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Interaction between neuropsychology and genetics
in mild cognitive impairment
Szabolcs Kéri, M.D., Ph.D., D.Sc. Semmelweis
University, Budapest, Hungary
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I. Will recent discoveries in the genetics of
memory help the identification of susceptibility
genes for amnestic mild cognitive impairment
(aMCI)?II. What is the effect of genes on
neuropsychological performance in aMCI?
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Mild cognitive impairment (MCI)

• Subjective cognitive complaint
• Abnormal functions for age in one or more
  cognitive domains
• Decline in one or more cognitive functions
• Essentially normal functional activites
• Absence of dementia
• Types amnestic vs. non-amnestic, single domain
  vs. multiple domains

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What genes?

• Genes for cell membrane turnover and protein
  clearance - apoE
• Genes for neural plasticity BDNF
• Genes for signal transduction related to
  long-term potentiation in the hippocampus -
  KIBRA and others

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Brain activation during a memory task in healthy
elderly with and without genetic risk for AD
Comparisons of the carriers of the APOEe4 and
APOEe3 allele (bottom panel) greater extent and
magnitude of activity in the left prefrontal,
bilateral orbitofrontal, superior temporal, and
inferior and superior parietal regions in the
carriers of the APOEe4 allele.
Bookheimer SY et al. N Engl J Med 2000343450.
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What will predict progression from aMCI to
AD? Are genetics and hippocampal measurements
important?
Outcome measure progression to Alzheimer
disease (AD) from amnestic mild cognitive
impairment (aMCI) in 36 months. This is a
graphical plot representing a measure of relative
sensitivity for distinguishing those who
progress to AD in 36 months (n53) from those who
do not (n76).
Flesiher AS et al. Neurology 200870191., see
also Devanand DP et al. Neurology 200768828.
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Frequency of BDNF Val66Met in healthy elderly and
in aMCI

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BDNF Val66Met polymorphism and memory in healthy
elderly and in aMCI
WMS-R logical memory
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Is KIBRA really associated with memory? Is it
important in aMCI?
The frequency of the bad CC KIBRA genotype -
Healthy elderly 75 out of 179 (41.9) - aMCI
63 out of 133 (47.4)
Almedia O.P. et al. J Cell Mold Med, in press
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Multiple genes of signal transduction and
synaptic plasticity contribute to human
declarative memory
Significant SNPs rs263249 in ADCY8, rs3730386 in
PRKACG, hCV3114928 in CAMK2G, multilocus
haplotype in GRIN2B, rs1868291 in GRIN2A,
multilocus haplotype in GRM3, and hCV11612258 in
PRKCA.
- adenylyl cyclase 8 (ADCY8) - catalytic subunit
of cAMP-dependent protein kinase (PRKACG) -
subunit of calciumcalmodulin-dependent protein
kinase II (CAMK2G) - 2a and 2b subunits of the
ionotropic NMDA glutamate receptor (GRIN2A/2B) -
metabotropic glutamate receptor 3 (GRM3) -
protein kinase C (PRKCA)
De Quervain DJ et al. PNAS 20061034270.
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A new approach to test the hippocampal
systemacquired equivalence
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You experience these facts many times and receive
feedback (e.g. John smiles when Coke is offered)
John likes Coke. John likes baseball. Jim likes
Coke. Does Jim likes baseball?
How can you get new associations?
Acquired equivalence you need your hippocampal
region
The FISH-FACE task by Catherine E. Myers and Mark
A. Gluck
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A
Melyik hal tartozik hozzá?
HELYES!
B
Melyik hal tartozik hozzá?
HELYES!
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What does the FACE-FISH test tell about the
neuroscience of memory?

• Patients with hippocampal pathology can use
  feedback to learn associations
• Patients with basal ganglia disorders are
  impaired at using feedback to learn associations
• Patients with hippocampal pathology are impaired
  at acquired equivalence (new associations)

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The effect of BDNF Val66Met polymorphism on
FACE-FISH performance
Healthy elderly n123 aMCI n115
OLD old associations learned with feedback, NEW
new associations (acquired equivalence)
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The effect of KIBRA C/T polymorphism on
FACE-FISH performance
Healthy elderly n123 aMCI n115
OLD old associations learned with feedback NEW
new associations (acquired equivalence)
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Healthy elderly people with low and normal plasma
levels of TNF-alpha, IL-1alpha, IL-3
relationship with FACE-FISH performance
OLD old associations learned with feedback NEW
new associations (acquired equivalence)
Low protein -2SD below normal
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Lessons learned

• The genetic factors investigated in these studies
  are not associated with aMCI
• Genetic factors may modulate memory loss in aMCI
• Acquired equivalence a new and sensitive
  behavioral marker for hippocampal functions and
  aMCI

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What is the next step?

• Relationship between genetic and environmental
  factors (GxE interactions)
• Genes and conversion of aMCI to AD
• Network of multiple genes and their products
• (bioinformatic approach, omics)
• Relationship with new behavioral markers (e.g.
  FISH-FACE) and imaging/biomarkers

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The real challenge to find a therapeutic option
that prevents conversion to AD