Subjective Cognitive Decline May Be The Earliest Clinical Indicator Of Alzheimer's Disease

There is increasing evidence that subjective cognitive decline (SCD) — the self-reported perception of memory or cognition problems — is a potentially valid early clinical marker of brain and cognitive changes that may indicate Alzheimer's disease, according to five research studies reported at the Alzheimer's Association International Conference® 2013 (AAIC® 2013) in Boston.
"The emerging field of SCD is of great interest in the Alzheimer's community, particularly among clinicians who are looking for new and reliable ways of identifying people at risk for Alzheimer's at the earliest possible stage," said Maria Carrillo, Ph.D., Alzheimer's Association vice president of medical and scientific relations.
"Early detection is extremely important for the success of therapy trials, where earlier intervention may be the key to producing positive treatment and prevention results. In addition, to obtain the greatest effect from newly approved therapies, and even lifestyle changes, we will want to administer those therapies as early as possible in the course of the disease. SCD may prove a valuable clinical complement to other early detection methods that employ genetics and biomarkers," Carrillo said.
Ronald Petersen, Ph.D., M.D., a member of the Alzheimer's Association board of directors, noted another possible benefit in establishing SCD as a clinical marker for Alzheimer's: insight into the proposed NIA/Alzheimer's Association diagnostic criteria, which include a preclinical (or pre-symptomatic) "stage" of the disease. "A preclinical signal such as SCD, besides functioning as a practical early warning system for Alzheimer's, could also help expand the concept of preclinical Alzheimer's," Petersen said.
International initiative establishes a research agenda for subjective cognitive decline
Recent data from several research groups have provided evidence that self-experienced decline in cognitive performance in elderly people, even those with normal performance on cognitive tests, is a risk factor for future dementia and Alzheimer's disease, and may indicate an increased likelihood for the presence of preclinical Alzheimer's. However, research on SCD is limited by lack of a common research framework, which prevents comparability across studies and hinders deeper research into the topic.
In response, in November 2012, Frank Jessen, Ph.D., of the University of Bonn, Germany, led an international group of Alzheimer's researchers to form the Subjective Cognitive Decline Initiative (SCD-I). The working group includes the primary authors of the recently presented diagnostic criteria as well the lead investigators of prominent biomarker initiatives (ADNI, AIBL, DESCRIPA, Dementia Competence Network) and large population-based cohort studies. The group concluded that, "The currently available data is too limited and too heterogeneous to define SCD… as a clear-cut entity and highlights the need for intensified research on this topic."
The initial goal of the SCD-I then became to develop and disseminate a research framework for SCD, with a focus on SCD during the preclinical stage of Alzheimer's.
"This framework provides guidelines on terminology and assessment of SCD in various research settings," said Jessen. "It also describes key features that increase the likelihood that SCD in an individual is related to preclinical Alzheimer's."
Jessen says the new research framework "will greatly support research on the earliest stage of Alzheimer's."
Subjective concerns about memory are linked with Alzheimer's-associated brain changes
Subjective concerns about decline in memory and cognitive ability may be associated with early pathological changes in Alzheimer's disease biomarkers, according to research reported at AAIC 2013 by Rebecca Amariglio, Ph.D., of Brigham and Women's Hospital and Massachusetts General Hospital, and colleagues.
At AAIC 2013, Amariglio reported that results from her research team (and another group) show a significant relationship between self-reported cognitive concerns and evidence of buildup of beta-amyloid, a protein implicated in the development of Alzheimer's disease, as revealed by PET scans of 131 people (mean age 73.5 years, 53% women) who are otherwise clinically normal with no history of serious neurological and psychiatric illness. In particular, individuals who reported worse memory relative to their peers were more likely to have increased beta-amyloid levels, as were individuals who reported declines on tasks that required higher-level cognitive processing, such as prioritizing and organizing tasks.
Amariglio noted that the relationship between self-reported cognitive problems and evidence of Alzheimer's pathology is stronger in people with higher levels of education and occupational attainment, who may notice cognitive changes more readily.
"We suggest that individuals can be accurate judges of their own cognitive decline at the earliest stages of Alzheimer's disease," Amariglio said. She anticipates that this line of research "will provide critical information for future Alzheimer's prevention trials that will be seeking participants at the preclinical stage of Alzheimer's."
Link between subjective memory concerns and memory decline is strong in ApoE4 carriers
A subjective concern about memory could be a marker of subsequent decline in objectively measured memory, especially among carriers of ApoE4, the strongest known genetic risk factor for Alzheimer's disease, according to a study by Cecilia Samieri, Ph.D., of Research Center Inserm U897 in Bordeaux, France, and colleagues at the Nurses' Health Study and Brigham and Women's Hospital.
The researchers conducted telephone interviews with 3,861 nurses, age 70 years and older, from the Nurses' Health Study (which is a large cohort of older U.S. nurses) in whom APOE status had been assessed. The study included 889 ApoE4 carriers and 2,972 non-carriers. At the beginning of the study, participants were asked about seven specific memory symptoms. They were then given a battery of objective memory tests four times over six years, from 1995 to 2001. When the researchers analyzed the relationship between self-reported memory concerns and objective test performance, they found that:
  • In ApoE4 carriers, concern about a single memory symptom predicted verbal memory decline over the next six years.
  • Among non-ApoE4 carriers, concern about three or more symptoms was associated with memory decline.
The researchers also found that the overall strength of the relationship between self-reported memory problems and objective memory decline was stronger among ApoE4 carriers. "Subjective memory symptoms seemed to be a better predictor of subsequent cognitive decline in ApoE4 carriers than in non-carriers, likely because there is a larger degree of true memory decline in carriers," said Samieri.
She cautioned that the study results were preliminary and need confirmation in additional studies. Should the findings be confirmed, Samieri said, "The initial value would be in research, as a way of identifying potential target populations for therapy trials. ApoE4 carriers with self-assessed memory symptoms have accelerated verbal memory decline and may therefore be an interesting and easily identified target population for research on early interventions."
Self-reported memory changes linked with almost double the risk of MCI or dementia
Older people who reported a change in memory since their last annual cognitive assessment were almost twice as likely to be diagnosed with mild cognitive impairment (MCI) or dementia during follow-up than those who did not report such a change, according to a research report from Richard J. Kryscio, Ph.D., professor, Department of Statistics, College of Arts and Sciences, and Chair, Biostatistics, College of Public Health at the University of Kentucky, at AAIC 2013.
Kryscio and colleagues studied the records of 531 individuals with an average age of 73 enrolled in the Biologically Resilient Adults in Neurological Studies who underwent annual cognitive assessments for an average of 10 years. Before each exam, participants were asked if they had noticed any changes in their memory since their last visit. More than half (55.7 percent) of the participants noted a change in memory during the course of the study.
Those who had noticed changes were almost twice as likely to be diagnosed with MCI or dementia in follow-up visits as those who had not. Initial memory complaints occurred an average of six years before dementia diagnosis and nine years before a diagnosis of MCI.
Self-reported memory changes were associated with a family history of dementia, female gender, estrogen use and being overweight. The researchers found that family history of dementia was associated with an increased risk of MCI, while smoking was associated with a decreased time to MCI diagnosis from nine to six years. Women who used estrogen had an increased risk of dementia, although estrogen was associated with an increased time to dementia diagnosis from six to 15 years.
"Although not all older persons with subjective memory complaint proceed to a serious cognitive impairment, our data indicate that these self-reported concerns should be taken very seriously by clinicians," said Kryscio. "In terms of research, the identification of specific risk factors coupled with a memory complaint could help identify a high-risk group that might help inform the design of future prevention trials."
Subjective memory impairment predicts decline of episodic memory
The subjective perception of memory impairment in older adults was associated with a subsequent significant decline in episodic memory — recollection of specific events in the past — but not with a decline in working memory or overall cognitive status. The results are reported in a study by Alexander Koppara, Dipl.Psych., of the University of Bonn, and colleagues.
The researchers studied data collected from 2,230 cognitively normal older adults with an average age of 80 who were enrolled in the prospective, longitudinal, German AgeCoDe study and assessed every 18 months for an average of eight years. At the beginning of the study, participants were tested for memory and cognitive abilities and asked, "Do you feel like your memory is becoming worse?"
The 993 participants who answered "yes" were identified as having subjective memory impairment (SMI). Another group of 372 who answered "yes" and, in addition, expressed concern about memory loss were classified as SMI-plus-concern. At baseline, both SMI and SMI-plus-concern participants performed worse on a word-recall test than non-SMI participants.
After eight years, the SMI group showed significant decline in episodic memory compared with the non-SMI group; the SMI-plus-concern group showed even greater decline than the SMI group. The differences remained after the researchers adjusted for age, gender, ApoE4 status and education. There was no significant difference in working memory or overall cognitive status between the three groups.
"We show here that SMI is a predictor of episodic memory decline," said Koppara. "The assessment of subjective cognitive decline could help identify subjects for dementia prevention trials."
About AAIC
The Alzheimer's Association International Conference (AAIC) is the world's largest conference of its kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders.  As a part of the Alzheimer's Association's research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.

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