A Decade of Blood Biomarkers for Alzheimer’s Disease Research: An Evolving Field, Improving Study Designs, and the Challenge of Replication

Abstract

Blood-based biomarkers represent a less invasive and potentially cheaper approach for aiding Alzheimer’s disease (AD) detection compared with cerebrospinal fluid and some neuroimaging biomarkers. Acknowledging that many in the field have made great progress, here we review some of the work that our group has pursued to identify and validate blood-based proteomic biomarkers through both case control and AD pathology endophenotype-based approaches. Our focus is primarily to identify a minimally invasive and hopefully cost-effective blood-based biomarker to reduce screen failure in clinical trials where participants have prodromal or even pre-clinical disease. We summarize some of the key findings and approaches taken in these biomarker studies, while addressing the main challenges, including that of limited replication in the field, and discuss opportunities for biomarker development.

Integrated lipidomics and proteomics network analysis highlights lipid and immunity pathways associated with Alzheimer’s disease

“…From the nominated biomarkers, only some have been replicated. The reason for such imbalance might be caused by the heterogeneity of the disease itself as well as the complexity of analysing blood [3]. Meta-analyses will help translate discovery findings to reproducible and useful biomarkers.…”

“…In the past decade a large number of untargeted and targeted blood biomarker studies have nominated and replicated proteins and combinations of proteins associated with AD and AD endophenotypes. These endophenotypes include brain atrophy, rate of cognitive decline and amyloid burden [3,4]. Although the majority of protein biomarkers have failed to replicate, several proteins, especially inflammatory proteins and proteins involved in the complement pathway, have been consistently associated with AD or AD endophenotypes, including complement C6 and C-C motif chemokine 15 [3].…”

Dielectric Constant and Conductivity of Blood Plasma: Possible Novel Biomarkers for Alzheimer’s Disease

“…Alzheimer's disease (AD) is the most common form of dementia, currently affecting 75 million people worldwide and is projected to increase to 135 million individuals by 2050 [1][2][3]. The disease is mostly characterized by a progressive mental deterioration manifested by loss of memory, impaired cognitive ability and visual-spatial orientation, confusion, and disorientation [4][5][6].…”

“…According to Mattsson et al [14], these techniques may identify persons at risk for AD prior to the development of symptoms. However, translation of the benefits of these techniques to a large public has not yet materialized due to the high cost and/or the limited access to the equipment (PET, MRI) and mostly to the relative invasiveness of sample collection, e.g., the cerebrospinal fluid [3,15]. In the meantime, the irreversibility of AD has prompted current treatment strategies to focus on drugs that can alleviate cognitive symptoms by improving basal forebrain cholinergic functioning.…”

Identification of common molecular biomarker signatures in blood and brain of Alzheimer’s disease

“…However, these procedures suffer serious limitations, including the invasiveness of collecting CSF as well as the sensitivity, specificity, cost and limited access of neuroimaging [10]. Considering the shortcomings of available resources for the detection of neurodegenerative diseases, many studies have attempted to explore biomarkers in the blood of AD patients [11,12]. Circulating cells and proteins are easily accessible from fresh blood samples, the collection procedure is less invasive.…”