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Neuropsychological function in nondemented carriers of presenilin-1 mutations

From the Alzheimer's Disease Center (Dr. Ringman), Department of Neurology, and Department of Psychiatry and Biobehavioral Science (Dr. Fairbanks), University of California, Los Angeles, Department of Neurology (Dr. Varpetian), Keck School of Medicine, University of Southern California, and Rancho Los Amigos National Rehabilitation, Downey, CA, Departments of Neurology, Neurobiology, and Behavior (Dr. Kawas), Irvine Gillespie Neuroscience Research Facility, University of California, Irvine, and Department of Pathology and Laboratory Medicine (Drs. Murrell and Ghetti), Indianapolis, IN; and National Institute of Neurology and Neurosurgery (Drs. Diaz-Olavarrieta and Rodriguez, M. Chavez and F. Paz), Mexico City, Department of Neurology (Dr. Maldonado), Mexicali General Hospital, Mexico Madero, Mexicali, Neurosciences Department (Dr. Macias-Islas), CUCS, University of Guadalajara, and Department of Neurosciences (Dr. Macias-Islas), CUCS Beethoven, Jalisco, Mexico.

Address correspondence and reprint requests to Dr Ringman, Alzheimer's Disease Center, UCLA Department of Neurology, 710 Westwood Plaza, Suite 2-238, Los Angeles, CA 90095-1769; e-mail: jringman{at}mednet.ucla.edu

Background: Prospective and case-control studies have demonstrated that memory loss and executive dysfunction occur early in Alzheimer disease (AD).

Objective: To investigate these observations by the study of persons at risk for autosomal dominant forms of AD.

Methods: Neuropsychological and genetic tests were performed on 51 nondemented at-risk members of 10 Mexican families with two distinct presenilin-1 (PS1) mutations. Test scores were compared between PS1 mutation carriers (MCs; n = 30) and noncarriers (NCs; n = 21) by analyses of variance, co-varying for family and specific mutation. Regression analyses were performed, taking into account age relative to the median age at dementia diagnosis in the family (adjusted age), gender, Beck Depression Inventory (BDI) scores, education, and number of APOE 4 alleles. Subjects were divided into age tertiles and scores compared within these groups. Composite scores for Verbal Memory, Executive Function/Working Memory, Language, and Visuospatial Function were created, and these scores compared between MCs and NCs.

Results: MCs performed worse than NCs on the Mini-Mental State Examination, Trails Making Tests A and B, Delayed Recall of a 10-Word List, and Wechsler Adult Intelligence Scale WAIS Block Design. In multiple linear regression analyses, BDI score, gender, and number of APOE 4 alleles did not consistently affect test scores. The differences seen between MCs and NCs were due to differences in the oldest tertile. MCs had lower Visuospatial and Executive Function/Working Memory but not Verbal Memory or Language composite scores.

Conclusions: This study is consistent with findings in sporadic Alzheimer disease of early problems with memory, visuospatial function, and particularly with executive function in PS1 mutation carriers. Depression, gender, and presence of an APOE 4 allele did not demonstrate large influences on neuropsychological performance.

Supported by Alzheimer's Disease Research Center Grants AG-16570, AG-10133, AG-16573, and PHS R01 AG-21055 from the National Institute on Aging, an Alzheimer's Disease Research Center of California Grant, and the Sidell Kagan Foundation. Dr. Ringman is supported by Alzheimer's Association New Investigator Research Grant 01-2797 (PHS K08 AG-22228) and the Shirley and Jack Goldberg Trust.

Disclosure: The authors report no conflicts of interest.

Received January 9, 2005. Accepted in final form May 4, 2005.

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