1. APOE, BDNF, and COMT play different roles in prediction of
neural and cognitive decline in normal aging and dementia
S.M. Landau , A.J. Saykin , H. Schwimmer , W.J. Jagust
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Helen Wills Neuroscience Institute, UC Berkeley; Indiana University School of Medicine
Introduction Methods Results and Summary
Several candidate gene polymorphisms may Participants Baseline: Cognitive tests and FDG ROIs
ApoE4+ subjects had marginally lower FDG-uptake in AD-related regions (p = 0.11) and marginally low
influence cognitive and neural decline in 72 healthy older individuals
Genotype distributions ADAS-cog scores (p = 0.10) than ApoE- subjects
normal aging 35% female
age = 76.1 +/- 4.8y ApoE BDNF COMT COMT val+ subjects had higher Logical Memory recall than COMT val- subjects (p = 0.01)
education = 16.1 +/- 2.9 y 4+ e4- met+ met- val+ val-
Apolipoprotein E (ApoE) follow-up time = 2.9 +/- 0.36 y N 20 52 21 51 49 23
BDNF met +/-, and COMT val +/- groups showed no other differences in cognitive tests or FDG ROIs at
baseline
Three isoforms ( 2, 3, 4) Genotype groups did not differ with respect to age,
education, MMSE, or hippocampal volume.
4 allele associated with cognitive and neural changes PET Imaging Longitudinal decline: Cognitive tests and FDG ROIs
in Alzheimer’s disease and normal aging ApoE4 + individuals showed greater decline in the hippocampus than ApoE- individuals (p = 0.001)
18F-Fluorodeoxyglucose images at multiple
Brain-derived neurotrophic factor (BDNF) timepoints downloaded from the ADNI database Regions of interest
ApoE4 +/-, BDNF met +/-, and COMT val +/- groups showed no differences in decline in AD-related ROIs or
(individual frames co-registered, averaged; uniform cognitive tests
val to met substitution at codon 66
(val66met)
resolution, voxel size, smoothing kernel = 8mm Significant longitudinal effects of genotype on metabolism
FWHM)
met carriers have lower hippocampal Regions in which BDNF met+ individuals show more FDG decline than met- individuals
volume, poorer episodic memory function Images were spatially normalized to the MNI
template, intensity normalized using a pons/vermis
Catechol-O methyl transferase (COMT) reference region AD-related regions Right
putamen
val to met substitution at codon 158 Regions of interest
(val158met) (1) pre-existing set of bilateral temporal, parietal, Bilateral
val carriers have higher dopamine Hippocampus
metabolism in the prefrontal cortex, leading to lower
and posterior cingulate regions known to decline in parahippocampal
AD and lingual gyri
dopamine availability and poorer dopamine-dependent (Landau et al., Neurobiol aging 2009)
working memory function (2) AAL-defined bilateral hippocampus Regions in which COMT val+ individuals show more FDG decline than val- individuals
Questions Cognitive testing
Right Bilateral
Longitudinal measurements obtained:
Do BDNF and COMT polymorphisms influence age-related Episodic memory (AVLT, Logical Memory) postcentral middle frontal
changes in (1) cognition and (2) decline? Global cognition (MMSE, ADAS-cog) Baseline Month 24 gyrus gyrus
Experimental design Statistical analysis Met+
Healthy older individuals (N = 72) from the Alzheimer’s Mixed effects regression models were used to Group
Disease Neuroimaging Initiative (ADNI) underwent ApoE, examine the influence of ApoE+/-, BDNF+/- and X Summary
BDNF, and COMT genotyping, and participants were COMT+/- genotype on rate of decline in regions ApoE+ subjects showed expected lower cognitive scores and FDG decline in hippocampus
categorized as follows: of interest and cognitive tests Time
Little effect of COMT/BDNF genotypes on cognition or FDG at baseline; lower Logical Memory scores for COMT
ApoE 4+/ 4-
Effect
SPM5: Group (+/-) X Time (Baseline, Month 24) val+ subjects is consistent with recent evidence that the val+ allele may have a protective effect in aging (Fiocco et
BDNF met+/met- Met-
ANOVAs were carried out for BDNF met+/met- al. Neurology, 2010)
COMT val+/val- and COMT val+/val- groups to determine FDG declines in hippocampal regions for BDNF met+ subjects, consistent with data suggesting that the met
whether genotype influenced longitudinal FDG
Cognitive testing and 18F-fluorodeoxyglucose decline allele impacts hippocampal morphology and function
(FDG-PET) imaging data for baseline and longitudinal FDG declines in prefrontal (and parietal) regions for val+ subjects, consistent with lower dopamine in the PFC
follow-up visits up to 36 months All models included age and ApoE as nuisance and related networks
variables