Aberrant functional connectivity between the retrosplenial cortex and hippocampal subregions in amnestic mild cognitive impairment and Alzheimer’s disease

The posterior cingulate cortex and hippocampus are the core regions involved in episodic memory, and they exhibit functional connectivity changes in the development and progression of Alzheimer's disease. Previous studies have demonstrated that the posterior cingulate cortex and hippocampus are both cytoarchitectonically heterogeneous regions. Specifically, the retrosplenial cortex, typically subsumed under the posterior cingulate cortex, is an area functionally and anatomically distinct from the posterior cingulate cortex, and the hippocampus is composed of several subregions that participate in multiple cognitive processes. However, little is known about the functional connectivity patterns of the retrosplenial cortex or other parts of the posterior cingulate cortex with hippocampal subregions and their differential vulnerability to Alzheimer's disease pathology. Demographic data, neuropsychological assessments, and resting-state functional magnetic resonance imaging data were collected from 60 Alzheimer's disease participants, 60 participants with amnestic mild cognitive impairment, and 60 sex-matched normal controls. The bilateral retrosplenial cortex, other parts of the posterior cingulate cortex, and hippocampus subregions (including the bilateral anterior hippocampus and posterior hippocampus) were selected to investigate functional connectivity alterations in amnestic mild cognitive impairment and Alzheimer's disease. Resting-state functional connectivity analysis demonstrated heterogeneity in the degree of connectivity between the hippocampus and different parts of the total posterior cingulate cortex, with considerably greater functional connectivity of the retrosplenial cortex with the hippocampus compared with other parts of the posterior cingulate cortex. Furthermore, the bilateral retrosplenial cortex exhibited widespread intrinsic functional connectivity with all anterior-posterior hippocampus subregions. Compared to the normal controls, the amnestic mild cognitive impairment and Alzheimer's disease groups showed different magnitudes of decreased functional connectivity between the retrosplenial cortex and the contralateral posterior hippocampus. Additionally, diminished functional connectivity between the left retrosplenial cortex and right posterior hippocampus was correlated with clinical disease severity in amnestic mild cognitive impairment subjects, and the combination of multiple functional connectivity indicators of the retrosplenial cortex can discriminate the three groups from each other. These findings confirm and extend previous studies suggesting that the retrosplenial cortex is extensively and functionally connected with hippocampus subregions and that these functional connections are selectively affected in the Alzheimer's disease continuum, with prominent disruptions in functional connectivity between the retrosplenial cortex and contralateral posterior hippocampus underpinning episodic memory impairment associated with the disease.