30 December 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.
In healthy Brains, Does Aβ Really Matter?
Research Brief: How Normal Is Normal? ADNI Data Begs The Question
Research Brief: Hippocampal Hyperactivity Tied to Early MCI Atrophy
Miami: Women Rock at Human Amyloid Imaging Meeting
F18 PET Tracers, New MRI Method to Expand Reach of Brain Imaging
Revised Diagnostic Criteria for Alzheimer’s Are Published
Two New Sets of Diagnostic Criteria—Which Is Right for Your Clinic?
New Neuropathologic Guidelines for AD Almost Ready for Primetime
Phase 3 Paper on Amyloid Ligand Out Just Before FDA Meeting
Committee Shoots Down Florbetapir, Raising Bar for Field at Large
The EMA Deems Brain Atrophy Valid Trial Selection Measure
New AD Data Standard: FDA Wants It; Will Trial Groups Use It?
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.
Colombians Come to Fore in Alzheimer’s Research, Mass Media
A Neurologist’s Devotion Puts Familial AD Research Onto New Plane
Can Adaptive Trials Ride to the Rescue?
DIAN Forms Pharma Consortium, Submits Treatment Trial Grant
Reeling In Biomarker Data in Young Carriers, API Rocks Staging Boat
Australia Report: The Way Forward—Pre-symptomatic Trials
Treating Before Symptoms—ADCS Invites Ideas for Clinical Trials in Very Early AD
Commentary on Sperling et al., Testing the right target and right drug at the right stage
Pros and cons of screening in primary care
Anti-Amyloid Treatment in Asymptomatic AD Trial
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.
Clearing the Fog Around Aβ Oligomers
Patient Aβ Dimers Sufficient for Tau, Neuritic Changes
Patient-Derived Aβ Needs Prion Protein to Harm Synapses
X-raying Aβ Oligomers, Unraveling Mysteries of Amyloid Aggregation
What’s Another Amino Acid? Aβ43 Drives Amyloid Pathology
An α-Synuclein Twist—Native Protein a Helical Tetramer
Amyloid-Blocking Drug Poised for Approval for Rare Disease
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.
AlzRisk Adds Fifth Factor to Database: Meta-Analysis of Hypertension
Hormone Replacement Therapy Latest Entry to AlzRisk Database
AlzRisk: Inflammatory markers
AlzRisk: Nutritional Antioxidants
DC: Does Estrogen Fine-Tune the Brain?
DC: Ways to Slow Brain Aging: Exercise, Estrogen, and Sleep?
New Clues to How Estrogen Shields the Brain
Slow Aβ Clearance Is ApoE4’s Modus Operandi in Late-Onset AD
Paper Alert: ApoE Affects Alzheimer's Risk via Aβ Clearance
Lowering ApoE Brings Down Amyloid in Mice
ApoE Disrupts Brain Networks, Helps Microglia Clear Aβ
Stress and Trauma: New Frontier Lures Alzheimer’s Researchers
Exercise and the Brain: More Support for Protective Effects
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.
Aβ Antibody Gantenerumab Clears Plaques
Pfizer Halts Development of Aβ Antibody
Paris: Renamed ARIA, Vasogenic Edema Common to Anti-Amyloid Therapy
Paper Alert: First BACE Trial Published—New Inhibitor On Deck
Barcelona: Out of Left Field—Hit to The Eye Kills BACE Inhibitor
First Phase 2 Success for Gene Therapy in Parkinson’s
Resolving Controversies on the Path to AD Therapeutics
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.
Alzheimer’s Neurons Made to Order: Direct Conversion From Skin Cells
Turning Human Fibroblasts Into Neurons; Making Safer Stem Cells
Stem Cell Recipe for Astrocytes
Therapeutic-Grade Dopaminergic Neurons From Stem Cells?
Editing Stem Cell DNA to Make the Perfect Cells for Study, Therapy
Hedgehog Protocol Turns Supersonic in Faster Route to Motor Neurons
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.
Mind the IGAP—Transatlantic Consortium to Map AD Genes
Large Genetic Analysis Pays Off With New AD Risk Genes
Parkinson’s GWAS—Genes Could Explain a Quarter of Late-Onset PD Risk
Corrupt Code: DNA Repeats Are Common Cause for ALS and FTD
Can a Fly Screen Trap Alzheimer’s Gene Candidates?
Barcelona: What Lies Beyond Genomewide Association Studies?
Sorting Out Parkinson’s: Exome Sequencing Points to Recycling Defect
Australia Report: Genetics and Aging
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.
Funding Woes: What’s Behind the Falling NIA Payline?
Department of Defense Offers Alzheimer’s Research Dollars
NAPA Advisory Council Named, Seeks Input From Researchers
From Australia, Impulse for a New Alzheimer’s Research Agenda
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.
Do Overactive Brain Networks Broadcast Alzheimer’s Pathology?
Brain Activity and Aβ—The Interstitial Plot Thickens
Brain Microdialysis Reveals Tau, Synuclein Outside of Cells
Monomeric Aβ’s Disappearing Act in AD Brain: Two Theories
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.
Do Synaptic Tags Code Memories for Storage?
The Guardians of Forever: Forming and Keeping Memories
A Time and a Place...Hippocampal Cells Map Both
Research Brief: Cortex Gets Into the Memory Game
Cortical Hubs Form "Rich Club" in Human Brain
Do Overactive Brain Networks Broadcast Alzheimer’s Pathology?