Susan Jeffrey

July 29, 2013

BOSTON, Massachusetts — If a patient is reporting cognitive problems, doctors should listen. New evidence from a broad spectrum of studies suggests that subjective cognitive impairment reported by patients, particularly if they express concern about the deficits, is strongly correlated with subsequent Alzheimer's disease risk.

Finding patients in the very earliest stages of cognitive decline by using a clinical marker such as this one and correlating it to the development of AD over time could represent an enormous opportunity, both to enrich clinical trials and, when the time is right, to offer treatment with some hope of changing the outcome for these patients, experts say.

"The whole field has moved from the dementia stage of a decade or so ago to the mild cognitive impairment (MCI) stage, where people are partially symptomatic, and now we're talking about a pre-MCI stage," said Ron Petersen, MD, PhD, from the Mayo Clinic in Rochester, Minnesota, and a member of the board of directors for the Alzheimer's Association, who moderated a press conference on this topic here. "That is, people are clinically normal when they're evaluated, but they're expressing some concern over a change in their cognitive function, usually memory, but not always."

Dr. Ron Petersen

As we age, many of us get forgetful, Dr. Petersen said, but the challenge is to determine how subjective memory symptoms are related to future risk for MCI or dementia. "When should somebody be concerned that this is not just incidental forgetfulness of aging, but may be a harbinger of something more serious?" he said. "You clearly don't want to worry everybody who's aging; at the same time, I think the public and clinicians need to be aware that individuals who have these concerns might in fact be telling us something that we need to understand and use in our clinical context."

At the Alzheimer's Association International Conference (AAIC) 2013, a variety of papers showed a relationship between subjective memory symptoms and clinical progression to MCI and dementia, as well as with biomarkers already related to Alzheimer's disease. Further, a consensus document that aims to further define the concept was also presented.

"I think one take-away message about this is in spite of a variety of clinical contexts, subjects coming from different sources, international subjects, different measuring instruments, there still is a kernel of something coming out at the end of the day, that what people are perceiving early on, when they're clinically and cognitively normal, may have implications for the future," Dr. Petersen said.

One immediate application is finding patients who are candidates for prevention trials, he said. For example, in the fall of 2013, the Anti-Amyloid Treatment of Asymptomatic AD (A4) trial, sponsored by the National Institute on Aging, will begin enrolling people who are clinically normal but amyloid positive on brain positron emission tomography (PET) imaging. Because the prevalence of amyloid imaging positivity in normal elderly adults is about 30%, he points out, a large number of patients will need to undergo amyloid imaging in order to find suitable candidates.

"If an instrument like this construct [SCI] proved useful at stratifying subjects for their risk of being amyloid positive, that would greatly reduce the cost of these things," Dr. Petersen pointed out.

Another application would be to potentially supplement the recently published National Institute on Aging/Alzheimer's Association criteria for preclinical Alzheimer's disease, he added. The criteria include stage 1, asymptomatic cerebral amyloidosis; stage 2, amyloid plus downstream neurodegeneration; and stage 3, amyloidosis and neurodegeneration plus what is described as "subtle cognitive/behavioural decline."

"That's probably been the slipperiest part of the criteria right now because what does that mean?" Dr. Petersen said. "Wouldn't it be interesting of some index of subjective cognitive concern fulfilled that criteria, such that amyloid positive, neurodegeneration, and a subjective cognitive concern index really characterized people who are at the highest risk of progressing."

Subjective Cognitive Decline Initiative

Already, a new research initiative is underway to define this new concept.

Frank Jessen, PhD, from the University of Bonn, Germany, and the German Center for Neurodegenerative Diseases (DZNE), is leading an international project, the Subjective Cognitive Decline Initiative. Begun in November 2012, the initiative aims to conceptualize the idea of subjective cognitive impairment and then set the research agenda to explore it further. He outlined progress in a presentation here.

Dr. Frank Jessen

"This may seem simple, but it was not that simple in the consensus process to get some basic definitions," Dr. Jessen said wryly. Some of the major points of contention including questions of what constitutes "subjectivity," whether they should consider subjective "decline" vs "impairment," the role of any informant — which would be inherently not subjective.

One of the major difficulties was overcoming the view of some researchers that when a patient expresses concern about cognitive problems, the problem is most likely depression and not a subjective memory concern at all, Dr. Jessen told Medscape Medical News.

The international working group for the initiative includes the main authors of the recent diagnostic criteria for Alzheimer's disease, MCI due to AD, and prodromal AD, as well as the main investigators of ongoing biomarker initiatives, including ADNI (Alzheimer's Disease Neuroimaging Initiative), AIBL (Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing), DESCRIPA (Development of Screening guidelines and CRIteria for Predementia Alzheimer’s disease), and the Dementia Competence Network, from the United States, Europe, and Australia.

After discussion, the group settled on the following definition: "A subjectively experienced persistent continuous cognitive decline, or decline in cognitive capacity, compared with a previously normal state, which is not related to an acute event. Performance on standard tests used to define, for example, mild cognitive impairment, is normal."

They elected to use "decline" instead of "impairment," implying a change from a previous state, but that could not yet be described as an impairment, Dr. Jessen noted. In other papers presented here on this same topic, for example, this condition was variously called "subjective cognitive impairment," "subjective memory complaints," and "subjective cognitive decline" (SCD).

SCD is excluded if the patient already meets criteria for MCI or has any other obvious explanation, including depression, other neurologic disorders, use of medications that interfere with cognition, or substance abuse.

They also developed a list of features that should be made clear in studies of SCD and systematically coded to ensure the comparability of data across studies, including whether the patient referred himself or herself for evaluation in a memory clinic, for example, or was identified during population screening, or whether the memory decline is associated with concern on the part of the patient.

Finally, they identified many other features that they feel, with the current information, are most likely to indicate that SCD is a precursor to AD, features they have called "SCD+": among them, more recent onset of memory impairment (ie, development within the last 5 years), patient age older than 60 years, particular concerns, and feeling that one's performance is worse than that of others of the same age (for these we have data, and others are confirmation by an informant, the presence of the APOE ε4 genotype, and biomarkers for AD.

SCI and Amyloid Imaging

Other papers presented here linked subjective cognitive symptoms to biomarkers of AD, and subsequent development of MCI and dementia.

In one, researchers led by Rebecca Amariglio, PhD, a clinical neuropsychologist from Brigham and Women's Hospital and Massachusetts General Hospital and an instructor in neurology at Harvard Medical School, Boston, correlated subjective cognitive symptoms among 189 clinically normal individuals over age 65 with amyloid burden on 11C Pittsburgh compound PET (PiB-PET) brain imaging.

Dr. Rebecca Amariglio

"What we found is that the greater amount of concern that somebody had about their memory in their everyday life was related to a greater amount of amyloid buildup in their brains," Dr. Amariglio told reporters here.

In addition, they correlated self-reports of decline on tasks requiring higher-level cognitive processing, such as prioritizing and organizing tasks, and again found that those reporting decline on these tasks had higher amyloid burden on PiB-PET imaging. By contrast, informant reports by friends or family of cognitive concerns in the patient were not associated at all with PiB binding on PET scanning.

When they stratified by education and reading ability, the investigators found that patients with both high and low education and reading abilities reported similar concerns about subjective decline, "but we found the concerns may be a stronger indicator of amyloid build-up for the high education, high reading ability group."

Nurses' Health Study

A separate study used data from the well-known Nurses' Health Study to examine subjective memory symptoms, verbal memory decline, and the presence of the APOE ε4 allele, the strongest genetic predictor of AD risk.

But although it is a strong predictor, the rate of cognitive decline among APOE ε4 carriers still varies, researchers point out.

To see whether subjective cognitive symptoms may be a simple way to identify those most at risk for cognitive decline among ε4 carriers, Cecilia Samieri, PhD, from the Research Center INSERM, in Bordeaux, France, with colleagues at Brigham and Women's Hospital and Harvard Medical School, looked at the relationship between self-report of 7 specific memory symptoms and verbal memory decline in ε4 carriers and noncarriers over 6 years of follow-up in a cognitive subcohort of the National Health Service. They included 975 carriers and 3265 noncarriers of the ε4 allele, aged 70 years or younger. All underwent cognitive testing by telephone on 4 occasions over the 6 years beginning in 1995 to 2001.

Dr. Cecilia Samieri

Compared with noncarriers, carriers were similar in age and the rate of depression, but they were more likely to report subjective cognitive concerns, such as a recent change in memory (59.4% vs 53.8%) or remembering things from 1 second to the next (26.3% vs 24.0%). Expressed as the number of symptoms, ε4 carriers were more likely to have 1 or more concerns than were noncarriers.

With follow-up over 6 years, the study showed that cognitive symptoms at baseline predicted the slope of change in verbal memory in women carrying the ε4 allele, such that those with 1 or more symptoms had a significantly greater slope of verbal memory change than those without such symptoms. For noncarriers, it required 3 or more subjective memory symptoms at baseline before these symptoms were significantly related to change in the slope of verbal memory change.

"What we found was that the highest slope of verbal memory change for having 1 complaint or more was equivalent in APOE ε4 carriers to the decline seen in a woman who was 10 years older in age having no complaint," Dr. Samieri noted. "In contrast, in noncarriers, the significant slope we found for the bottom 3 cognitive complaints or more was equivalent to being 3 years older in age, but without complaint, so again, the association was stronger in carriers."

Subjective memory concerns, then, may be a way to identify those at risk for cognitive decline, particularly within APOE ε4 carriers who are most at risk, she concluded.

Self-Reported Decline Predicts MCI, Dementia

A separate analysis of a large group of participants enrolled in a study called the Biologically Resilient Adults in Neurological Studies (BRAiNS) at the University of Kentucky asked about subjective memory symptoms and followed the first 531 participants. Each person in the BRAiNS cohort agrees to annual cognitive assessment and to donate their brain upon death, said lead author Richard J. Kryscio, PhD, professor in the Department of Statistics, College of Arts and Sciences, and chair, biostatistics, College of Public Health at the University of Kentucky, Lexington.

Dr. Richard J. Kryscio

At each assessment, participants are asked about subjective memory symptoms: simply, whether they've had any change in their memory since the last visit, Dr. Kryscio noted. Of the 531 participants in this analysis, 296 (55.7%) have answered "yes" at any point, on average 8.3 years after beginning the study.

Risk for conversion to MCI or dementia was increased for participants reporting subjective memory symptoms, the researchers noted. Participants who said they had subjective memory symptoms were 2.8 times more likely to convert to MCI or dementia than those reporting no such symptoms.

"But on the positive side of course, just because you said you had a complaint, there's absolutely no guarantee that you'll have MCI or dementia," he noted. About one third of those with such symptoms, 127 participants, died without ever developing a serious impairment.

In terms of timing, it took an average of 8 years for participants to express subjective memory decline, and another 9 years, on average, to develop serious impairment, "unless they were on the fast-track, in which case they went immediately from subjective memory complaints into dementia," he noted. Again, though, there was wide variability between individuals.

In terms of factors associated with progression with subjective symptoms, they found, for example, that overweight people, or those with a positive family history, had decreased time to subjective memory problems by 2 years and that smoking decreased the transition from subjective symptoms to MCI by 3 years. Female patients receiving hormone replacement took longer to transition from subjective symptoms to dementia.

Of interest, 253 members of the cohort have come now to autopsy. Neuropathology confirmed that those with no subjective memory symptoms and no MCI showed low numbers of neuritic plaques and neurofibrillary tangles, and those with subjective symptoms and MCI had high levels of plaques and tangles, as expected.

"What was interesting for us is the middle cohort," Dr. Kryscio. Those with subjective symptoms but no MCI were a "mix," he noted, some with low plaques and tangles, some with high pathology. "So we feel there is something to the subjective memory complaints, but at the same time, it's not a guarantee that you'll end up with dementia or even dementia-like pathology."

Table. Neuropathology With and Without Subjective Memory Symptoms and/or Mild Cognitive Impairment

Memory Symptoms Neuritic Plaques Neurofibrillary Tangles
No SMC, no MCI Low Low
SMC, no MCI Moderate* Moderate*
SMC, MCI High** High**

*P < .05 when compared with "low" in 7 of 9 brain regions examined.

**P < 0.001 when compared with "moderate" in 8 of 9 brain regions examined.

Subjective Symptoms and Episodic Memory

Finally, researchers led by Alexander Koppara, DiplPsych, a clinical neuropsychologist from the University of Bonn, Germany, described their work following healthy elderly participants with subjective memory impairment for decline in episodic memory over time.

Their project, called AgeCoDe, is a primary care–based prospective longitudinal study tracking the trajectory of 2319 cognitively healthy individuals over about 8 years of follow-up. Participants were on average 80 years of age at baseline and were assessed every 18 months.

Dr. Alexander Koppara

The investigators mapped the trajectory of decline for a battery of cognitive tests, including CERAD (Consortium to Establish a Registry for Alzheimer's Disease) immediate recall, CERAD delayed recall, verbal working memory, and the Mini-Mental State Examination (MMSE) score, adjusting for age, sex, the APOE ε4 genotype, and education for 3 groups: those with subjective memory impairment and some concern about those symptoms at baseline (SMI+C), those with SMI but no particular concern about that (SMI-C), and those without any subjective concerns, that is, healthy controls.

At baseline, the SMI+C and SMI-C groups both differed significantly from healthy controls on delayed memory performance, Dr. Koppara reported. The rate of change in this measure of delayed memory was also steeper for those with SMI than for controls, but even more so for those with SMI and concerns than for those with no concerns (P = .028).

Group differences became significant only after 6 years of follow-up, he noted. "Extrapolating the data, we saw that the memory trajectories probably began to diverge 2 to 4 years before the baseline assessment," he said. The effect remained the same when they excluded those who became demented over the course of the study.

However, change in the MMSE and working memory was not predicted by the presence of SMI at baseline, he said.

"The take-home message of this analysis is that SMI in old age really represents slight deficits in episodic memory, and predicts incipient memory decline," Dr. Koppara said. Those with concerns about their SMI declined faster than those without concerns. "SMI and memory concerns may constitute risk factors for and early indicators of Alzheimer's dementia."

Maria Carrillo, PhD, vice-president of medical and scientific relations for the Alzheimer's Association, told Medscape Medical News that this new concept of subjective cognitive impairment, being viewed as a kind of pre-MCI, is an exciting opportunity.

The evidence presented here represent "hugely robust studies" examining subjective cognitive decline, including 2 correlating SCI with the presence of APOE ε4 risk allele and with amyloid on brain PET imaging, she pointed out.

"What that says is there is something to it when someone thinks they have something wrong with their memory even early on," Dr. Carrillo said. "We have to find a way to define this concept, so that ultimately we can use it to our advantage in the clinic when we are ready with the therapeutics."

The SCD-I is funded by the University of Bonn–DZNE. Dr. Amariglio's study was funded by the Alzheimer's Association. Dr. Samieri's study was supported by the National Institutes of Health/National Cancer Institute, Fulbright Research Scholar award. Dr. Kryscio's study was funded by the National Institute on Aging. Dr. Koppara's study was funded by the Federal Ministry of Education and Research–BMBF.

Alzheimer's Association International Conference (AAIC) 2013. Abstracts F5-01-01, F5-01-04, P4-198, P4-178, P4-206. Presented July 17 and 18, 2013.

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