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Subjective Cognitive Decline May Be the Earliest Clinical Indicator of Alzheimer's Disease

Five studies reported at AAIC 2013 point to subjective concern about memory as a potential early warning sign of cognitive impairment and Alzheimer's

BOSTON, July 17, 2013 – 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:

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.

About the Alzheimer's Association

The Alzheimer's Association is the world's leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research; to provide and enhance care and support for all affected; and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800.272.3900.

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Proposal ID: 38262
Topic: Diagnosis and Prognosis
Presentation: Featured Research Session, Thursday, July 18, 2013
Session Title: Subjective Cognitive Decline (SCD) in Preclinical Alzheimer's Disease

A Conceptual Framework of Subjective Cognitive Decline (SCD) in preclinical Alzheimer's Disease (FRS #1)

Presenting Author: Frank Jessen, University Hospital, Bonn, Germany, and German Center for Neurodegenerative Diseases (DZNE).

Background: Biomarker-based early recognition research in AD is moving to the preclinical stage. One challenge is identifying individuals, which are at increased risk of having preclinical AD and of progressing to dementia. Growing evidence suggest that the self-experienced decline in cognitive performance in elderly subjects with otherwise normal performance on cognitive tests (subjective cognitive decline, SCD) is a risk factor for future AD dementia and indicates an increased likelihood for the presence of preclinical AD in individuals. A major limitation for further refinement of SCD as an indicator of preclinical AD is the lack of a common framework and common research standards on this topic.

Methods: In November 2012, the SCD-Initiative (SCD-I) was founded to develop a common framework on the research on SCD in preclinical AD. The working group includes main authors of the recently presented criteria of preclinical AD, MCI due AD and prodromal AD as well a main investigators of prominent biomarker initiatives (ADNI, AIBL, DESCRIPA, Dementia Competence Network) and large population-based cohort studies. In a number of e-mail discussions, the common research framework was developed.

Results: The group concludes that the currently available data is too limited and too heterogeneous to define SCD in preclinical AD as a clear-cut entity and highlights the need for intensified research on this topic. The SCD-I created a research framework which defines terminology and provides guidance on the coding of key features of SCD in research projects. Thus, it allows the integration of a wide variety of research approaches in different settings and cohorts and achieves comparability across different studies. The core components of the framework will be presented in the session.

Conclusions: The research framework sets the stage for intensified and comparable research on SCD in preclinical AD. It provides the basis to investigate characteristics and dynamics of the earliest symptomatic stage of AD and to eventually evaluate the usefulness of SCD as a clinical sign of the biomarker based diagnosis of preclinical AD.

* * *

Subjective Cognitive Concerns as an Early Indicator of AD Pathology (FRS #4)

Rebecca Amariglio:, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston.

Background: Although self-reported cognitive concerns (SCC) have previously been dismissed as a sign of the "worried well," there is emerging evidence to suggest that SCC may herald initial cognitive decrements at the stage of preclinical Alzheimer's disease (AD). Recent preliminary data from our own group and others suggests that specific SCC may in fact indicate early awareness prior to objective impairment on standardized tests and may be associated with evidence of early pathology on AD biomarkers.

Methods: Multimodality studies relating SCC with AD biomarker evidence in clinically normal (CN) individuals have revealed associations between decreased gray matter volume and cerebral hypo metabolism in parietotemporal and parahippocampal regions, suggesting that SCC may coincide with early pathological changes. More recently, the relationship between Ab burden, using 11 C PiB-PET amyloid imaging, and SCC has been investigated.

Results: We, as well as another research group, have reported a significant relationship between SCC and cortical PiB binding in CN individuals. In particular, individuals who reported worse memory relative to their peers were more likely to have increased PiB retention. Additionally, a relationship between an individual's self-report of decline on tasks that required higher-level cognitive processing (i.e., prioritizing and organizing tasks) was associated with amyloid burden. By contrast, informant report was not associated with increased PiB binding.

Conclusions: Accumulating evidence suggests SCC may be an early indicator of AD pathology. The strength of the relationship between SCC and amyloid burden appears to depend on the types of questions used to assess subjective changes. Going forward, SCC that probe a range of cognitive functions that are framed relative to a reference group (self and/or age-matched peers) with consideration of temporal course may be important in understanding relationships to early AD pathology. Findings will provide critical information for future secondary prevention trials that will be seeking subjects at the preclinical stage of AD.

 

Proposal ID: 38959
Topic: Diagnosis and Prognosis
Subtopic: Clinical
Presentation: Poster session, Wednesday, July 17, 2013, 11:45 a.m. ET

Subjective memory symptoms, verbal memory decline and the ApoEe4 allele

Presenting Author: Cécilia Samieri, Research Center Inserm U897 "Epidemiology and Biostatistics," Bordeaux, France.

Background: Although ApoE4 is the strongest genetic predictor of dementia and cognitive decline, it only explains a fraction of risk, and there is variability in the rate of cognitive decline among carriers. Identifying carriers at highest risk of cognitive decline will be important, both in conducting research to evaluate interventions to reduce dementia and cognitive decline and, eventually, to administer interventions. Subjective memory complaints may represent a simple method to differentiate risk of cognitive decline by ApoE4 carrier status.

Methods: We examined the relationship of a subjective memory symptom score, based on self-report of seven specific subjective memory symptoms, to verbal memory decline over six years among ApoE4 carriers and non-carriers from the Nurses' Health Study. We included 975 ApoE4 carriers and 3,265 ApoE4 non-carriers, aged =70 years, who underwent cognitive testing by telephone four times over six years, beginning in 1995-2001. The primary outcome was a composite score of verbal memory, averaging together results from four tests of word list and paragraph recall.

Results: In both ApoE4 carriers and non-carriers, increasing number of subjective memory symptoms at baseline was related to worse baseline verbal memory (P for trend<0.001 in both groups) and to higher rates of verbal memory decline over time (P for trend = 0.006 and <0.001 in ApoE4 carriers and non-carriers, respectively), after adjustment for age and depression. However, in ApoE4 carriers, a single subjective memory symptom was sufficient to predict verbal memory change, while in ApoE4 non-carriers, =3 symptoms were necessary to predict memory decline. For example, mean differences in slopes of verbal memory change (95% CI) for one symptom, two symptoms, three symptoms and four to seven symptoms = -0.05 (-0.08, -0.01), -0.05 (0.09, -0.01), -0.06 (-0.10, -0.01) and -0.06 (-0.11, 0.002) standard units, respectively, in ApoE4 carriers, and -0.01 (-0.02, 0.01), -0.01 (-0.03, 0.01), -0.03 (-0.05, -0.003) and -0.10 (-0.13, -0.06) standard units in ApoE4 non-carriers.

Conclusions: ApoE4 carriers with self-assessed memory symptoms have accelerated verbal memory decline and may therefore constitute an interesting and easily identified target population for research on early interventions.

Proposal ID: 39158
Topic: Diagnosis and Prognosis
Subtopic: Clinical
Presentation: Poster session, Wednesday, July 17, 2013, 11:45 a.m. ET

Self-reported memory decline predicts mild cognitive impairment and dementia

Presenting Author: Richard Kryscio, Richard Kryscio*1, Erin Abner1, David Fardo2, Peter Nelson1, Gregory Jicha1, Charles Smith3, Gregory Cooper4, Allison Caban-Holt4, Linda Van Eldik1, Frederick Schmitt1 1University of Kentucky, Lexington, Kentucky, United States; 2College of Public Health, Lexington, Kentucky, United States; 3UK MRISC, Lexington, Kentucky, United States; 4UKMC, Lexington, Kentucky, United States.

Background: There is considerable interest in the role of subjective (self-reported) memory complaints and their association with the transition to clinical MCI and/or dementia.

Methods: We examined the role of subjective memory complaints as predictors of serious cognitive impairment in subjects (n = 539) enrolled in the Biologically Resilient Adults in Neurological Studies at the University of Kentucky. Each participant was asked if they perceived any changes in memory since the last visit. A Cox model was used to determine if the reported subjective memory complaint was related to two endpoints: age at dementia or age at conversion to either mild cognitive impairment (MCI) or dementia. Each model was adjusted for gender, APOE 4 carrier status, family history, low educational attainment and baseline age, presence of hypertension and smoking.

Results: The mean age at baseline was 73.2 ± 7.4 years and participants received a mean of 10.3 ± 4.1 cognitive assessments. For the endpoint of the age at which either a dementia or MCI occurred, 72.5 percent of 160 converters reported a change in memory before the transition compared to 48.8 percent of the non-converters (P < 0.0001). This response remained significant when adjusted for other predictors in the Cox model (hazard rate or HR = 1.9, 95 percent CI: 1.3 – 2.8). For the endpoint of age at which dementia occurred, 80.2 percent of the 91 converters reported a change in memory compared to 51.1 percent of the non-converters (P < 0.0001). This result also remained significant when adjusted in the Cox model: HR = 2.6 (95 percent CI: 1.5-4.6). The time interval between the age of conversion and age at which the memory change was first recorded was 6.1 ± 3.9 (6.5 ± 3.9) years for the onset of MCI/dementia (dementia).

Conclusions: A subjective memory complaint, as measured by a self-reported memory change, is predictive of transition to a seriously impaired cognitive state with the subjective memory complaint occurring approximately six years in advance of an overt dementia diagnosis.

Proposal ID: 38988
Topic: Diagnosis and Prognosis
Subtopic: Clinical; Normal cognitive aging
Presentation: Poster session, Wednesday, July 17, 2013, 11:45 a.m. ET

Subjective memory impairment in healthy elderly specifically predicts decline in episodic memory over eight years

Presenting Author: Alexander Koppara, Alexander Koppara*1, Steffi Riedel-Heller2, Siegfried Weyerer3, Horst Bickel4, Michael Pentzek5, Martin Scherer6, Wolfgang Maier7, Frank Jessen7,8, Michael Wagner7 1Rheinische-Friedrich-Wilhelms University Bonn, Bonn, Germany; 2University of Leipzig, Leipzig, California, Germany; 3Central Institute for Mental Health, Mannheim, Germany; 4Technical University, Munich, Germany; 5University of Düsseldorf, Düsseldorf, Germany; 6University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 7University of Bonn, Bonn, Germany; 8German Center for Neurodegenerative Diseases (DZNE).

Background: Subjective memory impairment (SMI) is considered a risk factor for conversion into dementia. This longitudinal study investigates the predictive effects of SMI with concerns and without concerns on objective cognitive decline.

Methods: Data from six waves of the primary care-based, prospective longitudinal AgeCoDe study was used. Subjects included in this analysis were not demented and not MCI at baseline (N=2319, mean age 79,7 years at baseline, 64 percent female, mean MMSE 27,95) and followed up over 95 months (five intervals of approx. 18 months). Latent growth curve models (LGCM) with FIML were calculated in Mplus to estimate the trajectories of decline in CERAD immediate recall, CERAD delayed recall, SISCO working memory and MMSE. Group contrasts for slope and intercept of the growth curves were calculated between SMI without concerns at baseline (n=961), SMI with concerns at baseline (n=369) and subjects without SMI (n=989), adjusting for age, gender, ApoE4-genotype and education.

Results: At baseline, groups differed with regard to delayed memory performance, but not for working memory or MMSE. In delayed memory, Controls and SMI group differed(p=0.003), as well as Controls and SMI group with concerns (p=0.000). Slope of delayed memory decline was steeper in SMI (p= 0.003) and SMI with concerns (p= 0.000) as compared to controls. Also, decline in SMI with concerns was steeper than in SMI (p=0.028). Almost identical group differences were obtained for the intercept and slope of immediate memory. In contrast, the time course of working memory or MMSE was not predicted by the presence of SMI at baseline. Subsequential analysis with reduced waves revealed the group differences for memory slopes became significant only after at least six years of observation were covered. We estimated memory trajectories in the three groups began to diverge two to four years before baseline assessment. Results remained largely identical when subjects who became demented over the track of the study were excluded from analysis.

Conclusions: SMI is an important predictor of memory decline in old age. Longitudinal follow-up reveals that working memory is not impaired in SMI subjects; however, delayed memory is strongly affected. In delayed memory, SMI subjects with concerns declined stronger than subjects without concerns.

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Make history at AAIC 2013 • Boston, MA • July 13-18, 2013