Functional Connectivity of the Locus Coeruleus Identifies Individuals at Familial Risk for Alzheimer's Disease

Abstract

Background: Prevention and early treatment strategies for Alzheimer´s Disease (AD) are hampered by the lack of risk biomarkers. Neuropsathological changes in de Locus Coeruleus (LC) are detected early in AD, and noradrenaline plays a neuroprotective role in LC projecting areas. We assessed functional connectivity (FC) of the brainstem in asymptomatic individuals at familial risk for AD hypothesizing that FC of the LC will be decreased in relation to non-at-risk individuals. Methods: 31 offspring of patients with late-onset AD (O-LOAD) and 28 controls underwent a neuropsychological evaluation and a resting state functional MRI acquisition. In FC analysses we evaluated whole-brain global connectivity of the brainstem area, and subsequently assessed seed-to-voxel FC patterns from regions showing between-group differences.Results: O-LOAD scored worse in the MMSE and the RAVLT verbal recognition and delayed recall (pFDR<0.05). In imaging analyses, we identified a cluster encompassing the left LC (peak=-4, -34, -32, PTFCE<0.05) showing a decreased global connectivity and a positive correlation with verbal delayed recall scores in O-LOAD subjects (r=0.441, p=0.035). Seed-to-voxel analyses revealed that above findings were largely explained by decreased LC-cerebellar connectivity. Specifically, FC between the LC and the left Crus 1 correlated positively with verbal delayed recall in the O-LOAD group (r=0.464, p=0.022).Conclusions: FC between the LC and the cerebellar cortex is decreased in the healthy offspring of patients with LOAD, such connectivity measurements being associated with verbal memory scores. FC between the LC and the cerebellum may eventually enable the development of prevention and early treatment strategies in AD.