Project Summary / Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide, accounting for
approximately half to two-thirds of all cases of dementia. It is associated with cognitive impairments and an
increase in ß-amyloid plaque (Aß) deposits. Moreover, alcohol use disorder (AUD) has been associated with
neurodegeneration and cognitive impairments, but the role of alcohol dependence on AD has been somewhat
controversial. Recent evidence suggests a likely role for alcohol use as a risk factor in onset and severity of
Alzheimer's disease, however overall reports have been mixed. Given the pervasive use of alcohol, it is critical
to understand the potential impact of alcohol drinking on AD. We will examine the impact of a history of alcohol
dependence on the onset and severity of behavioral and neuropathological symptoms associated with AD. We
will further examine how alcohol dependence influences neural network function in AD. We will assess whether
or not treatment with Memantine can reverse the behavioral and neuropathological symptoms. We hypothesize
that a history of alcohol dependence will result in an earlier onset of cognitive impairment in AD mice as well as
a greater presence of Aß deposits and that these deficits will be rescued by chronic treatment with Memantine.
We hypothesize that a history of alcohol dependence in AD mice will alter network connectivity (decrease
modularity and change hub regions) and that these effects will be alleviated by Memantine treatment. Alterations
of functional network connectivity that are caused by alcohol dependence will be assessed in a mouse model of
AD. These changes will be compared with the brain-wide spread of Aß deposits, which will indicate the way in
which AD affects brain-wide function, potentially beyond brain areas with signs of neuropathology. Furthermore,
the role of alcohol dependence in AD (e.g., changes in network connectivity and behavioral and
neuropathological symptoms) will be examined using a relevant translational preclinical model of AUD. Cognitive
function, anxiety-like behavior, and irritability-like behavior will be assessed in AD and wildtype alcohol drinking
and alcohol naive mice. The number and location of Aß deposits will be assessed AD mice. Differences in
network connectivity in AD and wildtype mice will be examined using hierarchical clustering and graph theory. If
alcohol dependence is found to impact the onset of neurological and behavioral symptoms of AD, then this will
be a highly significant finding that will have a broad impact on preclinical and clinical research. These potential
findings may also directly influence public guidelines for alcohol consumption, especially in those with a familial
risk for AD.