A special May issue of the Journal of Alzheimer’s Disease, guest editors Judith Miklossy, from The University of British Columbia, and Ralph N. Martins, from Edith Cowan University and Hollywood Private Hospital, Perth, Western Australia, and a group of experts explore the topic of how pathogens may suppress, subvert or evade host defenses and establish chronic or latent infection, which has received little attention in the past.

It appears that during an infection cells generated by inflammatory cells may cause DNA damage. Depending upon the biology of the pathogen and the host defense mechanisms the organism can persist in the infected tissues and cause chronic inflammation and amyloid plaque. The outcome of infection is as much determined by the genetic predisposition of the patient as by the virulence and biology of the infecting agent.

This special issue contains a series of reviews from both a historical and recent perspective. The first review shows the importance of chronic inflammation in AD, followed by three articles presenting evidence on the involvement of spirochetes, Chlamydia pneumonia and Herpes simplex virus type 1 in Alzheimer’s disease. These are followed by a review of amyloid proteins, which occur in many cellular forms in Eukaryotes and Prokaryotes.

The editors feel that treatment of a bacterial infection and associated viral infection may result in regression and, if started early, prevention of disease. The impact on reducing health-care costs would be substantial.

Donna Kritz-Silverstein, PhD, adjunct professor, Family & Preventive Medicine, University of California, San Diego, and colleagues, studied effects of DHEA supplements on 110 men and 115 women, between 55-85. The participants received either 50 mg doses of DHEA or a look-a-like placebo. Six cognitive function tests were given and measures of depression, perceptions of physical and emotional health, life satisfaction and sexual function were recorded at the beginning of the study and again at the conclusion of the study one year later.

Although the group receiving DHEA had returned to youthful levels of the drug there were no benefits for cognitive function. Also, there were no differences seen between those taking DHEA and those taking placebo in quality-of-life measurement scores.

Previous clinical trials examining the effects of DHEA supplementation on cognitive function and quality-of-life have inconsistent results, with some showing positive effects and others showing no effect. However, these trials used small sample sizes, were of short duration (generally 2 weeks to 4 months) and did not include older men and women who were at an age when memory loss and cognitive impairment become more apparent. Also, unlike the participants in the majority of previous studies, the participants in this study were not selected for lower levels of DHEA, meaning the results reflect what would be found in the general population.

The study is published in the Journal of American Geriatrics Society.

William Bowers, associate professor of neurology, microbiology, and immunology, University of Rochester Medical Center, believes he and his co-workers have demonstrated a way to create a potent, but safe, version of a vaccine that causes an immune response that prevents Alzheimer’s disease and memory deficits.

Mice, genetically engineered to develop Alzheimer’s, were given a vaccine that caused the immune system to target amyloid beta proteins–considered to be the cause for Alzheimer’s disease. Previous to the 10-month study the mice were trained to navigate through a maze. During the study the mice were timed on how long it took to successfully get to the maze’s exit. The maze test results excited researchers because it indicated their vaccine was able to prompt the immune system to successfully remove amyloid beta before it mutated into the Alzheimer’s disease causing form.

A number of studies will be needed to meet regulatory requirements before the vaccine can be tested on humans, which is expected to take at least 3 years.

Shirley E. Poduslo, PhD, neuroscientist, Medical College of Georgia Schools of Medicine and Graduate Studies, studied the genetic profile of 2 large Georgia families with high rates of late-onset Alzheimer’s disease. Poduslo was shocked when she found that the single nucleotide polymorphisms (SNP) occurred 9 out of 10 times in affected family members. SNPs also were found in the DNA of 36% of 200 late-onset patients stored in the Alzheimer’s DNA Bank.

The gene variation was in the TRPC4AP; part of a large family of genes that is not well-studied, but believed to regulate calcium. Calcium is needed throughout the body and its dysregulation can result in inflammation, nerve cell death and possibly plaque formation.

The next step is to identify the specific genetic mutation responsible. The mutation could be a deletion of some of the nucleotides, an insertion into the gene, or something that prevents the gene from duplicating correctly.

James Shorter, PhD, Assistant Professor of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, has made a surprising discovery. A small molecule, called DAPH, can be used to target the areas that hold the amyloid fibers together and convert the fibers to a form that makes them unable to grow. DAPH accomplishes this remarkable goal by preventing growth from the ends of the fibers.

The DAPH molecule remodels the fiber architecture, which is something researchers have not been able to accomplish before. DAPH was originally found in a screen of small molecules that reduce amyloid-beta toxicity by Vernon Ingram, Massachusetts Institute of Technology (MIT), and co-researcher.

When a small amount of amyloid (or prion) fiber is added to the normal form of the protein it is converted to the fiber form. However, when DAPH is added the conversion process is prevented and essentially stops fiber formation in its tracks.

Some types of amyloids may be helpful–like in formation of memories–so, researchers are now looking for a way to selectively choose which type of amyloid protein is affected.

The Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT) Research Group studied 2,117 individuals, 70 years and older, who have a family history of Alzheimer’s. For 3 years the participants were tested annually for cognitive function.

• 29% were given 200 milligrams of celecoxib twice daily.
• 28% were given 220 milligrams of naproxen sodium twice daily.
• 43% were given a placebo.

Six months after the study was terminated (because another study found celecoxib increased cardiovascular risks) the use of NSAIDs did not show a protective effect and in fact naproxen users had a lower cognitive assessment score when compared to celecoxib and the placebo.

Why the difference? Several explanations were offered:

• Previous studies analyzed behavior rather than assigning subjects to treatment groups.
• Factors not measured in the previous study may have confounded or affected the results.
• The findings of this study apply only to celecoxib and naproxen.
• NSAIDs may be protective only when given several years before the decline of cognitive function.

Researchers conclude that naproxen and celecoxib should not be used for the prevention of Alzheimer’s disease.

Nikolaus Grigorieff, biophysicist, Brandeis University, along with researchers at Leibniz Institut, Jena, Germany, have successfully created an A-beta peptide 3-D image. Grigorieff, and colleagues, overcame the barrier to determining the structure of A-beta fibrils by generating them in a test tube under conditions that reduce the variability between fibrils, then selecting about 200 images of fibrils that were similar and averaging them on a computer.

Researchers plan to create a 3-D image that shows where all of the amino acids are located in hopes to learn more about the chemical and biological properties of A-beta Fibrils to have a better understanding of their role in Alzheimer’s disease.

French researchers studied nearly 7,000 people over 65 years from the general population of 3 French cities. None of the subjects had dementia, but 4 out of 10 had mild cognitive impairment at the onset of the study. At 2 and 4 years the participants were re-evaluated.

• Approximately 6.5% initially considers to have mild cognitive impairment developed dementia.
• One in three of those with mild cognitive impairment reverted to normal levels of cognitive agility.
• Depressed individuals were more likely to progress from mild cognitive impairment to dementia.
• Men who had a stroke were nearly 3 times more likely to progress from mild cognitive impairment to dementia.
• Men with mild cognitive impairment were more likely to be overweight, diabetic, and have a stroke.
• Women with mild cognitive impairment were more likely to be in poor general heath, disabled, suffering from insomnia, and have a poor support network.
• Women unable to perform routine daily tasks were 3.5 times more likely to develop dementia.
• Women who were depressed and had mild cognitive impairment were twice as likely to develop dementia.
• Strokes in women occurred as frequently as in men, but did not factor statistically in developing dementia.

David R. Schubert, PhD, professor Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, reports that blood vessels in the brain of young diabetic mice are damaged by the interaction of elevated blood glucose levels characteristic of diabetes and low levels of beta amyloid (a peptide that clumps to form a plaque in the brain associated with Alzheimer’s).

Recent studies show that both type 1 & 2 diabetic patients have a 30-65% higher risk of developing Alzheimer’s disease compared to non-diabetic individuals. Most previous studies investigating the diabetes-Alzheimer’s connection have focused on altered insulin signaling in the brain, but have paid little attention to the effects of increased blood glucose levels on brain function and the role they play in development of Alzheimer’s.

Using genetically engineered mice researchers found that vascular damage was due to overproduction of free radicals, which damage the cells lining the brain’s blood vessels. There may be a synergistic toxicity between the amyloid protein and a high level of blood glucose that is causing problems with blood vessel formation.

While this initial trial was only marginally successful a new family of drugs has shown promise for preventing Alzheimer’s disease and perhaps the vascular damage associated with diabetes.

Kaycee M. Sink, MD, MAS, Wake Forest University School of Medicine, and colleagues, studied 3,141 Indiana nursing home residents who were taking dementia medication, which included 395 residents who were taking both dementia and urinary incontinence medication. Subjects were 65 years or older.

Subjects of the study had at least 2 consecutive prescriptions for cholinesterase inhibitors–i.e. Aricept®, Razadyne®, Exelon®, Cognex®–used to treat dementia. Of the subjects in the study approximately 33% of the people with dementia also take a drug for incontinence. Approximately, 10% of the residents also took one of the 2 most commonly prescribed urinary incontinence drugs–oxybutynin or tolterodine.

Researchers found that nursing home residents who took medications for dementia and incontinence at the same time had a 50% faster decline in function than those who were being treated only for dementia.

Also noted by researchers is that their study was conducted between 2003 and 2004, which is before newer incontinence medications were introduced that may have less of an effect on the brain.