Alzheimer’s disease, the most common form of dementia in the elderly, affects 5-10% of the population over the age of 65 to some degree, but early-onset familial Alzheimer’s disease (approximately 10% of all Alzheimer’s disease sufferers) may show symptoms by the age of 50.
     Degeneration of neurons in the Alzheimer’s patient results in reductions of neurotransmitter levels and thus reduced communication between remaining viable neurons. Symptoms generally appear gradually, beginning with impairment of short-term memory, difficulty in finding the right words to carry on conversation, and progressing to personality and behavioral changes, agitation, depression, delusions, and impaired judgment. Total inability to care for oneself is not unusual as the disease progresses.
     Amyloid plaques, aggregations of amyloid fibrils in particular areas of the brain, seem to be a primary factor in disease development, disrupting intracellular calcium homeostasis important for neurotransmission via release of acetylcholine and other neurotransmitters as well as for viability. Changes in oxidative metabolism are also attributed to build-up of amyloid fibrils, and microglia and astrocytes (glial cells) are observed to invade plaques to stimulate release of inflammatory cytokines and influence APP production, which explains why anti-oxidants and anti-inflammatory agents can help delay progression of disease. (Source: Alzheimer’s Web, http://dsmallpc2.path.unimelb.edu.au/adpath.html)
     Genetic factors, environmental factors, and the aging process itself are all undeniably important considerations in the pathophysiology. The actual cause of Alzheimer’s, of course, remains a mystery, but research continues to uncover data on possible contributing or precipitating factors. Source: Doctor’s Guide To The Internet, Neurological Diseases, http://www.aan.com/public/Alzheimer’sh.html.
 
Infectious factors
      A study at Wayne State School of Medicine has established a possible link between Alzheimer’s and Chlamydia pneumoniae, a common respiratory pathogen in bronchitis, sinusitis, pneumonia, and COPD. Though related to C. trachomatis responsible for the STD, C. pneumoniae has not been similarly implicated. The Journal of Medical Microbiology and Immunology (August, 1998) reports on the study that showed C. pneumoniae present in areas of the brain affected by Alzheimer’s in 17 of 19 patients with the disease, but not in areas of the brain not affected by the disease. The findings, though in need of corroboration, could lead to new diagnostic, treatment, and even preventive measures.
      Inflammation secondary to viral infection has been similarly implicated in Alzheimer’s, as reported in The Journal of Neurology, Neurosurgery, and Psychiatry (July 14, 1998). Comparing brain tissue samples of 97 AIDS or HIV fatalities with those of non-infected fatalities, researchers discovered the plaques characteristic of Alzheimer’s to be twice as common in those with HIV. Frequency of observed plaques increased with age in both groups; but 20% of the HIV patients under the age of 40 had plaques, while no non-infected patients in that age group showed plaques. The inflammatory response to infection is suspected as the ultimate contributory factor to developing Alzheimer’s.

Genetic Factors
     A small percentage of Alzheimer’s victims have mutations in the autosomal dominant gene on chromosome 21 that encodes the amyloid protein precursor or APP. A larger percentage familial Alzheimer’s cases are associated with presenilin-1 and presenilin-2 loci on chromosomes 1 or 14. Encoding for homologous proteins whose function remains unknown, mutations may increase the rate at which the amyloid protein is produced from its precursor. A C. elegans protein, sel-12, with amino acid sequences similar to the presenilins has also been associated with facilitation of signaling by the notch family of cell surface receptors. By far the greatest percentage of cases, though, are late-onset (after the age of 65) or sporadic and generally associated with the presence of one or two copies of the E4 allele of the apolipoprotein E gene (ApoE epsilon 4) on chromosome 19. (Source: Alzheimer’s Web, http://dsmallpc2.path.unimelb.edu.au/adcause.html)
     Identification of specific genes and forms of those genes with roles in Alzheimer’s development is an ongoing effort, and a study reported in the March, 1998 issue of Nature Genetics implicates another gene form as well. The BH gene occurs in a number of different forms that code for expression of bleomycin hydrolase, which may affect deposition of amyloid in the brains of Alzheimer’s victims.

      Nature (VOL.391, 22 January 1998) discusses Belgian research involving presenilin-1 (PS1), elevated levels of which are associated with Alzheimer’s. Cells from presenilin knockout mice (genetically selected to not produce PS1) were cultured to discover abnormal increases in accumulation of carboxyl terminal fragments of APP and a five-fold decrease in beta amyloid formation. Since higher levels of beta amyloid are characteristic of Alzheimer’s, this confirms the role of PS1 in the disease and lends credence to the idea that suppression of PS1 might be useful in treating the disease. One big problem with that idea may be that there may be other vital functions of PS1 as yet not known, for presenilin knockout mice die before birth. More will need to be learned about normal presenilin function, then a means for suppression will have to be devised.

About Knockout Mice
     Transgenic mice, bred selectively for such highly specific mutations are essential for uncovering and experimenting with genetic function; but their production is not only very time-consuming, but expensive. But that could soon change. Lexicon Genetics, a Texas-based company, is developing a new procedure that could revolutionize the process, though. Their technique involves random mutation in embryonic stem cells used to produce knockout mice and automatic identification of the mutated gene. The method produces a collection of thousands of cells, each of which bears a mutation in a single known gene. The company plans to provide noncommercial researchers with necessary specifically-mutated cells at no cost. (Source: Nature, April 9, 1998)

      Is it, or isn’t it? The Journal of the American Medical Association (August 18, 1998) reports conflicting studies – one that reports association of genes on chromosome 12 with Alzheimer’s and one that fails to corroborate that observation. The first article indicates increases in susceptibility to the disease of 40% to 65% with certain with expression of a particular group of genes on chromosome 12. These researchers discuss the possibility that susceptibility is further affected by variation in other genes as well. The second study, though failing to find a similar correlation, does not discount the possibility of genetic susceptibility located on chromosome 12; but researchers point out that the particular locus under scrutiny may not account for a significant number of cases of the disease.

So what do we do with this genetic information?     
     Eventually, one therapeutic option may be to insert a miniature extra chromosome into human cells to counter the actions of pathogenic genes. One of the main thrusts of gene mapping is to determine the rules for viable chromosome structure. Sites of DNA replication, which are specialized sequences at the ends of chromosomes (telomeres), and unique sequences in the middle of chromosomes (centromeres) are necessary for chromosome function. Mixing these elements in cells allows normal cell processes to rearrange them into artificial chromosomes, but uncharacterized fragments are always necessary, which makes the exact composition of the artificial chromosomes only a guess. (Source: Alzheimer’s Research Forum, http://www.Alzheimer’sforum.org/members/research/news/index.html#Progress in Anti-inflammatory)

Yet another reason not to smoke
      The Lancet (June 19, 1998) reports on a study in The Netherlands that links smoking with Alzheimer’s and other types of age-related dementia. Of 6,870 subjects of both sexes over the age of 55, 105 had Alzheimer’s. Examination of smoking habits (never-smokers, former-smokers, or current-smokers) showed that current-smokers to be twice as likely to have Alzheimer’s as never-smokers. Strangely enough, no commensurate increase was seen with increased incidence among smokers with ApoE epsilon 4, leading to the assumption that such patients may tend to die early before Alzheimer’s has a chance to show itself.

Other factors
      Moderate elevations in the amino acid homocysteine are a documented risk factor for development of cardiovascular disease, but a study discussed at the second International Conference on Homocysteine Metabolism indicates similar implication in development of Alzheimer’s. Patients with documented Alzheimer’s consistently had higher levels of homocysteiene and lower levels of vitamin B12 and folic acid (which are understood to help regulate homocysteine levels) than subjects without Alzheimer’s. Researchers were quick to acknowledge that the findings could as easily be a result of Alzheimer’s as a causative factor; but speculation persists as to whether increasing dietary intake of folic acid and vitamin B12 might prevent or delay Alzheimer’s onset or progression in some patients. (Source: Doctor’s Guide To The Internet, http://www.pslgroup.com/dg/6f772.htm)

     At the sixth International Conference on Alzheimer’s Disease and Related Disorders in July, a presentation discussed results of a study that examined the effects of poverty on Alzheimer’s incidence. Earlier studies had indicated that larger brain size secondary to better development is associated with reduced incidence of the disease, presumably by establishing a surplus of brain tissue that tends to mask symptoms in affected individuals. In other words, starting with more tissue is an advantage in that more extensive damage is necessary to produce symptoms. This study arrived at the conclusion that poverty during childhood and poor education are definite risk factors for developing Alzheimer’s for those with a family history of the disease. Though the statistics did not hold in the absence of family history of Alzheimer’s, those with family history and childhood poverty were 30 times as likely to develop Alzheimer’s than subjects not affected by poverty. Thus, many cases may be preventable simply by ensuring adequate nutrition during childhood and providing good education. (Source: Doctor’s Guide To The Internet, http://www.pslgroup.com/dg/8fcae.htm)

Women and Alzheimer’s
     Statistically, more women get Alzheimer’s than men, an average of almost 15%. As in the case of cardiovascular disease, hormone replacement therapy with estrogen seems to play a role in either preventing or delaying onset of the disease. Far fewer postmenopausal women on hormone replacement therapy get Alzheimer’s (5.8%) than those not on HRT (16.3%); and those on HRT who get Alzheimer’s experience later onset, slower progression, and milder symptoms.

      There are several possible reasons for the benefits observed.
* Estrogen boosts the production of acetylcholine.
* Estrogen improves blood circulation through the brain.
* Estrogen stimulates nerve cell growth in areas of the brain affected by Alzheimer’s.
* Estrogen impedes the deposition of beta-amyloid.
* Estrogen helps maintain the integrity of the hippocampus, an area of the brain involved in memory. Source: Alzheimer’s.com, http://www.Alzheimer’sheimers.com/L3TABLES/L3T10516.HTM

Zinc
      Research in Australia has demonstrated that very high intake of zinc promotes neural changes similar to the neurofibrillary plaques seen in Alzheimer’s, with brain levels of zinc only slightly higher than normal producing plaques. Beta-amyloid peptide has a chemical affinity for zinc, and abnormalities of zinc metabolism have been noted in early Alzheimer’s disease as well as Down’s syndrome. Alzheimer’s almost always occurs in Down’s patients who live to the age of 40 or 50. Victims of Alzheimer’s given zinc supplements show accelerated cognitive deterioration. Source: Alzheimer’s. Com, http://www. Alzheimer’s.com/L3TABLES/L3T10516.HTM

Aluminum
     Similarly, aluminum is found in large concentrations in amyloid plaques; but don’t throw away your aluminum pots and pans just yet. As one of the most abundant elements in our natural environments, almost everyone is continually exposed to tremendous amounts on a daily basis, far in excess of what you might get from aluminum soda cans. At least one study, though, has associated Alzheimer’s with high levels (over 11 micrograms per liter) of aluminum in drinking water. For about a hundred dollars, the National Testing Laboratory of Cleveland (800-458-3330) will tell you how your drinking water stacks up, reporting not only aluminum content, but the content of 73 other entities as well. Source: Alzheimer’s.com, http://www.Alzheimer’sheimers.com/L3TABLES/L3T10516.HTM


Advances In Treatment
      Donepezil (Aricept™), the only acetylcholinesterase inhibitor currently on the market, acts by slowing the breakdown of acetylcholine and effectively increasing useful levels of the neurotransmitter in the brain. It is only the first of a string of similar agents in line for approval within the next few years. Studies have shown it to improve symptoms of apathy, hopelessness, hallucinations, repetitive movements, and even cognitive decline, working as well in patients living at home as in those who are institutionalized. Not only do the patients benefit, but caregivers report significant reductions in stress related to patient care, an important consideration in caregiver burden and nursing home placement. Source: Doctor’s Guide To The Internet, http://www.pslgroup.com/dg/6f99a.htm
 
      Patients can be difficult to manage, and family caregivers often opt for institutionalization. In the absence of a cure, the best current treatments can offer is some hope for minimal amelioration of symptoms and possible slowing of deterioration. Available medications are expensive in spite of what can be nebulous benefit, and families face the dilemma of balancing uncertain benefit with expense and side effects. Though donepezil has been shown to slow the progression of the disease in many patients, families frequently opt not to utilize it, commonly based on the extent of progression when faced with the decision. Patients still at home and being cared for by family members typically receive the treatment; while those in nursing homes with advanced disease are more often denied access. Source: Medscape News, http://www.medscape.com/Home/News/archive/Headlines.html
 
      Antiepileptic drugs (AEDs) are showing some promise in controlling some of the symptoms of Alzheimer’s, particularly agitation and aggression. While using sedatives or even antipsychotics like thioridazine and haloperidol has provided very limited success, carbamazepine and divalproex sodium have been used in this application for some time without the benefit of placebo-controlled studies to back up the practice. These two AEDs have been shown to help control tension, hostility, screaming, hitting, spitting in nursing home patients with Alzheimer’s in studies discussed in a media briefing at the sixth International Conference on Alzheimer’s Disease and Related Disorders. Evidence is sufficient to mount large multi-center trials. (Source: Doctor’s Guide To The Internet, http://www.pslgroup.com/dg/8fa2e.htm)

      AIDS, hypertension, myocardial infarction, stroke, diabetes, multiple sclerosis, Lou Gehrig's disease, scleroderma, and Alzheimer’s are all associated with elevated levels of cortisol. Originally deemed a result of these disease states, the current view is that these elevations in cortisol levels are contributory factors in pathogenesis. Correcting the elevations, then, should logically at least slow the progression of such diseases; and that is exactly what Acticort™ (procaine HCl) is designed to do. Termed a steroidogenesis inhibitor, the agent’s anti-cortisol activity coupled with its anticholinesterase activity make it a promising candidate for the effective treatment of Alzheimer’s. Testing is scheduled to begin late in 1998. (Source: Doctor’s Guide To The Internet, http://www.pslgroup.com/dg/6d5e2.htm)

New agents in Phase III trials
      Janssen Pharmaceutica’s Reminyl™ (galantamine) recently completed Phase III trials, producing improvemnts in memory and learning ability in Alzheimer’s patients and sustaining cognitive scores at or above baseline for a full year of treatment in test subjects expected to deteriorate. Galantamine appears to have a dual mechanism of action, decreasing the deactivation of acetylcholine as an acetylcholinesterase inhibitor like tacrine and donepezil (both already on the market), but also stimulating nicotinic receptors, which may release more acetylcholine. Nicotinic stimulation represents a new area of Alzheimer’s research that may result in fewer amyloid plaques. (Source: Doctor’s Guide To The Internet, http://www.pslgroup.com/dg/8F5D6.htm)

      Neurology (May, 1998) reports on Bayer’s metrifonate, an organophosphorous compound and acetylcholinesterase inhibitor originally used in the treatment of schistosomiasis. Now in Phase III trials, the new agent not only slows the symptomatic progression of the disease like donepezil and tacrine, but also ameliorates the hallucinations , apathy, depression, and agitation for many patients. Researchers emphasize that acetylcholinesterase inhibitors are most appropriately used in mild to moderate disease, where they produce the most favorable results.

      The International Journal of Geriatric Psychopharmacology (July, 1998) reports on Novartis Pharmaceuticals’ Exelon (rivastigmine tartrate), yet another acetylcholinesterase inhibitor in phase III trials. Fifty-six percent of patients treated with 6mg to 12mg of rivastigmine tartrate per day showed either improvement or stabilization of ability to perform daily living activities after 26 weeks of therapy.

      The neuritic plaques that have come to characterize Alzheimer’s are microscopic, spherical structures containing deposits of beta amyloid peptide, dead and dying neurons and evidence of inflammation, presumed a response to injury but suspected of perpetuating the neural damage. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the risk of developing the disease, but side effects limit their use. NSAIDs produce their anti-inflammatory action by inactivating cyclooxygenase 2 (COX-2), while side-effects result mostly from inactivation of COX-1. Several new agents that selectively inhibit COX-2 are already in clinical trials, the most potent of which, o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS) is 60 times as effective against COX-2 and 100 times as selective for COX-2 as aspirin. APHS is also the first new agent to actually inactivate COX-2 irreversibly manner like aspirin. Source: Kalgutkar, A., et. al. "Aspirin-like Molecules that Covalently Inactivate Cyclooxygenase-2" Science, 22 May 1998)