Is Alzheimer’s Disease Genetic?

Meryl Comer:  Dr. Guarente, let’s move to the genetics of Alzheimer’s disease. 

Dr. Guarente:  Yes.  Some genes have been identified by virtue of studying families in which early onset of Alzheimer’s occurs and is inherited. So using regular standard genetic means scientists have identified a few genes that are important.  One is a gene called APP and that gene encodes a protein that gets cut up into bits. And one of those bits is the offending substance, the Abeta amyloid peptide that gives rise to plaques and gives rise to toxic species, oligomers, that figure in the disease.  Another gene that was identified through genetics is a protein called presenilin, which is the enzyme that cuts the APP protein into pieces that actually makes the last cut to liberate this offending A-beta peptide, so we can learn about the disease... And another locus that has been identified is APOE4, which is a risk factor for Alzheimer’s disease and is sort of less central in a molecular sense then are APP and the presenilin. So what the genetics tells us...  First of all, we can’t really do anything about our genes, so our genes are what they are, but genetics clues us in on what the players are that are important in a disease and what we do is we study those players and how they interact in the context of cells and organs, like the brain. And I think that it opens a door for us to develop strategies to tinker with these steps, but not with genes, but with drugs. And I think that drug development in this field there really is nothing right now for people with Alzheimer’s disease. And it’s really where there is an incredible demand, and a growing demand. And based on the biology that I just described really in a skeletal way of the relevant genes and the relevant pathways I think we have to hammer home to get to drugs and that is only going to come from experimentation and funding and a really intense effort because it’s not easy to develop drugs. And we’ve seen sort of a template for this with AIDS.  There was a tremendous emphasis put on getting drugs for AIDS, starting maybe 20, 25 years ago and it has led to drugs that don’t cure the disease, but treat it quite well. And I think that illustrates that once a society decides that they want to do something like this it can be done.

Meryl Comer:  Let’s put the genetic predisposition into perspective Dr. Gandy.  What percent?  If you say age is the greatest determinate of getting Alzheimer’s, what percentage of those are early onset or familial?

Dr. Gandy:  Well only about 3% of all of Alzheimer’s is early onset and completely familial, but APOE4 before increases the risk for Alzheimer’s and there are probably certainly more people with Alzheimer’s disease, partially because they have an APOE4 gene than with any other genetic risk factor. So it has been very challenging to understand exactly how APOE4 works and in fact that is an important clue for us to continue to follow because more people have APOE4 related Alzheimer’s disease than Alzheimer’s disease related to either APP or presenilin.

Dr. Guarente:  If I might just comment on that.  These other 90% of AD patients who don’t have a frank mutation in APP or the presenilin that is not to say that that pathway and those proteins, APP and A-beta are not critical in the disease.  I believe that very likely they are in all of Alzheimer’s cases, so by leveraging the genetics to get at these players and developing drugs I think we wouldn’t be just treating the 3%.  We potentially could treat everybody.

Dr. Gandy:  Yeah, but by the part of the power of these early onset genes is that the clinical manifestations and the pathology of the early onset genetic forms and the common later onset forms are indistinguishable except for the age at onset.  They look the same in your waiting room.  They look the same under the microscope, so Lenny is exactly right that this pathway points the way for all of Alzheimer’s disease.

Meryl Comer: Dr. Arancio, you wanted to make a point.

Dr. Arancio:  Yeah, my point is that I definitely agree with my friends here that interfering with this protein tau and A-beta could be beneficial in terms of therapy and to take advantage of that.  However, there is one thing that... an area that I think is underdeveloped in all our studies, which is what is behind that, what comes before that.  This is an area that when I see... which it’s my belief that there is... we need more attention because it’s totally a dark area because yes, in the 3% of cases there is for sure with a mutation these proteins are affected, but the remaining 97%, we should find out why.  It is not them directly.  It is something behind them that through them caused the damage and that is the area, a big area that could be very, very useful and I’d like to sort of find... to draw the attention on all of us that perhaps interfering with the protein that some of the protein that regulates the APP like Lenny just said for instance, also tau, we can interfere with physiological normal function of this factor and therefore we’re hoping to get rid of disease and we are causing other trouble and this could be the reason for failure of some of the drugs that even recently have failed.

Meryl Comer: Well let’s look at one of the other challenges and that is the area around finding biomarkers that will help in the early diagnostics and detection of this disease.

Dr. Gandy:  So biomarkers are sort of surrogates for the disease that can be measured perhaps before the clinical manifestations begin. And they primarily included things like blood tests, spinal fluid tests and brain scans. And we know now that we can visualize the buildup of amyloid in the brain long before any cognitive changes occur clinically.  About half of the people age 65 and older already have significant visualizable amyloid buildup in their brain yet they mostly aren’t demented. 

Dr. Troncoso:  I would like to add something, just one more point to the genetics.  It’s something that it’s very important to recognize that patients with Down Syndrome which have a definite genetic abnormality, all of them will have at least pathological Alzheimer’s diseases, if not necessarily a manifestation of dementia. And since they they have the APP gene is in chromosome 21 in the segment that is extra in patients with Down Syndrome, this also it supports the hypothesis that the APP and the amyloid is a triggering factor in the disease, but it’s also a very important genetic component.

Genes such as ApoE4 may signal a risk factor for Alzheimer’s. But how do we separate risk factor from an unalterable sentence for the disease?

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Kosovo land swap could end conflict - or restart war

Best case: redrawing borders leads to peace, prosperity and EU membership. But there's also a worst case

Image: SRF
Strange Maps
  • The Yugoslav Wars started in 1991, but never really ended
  • Kosovo and Serbia are still enemies, and they're getting worse
  • A proposed land swap could create peace - or reignite the conflict

The death of Old Yugoslavia

Image: public domain

United Yugoslavia on a CIA map from 1990.

Wars are harder to finish than to start. Take for instance the Yugoslav Wars, which raged through most of the 1990s.

The first shot was fired at 2.30 pm on June 27th, 1991, when an officer in the Yugoslav People's Army took aim at Slovenian separatists. When the YPA retreated on July 7th, Slovenia was the first of Yugoslavia's republics to have won its independence.

After the wars

Image: Ijanderson977, CC BY-SA 3.0 / Wikimedia Commons

Map of former Yugoslavia in 2008, when Kosovo declared its independence. The geopolitical situation remains the same today.

The Ten-Day War cost less than 100 casualties. The other wars – in Croatia, Bosnia and Kosovo (1) – lasted much longer and were a lot bloodier. By early 1999, when NATO had forced Serbia to concede defeat in Kosovo, close to 140,000 people had been killed and four million civilians displaced.

So when was the last shot fired? Perhaps it never was: it's debatable whether the Yugoslav Wars are actually over. That's because Kosovo is a special case. Although inhabited by an overwhelming ethnic-Albanian majority, Kosovo is of extreme historical and symbolic significance for Serbians. More importantly, from a legalistic point of view: Kosovo was never a separate republic within Yugoslavia but rather a (nominally) autonomous province within Serbia.

Kosovo divides the world

Image: public domain

In red: states that have recognised the independence of Kosovo (most EU member states – with the notable exceptions of Spain, Greece, Romania and Slovakia; and the U.S., Japan, Turkey and Egypt, among many others). In blue: states that continue to recognise Serbia's sovereignty over Kosovo (most notably Russia and China, but also other major countries such as India, Brazil, Mexico, South Africa and Iran).

The government of Serbia has made its peace and established diplomatic relations with all other former Yugoslav countries, but not with Kosovo. In Serbian eyes, Kosovo's declaration of independence in 2008 was a unilateral and therefore legally invalid change of state borders. Belgrade officially still considers Kosovo a 'renegade province', and it has a lot of international support for that position (2). Not just from its historical protector Russia, but also from other states that face separatist movements (e.g. Spain and India).

Despite their current conflict, Kosovo and Serbia have the same long-term objective: membership of the European Union. Ironically, that wish could lead to Yugoslav reunification some years down the road – within the EU. Slovenia and Croatia have already joined, and all other ex-Yugoslav states would like to follow their example. Macedonia, Montenegro and Serbia have already submitted an official application. The EU considers Bosnia and Kosovo 'potential candidates'.

Kosovo is the main stumbling block on Serbia's road to EU membership. Even after the end of hostilities, skirmishes continued between the ethnically Albanian majority and the ethnically Serbian minority within Kosovo, and vice versa in Serbian territories directly adjacent. Tensions are dormant at best. A renewed outbreak of armed conflict is not unthinkable.

Land for peace?

Image: BBC

Mitrovica isn't the only area majority-Serb area in Kosovo, but the others are enclaved and fear being abandoned in a land swap.

In fact, relations between Kosovo and Serbia have deteriorated spectacularly in the past few months. At the end of November, Kosovo was refused membership of Interpol, mainly on the insistence of Serbia. In retaliation, Kosovo imposed a 100% tariff on all imports from Serbia. After which Serbia's prime minister Ana Brnabic refused to exclude her country's "option" to intervene militarily in Kosovo. Upon which Kosovo's government decided to start setting up its own army – despite its prohibition to do so as one of the conditions of its continued NATO-protected independence.

The protracted death of Yugoslavia will be over only when this simmering conflict is finally resolved. The best way to do that, politicians on both sides have suggested, is for the borders reflect the ethnic makeup of the frontier between Kosovo and Serbia.

The biggest and most obvious pieces of the puzzle are the Serbian-majority district of Mitrovica in northern Kosovo, and the Albanian-majority Presevo Valley, in southwestern Serbia. That land swap was suggested previous summer by no less than Hashim Thaci and Aleksandar Vucic, presidents of Kosovo and Serbia respectively. Best-case scenario: that would eliminate the main obstacle to mutual recognition, joint EU membership and future prosperity.

If others can do it...

Image: Ruland Kolen

Belgium and the Netherlands recently adjusted out their common border to conform to the straightened Meuse River.

Sceptics - and more than a few locals - warn that there also is a worst-case scenario: the swap could rekindle animosities and restart the war. A deal along those lines would almost certainly exclude six Serbian-majority municipalities enclaved deep within Kosovo. While Serbian Mitrovica, which borders Serbia proper, is home to some 40,000 inhabitants, those enclaves represent a further 80,000 ethnic Serbs – who fear being totally abandoned in a land swap, and eventually forced out of their homes.

Western powers, which sponsored Kosovo's independence, are divided over the plan. U.S. officials back the idea, as do some within the EU. But the Germans are against – they are concerned about the plan's potential to fire up regional tensions rather than eliminate them.

Borders are the Holy Grail of modern nationhood. Countries consider their borders inviolate and unchanging. Nevertheless, land swaps are not unheard of. Quite recently, Belgium and the Netherlands exchanged territories so their joint border would again match up with the straightened course of the River Meuse (3). But those bits of land were tiny and uninhabited. And as the past has amply shown, borders pack a lot more baggage in the Balkans.

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Scientists claim the Bible is written in code that predicts future events

The controversy around the Torah codes gets a new life.

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  • Mathematicians claim to see a predictive pattern in the ancient Torah texts.
  • The code is revealed by a method found with special computer software.
  • Some events described by reading the code took place after the code was written.
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