27 Sep 2014

A perceived slip in memory could signal future cognitive decline, suggests a paper in the October 7 Neurology. Researchers led by Richard Kryscio, University of Kentucky, Lexington, found that ostensibly normal volunteers who reported a subjective memory complaint were nearly three times likelier than non-complainers to meet criteria for mild cognitive impairment (MCI) or dementia over the next 10 years. They also had more amyloid in their brains. Alzforum reported on these findings when they were presented at a conference last year (see Jul 2013 conference story). The study was covered by CBS, CNN, and The Los Angeles Times. “This is one of the few studies that chronicles the transition from subjective memory complaint to impairment,” said Frank Jessen, German Center for Neurodegenerative Diseases, Bonn.

Subjective cognitive decline, also known as subjective memory complaint (SMC), was recently defined as “self-experienced persistent decline in cognitive capacity in comparison with a previously normal status and unrelated to an acute event” (see Jessen et al., 2014). This can be rooted in depression, lack of vitamin B12, certain medications, or normal aging processes, but it may also reflect early Alzheimer’s disease. “Not everyone who complains develops an impairment,” Kryscio told Alzforum. His group wanted to determine how many people progress from SMC to MCI or dementia, what they term an "impaired state" in this study, and how fast, and how that correlated with AD pathology.

In 1989, Kryscio and colleagues began studying 531 cognitively healthy people, average age 73, from the Biologically Resilient Adults in Neurological Studies (BRAiNS) cohort, a longitudinal observational study and brain donation program at the University of Kentucky. Yearly psychological tests assessed memory, language, executive and visuospatial function, and whether the subject had progressed to MCI or dementia. Before each round of testing, researchers asked the participants if they had noticed any change in memory since their last visit. If they answered yes, they were tagged as reporting an SMC. They donated their brain after death to be examined for signs of plaques or neurofibrillary tangles, the two hallmarks of Alzheimer’s pathology.

Of 296 people who declared an SMC, 114 progressed to MCI or dementia over about nine or 12 years, respectively. Having an ApoE4 allele doubled a person’s risk of becoming impaired, and smokers progressed to MCI almost three years faster. Interestingly, women on hormone replacement therapy progressed more slowly. Research conflicts about whether supplemental estrogen protects from dementia or enhances risk (see Nov 2011 news story). Because the time to impairment varied depending on environmental factors, the study suggests that interventions could target the disease during this period, the authors wrote. Jessen agreed. “I predict these will be the subjects we treat in the future,” he told Alzforum.

Almost half of the original participants have come to autopsy. About a quarter of those who died without SMC or impairment had moderate to severe Aβ pathology in the brain, as did roughly a third of those who declared an SMC but did not progress to MCI or dementia. Of the 50 with SMC who became impaired, three-quarters accumulated abundant plaques and tangles. That amyloid built up in the SMC group but neurofibrillary tangles only appeared at impairment suggests that amyloid has an effect on cognition, said Jessen.

The researchers have not scanned the living volunteers to see if they have brain amyloid because PET amyloid ligands were not available when this study started, said Kryscio. He has no plans to add it at this point.

The study agrees with several others that use postmortem evidence or PET to correlate SMC with elevated amyloid build-up (see Barnes et al., 2006; Perrotin et al., 2012; Amariglio et al., 2012). It also jibes with a recent meta-analysis that found older people with SMC are twice as likely to develop dementia as people with no complaint (see Mitchell et al., 2014).

Researchers have yet to agree on a standard way to measure SMC, said Ron Petersen, Mayo Clinic, Rochester, Minnesota. The single survey question used in the Kryscio study captures some element of subjective concern but is quite basic, he said. Predicting whether an SMC could lead to dementia may depend on the type of memory change, suggested one study (see Amariglio et al., 2011). Results imply that getting lost in familiar places or being unable to follow a group conversation predict future cognitive decline better than forgetting things from one second to the next.—Gwyneth Dickey Zakaib

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References

News Citations

1. Are Subtle Memory Concerns a Sign of Future Dementia? 31 Jul 2013
2. Hormone Replacement Therapy Latest Entry to AlzRisk Database 3 Nov 2011

Paper Citations

1. Jessen F, Amariglio RE, van Boxtel M, Breteler M, Ceccaldi M, Chételat G, Dubois B, Dufouil C, Ellis KA, van der Flier WM, Glodzik L, van Harten AC, de Leon MJ, McHugh P, Mielke MM, Molinuevo JL, Mosconi L, Osorio RS, Perrotin A, Petersen RC, Rabin LA, Rami L, Reisberg B, Rentz DM, Sachdev PS, de la Sayette V, Saykin AJ, Scheltens P, Shulman MB, Slavin MJ, Sperling RA, Stewart R, Uspenskaya O, Vellas B, Visser PJ, Wagner M, Subjective Cognitive Decline Initiative (SCD-I) Working Group. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease. Alzheimers Dement. 2014 May 3; PubMed.
2. Barnes LL, Schneider JA, Boyle PA, Bienias JL, Bennett DA. Memory complaints are related to Alzheimer disease pathology in older persons. Neurology. 2006 Nov 14;67(9):1581-5. PubMed.
3. Perrotin A, Mormino EC, Madison CM, Hayenga AO, Jagust WJ. 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.
4. Amariglio RE, Becker JA, Carmasin J, Wadsworth LP, Lorius N, Sullivan C, Maye JE, Gidicsin C, Pepin LC, Sperling RA, Johnson KA, Rentz DM. Subjective cognitive complaints and amyloid burden in cognitively normal older individuals. Neuropsychologia. 2012 Oct;50(12):2880-6. PubMed.
5. Mitchell AJ, Beaumont H, Ferguson D, Yadegarfar M, Stubbs B. Risk of dementia and mild cognitive impairment in older people with subjective memory complaints: meta-analysis. Acta Psychiatr Scand. 2014 Dec;130(6):439-51. Epub 2014 Sep 13 PubMed.
6. Amariglio RE, Townsend MK, Grodstein F, Sperling RA, Rentz DM. Specific subjective memory complaints in older persons may indicate poor cognitive function. J Am Geriatr Soc. 2011 Sep;59(9):1612-7. Epub 2011 Sep 15 PubMed.

External Citations

1. CBS
2. CNN
3. The Los Angeles Times

Further Reading

No Available Further Reading