Familial Alzheimer disease

Introduction

According to Harrison's Principles of Internal Medicine, dementia is a syndrome with many causes. The term is applied when a deterioration in cognitive abilities impairs the previously successful performance of activities of daily living. Memory is the most common and most important cognitive ability that is lost. (1)

The most common causes of dementia are: (2)

* Alzheimer's disease

* Vascular dementia (caused by multiple strokes)

* Alcoholism

* Parkinson's disease

* Drug intoxication

This article will focus on * disease (AD) which is more than 50% of all cases of dementia. The term AD originally defined presenile or early onset dementia, but is now used to describe any progressive dementia with the characteristic pathological changes. (3)

The prevalence of AD goes up rapidly with age because of the entry of the late onset type of AD. (4)

These figures show that more than 50% of people over 95 years will have dementia. AD should not be a consequence of aging! This steep rise in incidence with age means that halving the risk for AD at any given age might only translate to a delay in onset of several years. Due to people living longer, the incidence of AD in the general population is increasing; for example deaths from AD in 1993 were 20 times those in 1979.

The following graph of nerve cell loss in the brain illustrates the reason behind this phenomenon. (5)

The nerve cell loss that happens in AD might start around 40 years, but the symptom threshold line is such that by the time the person shows symptoms of AD (say in their 60s or 70s) a large percentage of the damage has already been done to their brain. This is, therefore, a disorder which is best prevented.

From the addition of two vertical lines -- life expectancy in 1920 and life expectancy in 1990, it can be seen that in 1920 many people died before they had a chance to develop AD. (5) Now we are living longer, more people are developing AD and it is likely to become an even more serious social problem over the next 30 years.

AD is expected to cost the United States $100 billion by the year 2010. (4) It has been well put by Zaven Khachaturian that "AD is a scientific puzzle, a medical whodunit, a psychosocial tragedy, a financial disaster and an ethical, legal and political dilemma." (6) The seriousness of this problem cannot be overstated, and as we make greater inroads into the prevention of cancer and heart disease, AD could become the most serious health problem that faces the industrialized world.

Definition and Neurophathology of AD

AD is characterized by a progressive process that kills brain cells and destroys synaptic connections between nerve cells in the brain. The disease is traditionally characterized by the presence of what are called neuritic or senile plaques and neurofibrillary tangles and loss of nerve cells which rely on acetylcholine as a neurotransmitter.

The core of the neuritic plaques is composed of beta-amyloid protein (A[beta]) which is a minor breakdown component of amyloid precursor protein (APP). (This protein gets broken down in the brain and one of the fragments can be beta-amyloid protein which seems to deposit and cause the neuritic plaques.) Neurofibrillary tangles consist of paired helical filaments of abnormally phosphorylated tau protein (tau is normally an important component of the neuronal cytoskeleton (nerve cell architecture)). The tau protein goes into little helical twists which is associated with the excessive attachment of phosphate groups (phosphorylation). It is not clear why this happens. The phenomenon of amyloid precursor protein in the brain not being handled properly and the deposition of beta-amyloid protein to form neuritic plaques is considered to be a primary or at least a very significant pathogenic event. (7)

One group of authors have divided the sequence of changes that can occur in the brain in AD into four basic categories of primary, secondary, tertiary and quarternary events. (8) The primary events relate to genetic factors and some death of nerve cells - apoptosis or spontaneous cell death. The secondary events include the beta-amyloid deposition, cytoskeletal and tau changes resulting in synaptic loss, especially of the cholinergic neurons. Tertiary events then occur with neurotransmitter deficits, trophic alterations and immune dysfunction. When brain cells start dying they release amino acids such as glutamine which results in an excitotoxic reaction from these agents. These events also result in changes in calcium metabolism, free radical formation (metal ions binding to A[beta] may play a role in this) and circulatory alterations in the brain which impair adequate nutrition via the circulation. These are then the quarternary events in AD.

There is much made of genetic factors in AD, but I wish to down-play these. The strongest genetic links are for early onset familial dementia (presenile dementia). (3) The apolipoprotein E genotype has also been proposed as a major genetic factor in late onset AD. (3,9) (ApoE is a lipid-transport protein in serum and the major lipid transporter for the central nervous system.) Overall, genetic factors are currently proposed to account for about 50% of late onset cases. However, this has recently been questioned with some researchers suggesting that genetics may not be important in late onset AD. If they are relevant they might only account for 10% of cases. (10,11)

So if there are genetic links with late onset AD, there is no current consensus at this point in time. This highlights that late onset AD is probably more a lifestyle/environmental disease -- perhaps with some genetic tendencies, as opposed to early onset AD which definitely has a high genetic association.

Risk Factors

The generally acknowledged risk factors for AD are: (3,12)

* Age

* Family history

* ApoE genetics

* Gender (risk is higher in females, HRT is thought to be protective although this is unproven)

* Down's syndrome

The unfortunate thing about all of these generally acknowledged risk factors is that there is little that can be done to change their influence.

Risk factors which are generally acknowledged as possible are: (12)

* Head injury

* Hypothyroidism

* Advanced maternal age

* Low educational attainment

* Smoking (protective, thought to be due to nicotine)

* Vascular risk factors (hypertension, raised LDL cholesterol, (13) etc)

There are a number of controversial risk factors for AD: (12)

* History of depression

* Zinc deficiency or zinc exposure (14)

* Stress (15)

* Solvent exposure (especially people working in industry) (16)

* HSV-1 exposure (herpes simplex 1 virus can cause brain infections) (17)

* Aluminum exposure

* Elevated plasma homocysteine (18)

* Thiamine deficiency (19)

In addition to the possible protective effects of nicotine exposure, the following have been identified as possible protective factors (some are quite controversial):

* Vegetarian diet (20) and monounsaturated fatty acids (e.g. olive oil) (21)

* Vitamin C and E supplementation (22)

* Use of benzodiazepine drugs (e.g. Valium) (23)

* Use of anti-inflammatory drugs (24)

* Wine intake (25)

* Calcium and silicon levels in drinking water (26,27)

The Aluminum Debate

There is equally as good evidence that aluminum exposure is not a risk factor as there is evidence that it is a risk factor. But why not avoid it? Aluminum binds to an iron carrier protein known as transferrin and concentrates in brain regions. The Al (3+) ion is about the same size as the Fe (2+) ion so it quite happily latches onto transferrin (and latches on quite tightly) and then can be transferred into the brain by that mechanism. Aluminum accumulates in the brain in regions where transferrin receptors are highest. (28) It also displaces magnesium in key metabolic reactions in brain cells. The first utilization of alum (which contains aluminum) to rapidly filter drinking water occurred in Frankfurt in 1880 and the first cases of AD were described in 1907 by Alois Alzheimer in the Frankfurt vicinity. (3,29)

There are several substantial epidemiological studies which link aluminum in drinking water with AD (30-32) and some suggest a protective role for silicon. (33) Desferrioxamine, an aluminum, iron and copper chelator, was successfully used in a clinical trial on AD. This is not necessarily proof for aluminum's role. The drug was used to clear these ions out of the system of these patients and there was clinical improvement. (34) Other authors have looked at these results and disputed the validity of the trial. (35)

One of the reasons why the "anti" case for the aluminum controversy has held sway in the scientific community is that serum aluminum is generally not significantly raised in people with dementia. But a recent study found that it was (up to 2 to 3-fold) (28) and silicon appeared to help aluminum excretion. (36) Aluminum and silicon bind tightly together so silicon is a protective factor against aluminum exposure. Avoiding aluminum is easy to do: avoid drinking out of aluminum cans, avoid aluminum pots and stop drinking unpurified town water.

The Homocysteine Controversy

The homocysteine controversy is a fascinating story. Recently, a few studies have linked increased levels of plasma total homocysteine with increased risk for AD and increased rate of progression. The authors (37) had trouble publishing their findings in major medical journals, such as Lancet, BMJ, JAMA. The reason that the editors gave for rejecting publication was that there is no evidence that lowering homocysteine (or taking folate to lower homocysteine) is associated with a benefit in AD, and people should not needlessly supplement themselves with folate! Elevated homocysteine is a recognized cardiovascular risk factor. Homocysteine levels are linked to folate, B12 and B6 status, but have also been recently linked to stress. In one of the studies, the elevated homocysteine was correlated with low folate and B12 status.

In one of the most important papers linking homocysteine and AD, Clarke states "The stability of homocysteine levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease." (37) In other words if you have had AD for 10 years and your homocysteine was not trending higher, it is not a consequence of the disease. He therefore argues strongly against it being a result of the disease process. Elevated homocysteine levels are either a marker of something else that is producing an increased risk of AD (such as folate deficiency) or they are a risk factor on their own, a causative risk factor.

A recent study made it into the New England Journal of Medicine. (38) In a retrospective epidemiological study it was found that an increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and AD.

Current Treatment of AD

The currently approved drugs for the treatment of AD are acetylcholinesterase inhibitors. In AD, degeneration of presynaptic cholinergic (acetylcholine-releasing) neurons occurs leading to a reduction in the availability of acetylcholine, resulting in an underactivation of postsynaptic neurons (which remain preserved for some time). (3) Commonly used drugs are tacrine, donepezil and rivastigmine. They increase the acetylcholine by inhibiting its breakdown in the synaptic cleft. The postsynaptic neurons, the ones receiving the message, will still get the message. Benefits from these drugs are limited (some experts are of the opinion that tacrine is ineffective) and they can have pronounced side effects (e.g. tacrine is hepatotoxic).

Promising leads in the natural products area include rivastigmine (an analogue of physostigmine), (39) galanthamine (from the narcissus bulb and the snowdrop), (40,41) and huperzine A (from the Chinese herb Huperza serrata). (42)

"The evidence to date is that treatments based on the cholinergic hypothesis are essentially symptomatic. No substantial data support the hypothesis that these medications modify the disease -- that is, delay its progression. There is little evidence that these medications work in patients with either incipient dementia or advanced disease...." (Leon Flicker Professor of Geriatric Medicine. (43) So essentially these drugs, be they of natural origin or not, are a symptomatic treatment of very limited benefit. The Cochrane report (which analyzes the efficacy of treatments) concluded that tacrine was ineffective for AD.

Herbal Treatments

Our really major lead is Ginkgo. Early studies on Ginkgo biloba were on patients with "cerebral insufficiency" which is not an accepted medical entity, merely a collection of symptoms poorly related to dementia. Recently a number of trials have been published which investigated the use of Ginkgo in AD. A meta-analysis of these concluded that there was a small but significant effect of 3 to 6 months' of treatment with 120 to 240 mg of standardized extract on objective measures of cognitive function. Results on noncognitive behavioral and functional measures as well as global rating were inconclusive. Since then further positive studies have been published. (45,46)

The evidence for Ginkgo as a proven treatment for AD is probably as good as it is for tacrine. Ginkgo at least is a treatment without side effects and possibly with a whole lot of other benefits in terms of arresting the disease process (see later in this article). Tacrine and donepezil are just symptomatic treatment, they do not stop the progression of the disorder.

A separate analysis of clinical data concluded that Ginkgo was as effective as donepezil and rivastigmine in mild to moderate AD. (47) Since a recent JAMA study suggested, based on pathological findings, that cholinesterase inhibitors are less appropriate for mild (compared to severe) AD, (48) using EBM criteria (proof of efficacy, safety profile and relevance to the known pathological processes) Ginkgo should be the preferred treatment for mild AD. I would suggest that the reasons why it is not are more related to commercial factors than scientific issues.

A group of British scientists investigated plants reputed in herbal texts to enhance memory for inhibition of acetylcholinesterase in vitro (in test tubes) and the highest activity was found for sage (Salvia officinalis). The essential oil had the highest activity. (49) Follow-up studies on the essential oil of Spanish sage (Salvia lavandulifolia) demonstrated activity in vivo in rat brain tissue. (Spanish sage essential oil does not contain thujone, which is potentially neurotoxic.) Protopine from Corydalis ternata has anticholinesterase activity in vitro and in vivo at least as strong as tacrine and donepezil. (50) Protopine is found in many other herbs, including fumitory (Fumaria officinalis). Such plants may be of value, but remember the limitations of using acetylcholinesterase inhibitors.

Bacopa monniera, is a herb rich in steroidal saponins. This is a herb that shows promise, despite lacking in clinical trials for AD. In experimental models, Bacopa improved motor efficiency and learning, (51) improved acquisition and retention and delayed extinction of newly acquired behavior, (52) and has shown sedative and anticonvulsant activity. (53,54)

Other herbs traditionally regarded as cognition enhancers or anti-aging include:

* Rosmarinus officinalis (rosemary)

* Melissa officinalis (lemon balm)

* Centella asiatica (gotu kola)

* Polygonum multiflorum

* Panax ginseng (ginseng)

* Withania somnifera

* Schizandra chinensis

Several of these could prove to have potential in the treatment and prevention of AD.

Prevention

"It is becoming clear that the etiopathogenic factors responsible for AD are undermining the brain of people at risk during 30 to 40 years prior to the onset of the disease.... Available and expected treatments in the near future are unlikely to be fully effective due to the severity of the brain damage when the clinical symptoms appear." (4) Therefore prevention will be the best strategy.

"Because the etiology and pathogenesis of AD has not yet been clearly defined, and therefore the therapeutic targets central to this still need to be found, the current strategies to help patients during the course of this devastating disease are directed against various factors and events that are associated with AD." (55) The same strategy can be adopted for prevention. Primary prevention is the control of recognized risk factors in the general population to prevent the disease. Secondary prevention is stopping or slowing the disease process for those defined at risk via use of markers for preclinical or early phases of the disease. Tertiary prevention is intervention to reduce severity in those who already have the disease. (12)

All of these approaches are relevant, but particularly secondary prevention -- identifying and treating people who are at risk. Brain scan tests and other tests are beginning to be used: from MRI imaging we can now identify people at risk. Primary prevention is a lot more difficult to do.

Some of the possible risk factors that can be addressed are:

* Wear protective head gear as appropriate

* Attend to vascular risk factors, especially hypertension

* Be mentally active, always learning new things

* Maintain good thyroid function

* Avoid or deal positively with stress, deal with depression

* Avoid exposure to solvents

* Avoid aluminum exposure and improve silicon intake (e.g. nettle tea)

* Reduce homocysteine levels -- folate supplementation (and nettle tea)

* Have a good calcium intake (possibly magnesium as well)

* Have a good antioxidant intake

* Possibly have a vegetarian diet and increase monousaturated fatty acid intake (e.g. olive oil).

Immune Activation and Oxidative Damage

Of the etiopathogenic events in AD discussed earlier, immune dysfunction and free radical formation by metal ions binding to amyloid [beta] are particularly important. Recent research could elevate these factors up to tertiary or even secondary pathogenic events. (56,57)

What is generating the reactive oxygen species? It could well be immune cells. All of the changes in AD could be brought about by local immune cells: microglia and astrocytes. AD could be an immune-mediated localized inflammatory reaction. (58)

The intake of anti-inflammatory agents certainly decreases the risk of AD, as illustrated by the following meat-analysis. (58)

The calculated odds ratios and P values are shown for each group. (58) Rheumatoid arthritis patients only have 20% of the risk of the general population of developing AD. The reason is possibly because, as well as taking anti-inflammatory drugs, the immune dysfunction is controlled with agents such as methotrexate.

Beta-amyloid induces lipid peroxidation and can generate reactive oxygen species (types of free radicals) via metal-ion-dependent pathways (Fe, Cu,Al). (59) An article in the June 1999 New Scientist entitled "Bleached Brains" outlined that cells containing beta-amyloid protein also have raised levels of hydrogen peroxide. (The hydrogen peroxide could then be broken down further into reactive oxygen species.) The type of beta-amyloid associated with the most aggressive form of AD was the best at binding copper and iron (and hence at generating peroxide)."

Chemicals known as isoprostanes accurately reflect brain oxidative damage and are increased in frontal and temporal parts of the brain in AD. (61) DNA and protein oxidation and lipid peroxidation are higher in the brains of AD patients than controls. (62) There is evidence for oxidative stress and mitochondrial dysfunction in the brains of AD patients. (63) Vitamin E slowed progression of AD in one clinical trial. (64) Plasma vitamin C is lower mAD patients in proportion to the degree of cognitive impairment and is not explained by lower intake. (65)

The following quotations highlight the importance of oxidative damage in AD:

* "The hypothesis that oxidative stress might play an important role within the framework of the pathogenesis of AD is currently the subject of intense discussion." (66)

* "Recent evidence supports oxidative damage as the earliest cytopathological and biochemical change in AD." (67)

* "Oxidative damage to brain cells may be a principal indicator of AD activity according to new research that has identified increased concentrations of free radicals in certain areas of patients' brains." (68)

A study in the Bordeaux region (the PAQUID study) found that mild drinkers had a 55% chance of developing AD compared to non-drinkers. For moderate drinkers the relative risk was 28%. When the data were reanalyzed by several statistical techniques the protective association was still evident. (25) The protective factors in wine could be oligomeric procyanidins (OPCs in grape seeds and skin) or resveratrol (in grape skin) which are both powerful antioxidants.

Until recently resveratrol was not thought to be bioavailable but recent research shows that it is. It is also found in dark grape juice. Resveratrol has numerous pharmacological properties including antioxidant, chemoprotective and anti-inflammatory. One researcher has even suggested that its estrogenic properties maybe significant in the context of AD. (69)

In vitro, resveratrol increases certain agents which stimulate and regenerate nerve cells. (70) Resveratrol is also found in certain species of Polygonum (the Chinese herb Polygonum cuspidatum). Polygonum multiflorum (He Shou Wu) contains a tetrahydroxystilbene glycoside. Tetrahydroxystilbene is very similar in chemical structure to resveratrol, and could in fact be an important brain antioxidant.

It is almost identical to resveratrol except that it has an extra hydroxy group and that means that it may be even better as an antioxidant than resveratrol. Polygonum multiflorum is said to be named after a man who was, so the legend goes, locked into an area. He had nothing to eat but this herb and when he came out a few years later, his gray hair had turned to black, and he was rejuvenated. It is used in Traditional Chinese Medicine to treat dementia.

Is it really valid to suggest herbs to prevent AD? I would like to quote Ramon Cacabelos and coworkers who published recently, an excellent article on AD in the International Journal of Geriatric Psychiatry. Talking about prevention, they wrote: "Since these treatments are to be administered for many years prior to the onset of the disease to protect the neuron against exogenous insults, as well as endogenous degeneration inducers, they do not need to display specific therapeutic efficacy [but I would add it is a bonus if they do] according to the conventional standards of AD in clinical trials, but to prove their efficacy as neuroprotectors and enhancers of neuronal survival without adverse effects.("4) This well describes Ginkgo biloba and, as a bonus, it is also therapeutically proven in AD.

Numerous studies have demonstrated that Ginkgo is neuroprotective. It possesses antioxidant (71) and anti-inflammatory properties and reduces the oxidative damage observed in brain and liver mitochondria, (72,73) (there is a theory about brain mitochondria being damaged in AD). It is clinically valuable (its active components have access to the human brain) and it is nontoxic and relatively free of side effects. The preventative dose could probably be lower than the therapeutic dose at 80 mg/day of 50:1 standardized extract (equivalent to 4 g of leaf).

A study at the University of Washington in Seattle found that cat's claw (Uncaria tomentosa) prevented the deposition of [beta]amyloid in vitro and in vivo. When the cat's claw was mixed with Ginkgo, gotu kola and rosemary it worked even better in vitro. The formula is being clinically trialed in patients with mild to moderate AD. (74-76)

Silicon is a protective factor against aluminum and soluble silicon reduces aluminum absorption and increases aluminum excretion. Dried horsetail (Equisetum arvense) is a good source, but a Polish study showed that you have to decoct it for several hours to release a significant level of soluble silicon. (77) However, nettle leaf (Urtica dioica) is a better source because a decoction over 30 minutes releases significant levels of soluble and therefore absorbable silicon (5 mg/g of dried leaf) from the dried leaves. (78)

Summary: Plants and the Prevention of AD

Ginkgo biloba standardized extract

Vitis vinifera in the form of grape seed extract (OPC) or grape seed and skin (OPC and resveratrol)

Other antioxidant plants with protective activity on the microvasculature e.g. Vaccinium myrtillus (bilberry), Allium sativum (garlic)

Urtica dioica tea (decocted) as a source of silica

The Chinese Polygonums

Cat's claw, rosemary and the cognition-enhancing herbs listed previously

Anti-inflammatory herbs may have a role, but more research is needed, e.g. Boswellia

These are all candidates but we need to do more research which requires a large amount of funding. I would argue that it is in the public interest that such studies be funded by government grants.

Case History

When Don first came for herbal treatment more than 3 years ago, he was 63 years of age. Don had been a music teacher (trumpet) but was retired because he could not cope with teaching any longer. Shortly afterward he was diagnosed with early AD. Apart from mental deterioration he also suffered from uncharacteristic violent outbursts. After a few months he was put on donepezil (previously on antidepressants).

b) Vitanox tablets, two per day -- herbal antioxidant tablets containing grape seed, green tea, turmeric and rosemary.

c) Tablets at 3 per day containing: Bacopa, Schisandra, Siberian Ginseng and Rosemary oil

d) Antioxidant supplements were also recommended

Since being on the herbal treatment Don has deteriorated, but this is substantially less than other patients diagnosed at the same time (according to his wife who is in contact with an AD caretaker support group). The inclusion of skullcap in his formula has completely solved the violent outbursts. Don's psychiatrist is impressed with his slower than expected deterioration and has told him to 'keep on doing whatever he is doing.'

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