The Role of Alternative Therapies in the Management of Alzheimer’s Disease and Dementia, Part II

Part I of this article appeared in the July issue of the Journal.

INTRODUCTION

Potential alternative strategies mentioned in the medical literature for the prevention and treatment of Alzheimer’s disease and/or dementia include the following categories of agents and processes: immunization, aggregation inhibitors, secretase inhibitors, transition metal chelators, growth factors, herbs, nonsteroidal anti-inflammatory drugs (NSAIDs), antioxidants, lipid-lowering agents, antihypertensives, selective phosphodiesterase inhibitors, and vitamins (E, B12, B6, C).¹ Part II of this article discusses common alternative therapies currently in use, and the most recent peer-reviewed evidence that does or does not support their use. This includes discussion of herbals, hormones, nicotine, statins, alcohol, exercise, and socialization.

Prior to considering the use of any agent, prescription or nonprescription, the treating physician is reminded that reversible cognitive dysfunction secondary to prescription medications and even depression must be ruled out (pseudodementia). Commonly prescribed medications may cause cognitive dysfunction to a mild degree, including amitriptyline, imipramine, propranolol, clonidine, high doses of antipsychotic medications (especially highly anticholinergic and atypical agents), long-acting benzodiazepines, barbiturates, phenytoin, NSAIDs, neuroleptics, H2 blockers (in high doses), narcotics (anticholinergic), gabapentin, carbamazepine, digoxin, corticosteroids, and some antibiotics.² If possible, reduction or elimination of the agent in question may result in a significant improvement in cognition.

HERBALS (GINKGO BILOBA)

Ginkgo biloba is a very popular over-the-counter herb used by the lay public for subjective memory complaints and dementia. The published literature, however, suggests that ginkgo biloba may be of questionable value for memory loss and tinnitus of vascular origin, but may have some clinical value in the management of intermittent claudication.³ To some extent, this is related to the lack of long-term data and well-done studies. It appears to be well-tolerated on one hand, but can increase the risk of bleeding if used in combination with warfarin and certain other herbal medications.⁴

A 24-week randomized, double-blind, placebo-controlled, parallel-group study in the Netherlands evaluated 214 elderly patients (recruited from homes for the elderly) with dementia and age-associated memory impairment who were taking ginkgo biloba special extract EGb 761.⁵ They were randomized to either 240 mg or 160 mg per day or placebo. At 12 weeks, the two subgroups receiving the ginkgo were randomized to continue ginkgo or placebo. Patients were evaluated by the Syndrome Kurz Test (psychometric functioning), the Clinical Global Impression-Change (CGI-C; psychopathology), and the Nuremberg Gerontopsychological Rating Scale for Activities of Daily Living (behavioral functioning). There was no difference in the scores on any of these tests between the active treatment and placebo groups.

A 52-week randomized, placebo-controlled trial in patients with Alzheimer’s disease or vascular dementia involved an active treatment group of subjects taking 40 mg of ginkgo extract 3 times per day.⁶ The subjects taking ginkgo had significant but limited improvement at 52 weeks in mean scores for cognitive function and daily behavior. Cognition was measured by the Alzheimer’s Disease Assessment Scale-Cognitive Subsection (ADAS-Cog) and behavior was measured by the Geriatric Evaluation by Relative’s Rating Instrument. The significant difference in cognition and behavior between the two groups occurred at 26 weeks. However, there was no difference in scores between the two groups relative to the Clinical Global Impression (CGI) scale. The analysis indicated that six patients would have to be treated to attain improvement in one patient. Another much shorter trial did not show positive results, however.⁷ This study involved a 26-week trial of patients with mild-to-moderate dementia or age-associated memory impairment, in which the active treatment group was prescribed 80-120 mg of the same ginkgo extract twice daily.⁷

HORMONES

In vitro and animal investigations have shown testosterone to be neuroprotective, and to reduce the levels of beta-amyloid and the phosphorylation of tau (related to the development of Alzheimer’s disease). However, current clinical evidence is limited to a small number of cross-sectional and randomized trials of testosterone supplementation for healthy older men. The results of these studies are inconsistent and indicate a weak association with visuospatial and memory scores only. Studies also indicate that serum levels of testosterone in men with Alzheimer’s disease are comparable to those of controls.⁸

Prior to 2002 and relative to estrogen and hormone replacement therapy (HRT) for dementia, a meta-analysis of observational studies that involved patients with a mean age over 65 years indicated a reduced risk in current and ever-users.⁹ The Cache County Study involved a prospective design and outcome of incident dementia among 1357 men (mean age, 73.2 years) and 1889 women (mean age, 74.5 years) in a single county in Utah.¹⁰ Patients were initially assessed between 1995 and 1997 and were followed up between 1998 and 2000. A history of the women’s current and former use of hormone replacement therapy and calcium and multivitamin supplements was ascertained at initial contact. Thirty-five men and 88 women developed Alzheimer’s disease at follow-up. The incidence of Alzheimer’s disease increased after age 80 and exceeded the risk among men of similar age with an adjusted hazard ratio of 2.11. Women who used HRT had a reduced risk of Alzheimer’s disease, as compared to nonusers, with a relative risk of 0.59. The risk varied with the duration of hormone use such that a woman’s sex-specific increase in risk disappeared with more than 10 years of use. Almost all hormone-related reductions in Alzheimer’s disease incidence were associated with former use, but no effect was seen with current use unless duration of use exceeded 10 years.¹⁰

A small clinical trial conducted at 32 clinical sites between October 1995 and January 1999 involved 120 postmenopausal women with mild-to-moderate Alzheimer’s disease, a Mini-Mental State Examination (MMSE) score of 12-28, and a previous hysterectomy.¹¹ Participants were randomized to estrogen (0.625 or 1.25 mg/day) or placebo, and followed for 2, 6, 12, and 15 months with the main outcome of change on the CGI-C 7-point scale. Other measures included mood, specific cognitive domains (eg, memory, attention, and language), motor function, and activities of daily living. There was no difference between the groups in the progression of Alzheimer’s disease, or in global, cognitive, or functional outcomes. However, women taking estrogen had a lower score on the Clinical Dementia Rating (CDR) scale.¹¹

The most recent clinical evidence was a component of the Women’s Health Initiative (WHI), the Women’s Health Initiative Memory Study (WHIMS), which involved two arms: postmenopausal women with or without a uterus. The first arm was a double-blind, placebo-controlled ancillary study of 4984 women with a uterus without dementia taking conjugated equine estrogen (> 0.625 mg) plus medroxyprogesterone (2.5 mg), compared to placebo.¹² The study evaluated the incidence of probable dementia among the participants, who were community-dwelling women age 65-79 years, over a 4-year follow-up period. Women taking the estrogen/progesterone combination were noted to have an increased risk for probable dementia. The estrogen/progesterone combination did not prevent mild cognitive impairment. The analysis indicated that 23 new cases of dementia would occur in the treatment group for every 10,000 women treated. The second study arm involved a double-blind, placebo-controlled ancillary study of the WHI in 2947 postmenopausal hysterectomized women taking 0.625 mg of conjugated equine estrogen compared to placebo.¹³ Participants were community-dwelling women age 65-79 years and were followed for 5.4 years. In women taking conjugated equine estrogen, a significant adverse effect on cognition was noted compared to placebo, which was greater among women with lower cognitive function at initiation of treatment.¹³

The Multiple Outcomes of Raloxifene Evaluation (MORE) study, involving 7700 postmenopausal women, evaluated the selective estrogen receptor modulator, raloxifene, versus placebo relative to fracture outcomes.¹⁴ Patients were also evaluated according to six cognitive tests administered at baseline, and at 1, 2, and 3 years. There was no significant difference in the active treatment (raloxifene 60 and 120 mg) and placebo groups in cognitive decline in four of the six tests, although there was a trend toward less decline in the active treatment groups combined on the two tests of verbal memory.¹⁴

A randomized, double-blind study evaluated postmenopausal women on high-dose estrogen versus estrogen plus methyltestosterone.¹⁵ Participants were studied for 4 months. Various memory tests (eg, Identical Pictures, Cube Comparisons, Building Memory, and Shape Memory tasks) were performed before and after a 4-month treatment period. Women receiving the combined estrogen/methyltestosterone therapy maintained a steady level of performance on the Building Memory task. Those taking only estrogen showed a decline in performance on this test.

NICOTINE

Nicotinic cholinergic receptor-binding has been noted to be deficient in Alzheimer’s patients and has been the focus of numerous studies. One study in 1995 evaluated the effect of short-term, sustained nicotine administration on behavior, cognition, and physiology.16 This study was a double-blind, placebo-controlled design in which six patients with probable Alzheimer’s disease were exposed to 7, 8, and 7 days of placebo, nicotine, and washout, respectively. Memory, learning, global cognition, and behavior were evaluated daily during this period. Though improved memory occurred during the nicotine condition, memory, behavior, and global cognition were not significantly affected.¹⁶

Numerous case-control and cohort studies have evaluated the risk of Alzheimer’s disease or dementia in patients who smoke. Although many case-control studies have indicated a decreased risk of dementia or Alzheimer’s disease, an increased risk of Alzheimer’s disease has been noted in some cohort studies.¹⁷

A cohort study of 2820 participants age 60 years and older in Europe evaluated the association between cigarette smoking and the risk of dementia at 2-year follow-up.¹⁸ Dementia was diagnosed using the MMSE and the Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised. Participants were classified according to smoking status: never smokers, past smokers, and current smokers. Incident cases of dementia were recorded at follow-up. Of 121 incident cases of dementia that occurred, 84 had Alzheimer’s disease and 21 had vascular dementia. Current smokers had an increased risk of Alzheimer’s disease and vascular dementia, as compared to never smokers after adjusting for age, sex, education, blood pressure, and alcohol intake. There was a dose-dependent effect between light, moderate, and heavy smokers. There are no long-term clinical trials that either prove or disprove these results.¹⁸

STATINS AND ALCOHOL

An observational study of 1037 postmenopausal women with coronary heart disease who were enrolled in the Heart and Estrogen/pro-gestin Replacement Study (HERS) involving 10 of 20 centers was performed to determine whether serum lipo- protein levels and the use of statin drugs is associated with cognitive changes in older women without dementia.¹⁹ The Modified Mini-Mental State Examination (3MSE) was administered at the end of follow-up at 4 years. Lipoprotein levels (total, high-density and low-density cholesterol, and triglycerides) were measured at baseline and at follow-up. Statin use was documented at each visit. Women in the highest quartile for low-density lipoprotein (LDL) cholesterol at cognitive testing had lower mean 3MSE scores and an increased likelihood of cognitive impairment, as compared to women in the lower quartiles. A reduction in the LDL cholesterol level during the 4 years was associated with a lower odds of cognitive impairment versus women whose levels increased. Higher total and LDL cholesterol levels, adjusted for lipoprotein(a) levels, were associated with a lower 3MSE score and a higher likelihood of impairment. High-density lipoprotein cholesterol and triglyceride levels were not associated with cognitive decline. Patients taking statins had higher average 3MSE scores and a trend toward a lower likelihood of cognitive impairment than those not taking statins. These findings were independent of lipid levels.¹⁹

A 6-week double-blind, randomized, placebo-controlled, three-way Latin square design, cross-over study of 22 men with hypercholesterolemia involved the use of lovastatin (40 mg), pravastatin (40 mg), or placebo.²⁰ Patients were also administered a low-fat (< 30%), low-cholesterol diet (< 300 mg daily). There was no difference between the active treatments and placebo relative to cognitive function, although the active treatment patients had a significant decrease in total cholesterol, LDL cholesterol, and triglycerides. Though statin drugs appear promising in the long term for preventing cognitive decline in older people, recommendations for their specific use is pending the outcome of long-term, ongoing, randomized clinical trials.

A study of 1083 patients followed in a hypertension treatment trial between 1983 and 1984 involved follow-up of the cohort over a 9- to 12-month period with initial and updated cognitive function testing using the MMSE.²¹ Premorbid IQ, cardiovascular risk exposure, and cognition of all patients were collected at baseline and follow-up. After adjustment for baseline cognition in the 387 survivors, poorer cognition was noted to be associated with a family history of dementia, increasing age, less decline in systolic blood pressure, lower premorbid IQ (rather than limited education), and abstinence from alcohol.²¹

Specific to the association of alcohol intake and Alzheimer’s disease/dementia, use of alcohol is associated with both risks and benefits, depending, to some degree, on extent and duration of exposure. A prospective study published in 1997 of 3777 community residents age 65 and older in France were followed for 3 years for reported alcohol intake, and to detect incident cases of dementia and Alzheimer’s disease.²² Wine intake in the amount of three to four standard glasses per day (> 250-500 mL [moderate drinkers]) was associated with a decreased risk of dementia (relative risk [RR] = 0.18) and Alzheimer’s disease (RR = 0.25) after adjustment for age, sex, education, occupation, baseline MMSE status, and other possible confounders (medical, psychological, or sociofamilial). On the other hand, chronic alcoholism (excessive intake) is associated with an increased risk of dementia, and may be as high as 10.5% in some studies.

EXERCISE AND SOCIALIZATION

Nonpharmacologic options have also shown some benefit in the prevention or treatment of Alzheimer’s disease/dementia. A retrospective study involving patients with dementia in medical adult day care centers in North Carolina between 1991 and 1992 indicated that patients who were less socially active dropped out of day care more often than those who were more socially active.²³

A cohort study of 5925 mostly Caucasian women (mean age, 70.5 years), with exclusion of those with baseline cognitive deficits or physical mobility problems, were followed for 6-8 years.²⁴ Cognition was measured by the MMSE. Regular exercise was associated with a decreased risk of dementia, and a dose-response was noted.

A recent study involving 2257 physically capable men aged 71-93 years who were assessed from 1991-1993 in the Honolulu-Asia Aging Study were followed for incident dementia.²⁵ Distance walked per day was assessed, and outcomes measured included overall dementia, Alzheimer’s disease, and vascular dementia. At follow-up, 158 cases of dementia were identified. After adjustment for age, men who walked the least experienced a 1.8-fold excess risk of dementia versus those who walked more than 2 miles per day. Those who walked 0.25-1 mile per day had a significantly greater risk of developing dementia than those who walked more than 2 miles per day.

A similar study, which was part of the Nurses’ Health Study, involved women age 70-81 years, and evaluated the association between exercise and cognitive function.²⁶ Older women were assessed by questionnaire twice per year regarding cognitive assessments and reports of leisure-time physical activities from 1995-2001. Long-term regular physical activity, including walking, was found to be associated with significantly better cognitive function and less cognitive decline.

DISCUSSION

Despite all of the “hype” about alternative therapies and their common use by the lay public amounting to a multi-million dollar business, there appears to be little evidence-based medicine that justifies use of specific agents.

Regarding supplements, only one year-long clinical trial indicates that ginkgo may have a mild beneficial effect in reducing cognitive decline in patients with Alzheimer’s disease or vascular dementia. The large-scale multicenter WHIMS, involving both the estrogen/pro-gestin and estrogen-only arms released in 2003 and 2004, respectively, provides definitive evidence of a detrimental effect on cognition in postmenopausal women, despite preliminary studies indicating a beneficial effect. Initial case-control studies indicated that smokers might have a reduced risk of Alzheimer’s disease. However, at least one cohort study indicates an increased risk of Alzheimer’s disease and vascular dementia associated with smoking. There appears to be some preliminary evidence that control of hypertension and hypercholesterolemia with statins and moderate alcohol intake has a protective effect on cognition. However, other studies are warranted. Long-term clinical trials are in progress to confirm findings relative to statin use. Lastly, there also appears to be evidence that socialization and regular exercise have beneficial effects in preventing cognitive decline.

As might be expected, there appears to be a significant amount of information in the literature on the association between various alternative therapies and Alzheimer’s disease or dementia. These preliminary findings from case-control or restrospective studies, as noted above, are seldom proven to be accurate when tested by the gold standard of research designs—the double-blind, placebo-controlled clinical trial format. Unfortunately, there appears to be few of these well-done clinical trials relative to these therapies. To some extent, this is due to the expense, time, expertise, and large populations of participants necessary to undertake such endeavors. Although these studies are necessary since they have the potential to do harm as well as provide benefit, the over-the-counter nature of these agents—and therefore ready access to the public— makes them a much less attractive option for pharmaceutical companies. It is likely that validation of these findings will be slow in coming, from academic medical centers with a special interest in such topics and with grant support provided by nonprofit or state or federal grant programs.