Neuroscience-based Tests for Assessing Cognitive Changes in Normal Aging and in the Prodromal Phase of Alzheimer’s Disease

Abstract

Slow decline in cognition is key to the clinical diagnosis of Alzheimer’s disease (AD). This diagnosis relies on screening tests insensitive to detection of prodromal AD, which occurs years before the appearance of clinical symptoms. Neuroscience-based tests of eyeblink classical conditioning, spatial navigation, and object recognition are associated with synaptic-level function. They show promise in detecting early changes in AD-impacted memory circuits. Eyeblink conditioning engages synapses dependent upon nicotinic acetylcholine receptors and medial septal cholinergic input to the hippocampus. Spatial navigation and object recognition engage perforant pathway entorhinal cortical input to the hippocampus. Synapses in these circuits are among the earliest impacted by beta amyloid. These three translational tests are well characterized in normal aging and AD in humans and pertinent animal models, including organisms expressing the AD risk factor apolipoprotein E4. They may detect cognitive decline in prodromal AD and prove useful for population screening and evaluation of therapeutic interventions.