For decades, we have known that loss of acetylcholine (ACh) and cholinergic markers is a hallmark
of cognitive decline in aging. Yet, pro-cholinergic medications, the most widely used palliative
treatments, have only a modest (at best) effect on cognitive symptoms. Improving therapeutic
efficacy requires a detailed accounting of cholinergic changes in aging (Aim 1), deeper insight
into the structural underpinnings of these changes and whether functional modifications (e.g.
therapeutic action) can compensate for them (Aim 2), and an early marker of decline, signaling the
need for intervention (Aim 3). Using a translational approach, with parallel analysis in rodents
and humans, this is the information our study will provide. Rodent studies with transgenic mouse
models allow for visualization and quantification of cholinergic cell bodies and projection fields
in health and models of Alzheimer’s disease (AD). Using these models, we have shown that the long,
highly branched cholinergic projections and their terminations are particularly vulnerable, and
therefore likely compromised early in cognitive decline. Further, we are one of the few
institutions that have regulatory approval for, and have synthesized, the new radiotracer,
[18F]VAT. This tracer binds specifically to the vesicular ACh transporter (VAChT; protein that
packages ACh into vesicles), a sensitive marker for cholinergic function in vivo. We have
performed both clinical (PET) and preclinical (microPET) imaging with this tracer, using pilot
funding from the Alzheimer’s Foundation of America. Our compelling pilot data in humans reveals a
significant relationship between cognitive ability and VAChT density in the entorhinal cortex (EC),
a region known to be affected early in AD. In Aim 1, we will quantify this association in rodents
and humans, specifically focusing on spatial recognition memory, which is EC-dependent and
compromised early in AD. The human cohort will have a spectrum of cognitive deficits -- controls
through moderate cognitive impairment. Spatial recognition memory will be assessed by an Object in
Place (OiP) task administered by an expert neuropsychologist. The carefully designed translational
analogue of these studies in rodents is a cohort of control and AD rodent models at 3 and 6
months. Rodent cognition will be assessed through a displaced object recognition task, which we
have previously validated to assess spatial recognition memory. We hypothesize decreased [18F]VAT
uptake (microPET and PET) will be correlated to impaired spatial recognition memory. All human
participants will also receive amyloid beta imaging, to relate AD pathophysiology to cholinergic
tone. In Aim 2, we use the rodent model to uncover the mechanism by which changes to the
cholinergic system observed in Aim 1 can affect cognition and whether they can be functionally
reversed (mimicking therapeutics). EC structure will be probed with high throughput,
high-resolution microscopy and novel, targeted genetic probes to create 3D maps of EC cholinergic
terminal fields. This will be related to function by examining the system response to optogenetic
modulation and electrophysiology. By probing cholinergic structure and function changes in aging
and cognitive decline, we will shed light on the time course of cholinergic deficits. We examine
whether these deficits are predictive of AD conversion in Aim 3. Such studies are critical to
develop the next generation medications for cognitive impairment, a growing worldwide need.
