With more money for Alzheimer’s research than ever before, 2016 is shaping up to be a promising year. How will the developments of 2015 influence your research decisions? Alzforum reflects on some of this year’s news.

Funding
December brought a huge boost for the National Institutes of Health with the passage of a major U.S. spending bill. Not only did the NIH see its budget climb by $2 billion per year, but $385 million of that was earmarked for dementia research, bringing the annual Alzheimer’s research budget to almost $1 billion (see Dec 2015 news). A cash injection came from Atlantic Philanthropies, a private foundation led by entrepreneur Chuck Feeney. Atlantic donated $177 million to establish the Global Brain Health Institute, to be managed at the University of California, San Francisco, and Trinity College in Dublin (see Nov 2015 news). The initiative will work to introduce care and prevention programs worldwide. In March the U.K. government announced the Dementia Discovery Fund, a venture capital initiative to stimulate drug-discovery research, to which public and private donors have pledged $100 million (see Mar 2015 news). This comes on top of an additional $80 million slated for the National Plan to Address Alzheimer’s in the United States in 2014, and the almost $130 million announced in February 2014 for the Accelerated Medicines Partnership to study AD biomarkers and therapeutic targets. After years of cutbacks and scientists leaving the field, researchers were almost disbelieving about a funding situation that looked suddenly a lot rosier. It is not yet clear how the new funds will be spent.

A research summit hosted by the NIH in February developed an agenda for how to move forward to fulfill the goals of the National Plan (see Feb 2015 conference news and conference news), and on May 1 the NIH released recommendations. They focused on understanding the basic biological, genetic, epigenetic, and environmental factors underlying AD, integrating data from a variety of sources to develop better prediction models, capitalizing on advanced clinical trial designs, and improving disease diagnosis and care (see May 2015 conference news). 

Clinical Trials
Lifestyle interventions appeared up-and-coming on news that aerobic exercise slowed mild cognitive impairment (see Aug 2015 conference news), though it is unclear if the effect works via Alzheimer’s pathology or vascular brain health and connectivity (Aug 2015 conference news). Likewise, the European trials MAPT and FINGER found that a controlled diet, cognitive training, and exercise sharpened cognition in older, cognitively healthy people. Researchers are awaiting results from the PreDIVA study to find out if improving cardiovascular health can ward off dementia (Nov 2015 conference news). The Global Brain Health Initiative hopes to build on these discoveries by training researchers and physicians to implement lifestyle measures for patients and caregivers.

Amyloid PET scan in an aducanumab trial participant at baseline (left), and after one year on treatment (right). [Image courtesy of Biogen.]

News from pharmacological intervention trials was mixed. Following some data-free promotion in the waning days of 2014, aducanumab enjoyed a massive boost in interest in March 2015, when Biogen scientists began sharing results of its Phase 1b trial of its anti-Aβ antibody. First analyses indicated that the immunotherapy dose-dependently removed amyloid from the brain and slowed cognitive decline in patients with early AD despite high rates of the ARIA-E side effect (see Mar 2015 conference news and Aug 2015 conference news). By November, two additional analyses had slightly cooled off the excitement. While both the MMSE and CDR-sb indicated that cognition might have stabilized in treated patients, no such benefit was apparent on either the free and cued selective reminding test (FCSRT) or a neuropsychological test battery (see Nov 2015 conference news). 

The vagaries of Aβ immunotherapy were also apparent in Roche’s Scarlet RoAD trial of its anti-Aβ antibody, gantenerumab. That trial halted dosing in December 2014 when a futility analysis indicated that the trial was unlikely to succeed. However, post hoc analysis presented at AAIC in July hinted at a treatment benefit in patients who were deteriorating fastest (see Aug 2015 conference news). At CTAD, a fuller picture emerged. Because the trial disallowed approved drugs for AD, fast decliners in the placebo group realized they were getting worse and dropped out to start symptomatic treatment instead. Their absence nullified a treatment effect the trial might have picked up among fast progressors in the treatment group, Roche scientists claimed (see Nov 2015 conference news). 

Clinicians expect to learn more from ongoing Phase 3 trials of aducanumab and gantenerumab in mild AD, and from the DIAN-TU trial, which tests both gantenerumab and Lilly’s anti-Aβ antibody solanezumab in people with familial AD mutations. Other immunotherapy trials expected to read out in the coming years include those for solanezumab, Roche’s crenezumab, Eisai’s BAN2401, and Novartis’ vaccine CAD-106. The A4 and API ApoE4 prevention trials will also evaluate solanezumab and CAD106, respectively. A newcomer, Astra Zeneca’s MEDI1814, is an anti-Aβ42 antibody engineered to have little effector function, and thus far looks safe in Phase 1

The year saw some good news for non-amyloid interventions. A Phase 2 trial of AVP-923 (aka Nuedexta) suggested reduced agitation in people with AD, while pimavanserin, a selective serotonin inverse agonist, showed promise in treating AD-related psychosis (see Sep 2015 news). However, Transition Therapeutics announced that cyllo-inositol (ELND005) did not calm anxiety and agitation in people with advanced AD (see Dec 2015 conference news). This drug started out as a plaque-buster but sponsors changed tacks when it failed to affect cognition but appeared to reduce brain myoinositol, which had been linked to psychiatric problems in AD. In July, Roche announced that sembragiline did not make the grade in Phase 2b (see Jul 2015 news). The hope had been that by slowing dopamine clearance and dampening production of free radicals, this monoamine oxidase B inhibitor might slow the progression of the disease. Likewise, Laboratories Servier in France pulled the plug on S 3803, a histamine H3 antagonist that was supposed to temper psychiatric symptoms.

Protein-based therapies fared poorly as well. Sangamo terminated CERE-110, a gene therapy that delivers nerve-growth factor to the brain. In a small study, detemir, a long-acting insulin, failed to stem memory decline, while the insulin sensitizer metformin neither slowed cognitive decline nor budged CSF Aβ, tau, or phospho-tau (see Dec 2015 conference news).

The anti-epilepsy drug Levetiracetam struck a positive note. In a Phase 2 study, this small molecule calmed hyperactivity in the hippocampus and improved memory in people with mild cognitive impairment; a Phase 3 study is planned (see Mar 2015 news). 

Hyper Hippocampus.

In this computerized model of a seizure, hippocampal neurons kick into overdrive. A similar phenomenon may impair memory and damage cells in people with mild cognitive impairment. [Courtesy of Ivan Soltesz, Flickr Creative Commons.]

A Phase 2 trial of deep brain stimulation (DBS) of the fornix was negative but hinted at a benefit in older people with mild AD (see Dec 2015 conference news). 

Tau continued in 2015 to be the target trying to break through. Researchers await results, in 2016, of two Phase 3 trials of TRx0237, a formulation of methylene blue that purportedly reduces tau aggregation. As for tau immunotherapeutics, AAD-vac1, a vaccine from AXON Neuroscience in Bratislava, Slovakia, reportedly was safe and elicited antibody titers in Phase 1. The company is planning a Phase 2 trial (see Dec 2015 conference news). Roche terminated RG7345, an antibody against a phosphorylated epitope on the microtubule binding protein, but other anti-tau antibodies by Bristol Myers Squibb, C2N, and ACImmune are in the running (see Therapeutics). 

Push to Prevent Needs Registries and Outcome Measures
All through 2015, the field’s intensifying ramp-up toward prevention focused attention on registries and the search for better outcome measures. Several online registries, started before 2015, increased their numbers and engagement strategies to create trial-ready cohorts of people willing to join trial opportunities as they come up. The Alzheimer’s Prevention Registry not only broke through 210,000 members but also launched GeneMatch as a first step to enable remote genotyping of large numbers of people to facilitate recruitment in trials requiring a particular ApoE genotype (Dec 2015 news). Other registries actively recruiting include the Brain Health Registry, which uses online card-sorting tests and gaming data to find people who might be subtly declining, TrialMatch, and others. For a listing, see Clinical Trial Registries

Besides people at elevated risk of developing dementia, prevention trials also need more sensitive measures that can detect subtle cognitive and even functional deficits before people are overtly impaired. Thus far, clinicians have struggled to find measures that pick up meaningful change at that stage. Variations on tests originally devised for patients with frank dementia, such as the CDR sum of boxes and the FCSRT, can fall short because of floor or ceiling effects (see Nov 2015 conference news). In March, the cognitive functional instrument (CFI) posted some promise in predicting subtle decline in healthy controls who became impaired over four years (see Mar 2015 news). Developed over 10 years by the Alzheimer’s Disease Cooperative Study, the CFI complements the Preclinical Alzheimer Cognitive Composite (mADCS-PACC), which detects cognitive changes in healthy people (see Jun 2014 news). Both are being used in the ongoing A4 trial. Some composites combine both cognitive and clinical scores into a single measure, whereas other researchers argue for using cognitive composites alone and deciding about the clinical meaningfulness of the effect in a separate, second step (see Alzforum Webinar with Suzanne Hendrix on constructing composites for trials in early Alzheimer’s). 

Regulators are following these developments closely. While the Food and Drug Administration traditionally has required that a drug sponsor demonstrate both cognitive and functional efficacy to get an AD medication approved, the agency has acknowledged that the latter is difficult to do in people who start therapy while unimpaired. The agency has indicated that it may consider a single measure instead (see Mar 2013 news). Throughout the year 2015, agency scientists met with AD scientists in both closed and public meetings, from AAIC to a year-end workshop seeking guidance for validating new measures and devices for cognitive decline (see Dec 2015 conference news). 

Biomarkers
Imaging and fluid markers continued to be a top priority for the field in 2015. While the FDA has approved three amyloid PET ligands, the Centers for Medicare and Medicaid Services have not qualified the procedure for reimbursement, hence its use in routine care remains limited. Whether that changes depends on the results of ongoing trials. In April the CMS approved a four-year, $100 million project to learn whether amyloid scans improve a patient’s diagnosis, management, and health. Because this study falls under the CMS “coverage with evidence development,” the agency will reimburse the cost of the 18,000-plus scans needed (see Apr 2015 news). In August, three previously started, smaller studies suggested that amyloid scans do change clinical practice and disease management (see Aug 2015 conference news). 

Worth the Money?

The IDEAS study aims to find out if amyloid PET scans change a patient’s diagnosis or disease management. [Image courtesy of Gil Rabinovici, University of California, San Francisco, and William Jagust, University of California, Berkeley. Prepared by Daniel Schonhaut, UCSF.]

Against this backdrop, development of tau PET imaging motors on. Researchers have begun incorporating tau scans into clinical trials, including the A4 and DIAN prevention trials, even though no tau ligand has yet been formally validated in lifetime scan/autopsy comparisons or approved by the FDA. Furthest along in that process is T807/AV1451 by Eli Lilly/Avid Pharmaceuticals. Staining of pathologically confirmed tauopathy tissue suggests that this tracer seems to label tau without cross-reacting to amyloids formed by synuclein and TDP43. Some anomalies also emerged at the Human Amyloid Imaging meeting last January, where researchers reported that the ligand poorly binds in the brains of patients with certain tauopathies, including Pick’s disease and corticobasal degeneration, but does bind neuromelanin and some other possibly non-specific sites (see Feb 2015 conference news; Marquie et al., 2015). Tracer uptake also seems to be a moving target, since binding kinetics varied among different brain regions, and in some areas of the brain never reached a steady state, researchers reported. This might make it difficult to standardize a practicable time window for T807 scans (see Feb 2015 conference news). Researchers agree that it’s early days for tau imaging, and some of these issues may resolve as more scans, pathological studies, and tau tracers become available. 

Debuting this year were the ligands RO6931643, RO6924963, and RO6958948 from Hoffmann-La Roche, which seem to rapidly enter and clear the brain with little non-specific binding to white matter. They have entered Phase 1 testing in healthy controls (see Feb 2015 conference news; Aug 2015 conference news). Other tau ligands include PBB3 from the National Institute of Radiological Sciences in Chiba, Japan. THK5351 is the latest in a line developed at Tohoku University, Sendai, Japan, and now licensed to GE Healthcare. In early human studies, THK5351 reached a steady state in the brain after about 50 minutes and then quickly cleared. Binding went up stepwise from controls to MCI to AD, and autopsy samples suggested a better signal-to-noise ratio than earlier THK ligands (see Feb 2015 conference news). 

New Tau Tracer.

Low uptake in controls, intermediate in mild cognitive impairment, and intense binding spreading across the frontal and temporal cortex in Alzheimer’s disease suggest THK-5351 might be a suitable tau tracer. [Image courtesy of Nobuyuki Okamura, Tohoku University.]

In longitudinal studies, early indications are that T807 uptake goes up as AD progresses, reflecting the increasing spread of tau pathology out from the medial temporal lobe to the cortices. Researchers expect that tau PET in various cortical regions will help with differential diagnosis of specific tauopathies and atypical forms of AD. For example, small studies are beginning to show tau deposits in language centers and posterior regions that deteriorate in primary progressive aphasia (PPA) and posterior cortical atrophy (PCA), though tracer uptake did not always match regions of neuropathology. This line of study is only just beginning (see Feb 2015 conference news and conference news). 

Other imaging modalities might help with differential diagnosis or even prognosis. Researchers found that PCA patients with a history of mathematical learning disability (dyscalculia) had focal atrophy on the right side of the brain, which may represent a specific subtype this form of dementia, whereas PCA patients with a history of language problems (dyslexia) predominantly had focal atrophy on the left side of the brain. Other findings on dyslexia and PPA hint that certain developmental disorders may predispose to specific forms of dementia (see Feb 2015 conference newsAug 2015 conference news). Researchers also found that among carriers of familial AD mutations, white-matter hyperintensities appear on MRI scans years before symptoms develop and soon after Aβ begins to deposit, suggesting that vascular pathology might occur early in the disease process (see Aug 2015 conference news). 

Deconstructing Aphasia.

Logopenic variant PPA patients with a history of learning disability have more focal atrophy (right). [Courtesy of Zachary Miller, University California, San Francisco, and Oxford University Press.]

Fluid biomarkers of AD advanced considerably in 2015. The FDA gave a nod to prodromal AD biomarkers CSF Aβ42, tau, and phospho-tau in “Letters of Support.” These letters represent a step toward FDA qualification, which would streamline the process trial sponsors go through to include fluid markers in their trials (see Apr 2015 news). 

The field also came closer to overcoming the problem of measurement variability, which continues to plague it despite years of a worldwide effort at quality control. Researchers aim to counter these fluctuations by introducing fully automated systems that take human handling largely out of the equation. Several companies are competing to have their machines take center stage in large studies such as ADNI 3 (see Aug 2015 conference news) and large European observational cohorts that are starting up. A major step was taken when the European Union’s Joint Committee for Traceability in Laboratory Medicine approved a mass spec protocol as a standard reference measurement procedure (RMP). With an RMP in place, the field is halfway to a standard that labs around the world can use to calibrate their equipment (see Oct 2015 news). The next step will be to make a certified reference material—a sample stable and homogenous enough that it can be shared with labs worldwide as a control standard.

On the clinical-research front, some of the earliest biomarker data from carriers of autosomal-dominant familial mutations in the Colombian API cohort study confirmed earlier DIAN data that Aβ begins to drop in the CSF as many as 20 years before the onset of symptoms (see Jan 2015 news). Other changes may occur even earlier, or indeed be developmental. For example, in the same cohort, researchers detected structural and functional changes in the brains of mutation carriers as young as nine years old (see Jul 2015 news).

Even as the most established markers move toward broader application, scientists are hunting for new ones. In particular, the synaptic proteins neurogranin and SNAP-25 emerged as potential markers of synapse loss (see Jan 2015 news). Studies supported the idea that high baseline neurogranin in cerebrospinal fluid correlates with impending dementia, and also with hippocampal atrophy and glucose hypometabolism, two other signs of synaptic decline (see Aug 2015 conference news; Sep 2015 news). Other researchers proposed neurofilament light chain, ferritin, and d-serine as potential markers of disease progression (see May 2015 news; Nov 2015 news). Total CSF prion protein level emerged as a marker to distinguish Creutzfeldt-Jakob disease from other rapidly progressing dementias (see Jan 2015 news). 

Last but not least, December saw the launch of AlzBiomarker, an interactive database of the collective CSF and plasma biomarker literature. Version 1 of this resource allows users to run 30 meta-analyses on 15 different markers and view at a glance how dozens or, in some cases hundreds of comparisons on a given marker stack up. The database will chart the growth of the literature for both established and newly emerging markers. 

APP Processing and Aβ
In 2015, researchers looked beyond Aβ to other fragments of APP that appear to affect synaptic health and may play a role in disease. Some groups reported the existence of numerous N-terminally extended Aβ peptides that suppress synaptic plasticity in vitro, and might have been mistaken for Aβ40/42 dimers in some earlier experiments (see May 2015 news). Other researchers reported a novel η cleavage of APP that occurs upstream of the α and β cleavage sites. Sequential processing by η- then either α- or β-secretases generates protein fragments of 108 and 92 amino acids, respectively. The longer Aη-α fragment dampened synaptic plasticity in culture and quieted neuronal calcium flux in vivo (see Aug 2015 news). All of these η fragments rise after BACE inhibition, suggesting they should be monitored in ongoing trials of BACE inhibitors. 

New Kid on the Chopping Block.

The newly identified η-secretase cuts APP 92 amino acids before the β-secretase site. [Adapted from interactive diagram in Alzforum's mutation database.]

Another secretase, dubbed δ, also debuted in 2015. Evidence suggests that by cleaving the N-terminal off APP, this asparagine endopeptidase facilitates cleavage by β-secretase and Aβ production (see Nov 2015 news). Meanwhile, other researchers found more evidence that the β-CTF fragment of APP may be toxic, reporting that it boosts tau protein levels (May 2015 news) and jams up endocytosis (Jul 2015 news). 

This year, researchers unveiled atomic-level structures of γ-secretase. They revealed how residues in the multi-subunit complex interact with one another as they snake through the membrane. One structure, derived from 4.32 Å resolution cryo-EM, attributed each of the 20 transmembrane regions in the horseshoe-shaped complex to one of the four subunits Aph1, nicastrin, Pen-2, and PS1 (see May 2015 news). In August, the same researchers stepped up their game and described a 3.4 Å resolution structure (see Aug 2015 news). This uncovered several mutation hotspots associated with familial AD. It also fits with a new model for how nicastrin modulates γ-secretase activity (see Dec 2015 news). Prior work had suggested that nicastrin helped present substrates to the secretase, but the new model implies that the subunit prevents access by all but substrates that have undergone prior shedding of most of their ectodomain by either α- or β-secretases.

Bend and Flex.

The short ectodomain of a γ-secretase substrate (purple) bends underneath nicastrin (green) as it interacts with presenilin (cyan). [Courtesy of Sjors Scheres, MRC, U.K.]

Tau
In 2015, researchers tried to get a better handle on how the neurofibrillary tangle protein tau gets mixed up in pathology, starting with a large network analysis of mouse models of AD that revealed distinct changes brought on by tau and Aβ (see Jan 2015 news). At a protein level, tau continues to baffle partly because it can undergo so many post-translational modifications. These can influence tau’s localization, processing, interactions, and toxicity. In July, researchers reported the most detailed catalog of tau modifications in mice to date, including methylations, acetylations, phosphorylations, ubiquitinations, and one site modified by N-acetylglucosamine (see Jul 2015 news). Surprisingly, the researchers found no difference between tau from wild-type and transgenic mice that had learning and memory problems, suggesting that a normal physiological form of the protein might be responsible for those deficits. Alternatively, toxic forms of tau may have gone undetected in tissue lysates used for this analysis, because they are present in such small amounts or perhaps concentrate in specific cellular locations. In keeping with this idea, another group reported that tau aggregation in presynapses impaired calcium signaling, reduced synaptic plasticity, and precipitated synaptic loss, revealing a new realm of tau troubles beyond the post-synaptic dendrites documented previously (see April 2015 news). Yet others found that acetylation of tau lysine 174 correlated with memory deficits in transgenic mice (see Sep 2015 news). This particular modification did not appear in the catalog published earlier in the year. 

The Big Picture. Competing acetylations and ubiquitinations dot the microtubule-binding region of tau (orange segments), while phosphorylations are largely confined to the proline-rich region (turquoise segment). [Courtesy of Morris et al., Nature Neuroscience.]

Some researchers believe that competition between acetylation and ubiquitination at the same tau amino acid underlies poor clearance of potentially toxic forms of the protein. In fact, it was reported that methylene blue, an experimental treatment for tauopathy, works in part by improving tau clearance via autophagy and the ubiquitin proteaseome system (see May 2015 news) and that boosting the proteasome system relieves tau toxicity and rescues learning and memory deficits (see Dec 2015 news; May 2015 news). 

Genetics
Since international collaborations have all but exhausted genome-wide association studies for AD, geneticists have been turning to whole-genome and whole-exome sequencing to search for less common variants that might influence risk for dementia. In March, researchers from Iceland reported whole-genome sequence analysis of more than 2,500 of that country’s citizens. The deep sequencing uncovered rare genetic markers that contribute to health and disease, notably, a loss-of-function mutation in the ABCA7 gene that doubles the risk of AD (see Mar 2015 news). Genetic variants near ABCA7 previously had been linked to AD in GWAS. The A673T protective APP mutation was originally identified in Iceland, as well, and this year came news that this particular variant turns up much less frequently in the U.S. population (see Feb 2015 news). Preliminary analysis from the Alzheimer’s Genome Project, which also uses whole-genome sequencing to identify risk alleles, revealed 180 novel rare variants that may alter function among known GWAS hits. Many of those variants lie in genes that contribute to immune function (see Apr 2015 conference news). In 2015 researchers called some prior exome-sequencing data into question. Several papers in Nature reported being unable to replicate association between the PLD3 gene and dementia (see Apr 2015 news). 

Many groups in 2015 focused intense effort on understanding how genes influence AD risk. Some genetic variants identified in GWAS lie outside coding regions, leaving scientists wondering what they might do, or with what functional variants they might co-segregate. Complicating matters, scientists poorly understand what many of these genes do normally. Variants in TREM2, for example, turn out to be the strongest genetic risk factors for AD after ApoE4, yet scientists are unsure how those variants change TREM2 function or how TREM2 fits into AD pathogenesis. Microglia and macrophages express this cell surface receptor, but scientists disagree on which may be more important for AD and whether this myeloid receptor helps promote or remove amyloid plaques (see Feb 2015 conference news). Researchers reported that lipids and nucleic acids activate the receptor, which would be in keeping with its role in stimulating microglial scavenging of dying cells (see Feb 2015 news). Hints emerged that TREM2 helps clear tau tangles (see Nov 2015 conference news). 

Tau Trouble.

Tau immunoreactivity ramps up in the cortices of htau mice that lack TREM2 (right). [Image courtesy of Shane Bemiller, Cleveland Clinic, Ohio.]

As for BIN1, it may lower Aβ production by shuttling BACE1 to lysosomes for degradation, or by speeding up BACE trafficking through endosomes in axons, while CD2AP may reduce Aβ production by facilitating recycling of APP in dendrites (see Apr 2015 conference newsNov 2015 conference news). PICALM may help internalize γ-secretase, pumping up Aβ levels, or it may help endothelial cells internalize Aβ and flush it into the bloodstream, removing it from the brain (May 2015 news). A protective variant of SORL1 dials up its expression and dials back Aβ production (Mar 2015 news). Like ApoE, Clusterin (aka ApoJ) in the brain appears to precipitate amyloid deposition in the parenchyma—without it, plaques end up almost entirely in blood vessels. On the other hand, evidence suggests that ABCA7 promotes Aβ clearance from the brain, and last year researchers reported that risk variants might cause alternative splicing of transcript that inactivates the protein. Researchers proposed that low expression of the CR1 gene in the plasma might also limit clearance of Aβ (see Nov 2015 conference news). Some groups report interaction of different GWAS hits, such as TREM2 and CD33, complicating interpretation of genetic data (Oct 2015 news). 

Drips and drops.

Cooling purified, wild-type FUS makes it spontaneously condense into a liquid form. [Courtesy of Neuron, Murakami et al., 2015.]

Protein Misfolding and Propagation
Protein misfolding stands out as a common characteristic among neurodegenerative diseases. Why do so many different proteins morph into nasty aggregates? This year, several research groups arrived at the same conclusion. They suggest that some proteins have a tendency to coalesce into highly concentrated liquid droplets, which could provide the ideal breeding ground for further condensation into solid fibrils (see Oct 2015 Webinar). Both FUS and hnRNPA1 phase separate in this manner, forming temporary, liquid-based organelles, such as stress granules (see Oct 2015 newsnews). Disease-linked mutations in FUS seem to accelerate this process (see Sep 2015 news). 

Even RNA may get in on the act. A hexanucleotide expansion in the C9ORF72 gene leads to the formation of RNA quadruplexes that seem to condense into similar structures, though further analysis is needed to prove that (see Oct 2015 conference news). 

A long-sought goal—the structure of proposed toxic oligomers—remained elusive in 2015. Researchers did report that Aβ oligomers with an anti-parallel β-sheet structure correlated with cognitive problems, while those with a parallel configuration were found near plaques but did not harm cognition (see Jun 2015 news). Similarly, α-synuclein aggregates with a ribbon-like shape were reported to seed Lewy bodies, while cylindrical fibrils precipitate neurodegeneration (see Jun 2015 news). Some groups used high-resolution microscopy to illuminate finer features of specific aggregate structures (see Sep 2015 news). 

β-Sheet Sandwich.

The core portion of α-synuclein forms β strands that pair up (top), then stack to make β sheets (bottom). [Courtesy of Rodriguez et al., Nature 2015.]

Evidence continued to accumulate that protein aggregates come in strains that propagate faithfully and affect cells differently (see Apr 2015 conference news). In one provocative, late-summer story, middle-aged adults who had received cadaver-derived growth hormone injections as children had amyloid plaques in their brains. The plaques were in addition to the prion deposits from the vCJD that had killed them. The study raised the frightening possibility that additional hormone recipients, including people who escaped vCJD, could be on the road to AD due to the prion-like properties and decades-long spread of amyloid (see Sep 2015 news). In other prion-related news, researchers reported that α-synuclein behaved like a prion in people with MSA but not PD, and spread across synapses into the brain when injected into the olfactory bulbs of mice (see Sep 2015 newsDec 2015 conference news). As a potential dampener of spread, researchers developed polythiophene compounds that stabilize prions, proposing that a similar treatment could work for other neurodegenerative disease proteins, as well (see Aug 2015 news). 

Immune System
In 2015, the role of the immune system in AD came to be more widely accepted, if more clear. Researchers continued in particular to dissect the role of microglia, which have emerged as more than just watchdogs for the brain. In 2015, more data came in to support the idea that these brain macrophages dine on dendritic spines, and may do so more voraciously as Alzheimer’s or other diseases kick in (see Mar 2015 conference newsNov 2015 conference news). Microglia respond to a combination of “eat me” and “don’t eat me” signals that adorn synapses and are delivered by complement proteins, and researchers posit that turning down the “eat me” signals might hold therapeutic potential. 

Evidence continued to build that microglia adapt a wide range of phenotypes and that relying on the classic M1 inflammatory and M2 non-inflammatory definitions is too simplistic. For example, analyzing postmortem brain samples to correlate gene expression patterns with pathology, researchers correlated certain microglial markers with tau and Aβ accumulation (see Apr 2015 conference news). More broadly, researchers found additional evidence that adaptive immunity, in particular peripheral cells that find their way into the brain, may be involved in AD. Once in the brain, these cells might squelch amyloid levels or cause neuronal damage (Apr 2015 conference newsSep 2015 newsAug 2015 news). 

Finally, the old idea that infectious agents, or the body’s response to them, might contribute to AD gained new traction when researchers in Spain reported finding fungal infections in AD brains (Oct 2015 news). 

Popular Press/Awareness
In 2015, neurodegenerative diseases seemed to capture the hearts and minds of the popular press and Hollywood more than ever before. Two movies struck it big at the box office, one on Alzheimer’s and the other on ALS, and both took home awards. Best actress in a leading role went to Julianne Moore for her depiction of Alice Howland, a linguistics professor stricken by Alzheimer’s (see Jan 2015 news); Eddie Redmayne took home the best actor award for his portrayal of Stephen Hawking’s struggle with ALS (see Feb 2015 news). Country music legend Glen Campbell was nominated for the original song award for “I’m Not Gonna Miss You” from “I’ll Be Me.” This documentary movie followed Campbell’s struggle with dementia as he brought his Goodbye Tour to millions of fans shortly after his diagnosis. On December 31, “Concussion,” the story of Nigerian physician Bennet Omalu’s efforts to expose chronic traumatic encephalopathies among retired National Football League players, hit the movie screens. Hollywood celebrity Robin Williams was posthumously diagnosed to have had dementia with Lewy bodies (DLB), an often-overlooked mixture of Alzheimer’s and Parkinson’s, raising public interest in this disease to new heights (see The Telegraph and Dec 2015 conference news series). And amongst glitz and glamour worthy of the American Academy of Motion Pictures, John Hardy, a geneticist from University College London, received the 2016 Breakthrough Prize in Life Sciences (see Nov 2015 news).—Tom Fagan

 

 

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References

News Citations

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  43. Could New Fluid Biomarkers Refine Alzheimer’s Diagnosis?
  44. Neurofilament Light Chain: A Useful Marker for AD Progression?
  45. Protein Marker Distinguishes Prion Disease from Rapid Alzheimer’s
  46. Do Extended Species of Aβ Poison Synapses, Masquerade As Dimers?
  47. Enter Aη: Alternative APP Cleavage Creates Synaptotoxic Peptide
  48. Does δ-Secretase Prep APP for BACE1, Boost Aβ production?
  49. New Wrinkle in APP Processing: Does C-Terminus Increase Tau Pathology?
  50. Partners in Crime: APP Fragment and Endosomal Protein Impair Endocytosis
  51. Gamma Secretase: Intramembrane Liaisons Revealed
  52. γ-Secretase Revealed in Atomic Glory
  53. Nicastrin Bounces Bulky Proteins from γ-Secretase
  54. Network Analysis Points to Distinct Effects of Amyloid, Tau
  55. Inventory of Tau Modifications Hints at Undiscovered Functions
  56. Not All About Dendrites: Presynaptic Tau Harms Plasticity, Too
  57. New Type of Toxic Tau? Acetylated Form Correlates With Memory Defects
  58. Et Tu, Methylene Blue? Drug Only Works as Prophylactic
  59. Protecting Proteasomes from Toxic Tau Keeps Mice Sharp
  60. Massive Icelandic Genome Analysis Offers Clues to Health and Disease, Including AD
  61. Let’s All Move to Iceland: Anti-Dementia Allele Rare in U.S.
  62. Could Adaptive Immunity Set the Brakes on Amyloid?
  63. The PLD3 Gene: Alzheimer's Risk Factor or False Alarm?
  64. United in Confusion: TREM2 Puzzles Researchers in Taos
  65. TREM2 Buoys Microglial Disaster Relief Efforts in AD and Stroke
  66. Alzheimer’s Risk Genes Give Up Some Secrets at SfN
  67. The Feud, Act II: Do Alzheimer’s Genes Affect Amyloid or Tau?
  68. Alzheimer’s GWAS Hits Point to Endosomes, Synapses
  69. New Role For PICALM: Flushing Aβ From the Brain
  70. Stem Cells Reveal Mechanism Behind Alzheimer’s Risk Factor
  71. Alzheimer’s Risk Genes Interact in Immune Cells
  72. Do Membraneless Organelles Host Fibril Nucleation?
  73. FUS Phase Transitions: Liquids and Gels
  74. ALS Protein Said to Liquefy, Then Freeze en Route to Disease
  75. Does C9ORF72 Repeat RNA Promote Protein Phase Transitions?
  76. Two Classes of Aβ Oligomers Act Differently in the Brain
  77. Shape of α-Synuclein Aggregates Influences Pathology
  78. Electron Microscope Yields Finer Structure of α-Synuclein, Aβ Fibrils
  79. Protein Propagation Real, but Mechanisms Hazy
  80. Alzheimer’s Transmission Between People? Amyloid Plaques in Hormone Recipients Hint at Prion-like Spread
  81. α-Synuclein from Multiple System Atrophy Acts Like Prion in Mice
  82. Lewy Pathology in DLB Spreads Fast, Maybe From the Nose
  83. Prion Stabilizers Boost Survival in Infected Mice—What About Other Proteinopathies?
  84. Microglia Rely on Mixed Messages to Select Synapses for Destruction
  85. Microglia Control Synapse Number in Multiple Disease States
  86. Microglia—Who Are You Really? New Clues Emerge
  87. Does Peripheral Immune Activity Tame Alzheimer’s Disease?
  88. Could Neutrophils Be the Newest Players in Neurodegenerative Disease?
  89. Dementia à la Mold? Fungi May Lurk in Alzheimer’s Brains
  90. ‘Still Alice’ Gives Voice to Patients with Early Onset Alzheimer’s
  91. Awareness Has Arrived: Two Oscars for Movies About Neurodegenerative Disease
  92. And the Oscar of Science Goes to …

Therapeutics Citations

  1. Aducanumab
  2. Gantenerumab
  3. Solanezumab
  4. Crenezumab
  5. BAN2401
  6. CAD106
  7. ELND005
  8. Sembragiline
  9. CERE-110
  10. TRx0237
  11. RG7345

Basic page Citations

  1. Clinical Trial Registries

Webinar Citations

  1. Suzanne Hendrix on Constructing Composites for Trials in Early Alzheimer’s
  2. Fluid Business: Could “Liquid” Protein Herald Neurodegeneration?

Mutations Citations

  1. APP A673T (Icelandic)

Conference Coverage Series Citations

  1. International Dementia with Lewy Bodies Conference 2015

Paper Citations

  1. . Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol. 2015 Nov;78(5):787-800. Epub 2015 Sep 25 PubMed.

Other Citations

  1. Therapeutics

External Citations

  1. DIAN-TU trial
  2. Phase 1
  3. Alzheimer’s Prevention Registry
  4. Brain Health Registry
  5. The Telegraph

Further Reading

No Available Further Reading