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There are approximately 4 million people with Alzheimer’s disease and it clearly increases, will be increasing over time, and you can see that the largest portion is in the age 85 and over group. So clearly the most important risk factor for Alzheimer’s disease is aging. Just to remind you, the definition of dementia - in general, Alzheimer’s is by far and away the most common cause - is loss of intellectual ability with sufficient severity to interfere with occupational functioning or with a persons usual social activities or relationships Alzheimer's Disease, alzerimers disease, alsheimers disease, alzeimer disease.
How do we make the diagnosis? These are just DSM-IV criteria to remind you. You need to have impairment in short and long term memory as the sine qua non. Plus at least one of the following: impaired reasoning, judgment, personality change, language or impaired perception. This diagnosis should technically not be made in the setting of delirium which commonly occurs.
In terms of what we see on the neurological exam, generally you find a non-focal neurological exam but in our research, and particularly at Columbia in association with some of our colleagues, we found some features on the neurological exams which are predictive of more rapid force and these are useful for you to find on your examination because you may be able to tell the patients and their caregivers whether or not the disease may progress more rapidly. These include: the presence of extra-parameter signs and by that I mean rigidity, gait impairment or stooped posture. People
What are the laboratory tests that you should include in your evaluation? These tests I have listed here are recommended by the American Academy of neurology. These are not the same tests one would use if you were screening a large population. If you were doing that you would probably get a CBC and TFT’s to start with and then go on from there. But if somebody comes to you with memory complaints, these are the tests that are recommended by the American Academy of Neurology. Of course HIV testing is not necessary, but necessary depends on the risk factors present.
What other risk factors, other than age, are predictive of the development of Alzheimer’s disease? I’ve listed some of them here. You can see that age is by far and away the most important. Family history of dementia may increase your risk up to three-fold in a first degree relative. What I am talking about are parents or siblings or children. History of Down’s syndrome. As most of you know, if a person with Down’s lives long enough they will most likely develop Alzheimer’s disease. Traumatic brain injury is also … it is controversial but in many studies has been shown it to be a risk factor for Alzheimer’s disease, particularly if it occurs late in life. Depression. Here again this is somewhat controversial because depression may appear as an early feature of Alzheimer’s disease and people argue over whether it is actually a predictor or an early feature. Various toxins have been implicated and low education as a risk factor also. This is also controversial, whether in fact this is a function of peoples ability to test or whether education is a surrogate for other socioeconomic factors.
The genetics of Alzheimer’s disease, as I’ve mentioned in your protocol, is exploding. I’ve listed here four of the known genetic risk factors for Alzheimer’s disease. I’ll go through each of them. Chromosome 21 is the ameboid precursor protein. This is very rare, as I will show you. Only a couple of families have been identified. The age of onset is 30-60 and the penetrance is complete. Chromosome 14 was identified in 1995. This is known as the presenilin 1 mutation and it accounts for a large proportion of the early onset Alzheimer’s disease. By early onset, I’m talking about under age 65. It’s important to know that you can send out a test for this because there has been over 20 or 30 mutations that have been identified, so you actually have to sequence the entire gene to see if there is a mutation. It presents very early, 35 -55. It is often associated with myoclonus and seizures. So it’s very important, one thing to stress, is that when you see a person with dementia you need to take a good family history; parents, siblings, and see if this is in fact an autosomal dominant disease. Because at least these first three are all autosomal dominant mutations.
Chromosome 1 was discovered because of its homology to chromosome 14. It’s now known as presenilin 2. It’s also called the Volga-German mutation. Only three families now have been identified with this mutation, which appears rather late. Then one that you’ve probably heard the most about is _ which we will talk about a little bit more. This is seen both late onset and early onset Alzheimer’s disease. I’m sure most of you are familiar with it because of the association with cardiac disease.
So just to belabor the point, mutations in the amyloid precursor protein, presenilin 1 and 2 predict early onset of Alzheimer’s disease. These are causative mutations. They are autosomal dominant. As opposed to ABL-E. ABL-E has three chromosomes, ABL-E2, ABL-E3 and ABL-E4. The ABL-E4 polymorphism is associated with a higher risk. It’s a risk factor. It’s not cause of mutation. If you remember one thing from this lecture that’s what you should remember, about late and early onset sporadic forms of Alzheimer’s disease. It may be modified by other genes as well.
This slide is to show you this curve here is homozygous, E4-E4 and again, this has probably been seen in over 100 different studies in every culture. But having an E4-E4 polymorphism raises your risk of developing Alzheimer’s disease anywhere from seven to nineteen-fold as opposed to having
Another caveat to this. This is looking at various ethnic groups. Most of the original work was done on Caucasians. What this is looking at is just people with the ABL-E3-3 genotype. This is the most common genotype in all cultures and what this is showing you is that if you just look at people with ABL-E3-3 and these are African-Americans and these are Caribbean-Hispanics and these are Caucasian subjects, you see that the increase in risk among the people with ABL-E3-3 is confined to those people who are of African-American or Caribbean-Hispanic descent. The overall prevalence of Alzheimer’s disease does not differ among these three groups so what they suggest is that in African-Americans and Caribbean-Hispanics and perhaps other groups, there are other genetic factors or environmental factors that may be contributing to the development of Alzheimer’s disease. Because these are, in the E3-3 group, these are the people who are not at the lowest risk for the development of Alzheimer’s disease.
This is showing you just genetic susceptibility in terms of attributable risk, and what I want to point out here is that there is a lot that we don’t know. There are many genetic factors and perhaps environmental ones that we don’t know about. If we consider first late onset disease, the ABL-E4 mutation accounts for approximately 30% of these cases. So there are 70% of these cases that we just have no idea what genetic risk factors are playing a role in. If we look at early onset disease, and I talked to you about the presenilin 2 and presenilin 1, I’ve mentioned to you that presenilin 1 accounts for the bulk of those that we know about. If you look here the ABL-E doesn’t account for very much and the presenilin 2 and the amyloid precursor protein are almost negligible. So again, in the vast majority of early onset of AD, we don’t know what the cause is.
Here is just a list of a variety of other genes that are now being looked at. This is Alpha 2 macroglobulin gene which is now very hot and there have been controversial reports as to its importance. But there are many many genes that are important.
Again, another caveat. You can’t use ABL-E testing yet to make a diagnosis, and this is from the New England Journal this past year by Richard Mayo and many of his other colleagues from the Alzheimer’s Disease Research Center. The ABL-E genotype doesn’t provide sufficient specificity or sensitivity to be used alone as a diagnostic test for Alzheimer’s disease. You need to use your clinical exam. When used in combination with clinical criteria, those that I’ve shown you, your clinical exam, perhaps your psych or imaging, it improves specificity with diagnosis. So if you think someone doesn’t have Alzheimer’s disease and you get a test you are going to improve your confidence in making the diagnosis that someone doesn’t have Alzheimer’s. But in fact it reduces sensitivity.
I want to switch gears now and talk to you a little bit about the treatment of dementia. First we will talk about symptomatic treatment then we will talk about slowing progression, then we’ll talk about treating mild cognitive impairment in a setting of prevention trials.
I’m going to cover for you first the cholinomimetic drugs particularly the cholinesterase inhibitors. I’m not going to spend any time on the muscarinic agonists. There have a few trials with M1 agonists which act at the acetylcholine receptor, notably a Lily compound called zinemoline. That never made it to market because of frequent syncope. Then I’ll talk to you in depth about the antioxidants, many of which I’m sure you’ve heard about; vitamese, allegaline and ginkgo. And then we touch at the end on estrogen, non-steroidals and I’m not going to talk today about acetyl l-carnitine but this has also been shown in trials, at least in young onset patients, to delay decline very very slightly but it has never come to market.
I want to review for you the cornerstone of why anti-cholinesterases are used in Alzheimer’s disease. This is based on the cholinergic hypothesis in Alzheimer’s disease that memory and cognitive disturbances result from reduced cholinergic transmission and the evidence of that stems from the fact that if you give anticholinergic drugs, if you give supalomine for example, to college students you can easily induce memory apparent. If you look at an Alzheimer’s frame and you see less choline acetyltransferases and you look at the brains of people with Alzheimer’s disease, the major areas of cell loss include the nucleus basalis minor, which is the main corner __. I’ve listed here all of the cholinesterase inhibitors that are currently under investigation. I’ll show you in a moment the only two that are approved in the US right now - are tacrine and donepezil. But these are others that in trial, that in other various phases of trial. None of them have yet made it to market. I need to point out to you that in terms of selectivity there are two acetylcholine receptors; butyl-cholinesterase and acetylcholinesterase. The butyl-cholinesterase is what is responsible for developing the nausea and the vomiting. So the more selective, the less likely you will have these peripheral side effects. But it has no effect on efficacy. It’s just side effect profile. The same thing can be said for the mechanism of inhibition. It doesn’t affect at all how effective the drug is. One thing, which I will show you in a couple of slides, is the dosing and I think it’s important to point out; we are talking about people who have memory impairment which already means that you often have to have caregivers involved in reminding people to take the medication. So the fewer times you have to take the medication - and particularly in this situation where people have memory problems - the more likely you are going to have compliance. So right away here that the tacrine is somewhat problematic in that you have to take that drug four times a day and it really involves a lot of work in terms of caregiver assistance.
I’m not going to talk about these other medications. I’ll tell you that retrifinate is an anti-helminthic agent used in schistosomiasis. One of the breakdown products is a cholinesterase inhibitor. This is currently not yet approved by the FDA. There were a couple of patients in a trial who developed pulmonary problems so it is now under investigation whether this should ever get to market. Rivastigmine or Exalon has received approval and now they are undergoing some of the packaging requirement kinds of things. So this should come to market fairly soon. I’ll show you in a moment some of the side effects. I’m not really certain that either of these two will ever get approved by the FDA. Just again, tacrine is a four-time-a-day drug. One of the biggest problems, given that it’s an aniline dye is that there are reversible ALT and AST elevations as well as nausea and vomiting because it isn’t selective. Donepezil, the other approved drug, Aricept is a once-a-day drug. Nausea and vomiting and diarrhea are the most common complaints for all of these. As I mentioned, natriphonate is also associated with leg cramps and rivastigmine, if you look at the studies, there us a tremendous - although it’s not emphasized - there’s a lot of weight loss among patients who were on the active substance, suggesting to many of us that in fact there is probably more nausea and vomiting than they let on. This _ cog score is the cognitive measure that is used in all FDA trials for medications for Alzheimer’s disease. One way to think about it that in general if you look at an Alzheimer’s population you see a 4 point decline in the natural history over a six month period. So the best that any of these drugs are doing is basically saving six months. These are symptomatic treatments and what that means is that if you stop these medications you go back to where you would have been on the curve. So you may get a little improvement, stop the medicine and come back to where you were. So at best, these medications are buying six months in terms of cognitive impairment.
This is a clinical global impression. This is what the doctor thinks in terms of whether there is improvement. As you see here, tacrine, one of the two approved medicines, has the highest improvement. It’s really significantly different as I’ll show you in a moment. But the problem is the dose that you need to get this improvement is not tolerated by over 60% of people. So that in fact for most of these other medications you are really talking more in the 3-3.5 improvement.
I just want to give you a comparison between the two approved FDA, FDA approved drugs that you can use right now. Tacrine and donepezil. As I have been trying to point out to you, the cognitive benefit is small in any of these drugs and when you are giving them to one of your patients, I think it’s important to point out to them that it would be extremely unlikely for them to see a dramatic improvement in their cognitive function. In fact they might not see any improvement. That you are basically trying to stabilize things. So I think it’s important to caution people so that their expectations aren’t too high. The clinical global effect is also small. The tolerability here is the big difference. As I mentioned to you, the tacrine is not well tolerated. The most effective dose in all of the studies is 160 mg and the vast majority of people could not tolerate that dose. With all of these cholinesterase inhibitors there does appear to be a dose effect with a higher dose, giving you more cognitive improvement but also more side effects. The dosing we’ve gone over and the medical monitoring, because of the liver function test abnormalities, for tacrine you need to monitor people. You don’t need any monitoring for donepezil. It has no other drug interactions, it’s a once-a-day drug. It is recommended that you take it at night before bedtime, with or without food. The reason to take it at night is to try to - if you were going to be nauseous, it would occur during the nighttime and so wouldn’t become problematic. But it doesn’t need any medical monitoring at all.
With the donepezil, which is the most commonly used medication. There are two different doses. A 5 mg dose and a 10 mg dose. There is a slight increase of improvement in using the 10 mg dose, not significantly different, but most people do try to aim to increase to 10 mg usually after a six-week period. Again, there are increased side effects with a 10 mg dose as opposed to the 5 mg.
Commonly asked questions: when to begin these drugs? The cholinesterase inhibitors are well established to use in mild to moderate Alzheimer’s disease. There is no other data in other forms of dementia at this point. There are anecdotal data but there are no good studies in other forms of dementia. And as I mentioned, it’s a symptomatic treatment. There is no data yet on protection or prevention. When we conclude I will show you that there is, or I will mention to you that there is a current trial using Aricept or donepezil in people with mild cognitive impairment who don’t yet meet criteria for dementia.
Another question: when do you raise the dose? From 5 mg, for example, to 10 mg. As I mentioned, there is a little bit of evidence suggesting that the higher doses have a better effect but you need to go slowly so in general we usually wait about six weeks on 5 mg before increasing to the 10 mg tablets.
When do you stop it? Of course, if people don’t tolerate the medication due to side effects you need to stop. As I’ve tried to point out, you may not see an improvement. There may be a stabilization, so if you do any sort of mental status testing, even a _ or even any of the other tests that are available and you were to see stabilization over a six month period, no worsening, I would consider that a success. Sometimes families are a little bit disturbed that they don’t see an improvement. You end up taking that person off the medication and in fact you may see worsening. And then they are convinced that perhaps this was helping a little bit and they want to go back on.
Okay, so those are the cholinesterase inhibitors. I want to now talk about slowing disease progression. The agents that we talk about are alpha-tocopherol like an a-selegiline. I’m not going to talk today about adebinon which is also been studied mostly in Japan but there has been a study here in the U.S. which showed a slight improvement. Neither of these is approved by the FDA. I’m sure many of your patients are taking ginkgo biloba for various reasons, and we’ll talk about that. I’m not going to talk about acetyl l-carnitine because these are all medications that have antioxidant properties and are being used to slow the progression. This is different than symptomatic treatment. You are basically trying to slow the progression to a specific outcome, and it says nothing about an improvement.
The largest study that has been done looking at vitamin E and selegiline was published in the New England Journal in 1997. This included a study of 341 moderately impaired patients. It was a two year, double blind study. There were three treatments. One was selegiline 10 mg a day. Used in 5 mg tablets, 5 mg twice a day. Vitamin E in 1000 i.u. twice a day. The combination of vitamin E and selegiline all compared to placebo. The primary outcome was the time to reach any of these four outcomes: death, institutionalization, loss of basic activities of daily living, dressing, toileting, bathing, and progressing to the next stage of dementia, from moderate to severe, using what we call the CDR or the clinical dementia rating scale, which is commonly used in Alzheimer’s disease research. So if you have any of these, that was considered an endpoint. What this study showed was that each of the treatments, vitamin E alone, selegiline alone or a combination of vitamin E and selegiline delayed the time to any of those outcomes. So there were positive effects. So compared to placebo, there was a 215 day delay to reach that outcome with selegiline, 230 day delay with selegiline vitamin E and 145 day with the combination. So in fact combining these two, selegiline - which is also known as deprenyl which is usually used in Parkinson’s disease - was actually less effective than either alone. What this is telling you is that vitamin E delayed institutionalization. That was really one of the main findings, that people on vitamin E were less likely to go into nursing homes, and there was 25% less deterioration in their basic activities of daily living. Interestingly, in spite of these improvements on vitamin E there was no effect on the neuropsychologic testings. So that’s sort of hard to explain why, despite the fact that you delayed these outcomes, you didn’t see any improvement in cognition. But still this report was taken to suggest that taking vitamin E, which has fewer side effects than for example selegiline, and is certainly less expensive, might be useful therapy for people with moderate Alzheimer’s disease. So most people feel now that people with moderate Alzheimer’s disease do treat their patients with 1000 i.u. of vitamin E twice a day. If there are no other contraindications.
As I’ve mentioned, and as I’m sure you know, many many people are on ginkgo. There have been a few trials. Ginkgo is supposedly an antioxidant although if you look at the literature it is very hard to substantiate it being an antioxidant. This was one of the trials that was done using ginkgo that was published in JAMA in 1999. It was a 52 double blind study using an extract of ginkgo. This is not what you can buy in a health food store. And the population included mild to severely demented individuals with either Alzheimer’s disease or multi-infarct dementia. So it was a mixed population. The results of this trial were that it had a small effect on the A Dos. Cog. Remember, this is the neuropsychological measure that was used before, as well as a small effect on the functional measure. There was no effect on the doctor’s assessment of improvement. The issues in this study were the large drawback - 50% on drug and 38% on placebo - and the fact that it was a mixed patient population. It wasn’t just Alzheimer’s disease. It was Alzheimer’s disease and multi-infarct dementia.
A meta-analysis that was published in November in the Archives of Neurology included four studies with 212 subjects in placebo and drug groups, and again a small but significant effect of 3-6 months treatment with 120-240 mg of ginkgo. This was found to be effective. So what I generally tell my patients is the data here is somewhat controversial but there is no absolute contraindications for you to take the ginkgo, so many people do choose to take the ginkgo along with vitamin E. But there is no evidence and, as I will show you on this next slide, we have absolutely no data on combination therapy in Alzheimer’s disease so that although many people do take a cholinesterase inhibitor, vitamin E and ginkgo there is no data yet on the combination being any more effective than any alone. As I showed you in an earlier slide, the combination of selegiline and vitamin E was less effective than either alone. So I think I’ve covered all this here. As I said, there is no data on the combinations with a cholinesterase inhibitor but no reason that we know of medically, in terms of contraindications, to combine any of those therapies. So many people do take multiple agents.
I want to conclude by looking at some of the prevention studies that are currently underway. This is just to remind you that secondary prevention would be looking at people at high risk for Alzheimer’s disease. For example, somebody with a family history of Alzheimer’s disease in trying to prevent disease. And primary prevention would not include prevention would not include those people in a high risk group. So much of the research in Alzheimer’s disease now is to try to push back the time that you can diagnose people and perhaps intervene earlier. That’s where this concept of mild cognitive impairment has come up, of determining neuropsychological criteria that are significantly different from normal aging and following those people on medication to try to prevent the development of Alzheimer’s disease.
The two agents I want to talk about are estrogen replacement therapy and non-steroidal antiinflammatory agents, and finish off with COX-2 inhibitors. These are very hot areas now in Alzheimer’s research. This is just to remind me to tell you some of possibilities about how estrogen works. This is a rat brain and what this is showing you in an ovariectomized animal, is that if you give it estrogen you see dendritic arborization. Estrogen co-lyses with acetylcholine receptors and it also leads to less formation of the a-beta 42 fragment of the amyloid precursor protein. So these are all positive in terms of the development of senile plaques. There actually have been no good prospective case control studies on the use of estrogen in Alzheimer’s. So we really have no data yet to suggest that people take estrogen once they have Alzheimer’s disease. There is a lot of suggestive evidence that in fact it may work. I’ve listed here some of the studies that have been done so far. These are all observational studies. These are not double blind case controlled studies so again there is really no data to support taking estrogen right now if you have Alzheimer’s disease. Although all those studies are currently being done. As we see here, from some of these cross-sectional studies there are some better scores on some of the memory tests. When we look at the two prospective studies--what I mean by prospective is that we were able to look back at what people took before the development of Alzheimer’s disease and see if taking estrogen delayed the onset of Alzheimer’s disease. I’ll show you some data from our study in Washington Heights. What this is showing you from that study is that taking estrogen, or people who reported … women who took estrogen for more than one year, were less likely to develop Alzheimer’s disease than people who took estrogen for one year or less compared to placebo. The outcome here is the development of Alzheimer’s disease. So it’s not that they don’t get Alzheimer’s disease. They are just delaying the onset of Alzheimer’s disease. Again, this is not a clinical trial. This is retrospective data.
Equally tantalizing, we were able in our population in Washington Heights to look at people who didn’t have Alzheimer’s disease. These are people who are cognitively normal but we see the same type of profile here. If you look at the blue, which is people who took estrogen for more than a year, the red is less than a year, and this is no use, you can see that if you look at the neuropsychological testing profile on memory testing, in terms of delayed recall and immediate recall as well as reasoning and naming, the women who took estrogen for a longer period of time performed better. Again, this is not a clinical trial and it is confounded by the fact that people perhaps who had access to estrogen were perhaps better educated and had higher socioeconomic status and all of the other variables that may have led to them having access or deciding to take estrogen. But it is somewhat tantalizing.
Before I go on to the nonsteroidals, I will mention to you that in the Women’s Health Initiative they are looking at estrogen and that result will be available probably in the next 5-7 years has just received an NIH-funded grant to do a first prevention trial using estrogen in women at high risk for Alzheimer’s disease. So she as well as our colleagues at Johns Hopkins and Mayo Clinic and Jacksonville as well as many other centers now on the east coast are recruiting 900 women with a family history of Alzheimer’s disease to see if in taking estrogen they can delay the onset of Alzheimer’s disease in that group of women. So for anyone interested, I’ve left flyers outside on the front desk because I think it’s a very important study to do. We wouldn’t want to be giving estrogen to women, with all the side effects, if in fact it is not going to help them in terms of prevention.
I’m going to move on now just to the nonsteroidals, which have also been studied. There is an inflammatory theory about Alzheimer’s disease and so the use of nonsteroidals has been suggested to try, both in terms of the treatment and more recently in terms of prevention of Alzheimer’s disease. I’ll just show you a couple of the studies that have been done on nonsteroidals. One of the first was a record review done at Johns Hopkins of medications in consecutively encountered patients with Alzheimer’s disease. There were 32 regular users of nonsteroidals and 177 non-users and what they did find was that the people who took nonsteroidals had a shorter duration of illness, higher in many mental status score. They were cognitively better and over time appeared to have a slower decline. Another study, which was one of the few clinical trials - a double blind placebo controlled study - over six months of 44 patients using indomethacin. As you can see there was a high drop-out rate. Only 53% were able to complete this trial and there was a non-significant trend indicating a benefit in the cognitive testing, the A Dos.Cog and the mental status score, which is also a measure of cognitive improvement. Twenty percent developed drug-related adverse events, so Indocin doesn’t appear to be the ideal choice for a non-steroidal in Alzheimer’s disease.
Another study that was just recently completed, in 1997 in neurology, examined a Baltimore longitudinal study. This was again retrospective data looking at a healthy population and trying to see that if by taking any of these patients whether there was a lower risk for the development of Alzheimer’s disease over time. What you can see here is that taking any non-steroidal antiinflammatory drug seemed to decrease the risk by half of developing Alzheimer’s disease over a two year period. So again, suggestive evidence that in the past an antiinflammatory might be effective in Alzheimer’s disease. I can tell you - it’s not yet published - but the Alzheimer’s disease cooperative study, another NIH-funded study, has just examined prednisone in 10 mg doses in moderately impaired Alzheimer’s disease and they did not see any effect. So again, controversial evidence as to whether non-steroidals will work.
One of the recent areas of interest is COX-2 inhibitors for Alzheimer’s disease. As you are all aware COX-1 gives gastric protection whereas COX-2 can alleviation inflammation. COX-2 is definitely present in the brain and both COX-1 and COX-2 are inhibited by traditional non-steroidals. So one of the big pushes now is to look at COX-2 inhibitors in both the treatment of Alzheimer’s disease as well as the prevention. Again, there are some flyers outside looking for a number that you can call if you have patients who are at risk for Alzheimer’s or who have mild cognitive impairment who are interested in a prevention trial for the development of Alzheimer’s disease. This is my last slide. This is just showing you that an algorithm has been developed. There are certain psychological test scores that have been determined and we are now able to predict for example what percentage of people will develop Alzheimer’s disease over time. So these mild cognitive impairment trials are designed to slow the development of Alzheimer’s disease using these various agents. Currently the agents that are being tried in mild cognitive impairment, one is an NIH-funded trial looking at vitamin E and Aricept, each compared to placebo in people with mild cognitive impairment who don’t meet the criteria for Alzheimer’s disease, to see if taking any of these agents delays the onset of Alzheimer’s disease and there are two inhibitors that are being studied. One a Merck agent and we are getting the other … Vioxx, so I think within the next two years we will have more information as to whether taking anti-inflammatories are useful for preventing Alzheimer’s disease.