disease. KIBRA studies have increasingly matched allele groups on some of the major factors that may negatively impact memory performance among older adults ( Wersching et al, 2011 ; Boraxbekk et al, 2015 ; Witte et al, 2016 ).…”

“…Last, we hypothesized that the hippocampus would be a region especially impacted by KIBRA such that T carriers would have greater hippocampal volumes than CC homozygotes and the difference in volumes would be greatest in the older old group. Multiple imaging studies of KIBRA have focused on the hippocampus ( Papassotiropoulos et al, 2006 ; Palombo et al, 2013 ; Boraxbekk et al, 2015 ; Witte et al, 2016 ) given KIBRA ’s links to episodic memory and hippocampal functioning ( Schneider et al, 2010 ; Milnik et al, 2012 ).…”

Phosphorylation of multiple sites within an acidic region of Alcadein α is required for kinesin-1 association and Golgi exit of Alcadein α cargo

“…Alcβ appears to have acquired other functions during evolution ( Pettem et al , 2013 ; Um et al , 2014 ; Wang et al , 2014 ), and Alcβ can also interact with kinesin-1 ( Kawano et al , 2012 ). Alcγ expression may be lower in adults than expression of Alcα and Alcβ ( Hata et al , 2011 ), but Alcγ also binds kinesin-1 and may be involved in memory performance and cognition ( Boraxbekk et al , 2015 ; Lipina et al , 2016).…”

Whole transcriptome profiling of the human hippocampus suggests an involvement of the KIBRA rs17070145 polymorphism in differential activation of the MAPK signaling pathway

“…Also more recent studies investigated the role of rs17070145 in memory performance in different population samples, reporting contrasting results. (Muse et al, 2014; Franks et al, 2014; Boraxbekk et al, 2015; Witte et al, 2016). Muse et al (2014) studied the correlation between rs17070145 and scores in cognitive tests in a Caucasian sample, detecting an association between better delayed recall performance in the T-carriers versus the C/C carries.…”