Predicting Cognitive Decline: Genetic, Environmental and Lifestyle Risk Factors
Date
2017
Authors
Andrews, Shea J
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Abstract
With advancing age individuals experience a deterioration in
cognitive abilities that is characterized by substantial
inter-individual variation in the observed trajectories of
cognitive decline. Late onset Alzheimer’s disease (LOAD)
susceptibility genes and environmental risk factors are good
candidates for association with cognitive decline, as the
pathological features of LOAD progress to varying degrees in
individuals without dementia or cognitive impairment and are
associated with nonclinical cognitive decline.
This thesis investigates whether Alzheimer’s disease risk
factors and genetic variants previously associated with cognitive
function are also associated with cognitive decline. Data
collected from the 60+ cohort of the Personality and Total Health
(PATH) through life project was used, in which 2,551 participants
were assessed at 4-year intervals for a total of 12 years on a
comprehensive battery of cognitive tests.
The publications in this thesis investigate the following. First,
whether APOE*4 moderates the association between high blood
pressure and cognitive function in late life. It was observed
that a APOE–hypertension interaction was associated with a
small but statistically significant increase in the rate of
decline of episodic memory, verbal ability and global cognition.
In contrast, the interaction between APOE and mean arterial
pressure interaction had no effect on rate of decline.
Second, the role of 25 LOAD risk loci in non-linear cognitive
change was examined, both individually and collectively as a
genetic risk score (GRS). Twelve LOAD risk loci were associated
with baseline cognitive performance (ABCA7, MS4A4E, SORL1),
linear rate of change (APOE, ABCA7, EPHA1, INPP5D, ZCWPW1, CELF1)
or quadratic rate of change (APOE, CLU, FERMT2). In addition, a
weighted GRS was associated with linear rate of change in
episodic memory and information processing speed.
Third, the role of 9 single nucleotide polymorphisms that have
been previously associated with cognitive performance was further
examined, with 6 SNPs observed to be associated with baseline
cognitive performance (BDNF, PDE7A, AKAP6), linear rate of change
(COMT, CTNNBL1, PDE7A) or quadratic rate of change (MIR2113).
Finally, it was examined whether a risk score comprised of
lifestyle, medical and demographic factors (the Australian
National University Alzheimer’s disease Risk Index; ANU-ADRI)
and a LOAD GRS were predictors of progression to Mild Cognitive
Impairment (MCI). A higher ANU-ADRI score was associated with a
higher probability of transitioning from normal cognition to
cognitive impairment, while the GRS was associated with an
increased risk of transitioning from normal cognition to
dementia.
These results suggest that a subset of LOAD related SNPs may be
associated with cognitive decline. However, the effect size of
each locus is small and when demographic and lifestyle factors
are taken into account, neither individual SNPs nor GRS explain a
significant proportion of the variance in cognitive decline in
our sample. Further research is required to verify these results
and to examine the effect of preclinical LOAD in genetic
association studies of cognitive decline. The identification of
LOAD risk loci associated with cognitive performance may help in
screening for individuals at greater risk of cognitive decline
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Cognitive Decline, Alzheimer's Disease, Dementia, Genetics, Risk Factors
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Thesis (PhD)
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