The largest international study ever conducted on Alzheimer’s disease, as part of the IGAP (International Genomics of Alzheimer Project) international consortium, coordinated by the joint research unit comprising Inserm, the Pasteur Institute at Lille-University Lille Nord de France ‘Public health and molecular epidemiology of diseases associated with ageing’ and LabEx DISTALZ, directed by Philippe Amouyel, has identified eleven new regions of the genome involved in the appearance of this neuro-degenerative disease. This work provides an overview of the molecular mechanisms at the root of the disease, revealing a better understanding of the physiopathology of this curse. These results, described in an article published in the journal Nature Genetics dated 27 October 2013, were obtained through a unique global collaborative effort by the best researchers in the field.

Since 2009, 10 genes linked to Alzheimer’s disease have been discovered, providing a better understanding of this dreadful illness. However, a large part of individual susceptibility to develop this disease still remains unknown. Characterising this individual susceptibility carried by our genome required being able to compare patients’ DNA with that from healthy people, to find a few hundred variations among more than 3.5 billion genes making up our genome. Such an approach meant analysing the genomes of thousands of individuals, which cannot be done at a team scale or even that of a single country.

For this reason, in February 2010, managers from the four largest international research consortia on the genetics of Alzheimer’s disease decide to join forces to accelerate the discovery of new genes. In less than 3 years, under the IGAP programme, researchers have succeeded in identifying more genes than over the previous 20 years. They set up their study in two phases. The first consisted of reanalysing all their existing data based on common criteria, a total of more than 17,000 cases of Alzheimer’s disease collected in Europe and North America, comparing them to some 37,000 non-diseased controls. Using advances in human genome sequencing (1000 Genomes project), they were able to compare the distribution of more than 7 million mutations between these cases and controls, so as to select only 11,632 of them from this first phase.

In the second phase, researchers verified these results in independent samples from 11 different countries, totalling 8,572 patients and 11,312 controls. This confirmed the discovery of 11 new genes in addition to those already known and to locate 13 others still being confirmed.

These 11 new genes offer new opportunities for understanding the appearance of Alzheimer’s disease. One of the most significant associations has been found in the HLA-DRB5/DRB1 region of the major histocompatibility complex. This discovery is interesting for more than one reason. Firstly, it confirms the immune system’s involvement in the disease. In addition, this same regions is also found associated with two other neuro-degenerative diseases, multiple sclerosis and Parkinson’s disease. Another link could also be made with the SLC24A4 locus, which codes a protein involved in development of the iris and in the colour variation of hair and skin, and which is associated with the risk of high blood pressure.

Some of these new genes confirm known hypotheses about Alzheimer’s disease, particularly the role of the amyloid pathway (SORL1, CASS4) and the Tau protein (CASS4, FERMT2). The role of the immune response and inflammation (HLA-DRB5/DRB1, INPP5D, MEF2C), already implicated by previous work from Inserm unit 744 (CR1[i], TREM2[ii]), is strengthened, as well as the role of cellular migration (PTK2B), lipid transport and endocytosis (SORL1). New hypotheses have also appeared, associated with hippocampal synaptic function (MEF2C, PTK2B), the cytoskeleton and axonal transport (CELF1, NME8, CASS4), as well as myeloid and microglial cell functions (INPP5D).

For the researchers, this discovery results in three main consequences. Firstly, this observation provides a better understanding of the physiopathology of Alzheimer’s disease, an essential step to discovering new treatments. Furthermore, this genome analysis better identifies the genetic profile of patients with a risk of developing Alzheimer’s disease. Finally, this work demonstrates that, faced with the complexity of such a disease, only the combined strength of global research will allow solutions to be found more quickly for this 21^st century curse.

Memory brain systems help resisting temptations – found a recent study led by researchers of the Brain & Spine Institute in Paris. How can some people resist the attraction of immediate pleasures and pursue long-term goals, while others easily succumb and compromise their ultimate expectations? One secret factor might lie in the activity of a deep brain structure: the hippocampus.

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Economists have been interested for decades in the conflict between smaller-sooner and larger-later rewards. Understanding how humans make inter-temporal choices, such as drinking tonight versus good health later, is crucial for designing insurance policy or anti-alcohol campaigns. This issue has recently been taken to brain scanners, in which volunteers were asked to make choices between monetary payoffs, for instance $10 now versus $11 tomorrow. Using this type of paradigm, scientists found that the dorsolateral part of the prefrontal cortex, a region known to implement behavioral control, was crucial for making patient choices – waiting for higher but delayed payoffs.

However, these paradigms miss an essential feature of the inter-temporal conflicts we have to face in everyday life, says study leader Mathias Pessiglione: immediate rewards can be perceived through our senses, whereas future rewards must be represented in our imagination. To reproduce this situation in the lab, the authors used more natural rewards like food items (for instance, a beer today or a bottle of champagne in a week for now). Volunteers were confronted to choices between immediate rewards presented as pictures, and future rewards presented as texts. In this case specifically, the ability to select future rewards was linked to the amount of hippocampus activity. To complete the demonstration, patients with hippocampus damage due to Alzheimer’s disease were tested in the same choice task. Contrary to patients with prefrontal degeneration, who exhibited excessive impulsivity in all sorts of choices, Alzheimer’s patients were specifically biased towards immediate rewards when future rewards had to be imagined.

This is because the hippocampus is necessary for imagining future situations with a richness of details that make them attractive enough – says Dr Pessiglione. Indeed, this structure has long been considered as essential for storing past episodes, but scientists have recently discovered that it is also involved in simulating future situations. The consequence is that patients with hippocampus damage suffer not only from memory deficits but also from a difficulty in imagining goals that would counter the attraction of immediate rewards and motivate their actions on the long run.