WEBVTT 00:01.061 --> 00:03.644 (gentle music) 00:10.602 --> 00:13.185 (upbeat music) 00:33.510 --> 00:34.980 Well, thank you very much, all of you, 00:34.980 --> 00:39.980 for coming out on a first sunny day in a few in Colorado, 00:40.470 --> 00:44.010 and learning about where we are in our understanding 00:44.010 --> 00:46.860 of the problem of Alzheimer's disease, 00:46.860 --> 00:51.060 and where we hope to be in a very few years 00:51.060 --> 00:54.000 with both your help as potential 00:54.000 --> 00:56.910 donors, supporters, caregivers, 00:56.910 --> 00:59.530 and, unfortunately, sometimes patients 01:00.600 --> 01:03.090 that will help us solve this problem. 01:03.090 --> 01:06.480 Now, to give you an idea of what this problem entails, 01:06.480 --> 01:09.210 if you look around the room, basically, 01:09.210 --> 01:11.640 if everyone in this room lives to be 85, 01:11.640 --> 01:14.010 half of us will have Alzheimer's disease. 01:14.010 --> 01:19.010 And because of the advances of medical care and support, 01:19.050 --> 01:21.870 many of us will live to be 85. 01:21.870 --> 01:23.580 Cancer is not cured, of course, 01:23.580 --> 01:25.710 but it's managed in many cases. 01:25.710 --> 01:27.750 Heart disease is beginning to go down 01:27.750 --> 01:31.230 because people are living more healthy lifestyles. 01:31.230 --> 01:32.980 And then they live to be 01:33.900 --> 01:35.970 what we would call their golden years 01:35.970 --> 01:39.540 and are faced with this problem of Alzheimer's disease. 01:39.540 --> 01:42.960 Now, it turns out, as indicated in this first slide, 01:42.960 --> 01:44.550 that people with Down syndrome 01:44.550 --> 01:46.470 are giving us tremendous insights 01:46.470 --> 01:50.220 into Alzheimer's disease because, in fact, 01:50.220 --> 01:51.390 people with Down syndrome 01:51.390 --> 01:53.040 and people with Alzheimer's disease 01:53.040 --> 01:56.220 are two sides of the same coin. 01:56.220 --> 01:58.020 Okay, so many of you know 01:58.020 --> 01:59.790 somebody who has Alzheimer's disease. 01:59.790 --> 02:03.360 You may have read about Alzheimer's disease in the paper. 02:03.360 --> 02:05.520 So, I'll just go through very briefly 02:05.520 --> 02:07.830 what Alzheimer's disease is 02:07.830 --> 02:10.290 so as to correct any misperceptions 02:10.290 --> 02:12.330 and give you some foundation 02:12.330 --> 02:14.700 upon which we can build this story. 02:14.700 --> 02:17.040 So, the majority of Alzheimer's disease 02:17.040 --> 02:18.720 is what we call sporadic, 02:18.720 --> 02:20.550 which is a scientist term of saying 02:20.550 --> 02:22.710 we don't know what causes it. 02:22.710 --> 02:26.370 We know something about what causes it, but not completely. 02:26.370 --> 02:29.640 These occur in people over the age of 65, 02:29.640 --> 02:34.290 and, as I indicated, about 50% of people over 85. 02:34.290 --> 02:37.200 Now, there is also a purely genetic form 02:37.200 --> 02:39.810 of Alzheimer's disease, which is extremely rare. 02:39.810 --> 02:41.760 And we'll talk a little bit about that 02:41.760 --> 02:44.970 because it's given us great insight to the disease. 02:44.970 --> 02:47.430 This occurs in people in their 50s, 02:47.430 --> 02:49.980 in their 40s, in their 30s, 02:49.980 --> 02:52.380 and sometimes even in their late 20s, 02:52.380 --> 02:57.060 depending upon the mutation that that family carries. 02:57.060 --> 03:00.030 And then, as I indicated in the title, 03:00.030 --> 03:01.530 Down syndrome individuals 03:01.530 --> 03:04.740 are a very special group of people who, 03:04.740 --> 03:08.100 because they have three copies of chromosome number 21, 03:08.100 --> 03:11.040 instead of two copies like everybody else has, 03:11.040 --> 03:14.790 they have a propensity for developing Alzheimer's disease, 03:14.790 --> 03:17.730 which essentially guarantees that their brains, 03:17.730 --> 03:20.970 by the age of 40, look like an Alzheimer's disease brain. 03:20.970 --> 03:23.850 And more than half of them develop dementia 03:23.850 --> 03:25.893 by the time they're 50 or 60. 03:26.730 --> 03:29.670 So in addition to all the other challenges they have, 03:29.670 --> 03:33.060 they all develop Alzheimer's disease pathology 03:33.060 --> 03:34.530 and most dementia. 03:34.530 --> 03:36.690 So Alzheimer's disease is, obviously, 03:36.690 --> 03:38.940 a neurodegenerative disease of the brain. 03:38.940 --> 03:41.160 That means that nerve cells die 03:41.160 --> 03:43.530 and the connections between nerve cells die. 03:43.530 --> 03:46.920 And over the course of time to death, 03:46.920 --> 03:50.280 the brain shrinks tremendously, as indicated here. 03:50.280 --> 03:52.210 Now, brain shrinkage alone is not 03:53.220 --> 03:55.830 the indication of Alzheimer's disease. 03:55.830 --> 03:58.650 These, what we call neuritic plaques, 03:58.650 --> 04:01.410 and these neurofibrillary tangles 04:01.410 --> 04:03.420 are the hallmarks of Alzheimer's disease, 04:03.420 --> 04:06.300 which Alzheimer himself found in 1907. 04:06.300 --> 04:10.080 Without these two lesions that occur by the millions 04:10.080 --> 04:13.140 in the parts of the brain involved in cognition and memory, 04:13.140 --> 04:14.890 you won't have Alzheimer's disease. 04:15.840 --> 04:16.950 And that's essentially 04:16.950 --> 04:20.880 what we knew about Alzheimer's disease until 1985, 04:20.880 --> 04:23.970 when George Glenner and Kenny Wong 04:23.970 --> 04:27.720 isolated the protein in the amyloid deposits 04:27.720 --> 04:31.260 and sequenced it and found this peptide. 04:31.260 --> 04:33.210 Now, you can memorize it if you like, 04:33.210 --> 04:34.770 and there'll be a test at the end of the day, 04:34.770 --> 04:36.047 but I haven't memorized it, 04:36.047 --> 04:38.340 and so that would be a waste of your time. 04:38.340 --> 04:43.020 But this peptide with 21 in his first study, 04:43.020 --> 04:46.380 and then we now know 40 or 42 amino acids, 04:46.380 --> 04:50.190 is the key to developing Alzheimer's disease. 04:50.190 --> 04:52.260 It's a natural product of the brain, 04:52.260 --> 04:54.180 but it occurs in greater amounts 04:54.180 --> 04:55.953 in people with Alzheimer's disease. 04:56.880 --> 04:59.970 Now, that alone was not enough 04:59.970 --> 05:02.160 to tell us what causes Alzheimer's disease. 05:02.160 --> 05:05.790 So, what happened is that in those families 05:05.790 --> 05:08.430 that have inherited Alzheimer's disease, 05:08.430 --> 05:12.030 some of them actually have a mutation 05:12.030 --> 05:14.290 in the gene that causes 05:16.734 --> 05:19.110 the production of that amyloid peptide. 05:19.110 --> 05:20.490 And here's a family like that. 05:20.490 --> 05:23.340 You can see over many generations these black squares 05:23.340 --> 05:25.170 are the people that get Alzheimer's disease. 05:25.170 --> 05:28.200 And basically, if a person has Alzheimer's disease, 05:28.200 --> 05:30.630 50% of their children get Alzheimer's disease too 05:30.630 --> 05:32.220 at about the same time. 05:32.220 --> 05:36.900 And the gene for Alzheimer's disease is on chromosome 21. 05:36.900 --> 05:37.950 Here's the chromosome, 05:37.950 --> 05:40.380 here's the amyloid precursor protein gene. 05:40.380 --> 05:43.170 And that explains why people with Down syndrome 05:43.170 --> 05:44.400 get Alzheimer's disease 05:44.400 --> 05:46.710 because they have three copies of chromosome 21 05:46.710 --> 05:47.940 instead of two copies. 05:47.940 --> 05:50.340 They make more of the APP protein. 05:50.340 --> 05:52.190 They make more of the A-beta peptide. 05:53.190 --> 05:55.080 So there are two genetic ways 05:55.080 --> 05:56.640 that you can get Alzheimer's disease 05:56.640 --> 05:57.870 that I've discussed so far. 05:57.870 --> 05:59.550 One is you can have Down syndrome. 05:59.550 --> 06:01.350 You get an extra copy of the gene. 06:01.350 --> 06:05.493 Or, as in this family, you have a mutation in that gene. 06:06.450 --> 06:09.150 Now, what does this help us 06:09.150 --> 06:10.650 to understand Alzheimer's disease? 06:10.650 --> 06:12.000 Well, one of the problems 06:12.000 --> 06:15.300 with Alzheimer's disease for that first 70 years 06:15.300 --> 06:17.580 was that there was no animal model 06:17.580 --> 06:18.993 for Alzheimer's disease. 06:19.830 --> 06:22.650 Now, it's true that monkeys 06:22.650 --> 06:25.320 get a kind of Alzheimer's disease if they get older, 06:25.320 --> 06:27.390 but there are ethical and financial reasons 06:27.390 --> 06:29.880 you can't use large numbers of monkeys. 06:29.880 --> 06:32.820 And polar bears get Alzheimer's disease a little bit, 06:32.820 --> 06:34.740 but I know my dean doesn't want me to have 06:34.740 --> 06:36.810 a lot of polar bears in the lab. 06:36.810 --> 06:41.490 So many of us had to deal with a lack of an animal model, 06:41.490 --> 06:46.470 and that was solved by taking the gene that is mutant 06:46.470 --> 06:49.560 in the families that have inherited Alzheimer's disease 06:49.560 --> 06:51.720 and putting it into a mouse. 06:51.720 --> 06:53.940 Now, mice normally don't get Alzheimer's disease, 06:53.940 --> 06:55.530 but if they have the human gene 06:55.530 --> 06:57.390 that gives humans Alzheimer's disease, 06:57.390 --> 06:58.860 then they get Alzheimer's disease. 06:58.860 --> 07:01.230 And we know that because, 07:01.230 --> 07:03.060 no, they don't know who the president is, 07:03.060 --> 07:04.860 and they don't know what they had for breakfast, 07:04.860 --> 07:08.910 but they also can't figure out how to get around a maze. 07:08.910 --> 07:11.790 Now, this is a water maze where we put the mouse here, 07:11.790 --> 07:12.990 and they can swim around. 07:12.990 --> 07:13.950 They're pretty good swimmers. 07:13.950 --> 07:15.540 They don't mind swimming. 07:15.540 --> 07:17.940 And if they get to this little glass platform 07:17.940 --> 07:20.670 right out underneath the water, which they can't see, 07:20.670 --> 07:23.700 but they can climb out of, they can get out of the water. 07:23.700 --> 07:26.970 And this is a tremendous benefit because 07:26.970 --> 07:30.150 normal mice, once they get on that platform, 07:30.150 --> 07:31.350 they can always find it again. 07:31.350 --> 07:32.370 They look around the room. 07:32.370 --> 07:34.350 They see where the clock is, where the door is, 07:34.350 --> 07:35.910 where the investigator is standing. 07:35.910 --> 07:38.490 They have a spatial understanding of where they are, 07:38.490 --> 07:40.320 and they go to that platform right away. 07:40.320 --> 07:41.730 If they have Alzheimer's disease 07:41.730 --> 07:44.040 because of this mutant human gene, 07:44.040 --> 07:45.903 then they can't find that platform. 07:47.430 --> 07:50.850 All of this has then allowed us to understand 07:50.850 --> 07:54.900 the structure of the brain in an Alzheimer's patient, 07:54.900 --> 07:56.970 why they develop Alzheimer's disease, 07:56.970 --> 07:59.220 and why that gene is so important. 07:59.220 --> 08:01.380 So, here's the amyloid precursor protein 08:01.380 --> 08:05.160 that I discussed that is created by a gene on chromosome 21. 08:05.160 --> 08:07.950 The amyloid peptide that Glenner and Wong found 08:07.950 --> 08:12.150 happens to be cleaved out of this precursor 08:12.150 --> 08:14.640 and make this little A-beta peptide. 08:14.640 --> 08:16.770 And normally it gets cleaved here, 08:16.770 --> 08:18.090 so that's pretty harmless. 08:18.090 --> 08:21.150 But if it gets cleaved here, then the peptide is generated, 08:21.150 --> 08:24.150 and it tends to make fibers 08:24.150 --> 08:26.910 by sticking to itself and making long fibers 08:26.910 --> 08:29.640 that aggregate into sort of Brillo pads 08:29.640 --> 08:31.260 in the brain by the millions, 08:31.260 --> 08:34.050 which kill the nerve cells that are nearby. 08:34.050 --> 08:37.380 And this A-beta peptide has this curious feature 08:37.380 --> 08:39.420 that it tends to aggregate 08:39.420 --> 08:41.670 and make these filaments all by itself. 08:41.670 --> 08:43.470 And furthermore, in the brains 08:43.470 --> 08:46.260 of people with Alzheimer's disease, there's another protein, 08:46.260 --> 08:50.400 which we call ApoE4, or ApoE3, or 2. 08:50.400 --> 08:52.620 And it turns out that if you inherit 08:52.620 --> 08:55.500 an ApoE4 allele from one of your parents, 08:55.500 --> 08:57.660 you have a threefold increased risk 08:57.660 --> 08:59.940 of developing Alzheimer's disease. 08:59.940 --> 09:01.680 So, that's a risk factor. 09:01.680 --> 09:04.560 It's not a genetic guarantee, but it's a risk factor. 09:04.560 --> 09:06.900 And if you happen to inherit ApoE4 09:06.900 --> 09:09.330 from both of your parents, you have two copies, 09:09.330 --> 09:10.950 we have two copies of every gene, 09:10.950 --> 09:13.170 and both of them are ApoE4, 09:13.170 --> 09:15.210 then you have a tenfold increased risk 09:15.210 --> 09:16.770 of developing Alzheimer's disease. 09:16.770 --> 09:19.620 And the reason is because ApoE4 helps 09:19.620 --> 09:23.400 the A-beta peptide make itself into fibers. 09:23.400 --> 09:27.480 So, everyone in this room can take a look at this picture, 09:27.480 --> 09:28.687 this diagram, and you say, 09:28.687 --> 09:32.457 "Well, all we have to do is keep this from happening." 09:33.510 --> 09:35.160 And the scientists agree with you. 09:35.160 --> 09:36.930 And they have developed inhibitors 09:36.930 --> 09:38.520 of the gamma secretase enzyme 09:38.520 --> 09:40.410 and the beta secretase enzyme. 09:40.410 --> 09:43.140 They've created inhibitors, as we have, 09:43.140 --> 09:46.200 of the ApoE4 interaction with A-beta. 09:46.200 --> 09:48.840 And there are ways to keep A-beta from killing cells. 09:48.840 --> 09:52.500 So, all of these steps in this pathogenic pathway 09:52.500 --> 09:54.480 are subject to investigation 09:54.480 --> 09:56.820 to develop new treatments for Alzheimer's disease. 09:56.820 --> 09:59.760 And many of them work pretty well in the mice, 09:59.760 --> 10:01.590 and they're now being tested in humans. 10:01.590 --> 10:03.480 So far, unfortunately, 10:03.480 --> 10:05.520 none of them have worked great in humans. 10:05.520 --> 10:07.050 So, we don't have a new drug. 10:07.050 --> 10:09.600 The drugs that are available basically are band-aids 10:09.600 --> 10:13.320 to help the neurons that are left work a little bit better. 10:13.320 --> 10:14.790 But we have great hope, 10:14.790 --> 10:17.550 especially with respect to this interaction here, 10:17.550 --> 10:20.103 that these drugs will come soon. 10:21.060 --> 10:24.210 Now, the reason it's so difficult 10:24.210 --> 10:26.790 to treat Alzheimer's disease with these drugs 10:26.790 --> 10:28.920 is because it turns out 10:28.920 --> 10:31.830 that Alzheimer's disease in the brain starts 10:31.830 --> 10:36.830 about 20, maybe 30 years before the symptoms are apparent. 10:37.980 --> 10:39.270 So, if you're walking around 10:39.270 --> 10:41.910 and you're 70 years old and you're fine, 10:41.910 --> 10:44.670 you have a 50-50 chance that Alzheimer's disease 10:44.670 --> 10:46.320 has already started. 10:46.320 --> 10:48.750 And we know that for several reasons. 10:48.750 --> 10:52.380 First of all, the dementia comes fairly late in the disease. 10:52.380 --> 10:53.760 But before that, 10:53.760 --> 10:56.610 you have what we call mild cognitive impairment. 10:56.610 --> 10:59.610 And with special tests, we can detect that. 10:59.610 --> 11:01.830 And then before that, you begin to have 11:01.830 --> 11:03.510 problems with brain shrinkage 11:03.510 --> 11:05.610 and with the development of those tangles, 11:05.610 --> 11:09.480 and the amyloid deposits can start much, much earlier. 11:09.480 --> 11:11.670 So, for instance, a person with Down syndrome 11:11.670 --> 11:14.310 may have the full-blown Alzheimer's disease brain 11:14.310 --> 11:16.080 by the time they're 30 or 40, 11:16.080 --> 11:18.510 but we can detect it in the teens 11:18.510 --> 11:21.033 and even younger than that in those people. 11:22.590 --> 11:24.810 Okay, so what about these people with Down syndrome? 11:24.810 --> 11:28.560 Why do I say that they're two sides of the same coin? 11:28.560 --> 11:31.440 I mentioned that they all get Alzheimer's disease pathology, 11:31.440 --> 11:33.840 and most of them develop dementia. 11:33.840 --> 11:36.630 But we had an interesting idea, or I did, 11:36.630 --> 11:37.920 a couple of years ago, 11:37.920 --> 11:40.290 many decades ago, actually. 11:40.290 --> 11:42.690 And that was that maybe the fact that 11:42.690 --> 11:43.830 people with Down syndrome 11:43.830 --> 11:47.070 have three copies of chromosome 21 might give us a hint 11:47.070 --> 11:51.000 about how typical Alzheimer's disease develops. 11:51.000 --> 11:53.373 So here's Professor Lejeune, 11:54.210 --> 11:57.180 and he was the one with an associate of his 11:57.180 --> 11:59.840 who found that there were three copies of chromosome 21 11:59.840 --> 12:02.370 in people with Down syndrome, 12:02.370 --> 12:07.370 and so came up with an idea that maybe 12:07.680 --> 12:09.900 the fact that you have three copies of chromosome 21 12:09.900 --> 12:12.450 in people with Down syndrome might give us a hint 12:12.450 --> 12:14.940 that over the course of the life of a person 12:14.940 --> 12:16.800 that develops Alzheimer's disease, 12:16.800 --> 12:18.930 they actually develop cells 12:18.930 --> 12:21.420 with three copies of chromosome 21. 12:21.420 --> 12:24.060 They're not born that way like people with Down syndrome, 12:24.060 --> 12:27.120 but they have a hidden disorder 12:27.120 --> 12:29.340 that has occurred during their life 12:29.340 --> 12:30.690 that generates these cells 12:30.690 --> 12:32.880 with three copies of chromosome 21. 12:32.880 --> 12:35.580 And so, I wrote up a theoretical paper, 12:35.580 --> 12:39.210 I submitted it to a journal, and I got rejected. 12:39.210 --> 12:40.320 That happens a lot, 12:40.320 --> 12:42.480 but this rejection was pretty bad. 12:42.480 --> 12:45.270 I wouldn't recommend publishing this manuscript 12:45.270 --> 12:46.713 anywhere at any time. 12:48.840 --> 12:51.000 Very few people get that kind of rejection, 12:51.000 --> 12:52.920 but we didn't pay attention to it. 12:52.920 --> 12:54.420 We sent it to another journal, 12:54.420 --> 12:55.920 American Journal of Human Genetics. 12:55.920 --> 12:59.490 They published it, and it turned out to be true. 12:59.490 --> 13:01.500 So how do we prove that? 13:01.500 --> 13:02.430 We make predictions. 13:02.430 --> 13:05.280 Scientists make predictions based on hypotheses. 13:05.280 --> 13:06.720 And if the predictions are right, 13:06.720 --> 13:08.010 then the hypothesis is right. 13:08.010 --> 13:09.030 And if the predictions are wrong, 13:09.030 --> 13:10.740 then the hypothesis is wrong. 13:10.740 --> 13:12.060 So, what's the first prediction? 13:12.060 --> 13:14.160 Okay, that Alzheimer's disease individuals 13:14.160 --> 13:17.073 should show trisomy 21 mosaicism. 13:18.270 --> 13:21.870 We also might predict that if you see mosaicism, 13:21.870 --> 13:24.420 there's an increased risk of developing Alzheimer's disease, 13:24.420 --> 13:27.420 and also that maybe those genes and proteins 13:27.420 --> 13:31.050 that are carrying mutations that cause Alzheimer's disease 13:31.050 --> 13:34.050 should have something to do with chromosomes. 13:34.050 --> 13:35.790 So we tested each of these, 13:35.790 --> 13:39.060 and the first one is done by just counting chromosomes, 13:39.060 --> 13:41.730 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, in the microscope. 13:41.730 --> 13:43.290 Or we can make a little probe 13:43.290 --> 13:45.720 that lights up in the microscope fluorescent, 13:45.720 --> 13:49.680 and this particular cell has two copies of chromosome 21. 13:49.680 --> 13:51.900 Pretty easy to count that way. 13:51.900 --> 13:53.610 So, what did we find out? 13:53.610 --> 13:56.790 We found out first that the skin cells 13:56.790 --> 14:00.120 of people with either sporadic Alzheimer's disease, 14:00.120 --> 14:02.040 one form of mutant Alzheimer's disease, 14:02.040 --> 14:05.640 all forms of mutant familial Alzheimer's disease, 14:05.640 --> 14:09.330 they all contain about 5% of cells 14:09.330 --> 14:13.080 with three copies of chromosome 21 instead of two copies. 14:13.080 --> 14:16.920 This has been repeated, and many cells in the body, 14:16.920 --> 14:20.730 including brain cells, including nerve cells in the brain, 14:20.730 --> 14:22.620 have three copies of chromosome 21. 14:22.620 --> 14:25.860 Here's some very nice work from Iourov 14:25.860 --> 14:29.430 and you can see that about 10% of the cells in the brain 14:29.430 --> 14:31.290 have three copies of chromosome 21 14:31.290 --> 14:34.560 instead of two copies if you have Alzheimer's disease. 14:34.560 --> 14:36.480 So, they're mosaic Down syndrome, 14:36.480 --> 14:39.060 and this was completely hidden. 14:39.060 --> 14:42.300 It developed silently, surreptitiously 14:42.300 --> 14:43.680 over the course of their life 14:43.680 --> 14:47.640 until suddenly they came to clinical attention 14:47.640 --> 14:52.260 and eventually died, and we can count their chromosomes. 14:52.260 --> 14:54.600 Now, is this important? 14:54.600 --> 14:57.930 Maybe it's just a side effect of Alzheimer's disease. 14:57.930 --> 15:00.150 It turns out to be absolutely critical 15:00.150 --> 15:04.500 because from this work by Thomas Arendt in Leipzig 15:04.500 --> 15:08.640 turns out that at the beginning of Alzheimer's disease 15:08.640 --> 15:10.740 or normal individuals, 15:10.740 --> 15:13.020 they don't have too many of these funny cells 15:13.020 --> 15:14.670 that have the wrong number of chromosomes 15:14.670 --> 15:16.440 cause you see it's not just chromosome 21, 15:16.440 --> 15:18.990 it's the other chromosomes as well. 15:18.990 --> 15:20.550 As they get Alzheimer's disease, 15:20.550 --> 15:24.240 they get almost 30% of the nerve cells in the brain 15:24.240 --> 15:26.130 have the wrong number of chromosomes. 15:26.130 --> 15:31.130 And then, as they get more developed Alzheimer's disease, 15:31.140 --> 15:34.290 late, late, late stages of Alzheimer's disease 15:34.290 --> 15:36.600 where they're almost comatose, 15:36.600 --> 15:39.720 the number of aneuploid neurons goes down, 15:39.720 --> 15:41.640 back to almost normal. 15:41.640 --> 15:46.440 And he could calculate that from this point to that point, 15:46.440 --> 15:48.090 there was a lot of cell loss. 15:48.090 --> 15:51.360 And the cell loss was specifically in those aneuploid cells, 15:51.360 --> 15:53.940 the cells with the wrong number of chromosomes. 15:53.940 --> 15:57.780 And you could calculate that 90% of the cell death 15:57.780 --> 15:59.463 that led to the atrophy, 16:00.300 --> 16:01.950 the shrinkage of the brain 16:01.950 --> 16:03.600 in people with Alzheimer's disease 16:03.600 --> 16:06.840 was the loss of these aneuploid cells. 16:06.840 --> 16:09.540 So the aneuploid cells are abnormal. 16:09.540 --> 16:11.220 And because they die, 16:11.220 --> 16:14.370 you begin to develop cognitive problems. 16:14.370 --> 16:16.890 So, that became the indication 16:16.890 --> 16:20.250 that the first prediction is absolutely correct. 16:20.250 --> 16:21.990 Second prediction, 16:21.990 --> 16:25.920 well, if you confine people with trisomy 21 mosaicism, 16:25.920 --> 16:29.220 it should predispose them to developing Alzheimer's disease. 16:29.220 --> 16:32.910 And Nicole Schupf made a very interesting observation 16:32.910 --> 16:34.740 a number of years ago 16:34.740 --> 16:37.860 in which she found that mothers 16:37.860 --> 16:40.560 who had a child with Down syndrome 16:40.560 --> 16:43.170 when they were less than 35 16:43.170 --> 16:44.940 had a five-fold increased risk 16:44.940 --> 16:46.640 of developing Alzheimer's disease. 16:48.210 --> 16:51.060 Now, if they had the child when they were older, 16:51.060 --> 16:53.340 then there was no increased risk. 16:53.340 --> 16:56.463 And the parent, the father, 16:57.810 --> 16:59.550 also didn't have an increased risk. 16:59.550 --> 17:01.290 It was only if they were young. 17:01.290 --> 17:04.200 And then Migliore came along and applied our theory, 17:04.200 --> 17:07.620 and he found out that the blood cells 17:07.620 --> 17:10.320 in the women who had a child with Down syndrome 17:10.320 --> 17:12.180 when they were less than 35 17:12.180 --> 17:15.660 have almost a four-fold increased, 17:15.660 --> 17:18.060 four or five-fold increased risk 17:18.060 --> 17:21.990 of chromosome missegregation for chromosome 21. 17:21.990 --> 17:25.110 They were developing these Down syndrome cells 17:25.110 --> 17:26.490 even when they were young 17:26.490 --> 17:28.950 and just had a child Down syndrome. 17:28.950 --> 17:30.240 So that makes now sense 17:30.240 --> 17:33.450 because they were probably mosaic Down syndrome. 17:33.450 --> 17:34.470 They didn't know it. 17:34.470 --> 17:36.540 That increases the risk of Alzheimer's disease, 17:36.540 --> 17:38.940 and it increases the risk of developing 17:38.940 --> 17:41.010 a child with Down syndrome. 17:41.010 --> 17:42.750 These data are new. 17:42.750 --> 17:45.600 They're not new, but they are not yet repeated 17:45.600 --> 17:47.190 by many, many other investigators. 17:47.190 --> 17:51.600 So it's unclear whether it's absolutely 100% true, 17:51.600 --> 17:52.920 but it makes completely sense, 17:52.920 --> 17:54.960 and these two are very good investigators. 17:54.960 --> 17:58.410 So we think that that satisfies the second prediction. 17:58.410 --> 18:00.570 Third prediction is that the genes and proteins 18:00.570 --> 18:03.090 should be involved in cell cycle, 18:03.090 --> 18:04.590 in chromosome segregation. 18:04.590 --> 18:07.050 Remember that family that had an APP mutation? 18:07.050 --> 18:09.240 We took it out and put it into a mouse. 18:09.240 --> 18:10.740 What about that mutation? 18:10.740 --> 18:13.800 Does it cause problems with chromosomes? 18:13.800 --> 18:16.170 And the answer is, yes, it does. 18:16.170 --> 18:18.030 If you look at that mouse, 18:18.030 --> 18:20.430 that mouse has cells in its brain 18:20.430 --> 18:22.410 that have the wrong number of chromosomes. 18:22.410 --> 18:24.480 This is for chromosome 16. 18:24.480 --> 18:26.760 We stain it with a stain that tells us 18:26.760 --> 18:28.200 that it's a nerve cell. 18:28.200 --> 18:33.200 And look at how many extra cells that are trisomy 21, 18:33.810 --> 18:36.603 sorry, trisomy 16, 'cause this is a mouse, 18:37.500 --> 18:40.350 in the brain of that mouse. 18:40.350 --> 18:42.900 Furthermore, if you take the A-beta peptide 18:42.900 --> 18:46.740 and you add it to cells and culture, 48 hours later, 18:46.740 --> 18:49.440 many of them have the wrong number of chromosomes. 18:49.440 --> 18:50.670 And that's shown here. 18:50.670 --> 18:52.950 This is two daughter cells. 18:52.950 --> 18:54.060 Used to be one cell. 18:54.060 --> 18:55.770 It was treated with the A-beta peptide. 18:55.770 --> 18:57.660 You can see that this daughter cell, 18:57.660 --> 18:59.160 instead of having two and two, 18:59.160 --> 19:01.800 has three copies of chromosome 21, 19:01.800 --> 19:04.590 sorry, 12, and one copy of chromosome 21. 19:04.590 --> 19:06.660 This has three copies of chromosome 21 19:06.660 --> 19:08.430 and one copy of chromosome 12. 19:08.430 --> 19:10.380 So, they just switch places, 19:10.380 --> 19:12.240 and that happens in the culture. 19:12.240 --> 19:14.190 We know exactly what the mechanism is. 19:14.190 --> 19:16.170 And we're now trying to develop drugs 19:16.170 --> 19:17.430 that will prevent it. 19:17.430 --> 19:19.380 That if we take early enough, 19:19.380 --> 19:21.150 it might help prevent 19:21.150 --> 19:23.523 the formation of those aneuploid cells. 19:24.420 --> 19:27.000 Now, I don't know whether you have ever heard 19:27.000 --> 19:29.640 of frontotemporal lobar degeneration, 19:29.640 --> 19:31.440 but it's a kind of dementia 19:31.440 --> 19:33.060 that is similar to Alzheimer's disease, 19:33.060 --> 19:35.400 but it's caused by other kinds of mutations. 19:35.400 --> 19:39.420 And it turns out that some of them have those tangles, 19:39.420 --> 19:42.570 some of them have another kind of deposit in the brain, 19:42.570 --> 19:47.490 and every single type of frontotemporal dementia 19:47.490 --> 19:49.890 has trisomy 21 cells in the brain. 19:49.890 --> 19:51.690 No one ever thought of looking. 19:51.690 --> 19:55.440 We looked, and every single type of 19:55.440 --> 19:57.030 frontotemporal dementia, 19:57.030 --> 19:59.280 sporadic, progranulin mutations, 19:59.280 --> 20:02.250 tau mutations, C9orf72 mutations, 20:02.250 --> 20:04.620 which I don't have to explain in great detail, 20:04.620 --> 20:06.300 but they're mutations that cause 20:06.300 --> 20:09.060 frontotemporal lobar degeneration. 20:09.060 --> 20:11.580 Chromosome 21, chromosome 12, 20:11.580 --> 20:14.430 they all have the wrong number of chromosomes 20:14.430 --> 20:17.310 in the nerve cells in the brain, 20:17.310 --> 20:21.630 and that's shown here that it's not only the glial cells 20:21.630 --> 20:23.160 that are the support cells in the brain, 20:23.160 --> 20:25.290 but the nerve cells themselves. 20:25.290 --> 20:28.470 And so this says that this whole idea 20:28.470 --> 20:31.710 that there is this silent catastrophe 20:31.710 --> 20:34.170 that is building up in the brains of people 20:34.170 --> 20:36.180 that eventually will get Alzheimer's disease, 20:36.180 --> 20:38.640 or, in this case, frontotemporal dementia, 20:38.640 --> 20:42.330 is due to cells with the wrong number of chromosomes, 20:42.330 --> 20:45.513 including trisomy 21 Down syndrome cells. 20:47.160 --> 20:49.020 What about other degenerative diseases? 20:49.020 --> 20:54.020 Niemann-Pick disease is a terrible childhood disease, 20:54.270 --> 20:58.650 and it turns out that the nerve cells in those children, 20:58.650 --> 21:03.650 when they die, have trisomy 21, as do the glial cells, 21:03.660 --> 21:05.550 as do the skin cells. 21:05.550 --> 21:08.010 So this is a completely different disorder. 21:08.010 --> 21:10.440 It has to do with cholesterol metabolism. 21:10.440 --> 21:11.700 We went on to study that, 21:11.700 --> 21:14.310 and we found out that cholesterol, all by itself, 21:14.310 --> 21:16.320 when added to cells, can cause them to 21:16.320 --> 21:18.390 segregate their chromosomes incorrectly 21:18.390 --> 21:21.420 and generate trisomy 21 cells. 21:21.420 --> 21:24.600 And that's interesting because high cholesterol 21:24.600 --> 21:27.150 is one of the risk factors for Alzheimer's disease. 21:28.290 --> 21:31.410 Okay, simple conclusion, 21:31.410 --> 21:36.270 there is a silent problem that is developing in all of us. 21:36.270 --> 21:40.320 All of us have some of these trisomy 21 Down syndrome cells. 21:40.320 --> 21:43.050 But when they accumulate in large numbers, 21:43.050 --> 21:44.970 and especially in the brain, 21:44.970 --> 21:47.400 then they can generate these diseases 21:47.400 --> 21:49.290 that we detect in the clinic, 21:49.290 --> 21:53.700 but the problem has started probably decades before. 21:53.700 --> 21:57.090 And we're now trying to develop drugs that would prevent it 21:57.090 --> 21:59.310 and ways to diagnose it early 21:59.310 --> 22:01.740 to see this problem arising. 22:01.740 --> 22:04.271 And I thank you very much for your time. 22:04.271 --> 22:06.854 (upbeat music) 22:20.030 --> 22:22.613 (gentle music)