Dr. Shahal Rozenblatt, Clinical Neuropsychologist, New York

NYTimes-Dementia’s Signs May Come Early

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The man complained of memory problems but seemed perfectly normal. No specialist he visited detected any decline.

“He insisted that things were changing, but he aced all of our tests,” said Rebecca Amariglio, a neuropsychologist at Brigham and Women’s Hospital in Boston. But about seven years later, he began showing symptoms of dementia. Dr. Amariglio now believes he had recognized a cognitive change so subtle “he was the only one who could identify it.”

Patients like this have long been called “the worried well,” said Creighton Phelps, acting chief of the dementias of aging branch of the National Institute on Aging. “People would complain, and we didn’t really think it was very valid to take that into account.”

But now, scientists are finding that some people with such complaints may in fact be detecting early harbingers of Alzheimer’s.

Studies presented Wednesday at an Alzheimer’s Association conference in Boston showed that people with some types of cognitive concerns were more likely to have Alzheimer’s pathology in their brains, and to develop dementia later. Research presented by Dr. Amariglio, for example, found that people with more concerns about memory and organizing ability were more likely to have amyloid, a key Alzheimer’s-related protein, in their brains.

And, in a significant shift highlighted at the conference, leading Alzheimer’s researchers are identifying a new category called “subjective cognitive decline,” which is people’s own sense that their memory and thinking skills are slipping even before others have noticed.

“The whole field now is moving to this area, and saying ‘Hey, maybe there is something to this, and maybe we should pay attention to these people,’ ” said Dr. Ronald C. Petersen, chairman of the advisory panel to the federal government’s new National Alzheimer’s Project.

Dr. Petersen, director of the Mayo Clinic’s Alzheimer’s center, said preliminary results of a Mayo study of healthy older adults in Minnesota suggested something similar.

“Lo and behold, those who had a concern about their memory in fact had more likelihood” of later developing mild cognitive impairment, an early phase of dementia, he said. He said study participants with memory concerns were 56 percent more likely to be given a diagnosis of such impairment, even when results were adjusted for factors like education, genetic risk and psychiatric issues like anxiety and depression.

“These people are sensing something, and there’s some biological signals that correlate,” Dr. Petersen said. “I think it’s real.”

Experts emphasize that many people with such complaints will not develop dementia. Some memory decline reflects normal aging, they say, and some concerns reflect psychological angst. People who forget what they wanted in the kitchen or the names of relatively unfamiliar people are probably aging normally. People who forget important details of recent events, get lost in familiar places or lose track of book or television plots may not be, especially if they have more problems than others their age.

And much remains unknown about subjective concerns. In some studies, like Dr. Amariglio’s, highly educated people noticed changes more readily, but in other studies, less educated people did. Some studies suggest people who worry more about memory deficits have more dementia risk, but it is unclear if the worry reflects the changes they sense or if worrying itself increases risk. People with family histories of dementia could be reporting problems simply because they know about the disease and its genetic component. And, while a study presented Wednesday found slight correlations between subjective concerns and the highest-risk genetic mutation, ApoE4, that relationship remains unclear.

Experts are not yet suggesting doctors regularly screen people for “subjective cognitive decline” because much more research is needed and no effective dementia treatment now exists.

Dr. Richard Caselli, a neurology professor at the Mayo Clinic in Arizona, said that when patients cited cognitive problems, he ruled out “reversible things,” but did not recommend testing for Alzheimer’s because “if we do a scan and say, ‘Hey, we found some amyloid in your brain,’ there’s really nothing you can do.”

But subjective screening has value now for clinical trials, experts say, because it can help pinpoint people at higher risk for dementia to better determine if treatments can delay or prevent Alzheimer’s.

Major studies like the Alzheimer’s Disease Neuroimaging Initiative are adding subjective memory complaint categories. So will an important trial to see if an anti-amyloid drug can prevent dementia in cognitively normal people with amyloid in their brains.

“People have been interested in this subjective concern for a long time, but we didn’t have a way to say is this normal,” said Dr. Reisa Sperling, who runs Brigham and Women’s Alzheimer’s program and is helping lead the coming anti-amyloid study.

Not long ago, most experts considered subjective concerns unmeasurable or related to depression or anxiety. Frank Jessen, a researcher at the German Center for Neurodegenerative Diseases, said his first study on the topic, submitted to journals around 2004, “got rejected everywhere,” but in 2012, the same study with more years of data was accepted by Neurology, a major journal.

In November, a working group of leading experts was formed, headed by Dr. Jessen. The name “subjective cognitive decline” was chosen after some debate, with some experts preferring other terms.

Dr. Jessen said in diseases from arthritis to Parkinson’s, people often feel something is wrong before others notice. In most phases of dementia, family members and friends see deficits, but the disease has usually stolen the person’s ability to recognize them. But at the subjective phase, studies suggest family members may miss problems; the person may feel his mind working harder, but he still functions well.

One of Dr. Caselli’s patients, Roger Siegel, 84, has noticed problems for at least five years, and said he now remembers about 30 percent of what he would like to, and has trouble concentrating. “I take a shower and wonder did I wash that leg,” he said. In books, “many times I forget which character is which.”

Recently, he bought six packages of pie filling instead of one “because I asked somebody where would I find it and the answer was Aisle 6, so I wrote down 6, but by the time I got to the aisle, I picked up six of the thing.”

Neither his wife nor Dr. Caselli perceive these difficulties.

“I know I’m losing my mind,” Mr. Siegel said, “but according to Caselli, I’m fine.”

Dr. Caselli said Mr. Siegel has “been saying he is declining for years,” and was given a diagnosis at another clinic of mild cognitive impairment three years ago “based on his subjective complaints, when he had no evidence of decline and I told him so.”

But recently fine-grained cognitive measures showed he had “slight decline on his tests, and so may possibly be at a very early stage of a very slowly progressive degenerative syndrome,” Dr. Caselli said.

The working group aims to develop standardized subjective cognitive tests so when treatments become available doctors can eventually use them as a “cheap and noninvasive” way to help identify people at greater risk, said Dr. Petersen. “We can’t do M.R.I.s and scanning on everyone,” he said.

Current tests range from an eight-page assessment in Dr. Amariglio’s research to one question included in a broader University of Kentucky study of dementia. But Richard Kryscio, a biostatistician and study leader, said those reporting memory changes since their last visit were 2.8 times as likely to develop mild cognitive impairment or dementia years later, and autopsies of participants who died found more Alzheimer’s plaques and tangles in people with subjective cognitive concerns.

Experts say the goal is a test identifying which subjective concerns are potentially worrisome, since not all are.

Sharon Atkinson-Mallory, 70, of Belmont, Mass., a participant in Dr. Amariglio’s study of people without symptoms, said she had occasional trouble putting names to faces and remembering why she entered a room. But Ms. Atkinson-Mallory, a psychotherapist, maintains a practice, exercises, pursues a genealogy hobby, and considers her issues similar to those of others her age.

Carol Miller, 61, of Rochester, Minn., part of the Mayo Clinic’s study of cognitively healthy adults, seems more concerned. A registered nurse who retired after being laid off a few years ago, she has forgotten cardiovascular and neurological vocabulary that once “I would recall very easily,” she said. “I don’t trust myself as a safe R.N. because I don’t have the knowledge anymore.”

When shopping for blueberry filling for her daughter’s birthday cake, she twice reached the checkout counter having forgotten it. And twice she has left the stove on. “I could’ve burned the house down,” she said. “That was scary, like ‘Wow, what’s the deal there?’ ”

Still, she said, “so far they tell me I’m normal.”