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Neuroscience Letters 458 (2009) 140–143

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Neuroscience Letters
journal homepage: www.elsevier.com/locate/neulet

Association of KIBRA and memory


Timothy C. Bates a,∗ , Jackie F. Price b , Sarah E. Harris a , Riccardo E. Marioni b , F. Gerry R. Fowkes b ,
Marlene C. Stewart b , Gordon D. Murray b , Lawrence J. Whalley c , John M. Starr d , Ian J. Deary a
a
Department of Psychology, University of Edinburgh, 7 George Square, EH89JZ, Scotland, UK
b
Division of Community Health Sciences, University of Edinburgh, Scotland, UK
c
Department of Mental Health, University of Aberdeen, Scotland, UK
d
Geriatric Medicine Unit, University of Edinburgh, Scotland, UK

a r t i c l e i n f o a b s t r a c t

Article history: We report on the association of KIBRA with memory in two samples of older individuals assessed on
Received 15 January 2009 either memory for semantically unrelated word stimuli (Rey Auditory Verbal Learning Test, n = 2091),
Received in revised form 21 April 2009 or a measure of semantically related material (the WAIS Logical Memory Test of prose-passage recall,
Accepted 22 April 2009
n = 542). SNP rs17070145 was associated with delayed recall of semantically unrelated items, but not
with immediate recall for these stimuli, nor with either immediate or delayed recall for semantically
Keywords:
related material. The pattern of results suggests a role for the T → C substitution in intron 9 of KIBRA in a
Memory
component of episodic memory involved in long-term storage but independent of processes shared with
KIBRA
AVLT
immediate recall such as rehearsal involved in acquisition and rehearsal or processes.
Logical memory © 2009 Published by Elsevier Ireland Ltd.
Association

Papassotiropoulos et al. [17] recently reported an association of an visual stimuli, the effect may be independent of stimulus modality
intronic substitution in KIBRA with better 5 min- and 24 h-delayed [17].
recall of a list of unrelated nouns. Understanding this associa- Since the initial report, three reports on replication attempts
tion provides both an opportunity for fractionating the complex have been published. In a small sample (64 subjects recruited for
memory phenotype into biologically distinct components and the studies on cognition in normal aging), Schaper et al. [20] reported
potential for novel therapeutic interventions in successful aging and a trend to better delayed recall on a German version of the AVLT,
memory retention. and a significant relationship of KIBRA with immediate recall and
The improved performance in T-carriers of the rs17070145 SNP delayed recognition. On the other hand, Need et al. [16] reported
was initially discovered in a pooled-DNA genome-wide association no support for association of rs17070145 with either immediate
study of 351 Swiss subjects aged 18–48 years. In the second sample or 30-min delayed recall in 384 German individuals aged 22–75
of 256 adult US subjects, this SNP again showed association with tested on the AVLT. Of 42 additional KIBRA SNPs tested only one
30-min delayed recall performance (but not immediate recall) on reached nominal significance (0.03) and this was not in LD with
the Rey Auditory Verbal Learning Test (AVLT)—a standardized test rs17070145. This group also found no support for association for
of learning a list of 30 unrelated nouns [AVLT: [15]], and improved rs17070145 in 300 individuals of European background aged 18–77
scores on Buschke’s Selective Reminding Test. Finally, in a sam- tested on immediate recall following a single presentation of 12
ple of 424 18–28-year-old Swiss adults, T-allele carriers showed unrelated words, nor for immediate or 30-min delayed recall of
improved 10-min delayed recall of semantically unrelated picture prose-passage recall in an overlapping sample of 76 individuals.
stimuli. In none of these samples was KIBRA associated with pro- The status and phenotype of KIBRA are thus important but
cesses of attention or working memory, nor with immediate recall. currently unclear. Here we report data from two samples, one
These three coherent findings suggest that KIBRA is specific for a of 2091 subjects from the general population participating in a
process affecting the retention of information across a delay, but clinical trial tested on the AVLT (an exact replication phenotype of
which does not alter short-term storage, rehearsal, or retrieval. As one of the Papassotiropoulos studies) and the second sample of 542
learning of unrelated information was affected for both verbal and subjects from a study of normal aging tested on a prose-passage
memory task (the Logical Memory subscale of the Wechsler
Memory Scale—Revised [LMT: 24]). These samples allowed us to
examine immediate and delayed memory for related and unrelated
∗ Corresponding author. Tel.: +44 131 6511945; fax: +44 131 6511771. information, with 99% power to detect an effect similar to that
E-mail address: tim.bates@ed.ac.uk (T.C. Bates). demonstrated previously for episodic memory in both samples

0304-3940/$ – see front matter © 2009 Published by Elsevier Ireland Ltd.


doi:10.1016/j.neulet.2009.04.050
T.C. Bates et al. / Neuroscience Letters 458 (2009) 140–143 141

Table 1
AVLT Memory Marginal Means (and SDs) for AAA sample by T-carrier status.

Female Male Female Male

AVLT trial CC C|T/T CC C|T/T NA


Trial 1 5.53 (1.78) 5.64 (1.82) 4.97 (1.68) 5.23 (1.83) 5.48 (1.78) 5.18 (1.38)
Trial 2 8.38 (2.29) 8.39 (2.30) 7.31 (2.10) 7.60 (2.01) 8.33 (2.48) 7.06 (2.22)
Trial 3 10.18 (2.45) 10.16 (2.41) 8.86 (2.52) 9.11 (2.41) 10.13 (2.34) 8.47 (2.00)
Trial 4 11.98 (2.45) 11.94 (2.38) 10.43 (2.66) 10.87(2.48 11.86 (2.46) 10.76 (2.08)
Trial 5 (list B) 5.03 (1.93) 5.04 (1.98) 4.41 (1.85) 4.88(1.82) 4.79 (1.82) 4.41 (1.12)
Trial 6 (delay) 10.02 (3.21) 9.72 (3.20) 8.17 (3.03) 8.56 (3.22) 9.51 (3.38) 7.71 (3.29)
Trial 7 10.15 (3.35) 9.86 (3.43) 8.11 (3.27) 8.44 (3.37) 9.24 (3.59) 6.82 (2.72)

and retained 95% power to detect an effect less than one-tenth of an interference trial learning the second list, and subsequent recall,
the reported magnitude [18]. and recognition memory trials for the original list. Subjects also
Sample one was recruited as a community sample from gen- completed the Raven’s Progressive Matrices: (RAVEN) [19], a test
eral practices throughout central Scotland for the Aspirin for of non-verbal reasoning scored as number of items completed cor-
Asymptomatic Atherosclerosis (AAA) randomized controlled trial rectly within 20 min.
of aspirin in the prevention of cardiovascular events and death in For the LBC sample, memory was assessed using the Wechsler
subjects with asymptomatic atherosclerosis (total n = 3350) [1]. The Logical Memory Test [24]. Participants were read aloud two themat-
subjects in this analysis consisted of all 2091 subjects from the origi- ically independent stories, with an immediate recall task following
nal 3350 recruited into the trial who: (a) were still alive after 5 years, the story, encouraging word-for-word recall. After a 30-min delay,
when the cognitive testing was done and (b) agreed to undergo during which a standard set of intervening tasks occurred, partic-
the cognitive testing and to provide a DNA sample. There were no ipants were asked to recall the stories without having heard them
other inclusion criteria and recruitment was random with respect to again. The Wechsler Memory Test used in the LBC sample is com-
aspirin/placebo condition (allocation to which also was random). To mon in memory and cognitive impairment research. It correlates
recruit subjects for the AAA trial, over 28,000 subjects aged over 50 around 0.4 with the AVLT reflecting substantial overlap, but also
years from the general population of central Scotland agreed to be distinct demands of learning and recall of prose-based rather than
assessed for asymptomatic atherosclerosis and possible inclusion unrelated word material [13]. In addition to the LMT, subjects had
in the trial. This screened population was found to be representa- available general cognitive ability measures at age 11 [6,21] and
tive of the general population of central Scotland in terms of age, sex including, at age 79 the Raven, administered as in the AAA sample.
and deprivation category of residence. Subjects were then selected LMT scores were normally distributed about a mean of 31.7
for participation in the trial on the basis of evidence of asymp- (range 2–73, SD = 12.8, 2 missing) and AVLT scores (sum of first
tomatic atherosclerosis and therefore poorer cardiovascular risk 5 trials + interference and recall trials) had a mean of 63.4 (range
factor profile. Compared to those not tested, subjects that under- 14–102, SD = 16.57, NA = 349). Tables of marginal means and SDs for
went cognitive testing were on average slightly younger, more likely the memory test scores separately for sex and genotype using a
to be female and had a slightly better cardiovascular risk factor pro- strict exclusion criterion of MMSE > 27 are given in Tables 1 and 2
file. Thus, the AAA Trial sample is a community-based sub-group for the LBC and AAA samples respectively. Counts of C/C, C/T, and
broadly representative of the general population. T/T genotypes were 254, 218 and 57 sample and 1040, 1020, and
AAA subjects underwent cognitive testing between 4 and 7 years 203 in the 2359 genotyped members of the AAA Trial sample. The
after recruitment into the trial when they were aged 55–82 years minor (T) allele frequency was 31% in both the AAA LBC1921 sam-
(mean 67.3). The test battery was administered in a quiet room ples. Analyses of KIBRA reported here used the two-level T-carrier
either in a research clinic or at the patient’s home by a trained status variable, as used in Papassotiropoulos et al. [17].
researcher. The order of tests in the battery was predetermined. As prior reports suggest that KIBRA affects only delayed recall,
Sample two consisted of 542 members of the Lothian Birth and is unrelated to learning-phase or immediate recall perfor-
Cohort 1921 (LBC1921) [8]. All subjects were born in 1921, and mance [17], we examined the effect of KIBRA on AVLT delayed
participated in the Scottish Mental Survey 1932, involving admin- recall performance, controlling for differences in initial learning.
istration of the Moray House Test (MHT) of intelligence at age 11. This was accomplished by creating a variable summing items
They have been traced and given both follow-up general ability tests correctly recalled on the 5 AVLT learning trials as a measure of
as well as a number of additional measures of cognitive and non- initial learning, then using multiple regression to test the relation-
cognitive function [8]. Subjects were a mean age of 79 at the time of ship of delayed recall performance to T-carrier status, controlling
testing for the present study, with a very narrow range. All subjects for the initial learning measure, age and sex. This analysis was
lived independently in the community. significant (adjusted R2 0.66, F(4,1926) = 936, p < 2.2e−16) and,
Genotyping was performed in the AAA Trial sample using either importantly, KIBRA T-carrier status significantly affected delayed
Competitive Allele Specific PCR (KASPar) or Taqman chemistry from recall (beta = −0.26, t = −2.890, p = 0.004). The effect of prior learn-
Applied Bioscience, as appropriate for the sample through vali- ing was of course highly significant (t = 57.532, p < 2e−16). Age was
dation assays, and in the LBC1921 sample using TaqMan. Primer
information is available on request.
Table 2
Genotypes were analyzed using PEDSTATS [25] to check
Logical Memory Marginal Means (and SDs) by T-carrier Status for LBC sample.
Mendelian errors, sample identity as well as Hardy-Weinberg
equilibrium. Where zygosity or sample identities were suspected, Sex
sample histories were reviewed and when necessary, genotyping Female Male
was repeated with DNA isolated from a backup sample: typing Genotype: CC C|T/T CC C|T/T
failed for 13 individuals in the LBC1921 and for 43 individuals in Logical memory 32.29 (12.61) 32.41 (11.94) 34.40 (15.24) 32.73 (10.63)
the AAA Trial sample. total
Immediate and delayed memory was assessed in the AAA sam- Immediate recall 19.29 (6.25) 19.33 (5.74) 20.30 (7.61) 19.74 (5.28)
Delayed recall 13.00 (6.81) 13.08 (6.68) 14.10 (7.98) 12.99 (5.90)
ple using the AVLT, consisting of 5 learning trials of a 15-word list,
142 T.C. Bates et al. / Neuroscience Letters 458 (2009) 140–143

not significant (p = 0.82: suggesting that the effects of age were and correlate around 0.4 [13], neuropsychological data indicate
accounted for by controlled for learning across the immediate- that the AVLT is a more sensitive discriminator of traumatic brain
learning trials), and sex had a marginal effect (p = 0.049), with injury patients than is the Logical Memory Test [2]. While a lack
males recalling 0.2 fewer items than females on average. To avoid of semantic context might simply make the unrelated word recall
confounding mild cognitive impairment with normal variation in task harder, perhaps via a reduction in support for recollection, the
memory, initial analyses excluded subjects if they scored less than lack of association to immediate recall or to working memory in any
24 on the Mini-Mental State Examination (MMSE) [10] a widely sample studied to date does, however, suggest that the KIBRA poly-
used screening test for dementia. However, in all cases analyses morphism is unrelated to differences in the encoding of information
were similar whether using strict MMSE criteria for exclusion, mod- or to short-term rehearsal processes. This suggests that KIBRA is
erate criteria, or no exclusion criterion. Similarly controlling for specific for processes involved in storage and/or recollection, specif-
Raven’s Matrices score (intelligence) did not alter the association ically in which storage and retrieval based on item-distinctiveness
of KIBRA to delayed recall performance, and neither Raven’s nor (rather than semantic-relatedness) is required.
MMSE were related to KIBRA (tested using linear models treating At a cognitive level, the Logical Memory Test rewards rela-
these as DVs, with KIBRA status, age, and sex as IVs, p = 0.68 and tional coding, while for the AVLT where specific items must be
0.84 respectively). Importantly, and unlike the original report [17], recalled, encoding the distinctive elements of each word (item-
delayed recall was not significantly associated with KIBRA status specific information) along with generating a context (relation
when initial learning was not controlled (p = 0.98). While KIBRA was context for recalling all the words) will best support recall at a later
related to specifically to delayed recall controlling for initial per- date. Deficits in either the distinctiveness of item representations,
formance on the learning trials, learning trial performance itself or in the generation of context to organize recall are candidate pro-
was unrelated to KIBRA status (p = 0.339). Thus results suggested an cesses for the involvement of KIBRA in selective poor recall for AVLT
effect of KIBRA, of modest size and specific to forgetting over the items while leaving LMT scores in tact.
delay interval. At a biological level, structures involved in long-term mem-
Analyses of Wechsler Logical Memory Test performance in the ory include the medial temporal lobe (MTL [23]) especially the
LBC sample showed no association of KIBRA to immediate or hippocampus and perirhinal [3] and parahippocampal circuits
delayed recall. The mean LMT scores for the “CC” and “T-carrier” that converge on the entorhinal cortex and from there enter
groups were 32.3 and 31.5 respectively: a difference both in the the hippocampus [14], and the prefrontal cortices. Imaging data
opposite direction to that reported, and non-significant (Welch 2- in the original report of the significance of KIBRA for mem-
sample t-test (t(497.7) = 0.72, p = 0.47, 95% CI: −1.38 to 3.00)). Unlike ory implicated the hippocampus [17] a finding supported by
delayed recall for semantically unrelated list material in the AAA lesion studies indicating that the hippocampus supports recall (as
sample, KIBRA T-carrier status remained non-significant in a lin- opposed to recognition), especially of relational material [11]. Fur-
ear model of delayed prose-passage recall, controlling for sex and ther work is required to determine whether hippocampal system
immediate recall (F(1,523) = .48, p = 0.49). No effects of sex were deficits alone could cause a selective inability to recall item-
seen for prose-passage recall (p = 0.71). A large effect of intelli- memory, leaving recall of relational material intact. Prefrontal
gence test scores on memory was found: both for ability measured lesions are associated with difficulties in learning, particularly
68 years earlier at age 11 (F(1,515) = 31.7, p < 0.00001) and concur- semantic encoding in the case of anterior and posterior ven-
rently, at age 79 (F(1,515) = 117.3, p < 0.000001)). However KIBRA trolateral prefrontal cortex [9], rehearsal during learning, and
was unrelated to intelligence at either age 79 or 11 (p = 0.65 and 0.40 with effective recall of relational material [22]. Intact learning-
respectively), and controlling for intelligence in addition to sex did phase performance suggests that KIBRA is not involved in these
not reveal any significant effect of KIBRA on immediate memory or prefrontal processes. A range of lesion and studies suggest that
delayed memory controlling for immediate memory (p = 0.65 and familiarity, assessed by item-recognition is dependent on intact
0.837 respectively). perirhinal cortex, with lesions outside this area not affecting item-
In order to increase the sensitivity of the analyses to specific memory and lesions to this area disrupting item-memory [26].
effects of KIBRA on logical memory, we explored the effects of A null effect for recognition, as opposed to recollection suggests
controlling for components of the “genetic pathway” for cognition that KIBRA may not be involved in perirhinal familiarity-based
and memory including the COMT Val158Met polymorphism [12], processing.
KLOTHO [5], NCSTN [4] and APOE [7] in addition to the behavioral In summary the present findings support a role for KIBRA in
controls of sex and immediate recall. Including these covariates processes specific to the conscious recall of item-based material,
failed to alter the non-significant nature of the analyses, though possibly reflecting hippocampal processing. The result suggests a
both APOE and COMT show significant associations with memory high degree of genetic specificity within the neuronal systems sup-
in this sample [7,12]. porting memory and underscore both the need for attention to
The present result, indicating genetic effects specific to the phenotype, and for research deploying sophisticated phenotypes
forgetting of unrelated-item material, independent of learning in large-scale genetic studies of human memory.
rates and immediate recall, and leaving relational (prose-passage)
material unaffected, helps to locate the role of KIBRA within the neu- Conflict of interest
roscience of memory, and emphasizes the articulated nature of the
memory system [14]. Two findings appear most important. Firstly, No author has any actual or potential conflict of interest, includ-
attention to the precise phenotype of a gene is likely to be important ing any financial, personal or other relationships with other people
in successful replications. Second, while our understanding of the or organizations that could inappropriately influence their work.
genetics of human memory is in its infancy, knowledge of genetic
phenotypes help specify and validate psychological and biological Disclosure statement
models of memory.
The effects of KIBRA on episodic memory appear in this sample None of the authors’ institutions has contracts relating to this
to be modest and specific for a particular cognitive component of research through which it or any other organization may stand to
memory related to item-based recall, rather than affecting a broad gain financially now or in the future. Nor did any author or institu-
range of memory phenotypes. While both the Wechsler and AVLT tion have any other agreements that could be seen as involving a
tests are common in memory and cognitive impairment research financial interest in this work.
T.C. Bates et al. / Neuroscience Letters 458 (2009) 140–143 143

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