evidence based treatment approaches for prevention of dementia

Evidence based treatment options for preventing Dementia

Dr Ravi SoniSenior Resident

Dept. of Geriatric Mental HealthKGMU, LKO

Aim of the discussion

• Reviewing data on emerging therapies for early AD

• What can be done for prevention of cognitive decline or progression of disease?

• What are the feasible options available?

• Systematic reviews

The Future of Alzheimer’s Disease

• Earlier recognition– Dependent on reliable biomarkers

• New medications– Current medications only address symptoms– New medications in development

• Disease-modifying therapy• Combination disease-modifying and symptomatic therapy

• Prevention

Antioxidant Therapies: prevention strategies• Vitamins: vitamin E (α-tocopherol), vitamin C, β- carotene, vitamin B2

• Antioxidant Enzymes: superoxide dismutase (MnSODMitochondrial, Cu/Zn SOD-cytoplasmic), catalase, glutathione peroxidase

• Mitochondrial targeted Antioxidants: vitamin A, carotenoids, vitamin C, and vitamin E and others (α-lipoic acid (LA), coenzymeQ10, NADH, Mito Q, Szeto Schiller (SS) peptide, and glutathione)

• Dietary supplements: omega-3 polyunsaturated fatty acid (docosahexaenoic acid), caffeine, and curry spice curcumin

• Traditional Herbal Antioxidants: three major alkaloids in CoptidisRhizoma-groenlandicine, berberine, and palmatine, silibinin (silybin), a flavonoid derived from the herb milk thistle (Silybummarianum), Ginkgo biloba, ginsenosides isolated from Panax spp. ginseng herb

• Other Antioxidants: Melatonin, Monoamine Oxidase-B Inhibitor (Selegiline), and Oestrogen

Can we prevent or reverse AD?

• Studies are evaluating agents to prevent AD by altering beta amyloid plaque formation– Monoclonal antibodies– Vaccines– BACE inhibitors [B site amyloid precursor protein cleavage

enzyme]– Innate immunity

Targets for Future Therapies

• A– -secretase inhibitors– -secretase inhibitors– Monoclonal antibodies

• Plaque stabilizers• Tau protein• Inflammation• Insulin resistance

A production A aggregation A clearance

tau aggregation or phosphorylation

Clinical trialsFailed Phase 2 Moving to Phase III Phase III

AN-1792 [failed] ACC-01 Lu AE58054 Solanezumab

Bapineuzumab Crenezumab EVP-6124 IVIg

Dimebon

Rosiglitazone

Semagacestat [gamma SE]Tarenflurbil [gamma SE]Tramiprosate

Systematic reviews: prevention of non-cognitively impaired

1. Omega 3 fatty acid for the prevention of cognitive decline and dementia: Authors' conclusions: [2012]

• Direct evidence on the effect of omega-3 PUFA on incident dementia is lacking.

• The available trials showed no benefit of omega-3 PUFA supplementation on cognitive function in cognitively healthy older people.

• Omega-3 PUFA supplementation is generally well tolerated with the most commonly reported side-effect being mild gastrointestinal problems.

• Further studies of longer duration are required. • Longer-term studies may identify greater change in cognitive function in

study participants which may enhance the ability to detect the possible effects of omega-3 PUFA supplementation in preventing cognitive decline in older people

2. Cognition-based interventions for healthy older people and people with mild cognitive impairment: [2011]

Authors' conclusions• There is evidence that cognitive interventions do lead to

performance gains but none of the effects observed could be attributable specifically to cognitive training, as the improvements observed did not exceed the improvement in active control conditions.

• This does not mean that longer, more intense or different interventions might not be effective, but that those which have been reported thus far have only limited effect.

• We therefore suggest more standardized study protocols in order to maximize comparability of studies and to maximize the possibility of data pooling - also in other cognitive domains than memory.

3. Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia: [2009]

Authors' conclusions

• There is no convincing evidence from the trials identified that blood pressure lowering in late-life prevents the development of dementia or cognitive impairment in hypertensive patients with no apparent prior cerebrovascular disease.

• There were significant problems identified with analysing the data, however, due to the number of patients lost to follow-up and the number of placebo patients who received active treatment.

• This introduced bias. • More robust results may be obtained by conducting a meta-

analysis using individual patient data.

4. Statins for the prevention of dementia: [2009]


• There is good evidence from RCTs that statins given in late life to individuals at risk of vascular disease have no effect in preventing AD or dementia.

• Biologically it seems feasible that statins could prevent dementia due to their role in cholesterol reduction and initial evidence from observational studies was very promising.

• Indication bias may have been a factor in these studies however and the evidence from subsequent RCTs has been negative

5. Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people: [2008]

Authors' conclusions• The small number of studies which have been done provide no

consistent evidence either way that folic acid, with or without vitamin B12, has a beneficial effect on cognitive function of unselected healthy or cognitively impaired older people.

• In a preliminary study, folic acid was associated with improvement in the response of people with Alzheimer's disease to cholinesterase inhibitors.

• In another, long-term use appeared to improve the cognitive function of healthy older people with high homocysteine levels.

• More studies are needed on this important issue.

6. Procaine treatments for cognition and dementia: [2010]Authors' conclusions• This review suggests that the evidence for detrimental effects

of procaine and its preparations is stronger than the evidence for benefit in preventing and/or treating dementia or cognitive impairment.

• There is some evidence from older studies that procaine preparations might improve memory in persons without cognitive impairment.

• However, the clear evidence of side effects suggests that the risks might outweigh the benefits.

• In the light of this, the strong marketing claims for procaine preparations should be withdrawn until trials of adequate size, duration and quality have been conducted.

7. Hormone replacement therapy for cognitive function in postmenopausal women: [2008]


• There is good evidence that both ERT and HRT do not prevent cognitive decline in older postmenopausal women when given as short term or longer term (up to five years) therapy.

• There is insufficient evidence to determine whether subgroups of women using specific types of hormone therapy could benefit from treatment.

• It remains to be determined whether factors such as younger age (< 60 years of age), type of menopause (surgical or natural) and type of treatment (type of estrogen with or without a progestagen), mode of delivery (transdermal, oral or intramuscular) and dosage have positive effects at a clinically relevant level.

• In addition, whether the absence or presence of menopausal symptoms can modify treatment effects should be investigated in more detail.

8. Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people: [2008]


• What little evidence there is from controlled trials does not support a beneficial effect of DHEA supplementation on cognitive function of non-demented middle-aged or elderly people.

• There is inconsistent evidence from the controlled trials about adverse effects of DHEA.

• In view of growing public enthusiasm for DHEA supplementation, particularly in the USA, and the theoretical possibility of long-term neuroprotective effects of DHEA there is a need for further high quality trials in which the duration of DHEA treatment is longer than one year, and the number of participants is large enough to provide adequate statistical power. Cognitive outcomes should be assessed in all trials.

9. Effect of the treatment of Type II diabetes mellitus on the development of cognitive impairment and dementia: [2005]


• There is no convincing evidence relating type or intensity of diabetic treatment to the prevention or management of cognitive impairment in Type II diabetes.

• Future research on treatments for diabetes should include standardized assessments of cognitive function as outcome measures.

10. Vitamin B6 for cognition: [2008]Authors' conclusions

• This review found no evidence for short-term benefit from vitamin B6 in improving mood (depression, fatigue and tension symptoms) or cognitive functions.

• For the older people included in one of the two trials included in the review, oral vitamin B6 supplements improved biochemical indices of vitamin B6 status, but potential effects on blood homocysteine levels were not assessed in either study.

• This review found evidence that there is scope for increasing some biochemical indices of vitamin B6 status among older people.

• More randomized controlled trials are needed to explore possible benefits from vitamin B6 supplementation for healthy older people and for those with cognitive impairment or dementia

11. Ginkgo biloba for cognitive impairment and dementia: [2009]


• Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo.

• Many of the early trials used unsatisfactory methods, were small, and publication bias cannot be excluded.

• The evidence that Ginkgo biloba has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unreliable.

Cognitive enhancement: Systematic Reviews

• Aerobic exercise to improve cognitive function in older people without known cognitive impairment: [2013]


• We found no evidence in the available data from RCTs that aerobic physical activities, including those which successfully improve cardiorespiratory fitness, have any cognitive benefit in cognitively healthy older adults.

• Larger studies examining possible moderators are needed to confirm whether or not aerobic training improves cognition

• Carbohydrates for improving the cognitive performance of independent-living older adults with normal cognition or mild cognitive impairment: [2011]

Main results• It involved 44 adults aged 60 to 80 years and compared a glucose drink

with a saccharin drink, given on only a single occasion. • Those receiving the glucose drink were significantly faster in completing

the switching condition of the modified Stroop test (F 1, 41 = 10.47; P < 0.01) compared to those receiving the saccharin drink.

Authors' conclusions• With only one RCT included, there is insufficient evidence to base any

recommendations about the use of any form of carbohydrate for enhancing cognitive performance in older adults with normal cognition or mild cognitive impairment.

• More studies of many different carbohydrates are needed to tease out complex nutritional issues and to further evaluate memory improvement.

• Ginseng for cognition: [2010]Authors' conclusions

• Currently, there is a lack of convincing evidence to show a cognitive enhancing effect of Panax ginseng in healthy participants and no high quality evidence about its efficacy in patients with dementia.

• Randomized, double-blind, placebo-controlled, parallel group trials with large sample sizes are needed to further investigate the effect of ginseng on cognition in different populations, including dementia patients.

Interventions aimed at causes of the disease: Systematic Reviews

• Latrepirdine for Alzheimer's disease: [2015] Anithistaminic drug [dimebon]

Authors' conclusions• Our meta-analysis is limited by the small number of studies,

imprecision, inconsistencies between studies and likelihood of bias.

• Nevertheless, the evidence to date suggests that while not associated with an increased risk of adverse events compared with placebo, there is no effect of latrepirdine on cognition and function in mild-to-moderate AD patients, though there appears to be a modest benefit for behaviour.

• Further studies should investigate the potential benefit of latrepirdine on neuropsychiatric symptoms in AD.

• Metal protein attenuating compounds for the treatment of Alzheimer's dementia: [2014]


• There is an absence of evidence as to whether clioquinol (PBT1) has any positive clinical benefit for patients with AD, or whether the drug is safe.

• We have some concerns about the quality of the study methodology; there was an imbalance in treatment and control groups after randomisation (participants in the active treatment group had a higher mean pre-morbid IQ) and the secondary analyses of results stratified by baseline dementia severity.

• The planned phase III trial of PBT1 has been abandoned and this compound has been withdrawn from development.

• The second trial of PBT2 was more rigorously conducted and showed that after 12 weeks this compound appeared to be safe and well tolerated in people with mild Alzheimer's dementia.

• Larger trials are now required to demonstrate cognitive efficacy

• Metal protein attenuating compounds for the treatment of Alzheimer's dementia: [2014] antifungal drug and antiprotozoal drug

• Has property to act as a chelator to copper and zinc ionsAuthors' conclusions• There is an absence of evidence as to whether clioquinol (PBT1) has any

positive clinical benefit for patients with AD, or whether the drug is safe.• We have some concerns about the quality of the study methodology;

there was an imbalance in treatment and control groups after randomisation (participants in the active treatment group had a higher mean pre-morbid IQ) and the secondary analyses of results stratified by baseline dementia severity.

• The planned phase III trial of PBT1 has been abandoned and this compound has been withdrawn from development. The second trial of PBT2 was more rigorously conducted and showed that after 12 weeks this compound appeared to be safe and well tolerated in people with mild Alzheimer's dementia.

• Larger trials are now required to demonstrate cognitive efficacy

• Thiamine for prevention and treatment of Wernicke-Korsakoff Syndrome in people who abuse alcohol: [2013]


• Evidence from randomised controlled clinical trials is insufficient to guide clinicians in determining the dose, frequency, route or duration of thiamine treatment for prophylaxis against or treatment of WKS due to alcohol abuse.

• Huperzine A for mild cognitive impairment: [2012]: It is a reversible acetylcholinesterase inhibitor and NMDA receptor antagonist that crosses the blood-brain barrier.


• The currently available evidence is insufficient to assess the potential for huperzine A in the treatment of MCI. Randomised double-blind placebo-controlled trials are needed.

• Vitamin E for Alzheimer's dementia and mild cognitive impairment: [2012]


• No convincing evidence that vitamin E is of benefit in the treatment of AD or MCI. Future trials assessing vitamin E treatment in AD should not be restricted to alpha-tocopherol.

• Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer's disease: [2012]


• Based on the studies carried out so far, the efficacy of aspirin, steroid and NSAIDs (traditional NSAIDs and COX-2 inhibitors) is not proven. Therefore, these drugs cannot be recommended for the treatment of AD.

• Ibuprofen for Alzheimer's disease: [2003]

Authors' conclusions• No evidence yet exists from randomized double-blind and

placebo-controlled trials on whether ibuprofen is efficacious for patients diagnosed as having Alzheimer's disease.

• Ibuprofen, like other NSAIDs, has an identifiable and in some instances a significant side-effect profile which may include gastrointestinal bleeding.

• Therefore, it needs to be shown that the benefits of such a treatment outweighs the risk of side effects before ibuprofen can be recommended for people with Alzheimer's disease

• Indomethacin for Alzheimer's disease: [2002]


• On the basis of this one trial and subsequent analysis of data as reported by the authors, indomethacin cannot be recommended for the treatment of mild to moderate severity Alzheimer's disease.

• At doses of 100-150 mg daily, serious side effects will limit its use.

• Aspirin for vascular dementia: [2012]


• There is still no good evidence that aspirin is effective in treating patients with a diagnosis of vascular dementia.

• There is increasing concern that low-dose aspirin is associated with increased risk of haemorrhages.

• Further research is needed to assess the effect of aspirin on cognition, and on other outcomes such as haemorrhages, mortality, institutionalisation and behaviour.

• Vitamin B12 for cognition: [2006]

Authors' conclusions• Evidence of any efficacy of vitamin B12 in improving the

cognitive function of people with dementia and low serum B12 levels is insufficient.

• The included trials (De La Fourniere 1997; Hvas 2004; Seal 2002) were restricted to a small number of patients with Alzheimer's disease and other types of cognitive impairment.

• No trials involving people without dementia or using other definitions of vitamin B12 deficiency were found.

• Nimodipine for primary degenerative, mixed and vascular dementia: [2010]

Authors' conclusions• Nimodipine can be of some benefit in the treatment of patients with

features of dementia due to unclassified disease or to Alzheimer's disease, cerebrovascular disease, or mixed Alzheimer's and cerebrovascular disease.

• It appears to be well tolerated with few side effects. • Data were not available from several trials, a total of more than 500

patients.• A meta-analysis of individual patient data from all trials is desirable. • Dementia is a chronic disorder and the short-term benefits of nimodipine

demonstrated in the trials reviewed do not justify its use as a long-term anti-dementia drug.

• New research must focus on longer term outcomes.

• Zhiling decoction for vascular dementia: [2008]• Zhiling decoction has a fixed composition of 15 Chinese herbs. The properties

of each of these herbs and in combination provide the therapeutic rationale for a possible action of Zhiling decoction in dilating cerebral vessels and increasing cerebral blood flow, as well as reducing serum cholesterol.


• The currently available evidence is insufficient to assess the potential for Zhiling decoction in the treatment of vascular dementia.

• The little objective data concerning the management of Zhiling decoction versus Naofukang suggests that Zhiling decoction may be effective in treating vascular dementia.

• There is no evidence for or against Zhiling as a treatment for vascular dementia.

• Further randomised, double-blind, placebo-controlled trials are urgently needed in order to define the relative efficacy and acceptability of Zhiling in vascular dementia.

• Yizhi capsule for vascular dementia: [2009]• Yizhi capsule is a herbal chinese medicine which is reported to improve

clinical symptoms significantly.


• There is no evidence from randomised controlled trials to support or proscribe against the use of 'Yizhi capsule' as a treatment for vascular dement

• All the systematic reviews are taken from COCHRANE DATABASE OF SYSTEMATIC REVIEWS

• http://www.cochranelibrary.com/cochrane-database-of-systematic-reviews/index.html

evidence based treatment approaches for prevention of dementia

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