ALZFORUM should be on your reading list if you have more than a passing interest in research into neurodegenerative conditions. It is a great example of what can be achieved in educational advocacy if any earnest institutional funding is devoted to the task. That investment in advocacy exists today because Alzheimer's disease research is by far the largest portion of the broader aging research community, measured by funding and volume of projects, and has been for some time. The situation is quite different for our area of interest, rejuvenation research to repair the causes of aging. Here, the scientific programs of our community are still bootstrapping towards success in the absence of any larger-scale institutional funding, powered almost entirely by philanthropy. There really is no comparison when it comes to funding infrastructure. Still, ALZFORUM turns out a quality of online advocacy and education that we can aspire to - and given the continued unremitting failure in clinical trials of potential Alzheimer's therapies, it has to be said that just having funding doesn't automatically make advocacy an easy goal.
Confronting failure in trying to stem symptomatic Alzheimer's disease (AD), the field's main thrust has turned toward retooling its drug trials for ever-earlier disease stages. To sustain enthusiasm among participants and sites, scientists were advised to focus on learning from failure rather than conveying a sense of nihilism, both in internal discussions and in speaking with reporters.
They got to practice a positive attitude when another setback hit home. Merck announced an end to the EPOCH mild to moderate AD trial of the BACE inhibitor verubecestat for lack of efficacy, and data released later indicated that the drug had nudged down amyloid plaques without a hint of benefit, even in the more mildly symptomatic participants. Even so, BACE inhibitors are very much alive and being evaluated to a collective tune of billions of dollars. Researchers believe EPOCH treated people too late, when they'd had brain amyloid for years and neuron loss was well underway. The hope now rests on Phase 3 trials in people with mild AD. In trials of anti-amyloid antibodies, the place to go in 2017 was up. The A4 trial joined the trend in Alzheimer's immunotherapy when it quadrupled the solanezumab dose and extended treatment time to five years. Solanezumab had shown hints of efficacy in its negative Phase 3 trial, suggesting a higher dose might work.
Two different α-synuclein antibodies advanced to Phase 2. Researchers desperately want biomarkers for the next round of α-synuclein trials, and the race is on for PET tracers that will detect it. This work currently plays out on the Parkinson's disease (PD) front, but tracers and therapeutics for this protein will come in handy in Alzheimer's and dementia with Lewy bodies as well, as they will help scientists dissect the significant overlap of pathology and symptoms across the AD-PD spectrum.
Biomarkers will continue to be a research priority until they are solidly in place as routine features of AD diagnoses and trials, and 2017 saw strides toward that end. Researchers improved the standardization of cerebrospinal fluid (CSF) amyloid and tau measurement with automated CSF assays that vary less between runs and can predict clinical progression in cognitively normal people. Ultimately, clinicians prefer to use blood over CSF, and this year saw the first signs that this may be possible. Trialists all over the world seek a blood-based indicator of brain amyloid deposition to help them cut down on the number of expensive amyloid PET scans currently needed to recruit for secondary prevention trials.
Whatever doubt might have lingered out there about microglia's role in Alzheimer's was put to rest when scientists fingered a protective polymorphism near the gene for a major microglial transcription factor. Called PU.1, it controls myriad responses, including expression of known AD genes. This protective variant reduces PU.1 expression, lowers amyloidosis, and delays onset of AD. In a bizarre twist, 2017 ended on news that microglia not only help clear amyloid plaques, they may also help seed them. Some activated microglia spew protein bundles that power inflammatory cascades and also latch onto amyloid, driving plaque assembly.
The gradual sickening and eventual death of neurons defines neurodegenerative disease, but how exactly do disease-related proteins do this to neurons? A single theme did not emerge from this line of research in 2017; rather, it seems toxic proteins have an arsenal of weapons at their disposal. Tau appears to mess with all manner of cellular functions. Researchers implicated toxic tau variants in mitochondrial dysfunction, bungling synaptic vesicle release, disrupting the nucleus, compromising the epigenome. No one mechanism rose to the fore, however.
Vascular dementia research used to be a slow backwater relative to the flow of data every year on AD, but 2017 was different. Researchers made inroads into the physiology underlying this disease, for example by toppling a long-held dogma with their demonstration that the human brain does have a lymph system. The finding comes two years after a dural lymph system was discovered in mice. Continuing this year, the rodent studies reported that the dural lymph vessels drain cerebrospinal fluid from the brain into the blood stream. Besides the excitement about lymphatics, there was buzz about the regulation of blood flow in the brain. Researchers found that microinfarcts shut down local clearance of amyloid from the brain, at least in mice. These tiny, "silent" strokes are known to occur in people with AD, and the findings suggest they could hasten amyloid buildup by blocking clearance.