Memory Test Mirrors Brain Pathology Found in Alzheimer’s Trial

February 23, 2022—(BRONX, NY)—In a large study of cognitively normal older adults, results from a simple memory test correlated closely with the early presence of toxic brain proteins that appear to cause Alzheimer’s disease. The test, developed by researchers at Albert Einstein College of Medicine, could potentially identify people in the very first stages of Alzheimer’s—before dementia is diagnosable—and help in selecting those especially likely to benefit from therapies. The findings were published today in the journal Neurology.

Ellen Grober, Ph.D.

Ellen Grober, Ph.D.

“We used to think that cognitive impairment developed long after toxic proteins, such as beta amyloid and tau, became well established in the brain,” said Ellen Grober, Ph.D., clinical professor in the Saul R. Korey Department of Neurology at Einstein and corresponding author of the Neurology study. “Results from this research add to the accumulating evidence that cognitive impairment, if measured properly, can be detected very early in the disease process.”

The Stages of Objective Memory Impairment (SOMI) system is based on the Einstein-developed Free and Cued Selective Reminding Test (FCSRT). The test begins with a study phase in which people are shown 4 cards, each containing drawings of 4 items, and are asked to identify the item belonging to a particular category (e.g., participants would name the item “grapes” after being asked to identify a “fruit.”). Then comes the test phase, in which participants are asked to recall the items; if they have trouble, they’re presented with the category cues used in the study phase to help prompt their recall.

Based on their recall, people are assigned to one of 5 stages, ranging from SOMI-0 (no memory impairment) to SOMI-4 (memory impairment compatible with dementia). The SOMI system’s ability to distinguish memory retrieval impairments from those involving memory storage may make the SOMI system superior to other memory tests at predicting mild cognitive impairment as well as dementia. Typically, impaired memory retrieval characterizes preclinical Alzheimer’s disease, while problems with memory storage that can’t be corrected with cueing predominate in the later stages.

The SOMI system was used to screen 4,484 possible participants (average age 71.3) in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study, an ongoing clinical trial of an Alzheimer’s drug. All participants were diagnosed as cognitively normal (i.e., showed no signs of Alzheimer’s disease). They then underwent positron emission tomography (PET) brain scans to detect beta amyloid, a protein whose build-up may cause Alzheimer’s.

Results from this research add to the accumulating evidence that cognitive impairment, if measured properly, can be detected very early in the disease process.

Ellen Grober, Ph.D.

Those individuals (1,262) with significant brain amyloid are now enrolled in the A4 clinical trial, which is evaluating a drug designed to slow memory and cognitive decline by targeting beta amyloid. In addition to PET scanning, the trial participants also underwent magnetic resonance imaging to measure the volume of the hippocampus and other brain regions, since brain atrophy is associated with Alzheimer’s disease.

The presence of Alzheimer’s pathology in the brains of participants was found to track closely with memory impairment based on SOMI testing. Among all trial participants, individuals classified in higher SOMI stages had significantly higher amyloid levels than those in lower SOMI stages. More specifically, the SOMI-3 and -4 subgroups had significantly higher levels of amyloid than SOMI-0 and SOMI-1 subgroups. In addition, the SOMI-4, -3, and -2 subgroups had smaller hippocampal volumes than the SOMI-0 and -1 subgroups. And even though all initial participants were carefully chosen to rule out anyone with impaired cognition (thinking ability), 511 of the 4,484 people screened (11.4%) were classified in SOMI-3 or -4, indicating that SOMI testing can detect significant memory impairment among people who ostensibly were cognitively normal.

“These findings support the notion that the SOMI system can improve our ability to detect cognitive decline during the preclinical stages of Alzheimer’s disease,” said Dr. Grober. “That should be especially helpful in recruiting appropriate participants for clinical trials evaluating therapies for preventing Alzheimer’s dementia from developing.”

The SOMI system was developed by Dr. Grober and by study co-authors Richard Lipton, M.D., the Edwin S. Lowe Chair in Neurology at Einstein and vice-chair of the Saul R. Korey Department of Neurology at Einstein and Montefiore, and Amy E. Veroff, Ph.D. The original version of the FCSRT did not include immediate recall and was described in Buschke, H. (1984) “Cued recall in Amnesia” Journal of Clinical Neuropsychology, 6, 433-440. The present version of FCSRT, the International Research Version, includes immediate recall as described in Grober, E and Buschke, H. (1987), “Genuine memory deficits in dementia” Developmental Neuropsychology, 3 (1), 13-36.

Ali Ezzati, M.D., is also an Einstein author. Other authors are: Reisa A. Sperling, M.D., Kathryn V. Papp, Ph.D., Keith A. Johnson, M.D., and Dorene M. Rentz, Ph.D., all with the Harvard Aging Brain Study at Massachusetts General Hospital/Harvard Medical School; and Paul S. Aisen, M.D., University of Southern California, San Diego. Dr. Grober receives small royalties for commercial use of the FCSRT.