The greatest hit from the ADPD2015 meeting was undoubtedly the announcement of Biogen’s phase 1b results for Aducanumab (BIIB037), an antibody directed at amyloid plaques. Treatment with Aducanumab produced a dose- and time-dependent reduction of amyloid plaques in the brain, as well as a slowing down of the clinical decline in patients shown by two different cognitive assessment scales (MMSE, Mini Mental State Examination and CDR, Clinical Dementia Rating). These results were generally acclaimed by everyone in the audience. The previous talk by Roger Nitsch was not less impressive. He described the process of B cell screening in large cohorts of unusually healthy elderly individuals that ultimately led to the identification and development of Aducanumab, using Neuroimmune’s Reverse Translational Medicine platform. Aducanumab specifically targets aggregated forms of beta amyloid including soluble oligomers and insoluble fibrils deposited in amyloid plaques.
The only genetics session of the meeting happened on Thursday morning, chaired by John Hardy and Rudy Tanzi. The first up was John Hardy who described the genetic analyses currently underway for Parkinson’s and Alzheimer’s diseases. He addressed the selective vulnerability shown by different brain regions to the different neurodegenerative diseases and proposed a catastrophic cliff theory. Rudy Tanzi shared the first results from the analysis of whole genome data from the NIMH cohort and Christine Van Broeckhoven gave an excellent overview of the genetics of early-onset Alzheimer’s disease. Her group developed a targeted sequencing approach to study all the Alzheimer’s and dementia associated genes. Julie Williams made a plea that people stop choosing their favourite inflammation marker to perform genetics studies and Ted Dawson, the only cell biologist in the session, discussed the molecular mechanisms of the genetic causes of PD with a focus on parkin. Capping off the session, Rita talked about the different strategies we currently apply in the lab to study familial cases using exome sequencing in different neurodegenerative diseases. She focused on the pleiotropic events resulting from the use of this technology and how the study of rare familial forms of dementias can give us important information on more common diseases like Alzheimer’s disease.
The epigenetics and genetic mechanisms session also had several interesting talks. The first speaker was Li-Huei Tsai presenting the main results from the epigenomics analysis of AD (Paper: Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease) based on the Epigenome Roadmap. Lars Bertram made a very convincing case for the involvement of microRNAs in AD and PD. Kenneth Kosik described the application of next generation sequencing to the study of a large kindred with the PSEN1 E280A mutation to search for phenotypic modifiers. Interestingly, this is not the only large Colombian family with neurodegenerative diseases which can possibly be due to multiple bottlenecks among founders of each settlement in the country’s history. A comprehensive story of the research being developed around this very large family can be found in Alzforum. Michael Nalls presented a very detailed description of the statistical methods used to establish an accurate predictive model for PD.
The conference saw two sessions dedicated exclusively to Dementia with Lewy Bodies, which was great given TheGBLab’s interest in this disease. Ian McKeith talked about the prodromal stages of DLB and how it is important that this stage is recognized so that therapies can be started earlier. It was also clear from this talk how difficult a clinical diagnosis of DLB can be, when so many symptoms are completely unspecific. Nir Giladi showed data from GBA studies in an Ashkenazi Jewish cohort from Israel. GBA mutation carriers seem to be associated with an overall worse disease progression. Also shown was surprisingly low penetrance rate for LRRK2 G2019S of about 30% in that population. Glenda Halliday did a great overview of the neuropathology of synucleinopathies in general and DLB in particular. The rapid and widespread onset of pathology in DLB, particularly when compared with PD, was really striking. Ilaria Guella presented their work on genetic variability in SNCA. This was a great talk for us to listen to, because it fully replicated our findings showing a differential association profile between PD and DLB at the SNCA locus (TheGBLab News here). Tony Futerman presented on their work with the CBE mouse model of Gaucher disease. This was a really great talk that certainly supported our hypothesis that other lysosomal genes may be involved in conferring risk to PD (and DLB to some extent). He also presented data showing that modulating Ripk3 can rescue the phenotype in the CBE mouse model. Pablo Sardi from Genzyme talked about enhancing GBA1 activity as a therapeutic strategy in Lewy Body diseases. One of the most interesting topics from this talk was a notion we are also pursuing that stems from the large number of pleiotropic events we are seeing in different diseases: therapeutic approaches should be used, not on clinically defined disease entities, but instead by involved molecular events. Starting in a rare, severe disease like Gaucher, can be informative for a more common and complex set of diseases like the synucleinopathies.
There were many talks about biomarkers, with a particular emphasis in CSF proteins. Also, TREM2 and neuroinflammation took a central stage in many of the sessions. Disparate results were presented for the molecular mechanism associated with TREM2 in Alzheimer’s disease, but all researchers seem to agree that TREM2 role in pathology is probably associated with Abeta clearance. These different results were more evident in two consecutive talks where the first speaker, Delphine Boche, affirmed that she couldn’t find any expression of TREM2 in microglia cells from the study of 299 brains and that TREM2 was a marker for monocytes. The next speaker, Karel Otero, started his talk by saying that the highest expression of TREM2 occurs in microglial cells.
It was great to see some of our results and slides being presented in different sessions and particularly to see our data on different profiles of SNCA associations with PD and DLB being independent replicated.