The Long Goodbye
(continued)

A CNN camera crew films one of the first surgeries performed on a gene-therapy patient at UCSD.

Douglas R. Galasko, M.D., a physician scientist with the UCSD Shiley-Marcos ADRC, was one of the early scientists who determined that beta amyloid and tau could be measured in spinal fluid and were useful markers for Alzheimer’s. It remains to be seen, however, whether plaques and tangles actually cause the disease or are byproducts of Alzheimer’s.

While many scientists support what is called the beta amyloid hypothesis, they also agree that it does not fully explain the disease. Other factors may contribute. While aluminum deposits in the brain and infections have been studied in past years, attention has more recently shifted to the role of inflammation, damage caused by too much oxygen, and vascular risk factors such as diabetes, hyperlipidemia (high fat levels in the blood) and stroke. Any of these mechanisms may trigger dementia or contribute to the degeneration in Alzheimer’s disease.

Douglas R. Galasko, M.D., was one of the scientists who determined that beta amyloid and tau could be measured as Alzheimer’s markers.

“Early-onset” Alzheimer’s can strike people as young 30, 40 or 50. These patients, who represent 5 percent of all cases, show mutations in certain genes, which inevitably lead to the disease. However, for the vast majority of late-onset Alzheimer’s patients, the cause of the disease remains unknown.

UCSD’s Masliah has found that damage to synapses, the structures that connect neurons and allow them to communicate, occurs early in Alzheimer’s disease and is a major contributor to the subsequent neuronal loss and plaque formation characteristic of the disease.

Another UCSD researcher, Lawrence S.B. Goldstein, Ph.D., believes that the protein APP clogs the movement of brain messages on long traffic lanes called axons, eventually leading to neuron cell death. His team is using human neurons grown from human embryonic stem cells to test their ideas.

Treatment Options
One of the world’s leading Alzheimer’s researchers, Leon Thal, M.D., is director of the UCSD Shiley-Marcos ADRC and director of the multicenter NIA-funded Alzheimer’s Disease Cooperative Study. An early pioneer in Alzheimer’s treatment, Thal published a 1993 study in the New England Journal of Medicine in which he provided some of the first evidence that memory could be enhanced in Alzheimer’s patients by stopping the action of a brain chemical called acetylcholinesterese (AChE). These findings led to the development of AChE inhibitors (e.g. Tacrine and Donepezil), some of the first drugs used to treat the disease.

Much of today’s current research centers on ways to decrease damage to the neurons, slow the progression of Alzheimer’s and, eventually, treat the causal factors.

A recently announced study by UCSD neuroscientist Mark Tuszynski, M.D., Ph.D., offered a promising therapy to delay memory and cognitive decay. In the first-ever gene therapy for Alzheimer’s patients, the Tuszynski team surgically implanted the genetically modified tissue of eight patients directly back into their brains. The researchers showed that the patients’ rate of cognitive decline was reduced by 36 to 51 percent. In addition, an examination of brain tissue from a study participant who had later died found robust growth of extensions from the dying neurotransmitter cells near the site of the gene therapy. This study continues under the direction of Rush Presbyterian Hospital in Chicago with clinical trials at multiple U.S. sites.

Another promising gene therapy developed by UCSD’s Masliah, in collaboration with scientists at the Salk Institute and the University of Kentucky, focuses on decreasing the build-up of beta amyloid, the sticky plaque deposits. The researchers developed mice with beta-amyloid and a loss of synapses similar to that seen in Alzheimer’s patients. The team then used gene therapy to deliver extra amounts of a naturally occurring gene called neprilysin. The treatment degraded the beta amyloid in the mice by nearly 50 percent and re-established synapse connections. The researchers hope to eventually test this therapy in human clinical trials.
In recent years, there was tremendous hope for an Alzheimer’s vaccine to combat beta-amyloid. However, clinical trials of the vaccine, developed by a company called Elan, were halted after several patients died from brain inflammation. Now, a clinical trial headed by the University of Michigan at 30 U.S. centers is testing a new version of the vaccine composed of beta amyloid antibodies, rather than the beta amyloid protein itself.

Several potential Alzheimer’s treatments are currently under investigation at the UCSD Shiley-Marcos ADRC and numerous centers through the Alzheimer’s Disease Cooperative Study. These include statins (used to lower cholesterol and reduce inflammation), valproate (an anti-seizure medication that may reduce tangle formation), homocysteine-lowering therapy (aimed at reducing damage to blood vessels in the brain), and a non-steroidal anti-inflammatory drug (NSAID) called R-flurbiprofen. The scientific basis for suggesting that NSAIDs may lower beta-amyloid production was provided in 2001 by UCSD Alzheimer’s researcher Edward Koo, M.D.

Earlier Diagnosis and Treatment
As scientists have studied normal aging and Alzheimer’s disease, they’ve identified a transitional state called mild cognitive impairment (MCI), which affects 15 percent of older adults, and is characterized by memory complaints not normal for the patient’s age. Compared to individuals with dementia, however, MCI patients have essentially normal general cognition and largely intact activities of daily living. Approximately 10 to 15 percent of MCI patients convert to Alzheimer’s compared to 1 to 2 percent of “normal” elderly.
Specific neuroimaging tests are not yet available to detect MCI. However, scientists at the University of Pittsburgh have recently developed a compound called PIB that attaches itself to beta amyloid plaques in the brain, making them stand out on neuroimaging scans. In additional studies, PET scans show MCI and Alzheimer’s patients metabolize glucose less than normal individuals.

New treatments for MCI have been developed and others are undergoing clinical trials. For example, in a recently published study by UCSD’s Thal and Ronald Petersen, M.D., of the Mayo Clinic, people with MCI who took the commonly prescribed drug donepezil (Aricept) were at reduced risk of progressing to a diagnosis of Alzheimer’s during the first two years of the trial, as compared to those who took vitamin E or a placebo. By the end of the trial’s third year, however, there was no benefit observed from the drug.

After the Diagnosis
As Bill Jacoby’s symptoms progress, Agnes is taking on more of the care giving. She manages Bill’s medications, helps him dress, shaves him and brushes his teeth. Through the ADRC, Agnes found a caregiver who stays with Bill occasionally, to allow her some time off, and they have both continued to participate in the UCSD Shiley-Marcos ADRC patient and caregiver support groups. “ It was tremendously helpful to come to the support group meetings,” Agnes said.

ADRC social worker and counselor Lisa Snyder leads the patient support group. The author of Speaking Our Minds (W.H. Freeman and Co., 2000), a book about personal reflections from individuals with Alzheimer’s, she describes the patients with whom she works, many of whom are like Bill Jacoby:

“These individuals are negotiating a world in which they may still be very active participants, even though their roles are changing... Regardless of the skills we bring to the far-reaching realms of Alzheimer’s, all efforts are ultimately motivated not by the disease itself but by the people living with the disease.”

Bill did not want to attend the meetings at first, but when he finally did, he was surprised at the mood of the patient group. “I walked into the room and these people were smiling. They were laughing. In spite of this terrible, incurable disease, they were joking and sharing their lives. I was lifted up.”

Sue Pondrom is a freelance writer based in San Diego.