Locating genes for clues to Alzheimer's risk, cause, diagnosis

Neuroscientists have zeroed in on some target genes that may be tied to the development of Alzheimer's disease, and they've shown what abnormalities appear on brain scans of people with these genetic variations.

Both bits of scientific progress are incremental steps toward understanding what causes the disease that afflicts more than 5 millon Americans. The study, lead by researchers in Boston and Cambridge, Mass., England and Wales, appears in this month's Archives of Neurology.

"The drought of genetic findings in Alzheimer's disease has lasted a long time," write scientists based in London and Wales in an editorial accompanying the Archives study. "These findings, and the genome-wide studies that presaged them, mark a new period of optimism for those of us who study the etiologies of complex diseases of the nervous system."

The study explains the association researchers made between genetic loci that are related to Alzheimer's disease and neuorimaging measures that are related to disease risk. (These measures include the volume of the hippocampus, amygdala and other brain structures.) They identify B1N1 and CNTN5 as additional specific locations of genetic variants on chromosomes, but say their findings warrant further study.

Just one genetic variant, known as APOE, has been shown to influence Alzheiemer's disease risk and age at onset, lead authors Drs. Alessandro Biffi and Christopher Anderson write in their background information.

Study participants included 168 people with probable Alzheimer's, 357 people with mild cognitive impairment, a precursor to Alzheimer's, and 215 people who were cognitively normal. "Our results indicate that APOE and other previously validated loci for Alzheimer's disease affect clinical diagnosis of Alzheimer's disease and neuroimaging measures associated with the disease," they write.

Will that bring us closer to genetic tests for Alzheimer's?

Somewhat, John Hardy, of the University College London Institute of Neurology, says in an email, "but I think this genetic determinism argument is oversold, frankly.

"About 5 percent of the population are at high risk. About 30 percent of the population are at a moderate risk, and about 65 percent are at lower risk. These numbers are little changed by the new data. And, this is not really so useful for genetic testing."

Read the study in the Archives of Neurology.

The National Institute on Aging's fact sheet on Alzheimer's disease genetics.

What is it like to have dementia?

What's it like for Dad, I've often wondered. Is he frustrated, trapped in a body with a malfunctioning mind? Does he understand that he is deteriorating? Did he, at the beginning?

Would I know, at the beginning, if I were to develop Alzheimer's? I don't want to suffer with a dementia; could I create a way out for myself now, in the event I lose my mind later?

That was one of the main character's thoughts in Lisa Genova's heartbreaking/inspiring/terrifying novel, "Still Alice." A neuroscientist, Alice Howland develops early-onset Alzheimer's disease. (The paperback, published by Pocket Books, sells for $15.)

It's a compelling question: What is it like to have dementia?

So when I got an email from WebMD with that subject line, I had to read more.

Writer R. Morgan Griffin does a good job of explaining how caregivers help themselves, and their loved one, by understanding what the disease is like for the person who has it. An excerpt:

Some people think of memory loss superficially, as merely forgetting words or names. But it’s much more profound than that. Everything we do is premised on memory. When you walk into the kitchen to make dinner, your actions are almost unconscious. You grab food from the fridge, turn on the oven, take out plates and silverware – your memories are a foundation, and they give you a context for what you’re supposed to do in a given situation.

For a person with dementia, that context is ripped away. A woman with Alzheimer’s disease may walk into a kitchen and have no idea why she’s there or what she’s supposed to be doing. She might still be able to make dinner – especially in the early stages of the disease – but it’s a struggle. Each step has to be reasoned out and thought through. That’s why people with dementia tend to act more slowly than they once did.

The rest of the article is full of additional observations and explanations. Read it, and you'll find yourself saying, "so that's why my Mom does..." or "that explains why Dad did..."

Understanding dementia from a patient's point of view can make caregiving less frustrating. Knowing the patient personally is important, too.

We fretted over how to convince Dad that he needed to live in a memory care facility. Stubborn and independent, he was unlikely to admit he needed help, that it was for his safety. Tell him he had dementia and he'd appear quietly stunned--and you could not tell if he was processing the information, angry about it, or considering what those words meant. But he was still Dad.

The facility we were considering, Silverado, had a calendar of events planned for the residents, and one of the outings was to the State Fair of Texas. Since Dad had run the midway there for years, we figured that would be an ideal day for Dad to visit Silverado. He knew Silverado was for people with various types of dementia, and he knew the residents would need help getting around the fairgrounds. He found a purpose in acting as their guide. Soon he began believing Silverado was where he worked--he returned home in the evenings to sleep at first--and the staff kept him busy stuffing envelopes and such. When I'd call, he answered the phone as he always had answered his work phone: "Cleveland Smith, may I help you?"

It broke my heart. But, I recognized Dad had found a way to cope with his diagnosis. So had we. We joined reality with his reality, and together we were understanding what it is like to have dementia.

Read more from Amber Smith, "What would Dad say about this blog?"

Read Bruce Bane's blog about living with dementia: "He Reminds me of my Dad."

Read the WebMD story, "What is it like to have dementia?"

A curious study of Agatha Christie and Alzheimer's -- and how our writings may one day be used for diagnosis

The language of people with Alzheimer's disease includes significantly more indefinite words and repetitions than the language of healthy people of similar age and level of education.

So, an English professor at the University of Toronto, Ian Lancashire, analyzed the writing of British mystery writer Agatha Christie.

Previously, the works of British novelist Iris Murdoch were analyzed for signs of the Alzheimer’s disease that was confirmed after her death. Science Blog reported in 2004 that "while the structure and grammar of Murdoch's writing remained roughly consistent throughout her career, her vocabulary had dwindled and her language simplified in her very last novel."

Christie was never diagnosed with Alzheimer's. She continued to write in her final years, though some people believed she suffered from dementia.

Lancashire says her 73rd book, "Elephants Can Remember" is universally dismissed by critics as being full of errors and poorly plotted. The main character is a female novelist who struggles with memory loss while trying to solve a crime that happened in the past.

The professor told National Public Radio that when he read the book, he felt Christie was sensing what was happening to her, and that she kept writing "struck me as heroic."

His study involved feeding the text of 16 of her novels into a computer program that analyzed the vocabulary for the frequency of different words and the number of different words in each novel. "The richness of the vocabulary of Christie’s novels declines with her age at composition. The three novels that she wrote in her 80s, (Nemesis, Elephants, and Postern of Fate,) have a smaller vocabulary than any of the analyzed works written by her between ages 28 to 63," he writes.

Christie was 81 when she wrote the Elephants novel. Her use spiked of what Lancashire called indefinite words--"thing," "anything," "something," "nothing." At the same time, the number of different words Christie used dropped by 20 percent. "That is astounding," Lancashire told NPR. "That is one-fifth of her vocabulary lost."

Most of us don't have large collections of writing done over the course of our lives. But Lancashire points out in his conclusion that "this will begin to change as more individuals begin to keep, if only by inertia, a lifetime archive of e-mail, blogs, professional documents, and the like.

"While the diversity of topics and genres in such an archive brings methodological problems to the analysis ... we can nonetheless foresee the possibility of automated textual analysis as a part of the early diagnosis of Alzheimer’s disease and similar dementias."

Lancashire's paper, "Vocabulary Changes in Agatha Christie’s Mysteries as an Indication of Dementia: A Case Study."

The National Public Radio report.

18 months later: physically healthy -- but my how that neuropsychological test was accurate

My Dad amiably answered the doctor's questions, even though the answers he provided were wrong. When asked to extend his arms, or draw shapes on paper, my Dad complied.

On the sidelines of the exam room in this geriatric psychiatrist's office in October 2008 at a medical center in downtown Dallas, I watched my Dad fail what I have since learned was a neuropsychological test. My Mom sat on my right. My then 10-year-old son sat on my left, and we all watched quietly. We encouraged husband/Dad/Grandpa with reassuring smiles and nods. But we all recognized he was not doing well.

My son stayed with his Grandpa in a waiting room while the doctor gave his assessment. It was most clearly frontotemporal dementia. He explained what that is. He mentioned some signs of Parkinson's disease, too. He told us Dad would likely live from 18 months to 3 years.

Which kind of knocked the wind out of us.

Physically, my Dad is so healthy. He was then, and he remains so now, 18 months later.

It would be easy--indeed, it was tempting--to dismiss the psychiatrist and the oddball "test" my Dad had "failed." But the doctor spoke with confidence about signs and symptoms we had not recognized previously. We still think back on things Dad said or did and wonder...was that the beginning of his decline? should that have signaled us that something was wrong with his brain? That gaze in his eyes? The appointments he showed up for a day early? The trouble he had hearing--or was it his comprehension that was off?

I asked the psychiatrist what would kill my Dad. He has this fatal disease, for which there is no treatment, but I wondered what would finally take my father down. Would his heart just stop? Would he just lapse into a coma?

The doctor explained that many people with FTD die after falls, or by choking on food, or by an out-of-control infection. They become incontinent. They forget how to swallow. It was both disconcerting and comforting to hear from a professional what lay ahead. My own subsequent research backed up every word.

So here we are, 18 months later. Dad very distinctly has that Parkison's gait. On most days, he is unaware of his loved ones, and I doubt that any pictures or memory cards I have sent him make any sense to him anymore--or that he can find them. I bet he still has his sweet tooth, but maybe not, (since some dementias steal taste, too.)

He used to fight the caregivers who tried to undress him for showers; now several of the female residents are on his arm. When we visited him once at Silverado where he lives now, Dad emphatically pointed out baboons in the trees outside his window. Since he managed a wildlife amusement park for several years, this "delusion" made sense. Sometimes I wonder if he still sees them. Or if FTD has replaced those delusions with others. He's also incontinent, a progression that adds $500 to the monthly bill.

And even though all of this was predicted by the doctor, even though we watched "Away From Her" and read Lisa Genova's "Still Alice," even though we prepared ourselves in the best ways possible.... sometimes I want to go back in time to that exam room and hear the doctor blame my Dad's confusion on his hearing, or a brain tumor. Something that could be fixed. Or if not fixed, treated. Or if not treated, immediately fatal. Anything but this lengthy deterioration that seems to be playing out just as the doctor predicted.

On the horizon: A better way to diagnose Alzheimer's disease

Autopsy provides the only way to definitively diagnose Alzheimer's disease. Brain tissue samples may reveal a buildup of amyloid plaques, (left, courtesy the University of Liverpool) thought to contribute to the disease--though scientists debate about whether it's the cause. Wouldn't it be nice to be able to determine if someone has Alzheimer's before they die? Or before they develop symptoms?

Medical imaging companies are heading in that direction, developing molecules with radioactive markers that will bind to amyloid plaques. Patients could receive an injection that would prompt regions of the brain to become colorized in a scan and reveal the location of those Alzheimer's-related plaques, the Wall Street Journal describes.

Learn more about those amyloid plaques.

Find out how doctors diagnose Alzheimer's.

Think you have memory loss? That could predict dementia

Believing that your memory is failing may actually be a predictor of a diagnosis of dementia or Alzheimer's disease, according to some fascinating German research in the April issue of the Archives of General Psychiatry.

Researchers from the Department of Psychiatry at the University of Bonn say their work--involving 2,415 subjects--helps describe Alzheimer's as a three-stage clinical manifestation. First there is subjective memory impairment. Then mild cognitive impairment. And then dementia.

"The concept of mild cognitive impairment as a predementia manifestation of Alzheimer's disease is substantiated by studies providing biologic evidence for the presence of Alzheimer's disease in patients with mild cognitive impairment," writes lead author, Dr. Frank Jessen. "However, Alzheimer's disease-related pathologic changes in the brain evolve several years before the onset of mild cognitive impairment."

He says subjective memory impairment, or believing you have memory loss, may be a clinical manifestation of Alzheimer's disease. In his study, patients who started out with subjective memory impairment and who went on to have mild cognitive impairment 18 months later had almost 10 times the risk of any dementia at three years, and almost 20 times the risk of Alzheimer's disease--compared to patients without subjective memory impairment.

Read the MedPage Today story.

Read the Doctor's Guide article.

Read the abstract in the Archives of General Psychiatry.

If there were a test for dementia, would you take it?

Especially if Alzheimer's disease "runs in the family," we listen when scientists talk of ways to predict who will develop such a dreadful disease. We've heard more about the brain than we care to, with its tau proteins and plaques and neurofibrillary tangles. Of course brain research is teaching us about the causes of dementia, and maybe it will eventually lead to methods of prevention or treatment. Will those advances come in time for us? For our children?

Earlier this year, research in the Neurobiology of Aging Journal explained how elevated levels of phosphorylated tau231 in cerebrospinal fluid may be used to diagnose a healthy person who will develop Alzheimer's disease. Researchers from New York University's School of Medicine said the levels could predict future memory decline and the loss of brain gray matter in the medial temporal lobe--a key memory center.

"Our research results show for the first time that elevated levels of P-tau 231 in normal individuals can predict memory decline and accompanying brain atrophy," said lead author Dr. Lidia Glodzik, an assistant research professor in the Department of Psychiatry at the school's Center for Brain Health and Center of Excellence on Brain Aging. "Our findings suggest that P-tau231 has the potential to be an important diagnostic tool in the pre-symptomatic stages of Alzheimer's disease."

Which is great.

Or at least, potentially, a great advance.

It's quite a ways off. When I go for my physical in a couple of weeks, I won't be able to ask my doctor to run this test and then...know. But there's a good chance something like this will be available if not in my lifetime, certainly within the lifetimes of my children.

We know what Alzheimer's and dementia do to the ones we love. We know how the diseases take them from us long before their bodies fail, leaving bits of their spirit and personality glimmering--only every now and then--in their eyes. One merciful aspect of the disease may be that our loved ones did NOT know what was happening to them until it already was. By the time symptoms of memory failure became evident, hopefully, they were too far gone to notice. What appears to us as suffering may be, to them, just the way life is.

Science may wind up changing that for us.

We may have the option of learning way before symptoms emerge whether dementia is part of our future. So, what if it is? What then?

Read the story in ScienceDaily.

Read the story in The Medical News.

The abstract in the Neurobiology of Aging.

Simple new test can detect early dementia

Sixty percent of Alzheimer's cases do not get diagnosed in primary care medical offices, which means missed opportunities to treat patients in the early stages of dementia.

A new Computerized Self Test, created by researchers from the University of Tennessee, could potentially bring a simple and inexpensive testing tool to family doctors and internists.

CST is a fitness test for the brain. It's a brief, interactive online test that assesses various impairments in the basic thinking functions that are affected by cognitive impairments and dementias including Alzheimer's. Researchers say it provides an objective way to determine what diseases may affect the patient, so providers can begin treatments that could blunt the effects of the disease.

“Early detection is at the forefront of the clinical effort in Alzheimer’s research, and application of instruments like CST in the primary care setting is of extreme importance,” Rex Cannon, an assistant professor in psychology, told Tennessee Today.

His work will be published in the April 2010 issue of the Journal of Alzheimer's Disease.

The study, "The Computerized Self-Test--an Interactive, Internet Accessible Cognitive Screening Test for Dementia"

The story from Tennessee Today, from the University of Tennessee, Knoxville.