Women’s Health Update:
Alzheimer’s Disease and Women
by Tori Hudson, ND

Dementia – a decline in cognitive function that is severe enough that thinking, remembering and reasoning, interfere with one’s job or social functioning – is considered to be a major medical condition. There are many causes of dementia, but Alzheimer’s disease (AD) is the most common, up to as many as 50% to 70% of the dementia cases.

About twice as many women as men have AD. This in part is due to women’s longer life expectancy, but women have risk factors that may affect them more than men, and have gender specific risk factors as well. The onset and course of AD are similar in women and men.¹ Some studies have found that women with AD tend to have lower scores on the Mini-Mental State Examination than men. Women may also have greater deficits in language skills than men,^2,3 and psychiatricand behavioral problems may also be more frequent in women with AD than in men.⁴ Women tend to survive longer after the onset of AD than men and the age-specific prevalence of AD may be 1.5 to 3 times greater for women.

Clinical Features

Symptoms of AD usually appear after age 65 although rare forms of the disease may become symptomatic in the 40s and 50s. A decline in the ability to learn and recall new information is usually the first sign of AD. Forgetting recent conversations or events and repeating stories or questions are typical symptoms. These changes progress slowly over the next 5, 10, 15 years. Difficulty with word recall, simple tasks like balancing the checkbook and getting lost on familiar streets become more problematic. Poor judgment, difficulty speaking and understanding speech and an inability to perform even simple tasks are signs of the disease progressing. Depression, apathy, irritability and agitation, hostility, paranoia and delusions can occur later in the disease course. Eventually, patients can lose basic motor skills and no longer recognize loved ones.

The two most significant changes in the brain are the development of neurofibrillary tangles within neuronal cell bodies of the cerebral cortex and hippocampus and plaques with a Beta amyloid core within the neurophil between cell bodies. Other specific changes in the brain include a deficiency in acetylcholine and the death of brain cells.

Risk Factors

Increasing age and family history of dementia are the most consistent risk factors for AD. A parent or a sibling with AD doubles the risk for developing AD. Early onset of AD prior to age 60 occurs in only about 5% of cases and is due to inherited mutations that are autosomal-dominant and occur at specific genetic loci on chromosome 21. Another strong influence of the degree of AD risk is due to polymorphisms of apolipoprotein E, involved in lipid transport and repair of neurons. This genetic train roughly triples the risk of AD. However, this risk is greater for women than for men. Some studies have suggested that head trauma, a history of depression and a family history of trisomy 21 may increase the risk. For women, there is some evidence that suggests that estrogen replacement therapy reduces the risk. Unfortunately, we know very little about risk factors and protective factors and not all are certain. They include the following:⁵

• Increasing age

• Family history of dementia

• Mutations at specific genetic loci on chromosomes 1,14,21

• E4 allele of apolipoprotein E gene

• Family history of trisomy 21

• Female

• Depression

• Head trauma

• Thyroid disease

• Low education level

• Solvent exposure

• Aluminum exposure

Other factors may be protective although are considered to be controversial:

• Estrogen replacement therapy

• Anti-inflammatory medications

• Antioxidants

• Smoking

Treatment

Currently available drugs are providing some symptom relief for limited periods of time in some individuals. Some of the behavioral symptoms such as agitation and depression can be managed with behavioral therapy and prescription drugs and natural therapies that function as antidepressants, mild sedatives, and anxiolytics.

Observational studies have suggested that there is a relationship between endogenous estrogen exposure and cognition.⁶ A number of other observational reports have demonstrated that HRT use may prevent or delay the onset or progression of Alzheimer’s disease (AD), but additional observational results have been conflicting.⁷ A meta-analysis and systematic review was done in March of 2001 in which twenty-nine studies were rated.⁸ In women who were symptomatic from menopause, postmenopausal estrogen use improved verbal memory, vigilance, reasoning and motor speed. There were no consistent effects on visual recall, working memory, complex attention, mental tracking, mental status, or verbal functions. Estrogen did not appear to enhance asymptomatic women’s performance consistently on formal cognitive testing. The meta-analysis did suggest that HRT was associated with a decreased risk of dementia, but the reviewers acknowledged that the studies analyzed had important methodology problems and inadequate information to properly assess the effects of various estrogen preparations or doses, progestin use, and duration of use.

Studies in animals and the laboratory suggest plausible mechanisms for the potential of estrogen and the prevention and/or treatment of Alzheimer’s disease. Estrogen increases dendritic spine growth, axonal elongation, synapse formation and neuronal survival. It also influences several neurotransmitters including acetylcholine, modulates nerve growth factor, increases apo E, enhances blood flow, is an antioxidant, and enhances the uptake and metabolism of glucose. All of these effects could possibly inhibit the neurotoxicity of beta-amyloid and the damaging effects of free radicals, moderate the inflammatory events involved in plaque formation in the brain, enhance cerebral blood flow, and facilitate neuronal repair after brain injury.

Results of randomized trials of ERT and AD, and the potential of estrogen for the treatment of AD have not been impressive in benefits. In fact estrogen replacement for 1 year did not slow disease progression nor improve global, cognitive, or functional outcomes in women with mild to moderate AD.⁹ However, in a recent review article and meta-analysis, randomized controlled trials and cohort studies were reviewed for the effects of HRT on cognitive decline; cohort and case-control studies were reviewed for the risk of dementia.¹⁰ Twenty nine studies were evaluated. Women who were symptomatic with menopause symptoms had improvement in verbal memory, vigilance, reasoning and motor speed with hormone replacement therapy (HRT). No improvement in other cognitive functions was observed. In women who had no other menopause symptoms, HRT delivered no observable cognitive benefits. A meta-analysis of observational studies on HRT and cognition suggested that HRT was associated with a decrease in the risk of dementia. Due to potential bias, lack of control in these studies, and inadequate information about kinds and dosages of estrogens and progestogens used, definitive conclusions are difficult to come by. Future prospective randomized studies may identify which women may most likely receive cognitive benefit and reduction in risk of AD from HRT or if any true clear benefit exists.

Preventing free radical damage to the brain, supporting sufficient circulation in the brain, preventing plaque formation, providing critical brain nutrients and supporting cellular activity are the fundamentals of utilizing natural therapies in reducing the risk of AD and treating AD. Both vitamin C and vitamin E play a critical role in protecting against oxidative damage, and specifically in this case, to the arteries and brain cells. Vitamin E in doses up to 2,000 IU per day is showing significant promise and benefit in slowing cognitive decline.¹¹ There is now sufficient evidence that oxidative damage plays a major role in the development and progression of dementia.^12-14

Both vitamin B12 and folic acid declines with age and both are found as major deficiencies in elderly individuals. Supplementing with B12 and folic acid can reverse impaired mental function. In Alzheimer’s patients, serum vitamin B12 levels are significantly low, and a deficiency is quite common.¹⁵ Folic acid and vitamin B12 are essential in order to make sufficient phosphatidylserine. Elevated homocysteine levels are now also being implicated in AD. Folic acid, B12 and B6 are used to lower homocysteine levels.

Huperzine A is an alkaloid isolated from Huperzia serrata (or Qi Ceng Ta), a Chinese herb. The interest in Huperzine A and dementia is focused on its ability to selectively inhibit acetylcholinesterase. This inhibitory effect in part explains the memory enhancing properties of Huperzine A. Huperzine A was studied and found to improve working memory in monkeys.¹⁶

Phosphatidlylserine plays a primary role in the integrity of brain cell membranes. Low levels of phosphatidylserine in the brain are associated with impaired mental function. Eleven double-blind studies have been completed using phosphatidylserine in the treatment of age-related cognitive decline with good results. In the largest study, improvements were observed in mental function, mood, and behavior.¹⁷

Vinpocetine is derived from vincamine, which comes from the Vinca minor plant or periwinkle. Vinpocetine increases blood flow to the brain, increases the rate at which the neurons produce energy, speeds the use of glucose and oxygen in the brain and increases the production or concentration of neurotransmitters involved in the function of memory, such as noradrenaline, dopamine, acetylcholine and serotonin. Vinocetine has proven benefits for vascular-based cognitive dysfunction.¹⁸

Ginkgo has the ability to normalize acetylcholine receptors in the brain, increase cholinergic transmission, improve vascularity to the brain and enhance oxygen levels, provide antioxidant benefits and increase numerous brain functions. Ginkgo may be effective in relieving the decline in mental functions associated with cerebral insufficiency due to brain ischemia. It appears that ginkgo extract helps to reverse or delay mental deterioration during the early stages of Alzheimer’s disease.^19-21

In a recent study, blueberry extract was given to animals who then showed fewer age-related motor changes and outperformed the non-blueberry fed group on memory tests.²² We know that blueberries contain antioxidants that may act to protect the body and brain from oxidative damage. In fact, the group studied who received not only blueberry extracts but strawberry and spinach extracts as well, showed signs of the presence of vitamin E in their brains.

In traditional herbal medicine, ginseng functions as a tonic, anti-stress agent and is known as an adaptogen. New scientific research has led to Ginseng extract being studied for its effects on mental performance. In a clinical trial of Italian university students, those receiving ginseng had improvements in attention, logical deduction, mental arithmetic, improved reaction times and a greater sense of well-being.²³

Gotu Kola has been used in traditional herbal medicine to strengthen and revitalize body and brain and even as a promoter of longevity. An ancient proverb goes, “Two leaves a day will keep old age away.”

Summary

AD disproportionately affects women. Not only do twice as many women as men have AD, women who do develop AD tend to have more severe disease and greater problems with impaired language and psychiatric issues.

References

1. Buckwalter J, Sorbel E, Dunn M, et al. Gender differences on a brief measure of cognitive functioning in Alzheimer’s disease. Arch Neurol 1993;50:757-760.

2. Henderson V, Buckwalter J. Cognitive deficits of men and women with Alzheimer’s disease. Neurology. 1994;44:90-96.

3. Ripich D, Petrill S, Whitehouse P, et al. Gender differences in language of AD patients: a longitudinal study. Neurology. 1995;45:299-302.

4. Cohen D, Eisdorfer C, Gorelick P, et al. Sex differences in the psychiatric manifestations of Alzheimer’s disease. J Am Geriatr Soc. 1993;41:229-232.

5. Paganini-Hill A, Henderson V. Estrogen in the treatment and prevention of Alzheimer’s disease. International Journal of Pharmaceutical Compounding. 1998;2(1):26.

6. Smith C, McCleary C, Murdock G, et al. Lifelong estrogen exposure and cognitive performance in elderly women. Brain Cogn 1999;39:203-218.

7. Grodstein F, Chen J, Pollen D, et al. Postmenopausal hormone therapy and cognitive function in healthy older women. J Am Geriatr Soc 2000;48:746-752.

8. LeBlanc E, Janowsky J, Chan B, Nelson H. Hormone Replacement Therapy and Cognition; Systematic Review and Meta-analysis. JAMA 2001;285(11):1489-1499.

9. Mulnard R, Cotman C, Kawas C, et al. Estrogen Replacement Therapy for Treatment of Mild to Moderate Alzheimer Disease. JAMA 2000;283(8):1007-1015.

10. LeBlanc E, Janowsky J, Chan B, Nelson H. Hormone Replacement Therapy and Cognition. JAMA 2001;285(11): 1489-1499.

11. Sano M, Ernesto C, Thomas R, et al. A controlled trial of selegiline, alphatocopherol, or both as treatment for Alzheimer’s disease. NEJM 1997;336:1216-1222.

12. Markesbery W. Oxidative stress hypothesis in alzheimer’s disease. Free radical biol Med 1997;23:134-147.

13. Ames B, Shigenaga M, Hagen T. Oxidants, Antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci 1993;90:7915-7922.

14. Smith M, et al. Oxidative damage in alxheimer’s disease. Nature 1996;382:120-121.

15. Van Goor H, et al. Review: Cogalamin deficiency and mental impairment in elderly people. Age Ageing 1995;24:536-542.

16. Ye J, Cai J. Improving effects of hyperzine A on spatial working memory in aged monkeys and young adult monkeys with experimental cognitive impairment. J Pharmacol Exp Ther 1999;288(2):814-819.

17. Cenacchi T, et al. Cognitive decline in the elderly: a double-blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration. Aging 1993;5:123-133.

18. Fischhof P, Moslinger-Gehmayr R, et al. Therapeutic efficacy of vincamine in dementia. Neuropsychobiology 1996;34(1):29-35.

19. Hofferberth B. The efficacy of Egb761 I patients with senile dementia of the alzheimer type, a double-blind, placebo-controlled study on different levels of investigation. Human Psychopharmacol 1994;9:215-222.

20. Kanowski S, et al. Proof of the efficacy of the ginkgo biloba special extract Egb 761 in outpatients suffereing from mild to moderate primary degenerative dementia of the alzheimer type of multi-infarct dementia. Phytomedicine 1997;4:3-13.

21. Le Bars P, et al. A placebo-controlled, bouble-blind, randomized trial of an extract of ginkgo biloba for dementia. JAMA 1997;278:1327-1332.

22. Joseph J, Shukitt-Hale B, et al. Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J of Neuroscience 1999;19(18):8114-8121.

23. D’Angelo L, et al. A double-blind, placebo controlled clinical study on the effect of a standardized ginseng extract on psychomotor performance in healthy volunteers. J Ethnopharmacol 1986;16:15-22.

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