Biomarkers in Alzheimer’s Disease—Perspectives for the Future
Tracking the Course of Alzheimer’s Disease with Biomarkers
Normal elderly people consist of three groups of individuals: those who will never develop AD, those who will develop AD but do not yet have any evidence of the disease in the brain, and those who have the initial manifestations of AD in the brain but remain within the normal range of cognitive function. The second of these groups is typically characterized by risk factors such as ApoE 4 genotype, older age, female sex, mid-life hypertension, diabetes, hypercholesterolemia, and history of head trauma.25,26
The third group of normal elderly—with AD pathology—is recognizable only with biomarkers that demonstrate the presence of AD-type pathology in the brain.
The first recognized change to occur in AD is the reduction of Aβ42 levels in the CSF; this is followed by positive amyloid imaging and
medial temporal lobe atrophy.27–29 The biomarker changes predict the
progression from AD pathology only to prodromal AD. In prodomal AD, cognitive changes occur, especially impairment of episodic memory,30 FDG PET reveals diminished metabolism in the posterior cingulate/ precuneus region and in the parietal lobes, and MRI atrophy progresses. With progression to AD-type dementia, cognition declines further and involves multiple cognitive domains. FDG PET demonstrates more widespread hypometabolism typically including the frontal lobes. MRI reveals diffuse cortical atrophy and ventricular enlargement. Amyloid imaging and CSF measures remain stably abnormal. Figure 3 shows the relationship of biomarkers to the course of AD.
Drug-activity Biomarkers
Drug development is facilitated by employing a combination of biomarkers, including assessments documenting a direct effect of the drug on the biological target and biomarkers demonstrating an effect of the treatment on disease course.31
Progress is being made in
developing disease-course biomarkers through collaborative efforts such as the AD Neuroimaging Initiative (ADNI).32
Adverse event
Few drug-activity biomarkers have been identified. One promising approach is stable isotope labeled kinetics (SILK) in which an indwelling spinal fluid catheter is used to make serial measures of Aβ production and clearance.33
shown with gamma-secretase inhibition.34
A decrease in Aβ production has been Similarly, serum Aβ declines
with gamma-secretase inhibition, suggesting that this measure may be responsive to drug treatment, although not a discriminating diagnostic measure.35
Aβ imaging may provide an opportunity to demonstrate reduced accumulation of Aβ in prevention trials (discussed below) or to measure disaggregation or removal of Aβ in trials of agents that interrupt protein aggregation or enhance removal. Bapinuezumab, a monoclonal antibody targeting Aβ, was shown to decrease brain Aβ burden as measured by PIB PET imaging.36
A wide variety of biomarkers for AD have been proposed that relate to many cellular signaling and disease pathways.2
Linking effects
of agents with specific mechanisms of action to these pathway- dependent biomarkers offers an opportunity to develop drug-activity
US NEUROLOGY
biomarkers critical to advancing AD drug development. Assessment of these biomarkers should begin in the pre-clinical phases of drug development to allow progressive understanding of collection, banking, measurement, and dose relationships prior to application in human drug trials. Putative disease-modifying agents should be advanced to clinical testing only if a plausible biomarker is available.
Toxicity Biomarkers
Biomarkers have a crucial role in detecting toxicity in drug development programs and clinical trials. Toxicity biomarkers include liver function tests, electrocardiograms, and other laboratory assessments, as well as biomarkers to evaluate toxicities specific to AD patients; for example, immunotherapies have been associated with cerebral vasogenic edema, which is routinely monitored in immunotherapy trials with MRI.37
25 monitoring
Adverse event
vulnerabilty
Pathology severity
AD dementia
Figure 3: Biomarker Changes in the Course of Alzheimer’s Disease
Clinical stage CSF Aβ PET FDG PET MRI
AD pathology (no symptoms)
Decreased Aβ42
Positive
Normal
Hippocampal atrophy
Prodromal AD (mild cognitive changes)
Decreased Aβ42
increased tau/p-tau
, Positive
Cingulate, parietal
hypometobolism
Hippocampal and cortical atrophy
Decreased Aβ42
increased tau/p-tau
, Positive
Cingulate,
parietal, frontal hypometobolism
Diffuse atrophy and ventricular enlargement
AD = Alzheimer’s disease; CSF = cerebrospinal fluid; FDG = fludeoxyglucose; MRI = magnetic resonance imaging; PET = positron emission tomography.
Figure 4: Roles of Biomarkers in Alzheimer’s Disease Drug Development
Patient selection
Drug–target engagement
Patient stratification
Efficacy
Biomarkers in clinical trials
Pathology type
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108