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Dementia: Assessment, management and support for people living with dementia and their carers. London: National Institute for Health and Care Excellence (NICE); 2018 Jun. (NICE Guideline, No. 97.)
Dementia: Assessment, management and support for people living with dementia and their carers.
Show detailsSeveral risk factors have been described for dementia, and most also apply to the main subtype of Alzheimer’s disease. These include factors such as: advancing age, female sex, low education, possession of certain genetic risk factors, such as apolipoprotein E4, family history of dementia, history of depression, history of head injury, pre-existing history of learning difficulties, especially Down’s syndrome. However, in addition, there has been much recent interest in several vascular risk factors which have also emerged as risk factors for dementia and also for Alzheimer’s disease. These include smoking, hypertension, hypocholesterolaemia, diabetes, ischemic heart disease, obesity, lack of exercise and atrial fibrillation. The main clinical implication of these vascular risk factors, as opposed to the other risk factors described, is that all are potentially modifiable. Epidemiological evidence has largely informed our knowledge about risk factors, but such evidence cannot indicate whether modification of any or all of these risk factors will either prevent the development of dementia or, more relevantly for the current guideline, delay the progression of cognitive or functional impairment in those with established dementia. This question concerns whether modifying risk factors may have an effect on slowing the progression of dementia in those with recognised dementia.
The mechanism by which such modification may delay the progression of dementia, if they are effective, is not entirely clear. The two broad hypotheses would be, firstly, that such modification will reduce the accumulation of additional vascular burden in such subjects, an effect which is known to accelerate the expression of dementia even in those with Alzheimer’s disease, for example by reducing the occurrence of subcortical vascular disease (white matter lesions and lacunar infarcts). The second is potentially through direct modification of degenerative (Alzheimer’s-type, i.e. plaque and tangle) pathology, since there is some evidence both from the animal literature and limited human studies that vascular factors such as hypertension and diabetes, as well as ischemic damage which might be secondary to vascular changes, can hasten the spread of Alzheimer-type changes.
10.1. Risk factors for dementia progression
Review question
- What effect does modifying risk factors have on slowing the progression of dementia?
10.1.1. Introduction
The aim of this review question is to assess whether interventions targeting underlying risk factors for progression can be used to slow progression of dementia, or its sequelae, after diagnosis. The interventions in question are based on known modifiable risk factors that have not been addressed in other sections of this guideline. The review identified studies that fulfilled the conditions specified in Table 42. For full details of the review protocol, see appendix C.
Table 42
Review summary: modifying risk factors for dementia progression.
10.1.2. Evidence review
A systematic literature search for systematic reviews and RCTs identified 3,217 references. These were screened at title and abstract level, with 43 papers (9 systematic reviews and 34 RCTs) ordered as potentially relevant. Of these studies, 6 RCTs assessing the effect of risk factor modification on dementia progression were included. Fifteen additional references were identified through assessment of the bibliographies of excluded systematic reviews and RCTs, all of which were included. In total, 20 studies (reported in 21 publications) were included, with 36 excluded at full-text review. The original protocol for this question specified that it should include studies of at least 12 months duration. However, due to the relatively low number of RCTs identified, this was expanded to include trials of at least 6 months duration. The studies excluded at full-text review, and the reasons for exclusion, are given in appendix F.
10.1.2.1. Description of included studies
Randomised controlled trials assessing 4 different types of interventions were found:
- Two studies evaluated the efficacy of antidiabetic drugs for reducing cognitive decline (namely, rosiglitazone). In these studies rosiglitazone was given to people living with Alzheimer’s disease who did not have diabetes.
- Ten trials were identified that assessed the safety and efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) for reducing cognitive decline in people living with Alzheimer’s disease. NSAIDs included naproxen, aspirin, indomethacin, tarenf lurbil (an R-enantiomer of flurbiprofen), ibuprofen, diclofenac, celecoxib and rofecoxib. It was noted that rofecoxib was withdrawn from the market in 2004; however, t he identified evidence was included in analyses to explore the class effect of NSAIDs.
- Four trials were identified that assessed the efficacy of statins (atorvastatin and simvastatin) for reducing cognitive decline in people living with Alzheimer’s disease. luded
- Four trials were identified that assessed the efficacy of antihypertensive drugs for reducing cognitive decline. Three of these studies inc people living with Alzheimer’s disease whereas 1 study included people with subcortical vascular dementia. It was noted that some of these studies included people who did not have hypertension. Antihypertensive drugs included telmisartan, nimodipine amlodipine, perindopril, captopril, enalapril imidapril, nifedipine and nilvadipine.
For the purpose of this review, studies which assessed the efficacy of dietary supplements, exercise and antipsychotics for treating aggression or psychosis, were not included. This is because the evidence on these interventions was considered elsewhere in the guideline. For the full evidence tables and full GRADE profiles please see Appendix E and Appendix G. References for the included studies are given in appendix I.
Table 43
Summary of included studies: antidiabetic medicines.
Table 44
Summary of included studies: NSAIDs.
Table 45
Summary of included studies: statins.
Table 46
Summary of included studies: antihypertensive medicines.
10.1.3. Health economic evidence
Standard filters plus social care extras were applied to the clinical search for this question, and a total of 1,455 citations was returned. Following review of titles and abstracts, no full text studies were retrieved for detailed consideration. Therefore, no relevant cost-utility analyses were identified for this question.
10.1.4. Evidence statements
10.1.4.1. Antidiabetic drugs versus placebo
Very low to low-quality evidence from up to 2 RCTs, including 882 people living with Alzheimer’s disease, found no meaningful differences in cognition, global assessment, behavioural and psychological symptoms, adverse events, serious adverse events or adverse events leading to discontinuation between people offered rosiglitazone or placebo.
10.1.4.2. NSAIDs versus placebo
Very low- to moderate-quality evidence from up to 8 RCTs, including 3,284 people living with Alzheimer’s disease, found no meaningful differences in cognition, global assessment, behavioural and psychological symptoms, dementia severity, quality of life, serious adverse events or mortality between people offered NSAIDs or placebo.
Low-quality evidence from up to 7 RCTs, including 2,989 people living with Alzheimer’s disease, found better functional ability in people offered NSAIDs compared with those who received placebo, but these differences were either not clinically significant or did not persist in a sensitivity analysis removing rofecoxib (a treatment that has been withdrawn from the market).
Low-quality evidence from up to 6 RCTs, including 3,533 people living with Alzheimer’s disease, found higher levels of adverse events leading to discontinuation in people offered NSAIDs compared with those receiving a placebo.
10.1.4.3. Statins versus placebo
Very low- to moderate-quality evidence from up to 4 RCTs, including 1,084 people living with Alzheimer’s disease, found no meaningful differences in cognition, behavioural and psychological symptoms, adverse events, serious adverse events or mortality between people offered statins or placebo.
Moderate-quality evidence from 1 RCT, including 639 people living with Alzheimer’s disease, found higher levels of adverse events leading to discontinuation in participants who were offered statins compared with those who received placebo.
10.1.4.4. Antihypertensive drugs
10.1.4.4.1. Calcium-channel blockers versus placebo
Low-quality evidence from 1 RCT, including 1,442 people living with Alzheimer’s disease, found no meaningful differences in cognition, measured by ADAS-cog scores, between people who received calcium-channel blockers and those who received placebo. However, moderate-quality evidence from the same trial found a smaller decline in cognition, measured by MMSE scores, in people treated by calcium-channel blockers compared with those who received placebo.
Low-quality evidence from 1 RCT, including 1,636 people living with Alzheimer’s disease, found no meaningful differences in global assessment, adverse events, or discontinuation due to adverse events between people who received calcium-channel blockers and those who received placebo. Moderate-quality evidence from the same trial found higher levels of serious adverse events in people who received calcium-channel blockers compared with those who received placebo.
10.1.4.5. Angiotensin II receptor antagonist versus calcium-channel blocker
Moderate-quality evidence from 1 RCT, including 20 people living with Alzheimer’s disease, found no meaningful differences in cognition between people treated by and angiotensin II receptor antagonist or a calcium-channel blocker.
10.1.4.6. Brain-penetrating angiotensin converting enzyme (ACE) inhibitor versus calcium-channel blocker
Moderate-quality evidence from 1 RCT, including 108 people living with Alzheimer’s disease, found smaller declines in cognition in people treated by brain-penetrating ACE inhibitors compared with those treated by calcium-channel blockers.
10.1.4.6.1. Non-brain-penetrating angiotensin converting enzyme (ACE) inhibitor versus calcium-channel blocker
Moderate-quality evidence from 1 RCT, including 108 people living with Alzheimer’s disease, found smaller declines in cognition in people treated by non-brain-penetrating ACE inhibitors compared with those treated by calcium-channel blockers.
10.1.4.7. Health economic evidence
No health economic evidence was identified for this review question.
10.1.5. Evidence to recommendations
| Relative value of different outcomes | The committee agreed that, since the aim of these interventions was to modify the underlying progression of dementia, the outcome measures that would provide the most information were measures of cognition. They noted that comparatively small differences in cognition may prove to be meaningful, provided they are sustained over a long period of time. The original protocol specified that only trials of at least 12 months duration would be included. However, due to the relatively low number of RCTs identified, the committee agreed it was appropriate to expand this to include trials of at least 6 months duration. |
|---|---|
| Trade-off between benefits and harms | Antidiabetic drugs The committee agreed the included studies did not provide any evidence that antidiabetic drugs (specifically rosiglitazone) were effective in slowing the progression of Alzheimer’s disease. The committee discussed whether the evidence on rosiglitazone was sufficient to make generic recommendations about all antidiabetic drugs. It was agreed that clinicians would not offer a drug to patients without robust assessments of its disease modifying effects. As a result, the committee felt that a “do not offer recommendation” would apply to all antidiabetic drugs, as there is no evidence of clinical effectiveness. NSAIDs The committee noted there was weak evidence of a potentially small effect on some outcomes with NSAIDs for people with Alzheimer’s disease. Specifically, there was a small improvement in functional ability at 12 months. However, the magnitude of this benefit was below the level defined as being clinically significant, and there was no evidence of an effect on cognition or other clinical outcomes. The committee agreed this small difference may have been a direct result of the anti-inflammatory effects of NSAIDs, and there was no evidence it was mediated through changes in disease progression. The committee noted that although absolute rates of adverse events were similar between people who were treated with NSAIDs and those who received placebo, more adverse events leading to discontinuation were observed in people who were given NSAIDs. The committee agreed that the trend is not uncommon in trials which assess the safety of NSAIDs. This is because there are certain red-flag adverse events associated with NSAID treatment which will automatically lead to people being taken out of trials. The committee agreed that the evidence was consistent with a class effect for NSAIDs and therefore it was appropriate that a negative recommendation be made for the entire class. The committee agreed it was appropriate to specifically mention aspirin within the recommendation, as it was included within the evidence base but is not always recognised as being an NSAID. Statins The committee agreed the included studies did not provide any evidence that statins were effective in slowing the progression of Alzheimer’s disease. The committee agreed that the evidence was consistent with a class effect for statins and therefore it was appropriate that a negative recommendation be made for the entire class. As with NSAIDs, there was evidence of higher levels of adverse events leading to discontinuation with treatment, which was agreed to be consistent with what would be expected in trials of statins in people without dementia. Antihypertensive drugs The committee agreed there was no robust evidence of improvements in cognition for people living with dementia treated with antihypertensive drugs. Whilst there was a small positive benefit on the MMSE at 6 months, this effect was not replicated at 12 months, nor was the same benefit found on the other measure of cognition in the study (the ADAS-cog). Significant differences in cognition were found between ACE inhibitors and calcium-channel blockers, but this was based on a small study in which it was not clear if participants or assessors were blinded. The committee therefore agreed the balance of the evidence did not suggest a clear positive benefit with antihypertensive drugs, and therefore it was appropriate to include them within the ‘do not offer’ recommendation made. Future research The committee noted that there is currently ongoing research in a number of the drug classes included in this review, looking at long-term effects on cognition in people living with dementia. They therefore agreed it was appropriate to add a caveat to the recommendation, allowing for their use as part of randomised controlled trials. Since much of this research is already ongoing, the committee did not feel it was appropriate to make a specific research recommendation, as no specific intervention was found to be promising enough to justify a positive recommendation for research. |
| Trade-off between net health benefits and resource use | No positive recommendations were made for this review questions, and therefore the committee was not concerned by the lack of economic evidence identified. Furthermore, they agreed that the recommendations made would not result in any increase in resource use. |
| Quality of evidence | The committee noted that all but one of the identified studies only included people living with Alzheimer’s disease. The committee considered that it was unlikely that trial participants had mixed dementias because the diagnostic criteria for Alzheimer’s disease excludes other types of dementia. Furthermore, some of the studies explicitly stated that people were excluded if they had modified Hachinski score greater than 4, ruling out people with a high likelihood of vascular dementia. As a result, it was considered there was insufficient evidence to make recommendations on other types of dementia. In other areas of this guideline, in particular in areas around non-pharmacological interventions, evidence has been extrapolated from Alzheimer’s disease to other forms of dementia, as the committee agreed that there are some situations where people with similar symptoms need the same kinds of support, regardless of the underlying cause of the dementia. However, since the intention of these interventions is specifically to modify disease progression, and this effect is likely to differ based on the underlying disease, it was not appropriate to extrapolate the evidence to other types of dementia in this context. The committee noted the absence of studies evaluating non-pharmacological or behavioural interventions for modifying risk factors like poor diet, obesity, alcohol consumption and smoking. |
| Other considerations | The committee noted that studies that assessed the effect of antidiabetic drugs on dementia progression included people without diabetes at baseline. Abnormal insulin signalling has been identified as a feature of Alzheimer’s disease. As a result, it was considered that these studies focused on poor insulin signalling as a risk factor, rather than diabetes. The committee also noted that studies which assessed whether statins affected cognitive decline in people with Alzheimer’s disease included people without hypercholesterolaemia. Furthermore, some of the studies which assessed the efficacy of antihypertensive medicines included normotensive people (without primary hypertension). The committee agreed it was important to specify in the recommendation that the negative recommendations made only considered the use of these treatments for the purposes of slowing dementia, and people who needed to be treated fora co-morbidity should continue to receive treatment as normal. To clarify this, the committee agreed it was appropriate to cross-refer to the relevant NICE guidelines for the diagnosis and management of diabetes, hypercholesterolaemia and hypertension. |
10.1.6. Recommendations
- 59.
Do not offer the following specifically to slow the progress of Alzheimer’s disease, except as part of a randomised controlled trial:
- diabetes medicines
- hypertension medicines
- statins
- non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin.
- Modifying risk factors for dementia progression - DementiaModifying risk factors for dementia progression - Dementia
- Summary of recommendations - DementiaSummary of recommendations - Dementia
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