Topics:

• Down Syndrome
• Aluminum and Alzheimer's Disease
• Genetic basis of Alzheimer's disease, symptoms, prevalence.
• Multi-infarct dementia
• Schizophrenia and Alzheimer's Disease

Response from Dr. Ken Kosik, Harvard Medical School:
"Because Aricept has no effect on the underlying pathogenetic mechanism of the disease; rather it falls in the category of a neurotransmitter replacement--I would not see an indication in presymptomatic disease whether due to trisomy 21 or any other cause."

Response from Dr. Peter Davies, Albert Einstein College of Medicine:
The idea of treating Down's patients is controversial. What does informed consent mean in this population? Likewise, the diagnosis of Alzheimer's Disease in this population is very difficult, given that the mean IQ is about 45. I would not expect Aricept or Cognex to do anything in Down's prior to the onset of the Alzheimer's Disease and degeneration of the cholinergic neurons. Neither of these drugs is expected to postpone or slow the process of degeneration: they simply may compensate somewhat for the lack of acetyl choline caused by the degeneration of cholinergic neurons. In a population of Down's aged over 40 (and thus presumed to have Alzheimer pathology, including the cholinergic deficiency), one might predict small improvements in cognitive function, to about the same extent that one sees in non-Down's Alzheimer patients. But then again, the issues about cognitive tests that might be appropriate to measure this "improvement" again would be difficult in these patients. One would need a carefully designed study, with special behavioral testing appropriate for the Down's population, to determine if these drugs did anything. Then perhaps some discussion of the ethical issues may need to be raised.

Topic: Aluminum and Alzheimer's Disease

Response by Dr. Peter Davies, Albert Einstein College of Medicine
From my point of view, the aluminum issue in Alzheimer's Disease is essentially dead. Despite decades of work, it is clear that aluminum given to animals (or accidentally to humans) does not cause Alzheimer's Disease. This is not to say that one cannot demonstrate neurotoxicity of aluminum if it is given in the right salt form into the brains of some animals. However, even in these rather extraordinary circumstances, the pathology that results is NOT that of Alzheimer's Disease. Humans exposed to huge amounts of intravenous aluminum (through dialysis back in the 60's, in some countries) may suffer neurotoxicity, but again, do not appear to develop the pathology of Alzheimer's Disease with any reasonable frequency. Thus experimental work in this area, while not entirely over, is now at a very low level.

Response by David W. Walker (davidwaynewalker@netscape.net) -- Posted 28 August 2001

All aluminum beverage containers are coated with an inert polymer to keep the liquid and metal can separated. This is done primarily to protect the taste of the product. If this coating is damaged or missing and a significant amount of aluminum has leached into the product, the beverage will almost certainly have a noticable off-taste that would keep most people from finishing the can. Therefore, it would be highly unlikely that anyone would consume a canned soft drink or juice with a high aluminum level and not be aware of it. The typical amount of aluminum in canned beverages with an intact polymer barrier is the same as, or lower than, the public water supply used to manufacture them - that is to say, it is extremely low. Beverages in aluminum cans do not have anything close to the 4% aluminum mentioned by Bashara, but this continues to be a common mis-preception and a persistant internet rumor.

Topic: Genetic basis of Alzheimer's disease, symptoms, prevalence.

A: There are four genes that have now been linked to Alzheimer's disease. Three are implicated in inherited forms of AD, with onset at around age 30-50. These are the genes for amyloid precursor protein (APP), on chromosome 21, and two highly homologous proteins known as presenilin 1 and 2, located on chromosomes 1 and 14. The fourth gene, for apolipoprotein E (ApoE), is located on chromosome 19 and its E4 allele is considered to be a risk factor for late onset AD. In the three genes for early onset AD, the fault appears to lie in a variety of mutations that affect the functioning of the gene products in ways that are still being elucidated. All of these mutations appear to increase the production of a specific, 42-amino-acid form of beta amyloid peptide, which is theorized to cause neuronal degeneration and death in Alzheimer's disease. For further information on the amyloid theory, see on-line seminar by Dennis Selkoe.

With the ApoE gene, there appears to be an increased risk associated with one of the common alleles. A disproportionate number of AD patients have at least one E4 allele. However, the allele only contributes to risk. There are many people with one or two E4 alleles who live to an old age without any sign of dementia. See the Alzheimer Research Forum's Molecular Genetics page for further details.

A few researchers such as Peter Davies at Albert Einstein College of Medicine in New York and Huntington Potter at Harvard Medical School are also interested in the theory that AD may be linked to an increased propensity for chromosome 21 disjunction. People with Down's syndrome, caused by having an extra copy of chromosome 21 ("trisomy 21"), almost inevitably develop AD at a young age. Down's syndrome is caused by chromosome disjunction during the formation of ova. A study of women who gave birth to Down's babies before age 35 found that these women later developed AD at a disporportionately high rate. This gave rise to speculation that there is some kind of inherited disorder involving chromosome 21 disjunction. If the disorder affects the germ line, then Down's syndrome is the result. But if it affects cells in the brain during development, it might result in a smattering of trisomy 21 neurons that contribute to late onset AD. This is so far a theory, with some intriguing evidence to support it, but by no means proven yet.

Currently about 4 million Americans are affected. AD is the most common cause of dementia among people age 65 and older. (But many senile dementias have other causes, including stroke, depression, reactions to medications, etc., which can be treated.) It is thought that nearly half of all people age 85 and older have AD.

The symptoms involve a progressive, irreversible decline in memory and thinking abilities. The decline is related to a loss of neuron function, connections and eventually of the neurons themselves. On average, AD lasts from 4 to 8 years after diagnosis. However, it can continue for up to 20 years.
     --June Kinoshita, Alzheimer Research Forum

Topic: Multi-infarct dementia

A: This is a long and complex subject. There are several authorities interested in MID. I would consult Dr. Vladimir Hachinski , London, Ontario (Ph: 519 663-3652; Fax 519 663-3982) or Dr. Dennis Dickson at the Department of Pathology, Albert Einstein College of Medicine, Bronx. NY.
     -- Dennis Selkoe, 1/3/97

A: Now that you have put multi-infarct dementia on my radar screen, I can refer you to a recent paper on the subject that might be of interest to you. A group in France recently reported that the gene for Notch-3 is the site for the mutation that causes a disease called CADASIL, an autosomal dominant, inherited form of multi-infarct subcortical dementia. The paper was published by Elizabeth Tournier-Lasseve, et al., in Nature, Vol. 383, p. 707-710.
     -- June Kinoshita, Alzheimer Research Forum

Topic: Schizophrenia and Alzheimer's disease