- I'm a Kaj Blennow. I'm Professor in Clinical Neurochemistry
at the Gothenburg University.
I'm also senior physician at a clinical neurochemistry lab,
which is a clinical lab where we analyze CSF
and blood samples from patients.
AD pathology consists of three major parts.
One is plaques .
They are composed
of a small peptide, aggregated beta-amyloid.
Then we have tangles or neurofibrillary tangles.
They are composed of hyperphosphorated tau
And this is believed to lead to neurodegeneration
And also degeneration of a synapses in the neurons.
That's the typical AD pathology.
But in elderly people with dementia,
they often have multiple pathologies.
So not only plaques and tangles and neurodegeneration.
But a quite substantial proportion of them
also have TDP-43 pathology,
Lewy bodies composed of alpha-synuclein aggregates
and not the least, cerebrovascular disease.
One focus we have is Alzheimer's disease,
where we work on biomarkers, meaning CSF
and also today blood test for different mechanisms
in Alzheimer's disease.
And then you of course have to ask yourself,
why do we need biomarkers for Alzheimer's disease?
And one reason is for diagnostics of course,
because Alzheimer's is very difficult
to identify clinically.
So the symptoms are very vague
and they appear slowly
and it's hard for clinicians
to say that the patient has Alzheimer's disease
or whoever he or she has some other disease,
either a neurodegenerative disease or even depression
or secondary causes for this type of symptoms
such as hematomas or even brain tumors.
Then another implication for biomarkers is
in clinical trials,
because to identify a minor effect of a drug.
Then you need a very pure
and also early patient group that you study
and there you need a biomarkers for inclusion.
Meaning to include the correct population
in the clinical study.
Then we need the biomarkers in the trial
and that's for two different reasons.
The one is for target engagement
and then I refer to, if you develop a drug that you evaluate
in cell culture studies
or even in animal experiments.
Then you need to validate that this drug
really hits the targets also in men.
And one example is BACE inhibitor.
So BACE inhibitors, that's a class
of drugs that inhibit base,
which is the same as beta-secretase
where first enzyme cleaving-APP
to image generation of A-beta.
And there has been a number of phase 1 studies
to show that BACE inhibitors really lowers A-beta production
in the brain, that's in animals of course, in the brain.
And also in cerebrospinal fluid and plasma.
So that we can be certain that the this class
of drugs hits the target.
Then if you, for example,
go for anti-amyloid drugs.
Then it's also good to have evidence of what
we call downstream effects
and especially on neurodegeneration.
So if you give an anti-A-beta drug,
it's a good indication that the drug will really work
if you have a lowering of neurodegeneration
and that you can measure using biomarkers
for neuronal proteins
in either cerebrospinal fluid or blood.
Another implication is, of course in research studies.
This could be clinical studies
on the pathogenesis of the disease.
It could be genetic studies,
where you search for new risk genes for Alzheimer's disease,
but also in epidemiological studies
where you look for risk factors for AD.
And a new approach is
to evaluate these risk factors
and risk genes in populations where you have biomarker data
so that you can say whether a certain factor is a risk
for amyloid pathology or tau pathology
or neurodegeneration or just old age dementia.
That is important to understand the disease.
Recently there has been great technical developments
and this is on blood biomarkers
and this is based on new techniques
which we call ultrasensitive assays where
you can measure really minute amounts of a protein
in blood samples, meaning serum or plasma samples.
And this has enabled us to measure more
or less of all these AD biomarkers.
A-beta, tau, neurofilament light
and also phosphorated tau in plasma samples.
And there's a lot of work to be done still,
especially, especially for plasma biomarkers,
but they look promising.
And my thinking is that
they can be used in the future as screening tools.
Maybe in primary care,
when a patient comes with a memory complaints
or other cognitive symptoms that the primary care
physician can take a blood test
and get the screening tool for this type of pathology.
And based on the result, either send the patient back home
or to the specialist clinic for a more detailed evaluation.
One thing is that I think it's important to have tools
to monitor different aspects of the pathophysiology
in Alzheimer's disease and other brain disorders.
And one important aspect
of AD is synaptic dysfunction and degeneration.
And it's well known that there are a number
of synapse specific proteins
in the brain that regulates the neurotransmitter release,
and the synaptic function.
And one example of such a protein neurogranin
and we have a whole set of other proteins,
for example, SNAP25 and synaptotagmin and many more.
And many of these are measurable in CSF
and we already have assays to measure them.
And in AD, it has been shown that
for example, neurogranin, if we take that as an example.
The level in CSF is clearly increased,
and it's also been shown that higher levels
will predict the rate of future cognitive decline.
And that's maybe logical
since we know that synapsis, they are the functional unit
for communications between neurons in the brain.
So, if you have more severe neural dysfunction
or degeneration, that will predict also the rate
of cognitive change in Alzheimer's disease.
Interestingly, also this protein neurogranin seems
to be specific for Alzheimer's disease.
So very high levels of neurogranin is found in AD
but not in quite the number of other disorders,
for example frontotemporal dementia or Lewy body dementia .
We don't know the reason for that today,
but it may be related
to the specific function of nuerogranin.
It's involved in memory formation
and also in long term potentiation in neurons.
And maybe that's in some way related to
why the increase in CSF seems
to be specific for Alzheimer's disease.
So which biomarkers we have today?
That is to start with a-beta.
And there we measure the 42, amino acid form, a-beta-42.
That's also a form that is deposited in the plaques
in the brain.
So in cerebrospinal fluid you see a decrease in a-beta-42
and especially if you make a ratio to 40,
which is the most abundant a-beta peptide,
you see a marked decrease in the 42 to 40 ratio.
And today we can measure a-beta-42 and 40 also in plasma.
And you see this same type of change,
but the change is less pronounced
and there's a large overlap between patients and controls.
So if we have a CSF test ready for use in the clinic,
we need to work more on the blood test
before we can use them in trials or in the clinic, I think.
And especially to understand,
which proportion of a-beta that comes from the brain
and how much actually comes from peripheral organs
or for example, from the platelets in the blood.
We also have another test that's phosphorated tau.
It's phosphorated tau at position 181.
And that has been possible to measure
in cerebrospinal fluid for quite a number of years.
And there is a clear increase in phospho-tau
in Alzheimer's disease, in CSF.
And that actually seems quite specific
for Alzheimer's disease.
So don't see it in other tauopathies
or in other neurodegenerative diseases.
But today, there are also assays
on the way to measure phospho- tau 181 in blood
and they look very promising.
So, there is a clear increase in plasma.
And the good thing is that there is a tight correlation
between plasma and CSF, meaning that
most likely this assay measures brain pathophysiology,
even in blood samples.
So that's a promising new blood test for AD.