Kenneth Rockwood is Professor of Medicine (Geriatric Medicine & Neurology) and consultant geriatrician at Capital Health in Halifax, Nova Scotia, Canada and Honorary Professor of Geriatric Medicine at the University of Manchester. Here he reports from the 12th International Conference on Alzheimer’s and Parkinson’s Diseases, held in Nice.
At the March 2015 AD/PD meeting in Nice, the big news, for me anyway, wass that ageing is making its way back into dementia. Sessions such as “Impact of co-morbidities on Alzheimer’s pathogenesis and cognitive function in mouse models” and “Stress and telomere maintenance mechanisms in human life trajectories” elbowed their way into a program with presentations on “the analysis of longitudinal amyloid PET images” and “How do we treat Alzheimer’s disease a decade before dementia?”.
In doing so, they drew to attention that on a population basis, dementia is not a rare disorder occurring in young people with little else wrong. Instead, it mostly happens not just to older people, but to older people who have a lot of health problems.
I have a dog in this hunt. In 2011, our group re-analysed the risk factor data for dementia from the Canadian Study of Health and Aging. Started in 1991 under the leadership of Ian McDowell at the University of Ottawa, the CSHA was one of the first large scale epidemiological studies of the modern. Then and now, it was a team in which I proudly claim(ed) membership. The CSHA was part of an important blossoming of a re-appreciation of late-life dementia as being potentially preventable, in virtue of having potentially modifiable risk factors. One of these was high blood pressure. We were at pains to point out, in medical update lectures, that “hypertension as a risk for Alzheimer disease” was substantially different from “hardening of the arteries as the cause of senility” (for starters, they were spelled entirely differently).
Flash forward to July 2011. My colleagues Arnold Mitnitski and Xiaowei Song and I published a paper in Neurology showing that the inventory went beyond vascular risks, head injury and other items that by then had come to be known as “traditional” dementia risk factors. Instead a broad range of health deficits (such as wearing dentures, having diarrhoea, and painful feet, which we were obliged to call “non-traditional risk factors”) combined to trump any traditional one in predicting late life cognitive impairment.
The paper was published on a slow news days, and so had its 15 minutes. It was read, not incorrectly, as showing that a healthy body was conducive to a healthy brain in late life. The hope that this engendered in turn motivated a media mobbing, and the memorable clinic-interrupting query “can you take a call from the New York Times?” (I confess that I could). In 2014 we updated the paper to show that the best way to predict dementia risk was to combine all the factors, regardless of their status as traditional or otherwise. In short, dementia risk was related more to deficit accumulation than to age per se.
Howard Fillit (you might recognize his name, amongst other reasons, as being one of the Brocklehurst editors) was amongst the emphatic in making the point that many of the molecular causes of Alzheimer disease now being pursued are what is seen with ageing. Oxidative stress, failure of chaperone proteins and autophagy, protein misfolding, inflammatory proteins run amok, are not unique to AD, but seen broadly in ageing.
Perhaps I’m been optimistic, but we seem to be in the middle of a needed re-appreciation of what gives rise to dementia. First, the acceptable view of in what a mechanism consists has moved from being a gene (and, somewhat begrudgingly, its “gene product”) to being the interactions of many such proteins, and their impact on function… Happily, it is now no longer necessary to show that whichever mechanism is being proposed relates to amyloid. The AD/PD conference still had hundreds of papers on various aspects of amyloid, but under the rubric of “Other Neurodegenerative” papers on “20 years of cumulative risk factors affecting verbal memory performance”, stem cell therapy, the cholinergic system, GLP-1 receptor signalling pathways and autophagy, antioxidants and allosteric modulators of glutamate receptors were each heard.
It’s been a long time coming, and it’s not here yet, but it might be that it will become to be seen that the chief fact of dementia – that it mostly happens in old people, with a lot wrong – will not be seen as a coincidence, but as key to understanding. Of course it will be more complicated: not all frail people get dementia, and not all people with dementia were frail before the onset of their cognitive problems. Even so, that they – and even much younger people, with little else wrong – should be where proof of concept resides requires a leap of faith about a linear causality that is at odds with the evidence. This specifically includes evidence from autopsy-based community studies that no single type of neuropathological lesion distinguishes people with dementia from those without it. In that light, providing benefit to the people for whom the vicissitudes of ageing are the key to disease could teach us much about how dementia works.