Decoding the role of the glycoproteome in Alzheimer’s disease and related disorders.

ABSTRACT New therapies are needed for dementia and loss of ambulation that are impaired by Alzheimer's Disease and Related Dementia (AD/ADRD) pathologies. Mechanisms underlying pathologies are unclear and pathologies alone do not fully explain cognitive and motor decline. Proteome-wide studies have identified some proteins that contribute to AD/ADRD pathologies and others that more fully account for clinical decline. Yet, the specific CNS functions of many brain proteins requires posttranslational modifications (PTM), the most common being the addition of sugars (glycans). Identifying novel glycopeptiforms underlying AD/ADRD traits to catalyze mechanistic and drug discovery studies are scarce due to difficulties conducting glycoproteome-wide studies. Using our new method, this study will elucidate the role of the glycoproteome in AD/ADRD. It will identify glycopeptiforms related to AD/ADRD pathologies and clinical traits, test if glycopeptiforms link an active lifestyle with brain health and characterize the genetic architecture of the brain glycoproteome and AD. Compelling data support this study. 1) We identified >11,000 unique glycopeptiforms in a glycoproteome-wide study of dorsal lateral prefrontal cortex (DLPFC; N=366). 2) Six glycopeptiforms were related to AD/ADRD pathologies; 3) Eleven glycopeptiforms were related to cognitive decline; 3 were linked with cognitive decline via AD/ADRD pathologies and 8 were associated with cognitive decline but unrelated to AD/ADRD pathologies and may provide resilience. 4) Glycopeptiforms remained related to cognitive decline when controlling for protein abundance in the same model, suggesting a separate effect for the glycopeptiform. 5) GO analyses indicated that glycopeptiforms related to cognitive decline involve metabolic pathways. 6) Applying our bioinformatic analysis identified additional glycopeptiforms related to cognitive decline. 7) The resilience glycopeptiform (pentraxin-2) linked frequent social activities with slower cognitive decline. 8) Numerous common variants impact protein glycosylation; some glycoQTLs are recognized as AD risk variants. This postmortem study will use novel resources already collected from 800 decedents including annual clinical measures, indices of 10 AD/ADRD pathologies, proteome, glycoproteome and Whole Genome Sequencing data. Aims 1-2 will use novel integrative analyses to increase the yield of glycopeptiforms that are related to AD/ADRD pathologies and clinical traits identified in our discovery cohort (n=366). Aim 3a will replicate our findings in a 2nd test cohort (n=434). Aim 3b will increase our power by combining data from our discovery and test cohort. To move beyond simple correlations, Aim 4 will test if the benefits of an active lifestyle are mediated via resilience glycopeptiforms identified in Aim 3b. Aim 5 will examine the genetic architecture of the brain glycoproteome. This study will provide novel high-value targets that may be druggable or underlie resilience behaviors, inform on mechanisms underlying AD/ADRD pathologies and clinical traits and characterize the genetic architecture of brain glycoproteome and AD risk. This study can advance AD/ADRD research and its clinical care.