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Background:  Disruption of Wnt signaling has been implicated in dysfunctional synaptic plasticity, the degree of which correlates with Alzheimer’s disease severity. We sought to examine whether serum levels of Dickkopf-1 (Dkk-1), a Wnt antagonist, are associated with global disease progression in older adults with mild cognitive impairment (MCI) and mild-to-moderate AD.   Methods:  We prospectively followed 88 older adults with MCI and mild-to-moderate AD attending a Memory Clinic. Cognitive performance, functional performance and neuropsychological symptoms were assessed at baseline and after 1 year. We reviewed neuroimaging for white matter changes and medial temporal atrophy, and performed ApoE genotyping at baseline. Serum Dkk-1 was assayed at baseline and 1 year, along with blood biomarkers of inflammation and endocrine dysfunction. We defined global disease progression (“progressors”) as an increase in Clinical Dementia Rating Sum-of-Boxes (CDR-SB) score by  > 2 points at 1 year.   Results:  Fifteen (17.0%) participants had global disease progression. At baseline, there was no difference in cognitive performance and neuropsychiatric symptoms between groups, although progressors were more impaired in instrumental activities of daily living ( p  = 0.008). Progressors had significantly greater deterioration in cognitive performance ( p  = 0.002), with significantly worse functional performance and more severe neuropsychiatric symptoms ( p  = 0.042) at follow-up. Serum inflammatory and endocrine biomarkers at baseline and 1 year were similar between progressors and non-progressors. Serum Dkk-1 had increased significantly from baseline amongst progressors, while non-progressors exhibited decremental Dkk-1 over time (Dkk-1 change : 354.304 ± 670.467 vs. −173.582 ± 535.676 ng/ml,  p  = 0.001). Adjusting for age, gender and baseline cognitive performance, incremental Dkk-1 independently predicted global cognitive decline ( p  = 0.012).   Conclusion:  Our results suggest progressively dysfunctional Wnt signaling through Dkk-1 antagonism contributes to disease progression amongst older adults with MCI and mild-moderate AD.

frontiers in aging neuroscience

Elevations in Serum Dickkopf-1 and Disease Progression in Community-Dwelling Older Adults With Mild Cognitive Impairment and Mild-to-Moderate Alzheimer’s Disease