Science with a Human Face: Lessons from the Nun Study and Alzheimer’s Research

At a CME session held February 25, 2002 at the annual meeting of the American Association for Geriatric Psychiatry, two leading experts discussed the latest research on Alzheimer’s disease, including attempts to fill treatment gaps and a review of findings from the Nun Study.

This program was supported by an unrestricted educational grant from Forest Laboratories, Inc.

Strategies for Treating Alzheimer’s Disease Throughout the Course of Illness

P Murali Doraiswamy, MD, director of the Division of Biological Psychiatry, Duke University Medical Center, Raleigh, North Carolina, focused his presentation on the treatment gaps in Alzheimer’s disease. Currently, there are no FDA-approved treatments for patients in the severe stage or for those with mild cognitive impairment (MCI), who may be in a preclinical stage.

The three newer cholinesterase inhibitor drugs—donepezil, rivastigmine, and galantamine—are currently approved in the United States only for treating patients in the mild and moderate stages of Alzheimer’s disease, generally defined as patients with MMSE scores in the 10 to 26 range. These drugs may potentially prove useful for patients with MCI or for those in the severe stages, but more studies are needed. Several additional investigational treatment strategies are also under review.

For some patients with MCI, this condition is a prodromal stage of Alzheimer’s disease. The goal of therapeutic strategies for this population is to prevent the disease or to delay the onset. While there are no therapeutic agents that have been proven to accomplish this, there are some candidates.

Statin drugs for prevention of AD
Several epidemiologic, or retrospective, studies have examined the relationship between the use of statin drugs and the development of dementia. In general, these studies have found that older people who took statins had a lower risk of dementia, and the effects may be independent of hyperlipidemia or exposure to other lipid-lowering agents. The prevalence of Alzheimer’s disease in the cohort taking statins was about two-thirds lower than control populations.

While the results are promising, it’s still unclear how statins lower risk. An obvious explanation would relate to reduced lipid levels. However, in these studies, the relationship seemed to be independent of lipid-lowering effects.

Experimental studies have suggested that statins may have direct beneficial effects on amyloid and on cerebral blood flow. For example, simvastatin and lovastatin were found to reduce amyloid beta42 in vitro and in vivo. Pravastatin (20 mg daily for two months) was shown to increase cerebral blood flow. “These could be alternate explanations for how these drugs exert their protective effect,” said Dr. Doraiswamy.

He cautioned that it’s still premature to consider using statins to prevent or treat Alzheimer’s disease because there have been no randomized controlled trials showing efficacy. In addition, paradoxically, some patients taking statins report memory loss as an occasional side effect. This may be explained by the fact that many patients who take statin drugs have cerebrovascular disease. Bypass surgery, stroke, and other vascular events can result in memory loss. Dr. Doraiswamy said that a large study of the FDA MedWatch database is underway to examine this issue further.

There could also be differences within statins in their neural effects. Dr. Doraiswamy cited the case of a 51-year-old man with progressive memory loss when taking simvastatin. The condition resolved after switching to another statin. Therefore, an additional question for further study is, which statin drug will be most beneficial?

NSAIDs and vitamins
Two additional agents being studied for potentially preventing or delaying the onset of Alzheimer’s disease are NSAIDs and B vitamins.

A recent study has suggested that people who use NSAIDs continuously for at least two years have a lower risk of Alzheimer’s disease (N Engl J Med. 2001;345:1515-1521). These data are consistent with many other prior studies. However, it isn’t clear whether the COX-1 or COX-2 enzyme plays a more significant role.

There’s currently no clinical data with regard to the effects of COX-2 inhibitors (celecoxib and rofecoxib) on preventing Alzheimer’s disease. One unpublished trial with celecoxib for treating Alzheimer’s disease was negative.

Epidemiologic studies have also shown that people with low levels of vitamin B12 or folic acid may have a higher risk for cognitive impairment. And some recent data suggest that even a subclinical deficiency can result in variations in memory.

A surrogate marker for a disruption in the metabolism of B12 and folic acid is elevated homocysteine. Levels of homocysteine greater than 14 micromoles per liter has been reported to double the risk for Alzheimer’s disease in one recent study (N Engl J Med. 2002;346:476-483).

“There’s a lot of interest in seeing if supplementation with one of these B complex vitamins can be effective in reducing the risk for Alzheimer’s disease,” said Dr. Doraiswamy.

Treatment of advanced Alzheimer’s disease
On the other end of the spectrum from prevention and delay of onset is the other treatment gap, effective therapies for severe Alzheimer’s disease. Investigators are currently looking into the use of cholinesterase inhibitors, agents that affect other neurotransmitters (such as glutamate), and anti-amyloid agents.

“One of the challenges of assessing treatment effect among this population of patients is the fact that some tests of cognition have a floor effect,” said Dr. Doraiswamy. For example, the mini-mental state examination (MMSE), the traditional test used to assess cognition, is not sensitive enough at the lower end of the scale.

The severe impairment battery (SIB), a performance-based evaluation of cognitive functions, was developed to assess this population of severely impaired patients. The SIB has a high sensitivity to change in patients who score between 0 and 15 on the MMSE. It has been used in two recent studies of moderate to severe Alzheimer’s patients, one with donepezil and one with the investigational drug memantine. The donepezil study was a six-month trial comparing donepezil to placebo in 290 patients with moderate to severe Alzheimer’s disease (Neurology. 2001;57(4):613-620).

“In these patients, donepezil improved cognition, functioning, behavior, and caregiver perception of how the patient was doing,” said Dr. Doraiswamy.
Analyses of open label data with rivastigmine have found that initiation of early treatment may offer sustained cognitive benefits in patients with moderately severe dementia. Therefore, cholinesterase inhibitors may have a role in the treatment of severe Alzheimer’s disease, contrary to current beliefs.

Glutamate as a target for AD
Most of the development of Alzheimer’s disease drugs has focused on acetylcholine as a target. However, there is evidence that at least one other neurotransmitter, glutamate, is also involved. Glutamate acts on the AMPA receptor and the NMDA receptor. Drugs are currently being developed that target each of these receptors.

One theory about Alzheimer’s disease is that there may be an imbalance in the glutamatergic system, whereby excess glutamate leads to excitotoxicity and cell death. The appropriate amount of glutamate facilitates learning and storage of long-term memory through the NMDA receptor. Excessive amounts of glutamate permits too much calcium to enter cells, leading to excitotoxicity.

“Therefore, a drug that is an NMDA channel modulator may be an attractive option to treat Alzheimer’s disease,” said Dr. Doraiswamy. Ideally, the drug would permit normal glutamate transmission, but would also prevent excess glutamate spikes from harming the cell.

The drug memantine, marketed in Germany since 1982, is a voltage-dependent NMDA receptor antagonist. It recently received approval by the European Union for use in moderate to severe Alzheimer’s disease, and it is an investigational drug in the U.S. for the treatment of Alzheimer’s disease.

Memantine is reported to have rapid on/off NMDA binding characteristics. Preclinical data suggest that it permits physiological glutamate transmission, but under conditions of pathological glutamate concentrations, it blocks the channel, preventing excitotoxicity and cell death. It is reported to quickly disassociate the NMDA receptor to permit physiologic transmission to resume (See Figure 1).

Memantine was studied by Reisberg et al. in patients with moderate to severe Alzheimer’s disease in a 28-week randomized, double-blind trial in the U.S. The drug was compared to placebo in 252 patients with MMSE scores of 3 to 14, GDS stages 5 or 6, and a FAST score of 6a or greater.

Memantine was superior to placebo when measured with the SIB (cognitive function) and activities of daily living. “This was the first pivotal U.S. study of memantine for advanced Alzheimer’s disease and the results were very promising ,” said Dr. Doraiswamy.

A pilot interaction study in rats, by Wenk et al., showed that FDA-approved acetylcholinesterase inhibitors do not lose their therapeutic choline-sterase inhibitory effects in combination with memantine (Life Sci. 2000;66:1079-83). Because memantine has a different mechanism of action from cholinesterase inhibitors, there is a potential for using the two classes of drugs in combination. Further research on the safety and efficacy of this combination is ongoing.

Other treatment strategies
Another promising area of research for the treatment of Alzheimer’s disease involves anti-amyloid agents. This work suffered a setback recently when the amyloid-beta42 vaccine study was suspended because several cases of encephalitis-type inflammatory side effects were reported.

“This much heralded strategy awaits the development of an appropriate candidate agent with a good risk-benefit profile,” said Dr. Doraiswamy.

“Realistically speaking, we are unlikely to find a cure for Alzheimer’s disease in the next five years,” he said. Anti-amyloid approaches are several years away from FDA approval. Hence, neurotransmitter-based approaches are likely to remain the mainstay for treating dementia for the next several years.

It’s likely that research on the treatment of Alzheimer’s disease will be aimed at identifying agents that can be used as monotherapy or in combination to slow the rate of decline and to maximize function and quality of life. Choline-sterase inhibitors, vitamins, glutamatergic drugs, and anti-amyloid agents are all potential candidates for combination therapy. “There is a real sense of urgency to begin to test rational combinations,” concluded Dr. Doraiswamy.

Aging and Alzheimer’s Disease: Intriguing Findings from the Nun Study

Alzheimer’s disease appears to be the consequence of a long chain of events, starting with early life factors and extending to late life events, according to David Snowdon, PhD, professor, Department of Neurology, College of Medicine and the Sanders-Brown Center on Aging, University of Kentucky. Dr. Snowdon, who is director of the Nun Study, presented findings from this longitudinal study of health and aging among a group of Catholic nuns.

Participants in the Nun Study are 678 American members of the School Sisters of Notre Dame religious congregation who were 75 to 102 years old at the beginning of the study in 1991. These sisters have the same reproductive and marital histories; have similar social activities and support; did not smoke or drink excessive amounts of alcoholic beverages; and have similar occupations, income, and socioeconomic status. While it may be difficult to generalize from this unique population of Catholic sisters, many factors that confound most epidemiologic studies have been eliminated or minimized.

There are three basic sources of information available in the Nun Study. First, convent archives provide a wealth of information about potential early-, mid-, and late-life risk factors for Alzheimer’s disease and other disabling conditions. Second, annual exams of each participant document changes in their mental and physical function during the last years of their lives. Finally, because each of the sisters agreed to brain donation at death, the information garnished from the convent archives and annual exams are compared to the structure and pathology of the brain.

So far, the study’s findings suggest that Alzheimer’s disease is a consequence of a long chain of events spanning the life course. Additionally, late-life events, such as stroke, can increase the risk of Alzheimer’s disease and the severity of its symptoms.

Decline across the life span
Studies of brain and language development in early life provide some indication that Alzheimer’s disease results from a chain of lifelong events. For example, a study by Dr. Snowdon looked at autobiographies from the convent archives that were written by the study participants at a mean age of 22 (JAMA. 1996; 275(7):528-532). Cognitive function was evaluated approximately 58 years later, and for those who had died function was evaluated neuropathologically.

The study showed a strong relationship between low linguistic ability in early life and a high risk of Alzheimer’s disease in late life.

In a more recent study, Dr. Snowdon and his colleagues investigated the relationship between linguistic ability in early life and the neuropathology of Alzheimer’s disease and cerebrovascular disease. Analyses were done on 74 of the participants for whom early autobiographies were available. These participants died between the ages of 78 and 97 and neuropathologic studies were conducted on their brains. The researchers found a correlation between low idea density scores in early life and neurofibrillary tangle counts in late life.

Dr. Snowdon and his associatesconcluded that “low linguistic ability in early life may reflect suboptimal neurological and cognitive development, which might increase susceptibility to the development of Alzheimer’s disease pathology in late life.”

The autobiographies were scored for emotional content in addition to linguistic ability. Positive emotions expressed in the autobiographies correlated to longevity 60 years later.

The influence of late life events
The Nun Study also suggested that certain late-life events, such as stroke, can increase the risk for Alzheimer’s disease and increase the severity of its symptoms.

Dr. Snowdon and his colleagues conducted a study involving 102 nuns who were 76 to 100 years old and were college educated (JAMA. 1997;277(10): 813-817). Cognitive function and the prevalence of dementia were determined for these participants, who later died. Brain autopsies revealed that 61 participants had Alzheimer’s disease, based on the presence of abundant senile plaques and some neurofibrillary tangles in the neocortex. Lacunar and larger brain infarcts were also identified.

Among the participants with Alzheimer’s disease, those who had brain infarcts had poorer cognitive function and a higher prevalence of dementia than those without infarcts. For participants with subcortical lacunar infarcts (in the basal ganglia, thalamus, or deep white matter), the prevalence of dementia was 93%, compared to 57% in those without infarcts.

“While Alzheimer’s disease and brain infarction may represent separate disease processes, their combination may nonetheless increase the likelihood that dementia will occur,” Dr. Snowdon wrote in an editorial in JAMA. He also wrote that “because of the vital connections between the neocortex and the basal ganglia, thalamus, and deep white matter, infarcts in these subcortical regions may be particularly disabling if the neocortex has already been damaged by Alzheimer’s disease.”

Dr. Snowdon and his colleagues concluded that cerebrovascular disease may play an important role in determining the presence and severity of the clinical symptoms of Alzheimer’s disease.