A patient comes in to the doctor’s office because she can no longer recall cousins’ names, or once got lost in the local mall. Should she, and her doctor, be concerned? Physicians have often dismissed the memory-related complaints of otherwise healthy thinkers as the hypochondria of the “worried well.” But feeling that one’s thought processes are waning could be a sign of something real, according to research presented at the Alzheimer’s Association International Conference (AAIC), held July 13-18 in Boston. “The purely subjective feeling of cognitive decline may be the first sign of future Alzheimer’s disease,” said Frank Jessen of the German Center for Neurodegenerative Diseases in Bonn.

The idea has deep roots but is now growing with a new collaboration to develop standard definitions and approaches to measure subjective cognitive decline (SCD). Researchers at AAIC presented preliminary findings on SCD and suggested that testing for it might identify people at early risk for dementia, who would be ideal candidates for prevention trials. The phenomenon was profiled recently in the New York Times.

Ronald Petersen of the Mayo Clinic in Rochester, Minnesota, who moderated an AAIC press conference on SCD, commented that the new focus on subjective decline fits a trend in which researchers are looking at earlier and earlier stages of disease. A decade ago many scientists refocused their interests from dementia to mild cognitive impairment, and now are extending it to even earlier signs. This push has been spurred in part by disappointing clinical trial results and the suggestion that the earliest-stage patients might benefit from treatment, suggested Andrew Saykin of Indiana University in Indianapolis in an interview with Alzforum.

“This is not a new concept,” commented Rebecca Amariglio of Brigham and Women’s Hospital, but “it has gotten increasing attention.” She noted SCD was included in 1980s descriptions of cognitive decline and dementia (Reisberg et al., 1982, Reisberg, 1986), and in diagnostic criteria for MCI (Petersen et al., 1999). In 2005, researchers published the account of a chess player who reported his own memory loss two years before he fulfilled MCI criteria. The man noticed the decline because he could only plan two moves ahead in the game instead of his usual four (Archer et al., 2005). And an imaging study in 2006 suggested people with SCD have brain atrophy comparable to those with MCI (see Alzforum News story on Saykin et al., 2006).

Defining the Problem
Now that many scientists agree SCD is worthy of study, how should they go about it? SCD is difficult to capture objectively in similar ways that MCI was a decade ago, Petersen noted. The researchers who presented at AAIC all used somewhat different criteria and even names for the condition, such as “subjective memory impairment,” “self-reported cognitive concerns,” “subjective memory complaints” and “subjective cognitive concerns.” “We cannot compare data across studies because everyone is talking about their own concepts,” said Jessen. “There is no consensus of what we mean when we use these terms.” Jessen presented the work of the Subjective Cognitive Decline Initiative, an international working group of scientists who convened in November of 2012 to better describe this condition and propose standard research practices. Jessen expects the group to publish their consensus soon, and offered a preview at the meeting.

Defining SCD might seem like a simple task, Jessen said, but was far from it. Even deciding on the term “subjective cognitive decline” was tricky. The group concluded that the condition must be based on an individual’s own feelings, not on objective cognitive tests. They chose the broad category of cognitive problems to include functions other than memory. And they picked the word decline to indicate a worsening of thought processes. Notably, the label of SCD applies only to people with normal scores on cognitive tests. It does not include anyone with MCI or dementia, nor people whose cognitive problems can be explained by another neurological condition, medications, or drug use. AD biomarkers may be present, or not. SCD is not a requirement for a diagnosis of preclinical AD, nor is it expected to be present in all cases of preclinical AD.

The working group concluded that currently available data are too limited to define specific features of SCD, but they offered guidelines for future attempts to clarify the issue. Specifically, SCD studies should take note of several features of the decline, such as where someone first reports their concerns. For example, people who are specifically asked about memory loss in a research study questionnaire might be different from those who bring up SCD on their own. Another important feature could be undue worry, because some researchers suspect that may mean a greater likelihood of later MCI or dementia. Finally, the initiative recommends that researchers should record whether the decline is in memory or other domains, the age of onset, whether friends or relatives have noticed problems in the individual, and ApoE4 genotype if possible.

While no one can be certain how often SCD will turn into AD, the group suggested several features that might increase the odds. Problems in memory, onset in people over 60, worries about the issue, and feelings that one’s age-matched peers struggle less could be signs of impending AD. Confirmation of decline by an objective informant was another criterion that could indicate increased dementia risk, but this was controversial among the working group, Jessen said. Further indications of preclinical AD could come from the ApoE4 genotype or AD biomarkers such as cerebrospinal fluid tau or amyloid, hippocampal atrophy, amyloid or glucose utilization scans. The list continues to evolve, Jessen said.

Early Data
Presenters stressed that not everyone who thinks they are getting forgetful has started down the road to AD. “As people age, everybody gets a little forgetful, a little slower,” commented Petersen, who is also part of the SCD initiative. While the precise risk that SCD confers remains uncertain, Richard Kryscio, of the University of Kentucky in Lexington, has started to quantify it. In a longitudinal study with yearly follow-up, his group asked 531 people, average age 73, “Have you noticed a change in your memory since you last visited us?” Of these, 296 said yes, an average of eight years after they had entered the study. Of those, 36 went on to develop mild MCI, and 78 progressed to dementia. It took six or more years for the initial, subjective complaint to turn into a medically diagnosed condition. Another 127 of the 296 SCD participants died without developing noticeable cognitive impairment. Kryscio concluded that someone who believes their memory is failing is 2.8 times more likely to become impaired or demented in the future than a person who doesn’t. However, he noted that SCD “is not a guarantee that you will end up with dementia.”

Participants in Kryscio’s research donate their brains to the study. He has seen that people who report SCD and progress to MCI or dementia have severe AD-related plaques and tangles on autopsy, whereas people who reported SCD but never reached an impaired state had moderate AD pathology. This ties in with current thinking in the field that cognitively normal people who have brain amyloid as seen by PET imaging are in the asymptomatic stage of the disease (see Alzforum News story on Jack et al., 2013).

Kryscio’s findings paralleled those SCD initiative member Amariglio. Her group asked 131 cognitively healthy people, aged 65 or older, about their memory function and correlated responses with brain scans carried out with the amyloid marker Pittsburgh compound B. Amariglio reported that the worse someone reported their memory to be, the more amyloid had built up in their brain.

Carriers of the AD risk gene ApoE4, in particular, have reason to be concerned about memory decline. Cécilia Samieri of the Research Center Inserm in Bordeaux, France, examined subjective cognitive concerns as a potential marker for progression in ApoE4 carriers in a nearly 4,000-person subset of the long-running Nurses’ Health Study. The participants underwent cognitive testing four times over a six-year period from 1995 to 2001. They received ApoE4 screening but were unaware of their status at the time.

ApoE4 carriers made up nearly one quarter of the sample. They were more likely than non-carriers to report seven different concerns: recent memory changes, trouble remembering a short list, difficulty recalling things from one second to the next, trouble recalling recent events, struggling to understand verbal instructions, difficulty following conversations or television plots, and difficulty getting around familiar neighborhoods. These problem areas included in the Nurses’ Health Study predate the move to form an official SCD definition. The researchers found that memory decline occurred in ApoE4 carriers who made even one of the seven types of subjective complaint at the study outset. In contrast, decline occurred in non-carriers who made three or more kinds of complaint. Samieri concluded that subjective concerns were a stronger predictor of decline in ApoE4 carriers than non-carriers.

What kind of decline might await people with SCD? Alexander Koppara of the University of Bonn examined changes in episodic and working memory in 2,319 people, aged about 80 years, who were cognitively normal at the study’s outset. Over the following eight years, people with subjective memory impairment saw their episodic memory decline faster than those who perceived no cognitive problems. Those who were specifically concerned about their memory saw the steepest decline. However, working memory was not impaired, at least over the eight years of this study. Koppara suggested that subjective memory impairment and concerns could be an early indicator for AD, and useful for identifying subjects for prevention trials. This fits with literature reports that episodic memory deficits can occur early on, while working memory problems occur later in AD (Weintraub et al., 2012).

Applying the Concept
Petersen noted that, based on the prevalence of brain amyloid in people in their 70s, the upcoming Anti-Amyloid Treatment in Asymptomatic AD (A4) will have to screen three times the number of subjects the trial calls for in order to find people who meet the trial’s inclusion criteria (see Alzforum news story). An SCD questionnaire to stratify people for their likelihood of having brain amyloid buildup, could reduce costs in similar studies, he suggested. Reisa Sperling of Brigham and Women’s Hospital, Boston, told Alzforum that A4 researchers will assess the presence of SCD in enrollees and whether SCD increases their chance of having a positive amyloid scan, but will not treat those participants as a separate cohort. “About 30 percent of older adults are amyloid positive. Maybe we can get that up to 35 percent if we enrich on subjective complaints or family history,” she speculated in an email to Alzforum. “This will be an important learning piece in our screening process.”

The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging is already analyzing whether subjective memory complaint in people who test in the normal range on cognitive tests correlate with biomarkers or have predictive value.

Similarly, the Alzheimer’s Disease Neuroimaging Initiative (ADNI2) will be adding a new cohort of people with “subjective memory complaints,” wrote Michael Weiner of the University of California, San Francisco, in an email to Alzforum. These people were previously left out of ADNI because their complaints made them not “normal,” but they fell short of criteria for MCI. The Initiative expects to enroll 60-80 people in this category, according to Weiner. People with SCD will likely be enthusiastic about joining a study, noted Saykin, who is also part of the SCDI working group. “They are really concerned about what is happening,” he said. ADNI is now reaching out to people who tried to sign up but were eliminated due to cognitive concerns, inviting them to join the new cohort, Petersen told Alzforum. He expects this group will be heterogeneous but might contain a subset who are truly sensing impending cognitive decline.

The rising interest in SCD means physicians should no longer dismiss the concerns of older people who think their memories are faltering. However, there are many other potential causes of memory loss besides impending dementia, commented both Jessen and Creighton Phelps of the National Institute on Aging in Bethesda, Maryland. For example, attention deficit and visual or hearing problems frequently masquerade as memory impairment that interferes with the daily routine, such as following a conversation or a television program, Phelps noted. Moreover, certain other neurological conditions and medications can interfere with normal memory. “You need to eliminate these other things first,” Phelps said.

Amariglio offered examples of normal memory problems during aging that should cause no undue anxiety—such as forgetting why you went into the garage, or struggling with people’s names. More worrisome symptoms might include getting lost in your hometown, struggling to recall the details of recent activities, or noticing a worse memory than others in the same age group. As Phelps put it, if you forget where you left your keys, that’s no big deal, but “if you cannot remember how to use them, it is a problem.”—Amber Dance.

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References

News Citations

  1. I Told You I Was Sick: Brain Atrophy Associated with Subclinical Memory Loss
  2. HAI Chicago: PIB in Healthy People

Paper Citations

  1. . The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry. 1982 Sep;139(9):1136-9. PubMed.
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  1. Alzforum news story

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  1. New York Times
  2. Nurses’ Health Study

Further Reading

Papers

  1. . AD dementia risk in late MCI, in early MCI, and in subjective memory impairment. Alzheimers Dement. 2013 Jan 30; PubMed.
  2. . Cerebrospinal fluid Aβ42 is the best predictor of clinical progression in patients with subjective complaints. Alzheimers Dement. 2012 Dec 8; PubMed.
  3. . Subjective cognitive complaints and amyloid burden in cognitively normal older individuals. Neuropsychologia. 2012 Oct;50(12):2880-6. PubMed.
  4. . Glucose metabolism, gray matter structure, and memory decline in subjective memory impairment. Neurology. 2012 Sep 25;79(13):1332-9. PubMed.
  5. . Subjective Cognitive Complaint Is Associated with Increased Amyloid Burden in Cognitively Normal Individuals. Human Amyloid Imaging Abstract. 2012 Jan 1;
  6. . Subjective cognition and amyloid deposition imaging: a Pittsburgh Compound B positron emission tomography study in normal elderly individuals. Arch Neurol. 2012 Feb;69(2):223-9. PubMed.
  7. . Evidence of neuronal compensation during episodic memory in subjective memory impairment. Arch Gen Psychiatry. 2011 Aug;68(8):845-52. PubMed.
  8. . Interaction effects of subjective memory impairment and ApoE4 genotype on episodic memory and hippocampal volume. Psychol Med. 2011 Sep;41(9):1997-2006. PubMed.
  9. . Prediction of dementia by subjective memory impairment: effects of severity and temporal association with cognitive impairment. Arch Gen Psychiatry. 2010 Apr;67(4):414-22. PubMed.