Metabolic correlates of prevalent mild cognitive impairment and Alzheimer's disease in adults with Down syndrome

Abstract

Introduction Disruption of metabolic function is a recognized feature of late onset Alzheimer's disease (LOAD). We sought to determine whether similar metabolic pathways are implicated in adults with Down syndrome (DS) who have increased risk for Alzheimer's disease (AD). Methods We examined peripheral blood from 292 participants with DS who completed baseline assessments in the Alzheimer's Biomarkers Consortium–Down Syndrome (ABC‐DS) using untargeted mass spectrometry (MS). Our sample included 38 individuals who met consensus criteria for AD (DS‐AD), 43 who met criteria for mild cognitive impairment (DS‐MCI), and 211 who were cognitively unaffected and stable (CS). Results We measured relative abundance of 8,805 features using MS and 180 putative metabolites were differentially expressed (DE) among the groups at false discovery rate‐corrected q< 0.05. From the DE features, a nine‐feature classifier model classified the CS and DS‐AD groups with receiver operating characteristic area under the curve (ROC AUC) of 0.86 and a two‐feature model classified the DS‐MCI and DS‐AD groups with ROC AUC of 0.88. Metabolite set enrichment analysis across the three groups suggested alterations in fatty acid and carbohydrate metabolism. Discussion Our results reveal metabolic alterations in DS‐AD that are similar to those seen in LOAD. The pattern of results in this cross‐sectional DS cohort suggests a dynamic time course of metabolic dysregulation which evolves with clinical progression from non‐demented, to MCI, to AD. Metabolomic markers may be useful for staging progression of DS‐AD.

The AT(N) framework for Alzheimer's disease in adults with Down syndrome

“…Therefore, by use of the A/T(N) framework, it is anticipated that we will be able to conduct clinical trials in a more finely characterized participant sample. 20,36,41,42, we estimate that, between ages 35 to 55 years, there will be 80% A+, 40% T+, and 10% (N)+ for cognitively stable adults with DS; 80% A+, 60% T+, and 20% (N)+ for MCI-DS; and 80% A+, 80% T+, and 60% (N)+ for dementia in the DS group (Figure 1).…”

“…We intend to look at AT(N) classification across the different clinical diagnostic categories, that is, Cognitively Stable, Mild Cognitive Impairment, and Dementia in the ABC‐DS Study to calculate A+/T+/(N)+ prevalence and to correlate the various classifications with clinical and cognitive status. Based on a review of the literature, 20,36,41,42,59‐93 we estimate that, between ages 35 to 55 years, there will be 80% A+, 40% T+, and 10% (N)+ for cognitively stable adults with DS; 80% A+, 60% T+, and 20% (N)+ for MCI‐DS; and 80% A+, 80% T+, and 60% (N)+ for dementia in the DS group (Figure 1).…”

“…This more precise assessment will facilitate primary, secondary, and tertiary prevention trials for ADin individuals with DS. [27][28][29] In the general population [30][31][32] as well as in DS [33][34][35][36] the construct of mild cognitive impairment (ie, prodromal AD) as well as the identification of disease in the preclinical stage (eg, accumulation of amyloid in a cognitively stable individual) is central to the clinical diagnostic formulation of AD. Mild cognitive impairment (MCI) in the general population, as well as in DS, is generally regarded as the borderland between the cognitive changes of aging and early dementia where there is measurable decline in memory as well as some decline on instrumental activities of daily living (iADLs) but preservation of basic activities of daily functioning.…”

Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease

“…There is an increasing interest in defining the precise metabolic pathways involved in the pathogenesis of AD 9 , 16 – 19 . A significant correlation between reduced brain regional glucose metabolism and decreased α-ketoglutarate dehydrogenase complex (KGDHC) 20 , 21 has been described in AD.…”

Predicting gene regulatory networks from multi-omics to link genetic risk variants and neuroimmunology to Alzheimer’s disease phenotypes

“…3 70 . Xenobiotic Metabolic Processes are specific to Severe AD modules only, and studies 61 found links between dementia progression and various metabolic pathways.…”