Background

Background
Alzheimer's disease (AD) is the most common cause of cognitive impairment in the elderly, with About 6% of people aged over 65 years having some form of dementia; the incidence of AD doubles every five years after the age of 60 years,being rare before this age, and afflicts approximately 4 million people in the US. Dementia is rare before the age of 60 years.

The Memory Disorders
Dementia is a neurological disorder presenting chronic, global, and non-reversible impairment of cerebral function, typically resulting in memory loss (of recent events by initiation), loss of executive function (for example, decision-making ability or ability to sequence complex tasks), and personality changes.

Alzheimer's disease (AD) is considered a type of dementia demonstrating insidious onset and slow deterioration, and involving impairment of speech, motor, personality, and executive function.

Vascular dementia is considered a multi-infarct (multiple areas of brain have been injured due to inadequate blood supply) dementia involving stepwise deterioration of executive function - possibly with language and motor dysfunction - resulting from cerebral arterial occlusion. Vascular dementia usually occurs in the presence of vascular risk factors such as diabetes, hypertension, and smoking, and generally has a more sudden onset and stepwise progression than Alzheimer's disease.

Lewy body dementia is another type of dementia presenting insidious impairment of executive functions with (1) Parkinsonism, (2) visual hallucinations, and (3) fluctuating cognitive abilities, and increased risk of falls and/or autonomic failure.

Screening/Diagnosis
In 2003, the US preventive Services Task Force (USPSTF (2003): Screening for Dementia - Recommendations and Rationale) emphasized the importance of early recognition of cognitive impairment, noting that although current evidence does not support routine screening of otherwise symptomless patients or ones unsuspected of such impairment, nonetheless clinicians should assess cognitive function whenever cognitive impairment or deterioration is indeed suspected, based on direct observation, patient report, or concerns raised by family members, friends, or caretaker.

As to testing, the USPSTF determined that there are "some screening tests have good sensitivity but only fair specificity in detecting cognitive impairment and dementia", and that furthermore after examining the numerous diagnostic tests for AD and dementia available, the Mini-Mental Status Examination (MMSE) is the best-studied instrument for screening for cognitive impairment (for an online version of the Standardized MMSE, see International Psychogeriatric Association (IPA): SMMSE), although (1) the predictive value of a positive result is only fair, and (2) its accuracy depends upon a person's age and educational level. In addition, tests that assess functional limitations rather than cognitive impairment, such as the Functional Activities Questionnaire (FAQ), can detect dementia with sensitivity and specificity comparable to that of the MMSE (for the online FAQ and other AD-diagnostic tests, see IPA: A Guide to the Diagnosis and Assessment of Alzheimer's Disease). See also Karlawish and Clark, Ann Intern Med (2003): Diagnostic Evaluation of Elderly Patients with Mild Memory Problems,

Etiology/Risk Factors
Although the precise cause of Alzheimer's disease is to date unclear, a critical pathological process appears to be the deposition of abnormal amyloid in the central nervous system. In addition, the majority of patients with the relatively rare condition of early onset Alzheimer's disease (onset before age 60) show an autosomal dominant inheritance due to mutations on amyloid precursor protein genes or presenelin; in this connection, the APP, PS-1, and PS-2 genes have been identified. Furthermore ,later onset dementia can demonstrate some clustering in families, although here specific gene mutations have not yet been identified. Head injury, Down's syndrome, and lower premorbid intellect may be risk factors for Alzheimer's disease. Vascular dementia is related to cardiovascular risk factors, such as smoking, hypertension, diabetes, and more recent evidence suggesting also elevated homocysteine levels.

More particularly, Alzheimer's disease appears characterized by (1) the microscopic development of senile plaques between neurons, and (2) neurofibrillary tangles within neurons, which are associated with neuronal destruction, especially in cholinergic neurons.

As to the senile plaques, these are composed of b-amyloid polypeptides, seem to form as a result of disorders in processing b-amyloid and its precursor protein, probably consequent to a combination of both genetic predisposition and environmental influences It is speculated that one of these contributory influences may be subclinical ischemia, given that patients who are hypertensive as well as those with elevated cholesterol levels, tend to be at increased risk for Alzheimer's disease.

As to neurofibrillary tangles, these are partially composed of a protein called tau; tau links together to form filaments, with the density of these filaments within brain neurons being directly related to the severity of dementia. Why tangles form, and whether the tangles are linked to plaque formation, is as yet unclear, although it is known that different alleles of a gene create forms of tau more likely to tangle. However, the ultimate effect of the neurofibrilliary tangle formation is compromise of microtubular function and eventual destruction of the neuron. The involvement of cholinergic neurons in this process causes levels of acetylcholine within synapses to decline, with an accompanying drop in levels of acetylcholinesterase (possibly as compensation for the acetylcholine loss). Along with this is an increase in the the activity of still another cholinesterase enzyme called butyrylcholinesterase, which metabolizes a significant portion of acetylcholine as the disease progresses, eventually, leading to neuron destruction.

One surprising finding concerning AD risk factors has been that although observational studies suggested that hormone therapy might be protective for postmenopausal women against cognitive decline and AD, the results of the Women's Health Initiative Memory Study (WHIMS), a multicentre, randomised, double-blind, placebo-controlled clinical trial, were negative in women age 65 years and older (see WHI (2004): Study Findings (WHIMS) - Conjugated Equine Estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women and Study Findings (WHIMS) - Effects of estrogen plus progestin on cognitive functioning and the risk of developing dementia), leaving open the question of whether HT improves or worsens cognitive function in younger women using HT for the treatment of menopausal symptoms; see Craig et al (Lancet Neurol (2005): The Women's Health Initiative Memory Study: findings and implications for treatment).

Evidencewatch Commentary
However, Evidencewatch notes that the underlying cholinergic hypothesis of AD presents some serious conceptual and methodological problems (see especially Shanks and Venneri (Am J Geriatr Psychiatry (2005): Conventional Trial Designs Offer Limited Clinical Understanding of Cholinesterase-Inhibitor Treatment Effects in Alzheimer Disease), not adequately accounting for the observed clinical evidence of some treated patients deteriorating more rapidly than untreated ones, nor for the manifest wide variations in the presence and extent of individual responses. It may be that studies are collecting highly heterogeneous populations exhibiting marked variation in regional cerebral blood flow, regional atrophy, and modular cognitive dysfunction, and this may be fundamentally confounding.

In addition, the current therapeutic strategy of Alzheimer's disease therapy informing AChEI use is the targeting of cholinergic neurotransmitter pathways. However, autopsy and other pathological findings fail to find predicted cholinergic degeneration in at least 25% of cases, and it may be that such degeneration emerges only after the progression of AD beyond initial stage (Farlow, Geriatrics (2004): NMDA receptor antagonists. A new therapeutic approach for Alzheimer's disease [pdf]), suggesting that the disruption of cholinergic neurotransmission, although undeniably an important function in AD, is nonetheless not the whole story, and other processes involving (1) inflammatory pathways, (2) oxidative injury or stress, and (3) NMDA receptor-mediated glutamate excitotoxicity inducing neuronal loss (as suggested by the evidence for the clinical benefit of NMDA receptor antagonists) may ultimately be more fundamental.

Newer alternative approaches to blocking the pathological accumulation of the neurotoxic amyloid beta peptide in the brain are beginning to emerge: so for instance, passive immunotherapy appears to block cognitive decline in patients with Alzheimer's disease; to date the only preparation of human anti-amyloid beta peptide antibodies reported to reverse cognitive defects in patients with sporadic Alzheimer's disease is polyclonal anti-amyloid beta peptide antibodies contained in human IVIg, but research is in very early stage (see Weksler, Immun Ageing (2004): The immunotherapy of Alzheimer's disease).

The Current Treatment Standard

Acetylcholinesterase Inhibitors
Acetylcholinesterase inhibitors (AChEI), drugs that inhibit the degradation of acetylcholine within synapses, are the mainstay of therapy. Donepezil, rivastigmine, and galantamine are safe but have potentially troublesome cholinergic side effects, including nausea, anorexia, diarrhea, vomiting, and weight loss. These adverse reactions are often self-limited and can be minimized by slow drug titration. Acetylcholinesterase inhibitors appear to be effective, but the magnitude of benefit may be greater in clinical trials than in practice. The drugs clearly improve cognition, but evidence is less robust for benefits in delaying nursing home placement and improving functional ability and behaviors. See Kaycee et al. (JAMA (2005): Pharmacological Treatment of Neuropsychiatric Symptoms of Dementia - A Review of the Evidence), Stanbridge (Clin Ther (2004): Pharmacotherapeutic approaches to the treatment of Alzheimer's disease), Evans et al. (Int J Neuropsychopharmacol (2004): Evidence-based pharmacotherapy of Alzheimer's disease), Delagarza (AAFP (2003): Pharmacologic Treatment of Alzheimer's Disease: An Update).

Most guidelines for monitoring drug therapy in patients with Alzheimer's disease recommend periodic measurements of cognition and functional ability. The guidelines generally advise discontinuing therapy with acetylcholinesterase inhibitors when dementia becomes severe, although the evidence for this practice is not definitive.

Acetylcholinesterase inhibitors (AChEl)
Given that brain acetylcholine activity is reduced in many forms of dementia, with the level of reduction correlating with cognitive impairment, several AD treatments enhance cholinergic activity, notably the use of acetylcholinesterase inhibitors, which inhibit the degradation of acetylcholine within synapses, and which have become the mainstay of AD therapy, being until recently the only available treatment in the United States for patients with mild to moderate AD. For most patients, these inhibitors help maintain cognitive and functional abilities and may also confer beneficial behavioral effects. The balance of the evidence suggests that acetylcholinesterase inhibitors are effective, although as noted the magnitude of benefit is typically greater in clinical trials than in actual practice, and at present the balance of the evidence does not support a finding of significant differences between these agents (López-Pousa et al., Dement Geriatr Cogn Disord (2005): Differential Efficacy of Treatment with Acetylcholinesterase Inhibitors in Patients with Mild and Moderate Alzheimer's Disease over a 6-Month Period). The drugs clearly improve cognition, although their benefits in delaying nursing home placement and improving functional ability and behaviors is not as robustly demonstrated.

The three major acetylcholinesterase inhibitors currently in use are donepezil (Aricept), approved in 1996; rivastigmine (Exelon), approved in 2000, and galantamine (the prescription agent Razadyne, formerly Reminyl, also available as a nonprescription standardized herbal product), approved in 2001, with a fourth tacrine (Cognex), approved in 1993, no longer widely used due to serious adverse effects including liver damage. The three major agents have been demonstrated to be safe (see Lanctot et al, CMAJ (2003): Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis, and AHRQ Evidence Report/Technology Assessment (2004): Pharmacological Treatment of Dementia). Although all may have potentially troublesome cholinergic side effects (nausea, anorexia, diarrhea, vomiting, and weight loss), these adverse reactions are often self-limited with tolerance developing, and can typically be minimized by slow drug titration.

• Donepezil
  The recent Cochrane systematic review (Birks & Harvey, Cochrane Database Syst Rev (2005; last update: 2003): Donepezil for dementia due to Alzheimer's disease) included 16 double-blind randomized controlled trials (RCTs), of 12, 24 or 52 weeks duration, involving 4365 participants, concluded that "people with mild, moderate or severe dementia due to Alzheimer's disease treated for periods of 12, 24 or 52 weeks with donepezil experienced benefits in cognitive function, activities of daily living and behavior".
  
  Clinically, it is critical to initiate therapy early in the course of the disease, as demonstrated by Seltzer et al. (Arch Neurol (2004): Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial) who conclude that there are "significant treatment benefits of donepezil in early-stage AD, supporting the initiation of therapy early in the disease course to improve daily cognitive functioning".
  
  
• Rivastigmine
  One RCT (McKeith et al., Lancet (2000): Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study) and one systematic review of Eight trials, involving 3450 participants (Birks et al., Cochrane Database Syst Rev (2005; last update: 2003): Rivastigmine for Alzheimer's disease) found that rivastigmine improved cognitive function in people with Alzheimer’s disease or Lewy body dementia compared with placebo; adverse effects such as nausea, vomiting, and anorexia were common.
  
  Subgroup analysis from one RCT study (Kumar et al, Eur J Neurol, 2000: An efficacy and safety analysis of Exelon® in Alzheimer's disease patients with concurrent vascular risk factors) in people with Alzheimer’s disease found limited evidence that people with vascular risk factors may respond better to rivastigmine.
  
  Finally, two open label trials shed further light on the role of rivastigmine in AD therapy. One open label RCT in people with mild to moderate Alzheimer’s disease found cognitive function at 12 weeks to not differ significantly between rivastigmine and donepezil, although more patients in the rivastigmine group withdrew from the trial for any cause. In the second Farlow & Lilly (BMC Geriatr (2005): Rivastigmine: an open-label, observational study of safety and effectiveness in treating patients with Alzheimer's disease for up to 5 years) note the limitation that much of the data supporting the safety and efficacy of cholinesterase inhibitors such as rivastigmine are available for treatment up to 1 year, with limited data up to 2 1/2 years; their study found that long-term cholinesterase inhibition therapy with rivastigmine was well tolerated, with no dropouts due to adverse effects past the initial titration period, and that furthermore early initiation of treatment, with titration to high-dose therapy (4–6 mg. bid) may confer some benefit in delaying long-term progression of the disease and its symptoms.
  
  
• Galantamine
  Several RCTs included in a systematic review (Loy & Schneider, Cochrane Database Syst Rev (2006): Galantamine for Alzheimer's Disease) of seven trials with a total of 3777 subjects found that galantamine consistently improved cognitive function and global clinical state over 6 months compared with placebo in people with Alzheimer’s disease or vascular dementia. And In a later two month, open-label extension of an earlier five month, double-blind, placebo-controlled trial with a 6-week withdrawal phase, Lyketsos et al. (Am J Geriatr Psychiatry (2004): Long-Term Outcomes of Galantamine Treatment in Patients With Alzheimer Disease) showed that galantamine treatment was maintained cognitive function up to at least 14 months.
  
  In addition, one of the trials studied found that It appears that doses of 16 mg/d were the best tolerated, and given that this dose showed statistically indistinguishable efficacy with higher doses, it would appear the most most preferable at initiation of therapy.
  
  One single-blind RCT (Wilcock et al, Drugs Aging (2003): A long-term comparison of galantamine and donepezil in the treatment of Alzheimer's disease) found no significant difference between donepezil and galantamine in cognitive function or adverse effects at 1 year. However, Soininen et al. (Int J Geriatr Psychiatry (2004): A multinational, randomised, 12-week study comparing the effects of donepezil and galantamine in patients with mild to moderate Alzheimer's disease) concluded that "physician and caregiver ease of use/satisfaction scores, and assessments of cognition and ADL, showed significant benefits for donepezil compared with galantamine in this direct comparative trial. Both treatments were well tolerated, with more gastrointestinal AEs reported for galantamine vs donepezil". Similarly, R. Bullock (Expert Rev Neurother (2004): Galantamine: use in Alzheimer's disease and related disorders)
  
  But a more recent meta-analysis once again confirmed the equi-efficacy and tolerability of the two agents (Harry & Zakzanis (Hum Psychopharmacol (2005): A comparison of donepezil and galantamine in the treatment of cognitive symptoms of Alzheimer's disease: a meta-analysis).
  
  And although, as the authors note, previous controlled trials have demonstrated galantamine's positive effect on cognition, activities of daily living, behavior and global condition,the study of Bruno Vellas and coresearchers (Curr Med Res Opin (2005): Early onset effects of galantamine treatment on attention in patients with Alzheimer's disease) is the first to suggest that galantamine may specifically improve attention in patients with AD, and consequently was able to improved caregiver stress, time spent caring for patients and patients' interactions with others (see also below our discussion of reduction of caregiver burden).
  
  Studies in progress studies are to examine this head-to-head comparison further, and Evidencewatch will report on them as they appear. In this connection, it is worth considering the recent thoughtful commentary of Shanks and Venneri (Am J Geriatr Psychiatry (2005): Conventional Trial Designs Offer Limited Clinical Understanding of Cholinesterase-Inhibitor Treatment Effects in Alzheimer Disease) concerning the profound methodological problems inherent in both testing for Alzheimer's disease and in the study of therapeutic agents, especially acetylcholinesterase inhibitors (see out remarks above).
  
  (new) Galantamine-ER (Extended Release)
  A once-daily extended-release galantamine formulation, galantamine-ER, can improve tolerability compared with twice-daily immediate-release galantamine (galantamine-IR): galantamine-ER was associated with a significantly lower percentage of days with nausea than the immediate release formulation among subjects reporting nausea, and subjects with nausea or vomiting receiving galantamine-ER reported significantly less antiemetic use than those treated with galantamine-IR (F Dunbar et al, Clin Ther (2006): Post hoc comparison of daily rates of nausea and vomiting with once- and twice-daily galantamine from a double-blind, placebo-controlled, parallel-group, 6-month study).
  
  Galantamine and Reduction of Caregiver Burden
  Systematic review and meta-analyses of large-scale clinical trials have shown that galantamine administration for patients with Alzheimer’s disease can reduce the amount of time caregivers spend supervising their patients and assisting
  them with ADL (activities of daily living), easing the daily burden for caregivers. The beneficial effects of galantamine on behavioral symptoms result in a reduction in caregivers’ emotional distress, in part from the fact that galantamine neither causes nor exacerbates sleep disturbances, in addition to its other positive benefits for patients: preservation of cognition, function, and behavior, thus maintaining quality of life for both patients with Alzheimer’s disease and their caregivers (Kaufer et al., CNS Spectrum (2005): Reduction of Caregiver Burden
  in Alzheimer’s Disease by Treatment with Galantamine [pdf]).
  
  As noted above, galantamine is also available as nonprescription herbal phytonutrient extracted primarily from the common snowdrop (Galanthus nivalis), daffodil (Narcissus pseudonarcissus L.), and spider lily (Lycoris radiata).
  
  
• Memantine
  Memantine (Namenda (USA), Exiba, Axura) is a recently approved (October 2003) new class of agent, an NMDA (N-methyl-D-aspartate) receptor antagonist, regulating the activity of glutamate (glutamic acid), an amino acid with an essential role in in the neural pathways associated with learning and memory. Memantine's benefits in Alzheimer's disease is thought to be via partially blocking NMDA receptors to protect cells against excess glutamate overstimulation of NMDA receptors (which leads to neuronal cell dysfunction / disruption and cell death), an action wholly distinct from the acetylcholine boosting mechanism of the acetylcholinesterase inhibitors.
  
  The evidence shows that patients on memantine scored higher on measures of cognition, daily function (activities of daily living - eating, walking, toileting, bathing and dressing) and global performance, with relatively mild side effects (typically, dizziness, confusion, headache and constipation), compared to those on placebo.
  
  Numerous clinical studies (see the systematic review of seven RCTs (1532 people) of Areosa et al. (Cochrane Database Syst Rev (2005; last update 2004): Memantine for Dementia) have demonstrated memantine's efficacy in Alzheimer's disease, both as monotherapy, and in dual therapy in patients on continuous donepezil therapy, and it demonstrates significant improvement of cognitive performance in vascular dementia. In addition, its safety and tolerability are exceptional, with incidence of premature withdrawals from adverse events no greater than placebo, and overall low incidence of any total adverse events.
  
  And the 2006 Cochrane review update (McShane et al., Cochrane Database Syst Rev (2006): Memantine for dementia) confirmed a small but significant beneficial effect of memantine on cognition, activities of daily living, and behavior, supported by clinical impression of change, in moderate to severe Alzheimer's disease, while in mild to moderate disease there was evidence of a marginal beneficial effect at six months on intention-to-treat cognition which was barely detectable clinically, with no effect on behaviour, activities of daily living or observed-case analysis of cognition; in addition, patients taking memantine were slightly less likely to develop agitation in both mild to moderate and moderate to severe disease, but no evidence either way about whether it has an effect on already-present agitation. However, more recently, the limitation of memantine to the moderate to severe setting has been questioned: Elaine Peskind and coresearchers assessed the safety and efficacy of memantine in patients with mild to moderate Alzheimer's disease, finding that memantine resulted in significantly better outcomes than placebo on measures of cognition, global status, and behavior, and with good tolerability (Am J Geriatr Psychiatry (2006): Memantine Treatment in Mild to Moderate Alzheimer Disease: A 24-Week Randomized, Controlled Trial).
  
  Gauthier et al. (Int J Geriatr Psychiatry (2005): Effects of memantine on behavioural symptoms in Alzheimer's disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomised, controlled studies) found that memantine has a beneficial effect on the behavioral symptoms of patients with moderate to severe AD, exhibiting its most pronounced effect on agitation/aggression. And Heinen-Kammerer et al. (Clin Drug Investig (2006): Added therapeutic value of memantine in the treatment of moderate to severe Alzheimer's disease) conducted a systematic literature review that concluded a benefit for memantine in comparison with placebo in terms of (1) a decrease in nursing care, (2) a delay in care dependency and (3) a delay in admission to nursing homes, with an observed increase in quality of life.
  
  Memantine has been available in Germany since 1982 with no reports of serious adverse events, and was approved in 2002 by the European Medicines Agency (EMEA) for the treatment of moderately severe to severe Alzheimer's disease, with comparable approval in the US in 2003 for the treatment of moderate to severe Alzheimer's disease.
  
  (new) Combination Therapies with Memantine
  One new development with memantine is combination therapy with cholinesterase inhibitors; thus Tariot et al. (JAMA (2004): Memantine Treatment in Patients With Moderate to Severe Alzheimer Disease Already Receiving Donepezil - A Randomized Controlled Trial) have demonstrated the efficacy of memantine in patients receiving donepezil, memantine showing more sustained efficacy in this combination or dual therapy (see also MR Fallow, Expert Rev Neurother (2004): Utilizing combination therapy in the treatment of Alzheimer's disease). This agrees with the conclusions of the systematic review of Kirby et al. (Drugs Aging (2006): A systematic review of the clinical and cost-effectiveness of memantine in patients with moderately severe to severe Alzheimer's disease) which found that memantine appeared to be slightly more effective in patients already receiving a stable dose of donepezil.
  
  Another promising development is that of second-generation memantine derivatives designed specifically to enhance neuroprotective efficacy without compromising safety, with considerable research centering on the NitroMemantines which appear to be substantially more effective than memantine itself (Lipton, Neurorx (2004): Failures and Successes of NMDA Receptor Antagonists: Molecular Basis for the Use of Open-Channel Blockers like Memantine in the Treatment of Acute and Chronic Neurologic Insults).
  
  (new) Memantine + Galantamine
  The potential to modulate in Alzheimer's disease both acetylcholine and glutamate pathways by galantamine and memantine, respectively, presents a novel treatment strategy for the management of mild to moderately severe Alzheimer's disease, based on pharmacokinetic and pharmacodynamic as well as ongoing observation studies (as noted by George Grossberg et al., J Clin Pharmacol (2006): Rationale for Combination Therapy With Galantamine and Memantine in Alzheimer's Disease), and galantamine, among the other acetylcholinesterase (AChE) inhibitors (AChEIs), is of particular interest because of its dual mechanism of action, postulated to be both an AChEI and an allosteric modulator of nicotinic receptors, the latter activity therefore overlapping with the modulation of NMDA (N-methyl-D-aspartate) and nicotinic receptors that is the scope of memantine's own activity; thus modulation of NMDA and nicotinic receptors by memantine and galantamine, as well as of the acetylcholine pathway, with galantamine augmenting memantine's glutamatergic noise suppression while simultaneously enhancing the physiologic glutamatergic signal, may provide an optimal combination therapy for Alzheimer's disease, especially as cholinergic and glutamatergic neurotransmitter systems appear to share a close functional relationship and role in the pathogenesis of Alzheimer's (see Hugo Geerts & George Grossberg, J Clin Pharmacol (2006): Pharmacology of Acetylcholinesterase Inhibitors and N-methyl-D-aspartate Receptors for Combination Therapy in the Treatment of Alzheimer's Disease).
  
  Are AChEIs Effective? - The Controversy
  
• The Case Against Efficacy
  Recently a controversy has developed around the issue of whether the AChEIs ([acetyl]cholinesterase inhibitors: donepezil, rivastigmine, and galantamine) demonstrate sufficient sound scientific evidentiary foundation to recommend them for the treatment of Alzheimer's Disease/Dementia. Several studies and one national development (in the UK) have been the focal point of the controversy.
  
  An earlier systematic review by German researchers Kaduszkiewicz et al. (Fortschr Neurol Psychiatr (2004): Doubtful Evidence for the Use of the Cholinesterase Inhibitor Donepezil in Patients with Dementia - a Systematic Review [in German: Fragliche Evidenz für den Einsatz des Cholinesterasehemmers Donepezil bei Alzheimer-Demenz - eine systematische Übersichtsarbeit]) drew two conclusions : (1) that the evidence for the use of donepezil in moderate to severe Alzheimer's Disease is lacking due to, according to the researchers, severe methodological deficiencies; (2) that the clinical relevance of the postulated positive results [of efficacy of the cholinesterase inhibitors in the treatment of Alzheimer's Disease] would have to be questioned even if the trials had been conducted in a methodologically sound fashion.
  
  These controversial conclusions were followed by their more recent systematic review (Kaduszkiewicz et al., BMJ (2005): Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials) which concluded after review of 22 RCTs that the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer's disease is questionable due to (a) flawed methodology and (b) small clinical benefits (similarly, Therapeutics Initiative (Therapeutics Letter (2005): Drugs for Alzheimer's Disease) concluded that donepezil has not been demonstrated to improve outcomes of importance to patients and caregivers (e.g. institutionalization or disability), while rivastigmine and galantamine have not been studied for these outcomes). Evidencewatch has reviewed the conclusions of Kaduszkiewicz et al., and as we discuss below, we suggest that the conclusions themselves are in error primarily due to their own severe methodological deficiencies.
  
  In or around the same time, the UK authority NICE (National Institute for Health and Clinical Excellence), responsible for providing national evidence-based health guidance within the NHS (National Health Service) in England and Wales, reviewed the data available on the clinical and cost effectiveness of AChEI inhibitors (donepezil, rivastigmine and galantamine) and memantine, released three preliminary recommendations in March 2005 (NICE (2005): Appraisal Consultation Document: Alzheimer's disease - donepezil, rivastigmine, galantamine and memantine (review)), pending completion and publication of final guidance in February 2007: (1) donepezil, rivastigmine and galantamine are not recommended for use in the treatment of mild to moderate Alzheimer’s disease (AD); (2) memantine is not recommended for the treatment of moderately severe to severe AD, except as part of ongoing or new clinical studies that are designed to generate robust and relevant data on long-term outcomes, disease progression, quality of life and costs; (3) people currently receiving donepezil, rivastigmine, galantamine and memantine, whether as routine therapy or as part of a clinical trial, may be continued on therapy (including at the conclusion of a clinical trial) until it is considered appropriate to stop. See also the confidential document of 2/28/05 produced by the Southampton Health Technology Assessments Centre (Loveman et al., HTA (2005): Technology assessment report commissioned by the HTA Programme on behalf of The National Institute for Clinical Excellence: The Clinical and Cost-Effectiveness of Donepezil, Rivastigmine, Galantamine, and Memantine for Alzheimer’s Disease [pdf]).
  
  Note that these preliminary recommendations essentially represent the withdrawal of the previous NICE guidance in favor of the use of donepezil (Aricept) rivastigmine (Exelon) and galantamine ( Razadyne, formerly Reminyl) mild to moderate Alzheimer's disease (AD) under prescribed circumstances (NICE (2001): Drugs for Alzheimer's Disease - full guidance).
  
  
• (updated) The Case for Efficacy
  It is imperative however to understand that NICE found in favor of the clinical efficacy of the cholinesterase inhibitors in mild to moderate Alzheimer's Disease and of memantine in moderately severe to severe Alzheimer's disease, but disputes only their cost effectiveness (note an earlier study of donepezil alone, the so-called AD2000 study from the AD2000 Collaborative Group (Courtney et al., Lancet (2004): Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial), also concluded that it is not cost effective, with benefits below minimally relevant thresholds, and went on to state that more effective treatments than cholinesterase inhibitors are needed for Alzheimer's disease). And Kaiser et al. (Med Klin (Munich) (2005): Donepezil in Patients with Alzheimers Disease—a Critical Appraisal of the AD2000 Study, in German: Donepezil bei Patienten mit Alzheimer-Demenz Die AD2000-Studie). Donepezil in Patients with Alzheimers Disease - a Critical Appraisal of the AD2000 Study) despite questioning the validity of the AD2000 trial on the basis of its low statistical power to detect a significant difference between both treatments, and also because no true intention-to-treat analysis based on the first randomization was presented, nonetheless concluded that the beneficial effects on patient-relevant outcomes, and consequently the widespread use of cholinesterase inhibitors in patients with Alzheimer's disease, is not supported by current evidence.
  
  Evidencewatch notes further that the assessment of the cost effectiveness of galantamine was solely based of the prescription item (as Razadyne, formerly Reminyl, from Janssen-Ortho, hereafter galantamine-prescription); unrecognized by NICE is the fact that galantamine is alternatively available in equivalent pharmaceutical grade as the OTC (over-the-counter) herbal galantamine (galanatamine-OTC) but at approximately one third of the cost of the prescription item, and we would argue based on the AHEAD modeling framework used by NICE for determining cost effectiveness, that galantamine-OTC, against the other agents and against galantamine-prescription, if considered would have demonstrated both clinical efficacy and cost effectiveness, and therefore even if all other findings of NICE are uncontested, their conclusion on the status of galantamine is in error.
  
  Alzheimer's, Cholinesterase Inhibitors, and Down's Syndrome
  In addition, NICE has failed to take into consideration the impact on Down's Syndrome populations of the removal of approval for use of cholinesterase inhibitors in the treatment of Alzheimer's disease. It is well established that (1) Down syndrome patients, after the fourth decade of life, display some neuropathological features of the Alzheimer's disease (Folin et al., Int J Mol Med (2003): The impact of risk factors of Alzheimer's disease in the Down syndrome [pdf]) - almost all adults over the age of 40 years with Down's syndrome display Alzheimer's neuropathology, and that (2) more than a half of patients with Down's Syndrome above 50 years develop Alzheimer's disease (M Menéndez, Brain Dev (2005): Down syndrome, Alzheimer's disease and seizures; see also Stanton & Coetzee, Advan. Psychiatr. Treat (2004): Down’s syndrome and dementia, and Holland et al., Br J Psychiatry (1998): Population-based study of the prevalence and presentation of dementia in adults with Down's syndrome).
  
  Indeed, studies have shown that the prevalence of Alzheimer's disease in those with learning disability in general is higher than in those with no learning disability (Patel et al. (Br J Psychiatry (1993): Psychiatric morbidity in older people with moderate and severe learning disability. II: The prevalence study, and Shamas-Ud-Din, Br J Psychiatry (2002): Genetics of Down's syndrome and Alzheimer's disease). Furthermore, the cholinesterase inhibitors appear to offer some benefit to these populations (Prasher et al., Int J Geriatr Psychiatry (2002): A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Down syndrome and Alzheimer's disease - pilot study, Kondoh et al., Ann Pharmacother (2005): Dramatic improvement in Down syndrome-associated cognitive impairment with donepezil, Prasher et al., Int J Geriatr Psychiatry (2005): Review of donepezil, rivastigmine, galantamine and memantine for the treatment of dementia in Alzheimer's disease in adults with Down syndrome: implications for the intellectual disability population), and therefore both Arshad et al. (Br J Psychiatry (2001): Treatment for Alzheimer's disease in people with learning disabilities: NICE guidance) and Dolman & Poon (BMJ (2005): Acetylcholinesterase inhibitors for people with Down's Syndrome and Alzheimer's dementia [Rapid Response to: Kaduszkiewicz et al.) have expressed concerned about the fact that this population, with a high prevalence of dementia, has been to date ignored within the guidance of the UK NICE authority.
  
  Systematic Reviews & Meta-analyses - Efficacy: Cochrane
  There are several problems associated with the Kaduszkiewicz et al. study, the most global being that it appears against the evidence of many high-quality systematic reviews and meta-analysis: among these, the Cochrane reviews. Birks & Harvey, (Cochrane Database Syst Rev (2003): Donepezil for dementia due to Alzheimer's disease (Cochrane Review)), found that people with mild, moderate or severe dementia due to Alzheimer's disease treated for periods of 12, 24 or 52 weeks with donepezil experienced benefits in cognitive function, activities of daily living and behavior, and although no significant changes were measured on a patient-rated quality of life scales, the researchers note that the instrument used was crude and possibly unsuited to the task, and in addition although more evidence is still needed for the economic efficacy of donepezil, clinical efficacy is confirmed. Birks et al., Cochrane Database Syst Rev (2000): Rivastigmine for Alzheimer's disease (Cochrane Review)), found that rivastigmine appears to be beneficial for people with mild to moderate Alzheimer's disease, with comparisons with placebo showing improvements in cognitive function, activities of daily living, and severity of dementia with daily doses of 6 to 12 mg. Loy & Schnieder (Cochrane Database Syst Rev (2006): Galantamine for Alzheimer's disease (Cochrane Review)), found consistent positive effects for galantamine for trials of 3 to 6 months duration for doses above 8mg/d for mildly to moderately impaired outpatients (although galantamine's effect on more severely impaired subjects has not yet been assessed), and galantamine's safety profile is similar to that of other cholinesterase inhibitors with respect to cholinergically mediated gastrointestinal symptoms, with doses of 16 mg/d best tolerated, and with this dose showing statistically indistinguishable efficacy with higher doses, and finally, that longer term use of galantamine has not been assessed in a controlled fashion, and galantamine's effect on more severely impaired subjects has not yet been assessed. Areosa et al. (Cochrane Database Syst Rev (2005): Memantine for dementia (Cochrane Review)), found a small beneficial effect of memantine at six months in moderate to severe Alzheimer's disease but the beneficial effect on cognition in patients with mild to moderate vascular dementia was not detectable on global assessment at six months; whether memantine has any effect in mild to moderate Alzheimer's disease is unknown.
  
  Systematic Reviews & Meta-analyses - Efficacy: Other
  Other high-quality systematic reviews and meta-analysis attesting to the efficacy of the cholinesterase inhibitors and memantine: Forchetti (Prim Care Companion J Clin Psychiatry (2005): Treating patients with moderate to severe Alzheimer's disease: implications of recent pharmacologic studies [pdf]) found that RCT studies demonstrate that patients patients with moderate to severe Alzheimer's disease treated with donepezil monotherapy showed improved cognition, stabilized function, and improved behavioral symptoms, while those treated with memantine monotherapy showed less than expected decline in cognition, function, and behavioral symptoms, and those receiving memantine treatment adjunctive to stable, long-term donepezil treatment derived cognitive, functional, and behavioral benefits from the addon therapy. Fillit & Hill (Am J Geriatr Pharmacother (2005): Economics of dementia and pharmacoeconomics of dementia therapy) found that therapies that are efficacious early in the disease can postpone the progression of dementia to more severe stages and may offer economic benefit to patients' families, caregivers, and society. Farlow et al. (Dement Geriatr Cogn Disord (2005): Efficacy of Rivastigmine in Alzheimer's Disease Patients with Rapid Disease Progression: Results of a Meta-Analysis) found that patients experiencing rapid symptom progression may receive greater benefit from rivastigmine than those with slow progression. Doody (Geriatrics (2005): Refining treatment guidelines in Alzheimer's disease [pdf]) found from pivotal clinical trial data on memantine in the treatment of moderate-to-severe Alzheimer's disease that memantine, both alone and in combination with donepezil, was associated with positive, clinically relevant effects on cognitive and functional ability and that further, memantine in combination with donepezil also was significantly better than donepezil alone in management of behavioral symptoms. Xiong (Geriatrics (2005): Combination drug therapy for Alzheimer's disease: what is evidence-based, and what is not? [pdf]) found that to date, the best evidence-based combination strategy is for moderate-to-severe Alzheimer's disease, in which adding memantine to stable donepezil therapy was found to benefit cognition, behavior, and function, although In milder stages, the benefit of combination drug therapy has not been demonstrated. Lingler et al. (J Am Geriatr Soc (2005): Caregiver-Specific Outcomes in Antidementia Clinical Drug Trials: A Systematic Review and Meta-Analysis) found that cholinesterase inhibitors have a small beneficial effect on burden and active time use among caregivers of persons with Alzheimer's disease). Gauthier et al. (Int J Geriatr Psychiatry (2005): Effects of memantine on behavioural symptoms in Alzheimer's disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomised, controlled studies) found that memantine has a beneficial effect on the behavioral symptoms of patients with moderate to severe AD, with the most pronounced effect on agitation/aggression. Passmore et al. (J Neurol Sci (2005): Cognitive, global, and functional benefits of donepezil in Alzheimer's disease and vascular dementia: results from large-scale clinical trials) found that donepezil is effective and well tolerated in both types Alzheimer's disease and vascular dementia.
  
  (new) And Sophie Gillette-Guyonnet and colleagues investigated the effect of cholinesterase inhibitors on three clinically relevant domains (rapid cognitive decline, institutionalization, and weight loss) in patients with Alzheimer's disease, in the unique environment of all patients having been recruited and followed in the same center, with the same management care plan, and the same medical team, finding that the risk of rapid cognitive deterioration was significantly decreased in patients taking cholinesterase inhibitors for at least 1 year compared to untreated patients, with a potential benefit of cholinesterase inhibitors use also found on institutionalization and weight loss after 1 year of follow-up, thus demonstrating a clinically significant improvement in patient outcome over time (J Gerontol A Biol Sci Med Sci (2006): Outcome of Alzheimer's Disease: Potential Impact of Cholinesterase Inhibitors).
  
  (new) Similarly, Pierre Tariot, an Alzheimer's specialist at the University of Rochester Medical Center in New York, recently reviewed the efficacy issue, finding that (1) although memantine is currently the only agent approved for use in the moderate to severe setting, monotherapy regimens involving a ChEI or memantine have been shown to slow the progression of cognitive symptoms in patients with Alzheimer's disease; (2) combination therapy involving memantine plus a cholinesterase inhibitor yields increased cognitive benefits relative to cholinesterase inhibitor monotherapy, thought to be attributable to the distinct therapeutic mechanisms associated with NMDA receptor open-channel antagonists and cholinesterase inhibitors; (3) the therapeutic effects of these antidementia agents are not limited to cognition, also improving outcomes related to patient functioning and behavior, two domains of likely great significance for patients and caregivers; (4) antidementia agents may significantly delay nursing home placement; and (5) that in summary, both cholinesterase inhibitors and memantine provide substantial benefits extending across the spectrum of symptoms of Alzheimer's disease, improving outcomes for those affected by this debilitating condition, either directly or indirectly (P Tariot, J Clin Pyschiatry (2006): Contemporary issues in the treatment of Alzheimer's disease: tangible benefits of current therapies).
  
  The Methodological Deficiencies of Kaduszkiewicz
  Kaduszkiewicz et al. criticize the Cochrane research on a number of grounds. One claim is that there is no correction for multiple outcomes. But as Jacqueline Birks (Coordinating Editor of the Cochrane Dementia and Cognitive Improvement Group, and herself a medical statistician) points out (BMJ (2005): The Cochrane reviews of the cholinesterase inhibitors [Rapid Response to: Kaduszkiewicz et al.), nearly all trials surveyed by Cochrane show a significant effect for the drug for the primary outcomes, which are also highly significant in the meta-analyses, so that no correction for multiple comparisons would change this in any way. Furthermore, even if a post hoc adjustment for multiple comparisons in the absence of pre-specified primary outcomes, like the well-known Bonferroni correction (also known as Fisher's method of alpha splitting), were applied to the multiple pooled outcomes in the Cochrane meta-analyses, the effects of cholinesterase inhibitors would remain statistically significant (as noted by McShane & Schneider (also Coordinating Editors of the Cochrane Dementia and Cognitive Improvement Group), BMJ (2005): The baby has been thrown out with the bath water [Rapid Response to: Kaduszkiewicz et al. Furthermore, going beyond McShane & Schneider's observation concerning the Bonferroni correction, Evidencewatch has confirmed that neither under Bonferroni correction nor naïve Monte Carlo simulation applied to the multiple pooled outcomes in the Cochrane meta-analyses is the conclusion of statistical significance for the positive effects of cholinesterase inhibitors on Alzheimer's disease materially affected.
  
  (updated) Alzheimer's Watch:
  Conclusions on the Value / Efficacy of Current AD Therapies
  In sum, therefore, Evidencewatch has (1) reviewed the arguments of Kaduszkiewicz et al. with respect to putative deficiencies in the Cochrane meta-analyses of the efficacy of the cholinesterase inhibitors in the treatment of Alzheimer's disease, and does not find these arguments cogent, resting on misperceptions of and illicit deductions from that literature, moreover having successfully been responded to and refuted by Birks, McShane and Schneider (see above), and furthermore (2) we find these arguments against the balance of the evidence of the collective weight and findings of numerous independent methodologically high-quality systematic reviews and meta-analyses, cited above, and for these reasons Evidencewatch concludes upon the best evidence that both the cholinesterase inhibitors and memantine have demonstrated efficacy in the treatment of Alzheimer's disease / dementia.

(updated) Ginkgo
There is some evidence for the benefit of standardized Ginkgo biloba extract EGb 761 in improved cognitive function over 24–26 weeks compared with placebo in people with Alzheimer’s disease or vascular dementia: see Ahlemeyer & Krieglstein, Pharmacopsychiatry (2003): Pharmacological studies supporting the therapeutic use of Ginkgo biloba extract for Alzheimer's disease and Andrieu et al., J Gerontol A Biol SCI Med SCI (2003): Association of Alzheimer's disease onset with ginkgo biloba and other symptomatic cognitive treatments in a population of women aged 75 years and older from the EPIDOS study).

Evidencewatch Commentary: Gingko
Although it is often stated by clinicians that herbal nonprescription Ginkgo products differ in purity and concentrations of active ingredients compared with the high purity extract (EGb 761 used in most RCTs, Evidencewatch notes that some quality herbal providers do indeed market this formulation (for example, in the US, Life Extension Foundation (LEF)).

In addition, rigorous systematic reviews have found for the efficacy of Gingko biloba as demonstrating statistically significant mild effectiveness in the treatment of cognitive deficit in Alzheimer's disease (Birks & Grimley, Cochrane Database Syst Rev (2002): Ginkgo biloba for cognitive impairment and dementia); see also Santos-Neto et al., eCAM (2006): The Use of Herbal Medicine in Alzheimer's Disease—A Systematic Review), although it has remained until recently whether besides benefiting cognitive deficit, Ginkgo reduces the actual development of Alzheimer's. Fortunately, precisely this question has been addressed in the RCT by researchers from the Catholic University of Sacred Heart (Mazza et al., Eur J Neurol (2006): Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study) who assessed the efficacy of the Ginkgo biloba special extract Flavogin (160 mg/daily), from Baif International (Italy)), an EGb 761 formulation, in patients with Alzheimer type mild to moderate dementia in slowing down the disease's degenerative progression and the patients' cognitive impairment compared with 5 mg/daily donepezil (Aricept), and placebo. The study found no evidence of relevant differences in the efficacy of Flavogin/EGb 761 and donepezil in the treatment of mild to moderate Alzheimer's dementia.

Evidencewatch Commentary:
Issue of Safety of Gingko
Although numerous case reports have alluded to potential hemorrhagic adverse events from the intake of Gingko biloba preparations, postulated on its activity with platelet aggregation and blood coagulation, no studies of sufficient methodological power provide any confirmation to these largely anecdotal speculations, and the matter has been decisively address by the recent RCT of Kohler et al. (Blood Coagul Fibrinolysis (2004): Influence of a 7-day treatment with Ginkgo biloba special extract EGb 761 on bleeding time and coagulation: a randomized, placebo-controlled, double-blind study in healthy volunteers ) who investigated the influence of the Ginkgo biloba special extract EGb 761 on hemostasiological parameters, finding that among the 29 coagulation and bleeding parameters they assessed, "none showed any evidence of an inhibition of blood coagulation and platelet aggregation through EGb 761. Furthermore, the study did not reveal any evidence to substantiate a causal relationship between the administration of EGb 761 and hemorrhagic complications."

(new) Melissa
The chemical composition of the essential oil of Melissa (M. officinalis) / lemon balm extracts includes monoterpene aldehydes, polyphenol flavonoids (including rosmarinic acid) and monoterpene glycosides, all of which exhibit, in vitro, powerful anti-oxidative activity Hohmann et al., Planta Med (1999): Protective effects of the aerial parts of Salvia officinalis, Melissa officinalis and Lavandula angustifolia and their constituents against enzyme-dependent and enzyme independent lipid peroxidation) and an affinity to nicotinic and muscarinic receptor in the human cerebral cortex (Wake et al., J Ethnopharmacol (2000): CNS acetylcholine receptor activity in European medicinal plants traditionally used to improve failing memory), an affinity whose modulation of cholinergic systems should aid in improving cognitive function, especially in Alzheimer's disease.

Melissa has demonstrated reduction of cognitive deficits in patients with Alzheimer's, and with a good sedative effect in addition (Akhondzadeh et al., J Neurol Neurosurg Psychiatr (2003): Melissa officinalis extract in the treatment of patients with mild to moderate Alzheimer’s disease: a double blind, randomised, placebo controlled trial). Earlier clinical studies found that M. officinalis extract reduces laboratory-induced stress (Kennedy et al., Psychosom Med (2004): Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (lemon balm)), and hence may be of potential benefit in mood improvement (Kennedy et al., Pharmacol Biochem Behav (2002): Modulation of mood and cognitive performance following acute administration of Melissa officinalis (lemon balm); Ballard et al., J Clin Psychiatr (2002): Aromatherapy as a safe and effective treatment for the management of agitation in severe dementia: the results of a double blind, placebo controlled trial; Kennedy et al., Neuropsychopharmacology (2003: Modulation of mood and cognitive performance following administration of single doses of Melissa officinalis (Lemon balm) with human CNS nicotinic and muscarinic receptor binding properties)). However, the assessment of Clive Holmes and Clive Ballard (Adv Psychiat Treat (2004): Aromatherapy in dementia) quite sensibly notes that aromatherapy by itself should not be seen as a safe alternative to existing pharmacotherapy until properly conducted safety trials have been completed and and more well-designed, large-scale, randomised controlled trials on the effectiveness of aromatherapy are conducted.

The culinary herb sage (Salvia officinalis) may be effective for patients with mild to moderate Alzheimer's disease (AD), as found by Teresa Luvone and colleagues at the University of Naples (J Pharmacol Exp Ther (2006): The Spice Sage and Its Active Ingredient Rosmarinic Acid Protect PC12 Cells from Amyloid- Peptide-Induced Neurotoxicity); it appears that rosmarinic acid could contribute, at least in part, for sage-induced neuroprotective effect.

Vitamin E
One RCT (Sano, in N Engl J Med (1967): A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study ) in people with moderate to severe Alzheimer’s disease found limited evidence of the lack of significant difference in cognitive function between vitamin E and placebo after 2 years’ treatment, although it did find limited evidence that vitamin E reduced mortality, institutionalization, loss of ability to perform activities of daily living, and the proportion of people who developed severe dementia.

More recently, Helmer et al. (Eur J Clin Nutr (2003): Association between antioxidant nutritional indicators and the incidence of dementia: results from the PAQUID prospective cohort study ) have found that subjects with low plasma vitamin E concentrations are at a higher risk of developing a dementia in subsequent years.

Evidencewatch Commentary: Vitamin E
Note that quite recently there has been concern over high-dose Vitamin E and increased mortality risk, as per Miller et al. (Ann Intern Med (2005): Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality ). However, in this study the reviewed trials testing high dosages were of adults with chronic diseases, and therefore these findings cannot viably be seen as generalizable to healthy adults; further research is required to be dispositive on this issue.

(new) Folate and B Vitamins
Both elevated blood concentrations of homocysteine, and low-normal concentrations of the B vitamins B-12 and B-6 and folate are candidate risk factors for Alzheimer's disease (AD Smith, Nutr Health (2006: Prevention of dementia: a role for B vitamins?). Smith's review of 77 cross-sectional studies on > 34,000 subjects and 33 prospective studies on > 12,000 subjects in the literature up to the end of 2005 found (1) associations between cognitive deficit or dementia and homocysteine and/or B vitamins, and (2) that elevated plasma total homocysteine is a strong prognostic marker of future cognitive decline.

(updated) NSAIDs
Recent research in Alzheimer's disease and dementia has sought to understand and elucidate the inflammatory pathways involved in Alzheimers disease, and the alteration or inhibition of these pathways, the latter seen as a potential therapeutic intervention targeting the underlying cause of Alzheimer's disease rather than its symptoms, unlike the current use of the acetylcholinesterase inhibitors to prolong cognitive function through increased synaptic activity, without however providing underlying neuroprotection, that is, prevention of neuronal death (Stuchbury & Münch, J Neural Transm (2005): Alzheimer's associated inflammation, potential drug targets and future therapies ).

In this connection, early laboratory evidence as well as some observational epidemiological studies suggest that NSAIDs (nonsteroidal anti-inflammatory drugs) might prevent the onset of Alzheimer's disease. Etminan et al. (BMJ (2003): Effect of nonsteroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies )

Pursuing these investigations, Szekely et al. (Neuroepidemiology (2004): Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer's disease: a systematic review ) found that based on analysis of prospective and nonprospective studies, NSAID exposure was associated with decreased risk of Alzheimer's disease.

But Thal et al. (Neuropsychopharmacol (2005): A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment) assessed whether rofecoxib (Vioxx) delays the diagnosis of AD in the elderly MCI (mild cognitive impairment), finding in the negative that rofecoxib neither delayed the diagnosis of Alzheimer's disease nor influenced cognition or function.

However Yip et al. (BMC Geriatr (2005): Nonsteroidal anti-inflammatory drug use and Alzheimer's disease risk: the MIRAGE Study) more recently conducted a multi-center family study of genetic and environmental risk factors for AD, finding that daily use of NSAIDs for at least six months is associated with a decreased risk of developing Alzheimer's disease, which may be modified by the APOE genotype. And Greg Cole and colleagues (Nueurobiol Aging (2005): Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions) found that curcumin targeted multiple AD pathogenic cascades, and that the dietary omega-3 fatty acid, docosahexaenoic acid (DHA), also limited amyloid, oxidative damage and synaptic and cognitive deficits in a transgenic mouse model.

(new) Antioxidants and Polyphenols
Resveratrol appears to modulates multiple mechanisms of Alzheimer's disease pathology and neuronal degeneration (TS Anekonda, Brain Res Rev (2006): Resveratrol—A boon for treating Alzheimer's disease?). In addition, Qi Dai at the Vanderbilt-Ingram Cancer Center and colleagues (Am J Med (2006): Fruit and Vegetable Juices and Alzheimer’s Disease: The Kame Project) tested whether consumption of fruit and vegetable juices with a high concentration of polyphenols decreases the risk of incident probable Alzheimer’s disease in the Kame Project cohort (population-based prospective study of prospective study conducted among Japanese Americans living in King County, Washington), finding that fruit and vegetable juices may play an important role in delaying the onset of Alzheimer’s disease, particularly among those who are at high risk for the disease (those who were not physically active or with a certain apolipoprotein E allele), and that this may be in part due to the role played by hydrogen peroxide (H2O2)-mediated ß-amyloid peptide oxidative damage caused by the in the pathogenesis of Alzheimer’s disease. This is in keeping with earlier findings showing that polyphenols from apple and citrus juices, such as quercetin, cross the blood-brain barrier and exert neuroprotection against H2O2..with quercetin from apple juice conferring stronger neuroprotection than vitamin C (see Daniela Ortiz & Thomas Shea at the University of Massachusetts, J Alzheimers Dis (2004): Apple juice prevents oxidative stress induced by amyloid-beta in culture [pdf]; HJ Heo and CY Lee at Cornell University, J Agric Food Chem (2004):Protective Effects of Quercetin and Vitamin C against Oxidative Stress-Induced Neurodegeneration.

And Yvonne Freund-Levi at the Karolinska Institutet and
co-researchers in the OmegAD Study examined the effects of dietary omega-3 fatty acid supplementation on cognitive functions in patients with mild to moderate Alzheimer's disease finding that although such supplementation did not delay the rate of cognitive decline, there were positive effects in a small group of patients with very mild Alzheimer's disease, defined as MMSE >27 points (Arch Neurol (2006): Omega-3 Fatty Acid Treatment in 174 Patients With Mild to Moderate Alzheimer Disease: OmegAD Study).

(new) Green Tea / EGCG
In addition to these polyphenols and antioxidants, the polyphenols in green tea have been shown of benefit in that higher consumption of green tea is associated with a lower prevalence of cognitive impairment in humans (as demonstrated in the human observational study of Shinichi Kuriyama and colleagues, Am J Clin Nutr (2006): Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya Project), while in contrast, there was only a weak or null relation between consumption of black, oolong tea or coffee, and cognitive impairment; as the researchers note, green tea polyphenols, especially EGCG, might explain the observed association with improved cognitive function, in keeping with the earlier finding that EGCG has protective effects against Aß-induced neurotoxicity and regulates secretory processing of non-amyloidogenic APP via PKC pathway (Yona Levites and coresearchers at Haifa, FASEB J (2003): Neuroprotection and neurorescue against Aßtoxicity and PKC-dependent release of non-amyloidogenic soluble precursor protein by green tea polyphenol (-)- epigallocatechin-3-gallate [pdf]), and is consonant with the observation of relatively lower prevalence of Alzheimer's disease in Japan in contrast to Europe and North America (Karen Ritchie & Simon Lovestone, Lancet (2002): The dementias). [We note speculatively that there may also be a connection through the effect of EGCG and green tea extracts on atherosclerotic lesions: Claudia Hofmann and Gail Sonenshein at Boston University School of Medicine, noting that green tea polyphenols have been shown to inhibit the development of atherosclerotic lesions and functions to prevent the development of atherosclerosis (FASEB J (2003): Green tea polyphenol epigallocatechin-3 gallate induces apoptosis of proliferating vascular smooth muscle cells via activation of p53 [pdf])].

It should be noted, these benefits may derive from other polyphenolic compounds than just green tea, including Ginkgo biloba extract( EGb 761) discussed elsewhere in this review, blueberries extracts, wine components and curcumin (Charles Ramassamy, Eur J Pharmacol (2006): Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: A review of their intracellular targets).

(new) Bright Light Therapy and Melatonin
Several controlled trials have investigated the effect of bright light on sleep disturbance and behavioral disorders in dementia, and although some benefits were reported for restlessness, the most particular beneficial effect was found for sleep disturbances (Alistair Burns et al., BMJ: Sensory stimulation in dementia: An effective option for managing behavioural problems; see also the review of Simon Douglas et al., Adv Psychiatr Treat (2004): Non-pharmacological interventions in dementia). So in their earlier RCT, Constantine Lyketsos at Johns Hopkins and coresearchers (Int J Geriatr Psychiatry (2001): A randomized, controlled trial of bright light therapy for agitated behaviors in dementia patients residing in long-term care) found that patients with dementia in chronic care exhibiting agitated behaviors slept more hours at night when administered morning BLT for one hour daily, in agreement with earlier findings (A Satlin and colleagues at the Harvard Medical School, Am J Psychiatry (1992): Bright light treatment of behavioral and sleep disturbances in patients with Alzheimer's disease where it was found that evening bright light pulses (2 hours/day between 7:00 p.m. and 9:00 p.m. for 1 week) may ameliorate sleep-wake cycle disturbances in some patients with Alzheimer's disease; Scott Campbell at Cornell and coresearchers, J Biol Ryhthms (1995): Light Treatment for Sleep Disorders: Consensus Report who concluded that although less consistent than results with healthy elderly subjects, generally positive findings have been reported with regard to bright light treatment of sleep and behavioral disturbance in demented patients; Yvette Rheaume et al., Am J Alzheimer's Disease (1998): Effect of light therapy upon disturbed behaviors in Alzheimer patients; Lilian Thorpe et al., Am J Alzheimer's Disease (2000): Bright light therapy for demented nursing home patients with behavioral disturbance; PM Judith Haffmans and colleagues, Int J Geriatr Psychiatry (2001): Bright light therapy and melatonin in motor restless behaviour in dementia: a placebo-controlled study who found a positive effect of bright light therapy (30 minutes at 10,000 lux exposure) on motor restless behavior; BB Lovell et al., Pyschiatry Res (1995): Effect of bright light treatment on agitated behavior in institutionalized elderly subjects who found that bright light therapy (at 2500 lx for 2 hours in the morning for two 10-day periods) revealed a significant difference between light treatment days and nontreatment days, with less agitation being observed on treatment days). In addition, short-term evening bright light therapy (BLT) appears to exert beneficial effects on cognitive functioning in patients with dementia as determined by Andre Graf et al. (Biol Psychiatry (2001): The effects of light therapy on mini-mental state examination scores in demented patients) who found that patients treated with BLT showed a statistically significant increase in Mini-Mental State Examination (MMSE) total scores after light therapy.

However, these data required further confirmation in rigorous controlled studies, given that some inconsistent findings have been reported, such that of Glenna Dowling and colleagues at UCSF who found that one hour of bright light, administered to subjects with AD either in the morning or afternoon, did not improve nighttime sleep or daytime wake compared to a control group of similar subjects (Int J Geriatr Psychiatry (2005): Effect of timed bright light treatment for rest-activity disruption in institutionalized patients with Alzheimer's disease); in addition the systematic review of D Forbes et al. (Cochrane Database of Systematic Reviews (2004): Light Therapy for Managing Sleep, Behaviour, and Mood Disturbances in Dementia) concluded that there was insufficient evidence to assess the value of bright light therapy for people with dementia, given that available studies were of poor quality, so that further research is required, and another review in the same year by Arvid Skjerve and colleagues (Int J Geriatr Psychiatry (2005): Light therapy for behavioural and psychological symptoms of dementia) concluded that although there was some evidence for the influence of light therapy on sleep and circadian activity rhythmicity, it was insufficient to draw any conclusion about efficacy of light therapy for behavioral and psychological symptoms of dementia (BPSD). And yet, against these equivocal conclusions, later studies continue to demonstrate positive effects, as for instance in the pilot study of Anne Fetveit and colleagues who found that bright light exposure (2 hours/day of morning bright-light exposure for 2 weeks) was effective in reducing daytime sleep in nursing home patients with dementia (Am J Geriatr Psychiatry (2005): Bright-Light Treatment Reduces Actigraphic-Measured Daytime Sleep in Nursing Home Patients With Dementia: A Pilot Study). And Sonia Ancoli-Israel and colleagues at UCSD (Am J Geriatr Psychiatry (2003): Effect of Light on Agitation in Institutionalized Patients With Severe Alzheimer Disease) found that agitation was not ameliorated in severe Alzheimer's patients, although they speculated that it may indeed be of benefit in mild or moderate disease. Nonetheless, while pending studies may settle this issue, in the meantime bright light therapy appears to be without harm or significant adverse events.

One possible confounding factor in these and related studies may be the issue of melatonin levels, given that the decline in melatonin production in aged individuals has been hypothesized as a primary contributing factor for the development of age-associated neurodegenerative diseases, and given that melatonin has been shown to be effective in arresting neurodegenerative phenomena seen in experimental models of Alzheimer's disease. So in the review by V. Srinivasan and coresearchers (Nneurotox Res (2005): Role of melatonin in neurodegenerative diseases), it was concluded that therapeutic trials with melatonin have been effective in slowing the progression of Alzheimer's disease (but not of Parkinson's disease), probably via preservation of mitochondrial homeostasis, reduction of free radical generation, increasing mitochondrial glutathione levels, and safeguarding proton potential and ATP synthesis by stimulating complex I and IV activities. And V. Srinivasan and colleagues have more recently followed up this study and concluded their from review of the literature that melatonin may have potential value in both the prevention and treatment of Alzheimer's disease and other neurodegenerative disorders (Behav Brain Funct (2006): Melatonin in Alzheimer's disease and other neurodegenerative disorders).

Similarly, Ying-Hui Wu and Dick Swaab in their review (J Pineal Res (2006): The human pineal gland and melatonin in aging and Alzheimer's disease) concluded that there is evidence that a dysfunction of the sympathetic regulation of pineal melatonin synthesis by the suprachiasmatic nucleus (SCN) is responsible for melatonin changes during the early AD stages, and that reactivation of the circadian system by means of light therapy and melatonin supplementation to restore the circadian rhythm and to relieve the clinical circadian disturbances has shown promising positive results. And Almagan Altun & B Uqur-Altun (Int J Clin Practice (2006): Melatonin: therapeutic and clinical utilization), noting that melatonin not only plays an important role in the regulation of circadian rhythms but also acts as an antioxidant and neuroprotector, concluded that in both in vivo and in vitro studies of Alzheimer's disease, melatonin has been shown to be effective in arresting neurodegenerative phenomena.

Finally, another recent review by Jian-zhi Wang & Ze-fen Wang (Acta Pharmacologica Sinica (2006): Role of melatonin in Alzheimer-like neurodegeneration) noting melatonin's important role in aging and Alzheimer's disease as an antioxidant and neuroprotector, with a profound reduction in this hormone in Alzheimer's patients, concluded that melatonin supplementation improves sleep, ameliorates sundowning, slows down the progression of cognitive impairment in Alzheimer's patients, protecting neuronal cells from Aß-mediated toxicity via antioxidant and anti-amyloid properties, arresting the formation of amyloid fibrils by a structure-dependent interaction with Aß, attenuating Alzheimer-like tau hyperphosphorylation; additionally, melatonin also plays a role in protecting cholinergic neurons and in anti-inflammation, all suggesting its potential in the prevention or treatment of Alzheimer's disease. All these studies suggest a critical beneficial role of melatonin supplementation in the treatment of Alzheimer's disease and may help to explain known phenomenon in that disorder such as sundowning, or sundown syndrome, where some Alzheimer's and dementia patience experience behavioral symptoms clustered mostly in the afternoon and evening (Ladislav Volicer et al., Am J Psychiatry (2001): Sundowning and Circadian Rhythms in Alzheimer’s Disease).

(new) Exercise
An exercise program (twelve week, three times per week, each session of thirty minutes) slowed and reversed disability in some of the activities of daily living (John Stevens & Mark Killeen, Contemp Nurse (2006): A randomised controlled trial testing the impact of exercise on cognitive symptoms and disability of residents with dementia).

(new) Statins
The role of statins in Alzheimer's therapeutics is controversial, but some recent RCTs have found for significant benefit: so DL Sparks and co-researchers (Acta Neurol Scand Suppl (2006): Statin therapy in Alzheimer's disease) conducted a double-blind, placebo-controlled, randomized trial with a 1-year exposure to once-daily (80 mg) atorvastatin calcium (Lipitor), concluding that atorvastatin therapy may be of benefit in the treatment of mild-to-moderately affected Alzheimer's patients, but that the degree of benefit might be predicated on earlier treatment, and that atorvastatin may slow the progression of mild-to-moderate Alzheimer's disease, thereby prolonging the quality of life. And given the growing evidence for the role of vascular factors in Alzheimer’s disease, mixed dementia (Alzheimer’s disease with cerebrovascular disease), and of course vascular dementia, K Alagiakrishnan and colleagues in Canada reviewed the possibility of preventing or delaying the expression and progression of dementia by changing modifiable vascular risk factors (Postgrad Med J (2006): Treating vascular risk factors and maintaining vascular health: Is this the way towards successful cognitive ageing and preventing cognitive decline?), concluding that the practical and effective treatment of vascular risk factors - particularly but not only blood pressure and serum cholesterol - in middle age or even in old age may be the most effective preventive measure available for the prevention of dementia at this time

Reality Orientation /
Cognitive Stimulation Therapy
Reality Orientation (RO) or Cognitive Stimulation Therapy (CST) operate through the presentation of orientation information (time, place and person-related), in order to provide the person with a greater understanding of their surroundings, possibly resulting in an improved sense of control and self-esteem. Spector et al. (Cochrane Database Syst Rev (2000): Reality orientation for dementia ) concluded that "there is some evidence that RO has benefits on both cognition and behavior for dementia sufferers . . . [and] it appears that a continued programme may be needed to sustain potential benefits".

More recently, Spector et al. (Br J Psychiatry (2003): Efficacy of an evidence-based cognitive stimulation therapy programme for people with dementia: randomised controlled trial ) studied CST using topics like money, word games, the present day and famous faces, and using a ‘reality orientation board’, displaying both personal and orientation information. They found that CST improved both cognitive function and quality of life for people with dementia, with the degree of benefit for cognitive function appears similar to that reported with acetylcholinesterase inhibitors.