Lars Tjernberg

Our recent studies show that altered N-glycosylation of proteins in cerebrospinal fluid (CSF) and blood in nondemented individuals can predict future cognitive decline and Alzheimer´s disease (AD) dementia. We propose to elucidate the link between N-glycosylation and cognitive decline in this 5-year project. The overarching aim is to develop glycan and glycopeptide biomarkers for early detection and subgrouping of individuals at risk of developing dementia and decipher how glycans are related to disease mechanisms. Mechanistic studies will be performed by altering glycosyltransferase activities in neurons and studying the effects on morphology, subcellular localization and levels of pathogenic proteins by cutting-edge super-resolution microscopy and protein analysis. Time-course glycosylation alterations will be studied in animal models. Glycoproteomics will be performed to identify glycopeptide alterations in brain, cerebrospinal fluid and blood from AD and other dementias. The utility of glycopeptides as predictive biomarkers for AD or other dementias will be assessed by statistical analysis of associations with other biomarkers and, especially, with cognitive data in longitudinal cohorts. Mass spectrometric methods and well-plate assays will be implemented clinically. The findings from this project could revolutionize diagnostics in primary and secondary care by providing glycoprotein biomarkers for predicting future cognitive decline earlier than current biomarkers.

The presence of β-amyloid plaques and neurofibrillary tangles of tau are two main pathological hallmarks of Alzheimer disease (AD). Lowered efficiency of degradation pathways, such as the Ubiquitin Proteasome System, further exacerbates the aberrant protein accumulation. Proteolysis-Targeting Chimeras (PROTACs) are hetero-bifunctional molecules that can bring the E3 ligase into the vicinity of the protein of interest, leading to protein ubiquitination, followed by proteasomal degradation. We aim to perform intensive research to promote the development of small-molecule PROTACs for AD treatment, especially for tau degradation.Published small-molecule tau-targeting PROTACs are using ligands binding to two common E3 ligases: von Hippel-Lindau protein and cereblon. But they are distributed in all tissues and target many proteins, not only tau. To develop more specific and potent PROTACs, we will first explore tau-targeting E3 ligases in human AD brains, choose E3 candidates, and develop novel ligands binding to tau/E3 ligases. Then we will use different linkers to combine ligands and design new PROTACs. Protein-binding affinities and tau-reducing effects in vitro will be evaluated with follow-up structure-based optimization. The most potent PROTACs with the least off-target effects will move on to in vivo study.This project will increase our understanding of tau-targeting E3 ligases in AD brains and bring breakthrough medicines for AD and other neurodegenerative diseases.

This study aims to prevent the development of dementia in individuals with mild cognitive impairment (MCI) through innovative solutions for early detection, precision diagnostics, and individualized evidence-based prevention and treatment.The epidemiological part will focus on two aspects: the impact of depression and sleep disturbances on cognitive impairment and dementia development and use register data and AI to develop a risk prediction model to identify people at risk for MCI, Alzheimer disease, and other dementia early in primary health care. Both risk factors and protective factors will be examined, thus the model will suggest individuals who should be further evaluated for MCI, Alzheimer´s, and other forms of dementia and provide support for preventive advice and interventions.The clinical part aims to determine the clinical and health economic value of a precision diagnostic algorithm based on a combination of digital cognitive tests and blood-based biomarkers in the assessment of subjective cognitive complaints (SCC) in primary care. The study will actively screen for SCC among individuals at increased risk of dementia, with risk factors including age, hypertension, and/or type II diabetes mellitus. Digital cognitive tests and blood-based biomarkers will be utilized to diagnose SCC, mild cognitive impairment (MCI), and dementia due to Alzheimer´s disease, as well as to examine how these biomarkers predict disease conversion after two years.