Alzheimer's Disease (AD) is a debilitating form of dementia characterized by irreversible cognitive impairment.
AD diagnosis historically relied on identifying cognitive impairment but this diagnostic criterion has become
problematic as evidence grows that cognitive symptoms present long after neuropathology has set in.
Diagnosing AD in the preclinical stages is critical to develop new treatments to intervene prior to the
presentation of cognitive symptoms. Neuropsychiatric disorders, such as sleep impairments and emotional
problems (i.e. apathy), are readily observed in preclinical AD patients and therefore are target behavioral
symptoms for prodromal AD. Not surprisingly, the brain regions that regulate emotion and sleep are also the
sites where AD neuropathology is first detected. The isodendritic core (IC) is an interconnected group of
brainstem nuclei that are highly susceptible to AD pathology, which can be detected years before the
emergence of hallmark pathology in the cortex and hippocampus LH ¿-amyloid plaques, abnormal tau,
neurofibrillary tangles). IC pathology is proposed to underlie prodromal symptoms of AD, including apathy and
sleep disturbances. Animal models advance the ability to recognize and diagnose prodromal AD because
behavioral changes can be mapped onto early brain pathology. This proposal will study aging marmoset
monkeys, an ideal nonhuman primate model to study neurocognitive aging. The first aim of this proposal is to
evaluate neuropsychiatric symptoms by outfitting marmosets with activity monitors to study circadian activity
and presenting an emotion task to evaluate blunted emotional responding indicative of apathy. The second aim
will use neurohistology and stereology to look for AD-like pathology in brainstem tissues from the same
individuals. The final aim will draw together within-individual behavioral (i.e. sleep, emotion responding,
cognitive decline) and brain (i.e. brainstem, hippocampal and cortical pathology) measures to develop profiles
of prodromal and clinical AD in marmosets. If neuropsychiatric symptoms and/or brainstem pathology are
indicative of prodromal AD, then we will see these prodromal indicators in marmosets without significant
cognitive decline or advanced AD-like pathology in the cortex or hippocampus. The results from these aims will
advance diagnostic criteria for prodromal AD and facilitate targeted treatment development.