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Neuropathological Associates of Multiple Cognitive Functions in Two Community-Based Cohorts of Older Adults

Published online by Cambridge University Press:  22 November 2010

N. Maritza Dowling
Department of Biostatistics & Medical Informatics, School of Medicine & Public Health, University of Wisconsin, Madison, Wisconsin
Sarah Tomaszewski Farias
Department of Neurology, School of Medicine, University of California, Davis, California
Bruce R. Reed
Department of Neurology, School of Medicine, University of California, Davis, California Veterans Administration Northern California Health Care System, Martinez, California
Joshua A. Sonnen
Department of Pathology, University of Washington, Seattle, Washington
Milton E. Strauss
Case Western Reserve University, Cleveland, Ohio
Julie A. Schneider
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois
David A. Bennett
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois
Dan Mungas
Department of Neurology, School of Medicine, University of California, Davis, California
E-mail address:


Studies of neuropathology-cognition associations are not common and have been limited by small sample sizes, long intervals between autopsy and cognitive testing, and lack of breadth of neuropathology and cognition variables. This study examined domain-specific effects of common neuropathologies on cognition using data (N = 652) from two large cohort studies of older adults. We first identified dimensions of a battery of 17 neuropsychological tests, and regional measures of Alzheimer’s disease (AD) neuropathology. We then evaluated how cognitive factors were related to dimensions of AD and additional measures of cerebrovascular and Lewy Body disease, and also examined independent effects of brain weight. All cognitive domains had multiple neuropathology determinants that differed by domain. Neocortical neurofibrillary tangles were the strongest predictors of most domains, while medial temporal tangles showed a weaker relationship with episodic memory. Neuritic plaques had relatively strong effects on multiple domains. Lewy bodies and macroscopic infarcts were associated with all domains, while microscopic infarcts had more limited associations. Brain weight was related to all domains independent of specific neuropathologies. Results show that cognition is complexly determined by multiple disease substrates. Neuropathological variables and brain weight contributed approximately a third to half of the explained variance in different cognitive domains. (JINS, 2011, 17, 602–614).

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Copyright © The International Neuropsychological Society 2010

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Aarslanda, D., Londosa, E., Ballarda, C. (2009). Parkinson’s disease dementia and dementia with Lewy bodies: Different aspects of one entity. International Psychogeriatrics, 21, 216219.CrossRefGoogle Scholar
Alzheimer’s Association. (2009). 2009 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia, 5, 234270.CrossRefGoogle Scholar
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, 103116.CrossRefGoogle ScholarPubMed
Arriagada, P., Growdon, J., Hedley-Whyte, T., Hyman, B. (1992). Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology, 42, 631639.CrossRefGoogle ScholarPubMed
Baudica, S., Dalla, G., Thibaudetc, M.C., Smagghec, A., Remyd, F., Traykov, L. (2006). Executive function deficits in early Alzheimer’s disease and their relations with episodic memory. Archives of Clinical Neuropsychology, 21, 1521.CrossRefGoogle Scholar
Bennett, D.A., Schneider, J.A., Arvanitakis, Z., Kelly, J.F., Aggarwa, N.T., Shah, R.C., Wilson, R.S. (2006). Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology, 66, 18371844.CrossRefGoogle ScholarPubMed
Bennett, D.A., Schneider, J.A., Bienias, J.L., Evans, D.A., Wilson, R.S. (2005). Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions. Neurology, 64, 834841.CrossRefGoogle ScholarPubMed
Bennett, D.A., Schneider, J.A., Buchman, A.S., Mendes de Leon, C.F., Bienias, J.L., Wilson, R.S. (2005). The Rush Memory and Aging Project: Study design and baseline characteristics of the study cohort. Neuroepidemiology, 25, 163175.CrossRefGoogle ScholarPubMed
Bennett, D.A., Schneider, J.A., Wilson, R.S., Bienias, J.L., Arnold, S.E. (2004). Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Archives of Neurology, 61, 378384.CrossRefGoogle ScholarPubMed
Bowen, B.C., Barker, W.W., Loewenstein, D.A., Sheldon, J., Duara, R. (1990). MR signal abnormalities in memory disorder and dementia. AJR American Journal of Roentgenology, 154, 12851292.CrossRefGoogle ScholarPubMed
Braak, H., Braak, E. (1991). Neuropathological staging of Alzheimer’s related changes. Acta Neuropathologica, 82, 239259.CrossRefGoogle Scholar
Braak, H., Braak, E. (1997). Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiology of Aging, 18, S85S88.CrossRefGoogle ScholarPubMed
Chui, H.C., Zarow, C., Mack, W.J., Ellis, W.G., Zheng, L., Jagust, W.J., Vinters, H.V. (2006). Cognitive impact of sub-cortical vascular and Alzheimer disease pathology. Annals of Neurology, 60, 677687.CrossRefGoogle Scholar
Cohen, R.A., Poppas, A., Forman, D.E., Hoth, K.F., Haley, A.P., Gunstad, J., Gerhard-Herman, M. (2009). Vascular and cognitive functions associated with cardiovascular disease in the elderly. Journal of Clinical and Experimental Neuropsychology, 31, 96110.CrossRefGoogle ScholarPubMed
Cummings, J.L., Mega, M.S. (2003). Neuropsychiatry and behavioral neuroscience. New York: Oxford University Press.Google Scholar
Cupidi, C., Capobianco, R., Goffredo, D., Marcon, G., Ghetti, B., Bugiani, O., Giaccone, G. (2010). Neocortical variation of Abeta load in fully expressed, pure Alzheimer’s disease. Journal of Alzheimer’s Disease, 19, 5768.CrossRefGoogle ScholarPubMed
Dickerson, B.C., Feczko, E., Augustinack, J.C., Pacheco, J., Morris, J.C., Fischl, B., Buckner, R.L. (2009). Differential effects of aging and Alzheimer’s disease on medial temporal lobe cortical thickness and surface area. Neurobiology of Aging, 30, 432440.CrossRefGoogle ScholarPubMed
Duyckaerts, C., Delatour, B., Potier, M.C. (2009). Classification and basic pathology of Alzheimer disease. Acta Neuropathologica, 118, 536.CrossRefGoogle ScholarPubMed
Duyckaerts, C., Hauw, J.J. (1997). Diagnosis and staging of Alzheimer disease. Neurobiology of Aging, 18, 3342.CrossRefGoogle ScholarPubMed
Erten-Lyons, D., Woltjer, R.L., Dodge, H., Nixon, R., Vorobik, R., Calvert, J.F., Kaye, J. (2009). Factors associated with resistance to dementia despite high Alzheimer disease pathology. Neurology, 72, 354360.CrossRefGoogle ScholarPubMed
Fratiglioni, L., De Ronchi, D., Aguero-Torres, H. (1999). Worldwide prevalence and incidence of dementia. Drugs and Aging, 15, 365375.CrossRefGoogle ScholarPubMed
Giannakopoulos, P., Herrmann, F.R., Bussiere, T., Bouras, C., Kovari, E., Perl, D.P., Hof, P.R. (2003). Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology, 60, 14951500.CrossRefGoogle Scholar
Grundman, M., Jack, C.R. Jr., Petersen, R.C., Kim, H.T., Taylor, C., Datvian, M., Thal, L.J. (2003). Hippocampal volume is associated with memory but not nonmemory cognitive performance in patients with mild cognitive impairment. Journal of Molecular Neuroscience, 20, 241248.CrossRefGoogle Scholar
Guillozet, A.L., Weintraub, S., Mash, D.C., Mesulam, M.M. (2003). Neurofibrillay tangles, amyloid and memory in aging and mild cognitive impairment. Archives of Neurology, 60, 729736.CrossRefGoogle Scholar
Hamilton, J.M., Salmon, D.P., Galasko, D., Delis, D., Hansen, L.A., Masliah, E., Thal, L.J. (2004). A comparison of episodic memory deficits in neuropathologically-confirmed dementia with Lewy bodies and Alzheimer’s disease. Journal of the International Neuropsychological Society, 10, 689697.CrossRefGoogle ScholarPubMed
Iacono, D., Markesbery, W.R., Gross, M., Pletnikova, O., Rudow, G., Zandi, P., Troncoso, J.C. (2009). The nun study: Clinically silent AD, neuronal hypertrophy, and linguistic skills in early life. Neurology, 73, 665673.CrossRefGoogle ScholarPubMed
Jöreskog, K.G. (1969). A general approach to confirmatory maximum likelihood factor analysis. Psychometrika, 34, 183202.CrossRefGoogle Scholar
Jöreskog, K.G., Goldberger, A.S. (1975). Estimation of a model with multiple indicators and multiple causes of a single latent variable. Journal of the American Statistical Association, 70, 631639.Google Scholar
Katzman, R., Terry, R., DeTeresa, R., Brown, T., Davies, P., Fuld, P., Peck, A. (1988). Clinical, pathological, and neurochemical changes in dementia: A subgroup with preserved mental status and numerous neocortical plaques. Annals of Neurology, 23, 138144.CrossRefGoogle ScholarPubMed
Kirchhoff, B.A., Wagner, A.D., Maril, A., Stern, C.E. (2002). Prefrontal-temporal circuitry for episodic encoding and subsequent memory. The Journal of Neuroscience, 20, 61736180.CrossRefGoogle Scholar
Knopman, D.S. (2007). Cerebrovascular disease and dementia. British Journal of Radiology, 80, 121127.CrossRefGoogle ScholarPubMed
Kuczynski, B., Reed, B., Mungas, D., Weiner, M., Chui, H.C., Jagust, W. (2008). Cognitive and anatomic contributions of metabolic decline in Alzheimer disease and cerebrovascular disease. Archives of Neurology, 65, 16.CrossRefGoogle ScholarPubMed
Lezak, M.D., Howleson, D.B., Loring, D.W., Hannay, H.J., Fischer, J.S. (2004). Neuropsychological assessment (4th ed.). New York: Oxford University Press.Google Scholar
Marczinski, C.A., Kertesz, A. (2005). Category and letter fluency in semantic dementia, primary progressive aphasia, and Alzheimer’s disease. Brain & language, 97, 258265.CrossRefGoogle ScholarPubMed
Markesbery, W.R. (2010). Neuropathologic alterations in mild cognitive impairment: A review. Journal of Alzheimer’s Disease, 19, 221228.CrossRefGoogle ScholarPubMed
Meyers, L.S., Gamst, G., Guarino, A.J. (2006). Applied multivariate research: Design and interpretation. Thousand Oaks, CA: Sage Publications.Google Scholar
Mitchell, T.W., Mufson, E.J., Schneider, J., Cochran, E.J., Nissanov, J., Arnold, S.E. (2002). Parahippocampal Tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer’s disease. Annals of Neurology, 51, 182189.CrossRefGoogle ScholarPubMed
Molano, J., Boeve, B., Ferman, T., Smith, G., Parisi, J., Dickson, D., Petersen, R. (2010). Mild cognitive impairment associated with limbic and neocortical Lewy body disease: A clinicopathological study. Brain, 133, 540556.CrossRefGoogle ScholarPubMed
Morgan, G.A., Griego, O.V., Gloeckner, G. (2001). An introduction to use and interpretation in research. Mahwah, NJ: Lawrence Erlbaum.Google Scholar
Mungas, D., Reed, B.R., Ellis, W.G., Jagust, W.J. (2001). The effects of age on rate of progression of Alzheimer disease and dementia with associated cerebrovascular disease. Archives of Neurology, 58, 12431247.CrossRefGoogle ScholarPubMed
Muthén, L.K., Muthén, B. (1998–2008). Mplus user’s guide. Version 5. Los Angeles, CA: Muthén & Muthén.Google Scholar
Nagy, Z., Esiri, M.M., Jobst, K., Morris, J., King, E., McDonald, B., Smith, A. (1995). Relative role of plaques and tangles in the dementia of Alzheimer’s disease: Correlation using three sets of neuropathological criteria. Dementia, 6, 2131.Google Scholar
Nelson, P.T., Abner, E.L., Schmitt, F.A., Kryscio, R.J., Jicha, G.A., Santacruz, K., Markesbery, W.R. (2009). Brains with medial temporal lobe neurofibrillary tangles but no neuritic amyloid plaques are a diagnostic dilemma but may have pathogenetic aspects distinct from Alzheimer’s disease. Journal of Neuropathology and Experimental Neurology, 68, 774784.CrossRefGoogle Scholar
Nestor, P.T., Scheltens, P., Hodges, J.R. (2004). Advances in the early detection of Alzheimer’s disease. Nature Reviews Neuroscience, 5, 3441.CrossRefGoogle Scholar
Papka, M., Rubio, A., Schiffer, R.B. (1998). A review of Lewy body disease, an emerging concept of cortical dementia. Journal of Neuropsychiatry and Clinical Neuroscience, 10, 267279.CrossRefGoogle ScholarPubMed
Petersen, R.C., Stevens, J.C., Ganguli, M., Tangalos, E., Cummings, J.L., DeKosky, S.T. (2001). Practice parameter: Early detection of dementia: Mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 56, 11331142.CrossRefGoogle ScholarPubMed
Plassman, B.L., Langa, K.M., Fisher, G.G., Heeringa, S.G., Weir, D.R., Ofstedal, M.B., Wallace, R.B. (2007). Prevalence of dementia in the United States: The aging, demographics, and memory study. Neuroepidemiology, 29, 125132.CrossRefGoogle ScholarPubMed
Pratt, J.W. (1987). Dividing the indivisible: Using simple symmetry to partition variance explained. In T. Pukkila & S. Puntanen (Eds.), Proceedings of the Second International Conference in Statistics (pp. 245260). Tampere, Finland: University of Tampere.Google Scholar
Preobrazhenskaya, I.S., Mkhitaryan, E.A., Yakhno, N.N. (2006). Comparative analysis of cognitive impairments in Lewy body dementia and Alzheimer’s disease. Neuroscience and Behavioral Physiology, 36, 16.CrossRefGoogle ScholarPubMed
Raykov, T. (1998). Coefficient alpha and composite reliability with interrelated nonhomogeneous items. Applied Psychological Measurement, 22, 375385.CrossRefGoogle Scholar
Raykov, T., Shrout, P.E. (2002). Reliability of scales with general structure: Point and interval estimation using a structural equation modeling approach. Structural Equation Modeling, 9, 195212.CrossRefGoogle Scholar
Saris, W.E., Satorra, A., Sörbom, D. (1987). The detection and correction of specification errors in structural equation models. In C.C. Clogg (Ed.), Sociological methodology (pp. 105129). San Francisco: Jossey-Bass.Google Scholar
Schneider, J.A., Boyle, P.A., Arvanitakis, Z., Bienias, J.L., Bennett, D.A. (2007). Subcortical infarcts, Alzheimer’s disease pathology, and memory function in older persons. Annals of Neurology, 62, 5966.CrossRefGoogle ScholarPubMed
Schneider, J.A., Wilson, R.S., Bienias, J.L., Evans, D.A., Bennett, D.A. (2004). Cerebral infarctions and the likelihood of dementia from Alzheimer’s disease pathology. Neurology, 62, 11481155.CrossRefGoogle Scholar
Simard, M., van Reekum, R., Myran, D. (2003). Visuospatial impairment in dementia with Lewy bodies and Alzheimer’s disease: A process analysis approach. International Journal of Geriatric Psychiatry, 18, 387391.CrossRefGoogle ScholarPubMed
Staresina, B.P., Davachi, L. (2006). Differential encoding mechanisms for subsequent associative recognition and free recall. Journal of Neuroscience, 26, 91629172.CrossRefGoogle ScholarPubMed
Stern, Y. (2002). What is cognitive reserve? Theory and research application of the reserve concept. Journal of the International Neuropsychological Society, 8, 448460.CrossRefGoogle ScholarPubMed
Sze, C.I., Troncoso, J.C., Kawas, C., Mouton, P., Price, D.L., Martin, L.J. (1997). Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. Journal of Neuropathology and Experimental Neurology, 56, 933944.CrossRefGoogle ScholarPubMed
Traykov, L., Baudic, S., Thibaudet, M.C., Rigaud, A.S., Smagghe, A., Boller, F. (2002). Neuropsychological deficit in early subcortical vascular dementia: Comparison to Alzheimer’s disease. Dementia and Geriatric Cognitive Disorders, 14, 2632.CrossRefGoogle ScholarPubMed
Thomas, D.R., Hughes, E., Zumbo, B.D. (1998). On variable importance in linear regression. Social Indicators Research, 45, 253275.CrossRefGoogle Scholar
Thomas, D.R., Zhu, P., Decady, Y.J. (2007). Point estimates and confidence intervals for variable importance in multiple linear regression. Journal of Educational and Behavioral Statistics, 32, 6191.CrossRefGoogle Scholar
van der Flier, W.M., van den Heuvel, D.M.J., Weverling-Rijnsburger, A.W.E., Spilt, A., Bollen, E.L.E., Westendorp, R.G.J., van Buchem, M.A. (2002). Cognitive decline in AD and mild cognitive impairment is associated with global brain damage. Neurology, 59, 874879.CrossRefGoogle ScholarPubMed
Van Petten, C. (2004). Relationship between hippocampal volume and memory ability in healthy individuals across the lifespan: Review and meta-analysis. Neuropsychologia, 42, 13941413.CrossRefGoogle ScholarPubMed
Walhovd, K.B., Fjell, A.M., Brewer, J., McEvoy, L.K., Fennema-Notestine, C., Hagler, D.J. Jr., Dale, A.M. (2010). Combining MR imaging, positron-emission tomography, and csf biomarkers in the diagnosis and prognosis of Alzheimer disease. AJNR American Journal of Neuroradiology, 31, 347354.CrossRefGoogle ScholarPubMed
Wilson, R.S., Barnes, L.L., Bennett, D.A. (2003). Assessment of lifetime participation in cognitively stimulating activities. Journal of Clinical and Experimental Neuropsychology, 9, 634642.CrossRefGoogle Scholar
Wilson, R.S., Beckett, L.A., Barnes, L.L., Schneider, J.A., Bach, J., Evans, D.A., Bennett, D.A. (2002). Individual differences in rates of change in cognitive abilities of older persons. Psychology and Aging, 17, 179193.CrossRefGoogle ScholarPubMed
Wilson, R.S., Mendes, C.F., Barnes, L.L., Schneider, J.A., Bienias, J.L., Evans, D.A., Bennett, D.A. (2002). Participation in cognitively stimulating activities and risk of incident Alzheimer disease. Journal of the American Medical Association, 287, 742748.CrossRefGoogle ScholarPubMed

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