(3/3) Alzheimer’s disease: the challenges of the blood-brain barrier

(3/3) Alzheimer’s disease: the challenges of the blood-brain barrier


– One of the big challenges in dementia diagnosis and research is the fact that there
is a blood-brain barrier so that what is happening in the brain is not always reflected outside the brain. However, the easiest
fluid in which we can see what’s happening anywhere
in the body is the blood. It is much harder, it’s more expensive to do molecular imaging with modalities like amyloid, tau, and
other types of PET imaging. It is a little invasive, although doable, to take a sample of the spinal fluid which bathes the brain and spinal card to see what protein or
other biomarker alterations there may be. Fortunately, we are
increasingly recognizing that Alzheimer’s is
really a systemic disease, that injury to the vessels
contributes to the dementia, and that there are certain markers that freely cross the blood-brain barrier particularly in disease
when the blood-brain barrier is affected, anyway. Finally, there are little
pieces of cell membranes called exosomes that can break off. By looking at what proteins
are on these membranes, we can see where these exosomes came from. And neuronal exosomes
circulating in the blood, can be a source, of again, understanding what are the biochemical
and molecular changes happening in the brain. Over the years we have
realized that there are specific molecular changes that are fairly typical of brain injury,
neurodegenerative and vascular. For instance, there is
BDNF or brain-derived neurotrophic factor that
increases when one does exercise and decreases when there
is a high caloric diet, increases again with caloric restriction. So it may be one of the
biomarkers that reflects the biological pathway
that mediates the effect of a lifestyle intervention
such as exercise or a change in diet with
an impact on cognition. So there is, other markers
include things like neurofilament light or NF-L, that has a lot of interest recently. Markers that are specific growth factors, BDNF is one of them but also vascular endothelial
growth factor or VEGF, nerve growth factor or NGF. There are markers of specific microglial
inflammation like YKL-40. There are markers of
astrocytic injury like GFAP. And of course, there
are the classic markers of amyloid and tau. It used to be thought that
levels of amyloid and tau in the blood did not reflect what was happening in the brain. But one reason we thought that was because these are difficult
proteins to measure in the blood. Their concentrations are small. Amyloid, for instance, is sticky. And so it was more assay properties that were introducing noise. Over the last decade as
we have had better assays that are able to detect
smaller quantities, we have found that plasma
circulating beta amyloid for instance does correlate
with risk of future dementia. Just this year, we had a large
study on over 2,500 people where blood levels of
plasma tau, total tau, were strongly associated with future risk of clinical dementia as well
as of subclinical brain injury as reflected in the brain size, the hippocampal volume, on performance, on a range of cognitive tests from memory to executive function. So there is a lot of interest and hope that over the next five years we are going to identify a parsimonious set of blood markers that
could help us diagnose more accurately, track
treatment modalities and their impact on the brain, and divide people into clusters
of pathology or biology that might respond to
different types of treatments. In the past decade, we have been able to use genome wide genotyping
to take an agnostic look at what may be the biology
underlying Alzheimer’s and related disorders. So we’ve identified genetic pathways that were not previously suspected and are now exploring to understand fully the biology of these genes
and genetic pathways. For instance, in 2010, in the Journal of American
Medical Association, or JAMA, we published a paper that
brought together data from the CHARGE Consortium
or Cohorts for Heart and Aging Research in
Genomic Epidemiology, EADI, or European Alzheimer’s
Disease Initiative, and GERAD, or Gene Environment
Risk in Alzheimer’s Disease which was a sort of U.S.-U.K. consortium. And one of the genes we identified was a gene called BIN1 which is the second most important factor for sporadic or late
onset Alzheimer’s Disease as far as we can tell both in terms of the attributable risk,
the size of the effect, the fact that it has an impact in persons of European ancestry as well as persons of African American Hispanic ancestry. This is a very interesting gene. It seems to have multiple
ways in which it might be affecting cognition. For instance, it has a
role in the tau pathway. It has a role in endocytic
clearance of amyloid. It affects the vasculature. We recognize that mutations,
certain mutations in BIN1 can actually result in cardiomyopathy. So this is a gene that we
are studying in some detail to understand what is clearly
an important aspect of biology that we did not know before
these genetic studies. In the same paper, another
gene that we looked at was one on chromosome 19 called EXOC3L2. And this is a gene that
is close to the APOE gene. So initially it was a
little challenging to see if the effect we were seeing
was only because of APOE. But we did conditional analysis and did not believe that to be so. And increasingly there
is evidence emerging that this is actually a gene that may play a role in the link between vascular and
neurodegenerative processes. Jason Henman and Kalisz have
looked at genes in this area. EXOC3L2 is one of the genes in this area. Another one is something called MARK4. And we’re not completely
sure if there’s only one or more than one gene in this area. But this is something that’s, again, pointing us to new biology in the space between vascular and
neurodegenerative processes. And I’m looking forward
to seeing what we learn in the next few years.