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Memory impairment, executive dysfunction, and intellectual decline in preclinical Alzheimer's disease



In the Baltimore Longitudinal Study of Aging (BLSA), we examined the temporal unfolding of declining performance on tests of episodic memory (Free Recall on the Free and Cued Selective Reminding Test), executive function (Category Fluency, Letter Fluency, and Trails), and Verbal Intelligence (Nelson, 1982; American Version of the Nelson Adult Reading Test [AMNART]) before the diagnosis of dementia in 92 subjects with incident Alzheimer's disease (AD) followed for up to 15 years before diagnosis. To examine the preclinical onset of cognitive decline, we aligned subjects at the time of initial AD diagnosis and examined the cognitive course preceding diagnosis. We found that declines in performance on tests of episodic memory accelerated 7 years before diagnosis. Declining performance on tests of executive function accelerated 2–3 years before diagnosis, and verbal intelligence declined in close proximity to diagnosis. This cognitive profile is compatible with pathologic data suggesting that structures which mediate memory are affected earlier than frontal structures during the preclinical onset of AD. It also supports the view that VIQ as estimated by the AMNART does not decline during the preclinical onset of AD. (JINS, 2008, 14, 266–278.)Supported in part by grants AG017854, AG08325, AG03949, and AG16573 from the National Institutes of Health, and by the National Institute on Aging Intramural Research Program of the National Institutes of Health.

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Corresponding author

Correspondence and reprint requests to: Ellen Grober, Ph.D., Montefiore Medical Center, 111 East 210th Street, Bronx, New York 10467. E-mail:


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Albert, M., Moss, M., Tanzi, R., & Jones, K. (2001). Preclinical prediction of AD using neuropsychological tests. Journal of the International Neuropsychological Society, 7, 631639.
Almkvist, O., Fratiglioni, L., Aguero-Torres, H., Viitanen, M., & Backman, L. (1999). Cognitive support at episodic encoding and retrieval: Similar patterns of utilization in community-based samples of Alzheimer's disease and vascular dementia patients. Journal of Clinical and Experimental Neuropsychology, 21, 816830.
American Psychiatric Association. (1987). Diagnostic and Statistical Manual of Mental Disorders ( 3rd ed.). Washington, DC: American Psychiatric Association.
Backman, L., Jones, S., Berger, A.K., Laukka, E.J., & Small, B.J. (2004). Multiple cognitive deficits during the transition to Alzheimer's disease. Journal of Internal Medicine, 256, 195204.
Becker, J.T., Boller, F., Saxton, J., & McGoinigle-Gibson, K.L. (1987). Normal rates of forgetting of verbal and nonverbal material in Alzheimer's disease. Cortex, 23, 5972.
Blair, J. & Spreen, O. (1989). Predicting premorbid IQ: A revision of the National Adult Reading Test. The Clinical Neuropsychologist, 25, 119124.
Bozoki, A., Giordani, B., Heidebrink, J.L., Berent, S., & Foster, N.L. (2001). Mild cognitive impairments predict dementia in nondemented elderly patients with memory loss. Archives of Neurology, 58, 411416.
Braak, H. & Braak, E. (1991). Neuropathological staging of Alzheimer-related changes. Acta Neuropathologia, 82, 239259.
Buschke, H. (1973). Selective reminding for analysis of memory and learning. Journal of Verbal Learning and Verbal Behavior, 12, 543550.
Chen, P., Ratcliff, G., Belle, S.H., Cauley, J.A., DeKosky, S.T., & Ganguli, M. (2001). Patterns of cognitive decline in presymptomatic Alzheimer Disease. A prospective community study. Archives of General Psychiatry, 58, 853858.
Devanand, D.P., Folz, M., Gorlyn, M., Moeller, J., & Stern, Y. (1997). Questionable dementia: Clinical course and predictors of outcome. Journal of American Geriatric Society, 45, 321328.
Diggle, P.J., Liang, K., & Zeger, S.L. (1994). Analysis of Longitudinal Data. Oxford, UK: Oxford University Press.
Duff Canning, S.J., Leach, L., Stuss, D., Ngo, L., & Black, S.E. (2004). Diagnostic utility of abbreviated fluency measures in Alzheimer's disease and vascular dementia. Neurology, 62, 556562.
Elias, M.F., Beiser, A., Wolf, P.A., Au, K., White, R.F., & D'Agostino, R.B. (2000). The preclinical phase of Alzheimer's disease: A 22 year prospective study of the Framingham Cohort. Archives of Neurology, 5, 808813.
Fabrigoule, C., Rouch, I., Taberly, A., Letenneur, D., Commenges, D., Mazaux, J.M., Orgogozo, J.M., & Dartigues, J.F. (1998). Cognitive process in preclinical phase of dementia. Brain, 121, 135141.
Ferris, S.H., Aisen, P.S., Cummings, J., Galasko, D., Salmon, D.P., Schneider, L., Sano, M., Whitehouse, P.J., Edland, S., & Thal, L.J. (2006). ADCS prevention instrumentation project: Overview and initial results. Alzheimer's Disease and Related Disorders, 20, S109S123.
Gomez-Isla, T. & Hyman, B. (2003). Neuropathological changes in normal aging, mild cognitive impairment, and Alzheimer's disease. In R. Peterson (Ed.), Mild Cognitive Impairment: Aging to Alzheimer's Disease (pp. 191204). Oxford: Oxford University Press.
Graham, N.L., Emery, T., & Hodges, J.R. (2006). Distinctive cognitive profiles in Alzheimer's disease and subcortical vascular dementia. Journal of Neurology, Neurosurgery, and Psychiatry, 75, 6171.
Grober, E. & Buschke, H. (1987). Genuine memory deficits in dementia. Developmental Neuropsychology, 3, 1336.
Grober, E., Buschke, H., Crystal, H., Bang, S., & Dresner, R. (1988). Screening for dementia by memory testing. Neurology, 38, 900903.
Grober, E., Dickson, D.W., Sliwinski, M., Buschke, H., Katz, M., Crystal, H., & Lipton, R.B. (1999). Memory and mental status correlates of modified Braak staging. Neurobiology of Aging, 20, 573579.
Grober, E. & Kawas, C. (1997). Learning and retention in preclinical and early Alzheimer's Disease. Psychology and Aging, 12, 183188.
Grober, E., Hall, C., McGinn, M., Nicholls, T., Stanford, S., Ehrlich, A., Jacobs, L.G., Kennedy, G., Sanders, A., & Lipton, R.B. (2008). Neuropsychological strategies for detecting early dementia. Journal of the International Neuropsychological Society, 14, 113.
Grober, E., Lipton, R.B., Hall, C., & Crystal, H. (2000). Memory impairment on free and cued selective reminding predicts dementia. Neurology, 54, 827832.
Grober, E., Lipton, R.B., Katz, M., & Sliwinski, M. (1998). Demographic influences on free and cued selective reminding performance in older persons. Journal of Clinical and Experimental Neuropsychology, 20, 221226.
Grober, E., Merling, A., Heimlich, T., & Lipton, R.B. (1997). Comparison of selective reminding and free and cued selective reminding in the elderly. Journal of Clinical and Experimental Neuropscyhology, 19, 643654.
Grober, E. & Sliwinski, M. (1991). Development and validation of a model for estimating premorbid verbal intelligence in the elderly. Journal of Clinical and Experimental Neuropsychology, 13, 933949.
Hall, C.B., Derby, C., LeValley, A., Katz, M.J., Verghese, J., & Lipton, R.B. (2007). Education delays accelerated decline on a memory test in person who develop dementia. Neurology, 69, 16571664.
Hall, C.B., Lipton, R.B., Sliwinski, M., & Stewart, W.F. (2000). A change point model for estimating the onset of cognitive decline in preclinical Alzheimer's Disease. Statistics in Medicine, 19, 15551566.
Hall, C.B., Ying, J., Kuo, L., & Lipton, R.B. (2003). Bayesian and profile likelihood change point methods for modeling cognitive function over time. Computational Statistics and Data Analysis, 42, 91109.
Hall, C.B., Ying, J., Kuo, L., Sliwinski, M., Buschke, H., Katz, M., & Lipton, R.B. (2001). Estimation of bivariate measurements having different change points, with application to cognitive aging. Statistics in Medicine, 20, 36953714.
Herlitz, A., Hill, R.D., Fratiglioni, L., & Backman, L. (1995). Episodic memory and visuospatial ability in detecting and staging dementia in a community-based sample of very old adults. Journal of Gerontology: Medical Sciences, 50A, M107M113.
Ingles, J.L., Boulton, D.C., Fisk, J.D., & Rockwood, K. (2007). Preclinical vascular cognitive impairment and Alzheimer disease: Neuropsychological test performance 5 years before diagnosis. Stroke, 38, 11481153.
Ivnik, R.J., Smith, G.E., & Lucas, J.A. (1997). Free and cued selective reminding test: MOANS norms. Journal of Clinical and Experimental Neuropsychology, 19, 676691.
Jacobs, D.M., Sano, M., Dooneif, G., Marder, K., Bell, K.L., & Stern, Y. (1995). Neuropsychological detection and characterization of preclinical Alzheimer's disease. Neurology, 45, 957962.
Jorm, A.F. & Jolley, D. (1998). The incidence of dementia: A meta-analysis. Neurology, 51, 728733.
Kawas, C.H., Corrada, S., Brookmeyer, R., Morrison, A., Resnick, S.N., Zonderman, A.B., & Arenberg, D. (2003). Visual memory predicts Alzheimer's disease more than a decade before diagnosis. Neurology, 60, 10891093.
Kawas, C., Gray D., Brookmeyer, R., Fozard, J., & Zonderman, A. (2000). Age-specific incidence rates of Alzheimer's disease: The Baltimore Longitudinal Study of Aging. Neurology, 54, 20722077.
Laird, N.M. & Ware, J.H. (1982). Random effects models for longitudinal data. Biometrics, 38, 963974.
Larrieu, S., Letenneur, L., Orgogozo, J.M., Fabrigoule, C., Amieva, H., Le Carret, N., Barberger-Gateau, P., & Dartigues, J.F. (2002). Incidence and outcome of mild cognitive impairment in a population-based prospective cohort. Neurology, 59, 15941599.
Laukka, E.J., Jones, S., Small, B.J., Fratiglioni, L., & Backman, L. (2004). Similar patterns of cognitive deficits in the preclinical phases of vascular dementia and Alzheimer's disease. Journal of the International Neuropsychological Association, 10, 382391.
Lindenberger, U. & Reischies, F.M. (1999). Limits and potentials of intellectual functioning in old age. In P.B. Baltes & K.U. Mayer (Eds.), The Berlin Aging Study: Aging from 70 to 100 (pp. 329359). New York: Cambridge University Press.
Linn, R.T., Wolf, P.A., Bachman, D.L., Knoefel, J.E., Cogg, J.L., Belanger, A.J., Kaplan, E.G., & D'Agostino, R.B. (1995). The preclinical phase of probable Alzheimer's Disease. Archives of Neurology, 2, 485490.
Looi, J.C. & Sachdev, P.S. (1999). Differentiation of vascular dementia from AD on neuropsychological tests. Neurology, 53, 670678.
Masur, D.M., Sliwinski, M., Lipton, R.B., Blau, A.D., & Crystal, H.A. (1994). Neuropsychological prediction of dementia and the absence of dementia in healthy elderly persons. Neurology, 44, 14271432.
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, S. (1984). Clinical diagnosis of Alzheimer's Disease: Report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task force on Alzheimer's Disease. Neurology, 34, 939944.
Moss, M.B., Albert, M.S., Butters, N., & Payne, M. (1986). Differential patterns of memory loss among patients with Alzheimer's disease, Huntington's disease, and alcoholic Korsakoff's syndrome. Archives of Neurology, 43, 239246.
Nelson, H.E. (1982). National Adult Reading Test. Windsor, U.K: NFER-Nelson.
Nelson, H.E. & McKenna, P. (1975). The use of current reading ability in the assessment of dementia. British Journal of Social and Clinical Psychology, 14, 259267.
Petersen, R.C. (2004). Mild cognitive impairment as a diagnostic entity. Journal of Internal Medicine, 256, 183194.
Petersen, R.C., Smith, G.E., Ivnik, R., Tangalos, E.G., Schaid, D.J., Thibodeau, S.N., Kokmen, E., Waring, S.C., & Kurland, L.T. (1995). Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory-impaired individuals. Journal of the American Medical Association, 273, 12741278.
Petersen, R.C., Thomas, R.G., Grundman, M., Bennett, D., Doody, R., Ferris, S., Galasko, D., Jin, S., Kaye, J., Levey, A., Pfeiffer, E., Sano, M., van Dyck, C.H., & Thal, L.J. (2005). Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment. New England Journal of Medicine, 352, 23792388.
Petersen, R.C., Smith, G.E., Ivnik, R.J., Kokmen, E., & Tangalos, E.G. (1994). Memory function in very early Alzheimer's disease. Neurology, 44, 867872.
Rapp, M.A. & Reischies, F.M. (2005). Attention and executive control predict Alzheimer disease in late life. Results from the Berlin Aging Study (BASE). American Journal of Geriatric Psychiatry, 13, 134141.
Reitan, R.M. (1958). Validity of the Trail Making Test as an indicator of organic brain damage. Perceptual and Motor Skills, 8, 271276.
Ritchie, K., Artero, S., & Touchon, J. (2001). Classification criteria for mild cognitive impairment: A population-based validation study. Neurology, 56, 3742.
Rosen, W. (1980). Verbal fluency in aging and dementia. Journal of Clinical Neuropsychology, 2, 135146.
Royall, D.R., Chiodo, L.K., & Polk, M.J. (2004). Misclassification is likely in the assessment of mild cognitive impairment. Neuroepidemiology, 23, 185191.
Rubin, E.H., Storandt, M., Miller, J.P., Kinscherf, D.A., Grant, E.A., & Morris, L.B. (1998). A prospective study of cognitive function and onset of dementia in cognitively healthy elders. Archives of Neurology, 55, 395401.
Sarazin, M., Berr, C., De Rotrou, J., Fabrigoule, C., Pasquier, F., Legrain, S., Michel, B., Puel, M., Volteau, M., Touchon, J., Verny, M., & Dubois, B. (2007). Amnestic syndrome of the medial temporal type identifies prodromal AD: A longitudinal study. Neurology, 69, 18591867.
Saxton, J., Lopez, O.L., Ratcliff, G., Dulberg, C., Fried, L.P., Carlson, M.C., Newman, A.B., & Kuller, L. (2004). Preclinical Alzheimer disease: Neuropsychological test performance 1.5 to 8 years before diagnosis. Neurology, 63, 23412347.
Shock, N., Greulich, R., Andres, R., Arenberg, D., Costa, P.T., Lakatta, E.G., & Tobin, J.D. (1984). Normal human aging: The Baltimore longitudinal study of aging (NIH Publication No. 84-2450). Bethesda, MD: National Institutes of Health.
Sliwinski, M., Lipton, R.B., Buschke, H., & Stewart, W.F. (1996). The effect of preclinical dementia on estimates of normal cognitive function in aging. Journal of Gerontology; Psychological Sciences, 51B, P217P225.
Small, B.J., Herlitz, L., Fratiglioni, L., Almkvist, O., & Backman, L. (1997). Cognitive predictors of incident Alzheimer's disease: A prospective longitudinal study. Neuropsychology, 11, 413420.
Spreen, O. & Benton, A.L. (1969). Neurosensory Center Comprehensive Examination for Aphasia: Manual of directions. Victoria, BC: Neuropsychology Laboratory, University of Victoria.
Spreen, O. & Strauss, E. (1998). A compendium of neuropsychological tests: Adminstration, norms, and commentary. New York: Oxford University Press.
Stern, Y. (2002). What is cognitive reserve? Theory and research application of the reserve concept. Journal of the Neuropsychological Society, 8, 448460.
Stern, Y., Gurland, B., Tatemichi, T.K., Tang, M.X., Wilder, D., & Mayeux, R. (1994). Influence of education and occupation on the incidence of Alzheimer's disease. Journal of the American Medical Association, 271, 10041010.
Stuss, D. & Alexander, M.P. (2007). Is there a dysexecutive syndrome? Philosophical Transactions of the Royal Society of London, Series B Biological Sciences, 362, 901915.
Tierney, M.C., Yao, C., Kiss, A., & McDowell, I. (2005). Neuropsychological tests accurately predict incident Alzheimer's disease after 5 and 10 years. Neurology, 64, 18531859.
Tounsi, H., Deweer, B., Ergis, A., Van der Linden, M., Pillon, B., Michon, A., & Dubois, B. (1999). Sensitivity to semantic cuing: An index of episodic memory dysfunction in early Alzheimer disease. Alzheimer Disease and Associated Disorders, 13, 3846.
Tuokko, H. & Crockett, D. (1989). Cued recall and memory disorders in dementia. Journal of Clinical and Experimental Neuropsychology, 11, 278294.
Tuokko, H., Kristjansson, E., & Miller, J.A. (1995). The neuropsychological detection of dementia: An overview of the neuropsychological component of the Canadian Study of Health and Aging. Journal of Clinical and Experimental Neuropsychology, 13, 871879.
Wechsler, D. (1955). Manual for the Wechsler Adult Intelligence Scale-Revised. New York: The Psychological Corporation.
Welsh, K.A., Butters, N., Hughes, J., Mohs, R., & Heyman, A. (1991). Detection of abnormal memory decline in mild cases of Alzheimer's disease using CERAD neuropsychological measures. Archives of Neurology, 48, 278281.



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