Skip to main content
    • Aa
    • Aa

Machine Learning Amplifies the Effect of Parental Family History of Alzheimer's Disease on List Learning Strategy

  • Timothy S. Chang (a1), Michael H. Coen (a1) (a2), Asenath La Rue (a3), Erin Jonaitis (a3), Rebecca L. Koscik (a3), Bruce Hermann (a3) (a4) and Mark A. Sager (a3) (a5)...

Identification of preclinical Alzheimer's disease (AD) is an essential first step in developing interventions to prevent or delay disease onset. In this study, we examine the hypothesis that deeper analyses of traditional cognitive tests may be useful in identifying subtle but potentially important learning and memory differences in asymptomatic populations that differ in risk for developing Alzheimer's disease. Subjects included 879 asymptomatic higher-risk persons (middle-aged children of parents with AD) and 355 asymptotic lower-risk persons (middle-aged children of parents without AD). All were administered the Rey Auditory Verbal Learning Test at baseline. Using machine learning approaches, we constructed a new measure that exploited finer differences in memory strategy than previous work focused on serial position and subjective organization. The new measure, based on stochastic gradient descent, provides a greater degree of statistical separation (p = 1.44 × 10−5) than previously observed for asymptomatic family history and non-family history groups, while controlling for apolipoprotein epsilon 4, age, gender, and education level. The results of our machine learning approach support analyzing memory strategy in detail to probe potential disease onset. Such distinct differences may be exploited in asymptomatic middle-aged persons as a potential risk factor for AD. (JINS, 2012, 18, 428–439)

Corresponding author
Correspondence and reprint requests to: Timothy S. Chang, Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, 6795 Medical Sciences Center, 1300 University Avenue, Madison, WI 53706. E-mail:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

L. Bäckman , S. Jones , A.K. Berger , E.J. Laukka , B.J. Small (2005). Cognitive impairment in preclinical Alzheimer's disease: A meta-analysis. Neuropsychology, 19(4), 520531. doi:10.1037/0894-4105.19.4.520

D.E. Barnes , K. Yaffe (2011). The projected effect of risk factor reduction on Alzheimer's disease prevalence. The Lancet Neurology, 10(9), 819828. doi:10.1016/S1474-4422(11)70072-2

S.S. Bassett , D.M. Yousem , C. Cristinzio , I. Kusevic , M.A. Yassa , B.S. Caffo , S.L. Zeger (2006). Familial risk for Alzheimer's disease alters fMRI activation patterns. Brain, 129(5), 12291239. doi:10.1093/brain/awl089

A.L. Benton (1994). Neuropsychological assessment. Annual Review of Psychology, 45, 123. doi:10.1146/

A.K. Bousfield , W.A. Bousfield (1966). Measurement of clustering and of sequential constancies in repeated free recall. Psychological Reports, 19(3), 935942. doi:10.2466/pr0.1966.19.3.935

H. Braak , E. Braak (1990). Alzheimer's disease: Striatal amyloid deposits and neurofibrillary changes. Journal of Neuropathology and Experimental Neurology, 49(3), 215224. Retrieved from

G.A. Carlesimo , M. Sabbadini , L. Fadda , C. Caltagirone (1997). Word-list forgetting in young and elderly subjects: Evidence for age-related decline in transferring information from transitory to permanent memory condition. Cortex, 33(1), 155166. Retrieved from

J. Cohen (1988). Statistical power analysis for the behavioral sciences (2nd ed.). Hillsdale, NJ: Lawrence Erlbaum.

E.H. Corder , J. Caskey (2009). Early intervention in Alzheimer disease: The importance of APOE4 plus family history. Neurology, 73(24), 20542055. doi:10.1212/WNL.0b013e3181c67870

L.A. Cupples , L.A. Farrer , A.D. Sadovnick , N. Relkin , P. Whitehouse , R.C. Green (2004). Estimating risk curves for first-degree relatives of patients with Alzheimer's disease: The REVEAL study. Genetics in Medicine, 6(4), 192196. doi:10.1097/01.GIM.0000132679.92238.58

S. Debette , P.A. Wolf , A. Beiser , R. Au , J.J. Himali , A. Pikula , S. Seshadri (2009). Association of parental dementia with cognitive and brain MRI measures in middle-aged adults. Neurology, 73(24), 20712078. doi:10.1212/WNL.0b013e3181c67833

N.M. Dowling , B. Hermann , A. La Rue , M.A. Sager (2010). Latent structure and factorial invariance of a neuropsychological test battery for the study of preclinical Alzheimer's disease. Neuropsychology, 24(6), 742756. doi:10.1037/a0020176

M.F. Elias , A. Beiser , P.A. Wolf , R. Au , R.F. White , R.B. D'Agostino (2000). The preclinical phase of alzheimer disease: A 22-year prospective study of the Framingham Cohort. Archives of Neurology, 57(6), 808813. doi:10.1001/archneur.57.6.808

N.S. Foldi , A.M. Brickman , L.A. Schaefer , M.E. Knutelska (2003). Distinct serial position profiles and neuropsychological measures differentiate late life depression from normal aging and Alzheimer's disease. Psychiatry Research, 120(1), 7184. doi:10.1016/S0165-1781(03)00163-X

M. Grundman , R.C. Petersen , S.H. Ferris , R.G. Thomas , P.S. Aisen , D.A. Bennett , L.J. Thal (2004). Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Archives of Neurology, 61(1), 5966. doi:10.1001/archneur.61.1.59

K.M. Hayden , P.P. Zandi , N.A. West , J.T. Tschanz , M.C. Norton , C. Corcoran , K.A. Welsh-Bohmer (2009). Effects of family history and apolipoprotein E epsilon4 status on cognitive decline in the absence of Alzheimer dementia: The Cache County Study. Archives of Neurology, 66(11), 13781383. doi:10.1001/archneurol.2009.237

H.C. Hendrie , M.S. Albert , M.A. Butters , S. Gao , D.S. Knopman , L.J. Launer , M.V. Wagster (2006). The NIH Cognitive and Emotional Health Project. Report of the Critical Evaluation Study Committee. Alzheimer's & Dementia, 2(1), 1232. doi:10.1016/j.jalz.2005.11.004

B.P. Hermann , M. Seidenberg , A. Wyler , K. Davies , J. Christeson , M. Moran , E. Stroup (1996). The effects of human hippocampal resection on the serial position curve. Cortex, 32(2), 323334. Retrieved from

C.R. Jack , R.C. Petersen , Y.C. Xu , P.C. O'Brien , G.E. Smith , R.J. Ivnik , E. Kokmen (1999). Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology, 52(7), 13971403. Retrieved from

C.H. Kawas , M.M. Corrada , R. Brookmeyer , A. Morrison , S.M. Resnick , A.B. Zonderman , D. Arenberg (2003). Visual memory predicts Alzheimer's disease more than a decade before diagnosis. Neurology, 60(7), 10891093. doi:10.1212/01.WNL.0000055813.36504.BF

R.J. Killiany , T. Gomez-Isla , M. Moss , R. Kikinis , T. Sandor , F. Jolesz , M.S. Albert (2000). Use of structural magnetic resonance imaging to predict who will get Alzheimer's disease. Annals of Neurology, 47(4), 430439. doi:10.1002/1531-8249(200004)47:4<430::AID-ANA5>3.3.CO;2-9

N.T. Lautenschlager , L.A. Cupples , V.S. Rao , S.A. Auerbach , R. Becker , J. Burke , L.A. Farrer (1996). Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: What is in store for the oldest old? Neurology, 46(3), 641650. Retrieved from

G. McKhann , D. Drachman , M. Folstein , R. Katzman , D. Price , E.M. Stadlan (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(7), 939944. Retrieved from

L. Mosconi , M. Brys , R. Switalski , R. Mistur , L. Glodzik , E. Pirraglia , M.J. de Leon (2007). Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism. Proceedings of the National Academy of Sciences of the United States of America, 104(48), 1906719072. doi:10.1073/pnas.0705036104

I.H. Ramakers , P.J. Visser , P. Aalten , O. Bekers , K. Sleegers , C.L. van Broeckhoven , F.R. Verhey (2008). The association between APOE genotype and memory dysfunction in subjects with mild cognitive impairment is related to age and Alzheimer pathology. Dementia and Geriatric Cognitive Disorders, 26, 101108. doi:10.1159/000144072

I.H. Ramakers , P.J. Visser , P. Aalten , H.L. Maes , H.G. Lansdaal , C.J. Meijs , F.R. Verhey (2010). The predictive value of memory strategies for Alzheimer's disease in subjects with mild cognitive impairment. Archives of Clinical Neuropsychology, 25(1), 7177. doi:10.1093/arclin/acp093

D.A. Snowdon , S.J. Kemper , J.A. Mortimer , L.H. Greiner , D.R. Wekstein , W.R. Markesbery (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(7), 528532. doi:10.1001/jama.1996.03530310034029

R.A. Sperling , P.S. Aisen , L.A. Beckett , D.A. Bennett , S. Craft , A.M. Fagan , C.H. Phelps (2011). Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging and the Alzheimer's Association workgroup. Alzheimer's and Dementia, 7(3), 113. doi:10.1016/j.jalz.2011.03.003

E. van Exel , P. Eikelenboom , H. Comijs , M. Frölich , J.H. Smit , M.L. Stek , R.G. Westendorp (2009). Vascular factors and markers of inflammation in offspring with a parental history of late-onset Alzheimer disease. Archives of General Psychiatry, 66(11), 12631270. doi:10.1001/archgenpsychiatry.2009.146

P. van Vliet , R.G. Westendorp , P. Eikelenboom , H.C. Comijs , M. Frolich , E. Bakker , E. van Exel (2009). Parental history of Alzheimer disease associated with lower plasma apolipoprotein E levels. Neurology, 73(9), 681687. doi:10.1212/WNL.0b013e3181b59c2e

P. Verhaeghen , A. Marcoen , L. Goossens (1992). Improving memory performance in the aged through mnemonic training: A meta-analytic study. Psychology and Aging, 7(2), 242251. doi:10.1037/0882-7974.7.2.242

K. Welsh , N. Butters , J. Hughes , R. Mohs , A. Heyman (1991). Detection of abnormal memory decline in mild cases of Alzheimer's disease using CERAD neuropsychological measures. Archives of Neurology, 48(3), 278281. doi:10.1001/archneur.1991.00530150046016

N.M. Wisdom , J.L. Callahan , K.A. Hawkins (2011). The effects of apolipoprotein E on non-impaired cognitive functioning: A meta-analysis. Neurobiology of Aging, 32(1), 6374. doi:10.1016/j.neurobiolaging.2009.02.003

G. Xu , D.G. McLaren , M.L. Ries , M.E. Fitzgerald , B.B. Bendlin , H.A. Rowley , S.C. Johnson (2009). The influence of parental history of Alzheimer's disease and apolipoprotein E epsilon4 on the BOLD signal during recognition memory. Brain, 132(2), 383391. doi:10.1093/brain/awn254

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Journal of the International Neuropsychological Society
  • ISSN: 1355-6177
  • EISSN: 1469-7661
  • URL: /core/journals/journal-of-the-international-neuropsychological-society
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 1
Total number of PDF views: 14 *
Loading metrics...

Abstract views

Total abstract views: 118 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 20th September 2017. This data will be updated every 24 hours.