Molecular biomarkers of Alzheimer's disease: progress and prospects

Abstract

The neurodegenerative disorder Alzheimer's disease is characterised by the formation of β-amyloid plaques and neurofibrillary tangles in the brain parenchyma, which cause synapse and neuronal loss. This leads to clinical symptoms, such as progressive memory deficits. Clinically, these pathological changes can be detected in the cerebrospinal fluid and with brain imaging, although reliable blood tests for plaque and tangle pathologies remain to be developed. Plaques and tangles often co-exist with other brain pathologies, including aggregates of transactive response DNA-binding protein 43 and Lewy bodies, but the extent to which these contribute to the severity of Alzheimer's disease is currently unknown. In this ‘At a glance’ article and poster, we summarise the molecular biomarkers that are being developed to detect Alzheimer's disease and its related pathologies. We also highlight the biomarkers that are currently in clinical use and include a critical appraisal of the challenges associated with applying these biomarkers for diagnostic and prognostic purposes of Alzheimer's disease and related neurodegenerative disorders, also in their prodromal clinical phases.

CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges

“…They offer important advantages relative to expensive imaging modalities or the invasive lumbar puncture required for analysis of CSF biomarkers. However, drawbacks such as inconsistent results from different research groups and weak or non-existent correlation with disease severity or with CSF-derived or imaging biomarkers have hampered progress in this direction (Mehta and Adler, 2016;Lashley et al, 2018;Zhao et al, 2019). The relatively poor performance of blood-based biomarkers reflects the disconnect between the brain biochemistry and the blood composition, which is maintained by the BBB to protect the brain.…”

Mechanisms Influencing the Pharmacokinetics and Disposition of Monoclonal Antibodies and Peptides

“…Similar to deamidation, isomerization of aspartate to isoaspartic acid has been noted to play a significant role in alteration of protein structure and function. For instance, it has been speculated that isoaspartic acid is crucial for the aggregation of b-amyloid, and thereby facilitates the progression of neurodegenerative disorders like Alzheimer's disease (Lashley et al, 2018). There are also examples of the isomerization of aspartate to isoaspartic acid in the CDRs of mAbs that decrease target binding and mAb efficacy (Wakankar et al, 2007;Dick et al, 2010).…”

Review: Fluid biomarkers for frontotemporal dementias

“…In FTDs, the CSF concentration of the neurofilament light (NfL) subunit has been shown to be higher compared with Alzheimer's disease (AD) [14-16]; a result that was recently confirmed in a large retrospective analysis of data from the Swedish Dementia Registry [17]. Although CSF NfL is considered a general biomarker for neurodegeneration [18], a recent evaluation of its usefulness in a memory clinic setting suggests that it can be used to positively identify FTD, particularly so bvFTD [19]. Higher concentrations of CSF NfL are associated with shorter survival in FTD, which suggest that it is a marker of disease intensity/ severity [20].…”