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

Abstract

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-1change: 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.

Dysregulated Wnt Signalling in the Alzheimer’s Brain

“…The fact that the molecular fluid biomarker signature between normal ageing and AD is different (e.g., [184]) would support qualitative differences between the two. In this context, Wnt signalling components are yet to be firmly established as fluid biomarkers for AD, although recent studies have suggested serum DKK1 as a predictor of deteriorating disease both in AD and acute ischemic stroke patients [261,262].…”

“…Similarly, can DKK1 be detected in cerebrospinal fluid (CSF)? Further establishing DKK1 CSF or serum biomarkers [261,262] would be valuable in understanding where DKK1 fits in the pathophysiology of AD, as well as being a target biomarker for evaluating DKK1 therapeutics. It would also have the potential to enable precision medicine by identifying those patients who have upregulated DKK1.…”

Electroacupuncture promotes neurogenesis in the dentate gyrus and improves pattern separation in an early Alzheimer's disease mouse model

“…In the present study, we observed a reduction in both Wnt5a and its major receptor, FZD2, in the hippocampus of AD mice. Studies have demonstrated a significant upregulation in the expression of Wnt signaling inhibitor proteins (such as DKK-1, SFRP-1, and SFRP-2) in postmortem AD brain and transgenic AD mouse models [ 52 , 53 ].This upregulation effectively suppresses the Wnt signaling pathway in Alzheimer's disease (AD). Consequently, there is a subsequent decrease observed in the expression levels of WnT-related proteins (e.g., wnt5a, wnt3a) and various intracellular related proteins (e.g., FZD2, DVL2, GSK3β).…”

Formulating Treatment to Cure Alzheimer’s Dementia: Approach #2

“…Studies by Inestrosa et al showed that Wnt/β-catenin is involved in regulating synaptic plasticity and maintaining BBB integrity; Inestrosa et al also found that activated WNT/β-catenin signaling prevented neural toxicity caused by Aβ, that WNT/β-catenin participates in a normal degree of tau phosphorylation and in learning and memory, and that WNT/β-catenin dysfunction results in Aβ production and aggregation [ 74 ]. Tay et al followed 14 subjects with MCI and 74 with mild-to-moderate AD and measured the scores for the clinical dementia sum of boxes (CDR-SB) at baseline and after one year and assessed the correlations between changes in the CDR-SB and serum levels of Dickkopf-1 (Dkk-1), which is an antagonist of Wnt [ 75 ]. Decreased levels of Wnt as shown by the increase in Dkk-1, which is an antagonist of Wnt/β-catenin, were significantly associated with progressively higher CDR-SB scores (indicating more impairment) among patients with AD but not among patients with MCI.…”