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.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia, with significant impact on the individual, caregiver, health systems and society
Diagnostic Categories mild cognitive impairment (MCI) was operationalized as follows: (1) global Clinical Dementia Rating (CDR) (Morris, 1993) score of 0.5; (2) presence of subjective memory complaint with corroboration by a reliable informant; (3) delayed recall >1 SD below the age and educationadjusted means of healthy community-dwelling subjects based on an earlier normative study (Sahadevan et al, 2002); (4) relatively normal general cognitive function, defined as Chinese Mini Mental State Examination (CMMSE) (Sahadevan et al, 2000) score ≥21 for subjects with ≤6 years education and ≥24 for those with >6 years of education; (5) largely intact activities of daily living; and (6) no clinical dementia
There was no significant difference in age, gender, and baseline cognitive performance between participants who completed vs. those who were lost to follow-up
Summary
Alzheimer’s disease (AD) is the most common form of dementia, with significant impact on the individual, caregiver, health systems and society. Synaptic dysfunction occurs early in the course of AD, before evidence of neuronal cell death, and the loss of synapses correlates best with cognitive decline (Terry et al, 1991; Palop and Mucke, 2010). Wnt signaling has a key role in synaptic plasticity and memory, being neuroprotective against Aβ-induced toxicity, tau phosphorylation, neuroinflammation and apoptosis (Vallee and Lecarpentier, 2016; Tapia-Rojas and Inestrosa, 2018a). The study recruited participants with subjective memory concerns and excluded those with confirmed clinical diagnoses of mild cognitive impairment (MCI) and dementia. 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
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