Once again, before the world rings in the New Year is the time to let the major developments in the fields of Alzheimer’s and neurodegeneration pass before our collective mind’s eye. The year 2013 brought no breakthroughs, but many incremental steps did bring the fields closer to the goal of better diagnosis and treatment. Alzforum editors have compiled the main themes from a busy year.
1. Clinical Trials and Therapies
The last 12 months marked another year without a therapeutic breakthrough. After high-profile immunotherapy trials ended in disappointment, attention shifted to BACE inhibitors as the next big hope, but the road continues to be strewn with casualties. Eli Lilly halted trials of its BACE inhibitor LY2886721 in June due to liver toxicity issues, and Roche quietly terminated its inhibitor RG-7129 without disclosing the reason (see Jun research news). On the plus side, Merck reported positive interim safety data in a Phase 2/3 trial of its inhibitor, MK-8931, and started a new trial in prodromal AD (see Dec research news). Many other companies have BACE inhibitors in development. At the same time, newly proposed substrates and functions for BACE led some scientists to call for careful consideration of possible side effects related to blocking this enzyme (see Dec conference news).
Wah-wah trumpets greeted the intravenous immunoglobulin Gammagard when the first of two Phase 3 trials sank under the weight of missed endpoints. As is often the case, there appeared to be a hint that people with mild AD may have seen some benefit, but early in the year Octapharma’s version of these natural antibody preparations also failed to pass muster in Phase 2 (see May research news and Feb research news).
Solanezumab must go through another large Phase 3 trial in mild AD, as the data from both Expedition trials did not convince the FDA to approve this antibody. In addition, Solanezumab was selected for the A4 secondary prevention trial (see Jan conference news). Solanezumab is already being administered to people enrolling in the Dominantly Inherited Alzheimer Network (DIAN) trial along with Roche’s antibody Gantenerumab, which otherwise spent the year 2013 wending its way through the enormously large and long Phase 3 trials Alzheimer’s therapeutics require these days.
Beyond these studies, an adaptive Phase 2 trial of Eisai’s anti-protofibrillar Aβ antibody BAN2410 is enrolling apace. BIIB037, an anti-Aβ immunotherapy developed by Biogen Idec, appeared safe in Phase 1, without the amyloid-related imaging abnormalities that have plagued other immunotherapies. Affiris, Sanofi, and other companies are testing new immunotherapies in humans (see Apr conference news). For an overview of AD immunotherapies, see here. In other immunotherapy developments, European courts struck down a patent held by Janssen Alzheimer Immunotherapy for being too broad (see Jul community news).
Researchers continue to test a range of potential therapies. ABT-126, AbbVie’s α-7 nicotinic acetyl choline receptor agonist, looked promising in Phase 1 and Envivo’s EVP-6124 moved into Phase 3 for both Alzheimer’s and schizophrenia. Lundbeck dusted off a serotonin 6 receptor shelved after less-than-stellar results in schizophrenia and moved it into a Phase 3 trial for Alzheimer’s disease (see Lu AE58054).
Results of the SNIFF-LONG 21 trial of the insulin analog detemir suggested it may help people with high baseline insulin resistance (see Aug conference news). PQ912, a glutaminyl cyclase inhibitor designed to reduce the pyroglutamate form of Aβ, completed a Phase 1 trial (see Mar conference news). A drug targeting tau, TRx0237, entered Phase 3 for Alzheimer’s and frontotemporal dementia, though some site investigators privately have expressed chagrin at the way it is being managed (for an overview of trials of tau-based drugs, see the Therapeutics database).
Across the board, researchers in academia and industry continue to debate how best to evaluate potential therapies. AD presents unique challenges because the disease progresses slowly, starts years before symptoms are apparent, and may have many underlying causes. But after some 15 years of largely stagnant trial design, 2013 saw accelerated change. Buoyed by a new FDA guidance for the development of drugs for early stage Alzheimer’s, there was a budding effort to test combinations of unapproved drugs (see Feb conference news series; Jun conference news). A broad movement is afoot to devise tests that can detect subtle cognitive changes in people who appear cognitively normal or have very mild impairment (see Nov conference news), and an effort to speed up recruitment of trial volunteers is beginning, as well (see Nov conference news). A simulation tool that helps ensure that trials are adequately designed received regulatory approval from the FDA (see Jul research news). The European Medicines Agency announced that it plans to publish summary data on all trials, which will improve researchers’ access to trial data (see Nov community news).
2. Imaging and Biomarkers
In October, the FDA approved GE’s PET tracer flutemetamol (Vizamyl) for imaging Aβ in the brain (see Nov research news). Vizamyl joins Lilly’s Amyvid, which was approved last year, but neither tracer is widely available. The Centers for Medicare and Medicaid Services (CMS), a government agency that decides which medicinal costs are reimbursed, last July denied coverage of Amyvid on the grounds that there was insufficient evidence the scans improved health outcomes (see Jan community news). The decision outraged Alzheimer’s researchers (see Jul conference news). Under a process called “coverage with evidence development,” CMS will reimburse for one scan per patient conducted during a clinical trial, provided the trial addresses whether the scan helped improved health outcomes and submits a proposal to CMS (see Oct community news). Researchers vowed to do this for A4 and other trials.
Last January, an expert taskforce published guidelines on how Aβ imaging should be used in practice, while the “Centiloid Project” attempted to standardize and compare data generated with different tracers (see Jan conference news and Feb conference news).
Researchers made strides evaluating ligands specific for tau. Eli Lilly bought out the tracer program developed by Siemens and reported that the tracers bind brain areas seen laden with tau on postmortem analysis. Compounds developed by researchers at Tohoku University and PBB3 developed by scientists at the National Institute of Radiological Sciences, Chiba, both in Japan, appear specific for tau and have been tested in small numbers of people (see Apr research news and Aug research news). PBB3 appears to bind to tau aggregates in a variety of different tauopathies (see Sep research news). The Lilly tracers appear to track subtle memory problems in people who appear cognitively normal, suggesting they could serve as early biomarkers (see Nov conference news). These ligands contrast FDDNP, a less-specific compound that binds tau and Aβ. Its use to screen for chronic traumatic encephalopathy has generated controversy (see related New York Times article). Researchers reported that imaging with Pittsburgh compound B detects Aβ in the brain up to a year after a single traumatic brain injury (see Nov research news).
In other biomarker news, researchers updated their model for how fluid, imaging, and clinical markers change along the trajectory of Alzheimer’s disease (see Feb conference news). Evidence grew that fragments of tau in cerebrospinal fluid (CSF) correlate with disease progression (see Nov research news). Some researchers reported that Aβ*56, a toxic oligomeric form of the peptide, turns up in the CSF, where it tracks with tau markers of disease—though curiously only in people whose cognition is normal (see Mar research news). Scientists debated the value of Aβ in the lens of the eye as a biomarker (see May research news).
Several research groups confirmed that biomarkers improve the accuracy of an early stage AD diagnosis, the key proposal in the revised diagnostic criteria (see Aug conference news; Sep research news). Some groups have questioned this and much effort has ensued to refine the prediction of whether and when a given person will develop symptoms (see Jun research news). Hints are emerging that subjective memory complaints might prove useful in this regard (see Jul conference news). Scientists puzzle over a subset of patients who seem cognitively impaired but test negative for brain amyloid with a PET scan (see Aug conference news; Nov research news). Microstructural changes in the brain emerged as a potential biomarker to predict whether a person with mild cognitive impairment will progress to Alzheimer’s dementia (see Feb research news).
Longitudinal studies including the Australian Imaging, Biomarkers & Lifestyle Study of Aging, the Alzheimer Disease Neuroimaging Initiative, and DIAN continue to provide the bulk of serial biomarker and natural-history data that helps researchers sharpen their predictions of who is at risk for AD and how their disease may progress (see Apr conference news, conference news, and conference news).
In 2013, large genome-wide association studies in AD began to run their course after the International Genomics of Alzheimer’s Project (IGAP) analyzed pooled data from four previous GWAS to uncover 11 new risk variants (see Jul conference news and Oct research news). A resurgent genetics field is increasingly shifting to other techniques, and these are starting to bear fruit. Examining DNA from people with either very high or very low CSF Aβ and tau, researchers turned up novel risk alleles in known AD genes (Apr research news; Sep research news). Exome sequencing revealed a variant in the phospholipase D3 gene that doubles the risk of AD (see Dec research news). Rare runs of homozygosity (ROHs)—that is, regions where both maternal and paternal copies of a given chromosome are identical—led researchers to rare risk variants as well (see Aug research news).
Geneticists are increasingly searching for the functional variants responsible for risk associated with known genes. Researchers implicated an ADAM-10 variant in increased β-secretase activity and CD33 variants in reduced microglial phagocytosis (see Sep research news and Aug research news). High-throughput RNA sequencing emerged as a valuable tool to match risk variants with gene expression (see Sep research news). In other genetics news, the Alzheimer’s Disease Neuroimaging Initiative (ADNI) released whole-genome sequences for 809 study participants and the Alzheimer’s Disease Sequencing Project did the same for 410 people (see Sep research news and Dec community news).
4. Immune Cells and AD
The role of the brain’s immune cells grew to be a hot topic in AD research. Two microglial genes, TREM2 and CD33, emerged as key components of molecular networks perturbed in the disease (see Alzforum Webinar). Like these two genes, beclin1 emerged as an important promoter of microglial phagocytosis (see Sep research news), and Scara 1, CD36, and FcγRIIb as major microglial receptors for Aβ (see Jun research news; Jul research news; Jun research news).
Scientists still do not clearly understand how microglia become activated in AD and what functions they assume when they do (see Mar conference news), partly because no specific tracers are available for in-vivo study in humans. At the same time, scientists are beginning to understand what these cells do in normal brain biology. For example, they actively maintain synapses and neuronal circuits (see Aug conference news and Dec conference news).
5. Protein Strains and Transmission in the Brain
This year saw evidence that tau and Aβ, like prions, come in different strains or conformations that propagate from one neuron to another (see Aug conference news). Specific tau strains isolated from the brains of people with different diseases hinted that the 15 or more tauopathies that have been described may be defined, at least in part, by different forms of toxic tau. Likewise, researchers reported that different strains of Aβ occur in brain tissue taken from different donors (see Sep research news). The evidence suggests that only one strain of Aβ or tau arises in any one individual. That would support the idea that pathology begins and spreads from one seed, in one place in the brain.
While it may be easy to imagine that a secreted peptide such as Aβ spreads in the brain simply by drifting away in the extracellular space, the process may be more dramatic. Some evidence suggests that neurons explode, supernova style, spewing their contents like so much stellar debris. It remains to be seen if this truly is how intracellular proteins such as tau and α-synuclein escape neurons, but at least researchers have begun to get a handle on how they sneak into unsuspecting cells nearby. Both these proteins are taken up from extracellular space via specific cell-surface receptors, and this may even be a part of normal tau biology (see Mar conference news; Aug research news). Antibodies to tau can stop this spread, supporting the idea of tau immunotherapy as a treatment (see Sep research news).
Despite years of effort, the field has yet to pinpoint the most toxic forms of the various amyloidogenic proteins that are involved in neurodegenerative disease. Neurofibrillary tangles of tau appear to do less harm to neurons than certain fragments of tau (see Mar conference news; Feb research news). Researchers found that chaperones may exacerbate the toxicity of tau by keeping it from being degraded while folding it into toxic conformations (see Sep research news). And evidence for the idea that removing tau can ameliorate neuronal hyperactivity continues to grow (see Aug research news).
Though recent genetic and natural-history findings have entrenched the amyloid hypothesis even more deeply (see Apr conference news), Aβ itself continues to mystify researchers. The field has yet to fully understand its structure, function, toxicity, production, and clearance in the brain. In June, researchers reported the first direct in-vivo evidence for more production and less clearance of the peptide in brains of people with familial AD (see Jun research news). In related work, scientists showed that they could track clearance of solutes through the brain’s glymphatic system using MRI, and that this system flushes Aβ more quickly in mice when they are asleep (see Mar research news and Oct research news). Interestingly, sleep patterns become disturbed early in AD when plaques are growing (see Apr conference news).
On the molecular level, researchers came up with a new theory for Aβ toxicity—that the peptide releases a flood of glutamate from astrocytes, which then goes on to damage synapses (see Jun research news). Other researchers linked Aβ toxicity to AMP-activated kinase in neurons. This enzyme sets off a sequence of events, including phosphorylation of tau, which causes the destruction of dendritic spines (see Apr news story). This fits with the hypothesis that tau mediates Aβ toxicity, an idea that received further support when researchers found that fyn kinase seems necessary for Aβ toxicity in synapses; transport of fyn to synapses depends on tau (see Sep research news). Yet other researchers described an unholy alliance between Aβ, calcium, dendritic tau, and the microtubulin-chopping enzyme spastin (see Oct research news). Alas, none of the many pathways proposed over the years to explain Aβ toxicity has generated a wave of replication and subsequent consensus across the field to firmly establish itself.
Since scientists discovered in 2011 that a six-nucleotide repeat expansion in the C9ORF72 gene is a leading cause of inherited amyotrophic lateral sclerosis and frontotemporal dementia, interest in this gene has exploded. The year 2013 brought a bounty of papers that described surprising biology. Several groups reported that despite being located in an intron, the expansions are translated into poly-dipeptides. Of all things they could be doing, these dipeptides aggregate into a characteristic pathology that marks C9ORF72 cases, though whether these inclusions are toxic is unclear (see Feb research news and research news; Oct research news; MacKenzie et al., 2013). Surprisingly, this repeat-associated, non-ATG-initiated (RAN) translation turned out to occur in both sense and antisense directions with both forms of transcript and protein ending up in intracellular inclusions (see Nov research news).
In addition to figuring out how these sense and anti-sense transcripts and peptides contribute to disease, researchers are finding that the repeats grow and shrink and that hypermethylation may silence them (see Nov research news; Jan conference news; Jun research news). While a clear function for C9ORF72 has yet to emerge, early hints point to its involvement in membrane trafficking (see Jun research news).
Brain imaging analysis suggests that people with ALS caused by expansions in this gene have more frontotemporal degeneration than people with other types of ALS. That could eventually help doctors refine prognosis (see Jun research news; see also C9ORF72 in AlzPedia).
Despite ample genetic news, in 2013 ApoE remained the strongest risk gene for late-onset AD. This lipoprotein is still far from fully understood, but it did give up some secrets recently. Neuroimaging studies strengthened the idea that the increased risk associated with the ApoE4 allele begins decades before the first sign of Alzheimer’s, maybe even in infancy (see Jan research news; Dec research news). The findings indicate that the apolipoprotein somehow influences brain development. This expands established knowledge that ApoE4 slows clearance of Aβ from the brain, hastening formation of amyloid plaques. On the latter, news that ApoE fails to bind Aβ in vitro came as a surprise, since previous reports had suggested the two formed a complex (see Apr research news). ApoE4 interacts with other risk factors. In 2013 researchers reported that it conspires with hypertension and lack of sleep (see May research news; Oct research news), two factors linked to Aβ clearance from the brain, to exacerbate risk for AD.
The field continues to explore modulation of ApoE as a potential therapeutic. Animal data showing that boosting ApoE2 levels in midlife clears plaque in late life continued an earlier line of investigation into this idea (see Nov research news). The question of how to exploit the ApoE allele is increasingly being treated separately from the question of what to do with a person’s overall ApoE levels, regardless of isoform. Promoting ApoE production through activation of retinoid X receptors in the brain serves as the rationale behind clinical trials for the approved cancer drug bexarotene. A 2012 report that bexarotene dramatically reduced Aβ plaques in animal models of AD became more nuanced in 2013, when other research groups reported being unable to reproduce some or all of the original data (see May research news). Two clinical trials for bexarotene in AD have gotten underway amidst this controversy.
9. Funding and Policy
Notoriously cash-strapped when it comes to funding AD research, the U.S. government nonetheless scrounged together some extra dollars to support prevention trials in ApoE carriers, among other studies. In September the National Institutes of Health announced that it would allocate an additional $45 million for the API and DIAN trials, as well as a Phase1 study of a proposed regenerative agent, the neurosteroid allopregnanolone (see Sep community news, community news). Earlier in the year the NIH announced that it would fund four trials through the Alzheimer’s Disease Cooperative Study—the A4 prevention trial, a prevention trial based on exercise, a trial of the α-adrenergic blocker prazosin for agitation, and a study to look at pharmacodynamics in Phase 1 trials (see Jan community news). Those trials will be funded from the existing NIH budget.
The Obama administration announced support for the Brain Activity Map Project, which could pay dividends for neurodegenerative disease research (see Feb community news). As part of this initiative, the U.S. Defense Advanced Research Projects Agency announced a $70 million investment over five years to study deep-brain stimulation, which shows some promise as a therapy for AD and is used to treat Parkinson’s patients (see Oct research news). Overshadowing these isolated blips of good news, the U.S. government shutdown kept NIH researchers off the bench for two weeks, and the across-the-board 5 percent cut in funding bit into the already-stretched NIH budget, forcing some scientists to consider career alternatives (see Oct research news).
Recognition that dementia looms as a major public health-care crisis took root around the globe. In December, the G8 countries held a first summit on dementia, marking the year 2025 as the international community’s official goal for finding a better treatment. Contrasting an unfunded plan by the U.S. government, G8 leaders promised to spend more money on research (see Dec conference series).
In related funding news, the National Football League Players Association announced it had selected Harvard University to lead a $100 million research effort to study chronic traumatic encephalopathy (see Feb community news).
By some counts, the number of people diagnosed with Alzheimer’s disease will balloon to 135 million by 2050. If recent estimates of AD prevalence in China are realized, that number might be a gross underestimate. Meta-analysis suggests that in 2010, 9.2 million people had dementia in the world’s most populated country alone, almost twice the World Alzheimer Report’s figure of 5.4 million (see Jun research news). Counterbalancing these sobering numbers were hopeful hints that some developed nations may have checked the growth of dementia. Researchers reported that incidence in Sweden and England dropped in recent years (see May research news and Jul conference news). This may reflect lifestyle trends among baby boomers, including better diet, more education and exercise, and less smoking. What’s the rub? Indications that growing obesity, a major risk factor for Alzheimer’s (see latest AlzRisk update), plus the sheer numbers of elders in aging societies, could wipe out any recent gains in dementia prevention.
11. Not Alzheimer’s, but Deserving Honorable Mention
Alzforum always takes side glances at research that could help the field, including technical advances. In May, scientists announced they had generated human stem cells through somatic cell nuclear transfer, the first step in generating a human clone (see May research news). On a similar note, other researchers grew induced pluripotent stem cells into mini-brains, dubbed cerebral organoids (see Aug research news). Some predicted that these 3D structures might one day model wiring problems in neurological disorders. Other insights into brain architecture might come from an ultra-high resolution map of the human brain that debuted last June. “BigBrain” offers 50 times the resolution of the best brain maps to date (see Jun research news). CLARITY, a method of dissolving opaque lipid membranes to lay bare the rest of the cell structure, promised to revolutionize how scientists inspect brain tissue with the light microscope (see Apr research news adapted from Schizophrenia Research Forum).
On the less-than-shiny side of the coin, the scientific community continues to wrestle with how to publish negative data (journals often refuse to do it), as well as how to ensure that published data is independently reproduced so that it can become part of the canon of truth in science and provide a knowledge base for therapy development. In 2013, journal editors and scientists alike called for higher standards in conducting and reporting research (see May research news). —Tom Fagan and Gabrielle Strobel
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