Venue
This year the AAIC was held in Toronto Canada. This city of 2.6 million people has a very welcoming feel. The weather in July is amazing, and there are plenty of things to see and do. Highlights include the CN Tower, Niagara Falls, a baseball game at Rogers Stadium, and a visit to Kensington Market.
The conference centre itself is a huge building that straddles Union station in the middle of Toronto’s financial district. The conference rooms had good visibility, but maybe were set at a temperature a little low for those of us not accustomed to North American air conditioning. Snacks and coffee were available throughout the day, but lunch was not provided. This in one sense was a positive though as it gave the delegates the chance to enjoy the great food on offer in Toronto served at establishments such as Ravi’s Soups.
The conference
The plenary speakers gave a steer on the direction for Alzheimer’s Disease (AD) research. In summary there is a move for a broader view of AD, away from the narrow amyloid and tau disease construct. This move is ultimately driven by failure of new medications and with other targets needing to be assessed.
Gabrielle Constatin (Italy) reviewed many years of study on peripheral inflammation. She highlighted neutrophil cycling across blood vessels, attracted by amyloid plaques and the potential avenue of blocking translocation by drugs used to treat Multiple Sclerosis (MS). The systemic immune theme was also covered by John Hardy (UK). Genome Wide Association Studies (GWAS) hits from AD patients are involved in two main pathways; inflammation and lipid metabolism. Prof Hardy suggested that AD has a component mediated by innate immunity and that future research should focus, in part, on the systemic immune system. Prof Hardy divulged his thoughts on the selective vulnerability of cell types in various neurodegenerative diseases; AD-pyramidal cells fail due to vulnerability to proteasome pathways whilst Parkinson’s Disease (PD) neurons have vulnerability due to weaknesses in the mitochondrial complex 1; The other GWAS hits for risk factors for AD (including CLU, PICALM and CR1) do not approach APOE4 which has an odds risk of 4 compared to others with an odds risk of <1.5. APOE and selective vulnerability was also covered in the session by Jane Driver who switched careers from oncology to AD, motivated by the lack of therapies for AD. In the field of Oncology >200 cancers related drugs have been approved in the last 20 years. She highlighted the fact that the longevity of neurons, allowing them to survive for 80 plus years, is accomplished by passing critical metabolic functions to glial cells. The tradeoff of this relationship is the vulnerability to death. This is in contrast to peripheral cycling immune cells that replicate quickly and have an increased risk of cancer. This analogy becomes important when we consider the PIN1 gene which helps maintain telomeres in white cells but acts on Amyloid Precursor Protein (APP) in neurons. Thus there might be an inverse link between cancer and AD. There is data that suggests an inverse relationship between malignancy and AD, but clearly this is subject to many biases. Professor Driver suggested that early onset AD (genetic, rapid progression) is very different to Late Onset AD (metabolic disease, slower progres- sion). She summarised her comparison with a call for the investigation of multiple targets in AD, such as is seen in oncology therapies. In particular targeting metabolic health with exercise, mitochondrial support, insulin signaling, and metformin action on mitochondrial complex one activity.
Another plenary speaker, Laura Baker (USA) discussed how exercise might help to treat Mild Cognitive Impairment (MCI) and AD. This study selected sedentary patients with MCI. Dr Baker suggested that studies involving exercise need to last at least 6 months because the main effect, as shown on functional MRI, is on frontal network connections. She suggested longer studies are required to see if there is a long-term effect on improving or maintaining memory. As exercise may not be amenable to all patients other targets for a metabolic pathway intervention were mentioned as another way to exploit this type of intervention. Dr Suzanne Craft discussed the ketogenic diet as a treatment not just of epilepsy but also for AD. Dr Samuel Henderson presented further work from a company, Accera, which is running a phase three study of AC1202, a medium chain fatty acid that produces ketones/ketosis. There were two sessions on mitochondrial function in AD. Dr Eugenia Triushina from the Mayo clinic Rochester presented data on CP2, a complex 1 partial antagonist that is effective in cell based assays and animal models (3Tg models) of disease. This compound restores mitochondrial transport, protects against Reactive Oxygen Species (ROS) and against Abeta and tau toxicity. Metformin, another drug that inhibits complex 1, has been reported in data from United Kingdom–based General Practice Research Database (GPRD) to increase the risk of developing AD (an effect not seen with sulfonylureas). Thus the role of complex one and drug action on it requires considerably more work. There was not much out of therapeutic trials. There remained a lot of papers on amyloid and tau PET studies but this eld does not appear to be moving fast. There is increasing interest in the vascular contribution to Alzheimer’s disease and separation in clinical diagnosis is reducing. There was a debate as to whether white matter hyperintensities (WMH) should be part of the diagnostic criteria for AD, with some data from the Dominantly Inherited AD (DIAN) cohort.
On the clinical front there was an interesting paper which used laser-capture microdissected plaques from the hippocampus of rapidly progressive AD (rpAD) patients. rpAD is associated with having 14,3,3, in CSF and lower frequency of APOE4. Eleanor Drummond (NYU, Case Western) presented the data from 22 rpAD and 22 sporadic normal progressing cases. The rpAD cases had no mutations in genes known to cause fAD (PSEN or APP) nor in prion genes. Proteomic analysis using mass spectrometry found decreased protein expression including GFAP, gelsolin and abeta. There were less astrocytic proteins and more neuronal proteins, including vesicular proteins and actin cytoskeletal proteins. They found one protein 11 fold higher in the sporadic group but they had not identified or were not able to provide more information on this protein.
Finally the Canadian health system is under the same amount of pressure as the NHS. Waiting times to be seen in memory clinics are very long, up to 6 months. A series of talks on models to improve care and management of people with dementia in Ontario, Quebec and Saskatchewan were presented. Dr Linda Lee, has a long history in this area, developing the Primary Care Collaborative Clinics since 2006. This is a single point of access, integrated and collaborative, interdisciplinary clinic that included nurse practitioners, social workers and pharmacists. There is a 5-day training programme for the clinic for all personnel. This includes 2 days of workshops and mentoring. There are booster days to maintain skills. A population of over 1.7 million is covered by 170 primary care practices in Ontario. 90% of referrals were managed in primary care. The 10% referred on for secondary care assessment included complex co-morbidities, atypical presentation, FTD, DLB and rapid progression. Geriatrician chart audit had revealed high levels of agreement on diagnoses. In the UK, secondary care memory clinics are diagnostic rather than management led and more primary care diagnosis would be likely to be cost effective, but assessing accuracy of diagnoses would be important.
A final interesting point from the original amyloid immunisation study was presented by James Nicoll (Southampton, UK). Neuropathological follow-up of cases from the original immunisation trial (AN1792), con rmed AD in 16 out of 21 of the participants; leaving 5 without AD (1=PSP, 1=DLB, 1= VaD and 2- FTD-TDP43). This highlights the importance of neuropathological follow-up in clinical trials in AD. Of the 21 participants 18 received the active drug and 3 placebo. Professor Nicoll showed long term amyloid plaque removal in those who received immunisation, although these results are impaired by the fact that only 1 out of the 3 participants who received placebo had AD.
Overall the conference was in a great location, with excellent amenities. Topics covered in the conference were in general very interesting, and able to highlight important areas of future research and areas that need further development. Next year’s conference comes to London in the UK, hopefully the AAIC organisers will take a leaf out of the 2012 Olympics committees book and provide an excellent conference.
