Perturbations of neural circuitry in aging, mild cognitive impairment, and Alzheimer's disease

Alzheimer's disease (AD) is a global public health threat that continues to rise as the proportion of the population over the age of 60 rapidly increases. Aging and dementia are both associated with cognitive decline and share some features in terms of structural and functional alterations in neural circuitry. In this review, we attempt to highlight the network perturbations that occur in "typical" aging and emphasize how they may differ from those that manifest in dementia. We focus in particular on neuroimaging studies of the medial temporal lobe (MTL) network, which is involved in episodic memory and is known to change both with age and with AD pathology. We propose a temporal model of structural and functional alterations in the MTL along the aging-dementia continuum. The earliest changes are synaptic in nature and are detectable in particularly vulnerable white matter pathways such as the perforant path. These are followed by structural degradation in the transentorhinal region and subsequently neurodegeneration of the hippocampus as a result of accumulating pathology as well as deafferentation from entorhinal input. We believe that testing this model explicitly is an important direction for future research, particularly in the context of biomarker discovery and clinical trial design.