Toronto: 6th Sense—GWAS Picks Up New AD Risk Variant
A genetic variant near the gene for MTHFD1L on chromosome 6 likely doubles a person’s risk of late-onset Alzheimer disease, according to research presented today at the American Academy of Neurology meeting in Toronto, Canada. The discovery, from a large genomewide association screen, jibes well with what is known about the protein’s role in metabolizing homocysteine, a known risk factor for Alzheimer’s. First author Adam Naj and principal investigator Margaret Pericak-Vance, both of the University of Miami, Florida, outlined the finding in a poster session.
The study authors hunted for AD-linked genes in a genomewide association study encompassing nearly 500,000 SNPs and including more than 2,000 AD subjects, and over 3,000 controls in the combined discovery and confirmation datasets. They found that SNPs in and around the MTHFD1L gene were linked to AD risk, with the disease-associated variants doubling risk. In comparison, the ApoE4 allele increases AD risk by a factor of 3.68. However, the presenters noted that the odds ratio of two is likely to go down a bit with further study.
MTHFD1L encodes a protein, methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like, that may help convert homocysteine into methionine, so problems with this gene might lead to elevated homocysteine levels. Increased plasma homocysteine is a well-known AD risk factor (see ARF related news story on Seshadri et al., 2002). In addition, MTHFD1L variants have been linked to coronary disease (Coronary Artery Disease Consortium, 2009) and dementia can be caused by reduced blood flow to the brain, so the link among MTHFD1L, Alzheimer’s, and coronary disease is compelling, Pericak-Vance said.
Other studies have not found a significant association between SNPs near MTHFD1L AD (see AlzGene), although some GWAS have come close. Pericak-Vance and Naj suggested that their study met stringent statistical GWAS thresholds because of the particular SNPs they analyzed, and the size of the cohort.
The authors speculated that carriers of the MTHFD1L disease-linked variant are unable to properly convert homocysteine to methionine, allowing homocysteine to build up. This molecule could then cause disease by altering vasculature, increasing oxidative stress, or poisoning cortical neurons. However, Naj noted that it is too soon to be sure what happens in people with different MTHFD1L variants. “We have no evidence to go on as to what it actually does,” he told ARF. As with any GWAS, it will be necessary to look for the significance of this gene in other datasets to confirm its importance. The researchers are currently sequencing MTHFD1L and testing plasma homocysteine levels in control and AD samples.—Amber Dance.
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Toronto: Mucke, Miller Share Prestigious Potamkin Prize
The Potamkin Prize is one of the most prestigious awards for researchers working on Pick’s, Alzheimer’s, and related diseases. This year the prize goes to Lennart Mucke and Bruce Miller, who both have labs at the University of California, San Francisco. The award, sponsored by the Potamkin family of New York, Philadelphia, and Miami, was presented at the 62nd annual meeting of the American Academy of Neurology, held this week in Toronto, Canada.
Mucke, who is no stranger to Alzforum readers, was rewarded for his work relating amyloid-β and tau, hallmarks of Alzheimer disease (AD), to neural toxicity and the disruption of neural networks. His work has linked a variety of molecular players, including cytokines (ARF related news story and Wyss-Coray et al., 1997), calcium-binding proteins (see ARF related news story), Aβ-degrading enzymes (see ARF related news story) and even collagen, typically associated with connective tissue (see ARF related news story), to AD pathology in animal models of the disease. His discovery that mice overexpressing human Aβ have spontaneous non-epileptic seizures induced by hyperactive neurons, and a compensatory elevation in inhibitory neural network activity, offered a new rationale for Aβ toxicity (see ARF related news story), and a possible explanation for epileptic seizures in AD patients.
Miller, a behavioral neurologist, is a world leader in the study and treatment of patients with frontotemporal lobar degeneration (FTLD), also called Pick disease. FTLD is a rare form of dementia characterized by deposits of tau (Pick bodies) in the frontal and temporal lobes of the brain. Miller’s work has helped uncover genetic mutations and inheritance patterns (see Goldman et al., 2005) that increase risk for the disease and characterize different forms of FTLD (see, e.g., Johnson et al., 2005 and Miller, 2007). “He is a clinician scientist who has been able to bring together collaborators to solve the complex clinical heterogeneity of this group of disorders so that one can begin to plan clinical trials and understand how to use imaging and biomarker diagnostics to separate out complex phenotypes,” said John Trojanowski, University of Pennsylvania, Philadelphia. Mucke and Miller will share the $100,000 Potamkin Prize, which will go toward further dementia research.—Tom Fagan.
- TGF-β1 Linked to Plaque Formation
- Calbindin Study: Is Calcium the Molecular Handle on Dysfunction in AD?
- Metalloproteases—A Shining Challenge to Aβ
- Sticking It to Oligomers—Does Collagen Protect Neurons From Aβ?
- Do "Silent" Seizures Cause Network Dysfunction in AD?
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- Goldman JS, Farmer JM, Wood EM, Johnson JK, Boxer A, Neuhaus J, Lomen-Hoerth C, Wilhelmsen KC, Lee VM, Grossman M, Miller BL. Comparison of family histories in FTLD subtypes and related tauopathies. Neurology. 2005 Dec 13;65(11):1817-9. PubMed.
- Johnson JK, Diehl J, Mendez MF, Neuhaus J, Shapira JS, Forman M, Chute DJ, Roberson ED, Pace-Savitsky C, Neumann M, Chow TW, Rosen HJ, Forstl H, Kurz A, Miller BL. Frontotemporal lobar degeneration: demographic characteristics of 353 patients. Arch Neurol. 2005 Jun;62(6):925-30. PubMed.
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Toronto: In Small Trial, IVIg Slows Brain Shrinkage
There may be a new reason to support your local phlebotomist—if data from an extension trial of 24 people hold up in Phase 3, that is. A preparation of human blood immunoglobulins slows clinical decline in Alzheimer patients and protects their brains against shrinkage over 18 months, according to data presented at the 62nd annual American Academy of Neurology meeting, held last week in Toronto, Canada. Norman Relkin, Weill Cornell Medical Center, New York, presented results from the Gammagard Phase 2 clinical trial. The data extend nine-month findings shown last July at the International Conference on Alzheimer’s Disease (see ARF related news story), which suggested benefit in the primary endpoints of cognition (ADAS-cog) and global change (ADCS-CGIC). The 18-month data, which include MRI results, indicate that IVIg also protects against brain atrophy. “The results were certainly a surprise,” said Relkin, who told ARF that the brain volumetric analysis was neither a primary nor secondary outcome in the trial, but simply an exploratory outcome. “It was only because the effect size was so large that we saw the differences,” he said. The findings support the idea that immunotherapy might become an effective treatment for AD.
Relkin said that the original analysis of the MRI data, conducted by his collaborator Jim Brewer at University of California, San Diego, were so impressive that he found it hard to believe. But independent analysis of the data by Dana Moore at Weill Cornell, using different software, essentially told the same story: that patients on IVIg had rates of brain atrophy consistent with those of age-matched normal individuals.
That atrophy was normal in treated patients would be suggestive of a disease-modifying (DM) effect. In fact, as luck would have it, this Phase 2 trial of IVIg used a delayed start design, which is one potential way of demonstrating disease modification. By comparing the rate of progression of disease in groups of patients starting the therapy at different times, DM effects can be revealed, the theory goes. In this case, however, the delayed start was not designed from the outset to prove disease modification. It was more a case of how the study evolved—funding agencies initially required a six-month proof-of-concept trial, said Relkin, and the trial was later extended to 18 months. As a result, eight patients received placebo for six months and then IVIg for 12 months (the delayed start), while 16 patients received the treatment from the beginning of the trial. “The hope of having something which is disease modifying has eluded us in so many clinical trials. I’m reluctant to say that we found something that is disease modifying, but in terms of trajectory and biological changes, things seem to point in that direction,” said Relkin. The patients who received the optimal dose of IVIg had an initial symptomatic improvement that was maintained over the 18 months of the study. MR measurements showed that they also had less atrophy than patients who had the delayed start.
Patients received 0.2 g IVIg per kg body weight twice a month, 0.4 g/Kg twice a month, or 0.8 g/Kg once a month. The trial was blinded during the first six months and open-label afterwards. Patients knew they were receiving treatment, though not which dose; raters stayed blinded to who had initially been on placebo. Overall, the MRIs measured 46 percent reduction in annual brain atrophy in patients who received continuous treatment compared to those who initially received placebo, said Relkin. There was significantly less ventricular enlargement in the continuous treatment group as well (6.7 percent a year versus 12.7 percent a year). There appears to have been a dose-dependent effect, whereby patients on the optimal dose (0.4 g/Kg biweekly) had annual rates of atrophy similar to those seen in normal patients in the ADNI cohort, according to Relkin. “What makes the data exciting is a tight correlation between brain volumetric data and primary outcome measures of cognition (ADAS-cog) and global change (ADCS-CGIC),” said Relkin. At baseline no correlation was apparent between brain volumes and the primary measures, but the changes over the course of 18 months were highly correlated.
IVIg is a mixture of immunoglobulins, some of which Relkin believes target Aβ. He told ARF that these antibodies may differ from others currently being tested in that they recognize epitopes formed when Aβ aggregates. IVIg also has documented immunomodulatory effects, Relkin added, noting that this may convert pro-inflammatory microglia into phagocytic, non-inflammatory cell types that can mop up Aβ. Amyloid imaging with PIB-PET may be able to address the question of Aβ removal. Half the patients in this Phase 2 trial were scanned for PIB at six months and again at 18 to 24 months. Those data are currently being analyzed, Relkin said.
A Phase 3, multicenter trial of IVIg enrolling 360 AD patients is underway. It is sponsored by an NIA grant through the Alzheimer’s Disease Cooperative Study (ADCS) and is jointly funded by Baxter BioScience, who make the IVIg preparations. This non-patentable therapy is FDA approved and has been used for decades for certain life-threatening immunodeficiency disorders, including congenital pediatric immunodeficiency. The rising interest in an Alzheimer’s indication has certain patient groups worried that a successful Phase 3 trial could result in intense demand for the immunoglobulin mix, noted Relkin. He stressed that IVIg should not be used off-label and mentioned that there is an industry initiative afoot to guarantee IVIg to those patients who cannot live without it. Ultimately, if the ADCS Phase 3 trial is successful, then an analysis of the mixture could identify specific components that could be used to make more targeted immunotherapies, said Relkin.—Tom Fagan.