Abstract
Glycosylation, the process of adding glycans (i.e., sugars) to proteins, is the most abundant post-translational modification. N-glycosylation is the most common form of glycosylation, and the N-glycan moieties play key roles in regulating protein functions and many other biological processes. Thus, identification and quantification of N-glycome (complete repertoire of all N-glycans in a sample) may provide new sources of biomarkers and shed light on health and disease. To date, little is known about the role of altered N-glycome in Alzheimer’s Disease and Alzheimer’s Disease-related Dementias (AD/ADRD). The current study included 45 older adults who had no cognitive impairment (NCI) at baseline, followed and examined annually, and underwent brain autopsy after death. During about 12-year follow-up, 15 developed mild cognitive impairment (MCI), 15 developed AD, and 15 remained NCI. Relative abundances of N-glycans in serum at 2 time points (baseline and proximate to death, ∼12.3 years apart) and postmortem brain tissue (dorsolateral prefrontal cortex) were quantified using MALDI-TOF-MS. Regression models were used to test the associations of N-glycans with AD/ADRD phenotypes. We detected 71 serum and 141 brain N-glycans, of which 46 were in common. Most serum N-glycans had mean fold changes less than one between baseline and proximate to death. The cross-tissue N-glycan correlations were weak. Baseline serum N-glycans were more strongly associated with AD/ADRD compared to change in serum N-glycans over time and brain N-glycans. The N-glycan associations were observed in both AD and non-AD neuropathologies. To our knowledge, this is the first comprehensive glycomic analysis in both blood and brain in relation to AD pathology. Our results suggest that altered N-glycans may serve as mechanistic biomarkers for early diagnosis and progression of AD/ADRD.
Highlights
Alzheimer’s Disease and Alzheimer’s Disease Related Dementia (AD/ADRD) affects over 5 million older Americans in 2021, and the number is projected to double by 2050
The results revealed an interesting pattern such that baseline sera N-glycans with lower m/z ratios were associated with slower cognitive decline, lower risk of cognitive impairment or Alzheimer’s dementia, and less neuropathologies
For the outcome of incident Alzheimer’s dementia, we considered an increase in hazard ratio (HR) based on Cox regression
Summary
Alzheimer’s Disease and Alzheimer’s Disease Related Dementia (AD/ADRD) affects over 5 million older Americans in 2021, and the number is projected to double by 2050. AD/ADRD is characterized by cognitive decline and impairment in multiple cognitive domains. The neuropathologies of AD/ADRD are complex and include Alzheimer’s disease (AD), non-AD neurodegenerative and cerebrovascular conditions that commonly coexist in aging brain (Corrada et al, 2012; White et al, 2016; Boyle et al, 2021). Identifying mechanistic biomarkers is key to early diagnosis and effective prevention or intervention of AD/ADRD. Post-translational modifications (PTMs) represent an attractive mechanism, as many proteins implicated in AD (e.g., β-amyloid and tau) and non-AD neuropathologies (e.g., α-synuclein and TDP43) undergo PTMs (Marcelli et al, 2018; Pajarillo et al, 2019; Schaffert and Carter, 2020)
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