Bengt Winblad

Background: An increased understanding of neuronal development in the early stages of Alzheimer's disease (AD) could shed light on the pathogenesis of the disease. Our previous proteomics studies of the knock-in App ^NL-F AD mouse model showed changes in neuritogenesis and neurogenesis early in life. Objective: We aimed to characterize neuronal maturation across different stages of the progression of AD. Methods: To this end, we immunolabeled doublecortin and phosphorylated doublecortin in primary neurons, and brain sections from App ^NL-F mice of varying ages and postmortem AD brain. Results: Increased doublecortin and decreased phosphorylated doublecortin levels were observed in several cortical regions of embryonic App ^NL-F mice. Moreover, increased number of doublecortin positive cells was observed in the hippocampus of 6- and 12-month-old App ^NL-F mice. Doublecortin decreased over time in primary neuronal cultures of App ^NL-F and wild-type mice in a similar way. Likewise, doublecortin in postmortem human brains did not differ between AD patients and controls. Conclusions: We conclude that a marker of immature neurons is unchanged in AD patients and aged mice but is altered in the early lifespan of App ^NL-F mice, before the onset of symptoms and pathology. These results suggest that neuronal maturation may also be dysregulated in the early, but not later, stages of AD.

Background: Gait speed (GS) has been suggested as a predictor of incident dementia in old age. However, the mechanisms underlying this body–mind connection remain unclear, and it is still unknown whether trajectories of GS decline differ according to levels of blood biomarkers related to Alzheimer's disease ( AD ). This study aims to investigate the association between levels of seven blood biomarkers related to AD and long‐term GS changes in dementia‐free older adults living in the community. Methods: The present study included 1665 community‐dwelling adults ≥ 60 years, followed for 15 years, drawn from the Swedish National study on Aging and Care in Kungsholmen (SNAC‐K). GS (m·s ⁻¹ ) was assessed at baseline and at five subsequent follow‐up time points. Blood biomarkers, including serum amyloid‐ β 42 to amyloid‐ β 40 ratio (A β 42/40), phosphorylated Tau181 ( p ‐Tau181) and Tau217 ( p ‐Tau217), total Tau ( t ‐Tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), were collected from peripheral venous blood samples at baseline. Linear mixed‐effects models were implemented to investigate the association between blood biomarkers and GS changes over time. Results: After adjusting for potential confounders, participants in the highest quartile of p ‐Tau181 (Model I; 4th quartile β : −0.008, 95% CI: −0.013; −0.003), p ‐Tau217 (Model I; 4th quartile β : −0.010, 95% CI: −0.015; −0.005), NfL (Model I; 4th quartile β : −0.013, 95% CI: −0.019; −0.006) and GFAP (Model I; 4th quartile β : −0.007, 95% CI: −0.013; −0.002) exhibited a steeper decline in GS over time, as compared with those in the lowest quartile. Notably, participants in these highest quartiles developed mobility limitations (GS < 0.8 m·s ⁻¹ ), on average, 2.3 to 6.0 years earlier. Of note, only the association between NfL and GS changes over time persisted after further adjusting for time‐varying global cognition. Conclusions: Higher blood biomarker levels of AD are associated with accelerated trajectories of GS decline and earlier onset of mobility limitations. Consequently, a faster decline in GS may reflect underlying neurodegeneration and indicate changes in brain health.

Background: Intraneuronal accumulation of tau aggregates is one of the hallmarks of AD brain pathology. Lowered efficiency of degradation pathways, such as ubiquitin proteasome system, further exacerbates this accumulation. Proteolysis‐Targeting Chimeras (PROTACs) are hetero‐bifunctional molecules that can bring E3 ligase into the vicinity of the protein of interest, leading to protein ubiquitination followed by proteasomal degradation. Since 2016, PROTACs have been applied to resolve tau pathologies. The exploration of these PROTACs is still at the early stage. In this study, we aim to develop novel small‐molecule PROTACs to promote tau degradation for AD treatment. Methods: We manually generated an in silico library of novel PROTACs and modelled their ability to form the ternary complex (tau‐PROTACs‐E3 ligase) using targeted protein degradation tools on the dedicated platform – Molecular Operating Environment. Pharmacokinetic properties were predicted by in‐silico web server – Deep‐PK. The stability and membrane permeability of top‐ranked PROTACs are now evaluated by molecular dynamics simulations. Meanwhile, we established different cell models to evaluate PROTACs’ effects on tau pathology: human neuroblastoma SH‐SY5Y cells with human tau overexpression and mouse embryonic primary neurons with tau pathology. Now the effects of our synthesized PROTACs on total tau and phospho‐tau levels are studied by using western blot and immunofluorescence staining. Underlying mechanisms on tau degradation are investigated by using proteasome/autophagy inhibitors and co‐immunoprecipitation. Results: Within around 700 new designed PROTACs, we found by computational modelling more than 25 PROTACs that were predicted to have a better ability to form ternary complexes than the previously reported PROTACs. Pharmacokinetic predictions suggested that several PROTACs should have good oral bioavailability, brain permeability and low toxicity. Some of the selected PROTACs showed good stability during molecular dynamics simulations. The membrane permeability is currently being assessed. In primary neurons, Aβ42 treatment induces tau hyperphosphorylation, and the reported PROTACs (eg. C004019) can reverse tau hyperphosphorylation to normal levels. The evaluation of our new PROTACs in cell models are being performed according to methods listed above. Conclusions: The development of small‐molecule PROTACs may bring breakthrough medicines for AD and other neurodegenerative diseases.

Blood biomarkers of Alzheimer’s disease (AD) are promising for dementia prediction, but their association with progression across intermediate stages of cognitive decline in the general population remains unclear. We followed 2148 dementia-free individuals from a Swedish population-based cohort for up to 16 years. Associations between baseline AD blood biomarkers and transitions between normal cognition, mild cognitive impairment (MCI), and dementia were examined. Lower amyloid-β42/40 ratio and higher phosphorylated-tau181 (p-tau181), p-tau217, total-tau, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were associated with faster progression from MCI to all-cause and AD dementia, with the strongest associations for NfL and p-tau217. Elevated NfL and GFAP were linked to reduced MCI reversion to normal cognition, whereas no biomarker was associated with MCI development from normal cognition. These findings show robust group-level associations and indicate that AD blood biomarkers may help stratify dementia risk at the MCI stage in the community.

Evidence regarding the clinical validity of blood biomarkers of Alzheimer’s disease (AD) in the general population is limited. We estimated the hazard and predictive performance of six AD blood biomarkers for incident all-cause and AD dementia—the ratio of amyloid-β 42 to amyloid-β 40 and levels of tau phosphorylated at T217 (p-tau217), tau phosphorylated at T181 (p-tau181), total tau, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)—in a cohort of 2,148 dementia-free older adults from Sweden, who were followed for up to 16 years. In multi-adjusted Cox regression models, elevated baseline levels of p-tau181, p-tau217, NfL, and GFAP were associated with a significantly increased hazard for all-cause and AD dementia, displaying a non-linear dose–response relationship. Elevated concentrations of p-tau181, p-tau217, NfL, and GFAP demonstrated strong predictive performance (area under the curve ranging from 70.9% to 82.6%) for 10-year all-cause and AD dementia, with negative predictive values exceeding 90% but low positive predictive values (PPVs). Combining p-tau217 with NfL or GFAP further improved prediction, with PPVs reaching 43%. Our findings suggest that these biomarkers have the potential to rule out impending dementia in community settings, but they might need to be combined with other biological or clinical markers to be used as screening tools.

Background: The introduction of anti-amyloid treatments (AAT) for Alzheimer's disease (AD) has put the cost-effectiveness into focus. Objective: Estimate the potential cost-effectiveness of diagnostic pathways combined with AAT for early AD. Methods: Diagnostic accuracy of blood-based (BBM) and cerebrospinal fluid (CSF) biomarkers was obtained from Norwegian memory clinics using positron emission tomography (PET) as reference standard. In a health-economic model, the cost-effectiveness of three diagnostic strategies was estimated relying either on BBM (p-tau 217), CSF (Aβ _42/40 ratio), and BBM with CSF confirmatory testing and compared with standard of care (SoC) and compared with CSF-AAT. The model consisted of a decision tree reflecting the diagnostic process and a subsequent Markov cohort model starting at mild cognitive impairment due to AD. All strategies except SoC were combined with AAT including costs of treatment (assumed €5000/year), infusions and monitoring. Results: Compared with SoC all three strategies (CSF-AAT, BBM-AAT, and BBM-CSF-AAT) resulted in QALY gains at higher costs, with an incremental cost-effectiveness ratio (ICER) of 110k€, 141k€ and 110k€ respectively. Compared with CSF-AAT both BBM-AAT and BBM-CSF-AAT strategies resulted in QALYs lost at lower costs, with an ICER of 27k€ and 109k€ respectively. Results were particularly sensitive to the price of AAT and possible subcutaneous administration. Conclusions: Compared with SoC all three strategies are potentially not cost-effective as they exceeded the Swedish maximum willingness to pay threshold of €94,800 per QALY gained. BBM-CSF-AAT versus CSF-AAT is potentially cost-effective if willing to accept its QALY loss. Discussions on budget impact on different payers are needed after introducing AAT.