There are a number of criteria for a biomarker to qualify as a useful tool in the early detection and for the monitoring of treatment effects in AD. It needs to have face validity, ie, measure something known to be involved directly in the pathophysiology. It also needs to be detectable early in the disease process; to be quantifiable by an automated method; and to possess a dynamic range relevant to progression in the “natural course” of disease as well as regression due to therapeutic intervention, with sufficiently low variance to measure changes that are small relative to rates of progression or regression. In clinical trials of drug candidates, such biomarkers would enable enrichment of populations, confirmation of mechanisms of action (MoA), choice of dosing regimen (“dose-ranging”), quantification of treatment benefit, and dose titration to maximize benefit with least risk of adverse events. The enrichment of populations in clinical trials is particularly important due to the long delay in onset of symptoms and the low annual rate of conversion from MCI to mild AD. Because AD progresses slowly and treatment effects may only be manifest as a slowing or halting of progression, precise measurement of small changes is crucial to the design of clinical protocols with reasonable durations of therapy and achievable numbers of patients. Similar factors apply to diagnostic biomarkers being developed for direct patient care. The ability to diagnose AD pathophysiology prior to onset of symptoms will enable earlier intervention, when a patient has the best hope of efficacy and has retained maximum cognitive performance, In addition to their direct clinical benefit for AD patients and caregivers, early-disease biomarkers are also of interest to payers and purchasers of health care. Results of such a diagnostic test can serve as a baseline to quantify treatment benefit by longitudinal comparisons pre - and post-treatment. This will enable individualization of the treatment regimen, leading to optimal outcomes on a per-patient basis. Optimizing outcomes for individuals enables efficient delivery of health care, which in turn frees up resources to broaden access to the latest technology. The projected costs of AD in the US attendant upon aging of the baby boomers are astronomical; it is the development of novel therapeutics and biomarkers, or diagnostics, based on innovative technology, which offers hope to individuals and to society.
In this review, we identified a number of in vivo neurochemistry and neuroimaging techniques, which can reliably assess aspects of physiology, pathology, chemistry, and neuroanatomy of AD and hold promise as meaningful biomarkers in the early diagnostic process as well as for the tracking of disease modifying pharmacological effects. These neurobiological measures appear to relate closely to pathophysiological, neuropathological, and clinical data, such as hyperphosphorylation of tau, abeta metabolism, lipid peroxidation, pattern and rate of atrophy, loss of neuronal integrity, functional and cognitive decline, as well as risk of future decline. On the neurochemical level, CSF concentration of Aβ42, tau, and Ptau can distinguish subjects with MCI who are likely to progress to AD. They also show preclinical alterations that predict later development of early AD symptoms. Studies on plasma Aβ are not entirely consistent, but recent findings suggest that decreased plasma Aβ42 relative to Aβ40 may increase the risk of AD. Increased production of Aβ in aging is suggested by elevation of BACE-1 protein and enzyme activity in the brain and CSF of subjects with MCI. CSF tau and P-tau are increased in MCI as well, and show predictive value, Other biomarkers may indicate components of a cascade initiated by Aβ, such as oxidative stress or inflammation. Other interesting novel marker candidates derived from blood are being currently proposed (phase I). These merit further study in MCI and earlier stages. Manual hippocampal volumetry is currently the bestestablished biomarker for AD in the field of structural imaging, but due to the laborious nature of the procedure it will only be used in clinical studies for risk stratification of study populations and as an end point for treatment effects in the foreseeable future. Automated data-driven and rater- independent methods are currently being investigated to detect regional changes, namely VBM, DBM, and the measurement of cortical thickness. In the medium term, particularly in combination with multivariate statistical analysis methods, analysis algorithms are likely to be identified that are at least as effective as hippocampal volumetry in the early detection of AD in MCI subjects and will therefore be used in pharmacological studies. However, if secondary preventive treatment approaches are approved in the coming years, the use of these kinds of automated methods for the early detection of AD will be of socioeconomic importance in routine diagnostic practice as well. Besides structural neuroimaging, pilot studies using other neuroimaging approaches such as PET (FDG and PIB), DTI and MRS yielded promising results and should be prospectively applied to larger samples.
Apart from hippocampal volumetry, whole-brain volumetry is currently being investigated as a secondary end point in several clinical studies, and other studies are beginning on whole brain volumetry; however, the validity of this marker is limited. PET has been used as an end point in single-center studies.70
Tau protein has also been used as a secondary end point in clinical studies. In an immunization study, discontinued due to serious side effects, a reduction in t-tau in the CSF was observed in the group of antibody responders (development of a defined high antibody titer after vaccination) compared with the placebo group.127
Interestingly, MRI showed a decrease in whole brain volume in the responder group in this study.124
Amyloid reduction with consecutive changes in the CSF space is being discussed as a cause, although this interpretation is controversial. Changes in the concentrations of the Aβ peptides in the CSF and plasma were reported after administration of a y-secretase inhibitor, a potential drug that may modify amyloid pathology.2
Furthermore, various combinations of neurochemical and neuroimaging biomarkers are currently used in several ongoing clinical trials on substances with potential disease-modifying properties (Table I).