JUNE 2004
An unmistakably elderly woman with hot pink nails and lips tickled a little girl, about five years old, presumably the woman’s granddaughter. Both looked to be having a grand old time. The advertisement read: “THE #1 TUMMY TICKLER takes the #1 prescribed Alzheimer’s drug.” Alice had been flipping through Boston magazine but was unable to move past this page. A hatred of that woman and the ad filled her like a hot liquid. She studied the picture and the words, waiting for her thoughts to catch up to what her gut understood, but before she could figure out why she felt so personally antagonized, Dr. Moyer opened the door to the examining room.
“So Alice, I see you’re having some difficulty sleeping. Tell me what’s going on.”
“It’s taking me well over an hour to get to sleep, and then I usually wake up a couple of hours after that and go through the whole thing all over again.”
“Are you experiencing any hot flashes or physical discomfort at bedtime?”
“No.”
“What medications are you taking?”
“Aricept, Namenda, Lipitor, vitamins C and E, and aspirin.”
“Well, unfortunately, insomnia can be a side effect of the Aricept.”
“Right, but I’m not going off Aricept.”
“Tell me what you do when you can’t get to sleep.”
“Mostly I lie there and worry. I know this is going to get a lot worse, but I don’t know when, and I worry that I might go to sleep and wake up the next morning and not know where I am or who I am or what I do. I know it’s irrational, but I have this idea that the Alzheimer’s can only kill off my brain cells when I’m asleep, and that as long as I’m awake and sort of on watch, I’ll stay the same.
“I know all this anxiety keeps me up, but I can’t seem to help it. As soon as I can’t fall asleep, I worry, and then I can’t sleep because I’m worried. It’s exhausting just telling you about it.”
Only some of what she’d just said was true. She did worry. But she’d been sleeping like a baby.
“Are you overcome with this kind of anxiety at any other time of the day?” asked Dr. Moyer.
“No.”
“I could prescribe you an SSRI.”
“I don’t want to go on an antidepressant. I’m not depressed.”
The truth was, she might be a little depressed. She’d been diagnosed with a fatal, incurable illness. So had her daughter. She’d almost entirely stopped traveling, her once dynamic lectures had become unbearably boring, and even on the rare occasion when he was home with her, John seemed a million miles away. So yes, she was a little sad. But that seemed an appropriate response given the situation and not a reason to add yet another medication, with more side effects, to her daily intake. And it wasn’t what she’d come here for.
“We could try you on Restoril, one each night at bedtime. It’ll get you to sleep quickly and allow you to stay asleep for about six hours, and you shouldn’t wake up groggy in the morning.”
“I’d like something stronger.”
There was a long pause.
“I think I’d like you to make an appointment to come back in with your husband, and we can talk about prescribing something stronger.”
“This doesn’t concern my husband. I’m not depressed, and I’m not desperate. I’m aware of what I’m asking for, Tamara.”
Dr. Moyer studied her face carefully. Alice studied hers. They were both older than forty, younger than old, both married, highly educated professional women. Alice didn’t know her doctor’s politics. She’d see another doctor if she had to. Her dementia was going to get worse. She couldn’t risk waiting any longer. She might forget.
She had rehearsed additional dialogue but didn’t need to use it. Dr. Moyer got out her prescription pad and began to write.
SHE WAS BACK IN THAT tiny testing room with Sarah Something, the neuropsychologist. She’d reintroduced herself to Alice just a moment ago, but Alice had promptly forgotten her last name. Not a good omen. The room, however, was as she remembered it from January—cramped, sterile, and impersonal. It contained one desk with an iMac computer on it, two cafeteria chairs, and a metal file cabinet. Nothing else. No windows, no plants, no pictures or calendar on the walls or desk. No distractions, no possible hints, no chance associations.
Sarah Something began with what felt almost like regular conversation.
“Alice, how old are you?”
“Fifty.”
“When did you turn fifty?”
“October eleventh.”
“And what time of year is this?”
“Spring, but it already feels like summer.”
“I know, it’s hot out there today. And where are we right now?”
“In the Memory Disorders Unit at Mass General Hospital, in Boston, Massachusetts.”
“Can you name the four things shown in this picture?”
“A book, a phone, a horse, and a car.”
“And what is this thing on my shirt?”
“A button.”
“And this thing on my finger?”
“A ring.”
“Can you spell ‘water’ backwards for me?”
“R-E-T-A-W.”
“And repeat this after me: Who, what, when, where, why.”
“Who, what, when, where, why.”
“Can you lift your hand, close your eyes, and open your mouth?”
She did.
“Alice, what were those four objects in the picture you named before?”
“A horse, a car, a phone, and a book.”
“Great, and write a sentence for me here.”
I cannot believe that I won’t be able to do this someday.
“Great, now name for me as many words as you can in a minute that begin with the letter s.”
“Sarah, something, stupid, sound. Survive, sick. Sex. Serious. Something. Oops, I said that. Said. Scared.”
“Now name as many words as you can that begin with the letter f.”
“Forget. Forever. Fun. Fight, flight, fit. Fuck.” She laughed, surprised at herself. “Sorry about that one.”
Sorry begins with s.
“That’s okay, I get that one a lot.”
Alice wondered how many words she would’ve been able to rattle off a year ago. She wondered how many words per minute were considered normal.
“Now, name as many vegetables as you can.”
“Asparagus, broccoli, cauliflower. Leeks, onion. Pepper. Pepper, I don’t know, I can’t think of any more.”
“Last one, name as many animals with four legs as you can.”
“Dogs, cats, lions, tigers, bears. Zebras, giraffes. Gazelle.”
“Now read this sentence aloud for me.”
Sarah Something handed her a sheet of paper.
“On Tuesday, July second, in Santa Ana, California, a wildfire shut down John Wayne Airport, stranding thirty travelers, including six children and two firemen,” Alice read.
It was an NYU story, a test of declarative memory performance.
“Now, tell me as many details as you can about the story you just read.”
“On Tuesday, July second, in Santa Ana, California, a fire stranded thirty people in an airport, including six children and two firemen.”
“Great. Now, I’m going to show you a series of pictures on cards, and you’re going to just tell me the names of them.”
The Boston Naming Exam.
“Briefcase, pinwheel, telescope, igloo, hourglass, rhinoceros.” A four-legged animal. “Racquet. Oh, wait, I know what it is, it’s a ladder for plants, a lattice? No. A trellis! Accordion, pretzel, rattle. Oh, wait, again. We have one in our yard at the Cape. It’s between the trees, you lie on it. It’s not a hangar. It’s a, halyard? No. Oh god, it begins with h, but I can’t get it.”
Sarah Something made a notation on her score sheet. Alice wanted to argue that her omission could just as easily have been a normal case of blocking as a symptom of Alzheimer’s. Even perfectly healthy college students typically experienced one to two tips of the tongue per week.
“That’s okay, let’s keep going.”
Alice named the rest of the pictures without further difficulties, but she still couldn’t activate the neuron that encoded the missing name of the napping net. Theirs hung between the two spruce trees in their yard in Chatham. Alice remembered many late afternoon naps there with John, the pleasure of the breezy shade, the intersection of his chest and shoulder her pillow, the familiar scent of their fabric softener on his cotton shirt combined with the summer smells of his sunburned and ocean-salty skin intoxicating her every inhalation. She could remember all of that, but not the name of the damn h-thing they lay on.
She sailed through the WAIS-R Picture Arrangement test, Raven’s Colored Progressive Matrices, the Luria Mental Rotation test, the Stroop test, and copying and remembering geometric figures. She checked her watch. She’d been in that little room for just over an hour.
“Okay, Alice, now I’d like you to think back to that short story you read earlier. What can you tell me about it?”
She swallowed her panic, and it lodged, heavy and hulking, right above her diaphragm, making it uncomfortable to breathe. Either her pathways to the details of the story were impassable or she lacked the electrochemical strength to knock loudly enough on the neurons housing them to be heard. Outside of this closet, she could look up lost information in her BlackBerry. She could reread her emails and write herself reminders on Post-it notes. She could rely on the default respect her Harvard position embodied. Outside of this little room, she could hide her impassable pathways and wimpy neural signals. And although she knew that these tests were designed to unveil what she couldn’t access, she was caught unsuspecting and embarrassed.
“I don’t really remember much.”
There it was, her Alzheimer’s, stripped and naked under the fluorescent lighting, on display for Sarah Something to scrutinize and judge.
“That’s okay, tell me what you do remember, anything at all.”
“Well, it was about an airport, I think.”
“Did the story take place on a Sunday, Monday, Tuesday, or Wednesday?”
“I don’t remember.”
“Just take a guess then.”
“Monday.”
“Was there a hurricane, a flood, a wildfire, or an avalanche?”
“A wildfire.”
“Did the story take place in April, May, June, or July?”
“July.”
“Which airport was shut down: John Wayne, Dulles, or LAX?”
“LAX.”
“How many travelers were stranded: thirty, forty, fifty, or sixty?”
“I don’t know, sixty.”
“How many children were stranded: two, four, six, or eight?”
“Eight.”
“Who else became stranded: two firemen, two policemen, two businessmen, or two teachers?”
“Two firemen.”
“Great, you’re all done here. I’ll walk you over to Dr. Davis.”
Great? Was it possible that she remembered the story but didn’t know she knew it?
SHE WALKED INTO DR. DAVIS’S office surprised to see John already there, sitting in the seat that had remained conspicuously empty on her previous two visits. They were all there now. Alice, John, and Dr. Davis. She couldn’t believe that this was really happening, that this was her life, that she was a sick woman at her neurologist’s appointment with her husband. She almost felt like a character in a play, this woman with Alzheimer’s disease. The husband held his script in his lap. Only it wasn’t a script, it was the Activities of Daily Living questionnaire. (Interior of Doctor’s Office. The woman’s neurologist sits across from the woman’s husband. Enter the woman.)
“Alice, have a seat. I’ve just had a few minutes here with John.”
John spun his wedding band and jiggled his right leg. Their chairs touched, so he was causing hers to vibrate. What had they been talking about? She wanted to talk to John in private before they began, to find out what had happened and to get their stories straight. And she wanted to ask him to stop shaking her.
“How are you?” asked Dr. Davis.
“I’m good.”
He smiled at her. It was a kind smile, and it dulled the edges of her apprehension.
“Okay, how about your memory? Are there any additional concerns or changes since the last time you were here?”
“Well, I’d say I’m having a harder time keeping track of my schedule. I have to refer to my BlackBerry and to-do lists all day long. And I hate talking on the phone now. If I can’t see the person I’m talking to, I have a really hard time understanding the entire conversation. I usually lose track of what the person is saying while I’m chasing down words in my head.”
“How about disorientation, any more episodes of feeling lost or confused?”
“No. Well, sometimes I get confused as to what time of day it is, even looking at my watch, but I eventually figure it out. I did go to my office once thinking it was morning and didn’t realize until I got back home that it was the middle of the night.”
“You did?” asked John. “When was this?”
“I don’t know, last month, I think.”
“Where was I?”
“Asleep.”
“Why am I just finding out about this now, Ali?”
“I don’t know, I forgot to tell you?”
She smiled, but it didn’t seem to change him. If anything, the edges of his apprehension got a little sharper.
“This type of confusion and night wandering is very common, and it’s likely to happen again. You might want to consider attaching a jingle bell to the front door or something that would wake John up if it opened in the middle of the night. And you should probably register with the Alzheimer’s Association’s Safe Return program. I think it’s something like forty dollars, and you wear an ID bracelet with a personal code on it.”
“I have ‘John’ programmed into my cell phone, and I carry it with me in this bag at all times.”
“Okay, that’s good, but what if the battery goes dead or John’s phone is off and you’re lost?”
“How about a piece of paper in my bag that has my name, John’s, our address and phone numbers?”
“That’ll work, as long as you always have it on you. You might forget to bring your bag. The bracelet, you wouldn’t have to think about.”
“It’s a good idea,” said John. “She’ll get one.”
“How are you doing with the medications, are you taking all of your doses?”
“Yes.”
“Any problems with side effects, nausea, dizziness?”
“No.”
“Aside from your night at the office, are you having any trouble sleeping?”
“No.”
“Are you still getting regular exercise?”
“Yes, I’m still running, about five miles, usually every day.”
“John, do you run?”
“No, I walk to work and home, that’s about it for me.”
“I think it’d be a good idea for you to take up running with her. There’s convincing data in animal models that suggest exercise alone can slow the accumulation of amyloid-beta and cognitive decline.”
“I’ve seen those studies,” said Alice.
“Right, so keep up with the running. But I’d like it if you could pair up with a running partner; that way we don’t have to worry about you getting lost or skipping your run because you forgot about it.”
“I’ll start running with her.”
John hated running. He played squash and tennis and an occasional game of golf, but he never ran. He could certainly outpace her mentally now, but physically, she was still miles ahead of him. She loved the idea of running with him but doubted that he could commit to it.
“How’s your mood been, are you feeling okay?”
“Generally good. I’m definitely frustrated a lot and exhausted from trying to keep up with everything. And I’m anxious about what lies ahead for us. But otherwise, I feel the same, better actually, in some ways, since telling John and the kids.”
“Have you told anyone at Harvard?”
“No, not yet.”
“Were you able to teach your classes and meet all your professional responsibilities this semester?”
“Yes, it took a lot more out of me than it did last semester, but yes.”
“Have you been traveling alone to meetings and lectures?”
“I’ve pretty much stopped. I canceled two university lectures, and I skipped a big conference in April, and I’m missing the one in France this month. I normally travel a lot in the summer, we both do, but this year we’re spending the whole summer at our house in Chatham. We’re heading down there next month.”
“Good, that sounds wonderful. Okay, it sounds like you’ll be well taken care of for the summer. I do think you should come up with a plan for the fall that involves telling the people at Harvard, maybe coming up with a way of transitioning out of your job that makes sense, and I think traveling alone should be out of the question at that point.”
She nodded. She dreaded September.
“There are some legal things to plan now as well, advance directives like power of attorney and a living will. Have you thought about whether or not you’d like to donate your brain to research?”
She had thought about it. She imagined her brain, bloodless, formalin-perfused, and Silly Putty–colored, sitting in the cupped hands of a medical student. The instructor would point to various sulci and gyri, indicating the locations of the somatosensory cortex, the auditory cortex, and the visual cortex. The smell of the ocean, the sounds of her children’s voices, John’s hands and face. Or she imagined it cut into thin, coronal slices, like a deli ham, and adhered to glass slides. In such a preparation, the enlarged ventricles would be striking. The empty spaces where she once resided.
“Yes, I’d like to.”
John cringed.
“Okay, I’ll have you fill out the paperwork before you leave. John, can I have that questionnaire you’re holding?”
What did he say about me in there? They would never talk about it.
“When did Alice tell you about her diagnosis?”
“Just after you told her.”
“Okay, how would you say she’s been doing since then?”
“Very well, I think. It’s true about the phone. She won’t answer it at all anymore. Either I get it or she lets the machine pick it up. She’s become glued to her BlackBerry, almost like a compulsion. She sometimes checks it every couple of minutes in the morning before she leaves the house. That’s a little difficult to watch.”
More and more, it seemed he couldn’t bear to look at her. When he did, it was with a clinical eye, like she was one of his lab rats.
“Anything else, anything that Alice may not have mentioned?”
“Nothing I can think of.”
“How’s her mood and personality, any changes you’ve noticed there?”
“No, she’s the same. A little defensive, maybe. And quieter, she doesn’t initiate conversation as much.”
“And how are you doing?”
“Me? I’m fine.”
“I have some information for you to take with you about our caregivers’ support group. Denise Daddario is the social worker here. You should make an appointment with her and just let her know what’s going on.”
“This is an appointment for me?”
“Yes.”
“Really, I don’t need one, I’m fine.”
“Okay, well, these resources are here if you find you come to need them. Now, I have some questions for Alice.”
“Actually, I want to talk about some additional therapies and clinical trials.”
“Okay, let’s do that, but first, let’s finish up her exam. Alice, what day of the week is it?”
“Monday.”
“And when were you born?”
“October eleventh, 1953.”
“Who is the vice president of the United States?”
“Dick Cheney.”
“Okay, now I’m going to tell you a name and address, and you’re going to repeat it back to me. Then, I’m going to ask you to repeat it again later. Ready? John Black, 42 West Street, Brighton.”
“The same as last time.”
“Yes, it is, very good. Can you repeat it back to me now?”
“John Black, 42 West Street, Brighton.”
John Black, 42 West Street, Brighton.
John never wears black, Lydia lives out west, Tom lives in Brighton, eight years ago I was forty-two.
John Black, 42 West Street, Brighton.
“Okay, can you count to twenty forwards and then backwards?”
She did.
“Now, I want you to raise the number of fingers on your left hand which corresponds to the place in the alphabet of the first letter of the city you’re in.”
She repeated what he said in her head and then made the peace sign with her left index and middle fingers.
“Good. Now, what is this thing called on my watch?”
“A clasp.”
“Okay, now write a sentence about today’s weather on this piece of paper.”
It is hazy, hot, and humid.
“On the other side of that paper, draw a clock showing the time as forty-five minutes past three.”
She drew a big circle and filled in the numbers starting at the top with twelve.
“Oops, I made the circle too big.”
She scribbled it out.
3:45
“No, not digital. I’m looking for an analog clock,” said Dr. Davis.
“Well, are you looking to see if I can draw or if I can still tell time? If you draw me a clock face, I can show you 3:45. I’ve never been any good at drawing.”
When Anna was three, she’d loved horses and used to beg Alice to draw pictures of them for her. Alice’s renditions had looked, at best, like postmodern dragon-dogs and always failed to satisfy even the wild and generously accepting imagination of her preschooler. No, Mom, not that, draw me a horse.
“I’m actually looking for both, Alice. Alzheimer’s affects the parietal lobes pretty early on, and that’s where we keep our internal representations of extrapersonal space. John, this is why I want you to go running with her.”
John nodded. They were ganging up on her.
“John, you know I can’t draw.”
“Alice, it’s a clock, not a horse.”
Stunned that he didn’t defend her, she glared at him and raised her eyebrows, giving him a second chance to verify her perfectly valid position. He just stared back at her and spun his ring.
“If you draw me a clock, I’ll show you three forty-five.”
Dr. Davis drew a clock face on a new sheet of paper, and Alice drew the hands pointing to the correct time.
“Okay, now I’d like you to tell me that name and address I asked you to remember earlier.”
“John Black, something West Street, Brighton.”
“Okay, was it forty-two, forty-four, forty-six, or forty-eight?”
“Forty-eight.”
Dr. Davis wrote something lengthy on the piece of paper with the clock.
“John, please stop shaking my chair.”
“Okay, now we can talk about clinical trial options. There are several ongoing studies here and at the Brigham. The one I like the most for you starts enrolling patients this month. It’s a phase three study, and it’s a drug called Amylix. It appears to bind soluble amyloid-beta and prevent its aggregation, so unlike the drugs you’re on now, there’s the hope that this could prevent the disease from progressing further. The phase two study was very encouraging. It was well tolerated, and after a year on the medication, the patients’ cognitive functioning seemed to have stopped declining or even improved.”
“I assume it’s placebo-controlled?” asked John.
“Yes, it’s double-blind and randomized to placebo or one of two doses.”
So I might get only sugar pills. She suspected that amyloid-beta didn’t give a shit about placebo effects or the power of wishful thinking.
“What do you think of the secretase inhibitors?” asked John.
John liked these best. Secretases were the naturally occurring enzymes that released normal, unharmful levels of amyloid-beta. The mutation in Alice’s presenilin-1 secretase rendered it insensitive to proper regulation, and it produced too much amyloid-beta. Too much was harmful. Like turning on a faucet that couldn’t be turned off, her sink was rapidly overflowing.
“Right now, the secretase inhibitors are either too toxic for clinical use or—”
“What about Flurizan?”
Flurizan was an anti-inflammatory drug like Advil. Myriad Pharmaceuticals claimed it decreased the production of amyloid-beta 42. Less water into the sink.
“Yes, there’s a lot of attention on that one. There’s an ongoing phase two study, but only in Canada and the UK.”
“How do you feel about Alice taking flurbiprofen?”
“We don’t have the data yet to say whether or not it’s effective for treating Alzheimer’s. If she decides not to enroll in a clinical trial, I would say that it probably couldn’t hurt. But if she wants to be in a study, flurbiprofen would be considered an investigational treatment for Alzheimer’s, and taking it would exclude her from the study.”
“All right, what about Elan’s monoclonal antibody?” asked John.
“I like it, but it’s only in phase one and enrollment is currently closed. Assuming it passes safety, they won’t likely initiate phase two until spring of next year at the earliest, and I’d like to get Alice in a trial sooner if we can.”
“Have you ever put anyone on IVIg therapy?” asked John.
John also liked the idea of this one. Derived from donated blood plasma, intravenous immunoglobulin was already approved safe and effective for treating primary immune deficiencies and a number of autoimmune neuromuscular disorders. It would be expensive and not reimbursable by their insurance company because of its off-label use but worth any price if it worked.
“I’ve never had a patient go on it. I’m not against it, but we don’t know the proper dosing, and it’s a very untargeted and crude method. I wouldn’t expect its effects to be anything more than modest.”
“We’ll take modest,” said John.
“Okay, but you need to understand what you’d be trading off. If you decide to go ahead with IVIg therapy, Alice wouldn’t be eligible for any of these clinical trials with treatments that are potentially more specific and disease modifying.”
“But she’d be guaranteed not to be in a placebo group.”
“That’s true. There are risks with either decision.”
“Would I have to go off the Aricept and Namenda to participate in the clinical trial?”
“No, you’d keep taking them.”
“Could I go on estrogen replacement therapy?”
“Yes. There’s enough anecdotal evidence to suggest that it’s at least to some degree protective, so I’d be willing to write you a prescription for CombiPatch. But again, it would be considered an investigational drug, and you wouldn’t be able to participate in the Amylix trial.”
“How long would I be in the trial for?”
“It’s a fifteen-month study.”
“What’s your wife’s name?” asked Alice.
“Lucy.”
“What would you want Lucy to do if she had this?”
“I’d want her to enroll in the Amylix trial.”
“So Amylix is the only option you can recommend?” asked John.
“Yes.”
“I think we should do the IVIg along with flurbiprofen and the CombiPatch,” said John.
The room became still and quiet. An enormous amount of information had just been passed back and forth. Alice pressed her fingers on her eyes and tried to think analytically about her treatment options. She did her best to set up columns and rows in her head to compare the drugs, but the imaginary chart didn’t help, and she tossed it into the imaginary trash. She thought conceptually instead and arrived at a single, crisp image that made sense. A shotgun or a single bullet.
“You don’t need to make a decision on this today. You can go home and think about it some more and get back to me.”
No, she didn’t need to think about it any further. She was a scientist. She knew how to risk everything with no guarantees in search of the unknown truth. As she’d done so many times over the years with her own research, she chose the bullet.
“I want to do the trial.”
“Ali, I think you should trust me here,” said John.
“I can still draw my own conclusions, John. I want to do the trial.”
“Okay, I’ll get you the forms to sign.”
(Interior of Doctor’s Office. The neurologist left the room. The husband spun his ring. The woman hoped for a cure.)