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Published on: October 14, 2016
by Kristina Fiori for MedPage Today:
They were once dismissed as anxieties of the “worried well” — but now that subjective memory complaints may be a valuable tool for recruiting patients into disease-modifying drug trials, researchers are beginning to pay closer attention to them.
As those trials get underway, researchers are becoming convinced that these concerns — the feeling that your memory isn’t quite what it used to be — may indeed portend worse things to come.
“A number of years ago, these concerns were dismissed, but now they’re being taken more seriously,” said Zaven Khachaturian, PhD, editor of Alzheimer’s & Dementia, the journal of the Alzheimer’s Association. “Many trials are trying to recruit people as early in the disease process as possible, so this could be an important vehicle.”
Ron Petersen, MD, PhD, of the Mayo Clinic, a leading Alzheimer’s researcher, said subjective memory complaints are “a very important topic, especially as the field moves towards earlier and earlier intervention.”
And Frank Jessen, MD, of University Hospital Cologne in Germany, who has been at the forefront of trying to better define this potential early stage of cognitive impairment, said trial enrollment is “one reason” for doing so.
The research into subjective memory complaints is in relatively early stages; experts are still trying to flesh out a definition, and there’s no consensus on terminology. Other names appearing in the literature include age-associated memory impairment, subjective cognitive decline, and subjective cognitive impairment, all of which describe similar early-stage processes and could help define exactly what is meant by “preclinical Alzheimer’s disease.”
It’s also unclear how many people with these complaints will progress to definite cognitive impairment and, ultimately, dementia. And questions remain as to who will be more likely to transition from simple complaints to early signs of cognitive decline.
But researchers running Alzheimer’s clinical trials that require participants to enter at earlier stages of the disease are eager to put subjective memory concerns to work for them.
Memory Complaints in Enrollment
Dorene Rentz, PsyD, of Brigham & Women’s Hospital in Boston, who is involved in the A4 trial that’s testing the anti-amyloid agent solanezumab on people who have amyloid on brain scans but no symptoms, said she is advising primary care doctors to take those memory concerns seriously.
“In the past, when people have complained about their memory, we’ve thought of them as the worried well,” Rentz told MedPage Today. “But they may have an awareness of very early changes. That could ultimately lead to enrollment in a prevention trial.”
The A4 study must screen 10,000 people in order to enroll the 1,000 who meet the criteria for the three-year study. To get those numbers, the study team has worked with registries like the Global Alzheimer’s Platform and has done standard advertising. They have also appeared in a segment with Maria Shriver on NBC’s “Today Show.”
Garnering the interest of patients with a family history of the disease is one way to recruit for trials; another is to get primary care doctors thinking differently about those subjective memory complaints.
“Maybe primary care physicians don’t know that there are prevention trials, or that changes occur 15 to 20 years before a diagnosis,” Rentz said.
Eli Lilly, which makes solanezumab and has a financial stake in the imaging agent used to detect amyloid on brain scans, launched the TimeHidesAlz campaign that aims to get doctors thinking about their patients’ cognition. While it doesn’t mention subjective memory complaints, the campaign recommends screening with the Mini-Cog or the General Practitioner Assessment of Cognition.
There are no treatments that these physicians could offer patients who screen positive for cognitive dysfunction. Doctors could, however, refer them to a clinical trial — which may enrich for amyloid-positive scans needed for the A4 study.
When it comes to interpreting memory complaints, many questions remain.
First, why the focus on memory? While many domains of cognition are affected by dementia, memory is often the most noticeable, experts say.
“Memory is the most common symptom that people get concerned about,” Petersen said. “Sometimes people will call it a memory problem when it is actually some other cognitive domain. Memory is the colloquial term for all of that.”
What, then, do such complaints actually reveal about dementia risk?
A 2010 study by Barry Reisberg, MD, of New York University, and colleagues found that patients with subjective cognitive impairment — that was the outcome they used — had a 4.5-fold greater risk for cognitive decline over 7 years compared with those who didn’t have subjective complaints.
Erin Abner, PhD, of the University of Kentucky, conducted the PREADVISE study, which looked at a subpopulation of men age 62 and older who had been enrolled in the prostate cancer prevention trial SELECT. When these men were asked about their memory complaints, more than half of them said yes, their memory had changed over time, Abner said.
Those who reported memory changes at baseline had an 80% increase in the likelihood of dementia over 6 years compared with those who didn’t report memory concerns.
But Abner cautioned that, for most of the men who report these concerns, “nothing happens. They don’t develop dementia, they don’t develop mild cognitive impairment. They just report that their memory changed and most of them will go on that way until they pass away.”
Petersen noted from his studies that among people over age 70, about 80% report that their memory isn’t what it used to be. But of those, a smaller proportion are actually concerned about those changes, and it’s unclear which of those reports actually represent the “earliest manifestation of cognitive decline,” he said.
Determining how frequently those complaints develop into something worse has been a challenge, as has figuring out which patients are more likely to progress. Several papers have shown that patients with the APOE4 gene who complain about memory problems have worse decline over time than noncarriers.
But other clues are harder to come by. There’s also the possibility that memory concerns could have nothing to do with dementia at all. Rather, they could be due to a host of factors, including depression, anxiety, metabolic problems, or vascular problems, as well as medications or side effects.
“What we have to do as field is figure out what complaints are meaningful, and which are just ‘worried well’ or perhaps related to medications or side effects or some other other medical condition they have,” Abner said.
Researchers have been working on establishing standard criteria for understanding this early, preclinical phase of disease, and the model furthest along uses the term subjective cognitive decline, or SCD.
Jessen chairs the Alzheimer’s Association’s professional interest group in SCD, and he and an international group of experts published a guidance on SCD in 2014. This classification captures many forms of cognitive impairment, such as attention, judgment, and decision-making, as well as memory.
Petersen says SCD is a good start, but this very early stage of impairment needs more standardization and more objective ways to measure it.
Not long ago, the same was true for mild cognitive impairment (MCI), which is now a disease stage included in the National Institute on Aging/Alzheimer’s Association guidelines, released in 2011. Petersen and colleagues introduced the concept of MCI in 1999.
The NIA/AA guideline outlined three disease stages of Alzheimer’s disease: preclinical, MCI, and Alzheimer’s dementia. The preclinical stage suggests that amyloid buildup and other early nerve cell changes may be in process, but significant clinical symptoms aren’t yet evident. Biomarkers such as amyloid in cerebrospinal fluid or on PET scans were still being developed and not ready for use by clinicians, according to the guidance.
How SCD — or a different terminology that may ultimately prevail — fits into that preclinical stage remains to be seen. Jessen noted that the “SCD-plus” criteria takes into account biomarkers “which should enrich SCD for preclinical AD” — including having subjective memory complaints, the APOE4 genotype, biomarker evidence for Alzheimer’s, and being over age 60.
However, “these criteria still need validation,” Jessen said.
He added that SCD is “increasingly used” and that a follow-up paper on how to implement SCD in studies has been accepted by Alzheimer’s & Dementia and will publish in the following months.
Standardization has become more critical as clinical trials conducted in the later stages of Alzheimer’s disease have proved disappointing. Finding the right patients at the right stage of the disease — long before it starts killing off neurons — is a critical next step, researchers say.
But whether enrolling earlier-stage patients will lead to a successful drug remains to be seen.
Right now, the best patients with memory complaints can be offered is enrollment into a clinical trial, for a drug that may or may not work.
“This could be an important vehicle to give primary care physicians a way to handle [memory concerns], and to give researchers the tools to refer patients into clinical trials,” Khachaturian said. “But I raise the caution that we do not know enough about [subjective memory concerns] and we don’t have enough consensus to give doctors definitive instructions on how to diagnose this and what to tell their patients.”
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