Review: National Institute of Health State-of-the-Science Conference Statement: Preventing Alzheimer Disease and Cognitive Decline

This is a review of a consensus statement on prevention of Alzheimer’s Disease which is freely available here and in a slightly more detailed form here.

So firstly this is a National Institute of Health ‘State of the Science’ Conference statement – ‘Preventing Alzheimer Disease and Cognitive Decline’. There are 15 listed authors and the process by which the statement is arrived at is complex. Briefly stated and referring to the document this comprises

1. A systematic review of the literature

2. Presentations ‘during a 2-day public session’

3. ‘Questions and statements from conference attendees during open discussion periods that are part of the public session’

4. ‘Closed deliberations by the panel’

The consensus statement does not represent the NIH or government and is

an independent report of the panel

Before discussing the contents of the paper any further, its worth just pausing at this point and reflecting on the above. The question is a very significant one. An epidemic of dementia is predicted by the middle of the century and will occur in the context of aging demographics globally. So the issue of preventing dementia and cognitive decline is clearly very important and it’s good to see a very  creative approach to this problem. There is a difficulty with this approach however and that is the paper trail. From points 1-4 above you can see that much of the process by which the conclusions are arrived at are happening in the milieu of the conference and to some extent we are left with the end product of this process. However it is the process itself which would be very useful to look at.  If we consider the NICE guidelines, the lengthier documents contain details of the studies that have been examined. This makes it easier for the reader to cross-check with studies they think might have been useful to include. Here though it’s difficult to engage in the same type of analysis. We’re not presented with information on the presentations or the public sessions. This is a great opportunity for generating video footage and uploading to YouTube so that others can get a feel for the kind of discussions that were taking place and contextualising the end results. In terms of a paper trail, the systematic review could be published in the format of an article for closer inspection and systematic reviews themselves vary in quality.

Moving onto the contents – the summary paper divides up the discussion according to 6 questions.

Question 1 – ‘What factors are associated with the reduction of risk of Alzheimer’s Disease?

The consensus statement response here is non-specific. I would have preferred to have seen a point-by-point summary for the myriad risk factors that have been identified. The authors discuss the need for prospective studies (albeit much later in the article) but without further details it is difficult to know which of the many prospective studies have been discounted. Here for instance is a prospective longitudinal study showing a reduced prevalence of dementia associated with Mediterranean diet (it could be argued that they were interested more specifically in Alzheimer’s Disease however). In the News Round-Up from the end of last year, I included a number of references  for studies on dementia, more specifically Alzheimer’s Disease and cognitive decline and have included some of the relevant excerpts in the appendix below which can give the reader a flavour of the kind of interesting themes that might have been explored in such discussions. The authors point out that it is difficult to discriminate between cases with and without vascular involvement because of the complex interplay between vascular and Alzheimer’s Disease pathology but this is more a question of selection of studies with the relevant inclusion criteria (which would include for instance MRI exclusion of subjects with evidence of vascular pathology e.g. graded white matter hyperintensities).

Question 2 – ‘What factors are associated with the reduction of risk of cognitive decline in older adults?’

Although they identify hypertension as a strong risk factor for cognitive decline in older adults, I don’t think this is a particularly good question. It would make more sense to ask specific questions such as factors reducing the rate of decline in Mild Cognitive Impairment, healthy controls and the subtypes of dementia.

Question 3 – ‘What are the therapeutic and adverse effects of interventions to delay the onset of Alzheimer disease? Are there differences in outcomes among identifiable subgroups?

Again I think the first part o this question is just too broad although the second part is more sensible. The important point is about what the baseline characteristics of the sample population are. These would be expected to influence the likely benefits of interventions including antihypertensive medication, anticholinesterase inhibitors, exercise and so on. Unless the study is well powered, the heterogeneity of any baseline population implied by the question will likely dilute the valid effects.

Question 4 – ‘What are the therapeutic and adverse effects of interventions to improve or maintain cognitive ability or functions? Are there different outcomes in identifiable subgroups

There is an interesting story here which is around the ACE inhibitors and there are a number of studies coming up with interesting results with ongoing debate although some of the evidence presented has related to morbidity in Alzheimer’s Disease rather than cognitive decline per se. The authors consider the antihypertensives generically. I wasn’t entirely clear on what the authors meant when they referred to the anticholinesterase inhibitors as influencing the rate of cognitive decline is their  indication. The authors do refer to specific subgroups in places but again I think the entire question should be considered in terms of specific subgroups.

Question 5 – ‘What are the relationships between the factors that affect Alzheimer disease and the factors that affect cognitive decline?’

I thought this was a more useful question to ask in the context of the statement and which can be described in terms of qualitative relationships. Diet, exercise, APOE4 status and depression were among the risk factors that were important for both cognitive decline and Alzheimer’s Disease. It’s important to note here though that the question revolves around shared risk factors.

Question 6 – This question focuses on what  research needs to be done.

The authors talk about a need for large studies and tighter criteria for mild cognitive impairment etc. This kind of question has been tackled by other groups. I think it is more useful to produce very focused study designs for this type of question as it is perhaps readily apparent that studies with large numbers and epidemiological studies would be good to design. However they are very costly and labour intensive and there should ideally be a very concrete pathway from the consensus statement to the actuation of these study designs.

My Conclusions

I think that it is a great idea to get lots of people in the field involved in discussing how to prevent cognitive decline and Alzheimer’s Disease. However, I have a number of thoughts on this.

1. There should be some documentation of the ‘behind-the-scenes processes’ including the public debates. I refer to ‘behind the scenes’ as all of the action that we the readers are not privy too i.e. the events of the conference.

2. For similar reasons, I would argue that video footage at key points in the discussion would be very useful uploaded to a free hosting service such as YouTube for dissemination of conclusions and the process leading to those conclusions. I’m sure someone could bring their digital camcorder along!

3. A social media format for engagement of the public and global scientists would be useful

4. The statement would probably benefit from considering very restricted clinical questions where there is more likelihood of arriving at useful responses in this setting.

5. Some of the time in the process arriving at the statement should be spent on the actual process itself. For instance if this process is repeated in a year’s time why should the answer be any better? Indeed would the same panel come up with a worse answer? It’s difficult to know.

6. There should be commentary on the concrete consequences of this meeting. Were grants issued for studies on the recommendations in this statement? Were stakeholders from grant-issuing bodies present at the conference?

Appendix – Excerpts from News Round-Up 2009 of relevance

‘A prospective study looking at people with Alzheimer’s Disease found a significant association between the use of antihypertensive medications and a lower rate of cognitive decline and higher MMSE scores at baseline even after controlling for blood pressure’

‘A 32-year prospective study – the Prospective Population Study of Women in Gothenburg found an association between central adiposity in middle age and prevalence of subsequent dementia. They did not find the same relationship between BMI and subsequent dementia but the central adiposity was associated with an approximate doubling of the prevalence of subsequent dementia’

‘A prospective California study with 9000 subjects provided evidence of an association between higher levels of cholesterols in people aged in their 40’s and the subsequent prevalence of Alzheimer’s Disease in their 60’s to 80’s. The article is freely available here’.

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