Aging and Alzheimer's Disease Have Dissociable Effects on Medial Temporal Lobe Connectivity

Functional disruption of the medial temporal lobe-dependent networks is thought to underlie episodic memory deficits in aging and Alzheimers disease. Previous studies revealed that the anterior medial temporal lobe is more vulnerable to pathological and neurodegenerative processes in Alzheimers disease. In contrast, cognitive and structural imaging literature indicates posterior, as opposed to anterior, medial temporal lobe vulnerability in normal aging. However, the extent to which Alzheimers and aging-related pathological processes relate to functional disruption of the medial temporal lobe-dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity alterations in the medial temporal lobe and its immediate functional neighborhood - the Anterior-Temporal and Posterior-Medial brain networks - in normal agers, individuals with preclinical Alzheimers disease, and patients with Mild Cognitive Impairment or mild dementia due to Alzheimers disease. In the Anterior-Temporal network and in the perirhinal cortex, in particular, we observed an inverted U-shaped relationship between functional connectivity and Alzheimers stage. According to our results, the preclinical phase of Alzheimers disease is characterized by increased functional connectivity between the perirhinal cortex and other regions of the medial temporal lobe, as well as between the anterior medial temporal lobe and its one-hop neighbors in the Anterior-Temporal system. This effect is no longer present in symptomatic Alzheimers disease. Instead, patients with symptomatic Alzheimers disease displayed reduced hippocampal connectivity within the medial temporal lobe as well as hypoconnectivity within the Posterior-Medial system. For normal aging, our results led to three main conclusions: (1) intra-network connectivity of both the Anterior-Temporal and Posterior-Medial networks declines with age; (2) the anterior and posterior segments of the medial temporal lobe become increasingly decoupled from each other with advancing age; and, (3) the posterior subregions of the medial temporal lobe, especially the parahippocampal cortex, are more vulnerable to age-associated loss of function than their anterior counterparts. Together, the current results highlight evolving medial temporal lobe dysfunction in Alzheimers disease and indicate different neurobiological mechanisms of the medial temporal lobe network disruption in aging vs. Alzheimers disease.