Summary Biomarker development for neurodegeneration

Biomarker development for
neurodegeneration (Prof. Fujirebio)
1. Clinical unmet need in Alzheimer’s disease
 High prevalence in elderly population
 Early and accurate diagnosis
 Pending availability of disease-modifying therapies


1.1. What is dementia?
 = a group of conditions that cause cognitive decline
o Dementia is a syndrome involving impairment in cognitive
functioning to a degree that interferes with person’s ability to carry
out usual activities
o It can involve impairments in:
 Memory
 Language
 Reasoning, judgement and handling of complex tasks
 Higher-order perceptual/motor functioning
 Personality and behavioral changes
o Most dementia follows a deteriorating course, with a median life
expectancy after diagnosis of 5-6 years
o Accuracy of clinical diagnosis dependent on
 Disease stage
 Diagnostic setting or center


1.2. AD pathology
 Amyloid plaques indentified in the hippocampus
 Neurofibrillary tangles identified in the hippocampus
 Both leading to brain atrophy


1.3. Prevalence clinical symptoms vs pathology
 The graph illustrates the critical temporal lag between the accumulation of
Alzheimer's disease pathology in the brain and the onset of clinical
symptoms (dementia).
 Key Components of the Graph
o Solid Line: Represents the "Amyloid Plaques at
Autopsy" (Percent positive). This line shows the increasing
prevalence of Amyloid ß (Aß) deposition in the brain as a function of
age.
o Dashed Line: Represents the "Prevalence of AD
Dementia" (Percent positive). This line shows the rate at which
people are diagnosed with the clinical syndrome of Alzheimer's
disease dementia as a function of age.
 The Temporal Lag
o The most important takeaway is the gap between the two lines,
highlighted by the red text and the double-headed arrow.
o Pathology Precedes Symptoms: The graph clearly shows
that Amyloid plaques start accumulating many years before the

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, clinical symptoms of dementia become prevalent. For example, a
significant portion of the population (around 10-20% in the late 60s)
already has confirmed Aß pathology, but the clinical diagnosis of AD
dementia in that same age group is much lower.
o "Higher concentration of Aß; lower concentration of the
people with symptoms" (translated from Dutch source
commentary). This means the biochemical changes are present long
before the cognitive decline is severe enough for a dementia
diagnosis.
 The Need for Early Biomarkers
o This temporal lag creates a therapeutic window and explains
the "Need for biomarkers to identify patients at an early stage", as
indicated by the green box.
o Early Identification: Biomarkers, such as those measured in CSF or
blood, are necessary to detect the underlying Aß and Tau
pathologies before the onset of irreversible, severe dementia.
o Clinical Relevance: Identifying patients during the early, or even
preclinical, stages of Alzheimer's disease pathology allows for:
 Early diagnosis, which enables earlier treatment.
 Inclusion into clinical trials for disease-modifying therapies,
which are believed to be most effective when administered
early.




2. Biomarkers for AD: from CSF to blood
 Higher concentration of Aß; lower concentration of the people with
symptoms
 Why biomarkers:
o Mild Cognitive Impairment is heterogenous stage with regard to
variability in outcome
o Main focus is on the early/MCI stage. Why?:
 Early diagnosis enable early treatment and inclusion into
clinical trials.
 Early diagnosis facilitates research at a stage where there is
less co-pathology
 Why CSF as biomarker?
o CSF is in close proximity to the brain, and therefore biochemical
changes in the brain affect the composition of biomarkers in CSF.
Since AD pathology is restricted to the brain, CSF is an obvious
source of biomarkers for AD. CSF is also a rich source of brain-

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, specific proteins, and changes in these protein levels are observed
in CSF with disease progression. CSF biomarkers are also very
sensitive to the fine changes in brain that occur in the preclinical
stages of the AD. Therefore, CSF is probably the most informative
fluid sample available for preclinical as well as symptomatic AD
diagnosis



2.1. Biomarkers for AD
 Biomarkers = naturally occurring, measurable substance or condition in
the body that reliably indicates the presence of absence of disease, or the
risk of later developing a disease, or the pharmacological response to a
therapeutic intervention
 Biomarker for AD
o Reflect fundamental feature of neuropathology
o Diagnostic for AD
o Validated in neuropathologically confirmed patients
o Sensitivity > 80%, specificity > 80%
o Non-invasive, easily accessible
o Useful in prediction, monitoring of disease progression and/or
treatment effects


2.2. Biomarkers for AD diagnosis – CSF (cerebrospinal fluid)
 What happens in the brain with Alzheimer?
o ß-amyloid plaques are formed  extracellular accumulation
 stored in plaques  less ends up in CSF
o Tau gets hyperphosphorylated  forms neurofibrillary tangles in the
neurons
o Leads to neuronal loss/death
 This pathology influences what we measure in the CSF
 Improvements of early differential diagnosis of AD:
o Measure CSF Aβ1-42/Aβ1-40
 Many studies have shown that this is a more accurate marker
of AD (for example: the concordance between amyloid and
tau biomarkers – based on the IWG-2 criteria – increased by
24% when using this ratio instead of only Aβ1-42
o Adding this measurement will be very important for accurate
detection of preclinical AD and differential AD diagnosis




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