Hostname: page-component-f554764f5-fnl2l Total loading time: 0 Render date: 2025-04-13T08:13:32.993Z Has data issue: false hasContentIssue false
  • English
  • Français

Neuropsychological and neuroimaging changes in preclinical Alzheimer's disease

Published online by Cambridge University Press:  08 September 2006

ELIZABETH W. TWAMLEY ,
SUSAN A. LEGENDRE ROPACKI  and
MARK W. BONDI
ELIZABETH W. TWAMLEY
Affiliation:
Department of Psychiatry, University of California, La Jolla, California
SUSAN A. LEGENDRE ROPACKI
Affiliation:
Department of Psychology, Loma Linda University, Loma Linda, California
MARK W. BONDI
Affiliation:
Department of Psychiatry, University of California, La Jolla, California Psychology Service, VA San Diego Healthcare System, San Diego, California
Get access Rights & Permissions [Opens in a new window]

Abstract

Alzheimer's disease (AD) is a common, devastating form of dementia. With the advent of promising symptomatic treatment, the importance of recognizing AD at its very earliest stages has increased. We review the extant neuropsychological and neuroimaging literature on preclinical AD, focusing on longitudinal studies of initially nondemented individuals and cross-sectional investigations comparing at-risk with normal individuals. We systematically reviewed 91 studies of neuropsychological functioning, structural neuroimaging, or functional neuroimaging in preclinical AD. The neuropsychological studies indicated that preclinical AD might be characterized by subtle deficits in a broad range of neuropsychological domains, particularly in attention, learning and memory, executive functioning, processing speed, and language. Recent findings from neuroimaging research suggest that volume loss and cerebral blood flow or metabolic changes, particularly in the temporal lobe, may be detected before the onset of dementia. There exist several markers of a preclinical period of AD, in which specific cognitive and biochemical changes precede the clinical manifestations. The preclinical indicators of AD reflect early compromise of generalized brain integrity and temporal lobe functioning in particular. (JINS, 2006, 12, 707–735.)

Keywords

DementiaNeuropsychologyMagnetic resonance imagingPositron emission tomographyCognition disordersMemory disorders
Type
CRITICAL REVIEW
Information
Journal of the International Neuropsychological Society , Volume 12 , Issue 5 , September 2006 , pp. 707 - 735
Copyright
© 2006 The International Neuropsychological Society

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

REFERENCES

Albert, M.S. (1996). Cognitive and neurobiologic markers of early Alzheimer's disease. Proceedings of the National Academy of Sciences, 93, 13,547–13,551.Google Scholar
Albert, M.S., Moss, M.B., Tanzi, R., & Jones, K. (2001). Preclinical prediction of AD using neuropsychological tests. Journal of the International Neuropsychological Society, 7, 631–639.Google Scholar
Albert, S.M., Gurland, B., Maestre, G., Jacobs, D.M., Stern, Y., & Mayeux, R. (1995). APOE genotype influences functional status among elderly without dementia. American Journal of Medical Genetics, 60, 583–587.Google Scholar
Alzheimer, A. (1907). Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medizin, 64, 146–148.Google Scholar
American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders (4th ed.). Washington, DC: American Psychiatric Association Press.
Arnold, S.E., Hyman, B.T., Flory, J., Damasio, A.R., & van Hoesen G.W. (1991). The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cerebral Cortex, 1, 103–116.Google Scholar
Azari, N.P., Pettigrew, K.D., Schapiro, M.R., Haxby, J.V., Grady, C.L., Pietrini, P., Salerno, J.A., Heston, L.L., Rapoport, S.I., & Horwitz, B. (1993). Early detection of Alzheimer disease: A statistical approach using positron emission tomographic data. Journal of Cerebral Blood Flow and Metabolism, 13, 438–447.Google Scholar
Bäckman, L., Jones, S., Berger, A., Laukka, E.J., & Small, B.J. (2005). Cognitive impairment in preclinical Alzheimer's disease: A meta-analysis. Neuropsychology, 19, 520–531.Google Scholar
Bäckman, L. & Small, B.J. (1998). Influences of cognitive support on episodic remembering: Tracing the process of loss from normal aging to Alzheimer's disease. Psychology of Aging, 13, 267–276.Google Scholar
Bäckman, L., Small, B.J., & Fratiglioni, L. (2001). Stability of the preclinical episodic memory deficit in Alzheimer's disease. Brain, 124, 96–102.Google Scholar
Baxter, L.C., Caselli, R.J., Johnson, S.C., Reiman, E., & Osborne, D. (2003). Apolipoprotein E ε4 affects new learning in cognitively normal individuals at risk for Alzheimer's disease. Neurobiology of Aging, 24, 947–952.Google Scholar
Becker, J.T., Mintum, M.A., Aleva, K., Wiseman, M.B., Nichols, T., & DeKosky, S.T. (1996). Compensatory reallocation of brain resources supporting verbal episodic memory in Alzheimer's disease. Neurology, 46, 692–700.Google Scholar
Bennett, D.A., Schneider, J.A., Wilson, R.S., Bienias, J.L., Berry-Kravis, E., & Arnold, S.E. (2005). Amyloid mediates the association of apolipoprotein E ε4 allele to cognitive function in older people. Journal of Neurology, Neurosurgery, and Psychiatry, 76, 1194–1199.Google Scholar
Berr, C., Dufouil, C., Brousseau, T., Richard, F., Amouyel, P., Marceteau, E., & Alperovitch, A. (1996). Early effect of ApoE-ε4 allele on cognitive results in a group of highly performing subjects: The EVA study. Neuroscience Letters, 218, 9–12.Google Scholar
Bobinski, M., de Leon, M.J., Convit, A., De Saniti, S., Wegiel, J., Tarschish, C.Y., Saint Louis, L.A., & Wisniewski, H.M. (1999). MRI of entorhinal cortex in mild Alzheimer's disease. Lancet, 353, 38–40.Google Scholar
Bondareff, W., Mountjoy, C.Q., & Roth, M. (1982). Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia. Neurology, 32, 164–168.Google Scholar
Bondi, M.W., Houston, W.S., Eyler, L.T., & Brown, G.G. (2005). FMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer's disease. Neurology, 64, 501–508.Google Scholar
Bondi, M.W., Monsch, A.U., Galasko, D., Butters, N., Salmon, D.P., & Delis, D.C. (1994). Preclinical cognitive markers of dementia of the Alzheimer type. Neuropsychology, 8, 374–384.Google Scholar
Bondi, M.W., Salmon, D.P., Galasko, D., Thomas, R.G., & Thal, L.J. (1999). Neuropsychological function and Apolipoprotein E genotype in the preclinical detection of Alzheimer's disease. Psychology and Aging, 14, 295–303.Google Scholar
Bondi, M.W., Salmon, D.P., Monsch, A.U., Galasko, D., Butters, N., Klauber, M.R., Thal, L.J., & Saitoh, T. (1995). Episodic memory changes are associated with the ApoE-ε4 allele in non-demented older adults. Neurology, 45, 2203–2206.Google Scholar
Bookheimer, S.Y., Strojwas, M.H., Cohen, M.S., Saunders, A.M., Pericak-Vance, M.A., Mazziotta, J.C., & Small, G.W. (2000). Patterns of brain activation in people at risk for Alzheimer's disease. New England Journal of Medicine, 343, 450–456.Google Scholar
Braak, H. & Braak, E. (1991). Neuropathological staging of Alzheimer-related changes. Neuropathologica, 82, 259.Google Scholar
Braak, H. & Braak, E. (1995). Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiology of Aging, 16, 271–284.Google Scholar
Braak, H., Braak, E., Bohl, J., & Bratzke, H. (1998). Evolution of Alzheimer's disease related cortical lesions. Journal of Neural Transmission, 54, 97–106.Google Scholar
Bretsky, P., Guralnik, J.M., Launer, L., Albert, M., & Seeman, T.E. (2003). The role of APOE-ε4 in longitudinal cognitive decline: MacArthur studies of successful aging. Neurology, 60, 1077–1081.Google Scholar
Brookmeyer, R., Gray, S., & Kawas, C. (1998). Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. American Journal of Public Health, 88, 1337–1342.Google Scholar
Bunce, D., Fratiglioni, L., Small, B.J., Winblad, B., & Bäckman, L. (2004). APOE and cognitive decline in preclinical Alzheimer disease and non-demented aging. Neurology, 63, 816–821.Google Scholar
Burggren, A.C., Small, G.W., Sabb, F.W., & Bookheimer, S.Y. (2002). Specificity of brain activation patterns in people at genetic risk for Alzheimer's disease. American Journal of Geriatric Psychiatry, 10, 44–51.Google Scholar
Caselli, R.J., Graff-Radford, N.R., Reiman, E.M., Weaver, A., Osborn, D., Lucas, J., Uecker, A., & Thiobodeau, S.N. (1999). Preclinical memory decline in cognitively normal apolipoprotein E-epsilon4 homozygotes. Neurology, 53, 201–213.Google Scholar
Caselli, R.J., Osbourne, D., Reiman, E.M., Hentz, J.G., Barbieri, C.J., Saunders, A.M., Hardy, J., Graff-Radford, N.R., Hall, G.R., & Alexander, G.E. (2001). Preclinical cognitive decline in late middle-aged asymptomatic apolipoprotein E-ε4/4 homozygotes: A replication study. Journal of the Neurological Sciences, 189, 93–98.Google Scholar
Caselli, R.J., Reiman, E.M., Hentz, J.G., Osborne, D., Alexander, G.E., & Boeve, B.F. (2002). A distinctive interaction between memory and chronic daytime somnolence in asymptomatic APOE ε4 homozygotes. Sleep, 25, 447–453.Google Scholar
Chen, J.G., Edwards, C.L., Vidyarthi, S., Pitchumoni, S., Tabrizi, S., Barboriak, D., Charles, H.C., & Doraiswamy, P.M. (2002). Learning and recall in subjects at genetic risk for Alzheimer's disease. Journal of Neuropsychiatry and Clinical Neurosciences, 14, 58–63.Google Scholar
Chen, P., Ratcliff, G., Belle, S.H., Cauley, J.A., DeKosky, S.T., & Ganguli, M. (2000). Cognitive tests that best discriminate between presymptomatic AD and those who remain nondemented. Neurology, 55, 1847–1853.Google Scholar
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, 853–858.Google Scholar
Cohen, E.R., Ugurbil, K., & Kim, S.G. (2002). Effect of basal conditions on the magnitude and dynamics of the blood oxygenation level-dependent fMRI response. Journal of Cerebral Blood Flow & Metabolism, 22, 1042–1053.Google Scholar
Cohen, R.M., Small, C., Lalonde, F., Friz, J., & Sunderland, T. (2001). Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women. Neurology, 57, 2223–2228.Google Scholar
Collie, A. & Maruff, P. (2000). The neuropsychology of preclinical Alzheimer's disease and mild cognitive impairment. Neuroscience and Biobehavioral Reviews, 24, 365–374.Google Scholar
Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, H.L., & Pericak-Vance, M.A. (1993). Gene dose of apolipoprotein E ε4 allele and the risk of Alzheimer's disease in late onset families. Science, 261, 921–923.Google Scholar
Dartigues, J.F., Commenges, D., Letenneur, L., Barberger-Gateau, P., Gilleron, V., Fabrigoule, C., Mazaux, J.M., Orgogozo, J.M., & Salamon, R. (1997). Cognitive predictors of dementia in elderly community residents. Neuroepidemiology, 16, 29–39.Google Scholar
Deary, I.J., Whiteman, M.C., Pattie, A., Starr, J.M., Hayward, C., Wright, A.F., Visscher, P.M., Tynan, M.C., & Whalley, L.J. (2004). Apolipoprotein E gene variability and cognitive functions at age 79: A follow-up of the Scottish Mental Survey of 1932. Psychology and Aging, 19, 367–371.Google Scholar
DeKosky, S.T., Ikonomovic, M.D., Styren, S.D., Beckett, L., Wisniewski, S., Bennett, D.A., Cochran, E.J., Kordower, J.H., & Mufson, E.J. (2002). Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Annals of Neurology, 51, 145–155.Google Scholar
DeKosky, S.T. & Orgogozo, J.M. (2001). Alzheimer disease: Diagnosis, costs, and dimensions of treatment. Alzheimer's Disease and Associated Disorders, 15, S3–S7.Google Scholar
DeLaGarza, V.W. (2003). Pharmacologic treatment of Alzheimer's disease: An update. American Family Physician, 68, 1365–1372.Google Scholar
de Leon, M.J., George, A.E., Golomb, J., Tarshish, C.Y., McRae, T., De Santi, S., McRae, T., Ferris, S.H., Reisberg, B., Ince, C., Rusinek, H., Bobinski, M., Quinn, B., Miller, D.C., & Wisiniewski, H.M. (1997). Frequency of hippocampal formation atrophy in normal aging and Alzheimer's disease. Neurobiology of Aging, 18, 1–11.Google Scholar
den Heijer, T., Oudkerk, M., Launer, L.J., van Dujin, C.M., Hofman, A., & Breteler, M.M.B. (2002). Hippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes. Neurology, 59, 746–748.Google Scholar
D'Esposito, M., Zarahn, E., Aguirre, G.K., & Rypma, B. (1999). The effect of normal aging on the coupling of neural activity to the BOLD hemodynamic response. Neuroimage, 10, 6–14.Google Scholar
Diaz-Olavarrieta, C., Ostrosky-Solis, F., de al Cadena, C.G., Rodriguez, Y., & Alonso, E. (1997). Neuropsychological changes in subjects at risk of inheriting Alzheimer's disease. Neuroreport. An International Journal for the Rapid Communication of Research in Neuroscience, 8, 2449–2453.Google Scholar
Dickerson, B.C., Salat, D.H., Greve, D.N., Chua, E.F., Rand-Giovannetti, E., Rentz, D.M., Bertram, L., Mullin, K., Tanzi, R.E., Blacker, D., Albert, M.S., & Sperling, R.A. (2005). Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology, 5, 404–411.Google Scholar
Dik, M.G., Jonker, C., Bouter, L.M., Geerlings, M.I., van Kamp, G.J., & Deeg, D.J. (2000). APOE-epsilon4 is associated with memory decline in cognitively impaired elderly. Neurology, 54, 1492–1497.Google Scholar
Durany, N., Michel, T., Kurt, J., Cruz-Sanchez, F.F., Crevos-Navarro, J., & Riederer, P. (2000). Brain-derived neurotrophic factor and neurotrophin-3 levels in Alzheimer's disease brains. International Journal of Developmental Neuroscience, 18, 807–813.Google Scholar
Egan, M.F., Kojima, M., Callicott, J.H., Goldberg, T.E., Kolachana, B.S., Bertolino, E.Z., Gold, B., Goldman, D., Dean, M., Lu, B., & Weinberger, D.R. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112, 257–269.Google Scholar
Elias, M., Beiser, A., Wolf, P.A., Au, R., 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, 57, 808–813.Google Scholar
Ercoli, L.M., Siddarth, P., Dunkin, J.J., Bramen, J., & Small, G.W. (2003). MMSE items predict cognitive decline in persons with genetic risk for Alzheimer's disease. Journal of Geriatric Psychiatry and Neurology, 16, 67–73.Google Scholar
Fabrigoule, C., Rouch, I., Taberly, A., Letenneur, L., Commenges, D., Mazaux, J.M., Orgogozo, J.M., & Dartigues, J.F. (1998). Cognitive process in preclinical phase of dementia. Brain, 121, 135–141.Google Scholar
Fillenbaum, G.G., Landerman, L.R., Blazer, D.G., Saunders, A.M., Harris, T.B., & Launer, L.J. (2001). The relationship of APOE genotype to cognitive functioning in older African-American and Caucasian community residents. Journal of the American Geriatrics Society, 49, 1148–1155.Google Scholar
Flory, J.D., Manuck, S.B., Ferrell, R.E., Ryan, C.M., & Muldoon, M.F. (2000). Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults. American Journal of Medical Genetics (Neuropsychiatric Genetics), 96, 707–711.Google Scholar
Fox, N.C., Crum, W.R., Scahill, R.I., Stevens, J.M., Janssen, J.C., & Rossor, M.N. (2001). Imaging of onset and progression of Alzheimer's disease with voxel-compression mapping of serial magnetic resonance images. Lancet, 358, 201–205.Google Scholar
Fox, N.C., Warrington, E.K., Freeborough, P.A., Hartikainen, P., Kennedy, A.M., Stevens, J.M., & Rossor, M.N. (1996). Presymptomatic hippocampal atrophy in Alzheimer's disease: A longitudinal MRI study. Brain, 119, 2001–2007.Google Scholar
Fox, N.C., Warrington, E.K., Seiffer, A.K., Agnew, S.K., & Rossor, M.N. (1998). Presymptomatic cognitive deficits in individuals at risk of familial Alzheimer's disease: A longitudinal prospective study. Brain, 121, 1631–1639.Google Scholar
Goldman, W.P., Price, J.L., Storandt, M., Grant, E.A., McKeel, D.W., Rubin, E.H., & Morris, J.C. (2001). Absence of cognitive impairment or decline in preclinical Alzheimer's disease. Neurology, 56, 361–367.Google Scholar
Greenwood, P.M., Sunderland, T., Putnam, K., Levy, J., & Parasuraman, R. (2005a). Scaling of visuospatial attention undergoes differential longitudinal change as a function of APOE genotype prior to old age: Results from the NIMH BIOCARD study. Neuropsychology, 19, 830–842.Google Scholar
Greenwood, P.M., Lambert, C., Sunderland, T., & Parasuraman, R. (2005b). Effects of the apolipoprotein E genotype on spatial attention, working memory, and their interaction in healthy, middle-aged adults: Results from the National Institute of Mental Health's BIOCARD study. Neuropsychology, 19, 199–211.Google Scholar
Greenwood, P.M., Sunderland, T., Friz, J.L., & Parasuraman, R. (2000). Genetics and visual attention: Selective deficits in healthy adult carriers of the ε4 allele of the apolipoprotein E gene. Proceedings of the National Academy of Sciences, 97, 11,661–11,666.Google Scholar
Grober, E. & Kawas, C. (1997). Learning and retention in preclinical and early Alzheimer's disease. Psychology and Aging, 12, 183–188.Google Scholar
Gunter, J.L., Shiung, M.M., Manduca, A., & Jack, C.R. (2003). Methodological considerations for measuring rates of brain atrophy. Journal of Magnetic Resonance Imaging, 18, 16–24.Google Scholar
Hall, C.B., Lipton, R.B., Sliwinski, M., & Stewart, W.F. (2000). Statistics in Medicine, 19, 1555–1566.
Han, S.D., Houston, W.S., Eyler, L.T., Brown, G.G., Salmon, D.P., Fleisher, A.S., & Bondi, M.W. (2006). Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemisphere compensatory response. Neurobiology of Aging, [Epub ahead of print].Google Scholar
Haxby, J.V., Duara, R., Grady, C.L., Cutler, N.R., & Rapoport, S.I. (1985). Relations between neuropsychological and cerebral metabolic asymmetries in early Alzheimer's disease. Journal of Cerebral Blood Flow and Metabolism, 5, 193–200.Google Scholar
Haxby, J.V., Grady, C.L., Duara, R., Schlageter, N., Berg, G., & Rapoport, S.I. (1986). Neocortical metabolic abnormalities precede nonmemory cognitive defects in early Alzheimer's-type dementia. Archives of Neurology, 43, 882–885.Google Scholar
Helkala, E.L., Koivisto, K., Hänninen, T., Vanhanen, M., Kervinen, K., Kuusisto, J., Mykkänen, L., Kesäniemi, Y.A., Laakso, M., & Riekkinen, P. (1996). Memory functions in human subjects with different apolipoprotein E phenotypes during a 3-year population-based follow-up study. Neuroscience Letters, 204, 177–180.Google Scholar
Hofer, S.M., Christensen, H., Mackinnon, A.J., Korten, A.E., Jorm, A.F., Henderson, A.S., & Easteal, S. (2002). Change in cognitive functioning associated with ApoE genotype in a community sample of older adults. Psychology and Aging, 17, 194–208.Google Scholar
Hom, J., Turner, M.B., Risser, R., Bonte, F.J., & Tintner, R. (1994). Cognitive deficits in asymptomatic first-degree relatives of Alzheimer's disease patients. Experimental Neuropsychology, 16, 568–576.Google Scholar
Houston, W.S., Delis, D.C., Lansing, A., Cobell, C., Jacobson, M., Salmon, D.P., & Bondi, M.W. (2005). Executive function asymmetry in older adults genetically at risk for Alzheimer's disease: Verbal versus design fluency. Journal of the International Neuropsychological Society, 11, 863–870.Google Scholar
Howieson, D.B., Dame, A., Camicioli, R., Sexton, G., Payami, H., & Kaye, J.A. (1997). Cognitive markers preceding Alzheimer's dementia in the healthy oldest old. Journal of the American Geriatric Society, 45, 584–589.Google Scholar
Hulette, C.M., Welsh-Bohmer, K.A., Murray, M.G., Saunders, A.M., Mash, D.C., & McIntyre, L.M. (1998). Neuropathological and neuropsychological changes in “normal” aging: Evidence for preclinical Alzheimer disease in cognitively normal individuals. Journal of Neuropathology and Experimental Neurology, 57, 1168–1174.Google Scholar
Hyman, B.T., Van Hoesen, G.W., Damasio, A.R., & Barnes, C.L. (1984). Alzheimer's disease: Cell-specific pathology isolates the hippocampal formation. Science, 225, 1168–1170.Google Scholar
Jack, C.R., Petersen, R.C., Xu, Y., O'Brien, P., Waring, S., Tangalos, E., Smith, G., Ivnik, R., Thibodeau, S., & Kokmen, E. (1998). Hippocampal atrophy and ApoE genotype are independently associated with Alzheimer's disease. Annals of Neurology, 43, 303–310.Google Scholar
Jack, C.R., Shiung, M.M., Weigand, S.D., O'Brien, P.C., Gunter, J.L., Boeve, B.F., Knopman, D.S., Smith, G.E., Ivnik, R.J., Tangalos, E.G., & Petersen, R.C. (2005). Brain atrophy rates predict subsequent clinical conversion in normal elderly and amnestic MCI. Neurology, 65, 1227–1231.Google Scholar
Jacobs, D.M., Sano, M., Dooneief, G., Marder, K., Bell, K.L., & Stern, Y. (1995). Neuropsychological detection and characterization of preclinical Alzheimer's disease. Neurology, 45, 957–962.Google Scholar
Jacobson, M., Delis, D.C., Bondi, M.W., & Salmon, D.P. (2005a). Asymmetry in auditory and spatial attention span in normal elderly genetically at risk for Alzheimer's disease. Journal of Clinical and Experimental Neuropsychology, 27, 240–253.Google Scholar
Jacobson, M.W., Delis, D.C., Lansing, A., Houston, W.S., Olsen, R., Wetter, S., Bondi, M.W., & Salmon, D.P. (2005b). Asymmetries in global-local processing abilities in elderly with the Apolipoprotein-E ε4 allele. Neuropsychology, 19, 822–829.Google Scholar
Jacobson, M., Delis, D.C., Bondi, M.W., & Salmon, D.P. (2002). Do neuropsychological tests detect preclinical Alzheimer's disease: Individual-test versus cognitive-discrepancy score analysis. Neuropsychology, 16, 132–139.Google Scholar
Jernigan, T.J., Archibald, S.L., Fennema-Notestine, C., Gamst, A.C., Stout, J.C., Bonner, J., & Hesselink, J.R. (2001). Effects of age on tissues and regions of the cerebrum and cerebellum. Neurobiology of Aging, 22, 581–594.Google Scholar
Johnson, S.C., Baxter, L.C., Susskind-Wilder, L., Connor, D.J., Sabbagh, M.N., & Caselli, R.J. (2004). Hippocampal adaptation to face repetition in healthy elderly and mild cognitive impairment. Neuropsychologia, 42, 980–989.Google Scholar
Jonker, C., Schmand, B., Lindeboom, J., Havekes, L.M., & Launer, L.J. (1998). Association between apolipoprotein E ε4 and the rate of cognitive decline in community-dwelling elderly individuals with and without dementia. Archives of Neurology, 55, 1065–1069.Google Scholar
Katzman, R., Aronson, M., Fuld, P., Kawas, C., Brown, T., Morgenstern, H., Frishman, W., Gidez, L., Eder, H., & Ooi, W.L. (1989). Development of dementing illness in an 80-year-old volunteer cohort. Annals of Neurology, 25, 317–324.Google Scholar
Kawas, C. & Katzman, R. (1999). Epidemiology of dementia and Alzheimer disease. In R.D. Terry, R. Katzman, K.L. Bick, & S.S. Sisodia (Eds.), Alzheimer disease (pp. 95–116). New York: Raven Press.
Kaye, J.A., Moore, M.M., Dame, A., Quinn, J., Camicioloi, R., Howieson, D., Corbridge, E., Care, B., Nesbit, G., & Sexton, G. (2005). Journal of Alzheimer's Disease, 8, 51–56.
Kaye, J.A., Swihart, T., Howieson, D., Dame, A., Moore, M.M., Karnos, T., Camicioli, R., Ball, M., Oken, B., & Sexton, G. (1997). Volume loss of the hippocampus and temporal lobe in healthy elderly persons destined to develop dementia. Neurology, 48, 1297–1304.Google Scholar
Kennedy, A.M., Frackowiak, R.S., Newman, S.K., Bloomfield, P.M., Seaward, J., Roques, P., Lewington, G., Cunningham, V.J., & Rossor, M.N. (1995). Deficits in cerebral glucose metabolism demonstrated by positron emission tomography in individuals at risk of familial Alzheimer's disease. Neuroscience Letters, 186, 17–20.Google Scholar
Kim, K.W., Youn, J.C., Jhoo, J.H., Lee, D.Y., Lee, K.U., Lee, J.H., & Woo, J.I. (2002). Apolipoprotein E ε4 allele is not associated with the cognitive impairment in community-dwelling normal elderly individuals. International Journal of Geriatric Psychiatry, 17, 635–640.Google Scholar
Klages, J.D., Fisk, J.D., & Rockwood, K. (2003). APOE genotype, memory test performance, and the risk of Alzheimer's disease in the Canadian Study of Health and Aging. Dementia and Geriatric Cognitive Disorders, 15, 1–5.Google Scholar
Knopman, D.S., DeKosky, S.T., Cummings, J.L., Chui, H., Corey-Bloom, J., Relkin, N., Small, G.W., Miller, B., & Stevens, J.C. (2001). Practice parameter: Diagnosis of dementia (an evidence-based review). Neurology, 56, 1143–1153.Google Scholar
Lange, K.L., Bondi, M.W., Galasko, D.G., Delis, D.C., Salmon, D.P., & Thal, L.J. (2002). Decline in verbal memory during preclinical Alzheimer's disease: Examination of the effect of Apolipoprotein E genotype. Journal of the International Neuropsychological Society, 8, 943–955.Google Scholar
Laukka, E.J., Jones, S., Small, B.J., Fratiglioni, L., & Bäckman, L. (2004). Similar patterns of cognitive deficits in the preclinical phases of vascular dementia and Alzheimer's disease. Journal of the International Neuropsychological Society, 10, 382–391.Google Scholar
Levy, J.A., Bergeson, J., Putnam, K., Rosen, V., Cohen, R., Lalonde, F., Mirza, N., Linker, G., & Sunderland, T. (2004). Context-specific memory and apolipoprotein E (ApoE) ε4: Cognitive evidence from the NIMH prospective study of risk for Alzheimer's disease. Journal of the International Neuropsychological Society, 10, 362–370.Google Scholar
Lindeboom, J., Schmand, B., Tulner, L., Walstra, G., & Jonker, C. (2002). Visual association test to detect early dementia of the Alzheimer type. Journal of Neurology, Neurosurgery, and Psychiatry, 73, 126–133.Google Scholar
Lindsay, J., Laurin, D., Verreault, R., Hébert, R., Helliwell, B., Hill, G.B., & McDowell, I. (2002). Risk factors for Alzheimer's disease: A prospective analysis from the Canadian Study of Health and Aging. American Journal of Epidemiology, 156, 445–453.Google Scholar
Linn, R.T., Wolf, P.A., Bachman, D.L., Knoefel, J.E., Cobb, J.L., Belanger, A.J., Kaplan, E.F., & D'Agostino, R.B. (1995). The ‘preclinical phase’ of probable Alzheimer's disease: A 13-year prospective study of the Framingham cohort. Archives of Neurology, 52, 485–490.Google Scholar
Martins, C.A.R., Oulhaj, A., de Jager, C.A., & Williams, J.H. (2005). APOE alleles predict the rate of cognitive decline in Alzheimer disease: A nonlinear model. Neurology, 65, 1888–1893.Google Scholar
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, 1427–1432.Google Scholar
Mayeux, R., Saunders, A.M., Shea, S., Mirra, S., Evans, D., Roses, A.D., Hyman, B.T., Crain, B., Tang, M.-X., & Phelps, C.H. (1998). Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. The New England Journal of Medicine, 338, 506–511.Google Scholar
Mayeux, R., Small, S.A., Tang, M.-X., Tycko, B., & Stern, Y. (2001). Memory performance in healthy elderly without Alzheimer's disease: Effects of time and apolipoprotein-E. Neurobiology of Aging, 22, 683–689.Google Scholar
Medina, D., Detoledo-Morrell, L., Urresta, F., Gabrieli, J.D., Moseley, M., Fleischman, D., Bennett, D.A., Leurgans, S., Turner, D.A., & Stebbins, G.T. (2006). White matter changes in mild cognitive impairment and AD: A diffusion tensor imaging study. Neurobiology of Aging, 27, 663–672.Google Scholar
Morris, J.C., Storandt, M., McKeel, D.W., Rubin, E.H., Price, J.L., Grant, E.A., & Berg, L. (1996). Cerebral amyloid deposition and diffuse plaques in “normal” aging: Evidence for presymptomatic and very mild Alzheimer's disease. Neurology, 46, 707–719.Google Scholar
Mueggler, T., Sturchler-Pierrat, C., Baumann, D., Rausch, M., Staufenbiel, M., & Rudin, M. (2002). Compromised hemodynamic response in amyloid precursor protein transgenic mice. The Journal of Neurosciences, 22, 7218–7224.Google Scholar
Murphy, C., Bacon, A.W., Bondi, M.W., & Salmon, D.P. (1998). Apolipoprotein E status is associated with odor identification deficits in nondemented older persons. Annals of the New York Academy of Science, 855, 744–750.Google Scholar
Nielsen, H., Lolk, A., Andersen, K., Andersen, J., & Kragh-Sørenson, P. (1999). Characteristics of elderly who develop Alzheimer's disease during the next two years: A neuropsychological study using CAMCOG. The Odense study. International Journal of Geriatric Psychiatry, 14, 957–963.Google Scholar
Pendleton, N., Payton, A., van den Boogerd, E.H., Holland, F., Diggle, P., Rabbitt, P.M.A., Horan, M.A., Worthington, J., Ollier, W.E.R. (2002). Apolipoprotein E genotype does not predict decline in intelligence in healthy older adults. Neuroscience Letters, 324, 74–76.Google Scholar
Pericak-Vance, M.A., Grubber, J., Bailey, L.R., Hedges, D., West, S., Santoro, L., Kenmerer, B., Hall, J.L., Saunders, A.M., Roses, A.D., Small, G.W., Scott, W.K., Conneally, P.M., Vance, J.M., & Haines, J.L. (2000). Identification of novel genes in late-onset Alzheimer's disease. Experimental Gerontology, 35, 1343–1352.Google Scholar
Petersen, R.D., Stevens, J.C., Ganguli, M., Tangalos, E.G., Cummings, J.L., & DeKosky, S.T. (2001). Practice parameter. Early detection of dementia: Mild cognitive impairment (an evidence-based review). Neurology, 56, 1133–1142.Google Scholar
Plassman, B.L., Welsh-Bohmer, K.A., Bigler, E.D., Johnson, S.C., Anderson, C.V., Helms, M.J., Saunders, A.M., & Breitner, J.C. (1997). Apolipoprotein E ε4 allele and hippocampal volume in twin with normal cognition. Neurology, 48, 985–989.Google Scholar
Price, J.L. & Morris, J.C. (1999). Tangles and plaques in non-demented aging and “preclinical” Alzheimer's disease. Annals of Neurology, 45, 358–368.Google Scholar
Rapp, M.A. & Reischies, F.M. (2005). Attention and executive control predict Alzheimer disease in late life. American Journal of Geriatric Psychiatry, 13, 134–141.Google Scholar
Reed, T., Carmelli, D., Swan, G.E., Breitner, J.C., Welsh, K.A., Jarvik, G.P., Deeb, S., & Auwerx, J. (1994). Lower cognitive performance in normal older adult male twins carrying the apolipoprotein E ε4 allele. Archives of Neurology, 51, 1189–1192.Google Scholar
Reiman, E.M., Caselli, R.J., Chen, K., Alexander, G.E., Bandy, D., & Frost, J. (2001). Declining brain activity in cognitively normal apolipoprotein E ε4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease. Proceedings of the National Academy of Sciences, 98, 3334–3339.Google Scholar
Reiman, E.M., Caselli, R.J., Yun, L.S., Chen, K., Bandy, D., Minoshima, S., Thibodeau, S.N., & Osborne, D. (1996). Preclinical evidence of Alzheimer's disease in person's homozygous for the ε4 allele for apolipoprotein E. New England Journal of Medicine, 334, 752–758.Google Scholar
Reiman, E.M., Chen, K., Alexander, G.E., Caselli, R., Brandy, D., Osborne, D., Saunders, A.M., & Hardy, J. (2004). Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proceedings of the National Academy of the Sciences, 101, 284–289.Google Scholar
Reiman, E.M., Uecker, A., Caselli, R., Lewis, S., Brandy, D., de Leon, M., De Santi, S., Convit, A., Osborne, D., Weaver, A., & Thibodeau, S.N. (1998). Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer's disease. Annals of Neurology, 44, 288–291.Google Scholar
Riley, K.P., Snowdon, D.A., Saunders, A.M., Roses, A.D., Mortimer, J.A., & Nanayakkara, N. (2000). Cognitive function and apolipoprotein E in very old adults: Findings from the nun study. Journal of Gerontology, 55B, S69–S75.Google Scholar
Rocca, W.A., Cha, R.H., Waring, S.C., & Kokmen, E. (1998). Incidence of dementia and Alzheimer's disease: A reanalysis of data from Rochester, Minnesota, 1975–1984. American Journal of Epidemiology, 148, 51–62.Google Scholar
Rosen, V.M., Bergeson, J.L., Putman, K., Harwell, A., & Sunderland, T. (2002). Working memory and apolipoprotein E: What's the connection? Neuropsychologia, 40, 2226–2233.Google Scholar
Rubin, E.H., Storandt, M., Miller, P., Kinscherf, D.A., Grant, E.A., Morris, J.C., & Berg, L. (1998). A prospective study of cognitive function and onset of dementia in cognitively healthy elders. Archives of Neurology, 55, 395–401.Google Scholar
Salmon, D.P. & Bondi, M.W. (1999). Neuropsychology of Alzheimer disease. In D.P. Salmon & M.W. Bondi (Eds.), Alzheimer disease (2nd ed.) (pp. 39–56). Philadelphia: Lippincott Williams & Wilkins.
Salo, A., Ylikoski, R., Verkkoniemi, A., Polvikoski, T., Juva, K., Rastas, S., Kontula, K., Kainulainen, K., Niinistö, L., Notkola, I.-L., & Sulkava, R. (2001). Does apolipoprotein E influence learning and memory in the nondemented oldest old? International Psychogeriatrics, 13, 451–459.Google Scholar
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 prior to onset. Neurology, 63, 2341–2347.Google Scholar
Schiffman, S.S., Graham, B.G., Sattely-Miller, E.A., Zervakis, J., & Welsh-Bohmer, K. (2002). Taste, smell and neuropsychological performance of individuals at familial risk for Alzheimer's disease. Neurobiology of Aging, 23, 397–404.Google Scholar
Schmidt, H., Schmidt, R., Fazekas, F., Semmler, J., Kapeller, P., Reinhart, B., & Kostner, G.M. (1996). Apolipoprotein E ε4 allele in the normal elderly: Neuropsychological and brain MRI correlates. Clinical Genetics, 50, 293–299.Google Scholar
Schmitt, F.A., Davis, D.G., Wekstein, D.R., Smith, C.D., Ashford, J.W., & Markesbery, W.R. (2000). “Preclinical” AD revisited: Neuropathology of cognitively normal older adults. Neurology, 55, 370–376.Google Scholar
Small, B.J., Basun, H., & Bäckman, L. (1998). Three-year changes in cognitive performance as a function of Apolipoprotein E genotype: Evidence from very old adults without dementia. Psychology and Aging, 13, 80–87.Google Scholar
Small, B.J., Fratiglioni, L., Viitanen, M., Winblad, B., & Backman, L. (2000). The course of cognitive impairment in preclinical Alzheimer disease: Three- and 6-year follow-up of a population-based sample. Archives of Neurology, 57, 839–844.Google Scholar
Small, B.J., Graves, A.B., McEvoy, C.L., Crawford, F.D., Mullan, M., & Mortimer, J.A. (2000). Is APOE-ε4 a risk factor for cognitive impairment in normal aging? Neurology, 54, 2082–2088.Google Scholar
Small, B.J., Herlitz, A., Fratiglioni, L., Almkvist, O., & Bäckman, L. (1997). Cognitive predictors of incident Alzheimer's disease: A prospective longitudinal study. Neuropsychology, 11, 413–420.Google Scholar
Small, B.J., Rosnick, C.B., Fratiglioni, L., & Bäckman, L. (2004). Apolipoprotein E and cognitive performance: A meta-analysis. Psychology and Aging, 19, 592–600.Google Scholar
Small, B.J., Viitanen, M., & Bäckman, L. (1997). Mini-Mental State Examination item scores as predictors of Alzheimer's disease: Incidence data from the Kungsholmen Project, Stockholm. Journal of Gerontology, 52A, M299–M304.Google Scholar
Small, G.W., Komo, S., La Rue, A., Saxena, S., Phelps, M.E., Massiotta, J.C., Saunders, A.M., Haines, J.L., Pericak-Vance, M.A., & Roses, A.D. (1996). Early detection of Alzheimer's disease by combining apolipoprotein E and neuroimaging. Annals of the New York Academy of Sciences, 802, 70–78.Google Scholar
Small, G.W., Mazziotta, J.C., Collins, M.T., Baxter, L.R., Phelps, M.E., Mandelkern, M.A., Kaplan, A., La Rue, A., Adamson, C.F., Chang, L., Guza, B.H., Corder, E.H., Saunders, A.M., Haines, J.L., Pericak-Vance, M.A., & Roses, A.D. (1995). Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. Journal of the American Medical Association, 273, 942–947.Google Scholar
Smith, C.D., Anderson, A.H., Kryscio, R.J., Schmitt, F.A., Kindy, M.S., Blonder, L.X., & Avison, M.J. (1999). Altered brain activation in cognitively intact individuals at high risk for Alzheimer's disease. Neurology, 53, 1391–1396.Google Scholar
Smith, G.E., Bohac, D.L., Waring, S.C., Kokmen, E., Tangalos, E.G., Ivnik, R.J., & Petersen, R.C. (1998). Apolipoprotein E genotype influences cognitive ‘phenotype’ in patients with Alzheimer's disease but not in healthy control subjects. Neurology, 50, 355–362.Google Scholar
Snowdon, D.A., Kemper, S.J., Mortimer, J.A., Greiner, L.H., Wekstein, D.R., & Markesbery, W.R. (1996). Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the nun study. Journal of the American Medical Association, 275, 528–532.Google Scholar
Squire, L.R. (1992). Memory and brain (2nd ed.). New York: Oxford University Press.
Staehelin, H.B., Perrig-Chiello, P., Mitrache, C., Miserez, A.R., & Perrig, W.J. (1999). Apolipoprotein E genotypes and cognitive functions in healthy elderly persons. Acta Neurologica Scandinavica, 100, 53–60.Google Scholar
Terry, R.D., Masliah, E., Salmon, D.P., Butters, N., DeTeresa, R., Hill, R., Hansen, L.A., & Katzman, R. (1991). Physical basis of cognitive alterations in Alzheimer's disease: Synapse loss in the major correlate of cognitive impairment. Annals of Neurology, 30, 572–580.Google Scholar
Tohgi, H., Takahashi, S., Kato, E., Homma, A., Niina, R., Sasaki, K., Yonezawa, H., & Sasaki, M. (1997). Reduced size of right hippocampus in 39- to 80-year-old normal subjects carrying the apolipoprotein E e4 allele. Neuroscience Letters, 236, 21–24.Google Scholar
U.S.Census Bureau. (2004). U.S. interim projections by age, sex, race, and Hispanic origin. http://www.census.gov/ipc/www/usinterimproj/.
Whalley, L.J., Starr, J.M., Athawes, R., Hunter, D., Pattie, A., & Deary, I.J. (2000). Childhood mental ability and dementia. Neurology, 55, 1428–1429.Google Scholar
Wilson, R.S., Schneider, J.A., Barnes, L.L., Beckett, L.A., Aggarwal, N.T., Cochran, E.J., Berry-Kravis, E., Bach, J., Fox, J.H., Evans, D.A., & Bennett, D.A. (2002). The apolipoprotein E ε4 allele and decline in different cognitive systems during a 6-year period. Archives of Neurology, 59, 1154–1160.Google Scholar
Winnock, M., Letenneur, L., Jacqmin-Gadda, H., Dallongeville, J., Amouyel, P., & Dartigues, J.F. (2002). Longitudinal analysis of the effect of the apolipoprotein E ε4 and education on cognitive performance in elderly subjects: The PAQUID study. Journal of Neurology, Neurosurgery, and Psychiatry, 72, 794–797.Google Scholar
Wolf, H., Jelic, V., Gertz, H-J., Nordberg, A., Julin, P., & Wahlund, L-O. (2003). A critical discussion of the role of neuroimaging in mild cognitive impairment. Acta Neurologica Scandinavica, 107, 52–76.Google Scholar
Wu, C., Pike, V.W., & Wang, Y. (2005). Amyloid imaging: From benchtop to bedside. Current Topics in Developmental Biology, 70, 171–213.Google Scholar
Xu, Y., Jack, C.R., O'Brien, P.C., Kokmen, E., Smith, G.E., Ivnik, R.J., Boeve, B.F., Tangalos, R.G., & Petersen, R.C. (2000). Usefulness of MRI measures of entorhinal cortex versus hippocampus in AD. Neurology, 54, 1767.Google Scholar
Yaffe, K., Cauley, J., Sands, L., & Browner, W. (1997). Apolipoprotein E phenotype and cognitive decline in a prospective study of elderly community women. Archives of Neurology, 54, 1110–1114.Google Scholar
Yoshitake, T., Kiyohara, Y., Kato, I., Ohmura, T., Iwamoto, H., Nakayama, K., Ohmori, S., Nomiyama, K., Kawaon, H., Ueda, K., Sueishi, K., Tsuneyosh, M., & Fujishima, M. (1995). Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: The Hisayama study. Neurology, 45, 1161–1168.Google Scholar
Zonderman, A.B., Giambra, L.M., Arenberg, D., Resnick, S.M., Costa, P.T., & Kawas, C.H. (1995). Changes in immediate visual memory predict cognitive impairment. Archives of Clinical Neuropsychology, 10, 111–123.Google Scholar