29 Dec 2011

As 2012 comes knocking, it’s a good time to reflect on what happened in Alzheimer’s research over the past 12 months. The Alzforum news team assembled a snapshot of noteworthy stories from the past year. We grouped them into 10 themes. Did we get it right? As you reflect on yet another year gone by, what do you think were its most newsworthy findings? Do you care to nominate an 11th theme for 2011? Use the comment box below to add your picks.

1. Biomarkers and Diagnosis
Fluid and imaging biomarkers continued to be a major research focus in 2011, with researchers getting a better picture of which markers appear earliest in the disease trajectory. Diagnosis remained a major theme in the AD field. 2011 saw the publication of new diagnostic guidelines for AD formulated by committees sponsored by the National Institute on Aging and the Alzheimer’s Association. The NIA/AA also published guidelines for diagnosis of mild cognitive impairment due to Alzheimer’s disease, and for preclinical AD. Biomarkers informed early diagnostic efforts. In the U.S. an FDA advisory committee came down against approval of the PET amyloid imaging ligand AV-45, citing work to be done to ensure consistency in reading PET scans. The European Medicines Agency announced the likely approval of hippocampal atrophy as a marker of early AD for the purpose of clinical trials. Revised NIA/AA guidelines for postmortem diagnosis came close to completion. These would be compatible with diagnostic criteria in that pathology alone would be sufficient to declare the deceases had Alzheimer’s even if they were not demented at time of death.

2. Early Screening and Prevention
Both the Alzheimer’s Prevention Initiative and the Dominantly Inherited Alzheimer Network made strides towards getting early trials off the ground. The push toward pre-symptomatic trials in the general population gained momentum when scientists announced plans to seek funding in 2012 for the Anti-Amyloid Treatment in Asymptomatic Trial (A4), a secondary prevention trial. Debate persisted over how to implement successful clinical trials in different populations, as did debate over the pros and cons of screening for dementia in primary care.

3. Oligomers, Aβ, Tau
Even as Aβ oligomers grabbed some of the limelight, researchers began to question what the term “oligomer” actually means. In March, a Nature editorial called for clarity in the field, stressing that at the very least researchers need to accurately define the nature of oligomeric proteins used in experiments. Later in the year, researchers addressed the issue in an Alzforum webinar. In related news, scientists reported that patient-derived Aβ oligomers are toxic to cells at physiological concentrations (low nanomolar range) and that they interact with prion protein, as had been previously described for Aβ in animal models. The first x-ray structure of Aβ oligomers debuted, and a case emerged for the toxicity of Aβ43. Oligomers were among the many facets of tau biology explored at “Tau and Tauopathies: Pathogenic Mechanisms” a symposium that underscored a resurgence of interest in the neurofibrillary tangle protein. Oligomer insights came from other fields, as well. Reports of a natural, stable, tetrameric form of α–synuclein came as a surprise to many. On the clinical front, the European Medicines Agency approved tafamidis, a drug that stabilizes tetramers of transthyretin, mutations in which lead to familial amyloid neuropathy. Tafamidis protects against this disease by preventing transthyretin tetramers from dissociating into monomers that assume amyloidogenic conformations.

4. Epidemiology/Risk Factors
In 2011 the Alzrisk database grew by leaps and bounds, adding five new entries on inflammatory markers, homocysteine, hypertension, alcohol, and hormone replacement therapy. The curators expanded database entries and discussions on nutritional antioxidants. There was renewed interest in the role of estrogen in the brain. ApoE remains the dominant genetic risk factor for sporadic AD and the importance of the protein’s lipidation status and role in Aβ clearance both grew. Research suggests ApoE puts the brakes on removal of Aβ, with ApoE4 slowing it most. Scientists learned more about the link between traumatic brain injury and dementia, while evidence that exercise can protect against AD grew.

5. Clinical Trials
The field still eagerly awaits successful pivotal trials. Meanwhile, 2011 saw some mixed reports. Gantenerumab, a humanized monoclonal antibody against Aβ, clears plaques when given intravenously, according to results from a Phase 1 trial. However, Pfizer halted development in phase 2 of ponezumab, another humanized monclonal antibody. Vasogenic edema and microhemorrhages showing up on MRI scans were reclassified as amyloid-related imaging abnormalities (ARIA), complicating immunotherapy trials. 2011 brought the first peer-reviewed publication of results from a β-secretase inhibitor trial. Eli Lilly’s LY2811376 reduced CSF Aβ in human volunteers, but the company pulled the compound after safety tests in rodents revealed it caused damage to the retina. A Phase 2 gene therapy trial for Parkinson’s disease was deemed a success. Negative news on the trial front, particularly the failure in phase 3 of semagacestat, prompted intense debate within the field about the way forward.

6. Stem Cells
The potential of stem cells is attractive to researchers even as it remains far off as a mass therapy. 2011 saw several firsts. Skin cells from AD patients were converted into neurons for research purposes for the first time. Scientists devised ways of generating induced pluripotent stem (iPS) cells without using viral vectors and they managed to directly convert human fibroblasts to neurons, bypassing the iPS cell step. Researchers also claimed to have produced therapeutic-grade dopaminergic neurons, which showed efficacy in mouse models of Parkinson’s disease. Scientist made strides using stem cells to correct inherited mutations. Researchers took fibroblasts from a PD patient with an α-synuclein mutation, correct that mutation, and then made iPS cells. Neurons derived from those cells could help scientists understand why synuclein mutations are so dangerous. The method could one day provide cells for autologous transplantation.

7. Genetics and Beyond
Identifying genetic risk factors for Alzheimer’s and other neurodegenerative disease loomed large on the research agenda in 2011. February saw the launch of IGAP—the International Genomics of Alzheimer’s Project, a transatlantic collaboration to create the most detailed map of genetic variants that link to AD. Meta analysis of genome-wide association studies (GWAS) revealed four new genetic risk variants for Alzheimer’s. Meta analysis and new GWAS uncovered eight new genes for Parkinson’s. Finally solving the long-standing mystery of the ‘chromosome 9p linkage’, scientists found hexanucleotide repeats in the same orphan gene in substantial numbers of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, further tying these two disorders together on a genetic spectrum. Researchers also began to look in earnest beyond identifying risk loci to finding the causative mutations and what they do. Exome sequencing picked up pace as a method of the future.

8. Funding and Policy
Funding shortages continued to weigh on researchers minds. The NIA introduced austerity measures for grants over $500,000 to try to maintain funding levels for smaller grants. AD researchers got a modicum of good news with the announcement of a $15 million appropriation for the department of defense to create an AD research program. The National Alzheimer’s Project Act mandate began to take shape with the selection of the 12 non-federal members who are serving on the Advisory Council on Alzheimer’s Research, Care, and Services and are due to present a draft national plan shortly.

9. Interstitial Interest
In-vivo microdialysis to measure solutes in the fluid inside of the brain but outside of its cells, became more prominent as an up-and-coming method to probe biomarkers closer to the action than do spinal taps of the CSF. Researchers used the technique to link brain activity to production of Aβ. Scientists also reported that high brain activity can suppress release of Aβ into the interstitial space. Surprisingly to some, tau and a-synuclein, normally intracellular proteins, were also found in interstitial fluid and fairly high concentrations.

10. Networks, Hubs, Memory
Figuring out how the brain captures, stores, and retrieves memories is still one of biology’s great frontiers, but little by little researchers are making inroads. 2011 saw several novel developments. Molecular tagging of synapses emerged as potentially important for storing memories, while a simple kinase turned out to be perhaps crucial for solidifying them. Hippocampal “time” cells, which mark memories temporally, joined the better-known “place” cells, which code memories to spatial locales. The cortex, heretofore believed to purely solidify and store memories rather than capture them, was implicated in the latter. And scientists found that cortical hubs, areas of high network activity during rest, are organized into super hubs that are highly interconnected. Those hubs form part of the default-mode network. Scientist reported that activity in that network may help drive release of Aβ into the interstitial fluid in the brain.

Top 10 Hits of 2011—Editors’ Picks

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