Abstract: Despite the significant contributions of transgenic mouse models to our understanding of Alzheimer’s
disease, NIA has concluded that these models may be “of poor predictive value in human clinical trials” [RFA-
AG-21-003]. As a result, there is a need for new, innovative, non-rodent, mammalian models that better
recapitulate the cellular, neuropathological, and cognitive hallmarks of late-onset Alzheimer’s Disease (LOAD).
These should include models in which risk factors for LOAD can be systematically induced, and in which
cognitive deficits that are the earliest hallmarks of LOAD can be assessed. There is convincing epidemiological
evidence that diet and lifestyle are important determinants of cognitive function, but it is unclear how factors such
as high cholesterol, obesity, and diabetes increase the likelihood of cognitive deficits. The purpose of the current
proposal is to develop, characterize, and validate unconventional, mammalian models that recapitulate the
cellular, neuropathological, and cognitive hallmarks of LOAD. The strategy is to feed male and female rabbits a
long-term, low-dose cholesterol diet in Aim 1, a high-fat diet in Aim 2, and a diet high in both sugar and fat in Aim
3 to recreate LOAD-like pathology and study the effects of hypercholesterolemia, obesity, and hyperglycemia on
learning and memory using a range of increasingly complex tasks – well-understood paradigms that are altered
in LOAD patients and we have shown to be affected by dietary manipulations in rabbits. We will also assess the
cellular and neuropathological effects of hypercholesterolemia, obesity, and hyperglycemia including their impact
on the neurobiology of learning and memory. Compelling preliminary data provide evidence that a short-term,
high-dose cholesterol diet, a high-fat diet, and chemically-induced diabetes have deleterious effects on a range
of learning and memory tasks. Preliminary electrophysiological evidence shows that feeding a diet high in
cholesterol or high in fat can impair a well-known form of synaptic plasticity thought to underlie learning and
memory – long-term potentiation. Published and preliminary pathophysiological data show significant diet-
induced changes in cellular and neuropathological markers of LOAD. Taken together, these data provide proof
of concept, but the levels of hypercholesterolemia and hyperglycemia were high and, although they recapitulated
LOAD-like pathologies including beta amyloid accumulation, they also produced off-target pathology. It is
therefore important to establish, characterize, and validate the cognitive and pathophysiological effects of milder,
more long-term dietary manipulations that induce the types and levels of hypercholesterolemia, obesity, and
hyperglycemia that are more clinically relevant. Our expertise in and track record of inducing significant
behavioral, electrophysiological, and pathophysiological changes by manipulating diets in adult rabbits makes
us well-suited to develop, characterize, and validate these unconventional models of LOAD – models that may
represent improved translational potential by better replicating the cellular, neuropathological, and cognitive
features of LOAD than current rodent models.