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Alzheimer’s disease
By Ronald Steriti, NMD, PhD


Alois Alzheimer, a German psychiatrist, first described Alzheimer’s disease in 1907. He noted the pathologic hallmarks of the disease, including neurofibrillary tangles and senile plaques.


The symptoms of Alzheimer’s disease usually begin in the seventh to ninth decades of life, although early onset familial forms of the illness are well described (see below).

The most characteristic symptom of Alzheimer’s disease is a profound impairment of recent memory. Individuals begin to misplace everyday items, such as the car keys or eyeglasses, and become disoriented and get lost in familiar surrounds (such as when driving on well-known streets). As the disease progresses they may experience mood swings with anxiety, depression or aggressive behavior. They often become uninterested in usual activities. In the terminal phase there is apathy and an inability to communicate.

Neuropsychiatric symptoms that commonly accompany Alzheimer’s disease include: [1]
Agitation in 60% to 70% of patients
Apathy, 60% to 70%
Depression, 50%
Anxiety, 50%
Irritability, 50%
Delusional disorders and psychosis, 40% to 50%
Disinhibition, 30%
Hallucinations in 10%


Alzheimer’s disease is the leading cause of dementia in the elderly and is the fourth leading cause of death in developed nations (after heart disease, cancer and stroke). Up to 70% of dementias are due to Alzheimer’s disease, with blood vessel disease (stroke and atherosclerosis) being the second most common cause.

As age advances, the risk of developing Alzheimer’s disease rises sharply. The frequency of Alzheimer’s among 60-year-olds is about 1%. This incidence doubles approximately every 5 years, becoming 2% at age 65, 4% at 70, 8% at 75, 16% at 80, and 32% at 85. It is estimated that as many as two-thirds of those in their nineties suffer from some form of dementia. For those who aspire to live a very long life, dementia is a threat second only to death. Some believe that dementia is a natural way to end life.
There are over 100,000 deaths per year related to Alzheimer’s disease. Four million people and their families suffer from this disease. Annual costs to the United States from Alzheimer’s disease are over $60 billion. If a treatment that only delayed (not cured) the onset of the disease by five years, costs to society would decrease by about half and save $30 billion to $40 billion each year in this country alone. [2]


Alzheimer’s disease leads to death within an average of 8 years after diagnosis, the last 3 years of which are typically spent in an institution. Besides memory loss, Alzheimer’s patients show dramatic personality changes, disorientation, declining physical coordination and an inability to care for themselves. In the final stages, victims are bedridden, lose urinary and bowel control and are completely dependent on the care of others. Death is usually due to pneumonia or urinary tract infection.

Risk Factors

There are many of risk factors associated with the development of dementia. Many consider Alzheimer’s disease to be caused by several different factors. The risk factors are summarized below. [3-5]

Very likely

advanced age, family history of Alzheimer’s or Parkinson’s disease, apolipoprotein E-4, head trauma, depression, reduced blood flow, stroke, estrogen imbalance, poor word fluency.

Likely emotional stress, toxic damage, alcohol abuse, nutrient deficiencies, neurotransmitter deficits, metabolic defects, under-activity, lower educational level, occupational electromagnetic exposure.

Possible aluminum exposure, latent viruses, sugar consumption, olfactory deficit, coronary artery disease.


Alzheimer’s disease is the most common cause of dementia. However, it is a diagnosis of exclusion. The diagnosis is only 85% to 90% accurate and the diagnosis is only absolutely confirmed by brain biopsy after death. Brain biopsy is usually unacceptable prior to death, and other causes of dementia must be considered and eliminated before the diagnosis of Alzheimer’s is made.

Alzheimer’s-like symptoms can be manifested by a variety of different diseases including:

Space-occupying lesions in the brain, such as brain cancer and subdural hematoma.
Neurological damage, such as occurs after a stroke or with multiple infarctions.
Other neurological disorders, such as Parkinson’s disease (a deficiency of dopamine), Huntington’s disease, and multiple sclerosis.
Infectious diseases such as meningitis, late-stage syphilis, and AIDS.
Endocrine disorders, such as hypothyroidism and hypoglycemia.
Cardiovascular disorders, such as congestive heart failure and vascular disease.
Liver or kidney dysfunction.
Nutritional deficiencies of vitamin E, magnesium, and B vitamins (B12, folic acid, niacin and thiamin) can also produce symptoms which might be mistaken for dementia.


Currently, the most respected standard for assessing the status of Alzheimer’s patients is the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Memory, orientation, language and functionality are measured on a 70-point scale that increases (on average) by 7 to 10 points per year as the patient’s cognition worsens. An improvement of 4 points (4 point decline in score) corresponds to a clinically significant reversal of symptoms of nearly half a year.
The Mini-Mental Status Exam (MMSE) is frequently used for a quick clinical assessment in following patients with Alzheimer’s disease. The MMSE checks for orientation and simple thinking ability.


Standard lab tests for Alzheimer’s disease include:

Thyroid panel: T3, T4, TSH
Liver function tests
STD testing: VRDL for syphilis, HIV if young
EKG to assess heart function
EEG to differentiate focal vs. diffuse brain dysfunction
Vitamin B12 and folate levels

A CT or MRI of the head is usually ordered to determine if the symptoms are caused by multi-infarct dementia or a subdural hematoma.

Several alternative lab tests may be helpful in evaluating patients with Alzheimer’s disease to guide treatments. These include:

A comprehensive hormone panel, including estrogen (E1, E2 and E3), progesterone, testosterone, and melatonin
Adrenal function test, including cortisol and DHEA
Oxidative stress levels
Essential Fatty Acid Panel
Homocysteine, B6, B12, and folate levels
Markers of inflammation, including C-Reactive Protein (CRP)
Hair mineral analysis to assess heavy metal toxicity
A comprehensive vitamin panel (including vitamins A, C, E, and K and beta-carotene) should be considered.


The etiology (cause) of Alzheimer’s disease is unclear. Several mechanisms have been proposed which are described below.

Acetylcholine Depletion

The chemical defect in Alzheimer’s disease that produces the most striking symptoms is acetylcholine depletion which contributes significantly to loss of memory and loss of capacity for attentiveness. Also, other brain transmitters, such as serotonin, GABA, somatostatin, and norepinephrine, are reduced 50% or more.

The neurons in the cerebral cortex are the focal site of cellular degeneration in Alzheimer’s, but lower brain nuclei that send modulating neurotransmitters to the cortex are also severely affected. Neurons send signals to other neurons by releasing these chemicals into synapses. But signals are only effective when they have a beginning and an end. You can’t send Morse code by applying constant pressure on a telegraph key. Acetylcholinesterase, the enzyme that breaks down acetylcholine, ends the chemical signal that begins when acetylcholine is released into a synapse and then connects with a receptor.
The memory loss effect of acetylcholinesterase may be due to amplification of signals. Neural degeneration weakens or destroys the correct signal modulation so the correct neural messages are unable to be delivered at the synapse. In Alzheimer’s disease, levels of acetylcholine may be decreased by up to 90%. It has been found that giving young human subjects an anti-cholinergic agent (which counteracts acetylcholine), such as scopolamine, gives a profile similar to Alzheimer’s disease.


The most characteristic features of Alzheimer’s disease are senile plaques of beta-amyloid peptide, neurofibrillary tangles involving tau protein, loss of synapses, and (ultimately) the death of neurons. Although neurofibrillary tangles are more closely associated with neuronal death than beta-amyloid, the evidence is becoming convincing that beta-amyloid is the factor most responsible for starting the degenerative processes of Alzheimer’ disease.

Both neurofibrillary tangles and beta-amyloid senile plaques are due to protein abnormalities. The beta-amyloid peptide present in the core of senile plaques is a 42-amino acid chain produced by cleavage of a larger protein known as Amyloid Precursor Protein (APP). There are at least 3 different types of beta-amyloid, depending on the site of RNA splicing/cleavage. Amyloid Precursor Protein is normally found embedded in neural membranes and is thought to contribute to stabilizing the contact points between synapses. Some aggregates of beta-amyloid accumulate throughout brain tissue in normal aging. Beta-amyloid is degraded by at least three enzymes which cleave it into smaller molecules. As it is cleaved and destroyed, more beta-amyloid is formed and accumulates. The damage begins when the beta-amyloid becomes concentrated in senile plaques and an inflammatory reaction with ongoing oxidative stress and free radical damage ensues.

Tau Protein

Neurons, and in particular the axons of neurons, use microtubules to transport substances between the center of the neuron and its outer portions. The assembly and structural integrity of microtubules are dependent upon several proteins, the most important of which is a protein called “tau”.

When tau is abnormally phosphorylated, it forms the paired helical filaments known as neurofibrillary tangles. Why this abnormal phosphorylation occurs is unknown, but the loss of microtubule transport is particularly damaging in neurons that produce and release large amounts of neurotransmitters.

The large pyramidal neurons of the cortex and the forebrain (acetylcholine neurons among others) that are important for cognition have more microtubules than other neurons. These large neurons also have the most neurofibrillary tangles in Alzheimer’s disease. This may explain the decreases in cognitive ability that characterize Alzheimer’s disease.


Lipofuscin (age pigments) also accumulate in neurons and other cells as we age. Although much discussion has ensued as to whether lipofuscin is involved in the pathogenesis of Alzheimer’s disease, few neurologists today believe it is a central factor.

Free Radical Damage

Free radical damage (oxidative stress) is probably the most significant cause of biologic aging. It is well-known that neurons are extremely sensitive to attacks by destructive free radicals. The following evidence supports the hypothesis of free-radical damage being a central cause in Alzheimer’s disease: [6]

The brain lesions present in the brains of Alzhemier’s disease patients are typically associated with attacks by free radicals (for example, damage to DNA, protein oxidation, lipid peroxidation, and advanced glycosylation end products)

Metals (such as iron, copper, zinc, and aluminum) are often present. These metals have a catalytic activity which produces free radicals.

Beta-amyloid is aggregated and produces more free radicals in the presence of free radicals.

Beta-amyloid toxicity is eliminated by free radical scavengers.

Apolipoprotein E is subject to attacks by free radicals, and apolipoprotein E peroxidation has been correlated with Alzheimer’s disease. In contrast, apolipoprotein E can act as a free radical scavenger.

Alzheimer’s disease has been linked to mitochondrial anomalies affecting cytochrome-c oxidase. These anomalies may contribute to the abnormal production of free radicals.

Free radical scavengers (such as vitamin E, selegeline, and ginkgo biloba extract) have produced promising results in Alzheimer’s disease.


In Alzheimer’s disease, an inflammatory cascade begins in response to beta-amyloid. The inflammatory response, involving cytokines and prostaglandins, occurs around beta-amyloid in the neuron. This inflammatory process continues and accelerates the loss of neurons.

Inflammation is a protective response of the body that occurs during the process of repair. The four cardinal signs of inflammation are redness, swelling, heat and pain. The Russian biologist Elie Metchnikoff, proposed that the purpose of inflammation was to bring phagocytotic cells to the injured area in order to engulf invading bacteria. Both Metchnikoff and Paul Ehrlich (who developed the humoral theory of immunity) shared the Nobel Prize in 1908.

Alterations in blood flow occur with inflammation, primarily to increase local circulation and speed repair. The blood vessels become more permeable which allows protein-rich fluid (exudate) to collect between cells. This excess extravascular fluid is called edema.

The mechanism of inflammation is a complex interaction of chemical messangers. Arachadonic acid, via 5-lipoxygenase, forms leukotrienes that cause vasoconstriction, bronchospasm (i.e., asthma), and increased permeability. Alternatively, arachadonic acid can form, via cyclooxygenase, prostaglandins which have similar actions and cause pain. Aspirin and indomethican inhibit cyclooxygenase which results in pain relief, but does not address the underlying cause of the inflammation, or stop the actions of the leukotrienes.

Inflammation can be acute, as occurs after a physical injury, or chronic. There are several causes of chronic inflammation, including:

Persistent infections

Prolonged exposure to toxic elements

Autoimmune disease

Inflammation is considered to be an underlying cause of Alzheimer’s disease, primarily because amyloid-beta is an inflammatory protein. [7, 8]

C-reactive protein is a marker of inflammation that is associated with Alzheimer’s disease. [9]

Advanced Glycation End Products

Glycation is a process central to aging. Advanced glycation end products (AGEs) are formed when glucose binds tightly to protein (the Maillard reaction) forming abnormal (glycated) complexes that progressively damage tissue elasticity. This process causes an increased stiffness in the cardiovascular system leading to high blood pressure. Researchers are proposing that AGEs may be part of Alzheimer’s disease and present the following evidence to support this hypothesis:

AGEs have been found in the neurofibrillary tangles of Alzheimer’s disease.

Polymerization of beta-amyloid peptide is significantly accelerated by cross-linking through AGEs in vitro.

Since lipofuscin is composed of protein and carbohydrate, glycation may be involved in lipofuscin formation more than oxidative stress or inflammation.
The inflammatory process is thought to be more important in the progression of neuronal damage eventually resulting in Alzheimer’s disease. Because of this, researchers are proposing that AGEs may be a major contributor to the pathogenesis of Alzheimer’s disease. [10, 11]

Aluminum Toxicity

The relevance of aluminum as a cause of Alzheimer’s disease is hotly debated. No mention of it is found in recent medical texts, although it is given considerable attention in books by holistic doctors and naturopathic physicians. [12, 13]

The hypothesis that aluminum is a cause of (or a risk factor in) the development of beta-amyloid plaques and neurofibrillary tangles and dementia in Alzheimer’s disease is based on studies conducted in 1965 which showed that injection of experimental animals with aluminum compounds induces the formation of neurofibrillary tangles. [14] Although aluminum has been found to concentrate in the senile plaques of Alzheimer’s patients, it has not been found to be consistently elevated in the brain or spinal fluid. [15]

An article published in the journal Neurology found an astounding 250% increase risk of Alzheimer’s disease in people drinking municipal water with high levels of aluminum for 10 years or more. [16]

Aluminum has been found to inhibit choline transport and reduce neuronal choline acetyltransferase. This may contribute to the acetylcholine deficiency, which is a key component of Alzheimer’s disease. [17]

A study published in the journal Lancet, used desferrioxamine, a chelator of aluminum, to treat Alzheimer’s patients. Desferrioxamine treatment led to significant reduction in the rate of decline of daily living skills. The mean rate of decline was twice as rapid for the no-treatment group. [18]


Homocysteine is an amino acid produced during protein digestion. It is now recognized as a critical risk factor for coronary artery disease and stroke. Elevated homocysteine levels in the blood dramatically increase the production of atheromatous plaques (a mixture of fat and calcified inflammatory tissue that narrows and eventually blocks arteries.) Homocysteine levels reflect the levels of vitamin B6, B12, and folic acid.

Homocysteine has been proposed as a marker for the early detection of cognitive impairment in the elderly with the focus on Alzheimer’s disease. Several studies have found elevated homocysteine levels in Alzheimer’s patients. [19-23]

In a case-control study of 76 patients diagnosed with Alzheimer’s disease and 108 controls, serum homocysteine levels were found to be significantly higher and serum folate and vitamin B12 levels were lower in patients with Alzheimer’s disease. [24]

A study of 52 patients with Alzheimer’s disease, 50 non-demented hospitalized controls, and 49 healthy elderly subjects living at home found that patients with Alzheimer’s disease had the highest serum methylmalonic acid and total homocysteine levels. The study also found, however, that the folate and B12 levels did not correlate between the three groups. [25]

In a recent case-control study of 164 patients with clinically diagnosed Alzheimer’s disease including 76 patients with the diagnosis confirmed postmortem, mean total serum homocysteine concentrations were found to be significantly higher than that of a control group of elderly individuals with no evidence of cognitive impairment.[26]


Tetrahydrobiopterin is the cofactor in the hydroxylation of phenylalanine, tyrosine, and tryptophan leading to the eventual synthesis of the monoaminergic neurotransmitters, dopamine, norepinephrine, and serotonin.

A comparative study of the cerebrospinal fluid (CSF) and plasma of 30 patients with Alzheimer’s disease and of 19 healthy controls showed that the mean CSF biopterin concentration in patients with Alzheimer’s disease was significantly less than in age-matched controls. [27]

A study of four patients with Alzheimer’s disease showed significantly reduced activity of tyrosine hydroxylase and tryptophan hydroxylase, and significantly reduced concentrations of total biopterin in the putamen and substantia nigra, although the total neopterin concentrations did not change significantly. [28]

5-Methyltetrahydrofolate and vitamin B12 appear to be required for the biosynthesis of tetrahydrobiopterin. Patients with senile dementia could possibly be benefited by the administration of 5-methyltetrahydrofolate.[29]


Cobalamin (vitamin B12) deficiency is common in the elderly. Some authors propose that cobalamin deficiency is a risk factor for Alzheimer’s disease. [30]

A Japanese study of 64 patients with Alzheimer’s disease and 80 age-matched healthy adults found that the dietary behaviors of Alzheimer’s disease patients were markedly different. The Alzheimer’s disease patients tended to dislike fish and green-yellow vegetables and took more meats than controls. Nutrient analysis revealed that Alzheimer’s disease patients took less vitamin C and carotene, and consumed significantly smaller amounts of omega-3 polyunsaturated fatty acids (PUFAs) reflecting the low consumption of fish. These habits started from 3 months to 44 years before the onset of dementia, suggesting these dietary abnormalities are not merely the consequence of dementia. [31]

A study published in the journal Neuroepidemiology investigated the relationship between animal product consumption and evidence of dementia in two cohort studies of 272 and 2,984 subjects in California. The matched subjects who ate meat (including poultry and fish) were more than twice as likely to become demented in comparison to their vegetarian counterparts (relative risk 2.18, p = 0.065). The discrepancy was further widened (relative risk 2.99, p = 0.048) when past meat consumption was taken into account. [32]

A study of 5,386 non-demented people found that high intakes of total fat, saturated fat, and cholesterol were associated with an increased risk of dementia. Fish consumption was inversely related to the incidence of dementia and Alzheimer’s disease. [33]


Several forms of Alzheimer’s disease are genetic or inherited. These inherited forms are usually associated with early-onset Alzheimer’s that occurs before the age of 50, and as early as 30. Less than 10% of all Alzheimer’s disease is on a genetic basis. These inherited forms have been studied in the families in which they have occurred and also in Downs’s syndrome (trisomy 21). All of these mutations, including the apolipoprotein E alleles, involve the metabolism of beta-amyloid in some way. So, even in the genetic forms, beta-amyloid remains central to the development of the disease.

Chromosome sites that have been implicated in Alzheimer’s disease include chromosome 21, 19q, 12 and 1. Of the genetic types, the two most common are apolipoprotein E e4 allele and alpha-2-macroglobulin mutation. All the genetic types are inherited as autosomal dominants except for apolipoprotein E e4 allele, in which each dose of the allele increases the risk for developing the disease.

There are several families in which Alzheimer’s disease is very common. These include mutations of amyloid precursor protein, presenilin 1 or presenilin 2. One of the most extensively studied of these families is the Volga-German family. There have been multiple mutations identified involving these three proteins. They all lead to early-onset Alzheimer’s disease.

The genetic basis of Alzheimer’s was first studied in Downs’s syndrome which contains 3 copies of chromosome 21 (trisomy 21). Recent research indicates myoinositol levels are related to chromosome 21. Pre-dementia levels of myoinositol are higher in Down’s syndrome and rise even higher as dementia develops. [34]

Apolipoprotein E

Late-onset Alzheimer’s is associated with the apolipoprotein E e4 allele. In persons homozygous for the e4 allele, Alzheimer’s disease occurs 10 to 20 years earlier than in the general population. Persons having a double dose of the e4 allele (homozygous) have the most increased risk and those having a single dose (heterozygous) have some increased risk. Heterozygotes (a single dose of the e4 allele) develop Alzheimer’s disease 5 to 10 years earlier than the general population. The other 2 alleles possible are e2 and e3, with e3 being the most common. The alleles of apolipoprotein E vary in their affinity for beta-amyloid with e4 causing the most problems. The e4 allele increases its deposition and beta-pleated sheets of amyloid are seen.

The genetic test for apolipoprotein E alleles is easy to obtain. If you obtain this test and have one or two copies of e4 allele, remember that this is not a guarantee you will develop Alzheimer’s, although it does increase your risk. Routine testing for e4 is not usually recommended because it is not causative or predictive of the occurrence of disease. However, if you know you are positive for e4 allele, you would certainly want to institute aggressive preventive measures for dementia.


Alpha2-macroglobulin is another component of the senile plaque, along with beta-amyloid and other substances. Mutations here also increase the risk for developing Alzheimer’s disease. The frequency of occurrence of this mutation is somewhat less than for apolipoprotein E.

LDL Receptors

Mutations involving the LDL receptor (low density lipoprotein receptor) may also be important. This receptor binds both apolipoprotein E and alpha2-macroglobulin. LDL is a type of lipid or cholesterol, and cells, including neurons, contain receptor binding sites for LDL.

Conventional Treatment

At present, there is no true prevention for Alzheimer’s in conventional medicine but there are ways to decrease the risk for developing the disease and also, possibly, slow the progression. Treatments include:
&Mac1 Anti-cholinesterase inhibitors (such as tacrine and donepezil)
&Mac1 Anti-inflammatories (NSAIDs and Cox-2 inhibitors)
&Mac1 Estrogen replacement therapy

These various treatments target the pathways involved in the development of Alzheimer’s disease. These pathways include oxidative stress, inflammation, estrogen hormone status, production of beta-amyloid, apolipoprotein E status, and cholinergic neuron depletion (with resulting decrease in acetylcholine levels). These are all possible avenues for treatment now or in the future. At present, treatment, at best, slows progression of the disease. Future research will concentrate on slowing disease progression as well as lessening the burden on caregivers via patient improvement. Following is a list of therapies from the medical literature that have been tried in the treatment of Alzheimer’s disease.

Acetylcholinesterase Inhibitors

Drug treatment with the acetylcholinesterase inhibitors (such as tacrine, donepizil, metrifonate and rivastigmine) is now begun after the disease has actually developed. This class of drugs increases the amount of neurotransmitter acetylcholine at the nerve terminal by decreasing its breakdown by the enzyme cholinesterase. Remember that in Alzheimer’s disease the levels of multiple neurotransmitters, but especially acetylcholine, are decreased markedly. This loss of acetylcholine occurs mainly in the cortical areas of the brain.

Acetylcholinesterase inhibitors have been shown to modestly improve memory and language and decrease the emotional symptoms of apathy, anxiety, hallucinations, inappropriate behavior, and abnormal movement. None of these medications reverses the process and none is curative. The most that can be hoped for at this point is some improvement in symptoms. These drugs are begun after the disease has been diagnosed. Therefore, patients and their families should have realistic expectations with these drugs and not expect dramatic improvement or a reversal of the disease process. Less than half of patients show any benefit at all from acetylcholinesterase inhibitors, even when there are no side effects.


Donepezil (Aricept) is given for mild to moderate Alzheimer’s disease at a dose of 5 mg orally at bedtime for 6 weeks and then increased to a dose of 10 mg at bedtime if tolerated. Nausea and diarrhea are the most common side effects. In patients with prior abnormally slow heart rate, asthma, or ulcer disease, a worsening of these processes can occur and should be watched for. However, their presence prior to treatment does not prevent the use of acetylcholinesterase inhibitors.

A clinical trial with donepezil at 5 or 10 mg/day showed a 3.1 point ADAS-Cog improvement, with only 12% dropping out due to side effects. Patients on donepezil remain in a nonsevere disease state for a longer time. [35]

An article published in the French journal Encephale described the first large-scale study of donepezil at a daily dosage of 5 to 10 mg conducted over 14 weeks. The results show a significant improvement in cognitive function in the treatment groups, compared to the placebo groups. The difference emerged after 3 weeks of treatment, lasted throughout the 12 weeks of the study, and was still very marked 3 weeks post-treatment discontinuation. The results of a second study conducted over 30 weeks were similar. [36]

Phase II clinical trials of donepezil have demonstrated that donepezil improves cognition, global function, and activities of daily living. In addition, there were no clinically significant treatment-related effects on vital signs or laboratory values in any trial. Adverse events, when present, were generally mild in intensity, transient, and resolved during continued treatment with donepezil. [37]

A recent review of the clinical trials, however, concluded that donepezil produced only modest improvements in cognitive function and that study clinicians had rated global clinical state more positively in treated patients. Further, in two of the four studies, the patient's own rating of their quality of life showed no benefit of donepezil compared with placebo. A variety of adverse effects were recorded, with more incidents of nausea, vomiting, diarrhea, and anorexia in the 10 mg per day group compared with placebo and the 5 mg per day group. [38]


Tacrine (Cognex) is another acetylcholinesterase inhibitor, although possible liver toxicity makes donepezil the first choice.

Patients receiving 160 mg per day of tacrine in a 30-week double-blind, placebo-controlled study showed an ADAS-Cog improvement of 4.1 points if they completed the trial. But only 27% of the patients completed the trial, mostly because tacrine is so toxic to the liver and causes severe side effects. [38]

Estrogen Replacement Therapy

Estrogen replacement therapy (ERT) is useful both in preventing Alzheimer’s disease as well as in treatment.

Studies of 2,529 women in the Leisure World Retirement Community cohort, 472 women in the Baltimore Longitudinal Study of Aging, and 1,124 women in a Manhattan cohort showed a 30%, 50%, and 60% lower risk, respectively, for Alzheimer’s disease among postmenopausal women taking estrogen-replacement therapy over those who were not. [5, 39, 40]

Animal experiments show that surgical removal of the ovaries can reduce choline uptake in the frontal cortex and hippocampus by 24% and 34%, and cause a 45% decline in mRNA for Nerve Growth Factor (NGF) in the frontal cortex. Estrogen replacement reverses most of these effects.

Estrogen is an excellent neuroprotective agent and functions in a variety of ways, including antioxidant mechanisms (decreasing oxidative stress), protection against toxicity from beta-amyloid, encouragement of neuronal dentritic growth, increasing Nerve Growth Factor (NGF), stimulation of neuronal axonal sprouting, and modulation of apolipoprotein E (ApoE) expression. All of these pathways involve the development of Alzheimer’s disease. [41]

Risks of estrogen replacement therapy include increased risk of carcinoma of the breast, development of blood clots in the legs or lungs (with oral estrogen only and not transdermal or pellets). Benefits additional to treating and preventing Alzheimer’s disease with estrogen include decreased cardiovascular risk, longer lifespan, decreased osteoporosis risk, and decreased risk of other cancers such as lymphoma and colon cancer. ERT, at present, is not available for men; but, in the future, trials with less feminizing agents (as 17-alpha-estradiol) may be considered.

Anti-Inflammatory Drugs


Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) include drugs like aspirin, indomethicin (Indocin), ibuprofen (Motrin, Advil), relafen, and others. They all modulate inflammatory pathways but by a chemical mechanism slightly different from the Cox-2 inhibitors.

Recent research into the mechanism of NSAID use in Alzheimer’s disease found that it is more likely to be through the suppression of microglial activity than by inhibiting the formation of senile plaques or neurofibrillary tangles. [42]

A 50% reduction in risk against Alzheimer’s disease is seen in elderly arthritic patients who have been taking NSAIDs such as ibuprofen and indomethicin. Aspirin, however, was only effective in dosages over 2.4 grams per day.

A clinical trial of 100 to 150 mg per day of indomethicin for 6 months resulted in a 14-point ADAS-Cog improvement among the 79% of patients who did not drop out due to gastrointestinal side effects. Inflammation apparently contributes significantly to the final neurodegenerative processes which are initiated by beta-amyloid and neurofibrillary tangles.

In a population study in Cache County, Utah, 201 cases of Alzheimer’s disease and 4,425 participants with no indication of cognitive impairment were identified, interviewed, and their medicine chest assessed. Compared with cognitively intact individuals, the AD cases had significantly less reported current use of NSAIDs, aspirin, and histamine H2 receptor antagonists. [43]

A longitudinal study of 1,686 participants in the Baltimore Longitudinal Study of Aging, examined whether the risk of Alzheimer’s disease was reduced among reported users of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). The study found a decreased risk among those with 2 or more years of NSAID use (relative risk = .40) compared with those with less than 2 years of use (relative risk = .65). Aspirin use did not decrease the risk (relative risk = .74), nor did acetaminophen (relative risk = 1.35). [44]


Ibuprofen was used in a recent study of transgenic mice displaying widespread microglial activation, age-related amyloid deposits, and dystrophic neurites. These mice were created by overexpressing a variant of the amyloid precursor protein found in familial AD. Treatment with ibuprofen produced significant reductions in interleukin-1beta and in the number and total area of beta-amyloid deposits. [45]


These are also anti-inflammatory drugs that decrease inflammation by a pathway different from NSAIDs. They include medications like Celebrex. They have been shown to markedly decrease the chemicals causing inflammation. These and the NSAIDs block the free radical attack on brain tissue mediated by inflammation. [46]

New Drug Research

Acetylcholinesterase Inhibitors


Rivastigmine is an acetylcholinesterase inhibitor that has not yet been approved for use by the FDA. It has been found to be equally as effective as donepezil with comparable side effects, but the ADAS-Cog improvement is 4.9 compared to 3.1 with donepezil. [47, 48]


Metrifonate is an acetylcholinesterase inhibitor, not yet approved by the FDA, with research data indicating it is equally effective to donepezil. Metrifonate has shown a 2.8 point ADAS-Cog improvement, with very few side effects. Clinical trials with higher doses of metrifonate are underway. [47]

MAO-B Inhibitors


Selegilene (Eldepryl or Deprenyl) ia a drug approved for use in Parkinson’s disease that irreversibly inhibits monoamine oxidase type B (MAO-B). Monoamine oxidase is an enzyme that inactivates the monoamine neurotransmitters norepinephrine, serotonin and dopamine. Selegilene is degraded in the liver into desmethyldeprenyl (the major metabolite), amphetamine, and methamphetamine which are eliminated in the urine. Side effects include nausea, hallucinations, confusion, dizziness, depression, agitation, and tremors.

In a study using vitamin E, selegilene, or both in Alzheimer’s disease, there was a modest improvement in symptoms. [49]

In the Czech and Slovak Alzheimer’s disease Study Group using several well-accepted measurements of mental function (including MMSE, Sternberg’s Memory Scanning Test, and others), Selegilene had a long-term helpful effect on memory in mild to moderate Alzheimer’s disease. This was thought to be due to selegilene’s effect on dopamine-rich prefrontal brain areas. [50]

However, selegilene also has anti-apoptotic actions which may be helpful in Alzheimer’s disease where cell death is important. Remember, apoptosis is the process of programmed cell death that occurs when cells are damaged. Apoptosis plays a role in the death of neurons in Alzheimer’s disease as it does in all types of cell death. Limiting or reducing cell death in Alzheimer’s may help prolong the life of needed neurons and possibly slow the disease process. [51] [52]

Another study showed that selegilene protected cells from toxic effects of beta-amyloid. [53]

Selegilene was shown to significantly increase the number of branching points and intersections in both apical and basal dendrites in deprenyl-treated monkeys compared to controls. The authors of the study proposed that this may be the mechanism responsible for the enhancement of cognitive functions in Alzheimer’s disease patients following deprenyl treatment. [54]

A recent article suggested that stimulation of nitric oxide production could be central to the action of selegilene. Deprenyl stimulates vasodilation and increases nitric oxide production in brain tissue and cerebral blood vessels. Because nitric oxide modulates activities including cerebral blood flow and memory, and reduced nitric oxide production has been observed in the Alzheimer’s disease brain, stimulation of nitric oxide production by deprenyl could contribute to the enhancement of cognitive function in Alzheimer’s disease. [53]

Recent studies in rats show that the combination of selegilene with tacrine was remarkedly more effective than either agent alone. [55]

Nerve Growth Factor

Supplementing or increasing Nerve Growth Factor (NGF) may stimulate neuronal cell growth. This is an area of research, although no large trials have yet been done. [56]

Secretase Inhibitors

Secretase inhibitors are an area of future research. These substances decrease levels of beta-amyloid by affecting its cleavage and metabolism. [2]


Nicotine causes acetylcholine transmitter release and, therefore, is theoretically of benefit in Alzheimer’s disease with its decrease in acetylcholine levels. Some, but not all, studies have shown a reduced incidence of Alzheimer’s disease among light smokers (fewer than 10 cigarettes per day), but an increased incidence of the disease among heavy smokers (more than 20 cigarettes per day).

A pilot study with six patients using nicotine patches (to avoid the effects of the other toxic chemicals in cigarette smoke) showed some improvement in a learning task, but no effect on global cognition or short-term memory. The scientific studies, however, are not conclusive. [57]


Metanicotine is less toxic than nicotine and causes nearly the same acetylcholine release. Metanicotine is currently under clinical studies for use in Alzheimer’s disease. [58]


Although vaccine trials in rodents are promising and this work shows decreased behavioral effects and brain damage from beta-amyloid with the vaccine, a usable human vaccine is not likely in the near future. [59]

Innovative Drug Strategies


Hydergine (Ergoloid mesylates) is used in Europe for Alzheimer’s disease and other forms of dementia. It acts as a mild vasodilator.

A meta-analysis of studies using Hydergine showed modest improvement for Alzheimer’s symptoms, but only in dosages of 4 to 9 mg/day, rather than the typical dose of 3 mg/day. Hydergine increased the number of neuronal synapses and the plasticity of synaptic junctions in a rat study. However, when the dose is translated to human equivalents, about 2000 mg/day would be required and has never been used in humans. [60]

In another study, Hydergine decreased hypoxia (a lack of oxygen) in the early stages of Alzheimer’s disease but not in the late stages. In a PET scan analysis in multi-infarct dementia (not Alzheimer’s patients) and at a dose of 2.4 mg/day, Hydergine showed an improvement on the PET scans. [61]

A recent meta-analysis of the published research on hydergine found significant treatment effects in 13 of the trials that met the selection criteria. The overall review was very positive, despite the small number of trials. [62]


Piracetam is a derivative of gamma-aminobutyric acid (GABA) that has been used in European countries for the treatment of memory loss and other cognitive defects.

Several articles have explored the mechanism of piracetam. One study found that piracetam had beneficial effects on the fluidity of membranes from the hippocampus of Alzheimer’s disease patients. [63] Researchers have proposed that the mechanism of piracetam is due to it’s ability to alter the properties of cell membranes in the brain. [64]

A Phase IV study of piracetam in Hungary was conducted on 104 patients with cognitive decline from Alzheimer’s disease and/or cerebrovascular origin. Nearly all of the five factors of the modified Mini-Mental State Examination significantly increased, especially the factors of memory, and concentration-psychomotor speed. Despite this, statistical analysis of the results found no relevant difference between the treatment and control groups. The degree of cognitive improvement was most pronounced in patients with depressive symptoms. [65]


Memantine is a derivative of an old anti-influenza drug, Amantidine, that has been used for the treatment of dementia in Germany for more than twenty years. Memantine is a non-competitive NMDA (N-methyl-D-aspartate) antagonist that blocks the action of glutamate, which can over-stimulate the nervous system and become toxic to nerve cells. Memantine has yet to be approved by the FDA. [66, 67]

Memantine was used to treat patients with moderately severe to severe primary dementia (49% of the Alzheimer type and in 51% of the vascular type) in a recent study published in the International journal Geriatric Psychiatry. 82 patients received 10 mg per day of memantine, and 84 received a placebo. A positive response in the Clinical Global Impression of Change (CGI-C) was seen in 73% of those taking memantine, versus 45% for the placebo group, independent of the etiology of dementia. The results in the Behavioural Rating Scale for Geriatric Patients (BGP) subscore 'care dependence' were 3.1 points improvement under memantine and 1.1 points under placebo. [68]


One of the features of the Alzheimer brain is a loss of nicotinic acetylcholine receptors. Researchers have proposed that Nefiracetam may be useful in Alzheimer’s disease due to it’s ability to stimulate nicotinic acetylcholine receptors. [69]


Nimodipine, a calcium channel blocker, was found to be superior to placebo and Hydergine in Organic Brain Syndrome. However, Alzheimer’s disease was not differentiated from the other forms of dementia in this study. [70]


Aminoguanidine could be of value in reducing AGEs (Age-associated Glycosylation End-products) in Alzheimer’s disease. This therapy has shown some promise in small, isolated studies, but requires large clinical trials if merit is to be established with certainty. [71]

Innovative Surgery

Dr. Harry S. Goldsmith has developed a revolutionary surgical technique for the treatment of Alzheimer’s disease. The technique that involves placing a part of the body called the “omentum” directly on the brain. The omentum is a layer of fat and blood vessels that cover the intestines. The omentum has several key factors that make this technique useful. It provokes angiogenesis (new blood vessel growth) and increases choline acetyltransferase, the enzyme responsible for creating acetylcholine. [72-76]

Alternative Treatments

Acetylcholine Support


Lecithin (phosphatidylcholine) has a long history of use with Alzheimer’s disease. Phosphatidylcholine is a source of choline, the major component of acetylcholine, which is needed for cell membrane integrity and to facilitate the movement of fats in and out of cells.

When given to animals, lecithin causes increased acetylcholine levels. Clinical trials, however, failed to show actual improvement. Alzheimer’s disease and other dementias do show increased choline levels which may indicate inadequate metabolism. Therefore, simply supplementing the lecithin would not necessarily help the metabolic defect in the cellular use of phosphatidylcholine. [77-81]

A recent review article analyzed 12 clinical trials using lecithin to treat Alzheimer’s disease (265 patients), Parkinsonian dementia (21 patients), and subjective memory problems (90 patients). No trial reported any clear clinical benefit of lecithin for Alzheimer’s disease or Parkinsonian dementia. A dramatic result in favor of lecithin was obtained, however, in a trial of subjects with subjective memory problems. [82]


The body uses choline and pantothenic acid (vitamin B5) to form acetylcholine. Pantothenic acid is also needed to produce, transport and release energy from fats.


Oxidative stress is very important in the development of Alzheimer’s disease. Anti-oxidant supplements help block this process.

“Beta-amyloid is aggregated and produces more free radicals in the presence of free radicals; beta-amyloid toxicity is eliminated by free radical scavengers.” [83, 84]


Researchers have shown that cultured cells are prevented from beta-amyloid toxicity with the addition of vitamin E. [83]

Researchers at the University of Kentucky published a ground-breaking article showing that vitamin E prevented the increase of polyamine metabolism in response to free radical mediated oxidative stress caused by the addition of beta-amyloid to the rat neurons. [85]

Research conducted in Germany showed that both natural and synthetic vitamin E were more effective than estrogen (17-beta estradiol) in protecting neurons against oxidative death caused by beta-amyloid, hydrogen peroxide, and the excitatory amino acid glutamate. [86]

Research conducted at the University of California, San Diego, School of Medicine studied the protective effects of vitamin E in apolipoprotein E-deficient mice. Those treated with vitamin E displayed a significantly improved behavioral performance in the Morris water maze. Also, the untreated mice displayed increased levels of lipid peroxidation and glutathione, whereas the vitamin E-treated mice showed near normal levels of both lipid peroxidation and glutathione. [87]

A study of 44 patients with Alzheimer’s disease and 37 matched controls showed that vitamin E levels in the cerebral spinal fluid (CSF) and serum were significantly lower in Alzheimer’s patients. [88]

In the Alzheimer’s disease Cooperative Study, 2000 mg of vitamin E were given to Alzheimer’s disease patients. This slowed the functional deterioration leading to nursing home placement. [83]

An article published in the New England Journal of Medicine described a double-blind, placebo-controlled, randomized, multi-center trial of patients with Alzheimer’s disease of moderate severity. A total of 341 patients received the selective monoamine oxidase inhibitor selegiline (10 mg a day), alpha-tocopherol (vitamin E, 2000 IU a day), both selegiline and alpha-tocopherol, or placebo for two years. The baseline score on the Mini-Mental State Examination was higher in the placebo group than in the other three groups. Both vitamin E and segeline delayed the progression of the disease with vitamin E acting slightly better than segeline (median time 670 vs. 655 days respectively.) [49]

A recent review of the published research on vitamin E for Alzheimer’s disease stated that, although there is insufficient evidence of efficacy of vitamin E, there is sufficient evidence of possible benefit to justify further studies. [89] Researchers are suggesting that the combination of vitamin E and donepezil be a current standard of Alzheimer’s disease therapy. [90]


Ginkgo biloba is the world’s oldest living tree. It has been traditionally used for improving memory and Alzheimer’s disease. It is a powerful antioxidant and also functions as a mild vasodilator (improves circulation), anti-inflammatory (via antioxidant effects), membrane protector, anti-platelet agent and neurotransmitter modulator. [91, 92]

Ginkgo was shown to protect neurons against toxicity induced by beta-amyloid fragments, with a maximal and complete protection at the highest concentration tested. Ginkgo also completely blocked beta-amyloid-induced events, such as reactive oxygen species accumulation and apoptosis (cellular death). [93, 94]

A study of the effects of bilobalide, the main constituent of the non-flavone fraction of ginkgo biloba, provided the first direct evidence that bilobalide can protect neurons against oxidative stress. Bilobalide may block the apoptosis in the early stage and then attenuate the elevation of c-Myc, p53, and Bax genes and activation of caspase-3 in cells. [95]

An article published in the journal Brain Research showed that pretreatment of nerve cells with isolated ginkgolides, the anti-oxidant component of ginkgo biloba leaves, or vitamin E, prevented the beta-amyloid-induced increase of reactive oxygen species (ROS). Ginkgolides, but not vitamin E, inhibited the beta-amyloid-induced HNE (4-hydroxy-2-nonenal) modification of mitochondrial proteins. [96]

A 52-week, double-blind, placebo-controlled, fixed dose, parallel-group, multi-center study of ginkgo biloba at a dose of 120 mg (40 mg three times a day) was conducted and published in 2000. The placebo group showed a statistically significant worsening in all domains of assessment, while the group receiving ginkgo biloba was considered slightly improved on the cognitive assessment and the daily living and social behavior. No differences in safety between ginkgo biloba and placebo were observed. [97]

A similar 52-week, randomized double-blind, placebo-controlled, parallel-group, multi-center study of ginkgo biloba by the same research team was published in 1997. The group treated with ginkgo biloba had an ADAS-Cog score 1.4 points better than the placebo group (p=.04) and a Geriatric Evaluation by Relative's Rating Instrument (GERRI) score 0.14 points better than the placebo group (p=.004). [98]

In an analysis of various studies and as measured by the ADAS-Cog, the 4 anti-cholinesterases and ginkgo were equally effective in mild to moderate Alzheimer’s disease. Tacrine had a high drop-out rate due to side effects. Most studies showed benefit from ginkgo but one did not. [99]

Extracts of ginkgo contain different amounts of the various active substances and are also of variable quality. A high-quality product, such as those made by Life Extension Foundation, is recommended. [3]


An article published in the International journal Geriatric Psychiatry described a study of Alzheimer’s disease patients in the region of Toulouse, France. Plasma vitamin E and C levels were measured and consumption of raw and cooked fruit and vegetables was evaluated in order to determine the mean vitamin C intakes. Mini Nutritional Assessment (MNA) and plasma albumin were used to measure nutritional status. The hospitalized Alzheimer’s subjects had lower MNA scores and albumin levels but normal vitamin C intakes, but their plasma vitamin C was lower than that of community-living subjects. In the home-living Alzheimer subjects, vitamin C plasma levels decreased in proportion to the severity of the cognitive impairment despite similar vitamin C intakes. [100]

A prospective study of 633 persons 65 years and older examined the relation between use of vitamin E and vitamin C and incidence of Alzheimer’s disease. After an average follow-up period of 4.3 years, 91 of the participants with vitamin information met accepted criteria for the clinical diagnosis of Alzheimer’s disease. None of the 27 vitamin E supplement users and none of the 23 vitamin C supplement users had Alzheimer’s disease. There was no relation between Alzheimer’s disease and use of multivitamins. [101]

A study of ten patients with Alzheimer’s disease showed that one month supplementation of 400 IU vitamin E and 1000 mg vitamin C significantly increased the concentration of both vitamins in the plasma and cerebral spinal fluid. In contrast, supplementation with vitamin E alone increased its CSF and plasma concentrations but was unable to decrease lipoprotein oxidizability. [102]


There are multiple modes of action for acetyl-L-carnitine, including antioxidant effects, molecular chaperone effects, and others.

This agent possibly helps correct the acetylcholine deficit and has been tried in rodents. [103] Double-blind studies have been done and showed some benefit. [104]

Acetyl-L-carnitine was shown to protect neurons from the detrimental effects of beta-amyloid in the cortex of rats.[105]

In humans, a one-year controlled trial in early Alzheimer’s disease measured ADAS-Cog and the Clinical Dementia Rating Scale in 229 patients. Acetyl-L-carnitine use slowed the clinical deterioration. This study concluded by recommending more research using both acetyl-L-carnitine plus a cholinesterase inhibitor (such as donepezil, tacrine, Rivastigmine or Metrifonate). [106]


A recent study published in the European journal Neurology compared serum levels of beta-carotene and alpha-carotene, and vitamin A of 38 Alzheimer’s disease patients and 42 controls. They found that the serum levels of beta-carotene and vitamin A were significantly lower in the Alzheimer’s disease patient group. [107]


CoQ10 is used in the mitochondrial production of energy in the electron transport chain. A role for mitochondrial dysfunction in neurodegenerative disease is gaining support. Studies have implicated mitochondrial defects in Alzheimer’s disease and use of CoQ10 has been suggested for this reason. However, the appropriate clinical studies using CoQ10 have not yet been done. [108]


N-Acetyl-cysteine (NAC) is a precursor of glutathione, a powerful scavenger of free radicals. Glutathione deficiency has been associated with a number of neurodegenerative diseases, including Lou Gehrig’s and Parkinson’s disease.

A recent study showed that NAC significantly increased the glutathione levels and reduced oxidative stress in rodents treated with a known free-radical producer. [109]

NAC has been shown to protect mitochondrial respiration and neuronal microtubule structure from the toxic effects of HNE (4-hydroxy-2-nonenal), a reactive aldehyde product of lipid peroxidation. [110]


A recent study showed that flavonoids have a protective effect on neurons exposed to oxidized lipids in the form of low-density lipoprotein. [111]


A recent study examined the changed in the expression of genes encoding cytochrome c oxidase and NADH dehydrogenase in the brains of 10 Alzheimer’s disease patients and 10 age-matched controls. They found a decreased expression of the gene NADH-4 which may lead to a reduction in antioxidant activity of ubiquinone oxidoreductase. [112]

Anti-Inflammatory Supplements


Curcumin, the active ingredient in the herb turmeric, is being investigated for use in Alzheimer’s disease due to it’s potent anti-inflammatory action. [113, 114]


Essential fatty acids are found in oils including flax, borage, and fish oils. Fish oils contain EPA (eicosapentaenoic acid) and DHA (docosohexanoic acid), both of which are omega-3 oils. Essential fatty acids are important for healthy skin and hair. They also have significant anti-inflammatory action.

It has been proposed that a dietary deficiency of essential fatty acids could be a risk factor for Alzheimer’s disease. [115-117]

Several small studies have explored the use of essential fatty acids in the treatment of Alzheimer’s disease and found it to be beneficial. [118, 119]


The neuron is composed of about 30% DHA (docosohexanoic acid), which is an important fatty acid in the neuronal membrane. Most of our DHA comes from fish consumption but also may be taken as a supplement. Low DHA has been found to be a risk factor for development of Alzheimer’s disease. The decreased levels of DHA in later life could be related to decreased synthesis secondary to lower levels of delta 6-desaturase activity. [120, 121]


A Japanese study found that administration of EPA (900 mg per day) in patients with Alzheimer’s disease improved MMSE significantly with maximal effects at 3 months and the effects lasted 6 months. However, the score of MMSE decreased after 6 months. [31]


Researchers have proposed that fish oils and GLA (gamma linolenic acid) may help prevent Alzheimer’s disease by it’s anti-inflammatory effect of suppressing interleukin-1 production by monocytes. [122]



Research has shown that low cobalamin (vitamin B12) levels are related to dementias in general. A common cause of cobalamin deficiency in elderly people is protein-bound cobalamin malabsorption due to atrophic gastritis with hypo- or achlorhydria (low stomach acid). Often, however, the serum B12 levels are normal. The measurement of the metabolites homocysteine and/or methylmalonic acid is recommended as a more accurate assessment of cobalamin status. [123, 124]

Lower levels of vitamin B12 (below 200 pg/ml) in the blood are associated with dementia symptoms. Because of this, and the absence of toxicity with use of vitamin B12, the argument has been voiced to raise recommended minimum serum levels of vitamin B12 and also liberally administer vitamin B12 to the elderly. “Vitamin B12 could play a role in the behavioral changes in Alzheimer’s disease.” [125]

A study was recently conducted with outpatients at a geriatric memory clinic. Seventy-three consecutive outpatients with probable Alzheimer’s disease showed significant inverse associations between vitamin B12 status and the behavioral and psychological symptoms of dementia: irritability (p=0.045) and disturbed behavior (p=0.015). Of the 73 participants, 61 patients had normal and 12 patients (16%) had subnormal (<200 pg/ml) vitamin B12 levels. [126]

A population-based longitudinal study of 370 nondemented persons, aged 75 years and older, conducted in Sweden found that subjects with low levels of B12 or folate had twice higher risks of developing Alzheimer’s disease over the 3-year period of the study. [127]


Folate or folic acid derives its name from foliage (green plants). Folacin was first isolated from spinach and other leafy green vegetables in 1941. Folic acid is needed for DNA synthesis and is also needed to make SAMe (S-adenosyl methionine).

A study of 126 patients, including 30 with Alzheimer’s disease, found that the levels of folate in the cerebral spinal fluid (CSF) were significantly lower in late-onset Alzheimer’s disease patients. [128]

A study published in the American Journal Medical Science found low levels of folate (along with deficiencies of thiamin and vitamin B12) in elderly individuals with senile dementia of the Alzheimer's type (22 subjects) as compared to the cognitively normal control group (41 subjects.) [129]


SAMe (S-adenosyl methionine) is perhaps the safest and most effective antidepressant in the world. SAMe is a precursor for glutathione, coenzyme A, cysteine, and taurine.

One study measured the levels of SAMe in postmortem brain of 11 patients with Alzheimer’s disease. Decreased levels of S-adenosylmethionine (-67 to -85%) and its demethylated product S-adenosylhomocysteine (-56 to -79%) were found in all brain areas examined as compared with matched controls (n = 14). [130]

A review article of SAMe concluded that intravenous or oral administration of SAMe represents a possible treatment for Alzheimer's dementia, subacute combined degeneration of the spinal cord (SACD), and HIV-related neuropathies, as well as in patients with metabolic disorders such as folate reductase deficiency. [131]

Nervous System Support


Phosphatidylserine is a major building block for nerve cells. Phosphatidylserine has been studied for use with Alzheimer’s disease and age-related mental decline. [132-134]

In a study published in the journal Dementia, a six-month study of 70 patients with Alzheimer’s disease divided into four groups indicated that phosphatidylserine treatment has an effect on different measures of brain function. The improvements, however, were best documented after 8 and 16 weeks and faded towards the end of the treatment period. [135]


Inositol is required for the formation of cell membranes. It helps in transporting fats and affects nerve transmission.

A double-blind controlled crossover trial examined use of inositol, at a dose of 6 grams per day for one month, in eleven patients with Alzheimer’s disease. Language and orientation improved significantly more on inositol than on placebo (glucose). [136]


A recent article published in the journal Medical Hypothesis proposes that vitamin K deficiency may contribute to the pathogenesis of Alzheimer’s disease. The authors offer the following as evidence:
&Mac1 A relative deficiency of vitamin K is common in aging men and women.
&Mac1 The concentration of vitamin K is lower in the circulating blood of APOE4 carriers than in that of persons with other APOE genotypes. The ApoE4 genotype is associated with Alzheimer’s disease.
&Mac1 Vitamin K has important functions in the brain, including the regulation of sulfotransferase activity and the activity of a growth factor/tyrosine kinase receptor (Gas 6/Axl).
&Mac1 Vitamin K may also reduce neuronal damage associated with cardiovascular disease.

The authors propose that vitamin K supplementation may have a beneficial effect in preventing or treating the disease. [137]


Idebenone is a synthetic analogue of coenzyme Q10 (CoQ10), a cell membrane antioxidant and essential component of the mitochondrial electron transport chain which produces ATP (the energy molecule of the body). The following mechanisms have been proposed for the use of idebenone in Alzheimer’s disease:

Idebenone has been shown to stimulate nerve growth factor. [138-140]

Treatment with idebenone and alpha-tocopherol prevented learning and memory deficits caused by beta-amyloid in rats. [141]

Three hundred patients with Alzheimer’s disease were randomized to receive either placebo or idebenone, 30 mg three times per day, or 90 mg three times per day for six months. Statistically significant improvement was noted in the total score of the Alzheimer’s disease Assessment Scale (ADAS-total), and in one cognitive parameter (ADAS-cog) in the idebenone 90 mg three times per day group, as compared to placebo. [142, 143]

An article in the journal Neuropsychobiology described the results of a double-blind, placebo-controlled multi-center study using idebenone in patients suffering from mild to moderate dementia of the Alzheimer type. A total of 300 patients were randomized to either placebo or idebenone 30 mg or 90 mg 3 times a day (n=100, each) and treated for 6 months. After month 6, idebenone 90 mg, showed statistically significant improvement in both the Total and Cognitive Alzheimer’s Disease Assessment Scales. [144]

Natural Hormone Replacement

Estrogen replacement therapy (ERT) was discussed previously as conventional treatment for the prevention of Alzheimer’s disease. From a broader perspective, estrogen replacement is but one hormone in a complex system that includes three forms of estrogen (estrone, estradiol, and estriol), progesterone, testosterone, their precursors (DHEA and pregnenolone) and other hormones (melatonin and cortisol). A comprehensive hormone panel is highly recommended to determine which hormones are deficient or in excess and help guide appropriate supplementation.


Melatonin is a hormone that is released in mammals during the dark phase of the circadian cycle. Its production declines with age in animals and humans. The main use of melatonin is for insomnia and to establish normal sleeping patterns after long air flights. The doses used in the research studies were higher than the 1 to 10 mg most persons use. Higher doses may cause sleepiness, although no other serious side effects have been found with melatonin.

Melatonin is an antioxidant that has been shown to be highly effective in reducing oxidative damage to the central nervous system. Melatonin also stimulates several antioxidant enzymes, including glutathione peroxidase and glutathione reductase. [145]

Several studies have investigated the mechanism of action of melatonin in Alzheimer’s disease:

Melatonin was shown to significantly inhibit the release of free radicals in neuroblastoma cells. [146]

Treatment of cells with high doses of melatonin have been found to decrease the secretion of soluble beta-amyloid. [147]

Melatonin prevented damage by beta-amyloid to neuroblastoma cells. [148]

In a retrospective study, 14 Alzheimer’s disease patients received 9 mg melatonin daily for 22-35 months. A significant improvement of sleep quality was found. [149]

One study measured the melatonin levels in the cerebrospinal fluid (CSF) of 85 patients with Alzheimer’s disease and in 82 age-matched controls. In Alzheimer’s disease patients the CSF melatonin levels were only one-fifth of those in control subjects.[150]

A recent study examined the efficacy of melatonin in treatment of sleep and cognitive disorders of Alzheimer’s disease. Fourteen patients (8 females, 6 males, mean age 72 years) received 9 mg gelatin melatonin capsules daily at bedtime for 22 to 35 months. Overall quality of sleep was assessed from sleep logs filled in by the patients or their caretakers. At the time of assessment, a significant improvement of sleep quality was found in all cases examined. Clinically, the patients exhibited lack of progression of the cognitive and behavioral signs of the disease during the time they received melatonin. [151]


A novel study assessed the effects of music therapy on the concentrations of melatonin, norepinephrine, epinephrine, serotonin, and prolactin in the blood of 20 male patients with Alzheimer’s disease at the Miami Veterans Administration Medical Center, Miami, Florida. Patients listened to 30- to 40-minute morning sessions of music therapy 5 times per week for 4 weeks. Melatonin concentration in serum increased significantly after music therapy and was found to increase further at 6 weeks follow-up. Norepinephrine and epinephrine levels increased significantly after 4 weeks of music therapy, but returned to pretherapy levels at 6 weeks follow-up. The authors concluded that increased levels of melatonin following music therapy may have contributed to patients' relaxed and calm mood. [152]


Tryptophan is the precursor of serotonin and melatonin. It has been proposed that a dietary lack of tryptophan may make deficiencies of serotonin and melatonin common. [153, 154]

In a double-blind, crossover study of 16 patients with dementia of the Alzheimer type and 16 cognitively intact controls, subjects received either a tryptophan-free amino acid drink to induce acute tryptophan depletion, or a placebo drink containing a balanced mixture of amino acids. On each occasion, ratings of depressed mood were made at baseline and 4 and 7 hours later, and the Modified Mini-Mental State was administered at baseline and 4 hours later. Patients with dementia of the Alzheimer type had a significantly lower mean score on the Modified Mini-Mental State after acute tryptophan depletion than after receiving placebo, while the comparison group showed no difference. [155]

Adrenal Stress

The relationship between age-related memory loss and stress is central to the protocol used by Dharma Singh Khalsa. Excessive stress from a modern life causes the adrenal glands to secrete excessive amounts of cortisol eventually leading to adrenal fatigue. [156]


Alzheimer’s disease patients with higher DHEA levels did better on memory tests than those with lower DHEA levels. [157] [158]

Other data suggest that DHEA has a role in antioxidant status, Natural Killer (NK) cell immune function and other immune functions. This study showed low DHEA was a risk factor for the development of Alzheimer’s disease but did not show that replacing DHEA was of benefit. These studies still need to be done. [159]

A study of adrenal secretion in 23 healthy elderly subjects, 23 elderly demented patients and 10 healthy young subjects found a significant increase in cortisol levels during evening and nighttime in both groups of the aged subjects. In elderly subjects, particularly if demented, the mean serum dehydroepiandrosterone sulfate (DHEAs) levels throughout the 24-hour cycle were significantly lower than in young controls. [160]

A cross-sectional study, called the Berlin Aging Study, found lower levels of DHEA-s in cases that developed dementia of the Alzheimer type within 3 years as compared to matched controls. [159]

Inhibition of AGE Formation

Central to the process of forming Advanced Glycation End Products (AGEs) is the presence of sugar (glucose) which is central to the diagnosis of both diabetes and insulin insensitivity (referred to as Syndrome X). Appropriate lab tests would include the glucose tolerance test and insulin levels. Appropriate treatment is covered in the section on diabetes.


Derivatives of vitamins B1 and B6 (thiamine pyrophosphate and pyridoxamine) have been shown to decrease AGE formation. [161, 162]


Carnosine is a multi-functional dipeptide made from a combination of the amino acids beta-alanine and L-histidine. Meat is the main dietary source of carnosine. High doses of carnosine are necessary for therapeutic effect because the body naturally degrades carnosine with the enzyme carnisoninase.

Copper and zinc are released during normal synaptic activity. However, in the presence of a mildly acidic environment which is a characteristic of Alzheimer’s disease, they reduce to their ionic forms and become toxic to the nervous system. New research has shown that carnosine can buffer copper and zinc toxicity in the brain. [163, 164]

Carnosine has also been shown, in vitro, to inhibit non-enzymic glycosylation and cross-linking of proteins induced by reactive aldehydes, including aldose and ketose sugars, certain triose glycolytic intermediates, and malondialdehyde (MDA, a lipid peroxidation product). Carnosine also inhibits formation of MDA-induced protein-associated advanced glycosylation end products (AGEs) and formation of DNA-protein cross-links induced by acetaldehyde and formaldehyde. [11, 165-167]

Herbal Treatments


Huperzine A is an alkaloid isolated from the Chinese herb Huperzia serrata.

In experiments using rats, Hyperzine A improved the decrease in acetylcholine activity in cortex and hippocampus. [168-172]

Huperzine has also been found to protect against the toxic effects of beta-amyloid. [173, 174]

A double-blind, multi-center study of Huperzine A was conducted in China. Fifty patients were given 0.2 mg Huperzine and 53 patients were given placebo for eight weeks. About 58% (29/50) of patients treated with Huperzine showed improvements in their memory and cognitive and behavioral functions. The efficacy of Huperzine was better than placebo (36%, 19/53) (p < 0.05). No severe side effect was found. [175]


KUT is a Japanese herbal formula named “Kami-Umtan-To” that consists of 13 different herbs. KUT has been used since 1626 for neuropsychiatric problems. KUT has been shown to increase choline acetyltransferase levels and nerve growth factor in cultured rat brain cells.

In a 12-month open clinical trial using KUT and estrogen, vitamin E and NSAIDs, the rate of cognitive decline per year was measured using the Mini-Mental Status Exam (MMSE). Twenty patients with Alzheimer’s disease (MMSE score: 18.6 +/- 5.8) received extracts from original KUT herbs, 7 Alzheimer’s disease patients (MMSE score: 21.3 +/- 2.8) were placed on the combination therapy, and 32 patients served as controls (MMSE score: 20.8 +/- 5.6). The rate of cognitive decline per year was significantly slower in the KUT group (1.4 points) and the combination group (0.4 points) as compared to the 32 control patients who received no medicine (4.1 points). The efficacy of KUT alone was most noticeable after 3 months of use. [176]


The incidence of Alzheimer’s disease is increasing at an alarming rate along with the aging of our population. The vast majority of Alzheimer’s disease is acquired or idiopathic (of unknown cause) by conventional medicine. There is much discussion about the cause of Alzheimer’s disease and many consider that it may not be caused by a single agent. The causes discussed here encompassed many diverse medical theories, including the biochemistry of acetylcholine and neurotransmitters, inflammation, oxidative stress and free radicals, and homocysteine. Recent advances in lab testing may help identify the key areas in which to focus the therapies.

One interesting study showed that persons who had a love of reading and read frequently in childhood had a very decreased incidence of Alzheimer’s disease. Regularly engaging in mental activity is necessary for preservation of brain function.

Most of the medical treatments listed here are used only after Alzheimer’s disease develops. Some, such as estrogen, vitamin B12, and antioxidants, are important in preventing dementia also.

Treatment Protocols

There are a vast number of choices in both drugs and nutritional supplements available for patients with Alzheimer’s disease. A well-informed holistic or naturopathic medical doctor can be of great help in ordering the appropriate lab tests and identifying the key supplements that will provide the greatest benefit. The following are several of the supplements that have been covered in this protocol along with standard daily dosages:

Acetylcholine support
&Mac1 Phosphatidylcholine derived from lecithin or capsulized with other cognitive enhancers such as Cognitex

&Mac1 Ginkgo biloba, 120 mg in the morning or 60 mg three times daily
&Mac1 Vitamin E, 2000 mg per day
&Mac1 Vitamin C, 1,000 mg per day
&Mac1 Acetyl-L-carnitine, 500 mg twice a day
&Mac1 N-Acetyl cysteine, 500 mg twice a day

&Mac1 Essential fatty acids (including omega-3 and omega-6 fatty acids, DHA, EPA and GLA). Dosage depends on the form.
&Mac1 Curcumin (Turmeric), 400 mg three times a day

&Mac1 Vitamin B12, 1000 mcg a day or by injection
&Mac1 Vitamin B6, 500 mg a day
&Mac1 Folic acid, 400 mcg a day
&Mac1 SAMe, 400-1600 mg a day, particularly if there are signs of depression

Nervous system support
&Mac1 Methylcobalamin, the neurologically active form of vitamin B12; up to 5-10 mg daily for brain aging
&Mac1 Phosphatidylserine, 100 mg three times a day

Inhibit AGEs
&Mac1 Carnosine, 1000 mg per day (minimum) should be considered

Based upon the results of appropriate lab testing (see the lab section at the beginning of this article), the following may be used in addition:
&Mac1 Hormone replacement therapy, preferably with natural forms of progesterone and estrogen.
&Mac1 DHEA supplementation. The usual dose is 10-50 mg in females and 40-100 mg in males.
&Mac1 Melatonin, 10 mg at bedtime, particularly if there is insomnia

Innovative drug strategies can include the following:
&Mac1 Hydergine
&Mac1 Piracetam

Drug-Supplement Interactions

Ginkgo biloba

Ginkgo acts to thin the blood by reducing the ability of platelets (blood-clotting cells) to stick together. Care should be used when using Ginkgo with other agents that thin the blood, such as heparin, warfarin, aspirin, and some NSAIDs. [177]

Vitamin E

Vitamin E has a long history of safe use. Vitamin E may add to the blood thinning effect of aspirin and cause an increased risk of bleeding. Care should be taken when taking aspirin with vitamin E. [177]

Vitamin K

Vitamin K directly counteracts the action of warfarin. Patients taking warfarin should seek qualified medical advice before taking vitamin K. [177]


EPA and DHA have been shown to inhibit abnormal clotting in blood vessels. Care should be used with those taking anticoagulant medications such as warfarin.


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