Neuroscientist Predicts 'Much Better Treatment' For Alzheimer's Is 10 Years Away

TERRY GROSS, HOST:

This is FRESH AIR. I'm Terry Gross. I hope the new year has gotten off to a good start for you. Most people want to live a long life, but one of the things that terrifies people about growing old or about their parents or grandparents growing old is Alzheimer's disease. We're going to discuss what we know about how the disease attacks the brain and destroys memory, and what researchers are investigating that might delay its onset and reduce the damage it causes. My guest is British neuroscientist Joseph Jebelli, author of the new book "In Pursuit of Memory: The Fight Against Alzheimer's." The subject is personal for him because when he was 12, his grandfather developed Alzheimer's. He died seven years later. Jebelli's book is based in part on his travels around the world talking with scientists, conducting Alzheimer's research.

Joseph Jebelli, welcome to FRESH AIR. Is there a genetic test that is truly a predictor of whether you will get Alzheimer's?

JOSEPH JEBELLI: So there is for a very small group of Alzheimer's patients. So about 5 to 10 percent of Alzheimer's patients have what we call early-onset Alzheimer's disease, and these are patients who can develop it in their 50s, 40s and even 30s. And for them, you know, many of them have inherited a genetic mutation which gives them a 50-50 chance of developing the disorder. And so some patients will have a genetic mutation that if they carry that particular genetic mutation, they will certainly go on to develop Alzheimer's, and there is a test for those individuals.

And in the book, I interviewed many of the patients with early-onset Alzheimer's disease. And some of the patients decided to have the test and found out they were positive, and it sort of changed their life in many different ways. And other patients decided that they didn't want to know. But for the vast majority of Alzheimer's cases, what we call the late-onset Alzheimer's cases, the story's a little bit different. It's more that there are - as opposed to genetic mutations, there're what we call genetic risk factors. And these are just variance in DNA, just in the same way that you have variance in DNA that account for differences in eye color, height, hair, all these things that, you know, differentiates us from one another.

There are, you know, lots of the risk factors for Alzheimer's, and we've identified about 20 so far. And we know that they just slightly tip the scale in favor of Alzheimer's. But there is one in particular, a risk factor called APOE E4, and we know that that is a particularly strong risk factor for Alzheimer's. We know, for instance, that the APOE E4 gene is present in about 30 percent of the population, but it's also present in about 50 percent of all Alzheimer's cases. So you could, if you wanted to, you know, there are all these companies these days who allow you to have your genome sequenced or you can be tested for certain genes.

You can find out, for instance, if you carry the APOE E4 gene. And but as I said earlier, I don't - personally, I don't think I would want to know that information because having the APOE E4 gene certainly doesn't mean you're definitely going on to get Alzheimer's disease. It just means you have a higher risk. But it's relative risk, you know? It's not absolute risk, so it all depends on what your base-line risk is, and we don't know what that is. So it's - you know, there are tests for you to understand your risk, but there's not - for a vast majority of cases, there's not a test to know definitively if you're destined for Alzheimer's.

GROSS: There's several memory tests on the market. Can they tell you that you're having a memory decline because of Alzheimer's?

JEBELLI: It's very difficult to glean meaningful information from memory tests because memory works in very many ways to a muscle. And often, people have everyday forgetting simply because they're a bit tired, they might be a bit depressed, they haven't maybe given enough attention to the thing they're trying to remember in the first place. So there are all these different factors that can affect your memory. And when you go through the process of getting a diagnosis for Alzheimer's - so I did this in the book.

For one of my chapters, I actually went through the process of having the cognitive tests, and having the memory tests, and speaking to the memory specialists and going through every step along the way of someone who goes on to learn if they have Alzheimer's or not. And all the memory tests do is just - they add to a collection of evidence that then allows clinicians to say, there's a diagnosis of probable Alzheimer's disease, is what they call it. We can only tell definitively at post-mortem when pathologists then look in the brain, and they see the buildup of these sticky proteins that we call plaques and tangles. And they look at that, and that's in collaboration with the deficits in memory and the behavioral changes and all of the sort of clinical signs that you see in a patient during life. That is all put together to then tell the neurologist, OK, this person had Alzheimer's disease.

So the memory tests are only a small piece of the puzzle. And, you know, it's very interesting because recent research has actually suggested that although memory is one of the first things to go in Alzheimer's disease, there are other things that are actually maybe just as important. So we know, for instance that navigation is a very early telltale sign of Alzheimer's - navigation loss, rather I should say - the getting lost and wandering around. And this was certainly true for my grandfather, but I think before he actually forgot me and my sister and the rest of my family, he would often just wander out of our house and wander away from the dinner table. And we would - my father would have to go out into the neighborhood and find him.

And so there are memory tests, and there - you know, there are lots, as you say, advertised online. And I think it's good for people to do these sort of tests and to train their memory because you can train memory. You can do things to improve your memory, and so I would encourage people to do that. But in terms of whether or not that's a sign of Alzheimer's, I would be very cautious about that because it's just, as I said, a small piece of the puzzle as to what Alzheimer's is.

GROSS: There's also a lot of products on the market that claim to be able to strengthen your memory through various exercises and games. What's the research on that? How effective are those things? Do you have any idea?

JEBELLI: That's a great question. Yeah, so I write - I wrote about brain training in the book. I have a chapter where I travel to Japan to meet Ryuta Kawashima. I don't know if you remember Ryuta Kawashima. He was the Japanese neuroscientist that pioneered the Nintendo brain-training games that sort of created quite a stir for a long time, and he's still working on them now. The evidence for these memory games and these brain-training games is very conflicting. There is some evidence for it, but the trials are not - the problem is, the trials are not big enough. They're not sophisticated enough, and they haven't been replicated enough for us to say definitively, if you engage in this memory game, you will significantly increase your memory.

And lots of researchers think that actually, you know, you're just training certain parts of the brain and you're getting good at the game itself as opposed to increasing the capacity and the ability of your memory in a global sense. And so it's an ongoing area of research. It's just - it's something that we - there is evidence for. And again, I would certainly still encourage people to do these things because training your brain and remaining mentally engaged and active in as many ways as you can is good for the brain. But we still don't know for sure whether or not these are having a significant effect.

GROSS: Everybody who reaches a certain age and starts losing some of their memory thinks like, oh, my God, am I getting Alzheimer's? And what everybody always says is, if you lose your keys, you're just being forgetful. If you forget what your keys are for, then you're starting to have dementia. Is that a helpful way of looking at it?

JEBELLI: I think that's a very helpful way of looking at it because it helps to distinguish between just normal everyday forgetting and something that is potentially a bit more sinister. So as you said, you know, losing your keys or forgetting where you put your glasses is completely normal. It's - but when you find your glasses and your keys, and you think, what are these for? That's a sign that there's something else going on, that it's not just the memory loss because we know, for instance, that healthy brains shrink and lighten by about 10 percent between the ages of 50 and 80.

And it used to be thought that the reason they shrink and lighten by that degree is because you lose loads of brain cells. But actually, you don't. Actually, you keep a lot of the brain cells you have throughout your life. It's just that the brain cells shrivel up. They get a bit smaller. The contacts between each brain cell reduce in number, and so they just function a bit more slowly. And that's why, as you get older, you do have problems with just day-to-day tasks and everyday remembering. But, you know, not - suddenly not being able to understand what keys are for and what glasses are for is a sign that there's a deep underlying confusion that's setting in. And it's when you have that confusion that is a sign that it's something a bit more malign than just normal, everyday forgetting. So I think that is a good way of describing the difference.

GROSS: Why don't we take a short break here? And then we'll talk some more. If you're just joining us, my guest is neuroscientist and writer Joseph Jebelli, author of the new book "In Pursuit of Memory: The Fight Against Alzheimer's." We'll be right back. This is FRESH AIR.

(SOUNDBITE OF LOOP 2.4.3'S "ZODIAC DUST")

GROSS: This is FRESH AIR. And if you're just joining us, we're talking about Alzheimer's. My guest is Joseph Jebelli. He's a neuroscientist and writer and author of the new book "In Pursuit Of Memory: The Fight Against Alzheimer's."

So what are typically the first symptoms of Alzheimer's?

JEBELLI: The first symptoms of Alzheimer's are usually mild forgetting, confusion with day-to-day tasks - things like paying the bills, stocking the fridge - and a sort of mild confusion. So they're quite subtle, you know? They're the sort of things that people do experience in just a normal, healthy aging, and they're quite difficult to detect. And that's actually been a big problem in the field because, you know, lots of the old drug trials have failed because we think that actually, many of the people in the drug trials didn't have Alzheimer's disease. They just had sort of a normal, healthy forgetting. So the early signs are quite mild. It's when it then goes onto the sort of the moderate to the late-stage symptoms that you really start to see the true face and character of Alzheimer's disease.

GROSS: And you say that when a person gets Alzheimer's, the brain is actually under attack. Can you describe the attack?

JEBELLI: So yeah. So in Alzheimer's disease, there is a huge buildup of these sticky clumps of proteins that we call plaques and tangles. And in an Alzheimer's patient's brain, the brain is literally littered with plaques and tangles. And we know that plaques and tangles are toxic to brain cells, and some people refer to them as killer proteins. And so we still don't understand exactly how these plaques and tangles lead to cell death in the brain, but we know that the brain is essentially under attack by the presence of these toxic proteins.

And we know that also, once Alzheimer's starts, the immune system kicks in. When the immune system kicks in, you get a sort of runaway inflammation, which actually makes the whole process much worse, in many ways. And so, you know, the brain cells are sort of struggling to stay alive. The immune system to begin with, we think, tries to heal the brain, tries to remedy the situation and clear away the plaques and tangles. But for whatever reason, it seems to fail. So it very much is - very much can be seen as an attack in the sense that there are these bizarre buildup of these strange proteins that seem to be damaging brain cells in a massive degree.

GROSS: Is there a part of the brain that's typically attacked first?

JEBELLI: Yeah. So the hippocampus is the brain region that is typically attacked first. And the hippocampus is a region deep within the brain, and it controls the conversion of short-term memories to long-term memories. It's very important for the formation of new memories. It doesn't store memory. We don't think it stores memory. The memory itself we think is stored in the cortex, sort of the outer layers of the brain. But the hippocampus is a very important way station for memory. And the plaques and tangles seem to build up to a quite striking degree in the hippocampus. And then as the disease progresses, they slowly fan out to the rest of the brain.

GROSS: So does that explain why short-term memory is the first to go with Alzheimer's and why people with Alzheimer's often seem to be living in the past, thinking that their children who are now adults are actually still little children, thinking that they live in a home that they used to live in as opposed to where they currently live?

JEBELLI: Yeah, that's exactly right, so - because the hippocampus does have such a crucial role in short-term memory, and it's because it's one of the first things to go. Short-term memory is affected at the beginning of the disease. And, you know, as the disease progresses, you do - when you meet these patients, they are very much, as you said, sort of living in the past. And I - in the book, I described it as watching someone endlessly fall back through time.

And with my grandfather, it was certainly the case. He - I mean, he was confusing his wife for his first - his second wife for his first wife, for instance, and, you know, very much sort of being slightly aware of things in his distant past. You could show him photographs of when he was very young, and you would see some flicker of recognition. But, you know, the immediate past, the short term - the short-term memory was gone quite quickly.

GROSS: If you damage your skin, your skin will probably heal. If you damage - if - when the neurons get damaged in the brain, they don't heal, right? Correct me if I'm wrong there.

JEBELLI: Yeah, that's right. So in the central nervous system, the neurons don't appear to regenerate. They're what we call post-mitotic. So, you know, once you have those neurons, you have those neurons for the rest of your life. However, there is a lot of really exciting research coming out now into neural stem cells that suggests that actually, there are populations of cells in the brain that may provide regeneration, that may actually give birth to new neurons in the brain.

And some scientists think that if we can figure out where these populations of neural stem cells are and if we can figure out what the biochemical and genetic messages are that activate these cells, that, you know, we can develop a drug to switch those on, essentially, to allow the brain to heal itself. So, you know, it's a very exciting field at the moment because a lot is happening, a lot of things that we thought in the past, like - you know, like, neurons just sort of having them for the rest of your life - those concepts are being challenged now.

GROSS: So how far along is that research?

JEBELLI: Well, that's - I mean, it depends who you ask. I suppose I would say it's still very much in its infancy. We're still trying to figure out, you know, what these brain stem cells are and how they operate. It's still in its infancy, but at the same time, I would say, you know, it's important to remember that science doesn't operate in a linear fashion. Sometimes there are just these great breakthroughs, these great eureka moments that could just change the game entirely. So I'm always optimistic that's - you know, however, sort of whatever early stages the research is in, I'm always optimistic that there'll be a eureka moment just around the corner.

GROSS: So you mentioned that there was proteins called plaques and other proteins called tangles that when you have Alzheimer's basically attack the brain and make it difficult for the neurons to function. Correct me when I'm getting this wrong.

JEBELLI: Yes. No, that's right, yeah.

GROSS: And that the plaques appear before the tangles, and therefore, the plaques are very attractive targets for researchers who are trying to come up with some kind of way of preventing or slowing Alzheimer's. So how are plaques being targeted now by researchers?

JEBELLI: So the last 20 years have - you know, have seen many drug trials that have targeted plaques by developing a drug - an antibody drug - that stimulates the brain's own immune system to clear away the plaques from the brain. And unfortunately, this field has been littered by failures. A lot - all of these drug trials haven't worked, and we're still untangling the reasons as to why they didn't work. So you're right in the sense that, you know, the plaques are the most attractive target because they're the most obvious targets, and we know that the immune system does try to clear them away. So if we can keep trying to work on drugs that will stimulate that process, in theory, it should treat the disease, but we still don't know for sure if it will have a significant cognitive enhancement. We just don't understand the biology of the disease well enough.

Lots of scientists think that the tangles rather than the plaques - so the sticky proteins that are inside the neurons - actually are more important and that we should be targeting them rather than the plaques. But other scientists will say, well, the plaques come first, so you should target them to prevent the buildup of the tangles in the first place. So it's a very mysterious disorder, and we still don't know what the plaques and tangles are doing, you know? Maybe they have a normal physiological function that we still are not - we still don't fully understand. So scientists, at the moment, are targeting the plaques and tangles, but at the same time, we're working feverishly just to understand the neurobiology of the disease to find other targets. That's what we really need to do with them. We need to find as many targets as possible.

GROSS: My guest is Joseph Jebelli, author of the new book "In Pursuit Of Memory: The Fight Against Alzheimer's." We'll talk more after a break. And book critic Maureen Corrigan will have a new appreciation of Sue Grafton, who wrote the alphabet mystery series that started with "A Is For Alibi." She died last week. We'll also hear my 1989 interview with Grafton. I'm Terry Gross, and this is FRESH AIR.

(SOUNDBITE OF MARIA SCHNEIDER AND DAWN UPSHAW SONG, "WALKING BY FLASHLIGHT")

GROSS: This is FRESH AIR. I'm Terry Gross back with British neuroscientist Joseph Jebelli, author of the new book "In Pursuit Of Memory: The Fight Against Alzheimer's." His book is based in part on his travels around the world interviewing scientists who are conducting research into how the disease attacks the brain and research into drugs that might limit the damage.

So you mentioned earlier that there's a gene that in some cases seems to be - you know, to correlate with Alzheimer's. It's not a hundred-percent predictor, but it can help predict if you're going to develop Alzheimer's in the future. Is that being addressed through genetic medicine?

JEBELLI: Yes, it is. Absolutely. So the gene, APOE E4, does significantly increase one's risk. If you carry two copies of the APOE E4 gene, you have a significantly higher risk of developing Alzheimer's disease. And so now geneticists and neuroscientists are trying to figure out a way of either silencing that gene using genetic methods or actually changing the gene entirely. There's this revolutionary new genome-editing tool who CRISPR that lots of scientists are working on now.

And, you know, what would be really great is if we could use something like CRISPR to sort of cut out the APOE E4 gene and instead put an APOE E2 gene. So that's just a different version of this gene. But the APOE E2 gene actually seems to protect someone from Alzheimer's disease. It lowers the risk of developing Alzheimer's disease. So, you know, in conjunction with these drug trials targeting the plaques and tangles using antibodies and the immune system, there are lots of geneticists saying, hang on, this has probably got much deeper genetic roots, and let's see what we can do with the underlying genes to treat the disease.

GROSS: There are already several drugs on the market for people in I think early stages of Alzheimer's. And you can even hear ads for some of these drugs on TV. How do those drugs work, and what's the scientific consensus about whether they're effective or not?

JEBELLI: So the current medication for Alzheimer's disease is approved essentially because it's better than nothing. There's nothing else at the moment. But it's not good enough. So it's what we call the Aricept generation of drugs. These drugs were pioneered in the '70s and '80s, and they treat the symptoms as opposed to the underlying biology. And we found that in about 60 percent of patients, these drugs will delay the symptoms by about six months to a year. And that is certainly better than nothing.

It's certainly good enough for them to be approved and for patients to be taking them. And many of the patients I interviewed for the book said that, actually, they do feel much better taking these drugs. They feel - you know, one patient said to me that she felt - she feels much less fuzzy and, you know, just - things are a bit clearer. But six months to a year is just simply not good enough. And as I said before, it's just that they target the symptoms as opposed to the underlying biology.

GROSS: So you've discussed several different paths that researchers are taking to try to better understand Alzheimer's and to try to prevent it or slow it. How far is some kind of effective measure from actually being developed and approved? Like, are we talking decades, five years, 10 years? Any estimate?

JEBELLI: So I think the most optimistic estimate is about 10 years. We know that's - Alzheimer's is a disease process that evolves over decades of time, and so a lot of the research at the moment is looking into trying to detect the disease. There are these very early telltale signs of Alzheimer's that we can detect in things like spinal fluid, blood, maybe even the eye. And so, you know, the goal is to detect these early telltale signs and give the patient a drug at that point. It's difficult to say in terms of an exact date. I mean, 10 years - I mean, that's based on the fact that there are several big drug trials going on at the moment, and the results of many of them will be in sort of between 2022 and 2025.

It may take a bit longer, but as I said, you know, I'm optimistic because science doesn't work in a linear fashion. And, you know, there are these great leaps forward, what we call these - what we call paradigm shifts. And just the last few years alone have seen some serious breakthroughs in Alzheimer's research. So I'm one of the very optimistic people that think 10 years should be enough time for us to develop, you know, if not a cure, certainly a much better treatment than what we have at the moment.

GROSS: Well, why don't we take a short break here? If you're just joining us, my guest is Joseph Jebelli. He's a British neuroscientist and writer and author of the new book "In Pursuit Of Memory: The Fight Against Alzheimer's." We'll be right back. This is FRESH AIR.

(SOUNDBITE OF MUSIC)

GROSS: This is FRESH AIR, and if you're just joining us, my guest is British neuroscientist and writer Joseph Jebelli. He's the author of the new book "In Pursuit Of Memory: The Fight Against Alzheimer's."

So we've talked about research that's in the works. Some researchers say, well, lifestyle is an issue too - things like stress, sleep, diet, exercise. Is there any really hard evidence that any of those factors would have an influence on either the development or, you know, the speed of developing Alzheimer's?

JEBELLI: So I wouldn't say there's hard evidence. There is certainly evidence, and the evidence is growing rather than fading. I would - the jury is still very much out because the studies that look at lifestyle factors at the moment just aren't big enough. You know, they're done on sort of hundreds or thousands of people over a - quite a short period of time. But to really know definitively whether certain lifestyle factors have a significant impact on Alzheimer's, you need to look at, you know, much larger populations of people over much longer stretches of time, and just logistically, that's a very hard thing to do. But as I said, the evidence is growing. So we know, for instance, that anything that's good for the heart is good for the brain. Post-mortem studies have shown that in 80 percent...

GROSS: Wait, wait, why do we know that? What's the correlation?

JEBELLI: Oh, so for instance, anything that's - so we know that from post-mortem studies, 80 percent of people with Alzheimer's disease have some form of cardiovascular disease as well. So there does seem to be some link between the - you know, having a healthy heart and having a healthy brain. And having a healthy blood supply, as well, seems to do, you know, wonderful things for the brain. But it's - in terms of understanding exactly what's going on to reduce your risk of Alzheimer's, we know, for instance, that when you exercise, your brain releases this molecule we call BDNF, which just stands for brain-derived neurotrophic factor.

And we know that BDNF acts as a sort of fertilizer for the brain and can lead to the growth of new neurons and new synapses. And so we know, for instance, as well, that some studies have shown that having a Mediterranean diet seems to lower the risk of Alzheimer's. And there's a lot of really exciting research going on into turmeric at the moment because we know that there's a compound within...

GROSS: This is the spice turmeric?

JEBELLI: Yeah, the spice turmeric, the Indian spice turmeric. There's a compound within turmeric called curcumin, and curcumin seems to actually dismantle plaques and tangles. And you can see this happening beneath the microscope. And so, you know, there is - as I said, it's sort of fragmentary evidence, but it is accruing and it is getting - it is getting more convincing, but - and beyond sort of having a healthy diet and sort of exercising, we know that sleep has hugely beneficial effects for the brain. When you sleep, your brain essentially cleans itself. It uses cerebrospinal fluid to pump away the plaques and tangles that we think cause the disease.

And so lots of researchers now are looking into ways of using sleep to treat Alzheimer's disease and seeing if a certain level of sleep can somehow affect the symptoms or somehow slow the disease down. And so, you know, there is evidence for lifestyle factors. And, you know, most neuroscientists you speak to will be cautiously optimistic about it because, as I said, you know, the evidence isn't conclusive yet. But, you know, it is building.

GROSS: Do you consider Alzheimer's a death sentence? And if so, what is it that kills the person who has it?

JEBELLI: Yeah, so that's a great question. So Alzheimer's actually kills a patient indirectly, and what I mean by that is a patient will get to the stage where things like pneumonia or an infection due to a bed sore will actually be the thing that kills the patient. Sometimes the parts of the brain, you know, controlling coordination will have shut down to the point where they'll have a fatal fall or they'll forget to eat or - they sort of deteriorate to the point where, as I said - you know, I say in the book, that the brain essentially forgets to look after itself. And if you get past these phases, parts of the brain can shut down that control the autonomic nervous system. And so, you know, that's the part of the brain that controls things like heartbeat and breathing. So it does kill, but it does so in an indirect way.

GROSS: You say that for now the hope is to reach where we are currently with diabetes. What's that comparison?

JEBELLI: Mmm hmm. So - because, you know, not so long ago, diabetes was very much a death sentence, but now there are medications that can control it in a very effective way. And so I think it's the same - and it's very similar to Alzheimer's in the sense that the cure for Alzheimer's isn't actually what most people think. The cure for Alzheimer's will probably be something that manages it, that controls it or, rather, that pushes it back because we know that, for instance, if you can push Alzheimer's disease back by one year, there will be 9 million fewer cases of the disease. If you could push it back by five years, it would effectively half the globe's number of Alzheimer's patients.

GROSS: Why is that - because people would die of other causes before getting Alzheimer's?

JEBELLI: Because they would - exactly. Yeah, because they would die of other causes before getting Alzheimer's. So, you know, once you pass the age of 65, every five years your odds of Alzheimer's double. But, you know, obviously it depends what your baseline odds are. But, you know, because it's primarily a disease of old age, if we can just push it back or manage the symptoms to the point where they don't have the profound memory loss, they don't have the confusion and the fear and all of the things that come along with Alzheimer's disease - you can push that back and just let them - and then they will die naturally of some other process. So it's not - you know, it's similar to diabetes in the sense that, you know, it's finding a way to manage and to treat it and to try and keep the symptoms of it at bay.

GROSS: Well, I want to thank you so much for talking with us.

JEBELLI: Thank you for having me.

GROSS: Joseph Jebelli is the author of the new book "In Pursuit Of Memory: The Fight Against Alzheimer's." After a break, Maureen Corrigan will have an appreciation of mystery writer Sue Grafton, who died last week, and we'll hear the interview I recorded with Grafton in 1989, when she was up to the letter F - "F Is For Fugitive" - in her alphabet mystery series. This is FRESH AIR.

(SOUNDBITE OF MARY LOU WILLIAMS' "IT AIN'T NECESSARILY SO")

TERRY GROSS, HOST:

This is FRESH AIR. 2017 ended on a sad note for mystery fans with the death of alphabet mystery series author Sue Grafton. She was 77. We're going to hear an excerpt of my 1989 interview with Grafton. But first, our book critic, Maureen Corrigan, has an appreciation.

MAUREEN CORRIGAN, BYLINE: I think the last time I reviewed one of Sue Grafton's novels was in 2009. I wrote that "U Is For Undertow" was so good it made me wish that there were more than 26 letters at her disposal. Now, of course, that line falls flat. As Grafton's fans know, she died of cancer on December 28. Her last novel was "Y Is For Yesterday," which came out last summer. Turns out there were only 25 letters at her disposal.

In interviews, Grafton always described hitting upon the strategy of alphabet titles for her novels as a whim. She said she got the idea after reading Edward Gorey's alphabet picture book called "The Gashlycrumb Tinies," in which children die in grisly ways - B is for Basil assaulted by bears, G is for George smothered under a rug, and so on. But what started out as a lark became - if I may say this of a mere mystery series - something defiant, noble, even, because a series that projects itself to the end of the alphabet is a race against limitations, the limitations of time and the imagination.

Time ran out on Grafton, but her creative stamina barely flagged. Sure, not every one of her novels was a standout. How could that be when there were so many of them? But lots of the recent ones, like the aforementioned "Y," were terrific, and as the series went on, her plots grew more intricate, increasingly haunted by the past and its crimes. Throughout the series, Grafton's detective heroine, Kinsey Millhone, maintained her cheeky humor and cherished autonomy. Kinsey lived alone in what we would now call a tiny house and relied on that one black dress to see her through funerals and parties. She drank rotgut wine and refused to be cowed by patriarchal authority and the parasitic rich. In short, Kinsey was a fictional alter ego for every shy woman who hesitated to talk back. Grafton said she counted herself among those shy women.

I reread Kinsey's debut, "A Is For Alibi," every few years for the detective fiction course I teach. It came out in 1982, a signature moment in hard-boiled history. Sara Paretsky introduced her gal gumshoe, V.I. Warshawski, that very same year. Things were pretty bleak before then for women in hard-boiled mysteries. The two available roles were either femme fatale or corpse. But Grafton, Paretsky and other sleuthing sisters like Liza Cody, Eleanor Taylor Bland and pioneer Marcia Muller picked the locks on the doors of what had been mostly a men's club.

They tossed out the genre's racist, sexist and nativist cliches and its moldy cast of usual suspects, chief among them, those emasculating femme fatales. Once those female private eyes and police detectives went to work investigating what Raymond Chandler famously called a world gone wrong, the villains began to look radically different, mostly male and white. And in these feminist mysteries, evil wasn't imported into America from some exotic locale like it was, say, in "The Maltese Falcon," but rather, it sat squarely on Main Street in banks, churches and corporations.

Grafton and that post-'60s generation of mystery writers revolutionized what had become fossilized formula fiction. They helped make the detective novel matter again. Because of those quirky alphabet titles and Kinsey's humor, Grafton's novels were sometimes regarded as lighter than those of her colleagues. They shouldn't be. Those trademark wisecracks of Kinsey's were often wrapped around barbed social commentary. Here's Kinsey in "A Is For Alibi" describing the tedium of her workday, most of it spent (reading) checking and cross-checking, filling in blanks, detail work. The basic characteristics of any good investigator are a plodding nature and infinite patience. Society has inadvertently been grooming women to this end for years.

The conclusion of "A Is For Alibi" is deadly serious. It's an ingenious feminist rewriting of one of the most hateful mystery endings of all time, Mickey Spillane's misogynist masterpiece "I, The Jury." I won't spoil the fun. Just think Freud and womb imagery triumphantly vanquishing the phallic symbol. I'd like to think there's something fitting in the way Grafton's alphabet series is almost, but not quite, complete. The great hard-boiled mysteries never conclude with neat solutions, but rather with ambiguity. Grafton planned to call her last novel "Z Is For Zero," but like so many of Kinsey's cases, it remains open.

GROSS: Maureen Corrigan teaches literature at Georgetown University. I spoke with Sue Grafton in 1989, seven years after she started her alphabet mystery series with private eye Kinsey Millhone. When we spoke, she'd already written "A Is For Alibi," "B Is For Burglar," "C Is For Corpse," "D Is For Deadbeat" and "E Is For Evidence." Her book "F Is For Fugitive" had just been published. I asked her about the first Kinsey Millhone novel, which ended with her facing a moral crisis. She'd killed someone in self-defense.

(SOUNDBITE OF ARCHIVED BROADCAST)

SUE GRAFTON: What I am interested in doing, aside from the fact of the mystery itself, is talking about its effect on Kinsey Millhone. One of the things that always seemed true of me of mysteries in general is the prime character, the protagonist, seems not to be affected by the murder and mayhem. And I wanted to use Kinsey Millhone not only as a way of observing society, but showing her reaction and the changes it brings about in her own personality.

GROSS: When you started writing detective fiction, were you self-conscious about being a woman and self-conscious about figuring out how to make this a more feminist crime series than a macho one?

GRAFTON: No, I was self-conscious, but primarily because I was ill at ease with some of the technicalities of writing detective fiction. When I started "A Is For Alibi," I didn't even know what a private investigator did. So in the course of writing that book, I did a lot of reading on forensics and California criminal law, ballistics, auto and - theft, and burglary and that sort of thing. And I think my self-consciousness was the sense of not being qualified to do the writing. And one of the reasons I made Kinsey Millhone female is because I felt like that was an area in which I had a little expertise.

GROSS: What other kinds of research did you have to do before you felt confident in writing a convincing crime story?

GRAFTON: I learned to shoot a handgun. I took women's self-defense. All of the books take me down dark alleys. For instance, when I did "C Is For Corpse," I went to visit two morgues so that I would know what that looked like. I did a ride-along with the police in Santa Barbara one night, and that was a bit of an eye opener because I tend to go to bed very early, and to see what goes on in that town after 10 o'clock was sort of astonishing.

GROSS: Now, it's interesting. Your detective, Kinsey Millhone, has no family. Her parents were killed in a car accident when she was 5 years old. And I'd like to read something that she says in "F Is For Fugitive," your new book.

GRAFTON: All right.

GROSS: Now, in this scene, she's having dinner with a family. They're all pretty crazy in this family. And she says, (reading) as a child, I didn't experience much in the way of family, and I usually find myself somewhat taken aback to see one at close range. "The Donna Reed Show" this was not. People talk about dysfunctional families. I've never seen any other kind.

You know, one of the things I always find interesting in most detective novels is that the character has kind of given up on the idea of family. They don't have any expectations for it.

GRAFTON: Correct. Well, I know Kinsey will never marry again. She will never have children. But part of that is because I think the tradition of the hard-boiled private eye is that of a loner, the sort of knight-errant. And in part, I made those choices because in the writing of detective fiction, I didn't want to stop and deal with Aunt Maudie (ph) and Uncle Herman (ph) and everybody gathered around, so she has a sort of surrogate family in Henry Pitts and Rosie, the woman who owns the tavern in her neighborhood. But I didn't want to deal with family gatherings at Christmastime and that sort of thing. So it is an option I'm - the choice I made, and I feel it's the correct one, in terms of the kind of book I'm writing.

GROSS: When you started the series, how did you come up with the "A Is For Alibi," and did you think at that time that you would be committing yourself to a B, C, D, E, F and so on?

GRAFTON: It had been in the back of my mind to try a series based on something. So "A Is For Alibi" came out of a personal situation of my own in which I was going through a very bitter divorce. And at the time, I was not very effectual as a fighter. I have since learned quite a lot about how to fight legal battles, but I used to lie awake at night and think of ways to kill the man. However, because I am such a law-abiding little bun, I knew I'd get caught at it. For one thing, I think the cops are very smart. I think people are foolish who imagine they can outwit the police. And I am the sort of person who does not even turn a library book in late. Also, if I get a parking ticket, I know they're discussing me down at the police station.

GROSS: (Laughter).

GRAFTON: And I don't - that makes me uncomfortable. So I decided that the next best thing would be to take the murder, put it in a book and get paid for it. And in essence, I have launched an entire new career for myself out of mere homicidal rage.

GROSS: Each of your books has an epilogue in which Kinsey Millhone files her report.

GRAFTON: Yes.

GROSS: And in - the report is usually something of a summing up, but then she also always tells how much money she made and how much of an advance she was given and how much money she might have to give back, when that's the case. But yeah, she makes, like, a thousand, 2,000, maybe $3,000. It's so little money when you think of all she's put on the line to solve this case.

GRAFTON: She keeps her monthly nut quite modest. And what I need to talk about in that is that she is a professional. She does work for money. Many of the male detectives simply work for the spirit of it, which I don't think is very realistic in this day and age. I see Kinsey as capable and competent, and I think she should be paid for what she does. On the other hand, I don't want her to have to take money if she doesn't feel right about a case, so I like to keep her liberated in that respect.

GROSS: Have you found that Kinsey Millhone's courage is contagious?

GRAFTON: Yes. Often, I find that I look at the world through her eyes. And I think to myself, Kinsey Millhone would not be intimidated, and therefore, whether it scares me or not, I had better straighten up my act.

GROSS: Sue Grafton, thanks so much for talking with us.

GRAFTON: Thank you.

GROSS: Sue Grafton, recorded in 1989. She died last Thursday. She was 77.

Tomorrow on FRESH AIR, as President Trump pulls out of treaties and cuts back on U.N. spending under the banners of America First and make America great again, we'll talk about how China is trying to make China great again and using President Trump to its advantage. My guest will be Evan Osnos, who writes about this in the current New Yorker, where he's a staff writer. I hope you'll join us.

(SOUNDBITE OF MUSIC)

GROSS: FRESH AIR's executive producer is Danny Miller. Our interviews and reviews are produced and edited by Amy Salit, Phyllis Myers, Sam Briger, Lauren Krenzel, Heidi Saman, Therese Madden, Mooj Zadie, Thea Chaloner and Seth Kelley. I'm Terry Gross.

(SOUNDBITE OF MUSIC)

Transcripts are created on a rush deadline, and accuracy and availability may vary. This text may not be in its final form and may be updated or revised in the future. Please be aware that the authoritative record of Fresh Air interviews and reviews are the audio recordings of each segment.