Dementia: Update for the Practitioner

There are two models for prevention of Alzheimer's disease. One is the concept of primary prevention, targeting the induction phase in which we have no evidence of disease. To do trials of this kind of prevention, we want to find what we most hope to see in our practices: people with no cognitive loss. This requires large numbers of people. In these studies, individuals who have no problems will have a very low tolerance for adverse events or side effects. The risk-benefit ratio has to favor very low risk.

The other model for prevention, secondary prevention, is for someone with a complaint but no full-blown disease. Trials studying this kind of prevention require individuals who may be at high risk because of genetics, a family history of early onset AD, positive testing for an objective marker such as significant memory impairment, or positive testing for a biological marker, which is not yet available. These individuals, we believe, are in a stage in which some disease process can be identified, and we want to avoid this developing into a full-blown disease. Here the risk-benefit ratio may justify a little bit more discomfort or risk, but a dramatic effect will still be required to overcome the idea of any interference.

It has been suggested that if we could delay the onset of the disease by as little as six months in the next generation, we could reduce the incidence of dementia by as many as a million cases. If we could delay it by five years, we could actually reduce the number of cases by 50 percent. One concern is that this data is predicated on no significant change in life expectancy, and in coming years our lives may exceed our memories even more.


	Potential Impact of Interventions to Delay Onset of Alzheimer's Disease


	A model showing that interventions to delay onset of Alzheimer's disease could potentially reduce the incidence of dementia by as much as 50 percent. Courtesy of Dr. Mary Sano. Source of data: R. Brookmeyer et al., "Projections of Alzheimer's Disease in the United States and the Public Health Impact of Delaying Disease Onset," American Journal of Public Health 88, no. 9 (1998): 1337–42.

An MCI population could be used for secondary prevention trials. In a group of people who came into Alzheimer's centers around the country with memory complaints, those who have clear evidence of memory deficit rapidly deteriorated, while those with less deficit showed a much slower decline. In fact, with this rapid deterioration we have a population in which it becomes feasible to answer the question, can we delay onset in a secondary prevention trial?


	Conversion Rate of MCI to AD by Memory-Impairment Criteria


	Among patients who came into Alzheimer's centers in the United States with memory complaints, those whose memory testing showed clear evidence of memory deficit rapidly deteriorated, while those with less deficit showed slower decline. Courtesy of Dr. Mary Sano

To illustrate the number of subjects and length of time it would take to answer these questions, I have modeled some predictions. The sample size is determined by the frequency of an outcome measure. As you can see, the frequency of dementia is quite high for someone with mild cognitive impairment. In general, the sample size increases as the disease or symptoms decrease, so the number of patients that are needed to run a symptomatic study is going to be smaller than the number of MCI individuals needed to run a secondary prevention trial. The number needed for secondary prevention is smaller than the number needed to test healthy elders and to test primary prevention. Patients with disease and symptoms are likely to progress more rapidly, and consequently shorter trials are needed.

In AD patients, we can assess symptomatic changes in a sample size of two to three hundred over six months. To look at slowing progression as a study outcome in AD patients would take one to two years with several hundred patients. Looking at secondary prevention in an MCI population would take 700 to 1,000 patients followed over three to four years. To look at dementia as an outcome in a healthy elderly group in a primary prevention trial would take up to 4,000 individuals over up to seven years. As you can see, the task is long and difficult.


Clinical Trials in Dementia How many, How long
Group	Outcome	Sample Size	Duration
AD Patients	Symptom change Slow Progression	200–300	6 months 1–2 years
MCI	Dementia	700–1000	3–4 years
Healthy Elders	Dementia	2000–4000	5–7 years

The sample sizes and length of studies needed for clinical trails in dementia vary with the frequencies of outcome measures and rates of patient decline. Courtesy of Dr. Mary Sano

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