Prediction of Alzheimer's disease diagnosis within 14 years through Aβ misfolding in blood plasma compared to APOE4 status, and other risk factors

Abstract

Introduction:Alzheimer's disease (AD) has a long prodromal stage and identifying high-risk individuals is critical. We aimed to investigate the ability of A misfolding in blood plasma, APOE4 status, and dementia risk factors to predict diagnosis of AD.Methods: Within a community-based cohort, A misfolding in plasma measured by immuno-infrared sensor and APOE genotype were determined at baseline in 770 participants followed over 14 years. Associations between A misfolding, APOE4, and other predictors with clinical AD, vascular dementia, and mixed dementia diagnoses were assessed. Results:A misfolding was associated with a 23-fold increased odds of clinical AD diagnosis within 14 years. No association was observed with vascular dementia/mixed dementia diagnoses. APOE4-positive participants had a 2.4-fold increased odds of clinical AD diagnosis within 14 years.Discussion: A misfolding in blood plasma was a strong, specific risk prediction marker for clinical AD even many years before diagnosis in a community-based setting.

Amyloid-β misfolding as a plasma biomarker indicates risk for future clinical Alzheimer’s disease in individuals with subjective cognitive decline

“…These two groups might not have been differentiated in the raw data, as the average follow-up time in this cohort was only 2.7 years, which might be too short. Previous studies showed that our structure biomarker predicts conversion up to 14 years in advance [35]. In the ESTHER study, the average conversion time to ADdementia was 8 years after baseline blood sample was taken [25].…”

“…We have recently validated Aβ misfolding as a structure biomarker in plasma for probable AD (prospective Essen cohort) [24], for prodromal AD (BioFINDER) [25], and for preclinical cognitively unimpaired AD subjects (population-based ESTHER cohort) [25]. Including APOEε4 as a risk factor, early AD pathology could be identified with an AUC of 0.84 as early as 14 years before the clinical diagnosis of AD [35]. Remarkably, consistent cutoffs have been observed across all studies with a general threshold of < 1644 cm − 1 , indicating high misfolding in individuals with dementia due to AD.…”

Single cell analysis of the effects of developmental lead (Pb) exposure on the hippocampus

“…For example, we identified that protein folding pathways were significantly downregulated in microglial cells with Pb treatment. Dysregulation of protein folding is hypothesized to be a major underlying etiologic factor for the development of Alzheimer's disease (Selkoe 2003;Stocker et al 2019). One of our top downregulated genes overall, and within individual clusters, was Hbb-bs.…”

Quantitative amyloid PET in Alzheimer's disease: the AMYPAD prognostic and natural history study

“…Currently, the presence of A pathology can be determined either by cerebrospinal fluid (CSF), positron emission tomography (PET) imaging, or recently also by blood samples. 12,13 While prescribed for the same goal, a non-negligible proportion of patients can present with discordant results between CSF and PET. 14 CSF is considered to indicate the presence of amyloid pathology in its earliest stages, but it plateaus relatively early in the AD disease course, while amyloid PET imaging shows continued build-up of amyloid burden beyond the CSF plateau 15 and it provides information on the spatial distribution of the pathology in the brain.…”