"Where are my glasses?" "Remind me who that person is. I can't remember his name." "What's the word I'm looking for? It's right on the tip of my tongue."
Sound familiar? As people get older, they often have "senior moments," episodes of minor forgetfulness that can be frustrating. Are these moments part of healthy aging or the first sign of something more serious, like Alzheimer's disease (AD)?
"Recent research has greatly enhanced our understanding of how memories are formed and what really happens in the brain when memory loss occurs," says Dr. Marcelle Morrison-Bogorad, director of the NIA's Division of Neuroscience . "These findings are helping us focus on the very earliest stages, when normal aging may be giving way to a disease process such as AD. Knowing more about these early events will help us understand what may trigger the AD process and will contribute to improved diagnosis and effective treatments."
Studies have shown that the aging brain is much more adaptable than once thought. For example, as adults age, they improve in some cognitive areas, such as vocabulary and other forms of verbal knowledge. The brain also continues to develop new neurons (nerve cells) in certain regions, even late in life. Pathways used by neurons to transmit signals can reroute themselves to bypass obstructions and maintain essential communications.
However, studies of memory and cognition have found that healthy people also may lose some cognitive function as they get older. They may have more difficulty learning new information, remembering things, or doing tasks like planning or making decisions.
These minor declines in memory and cognitive ability may occur because the brain, like other parts of the body, changes with age:
For some people, the brain changes that come with age are minimal and result in occasional memory lapses, such as forgetting keys or blanking out on a person's name. Others experience progressive and significant declines in their ability to remember things, without having other problems characteristic of AD, such as difficulty processing and organizing information, problems with judgment and decision-making, personality changes, and psychiatric and behavioral problems.
|Normal Age-Related Memory Loss||Memory Loss in MCI||Memory Loss in AD|
|Sometimes misplaces keys, eyeglasses, or other items||Frequently misplaces items||Forgets what an item is used for or puts it in an inappropriate place|
|Momentarily forgets an acquaintance's name||Frequently forgets people's names and is slow to recall them||May not remember knowing a person|
|Occasionally has to search for a word||Has increasing difficulty finding desired words||Begins to lose language skills and may withdraw from social interaction|
|Occasionally forgets to run an errand||Begins to forget important events and appointments||Loses the sense of time; does not know what day it is|
|May forget an event from the distant past||May forget recent events or newly learned information||Has seriously impaired recent memory and difficulty learning and remembering new information|
|When driving, may momentarily forget where to turn, but quickly orients self||Becomes temporarily lost more often; may have trouble understanding and following a map||Becomes easily disoriented or lost in familiar places, sometimes for hours|
|Jokes about memory loss||Worries about memory loss; family and friends notice lapses||May have little or no awareness of cognitive problems|
Adapted from Rabins, P. Memory. In The Johns Hopkins White Papers . Baltimore: Johns Hopkins University, 2007.
Several recent NIA-supported studies have taken a close look at MCI, and the findings are helping us understand what really happens in the brain when memory loss occurs.
Scientists have learned that MCI has several subtypes. In the most common subtype, memory loss is the most prominent feature (other types of MCI feature other types of cognitive problems).
"We call the condition of memory impairment alone amnestic mild cognitive impairment (aMCI)," says Dr. Ronald Petersen, director of the NIA-funded Mayo Alzheimer's Disease Research Center , "Researchers are particularly interested in the brain changes and memory loss of aMCI, because more people with this condition go on to develop AD than do people without aMCI. We don't yet know for sure whether aMCI is a separate condition or a transitional stage between normal aging and AD."
Dr. Petersen notes that, until recently, only a handful of studies had been published describing the actual damage to brain tissue that occurs in aMCI. "Our knowledge has been limited because very few studies were done on people who died with this form of MCI," he says.
In one of these studies, begun in 1988, Dr. Petersen and his colleagues followed a group of more than 270 people diagnosed with aMCI who participated in the Mayo Clinic Alzheimer's Disease Patient Registry. These volunteers were diagnosed with aMCI based on their concerns about memory loss, the results of memory and cognitive function tests, and the facts that they were able to carry out normal activities of daily living and did not have other signs of dementia.
Two recent studies with the same group of Mayo Clinic volunteers have significantly increased our knowledge about the damage to brain tissue in aMCI.
During the first study , 15 participants with aMCI died. After their deaths, the research team compared the brain tissue of these participants with that of 28 people who were cognitively healthy at the time of death and 28 people who had AD at the time of death. In the people with aMCI, the researchers found damage to brain tissue that suggested an intermediate stage. This damage included many neurofibrillary tangles in the temporal lobes, which could account for the memory loss, and some amyloid plaques in the cortex, but not enough to constitute a definition of AD.
Amyloid plaques and neurofibrillary tangles are considered two hallmarks of AD. The brain tissue of the healthy participants had few plaques and tangles, but plaques and tangles were very common in the brain tissue of those with AD.
In the second study , the Mayo research team examined the brain tissue of 34 people who were followed from their diagnosis of aMCI through dementia to death. In slightly more than 70 percent of the cases, those with aMCI went on to develop AD that could be confirmed by damage to brain tissue. In the remainder, dementia had another cause.
"These findings suggest that we can't definitively say that someone with aMCI has early AD," says Dr. Petersen. "aMCI may indeed be a transitional state. Following up these findings in other studies will help us learn more about aMCI and may even point to some useful therapeutic targets to prevent the possible development of AD."
Why do recent memories disappear first in AD?
Multiple areas of the brain are responsible for memory-associated functions such as processing information and creating and recalling memories. Deep within the brain, new memories are formed and stored in the hippocampus and associated structures. Then, in a process called consolidation, memories are stored for the long-term throughout the cortex, the outermost layer of the brain.
Recent memory is affected first in AD because the hippocampus and nearby entorhinal cortex are the first brain areas damaged by the disease. As a result, a person with AD may remember every detail of a childhood event but be unable to recall something that happened yesterday or an hour ago. This pattern of damage also can lead to confusion about the past and present. A person may think a long-deceased relative is still alive, for example, because his or her memory of the relative from long ago is stronger than the memory of the relative's more recent death.
As AD spreads throughout the brain, it damages other structures involved in memory functions. Eventually, the disease destroys a person's ability to remember anything of the past or present, or even memories so ingrained as a loved one's name or face.
One of the great puzzles about aMCI is why, sometimes but not always, it leads to AD. Do people with this kind of memory loss who do not eventually develop AD have some special protective characteristics? Two research groups recently explored an approach for identifying individuals who are likely to progress from normal age-related forgetfulness to aMCI and from aMCI to AD.
As part of NIA's Alzheimer's Disease Cooperative Study , Dr. Charles DeCarli and colleagues  at the University of California at Davis used magnetic resonance imaging (MRI) to measure how shrinkage (atrophy) of the temporal lobes of 187 study participants with MCI predicted development of AD over an 18-month period. The temporal lobes, which run along the sides of the brain, deal with the formation and storage of memories.
Moderate to marked atrophy, based on simple visual inspection of MRI, was associated with a more than twofold increase in the likelihood of progressing to AD. This was true even after the scientists took into account other factors, including age, education, sex, and cognitive abilities at the beginning of the study.
"These findings suggest that using MRI during evaluations for aMCI may help us identify people at higher risk of progressing to AD. Knowing this may help us start treatments earlier, when they may be most effective," says Dr. DeCarli.
In the second study , Dr. D. P. Devanand and other researchers at Columbia University also used MRI to track atrophy of the hippocampus and entorhinal cortex, two temporal lobe structures critical to the formation and storage of memories. The researchers followed 139 people with aMCI and 63 healthy people for an average of 5 years and found that smaller hippocampal and entorhinal cortex volumes predict shorter progression times from aMCI to AD.
Dr. Devanand explains that combining these MRI findings with a person's age and results of cognitive function tests allowed improved accuracy in predicting progression from MCI to AD. "In the future, this improved accuracy may be useful for monitoring patients in clinical settings," he notes.
We often take memory for granted. Its importance in how we define ourselves as human beings and as individuals becomes very evident when it begins to disappear. AD researchers are working on many fronts to learn more about what happens when memory loss occurs. Their findings may help in the development of drug and non-drug therapies to help people hold on to their memories for as long as possible.
For more information on memory loss and dementia, see Findings from Memory Research Continue to Fascinate  (Connections volume 15, issue 3). The following free publications, available from the Alzheimer's Disease Education and Referral (ADEAR) Center, also provide more information about memory loss, MCI, and AD: