1 January 2011. The first day of the year is a time for personal reflection: Where did last year go? Why have I so many unfinished projects? Did I really drink that much champagne last night? It’s also a time to reflect on the last year of Alzheimer’s disease research. To help with the last item, we sifted through our news coverage and consulted scientific advisors. Here we offer you a list of notable 2010 developments and of trends to watch in 2011 and beyond. The list is by no means exhaustive, but we hope offers an idea of the key questions researchers are addressing. Did we miss anything? What stood out in your mind? Nominate your own favorites in the comment box below.
1. Funding Focus
The year started and finished with dismal news on research funding. In January, The Journal of the American Medical Association reported that, though biomedical research funding had doubled between 1998 and 2003, it fell by 2 percent in 2008. By November, it was apparent that the National Institute on Aging was facing a crisis that shocked AD researchers: The NIA pay line for the next fiscal year could be as low as 3 percent. There was some good news as various groups rallied to support research. Funding was found for ADNI2, the second phase of the Alzheimer’s Disease Neuroimaging Initiative, researchers jointly pulled off the Breakthrough Ride in support of better funding and two bills that were languishing in Congress, and one of those bills, the National Alzheimer’s Project Act, is likely to be enacted following successful passage in December through both houses of Congress.
News Brief: Biomedical Funding Dips, AD Research Feels the Pinch
Research Brief: Announcing ADNI2—Funding for Five More Years
Alzheimer’s Breakthrough Ride Rolls Into Washington
World Alzheimer Report: Care Costs 1.0 Percent of World GDP
Early Holiday Gift?—Alzheimer’s Act Goes to President’s Desk
San Diego: What—3 Percent? Money Woes Trump Science at SfN
2. Trials and Tribulations
Alzheimer’s drug development continues to struggle mightily. Dimebon looked good—too good to be true, perhaps—in a Phase 2 trial for Alzheimer’s and one for Huntington’s disease in early 2010, but in a Phase 3 trial, AD patients on Dimebon benefited none whatsoever. Later, the field was stunned when Eli Lilly’s Phase 3 trial of the γ-secretase inhibitor Semagacestat ended prematurely because patients taking the drug did worse cognitively than did those on placebo. Rosiglitazone failed, as did DHA. There were some glimmers of hope. Amyloid imaging showed that passive immunization with Bapineuzumab, a humanized monoclonal antibody, lowers amyloid in the brain. A small Phase 2 trial suggested that a mixture of human immunoglobulins given intravenously can slow clinical decline and brain atrophy in people with AD. A nicotinic receptor agonist is looking good in Phase 2 so far, and intranasal insulin showed some promise as well. Numerous trials are recruiting. On the "better trials" front, near perfect correlation between binding of Avid Pharmaceutical’s amyloid ligand florbetapir (AV-45) and postmortem plaque analysis seemed to put the ligand on the fast track for regulatory approval, and a pharma/academic/government coalition is developing shared tools for all to improve the process. What do you think—hopeful time? Disheartening time?
Dimebon for HD—A Hint of Cognitive Benefit?
Dimebon Disappoints in Phase 3 Trial
Lilly Halts IDENTITY Trials as Patients Worsen on Secretase Inhibitor
Trial Updates: B Vitamin Back in Vogue? Diabetes Drug Less Sweet
Paper Alert: Negative DHA Trial Fuels Soul-Searching in AD Field
PIB-PET Biomarker Study Confirms Bapineuzumab Lowers Amyloid
Toronto: In Small Trial, IVIg Slows Brain Shrinkage
Honolulu: Intranasal Insulin Trial Claims Promise in MCI, AD
Toulouse: Experimental Drug Sensitizes Receptor, Boosts Cognition
Honolulu: FDA Approval in Sight for 18F Amyloid Tracer Florβpir?
DC: Group Convenes Stakeholders to Reform Alzheimer’s Trials
3. Promoting Prevention, First in Familial Disease
The trial failures have intensified the field’s desire to test whether in AD, an ounce of prevention indeed is worth a pound of cure. Hopes that an intervention could be found to delay onset of AD got a boost from the Alzheimer’s Prevention Initiative, which convenes leaders in academia, industry, philanthropy, and the regulatory agencies to brainstorm prevention strategies, initially for familial disease. For its part, the Dominantly Inherited Alzheimer Network (DIAN) is enrolling for a six-year study to monitor clinical development of disease from as early as 20 years prior to predicted clinical onset. Spurred by DIAN, the European Medicines Agency hosted an international meeting in London to discuss prevention and therapy trials in families with autosomal-dominant AD, a group that has long been ignored by trialists. These initiatives tackling prevention research in a new way took on even greater significance when an independent expert NIH panel proclaimed that current evidence on prevention in the general population is too weak to warrant any public health recommendations on measures to head off AD. Do you agree that prevention research is the way to go? How would do it?
Phoenix: Vision of Shared Prevention Trials Lures Pharma to Table
DIAN Dispatch From Hawaii: After Slow Start, Network Is Humming
London: Europe-U.S. Regulators Mull Prevention Trial in Familial AD
NIH Calls for More (and Different) Research on Preventive Measures
4. Revised Diagnostic Criteria
Almost as controversial as the NIH expert panel’s verdict on the strength of current prevention data was the call for revised diagnostic criteria for AD, which were proposed in draft form at the International Conference on Alzheimer’s Disease last July. A majority of researchers and clinicians welcomed the new research criteria, which aim to diagnose years earlier with the help of cognitive testing and biomarkers, but there were detractors as well. Where are you on that one?
Noisy Response Greets Revised Diagnostic Criteria for AD
Revised Criteria for Preclinical AD, Exactly as Presented
What Do Clinicians Say? Peers Welcome Revised Criteria
Biomarkers enjoy exponential growth in interest. Researchers in Japan reported a potential diagnostic test for large Aβ oligomers; some colleagues called this a breakthrough provided others can replicate it. In general, scientists pushed toward finding markers that pop up earlier and earlier in disease progression. Researchers are increasingly focusing on cognitively normal individuals to search for factors that predispose to dementia. Proteomics platforms are broadening the range of potential plasma markers. Olfactory failure emerged as an early but non-specific marker. What does your nose tell you about where this field is headed?
A Diagnostic Test for Large Aβ Oligomers?
CSF Biomarkers Track With Atrophy, Cognition in Normal Aging
ApoE2 Carriers Have Less Brain Atrophy, AD Pathology in Spinal Fluid
ApoE and Brain Networks—The Anatomy of a Risk Factor
San Diego: Pre-AD Brain Changes May Allow Early Diagnosis
Blunted Sense of Smell Parallels Pathology in AD, PD
As ApoE continues to dominate as a risk factor for AD, human evidence grows that it can disturb brain networks even before Aβ can be detected in the brain. Researchers continue to wrestle with how the ApoE4 allele leads to AD, however, with the latest data suggesting that it has local synaptic effects. ApoE receptors and receptor ligands emerged as key mediators of synaptic plasticity. What has you most excited about this perennial but elusive player in AD?
A Foreshadowing? ApoE4 Disrupts Brain Connectivity in Absence of Aβ
San Diego: ApoE, Aβ, and AD—Strengthening the Synaptic Connection
San Diego: Aβ Oligomers Seen, With ApoE, at Synapses of Human Brain
St. Louis: ApoE Receptors—Hold Sway Over Synaptic Function
Research Brief: Reelin Loss Ramps Up Aβ Pathology
The question of whether ApoE itself or the adjacent gene Tomm40 puts people at risk continues to be debated. Meanwhile, new genetic risk factors emerged from genomewide association studies, and they held up in replication studies, quickly jumping into the AlzGene Top Results. Genotyping data from ADNI uncovered an obesity gene as a potential risk factor, and genetic variants were found that modulate cerebrospinal fluid levels of tau. The trend here is to mine biomarker datasets against genotyping information to fish out endophenotypes. On a historical note, researchers reported that they have likely pinned down the mutation carried by August D., Alois Alzheimer’s most famous patient, and it happens to be the one that today plagues the Wolga Germans, a large pedigree of U.S. citizens, some of whom participate in DIAN, others of whom advocate for more AD research funding in Congress. On a technical note, exome sequencing is the trend to watch in human genetics. What did we miss? Let us know.
Honolulu: Tomm40 Reported to Track With Brain Atrophy, Cognition
Genetics of FTD: New Gene, PGRN Variety, and a Bit of FUS
Toronto: 6th Sense—GWAS Picks Up New AD Risk Variant
Repeat Offenders—CLU, CR1, PICALM Hold Up in Association Studies
LOADing Up—Largest GWAS to Date Confirms Two, Adds Two Risk Genes
Research Brief: Clusterin Grabs Spotlight Among Elite Few LOAD Genes
Obesity Gene Depletes Brain Reserves, May Raise Alzheimer’s Risk
Tau Timing: New Findings on Disease Progression, Clearance
Research Brief: Auguste D.'s Mutation Identified?
8. Aβ Machinations
Aβ continues to claim the lion’s share of research studies. Advances were made in understanding its production, aggregation, function, and toxicity. Perhaps most striking was a human study showing that people with AD don't produce more Aβ but clear it more slowly. A γ-secretase-activating protein that specifically modulates APP processing made a splash, as did the provocative finding that Aβ planted in the periphery could seed amyloidosis in mouse brain. A new mouse model also hints that Aβ can spread from one area of the brain to another via synaptic connections. Soluble oligomers continued to dominate as the most toxic forms of the peptide and were shown to track with dementia severity. Did we skip an important paper?
There’s a GSAP for That: Novel APP Partner a New Therapeutic Target?
Sweet 16: Novel APP Processing Pathway and a New Biomarker?
Quantum Leap? Nanoprobes Track Aβ Aggregation in Real Time
Stable Aβ Oligomers?—A Little Protein Engineering Goes a Long Way
Aβ Neurotoxicity—Is it the Dimer? No, and Yes
San Diego: Flexible N-Termini Key to Aβ42 Oligomer Toxicity?
Peripheral Aβ Seeds CAA and Parenchymal Amyloidosis
The Insidious Spread of Aβ: More Evidence for Synaptic Transmission
New APP Model: No Plaques—Plenty of Pathology
Aβ—Made Globally, Acts Locally
San Diego: Aβ Oligomers Seen, With ApoE, at Synapses of Human Brain
New Paths to Protect Synapses From Aβ?
Aβ Downs EphB2 Kinase, Disrupts Glutamate Receptors
Aβ Oligomers: A Fatal Attraction for Glutamate Receptors?
Bad Guys—Aβ Oligomers Live Up to Reputation in Human Studies
Honolulu: Wake-Up Call—Aβ Clearance, Not Production, Awry in AD
Brain Aβ Patterns Linked to Brain Energy Metabolism
9. Tau Trouble
The link between the two hallmarks of AD, Aβ plaques and tau-laden neurofibrillary tangles, has long perplexed researchers. In 2010, the link between tau and Aβ synaptic toxicity grew stronger with the twin findings that tau ferries Fyn kinase to the synapse, where it can mediate Aβ-induced excitotoxicity, and that tau mediates Aβ’s toxic tweaking of axonal transport. Therapies aimed at tau oligomers are at the mouse stage. What intrigued you the most about tau last year?
Honolulu: The Missing Link? Tau Mediates Aβ Toxicity at Synapse
The Plot Thickens: The Complicated Relationship of Tau and Aβ
San Diego: The Future of AD—Can We Vaccinate?
San Diego: Tau Oligomer Antibodies Relieve Motor Deficits in Mice
Who’s on First? Multiphoton Imaging Suggests Caspases, Not Tangles
10. Gamma-Secretase Structure and Function
The complexity of γ-secretase makes it a tough molecule to study. This year, researchers succeeded in reconstituting γ-secretase activity using only presenilin-1 (PS1) and liposomes. Researchers made advances in figuring out the structure and function of PS1 even as a complex, which could aid design of better γ-secretase inhibitors. But questions about pleiotropism persist, with more evidence that the mysterious endoplasmic reticulum calcium leak channels are made up of presenilins. Does this work make γ-secretase a safer target?
Sole Perp—PS1 Alone Reconstitutes Gamma-Secretase Activity
Divide and Conquer: Structure-Function Victory With Presenilin 1
Research Brief: Presenilin Simplicity—Evidence for Autoproteolysis
Perplexing Presenilins: New Evidence for Calcium Leak Channels
11. Metals and AD
The relationship between metals and AD continually resurfaces, but not in the sense of aluminum leaching from your pots and pans. No, iron and zinc were the dominant metals this year. Researchers reported that mice lacking a zinc transporter develop symptoms that uncannily resemble AD, and that the amyloid precursor protein acts as an iron transporter. Shifting iron out of the brain could be beneficial, because older primates on a calorie-restricted diet have less iron in the brain and better synaptic activity and motor skills. Prana's PBT-2 drug is set to begin a phase 2b trial in 2011.
Iron Export? New Role Links APP, Metals, to Oxidative Stress
Think Zinc—Mice Missing Key Ion Transporter Develop AD-like Problems
Aging Primates—Brain Iron Up, Motor Skills and Plastic Synapses Down
12. Stem Cells
Stem cell therapy for AD may be a pipe dream, but the cells have plenty of uses. Researchers improved methods for making induced pluripotent stem cells, and for converting them into neurons that could reveal individual susceptibility to a variety of neurodegenerative diseases.
Stem Cells Move In, Set Up Shop in Brain
Research Brief: From Fibroblast to Neuron in One Easy Step
Where in the World Are the iPS Cells?
In Alzheimer Disease Research, iPS Cells Catch On Slowly
Hereditary Diseases: A Natural Fit For iPSC Modeling
Not So Fast: iPS Cells Have Potential Pitfalls
(Or read the iPS series as a pdf)
Finally, it is not always about neurons. Glia keep the brain ship-shape not only when neurodegenerative storm clouds gather. Researchers reported this year that microglia prune healthy synapses, which came as something of a surprise. In other glial news, knocking out glial cross-communication via chemokines actually prevents neuron loss in mouse models of AD. In contrast, microglial migration fueled by noradrenaline from the locus ceruleus seems to protect against Aβ toxicity. The great good-versus-evil debate on the nature of microglia continues at least into 2011. What is your take?—Tom Fagan.
No Rest for Microglia: These Immune Cells Manage Healthy Synapses
Death by Glia?—Chemokine Receptor Nudges Neuron Loss in AD Mice
Norepinephrine Fuels Microglial Migration, Aβ Phagocytosis
Noradrenaline: Fueling Microglial Fight against Aβ