Disrupted functional connectivity of the locus coeruleus in healthy adults with parental history of Alzheimer's disease

Abstract

Prevention and early treatment strategies for Alzheimer's disease (AD) are hampered by the lack of research biomarkers. Neuropathological changes in the 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 not-at-risk individuals. Thirty-one offspring of patients with late-onset AD (O-LOAD) (22 females; mean age ± SD = 50.36 ± 8.32) and 28 healthy controls (HC) (20 females; mean age ± SD = 53.90 ± 8.44) underwent a neurocognitive evaluation and a resting-state functional magnetic resonance imaging acquisition. In FC analyses we evaluated whole-brain global connectivity of the brainstem area, and subsequently assessed seed-to-voxel FC patterns from regions showing between-group differences. O-LOAD individuals scored worse in neurocognitive measures of memory and overall functioning (p_FDR<0.05). In imaging analyses, we observed that O-LOAD individuals showed decreased global connectivity in a cluster encompassing the left LC (peak = -4, -34, -32, p_TFCE<0.05). Seed-to-voxel analyses revealed that this finding was largely explained by decreased connectivity between the LC and the cerebellar cortex. Moreover, FC between the LC and the left cerebellum correlated positively with delayed recall scores. FC between the LC and the cerebellar cortex is decreased in the healthy offspring of patients with LOAD, such connectivity measurements being associated with delayed memory scores. The assessment of FC between the LC and the cerebellum may serve as a biomarker of AD vulnerability.

Keywords: Alzheimer's disease offspring; Biomarkers; Cerebellum; Functional connectivity; Locus coeruleus; Neurodegeneration.