Find all causes of Alzheimer's disease and a cure

Neurodegenerative Diseases of the central nervous system progressively rob patients of their memory, motor function, and ability to perform daily tasks. Advances in genetics and animal models across the field, but specifically through the Alzheimer’s Genome Project initiated by Cure Alzheimer’s Fund, are beginning to unearth an unexpected role for the immune system in disease onset and progression. Recent work into the genetics of Alzheimer’s disease has identified a compelling role for immune signaling pathways to play a role in the disease. This lays the ground work for immune-related therapeutic intervention.

Unraveling the genome in order to predict whether someone will get Alzheimer’s disease has been an area of focus for the neurodegenerative disease community. Two back-to-back research papers published in Nature Genetics analyzed the largest-ever genomic data sets to date in order to point to new genetic risk factors for Alzheimer’s disease. Not only that, but the researchers uncovered a role for how these genes contribute to Alzheimer’s disease – in some cases through the immune system. 94,437 individuals who had been diagnosed with late-onset Alzheimer’s disease participated in a genome-wide association study that identified variants in five new genes that put people at risk for Alzheimer’s disease. The data also confirmed 20 other genes that had been previously implicated in Alzheimer’s disease.

Another huge advance from these papers is the identification of the groups of genes that work together to influence risk and disease progression. Many of the genes identified play a role in the formation of beta-amyloid plaques, tau accumulation, and the immune system. The study independently identified ADAM10 and ACE as risk variants for Alzheimer’s disease providing much need replicated support for the findings. By themselves, each of these newly discovered variants contribute only a small amount of increased risk. That being said, this study advances the biological pathways that are involved in the onset and progression of the disease.

This new research paper is ground breaking for those interested in finding a way to predict who will get Alzheimer’s disease later in life. The goal of this research is to understand how the complex biological, environmental, and lifestyle factors interact to contribute to Alzheimer’s.

A “News and Views” piece published in Nature Reviews Neurology by Cure Alzheimer’s Fund researcher Lars Bertram and Chair of the Research Leadership Group of Cure Alzheimer’s Fund, Rudy Tanzi, outlined the major findings of this ground-breaking work. 

Links:

• Nature Reviews Neurology perspective piece
• Rudy Tanzi discussed the results of these studies with CNN

In healthy humans, the cerebrospinal fluid (CSF) is renewed approximately four times a day. In aging adults, impaired function of lymphatic vessels in the meninges can lead to accelerated accumulation of toxic amyloid beta protein in the brain. The meninges are made up of membranes that line the skull in order to protect the brain and spinal cord. The existence of these lymphatic vessels in the meninges was first mentioned toward the end of the 18th century, but it took more than 200 years for the hypothesis to be confirmed using state of the art imaging technology in the laboratory of Dr. Jonathan (Jony) Kipnis.

In the 30th Anniversary Issue of Neuron, Dr. Kipnis, along with his collaborators Drs. Sandro Da Mesquita and Zhongxiao Fu, put forth their perspective on the relevance of the meningeal lymphatic system for cerebral spinal fluid drainage, aging-associated brain dysfunction, and amyloid beta clearance in Alzheimer’s disease.

This research has challenged the conventional model for how cerebral spinal fluid remains in equilibrium. The existence of these lymphatic vessels in the meninges took a long time to confirm as this finding does not fit the previously prevailing hypothesis that the central nervous system has no direct contact with the immune system.

One of the keys to cracking the case of whether or not lymphatic vessels exist in the meninges of the central nervous system was confirming that these vessels expressed the same markers as other lymphatic cells, specifically lymphatic endothelial cells. The other requirement for confirmation was determining that these lymphatic vessels could efficiently drain both molecules and immune cells from a region of the brain called the subarachnoid space into lymph nodes.

The traditional model for how the cerebrospinal fluid drained was directly challenged when the scientists injected molecular tracers into the CSF and demonstrated that the drainage occurred through the lymphatic vessels – demonstrating a new route for clearing molecules from the brain. The presence of a “brain drain” is critical for maintaining intracranial pressure and removal of waste. The protein concentration of the CSF increases with aging and has been shown to be even higher in patients with age-associated dementia.

Meningeal lymphatic vessels are evolutionarily conserved and have been reported in fish, rats, non-human primates, and humans. A critical question that remains is whether the network of lymphatic vessels increases in complexity in humans with their more complicated cognitive behaviors and more convoluted brains.