Treatments for Alzheimer disease.

Abstract: As our population ages, the incidence and prevalence of Alzheimer disease (AD) will increase dramatically. A number of therapies have been investigated for the treatment and prevention of AD. Clinicians should be prepared to provide evidence-based answers to inquiries regarding AD treatment. There is insufficient evidence to recommend ginkgo biloba, estrogen, statins, or nonsteroidal anti-inflammatory drugs for the prevention or treatment of AD. The use of vitamin E is supported by a single randomized controlled trial, while data on other antioxidants is mixed. There is good evidence that cholinesterase inhibitors and memantine are modestly effective in the treatment of AD. Cholinesterase inhibitors appear to be effective throughout the spectrum of AD, while memantine, alone or in combination with cholinesterase inhibitors, is effective in late stage disease. There is insufficient evidence to suggest superiority of one cholinesterase over another.

Key Words: Alzheimer disease, cholinesterase inhibitors, memantine, treatment

**********

More than 33% of women and 20% of men aged 65 and older will develop dementia during their lifetime. (1) With the aging of the US population, the number of individuals with Alzheimer disease (AD) is expected to quadruple over the next 50 years. (2) AD and other dementias place an enormous financial burden on the health care system with annual treatment costs approaching $100 billion annually. Many patients and families feel frustrated by the lack of effective treatments for this disease and search the lay press and the Internet for the latest therapies. Interventions for the treatment of dementia will be reviewed in an effort to provide practitioners with evidence-based answers to their patients' questions regarding AD treatment. A review of issues surrounding screening, diagnosis, and the differential diagnosis of dementia is beyond the scope of this paper, and these topics have been reviewed elsewhere. (3-8)

Nonpharmacologic Interventions

Against a background of avid research into the pathogenesis of AD, there is increasing awareness that cognitive activity and social engagement may be protective against the development of dementia. Observational studies have suggested that remaining cognitively active may forestall symptoms of AD. (9-12) These studies do not prove that cognitive activity protects against the development of dementia since the lack of participation in cognitive activities may be an early marker for cognitive decline. Prospective randomized trials in this area are unlikely to be done, but it seems prudent to encourage our older patients to engage in cognitive leisure activities.

For those patients who have already developed dementia, there has been interest in emotion-oriented psychotherapy such as reminiscence therapy. Reminiscence therapy involves the recall of events in a person's life. Patients are encouraged to reminisce about family, early memories, transitions, jobs, and other meaningful memories. There have been two randomized controlled trials regarding reminiscence therapy. Neither study reported significant improvements in cognitive or behavioral outcomes, although there were trends toward improvement in the intervention group. Both studies reported subjective benefits including patients being more alert and staff becoming interested in the person's past. (13,14) Thus, reminiscence therapy may have subjective benefits that enhance the care of demented patients.

Pharmacologic Interventions

Ginkgo Biloba

Extracts from the gink go biloba tree leaf have been promoted as an herbal remedy for a variety of conditions. Ginkgo Biloba's antioxidant, neuroprotective, and cholinergic qualities have lead to its promotion for memory enhancement. The first US clinical study of ginkgo biloba extract for dementia demonstrated mild improvement in formal cognitive tests, and mild improvement in mood and social behavior. There was, however, a 60% dropout rate in this study and there was no effect on blinded physician assessment. (15) A 1998 meta-analysis that reviewed 50, but included only 4 methodologically sound studies, concluded that ginkgo biloba had a small but significant effect on cognitive function. (16) Since then, there have been two randomized controlled clinical trials involving ginkgo biloba. The first was an effort to see if ginkgo benefited individuals with mild to moderate dementia and the second to see if it improved memory in individuals without dementia. Neither study demonstrated benefit in any neuropsychological domain or in any patient subgroup. (17,18) Several cautions have been raised regarding the use of ginkgo biloba. There is an increased incidence of bleeding complications among patients taking ginkgo. Whether this is due to antiplatelet qualities or drug interactions is unclear. In addition, the pharmaceutical quality of various ginkgo preparations is highly variable. Levels of ginkgolic acids ranged from less than 50 parts per million to 90,000 parts per million despite similar dosing and labeling. (19) Based on data from several randomized controlled trials (RCTs), ginkgo biloba is not recommended for memory enhancement or treatment of dementia.

Estrogen Therapy

The issue of estrogens and hormone therapy as they relate to cognition and dementia has been highly publicized. There is a neurobiological rationale for the protective effect of estrogens on the risk of dementia. The hippocampus, which mediates verbal memory, is rich in estrogen receptors. (20) Estrogens have been proposed to have antioxidant, anti-amyloidogenic effects and to stimulate neurotransmitters involved in cognition. (21-24) Several large epidemiologic studies and small RCTs regarding estrogen's effect on cognition yielded mixed results. (25-32) Recent larger RCTs have demonstrated that estrogen replacement did not show any significant benefits among postmenopausal women diagnosed with mild to moderate AD. (33-35) The largest and perhaps most definitive study, the Women's Health Initiative Memory Study (WHIMS) was recently published. This study was a subset of the Women's Health Initiative, in which women were randomized to combination therapy with conjugated estrogen (0.625 mg daily) and medroxyprogesterone (2.5 mg daily), conjugated estrogen alone or placebo. (36) The WHIMS enrolled a total of 7,479 women aged 65 years or older who were free of dementia at baseline and were randomized to combination therapy, estrogen alone or placebo. During the follow-up period, the incidence of dementia was increased in both treatment groups compared with the placebo group (Hazard ratios: 2.05 for combination therapy and 1.45 for estrogen alone). When the data from both treatment groups were combined, the hazard ratio for incident dementia was 1.76. This risk remained present when the data was reanalyzed excluding those women who may have had subclinical dementia at study entry. The increase in dementia incidence appeared to be more pronounced with longer follow-up. There were more cases of mild cognitive impairment diagnosed among women receiving hormonal therapy than in the placebo group, but this trend did not reach statistical significance. (37-39) Thus, the WHIMS demonstrated that hormone therapy should not be given to women to prevent or delay the onset of dementia. There has also been interest in the synthetic estrogen receptor modulator, raloxifene, to see if it has beneficial cognitive effects. In the Multiple Outcomes of Raloxifene Evaluation Trial, the effect of two doses of raloxifene were compared with placebo in 7,478 postmenopausal women with osteoporosis. With an average of 3 years of follow-up there was no significant difference in cognitive function between the placebo and treatment groups. (40) Good quality RCTs indicate that neither estrogen replacement (alone or combination) therapy nor raloxifene is effective for the treatment or prevention of AD.

Cholesterol and Statins

The association between cholesterol metabolism and AD is intriguing. The apolipoprotein E (APOE) [SIGMA]4 allele, which is involved in cholesterol metabolism, is a genetic risk factor for late-onset AD. (8) In the central nervous system, APOE promotes the formation of insoluble amyloid, and it may modify the appearance of neurofibrillary tangles. (41,42) When neuronal cholesterol is reduced in experimental animals the synthesis of [beta]-amyloid peptide is reduced. Thus, it appears biologically plausible that lowering serum cholesterol can impact the development of AD. Observational studies have reported that statin use is associated with a decreased incidence of AD. (43,44) There are currently no randomized controlled trials to confirm the hypothesis that statin use protects against AD. Whether statins are beneficial in the treatment or prevention of AD awaits further study.

Nonsteroidal Anti-inflammatory Drugs

Inflammatory mechanisms have been proposed as important mediators in the pathogenesis of AD. Activation of the complement cascade, the presence of reactive microglia and numerous immune-associated proteins have been demonstrated in the brains of affected individuals. (45) A number of observational studies have suggested that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) delayed or reduced the occurrence of AD while others have shown no effect. (46-51) Several prospective randomized controlled trials have been done in an attempt to see if there is a relationship between NSAID use and AD. In two separate studies, the selective cyclooxygenase inhibitor rofecoxib failed to slow AD progression when compared with placebo. (52,53) Similarly, naproxen did not show any difference from placebo over 1 year of follow-up. (53) In two other trials, one with indomethacin and one with diclofenac (in combination with misoprostol), showed nonsignificant trends toward slowing the cognitive decline in patients with AD. (54,55) Gastric and renal effects of NSAID treatment are likely to be problematic in this population.

Recent laboratory data has suggested that there should be further research in AD prevention with different NSAIDs. NSAIDs have been found to have varying abilities to decrease production of the pathogenic form of [beta]-amyloid by cleaving its precursor molecule at a different site to produce a more soluble, less pathogenic amyloid protein. It is interesting to note that the NSAIDs with the greatest reductions in [beta]-amyloid production (flurbiprofen, meclofenamate, sulindac, and ibuprofen) were frequently used in the observational studies but have not been studied prospectively. (56) There has been a call for randomized controlled trials with one or more of these drugs before concluding that NSAIDs are ineffective in preventing AD. Based on data from RCTs, there is insufficient evidence to recommend NSAIDs for AD prevention.

Antioxidants

Oxidative stress may play a role in the degenerative neuronal changes in AD. (57,58) This hypothesis has lead to various investigations of antioxidants and AD. Observational studies have yielded conflicting results. (59-61) There is a single well-designed randomized controlled trial using vitamin E supplements in patients with moderate AD. Patients were enrolled and were given 2000 IU of [alpha]-tocopherol or placebo for 2 years. The primary outcome was the time to any one of the following: death, institutionalization, loss of activities of daily living (ADL), or progression to severe dementia. There was no statistically significant difference between the vitamin E and placebo groups, but the randomization process was imperfect and the placebo group had higher baseline Mini-Mental Status scores than the vitamin E group (13.3 and 11.3 respectively). When the results were adjusted for these differences, the treatment group had significant benefit in terms of time to reaching the primary endpoint (440 versus 670 days). (62) The net benefit in this study was relatively small, and it is unclear whether these results can be generalized to prevent or treat dementia at earlier stages. Based on this single RCT and the fact that antioxidant therapy is generally safe and well tolerated, some practitioners have added high dose vitamin E supplements to their AD treatment regimens. Further study in this area is necessary.

Cholinesterase Inhibitors

There have been clear demonstrations that cholinergic neurons are diminished in critical areas of the brain of AD patients. While acetylcholine deficiency plays a role in AD, there is increased recognition that this occurs within a complex milieu of neurotransmitter changes in the brains of AD patients. (63-65) By inhibiting the degradation of acetylcholine released by presynaptic cholinergic neurons, cholinesterase inhibitors increase the amount of acetylcholine available for neurotransmission. Emerging evidence suggests that long-term treatment with cholinesterase inhibitors not only improves cognitive and behavioral domains, but may influence neuronal function and survival. (66,67)

There are four FDA-approved cholinesterase inhibitors for the treatment of AD: tacrine, donepezil, rivastigmine, and galantamine. Tacrine was the first cholinesterase inhibitor that showed improved cognition in treated AD patients. Tacrine use is associated with hepatotoxicity and clinically significant drug interactions. (68-71) Because of the availability of other cholinesterase inhibitors with better side effect profiles and fewer drug interactions, tacrine is rarely used today. Randomized, placebo-controlled trials of donepezil, rivastigmine and galantamine have demonstrated that these drugs have clinically meaningful responses in AD patients. Outcome measures that show benefit with cholinesterase inhibitor therapy include cognition (as measured by the Alzheimer Disease Assessment Scale cognitive subscale and the Mini-Mental Status Examination), clinician's interview-based impression of change, ADL, disability, quality of life and nursing home placement (Table 1). The magnitude of response appears to be a stabilization or slowing of disease progression that is equivalent to 6 months of cognitive decline with this disease. (71-85) While most of these are short-term studies, there are several studies demonstrating durability of response for 1 to 2 years. (71,75,76,78,82,83) Donepezil has been shown to be effective in moderate to severe AD and improves neuropsychiatric symptoms. (77,79) Whether these latter effects are unique to donepezil await further investigation. Response rates to cholinesterase inhibitors do not appear to be influenced by APOE4 status. (85,86) A recent randomized controlled trial from Britain concluded that treatment of mild to moderate AD with donepezil was neither efficacious nor cost-effective. This study has serious flaws which question the validity of these conclusions. The study was underpowered (565 patients enrolled when designed for 3,000) and the protocol included planned "wash-out" periods varying from 4 to 6 weeks. Given these flaws the negative results are not unexpected. (87) While some have questioned whether the degree of benefit seen with cholinesterase therapy is worth the cost, others have shown that the numbers needed to treat are relatively small (number needed to treat was 3-7) and that despite their expense and modest benefits, the cholinesterase inhibitors have a valuable place in the current management of AD patients. (88,89)

While donepezil, rivastigmine, and galantamine have the same basic mechanism of action, inhibiting cholinesterase to allow more acetylcholine in the synaptic cleft, there are differences among the three drugs. These differences have been demonstrated in vitro, but it is unclear whether they are clinically relevant. As AD progresses, acetylcholinesterase levels fall and butyrylcholinesterase levels increase. The function of butyrylcholinesterase is unclear, but it appears to come from activated glial cells and is found in neuritic plaques. Rivastigmine inhibits butyrylcholinesterase in addition to acetylcholinesterase. (90) Thus, it has been hypothesized that rivastigmine may work differently in late disease. Galantamine induces an allosteric change in presynaptic nicotinic receptors, which increases presynaptic acetylcholine release and the amount of acetylcholine in the synaptic cleft. (91) It has been hypothesized that this mechanism will result in less down-regulation of the number of postsynaptic receptors and allow the drug to work longer as the disease progresses. The clinical relevance of these properties is unclear.

There are no randomized double-blind trials comparing cholinesterase inhibitors to one another. Two open label studies have been recently published. The first showed no difference in efficacy between donepezil and rivastigmine, while the second suggested that patients on donepezil performed better on cognitive testing and ADL functioning than patients on galantamine. (92,93) While these open label results are suggestive, double-blind studies are necessary before concluding that one cholinesterase inhibitor is superior to another.

Donepezil, rivastigmine, and galantamine share common cholinergic-mediated side effects. The most common cholinergic side effects include nausea, vomiting, diarrhea, anorexia, and abdominal pain (Table 2). Slow titration of these drugs to therapeutic doses may alleviate many of these symptoms since patients tend to develop tolerance to these gastrointestinal symptoms. (94) Two small open label studies have suggested that of the three commonly used cholinesterases, donepezil is associated with fewer side effects leading to discontinuation of the drug, but these studies require confirmation with prospective randomized double-blinded studies. (92,93) Because the cholinesterase inhibitors increase acetylcholine and may increase parasympathetic tone, these drugs should be used cautiously in patients with bronchospasm, active peptic ulcer disease, bradycardia or cardiac conduction disturbances. In addition, care should be exercised if patients taking cholinesterase inhibitors undergo general anesthesia since these drugs may prolong the effects of neuromuscular blocking agents. (94)

Donepezil, rivastigmine and galantamine are moderately effective in the treatment of mild to moderate AD, but there is little evidence to recommend one drug over another. A realistic discussion of the benefits of therapy, focusing on disease stabilization, as well as side effects, is warranted in all patients diagnosed with mild to moderate AD. Cholinesterase inhibitor therapy should be started early and there is emerging data that efficacy extends to the late stages of the disease. When and if cholinesterase therapy should be discontinued remains controversial.

Memantine

There is increasing evidence that disturbances in glutamatergic neurotransmission contribute to the pathogenesis and cognitive deficits in AD. Glutamine is an excitatory neurotransmitter that activates the N-methyl-D-aspartate receptor. Glutamatergic transmission is thought to be important in learning and memory, but glutamatergic overstimulation appears to be toxic to neurons. (95) Based on this theory, the N-methyl-D-aspartate receptor antagonist, memantine, has been tested in the treatment of AD. There have been three randomized placebo-controlled trials demonstrating that memantine is moderately effective in slowing the progression of AD. In the first study, 166 demented nursing home patients (49% AD; 51% vascular dementia) were randomized to 10 mg of memantine or placebo. At 12 weeks the treated patients had improved clinician's global impression scores independent of the etiology of dementia. (96) In another study, 252 patients with moderate to severe AD were randomized to memantine or placebo. At 28 weeks, patients treated with memantine had better ADL function and disability scores. Clinician's impression scores were also improved in the treatment group, but this difference did not reach statistical significance. (97) In the most recent study, 403 patients with moderate to severe AD who were already taking donepezil (stable dose of 5 or 10 mg) were randomized to an additional therapy with memantine or placebo in a blinded fashion. After 24 weeks of follow-up, the memantine-treated group had better cognitive, functional, and behavioral scores compared with the monotherapy group. (98) Whether memantine is effective with other cholinesterase inhibitors is unproven, but there is no reason to expect different results with other cholinesterase inhibitors. Clinical trials are under way to address this issue. Memantine is well tolerated with a side effect profile similar to placebo. (96,97)

The beneficial effects seen with memantine reflect a slower decline in treated patients rather than improvement, which is sometimes seen in patients treated with cholinesterase inhibitors. Thus, cholinesterase inhibitors remain the treatment of choice for patients with AD, although treatment with memantine may be a useful adjunct in later stage disease. There is limited data regarding memantine use in early AD, and it is not recommended for these patients.

Combination Therapy

Since the beneficial effects of cholinesterase inhibitors are only modest, there has been interest in whether combinations of therapies may have additive or even synergistic effects in the treatment of AD. As seen above, the addition of memantine to donepezil in later stage disease has benefit. (97) Unfortunately, adding vitamin E or hormone replacement therapy to cholinesterase therapy has not resulted in further benefit over monotherapy. (99,100)

Conclusion

The incidence and prevalence of AD will increase dramatically in the future. Even modest treatment effects can have significant impacts on the quality of life for these patients, their caregivers, families, and society. There is insufficient evidence to recommend ginkgo biloba, estrogen, statins, or nonsteroidal anti-inflammatory drugs. A single RCT supports the use of high dose vitamin E supplementation in the treatment of AD. There is good evidence that cholinesterase inhibitors and memantine are modestly effective in the treatment of AD. Cholinesterase inhibitors appear to be effective throughout the spectrum of disease, while memantine, alone or in combination with cholinesterase inhibitors, is effective in the later stages of the disease. There is no evidence to suggest superiority of one cholinesterase over another. Whether these pharmacologic interventions modify the underlying disease process or merely alter the expression of the disease awaits further study.

You must do the things you think you cannot do.
--Eleanor Roosevelt

Table 1. Randomized controlled trials of cholinesterase inhibitors in
Alzheimer disease (a)

                                         Statistically
                    Number of  Study     significant primary
Reference           patients   duration  outcomes

Tacrine
  Davis (68)        215         6 weeks  ADAS-Cog
  Farlow (69)       468        12 weeks  ADAS-Cog
  Knapp (70)        663        30 weeks  ADAS-Cog
  Knopman (71)      300         2 years  ECF placement
Donepezil
  Rogers (72)       473        24 weeks  ADAS-Cog
  Rogers (73)       468        12 weeks  ADAS-Cog
  Burns (74)        818        24 weeks  ADAS-Cog
  Winblad (75)      286         1 year   Global Assessment
  Mohs (76)         431         1 year   ADLs
  Feldman (77)      290        24 weeks  CIBC
  Cummings (79)      84        24 weeks  Behavioral disturbances
Rivastigmine
  Corey-Bloom (80)  699        26 weeks  ADAS-Cog
  Rosler (81)       625        26 weeks  ADAS-Cog
  Farlow (82)       699         1 year   ADAS-Cog
Galantamine
  Raskind (83)      636        24 weeks  ADAS-Cog
  Tariot (84)       978        21 weeks  ADAS-Cog
  Wilcock (85)      653        24 weeks  ADAS-Cog

                    Statistically
                    significant secondary
Reference           outcomes                Comments

Tacrine
  Davis (68)        ADLs                    CIBC, MMSE NS
  Farlow (69)       CIBC
  Knapp (70)        CIBC, QoL
  Knopman (71)                              Open label continuation ref
                                              68
Donepezil
  Rogers (72)       QoL, MMSE
  Rogers (73)       CIBC, MMSE
  Burns (74)        CIBC
  Winblad (75)      MMSE
  Mohs (76)
  Feldman (77)      MMSE, ADLs              Moderate to severe AD
  Cummings (79)
Rivastigmine
  Corey-Bloom (80)
  Rosler (81)
  Farlow (82)                               Open label after initial 26
                                              weeks
Galantamine
  Raskind (83)      CIBC, disability
  Tariot (84)       Global function/
                      behavior
  Wilcock (85)      CIBC, disability

(a) ADAS-Cog, Alzheimer Disease Assessment Scale-Cognition Subscale;
CIBC, clinician interview-based impression of change; MMSE, Mini-Mental
Status Examination; ADLs, activities of daily living; ECF, extended care
facility; QoL, quality of life; NS, not statistically significant.

Table 2. Currently used FDA approved drugs for the treatment of
Alzheimer disease

                                                   Starting  Dosing
Drug            Unique characteristics             dose      schedule

Cholinesterase
  inhibitors
  Donepezil     Acetylcholinesterase specificity    5 mg     Once daily
  Rivastigmine  Butyrylcholinesterase specificity   1.5 mg   Twice daily
  Galantamine   Nicotinic receptor modulator        4 mg     Twice daily
N-methyl-D-
  aspartate
  receptor
  antagonist
  Memantine     NMDA receptor antagonist            5 mg     Twice daily

                                                  Maximum
Drug            Titration                          dose

Cholinesterase
  inhibitors
  Donepezil     Increase to 10 mg after 6 weeks   10 mg daily
  Rivastigmine  Increase by 1.5 mg every 6 weeks   6 mg twice daily
  Galantamine   Increase by 4 mg every 6 weeks    12 mg twice daily
N-methyl-D-
  aspartate
  receptor
  antagonist
  Memantine     Increase by 5 mg weekly           10 mg twice daily

Table 3. Cholinesterase inhibitors: side effect profile from randomized
placebo controlled trials (a,b)

Drug          Nausea  Diarrhea  Vomiting  Abdominal pain  Weight loss

Donepezil     11-24%  13-16%     6-16%        10%           19%
Rivastigmine  20-50%  17%       16-34%        12%           21-24%
Galantamine   16-37%   5-12%     9-20%         6-11%         8-12%

Drug          Fatigue  Insomnia/anxiety

Donepezil        8%      9-18%
Rivastigmine    10%       NR
Galantamine     NR        NR

(a) NR, not reported.
(b) Adapted from Davis et al, 68 Farlow et al, 69 Knapp et al, 70
Knopman et al, 71 Winbald et al, 3 Mohs et al, 76 Geldmacher et al, 78
Cummings et al, 79 Corey-Bloom et al, 80.

Accepted September 21, 2004.

References

1. Ott A, Breteler MM, van Harkskamp F, et al. Incidence and risk of dementia: The Rotterdam Study. Am J Epidemiol 1998;147:574-580.

2. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health 1998;88:1337-1342.

3. Preventive Services Task Force. Screening for dementia: recommendation and rationale. Ann Int Med 2003;138:925-926.

4. Boustani M, Peterson B, Hanson L, et al. Screening for dementia in primary care: a summary of the evidence for the U.S. preventive services task force. Ann Int Med 2003;138:927-937.

5. Lopez OL, Litvan I, Catt KE, et al. Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias. Neurology 1999;53:1292.

6. Geldmacher DS, Whitehouse PJ Jr. Differential diagnosis of Alzheimer's disease. Neurology 1997;48:S2-S9.

7. Kaye JA. Diagnostic challenges in dementia. Neruology 1998;51:S4-52.

8. Farlow MR. Alzheimer's disease: clinical implications of the apolipoprotein E genotype. Neurology 1997;48:S30-S34.

9. Bassuk SS, Glass TA, Berkman LF. Social disengagement and incident cognitive decline in community-dwelling elderly persons. Ann Int Med 1999;131:165-173.

10. Wilson RS, Mendes De Leon CF, Barnes LL, et al. Participation in cognitively stimulating activities and the risk of incident Alzheimer disease JAMA 2002;287:742-748.

11. Fabrigoule C, Letenneur L, Dartigues JF, et al. Social and leisure activities and risk of dementia: a prospective longitudinal study. J Am Geriatr Soc 1995;43:485-490.

12. Verghese J, Lipton RB, Katz MJ, et al. Leisure activity and the risk of dementia in the elderly. NEJM 2003;348:2508-2516.

13. Baines S, Saxby P, Ehlert K. Reality orientation and reminiscence therapy: a controlled cross-over study of elderly confused people. Br Journal of Psychology 1987;151:222-231.

14. Goldwasser AN, Auerbach SM, Harkins SW. Cognitive, affective and behavioural effects of reminiscence therapy on demented elderly. Int J Aging and Human Development 1987;25:209-222.

15. LeBaars PL, Katz MM, Berman N, et al. A placebo-controlled, double blind, randomized trial of an extract of ginkgo biloba for dementia. JAMA 1997;278:1327-1332.

16. Oken BS, Storzbach DM, Kaye JA. Efficacy of ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurology 1998;55:1409-1415.

17. van Dongen MC, van Rossum E, Kessels AG, et al. The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: new results of a randomized clinical trial. J Am Geriatr Soc 2000;48:1183-1194.

18. Solomon PR, Adams F, Silver A, et al. Ginkgo for memory enhancement: a randomized controlled trial. JAMA 2002;288:835-840.

19. Kressmann S, Muller WE, Blume HH. Pharmaceutical quality of different ginkgo biloba brands. J Pharm Pharmacol 2002;54:661-669.

20. Weiland N, Orikasa C, Hayashi S, et al. Distribution and hormone regulation of estrogen receptor immunoreactive cells in the hippocampus of male and female rats. J Comp Neurol 1997;388:603-12.

21. Xu H, Gouras GK, Greenfield JP, et al. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med 1998;4:447-451.

22. Goodman Y, Bruce AJ, Cheng B, et al. Estrogens attenuate and corticosteroid exacerbates exitotoxicity, oxidative injury and amyloid B-peptide toxicity in hippocampal neurons. J Neurochem 1996;66:1836-1844.

23. McEwen BS. Clinical review 108. The molecular and neuroanatomical basis for estrogen effects in the central nervous system. J Clin Endocrinol Metab 1999;84:1790-1797.

24. Fillit HM. The role of hormone replacement therapy in the prevention of Alzheimer disease. Arch Int Med 2002;162:1934-1942.

25. Tang MX, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk and age of onset of Alzheimer's disease. Lancet 1996;348:429-432.

26. Kawas C, Resnick S. Morrison A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore longitudinal study of aging. Neurology 1997;48:1517-1521.

27. LeBlanc ES, Janowsky J, Chan BKS, et al. Hormone replacement therapy and cognition. Systematic review and meta-analysis. JAMA 2001;285:1489-99.

28. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA 2002;288:2123-2129.

29. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 1988;13:345-357.

30. Phillips SM, Sherwin BB. Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology 1992;17:485-495.

31. Binder EF, Schechtman KB, Birge SJ, et al. Effects of HRT on cognitive performance in elderly women. Maturitas 2001;38:137-146.

32. Shaywitz SE, Shaywitz BE, Pugh KR, et al. Effects of estrogen on brain activation patterns in postmenopausal women during working memory tasks. JAMA 1999;281:1197-1202.

33. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease. JAMA 2000;283:1007-1015.

34. Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial. Neurology 2000;54:295-301.

35. Wang PN, Liao SQ, Liu RS, et al. Effects of estrogen on cognition, mood, and cerebral blood flow in AD a controlled study. Neurology 2000;54:2061-2066.

36. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principle results from the women's health initiative randomized controlled trial. JAMA 2002;288:321-333.

37. Shumaker SA, Legault C, Rapp SR et al. Effect of estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the women's health initiative study: a randomized controlled trial. JAMA 2003;289:2651-2662.

38. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004;291:2947-2958.

39. Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004;291:2959-2968.

40. Yaffe K, Krueger K, Sarkar S, et al. Cognitive function in postmenopausal women treated with raloxifene. JAMA 2001;344:1207-1213.

41. Strittmatter WJ, Weisgraber KH, Huang Dy, et al. Binding of human aplipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA 1993;90:8098-8102.

42. Richey PL, Siedlak SL, Smith MA, et al. Apolipoprotein E interaction with the neurofibrillary tangles and senile plaques in Alzheimer Disease: implications for disease pathogenesis. Biochem Biophys Res Commun 1995;208:657-663.

43. Wolozin B, Kellman W, Ruosseau P, et al. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arch Neurol 2000;57:1439-1443.

44. Jick H, Zornberg GL, Jick SS, et al. Statins and the risk of dementia. Lancet 2000;356:1627-1631.

45. McGeer PL, McGeer EG. The inflammatory response system of the brain: implications for therapy in Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995;21:195-218.

46. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 1996;47:425-432.

47. Zandi PP, Breitner JC. Do NSAIDs prevent Alzheimer's disease? And, if so, why? The epidemiological evidence. Neurobiol Aging 2001;22:811-817.

48. Beard CM, Waring SC, O'Brien PC, et al. Nonsteroidal anti-inflammatory drug use and Alzheimer's disease: a case control study in Rochester, Minnesota, 1980 through 1984. Mayo Clin Proc 1998;73:951-955.

49. In't Veld BA, Launer LJ, Hoes AW, et al. NSAIDs and incident Alzheimer's disease: The Rotterdam Study. Neurobiol Aging 1998;19:607-11.

50. Stewart WF, Kawas C, Corrada M, et al. Risk of Alzheimer's disease and duration of NSAID use. Neurology 1997;48:626-632.

51. In't Veld BA, Ruitenberg A, Hofman A, et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. NEJM 2001;345:1515-1521.

52. Reines SA, Block GA, Morris JC, et al. Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study. Neurology 2004;62:66-71.

53. Aisen PS, Sehafer KA, Grundman M, et al. Effects of rofecoxib or naproxen vs. placebo on Alzheimer disease progression. A Randomized Controlled Trial JAMA 2003;289:2819-2826.

54. Rogers J, Kirby LC, Hempelman SR, et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology 1993;43:1609-1611.

55. Scharf S, Mander A, Ugoni A, et al. A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer's disease. Neurology 1999;53:197-201.

56. Eriksen JL, Sagi SA, Smith TE, et al. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest 2003;112:440-449.

57. Smith MA, Perry G, Richey PL, et al. Oxidative damage in Alzheimer's. Nature 1996;382:120-1.

58. Smith CD, Carney JM, Starke-Reed PE, et al. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci USA 1991;88:10540-10543.

59. Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 2002;287:3223-3229.

60. Morris MC, Evans DA, Bienias JL, et al. Dietary intake of antioxidant nutrients and the risk of incident Alcheimer disease in a biracial community study. JAMA 2002;287:3230-3237.

61. Zandi PR, Anthony JC, Khachaturian AS, et al. Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements. The Cache County Study. Arch Neurology 2004;61:82-88.

62. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol or both as treatment for Alzheimer's disease. NEJM 1997;336:1216-1222.

63. McGeer PL, McGeer EG, Suzuki J, et al. Aging, Alzheimer's disease, and the cholinergic system in the basal forebrain. Neurology 1984;34:741-745.

64. Rossor MN, Iversen LL, Reynolds GP, et al. Neurochemical characteristics of early and late onset types of Alzheimer's disease. BMJ 1984;288:961-964.

65. Arai H, Ichimiya Y, Kosaka K, et al. Neurotransmitter changes in early- and late-onset Alzheimer type dementia. Prog Neuropsychopharmacol Biol Psychiatry 1992;16:883-890.

66. Hock C, Maddalena A, Raschig A, et al. Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of A beta 42 in patients with Alzheimer's disease. Amyloid 2003;10:1-6.

67. Sadot E, Gurwitz D, Barg J, et al. Activation of m1 muscarinic acetylcholine receptor regulates tau phosphorylation in transfected PC12 cells. J Neurochem 1996;66:877-880.

68. Davis KL, Thal LJ, Gamzu ER, et al. A double blind, placebo-controlled multicenter study of tacrine for Alzheimer disease. The Tacrine Collaborative Study Group. NEJM 1992;327:1253-1259.

69. Farlow M, Gracon SI, Hershey LA, et al. A controlled trial of tacrine in Alzheimer's disease. The Tacrine Study Group. JAMA 1992;268:2523-2529.

70. Knapp MJ, Knopman DS, Solomon PR, et al. A 30-week randomized controlled trial of high dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group. JAMA 1994;271:985-991.

71. Knopman D, Schneider L, Davis K, et al. Long-term tacrine (Cognex) treatment: effects on nursing home placement and mortality, Tacrine Study Group. Neurology 1996;47:166-177.

72. Rogers SL, Farlow MR, Doody RS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group Neurology 1998;50:1136-1145.

73. Rogers SL, Doody RS, Mohs RC, et al. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Int Med 1998;158:1021-1031.

74. Burns A, Rossor M, Hecker J, et al. The effects of donepezil in Alzheimer disease. Results from a multinational trial. Dementia and Geriatr Cogn Disorders 1999;10:237-244.

75. Winblad B, Engedal K, Soininen H, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001;57:489-495.

76. Mohs RC, Doody RS, Morris, JC, et al. A 1-year, placebo-controlled preservation of function study of donepezil in AD patients. Neurology 2001;57:481-488.

77. Feldman H, Gauthier S, Hecker J, et al. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. Neurology 2001;57:613-620.

78. Geldmacher DS, Provenzano G, McRae, et al. Donepezil is associated with delayed nursing home placement in patients with Alzheimer's disease. J Am Geriatr Soc 2003;51:937-944.

79. Cummings JL, Donahue JA, Brooks RL. Ther between donepezil and behavioral disturbances in patients with Alzheimer's disease. Am J. Geriatr Psych 2000;8:134-140.

80. Corey-Bloom J, Anand R, Veach J, for ENA 713 B352 Study Group. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease. Int J Geriatr Psychopharmacol 1998;1:55-65.

81. Rosler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ 1999;319:633-638.

82. Farlow M, Anand R, Messina J, et al. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease. Eur Neurol 2000;46:236-241.

83. Raskind MA, Peskind ER, Wessel T, et al. Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 2000;54:2261-2268.

84. Tariot PN, Solomon PR, Morris JC, et al. A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology 2000;54:2269-2276.

85. Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer disease: multicentre randomized trial. BMJ 2000;321:1445-1449.

86. Aerssens J, Raeymaekers P, Lilienfeld S, et al. APOE genotype: no influence on glantamine treatment efficacy nor on rate of decline in Alzheimer's disease. Dementia Geriatric Cognitive Disorders 2001;12:69-77.

87. AD2000 Collaborative Group. Long-term treatment in 656 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-2115.

88. Neumann PJ, Hermann RC, Kuntz KM, et al. Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer's disease. Neurology 1999;25:1138-1145.

89. Livingston G, Katona C. How useful are cholinesterase inhibitors in the treatment of Alzheimer's disease? A number needed to treat analysis. Int J Geriatr Psychiatry 2000;15:203-207.

90. Enz A, Boddeke H, Gray J, et al. Pharmacologic and clinicopharmacologic properties of SDZ ENA 713, a centrally selective acetylcholinesterase inhibitor. Ann NY Acad Sci 1991;640:272-275.

91. Maelicke A, Samochocki M, Jostock R, et al. Allosteric sensitization of nicotinic receptors by galantamine, a new treatment strategy for Alzheimer's disease. Biol Psychiatry 2001;49:279-288.

92. Wilkinson D, Passmore P, Bullock R, et al. A multinational, randomized, 12-week comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer's disease. Int J Clin Practice 2002;56:441-446.

93. Jones RW, Soininen H, Hager K, et al. First head-to-head study comparing the tolerability, ease of use and efficacy of donepezil and galantamine in Alzheimer's disease. Poster Presentation at: The 7th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy (AAT); April 4, 2002; Geneva, Switzerland.

94. Nordberg A, Svensson AL. Cholinesterase inhibitors in the treatment of Alzhiemer's disease: a compariason of tolerability and pharmacology. Drug Safety 1998;19:465-480.

95. Butterfield DA, Pocernich CB. The glutamatergic system and Alzheimer's disease: therapeutic implications. CNS Drugs 2003;17:641-652.

96. Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Pysch 1999;14:135-146.

97. Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer disease. NEJM 2003;348:1333-1341.

98. Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291:317-324.

99. Sobow TM, Kloszewska I, Karlinska I. Addition of vitamin E to donepezil as a treatment for Alzheimer's disease. Alzheimer's Reports 1999;2:143-146.

100. Rigaud AS, Andre G, Vellas B, et al. No additional benefit of HRT on response to rivastigmine in menopausal women with AD. Neurology 2003;60:148-149.

RELATED ARTICLE: Key Points

* There is insufficient evidence to recommend gingko biloba, estrogen, statins or nonsteroidal anti-inflammatory drugs for the prevention or treatment of Alzheimer disease.

* The use of high dose vitamin E supplements is supported by a single randomized controlled trial, while data on other antioxidants is mixed.

* There is good evidence that cholinesterase inhibitors and memantine are effective in the treatment of Alzheimer disease.

Darryl Potyk, MD, FACP 

From the Internal Medicine Residency Spokane, University of Washington School of Medicine, Spokane, WA.

Reprint requests to Darryl Potyk, MD, FACP, Deaconess Medical Center, 800 West 5th Avenue, PO Box 248, Spokane, WA 99210. Email: [e-mail]