Measuring cognition and function in the preclinical stage of Alzheimer's disease

Sandra Weintraub, Maria C Carrillo, Sarah Tomaszewski Farias, Terry E Goldberg, James A Hendrix, Judith Jaeger, David S Knopman, Jessica B Langbaum, Denise C Park, Michael T Ropacki, Sietske A M Sikkes, Kathleen A Welsh-Bohmer, Lisa J Bain, Robert Brashear, Kumar Budur, Ana Graf, Ferenc Martenyi, Marta Segardahl Storck, Christopher Randolph, Sandra Weintraub, Maria C Carrillo, Sarah Tomaszewski Farias, Terry E Goldberg, James A Hendrix, Judith Jaeger, David S Knopman, Jessica B Langbaum, Denise C Park, Michael T Ropacki, Sietske A M Sikkes, Kathleen A Welsh-Bohmer, Lisa J Bain, Robert Brashear, Kumar Budur, Ana Graf, Ferenc Martenyi, Marta Segardahl Storck, Christopher Randolph

Abstract

The Alzheimer's Association's Research Roundtable met in November 2016 to explore how best to measure changes in cognition and function in the preclinical stage of Alzheimer's disease. This review will cover the tools and instruments currently available to identify populations for prevention trials, and measure subtle disease progression in the earliest stages of Alzheimer's disease, and will include discussions of suitable cognitive, behavioral, functional, composite, and biological endpoints for prevention trials. Current prevention trials are reviewed including TOMMOROW, Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Trial, the Alzheimer's Prevention Initiative Generation Study, and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's to compare current approaches and tools that are being developed.

Figures

Fig. 1
Fig. 1
Hypothetical interaction of amyloid and tau in preclinical AD. Abbreviations: AD, Alzheimer's disease; MTL, medial temporal lobe.

References

    1. Park D.C., Lautenschlager G., Hedden T., Davidson N.S., Smith A.D., Smith P.K. Models of visuospatial and verbal memory across the adult life span. Psychol Aging. 2002;17:299–320.
    1. Park D.C., Reuter-Lorenz P. The adaptive brain: aging and neurocognitive scaffolding. Annu Rev Psychol. 2009;60:173–196.
    1. Mormino E.C., Kluth J.T., Madison C.M., Rabinovici G.D., Baker S.L., Miller B.L. Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects. Brain. 2009;132(Pt 5):1310–1323.
    1. Rodrigue K.M., Kennedy K.M., Devous M.D., Sr., Rieck J.R., Hebrank A.C., Diaz-Arrastia R. beta-Amyloid burden in healthy aging: regional distribution and cognitive consequences. Neurology. 2012;78:387–395.
    1. Holtzman D.M., Herz J., Bu G. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2:a006312.
    1. Sperling R., Mormino E., Johnson K. The evolution of preclinical Alzheimer's disease: implications for prevention trials. Neuron. 2014;84:608–622.
    1. Dodge H.H., Zhu J., Lee C.W., Chang C.C., Ganguli M. Cohort effects in age-associated cognitive trajectories. J Gerontol A Biol Sci Med Sci. 2014;69:687–694.
    1. Derby C.A., Katz M.J., Lipton R.B., Hall C.B. Trends in dementia incidence in a birth cohort analysis of the Einstein Aging Study. JAMA Neurol. 2017;74:1345–1351.
    1. Villemagne V.L., Burnham S., Bourgeat P., Brown B., Ellis K.A., Salvado O. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol. 2013;12:357–367.
    1. Salthouse T.A. Why are there different age relations in cross-sectional and longitudinal comparisons of cognitive functioning? Curr Dir Psychol Sci. 2014;23:252–256.
    1. Hedden T., Lautenschlager G., Park D.C. Contributions of processing ability and knowledge to verbal memory tasks across the adult life-span. Q J Exp Psychol A. 2005;58:169–190.
    1. Chen X., Hertzog C., Park D.C. Cognitive predictors of everyday problem solving across the lifespan. Gerontology. 2017;63:372–384.
    1. Jekel K., Damian M., Wattmo C., Hausner L., Bullock R., Connelly P.J. Mild cognitive impairment and deficits in instrumental activities of daily living: a systematic review. Alzheimers Res Ther. 2015;7:17.
    1. Sikkes S.A., de Lange-de Klerk E.S., Pijnenburg Y.A., Scheltens P., Uitdehaag B.M. A systematic review of Instrumental Activities of Daily Living scales in dementia: room for improvement. J Neurol Neurosurg Psychiatry. 2009;80:7–12.
    1. Sliwinski M.J., Mogle J.A., Hyun J., Munoz E., Smyth J.M., Lipton R.B. Reliability and validity of ambulatory cognitive assessments. Assessment. 2018;25:14–30.
    1. Weintraub S., Dikmen S.S., Heaton R.K., Tulsky D.S., Zelazo P.D., Bauer P.J. Cognition assessment using the NIH Toolbox. Neurology. 2013;80(11 Suppl 3):S54–S64.
    1. Weintraub S., Dikmen S.S., Heaton R.K., Tulsky D.S., Zelazo P.D., Slotkin J. The cognition battery of the NIH toolbox for assessment of neurological and behavioral function: validation in an adult sample. J Int Neuropsychol Soc. 2014;20:567–578.
    1. Boyle P.A., Wilson R.S., Yu L., Barr A.M., Honer W.G., Schneider J.A. Much of late life cognitive decline is not due to common neurodegenerative pathologies. Ann Neurol. 2013;74:478–489.
    1. Boyle P.A., Yu L., Wilson R.S., Schneider J.A., Bennett D.A. Relation of neuropathology with cognitive decline among older persons without dementia. Front Aging Neurosci. 2013;5:50.
    1. McKhann G., Drachman D., Folstein M., Katzman R., Price D., Stadlan E.M. 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. 1984;34:939–944.
    1. Winblad B., Palmer K., Kivipelto M., Jelic V., Fratiglioni L., Wahlund L.O. Mild cognitive impairment - beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004;256:240–246.
    1. Petersen R.C., Smith G.E., Waring S.C., Ivnik R.J., Tangalos E.G., Kokmen E. Mild cognitive impairment–Clinical characterization and outcome. Arch Neurol. 1999;56:303–308.
    1. Villemagne V.L., Burnham S.C., Bourgeat P., Dore V., Brown B.M., Laws S.M. Revisiting, revising, and refining the natural history of Abeta deposition and its effects on neurodegeneration and cognitive decline in sporadic Alzheimer's disease. Alzheimers Dement. 2016;12:P350.
    1. Harrington K.D., Lim Y.Y., Ames D., Hassenstab J., Rainey-Smith S., Robertson J. Using Robust Normative Data to Investigate the Neuropsychology of Cognitive Aging. Arch Clin Neuropsychol. 2017;32:142–154.
    1. Donohue M.C., Sperling R.A., Salmon D.P., Rentz D.M., Raman R., Thomas R.G. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. 2014;71:961–970.
    1. Amieva H., Le Goff M., Millet X., Orgogozo J.M., Peres K., Barberger-Gateau P. Prodromal Alzheimer's disease: successive emergence of the clinical symptoms. Ann Neurol. 2008;64:492–498.
    1. Bateman R.J., Xiong C., Benzinger T.L., Fagan A.M., Goate A., Fox N.C. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012;367:795–804.
    1. Rentz D.M., Weintraub S. Neuropsychological detection of early probably Alzheimer's disease. In: Scinto L.F.M., Daffner K.R., editors. Early diagnosis and treatment of Alzheimer's disease. Humana Press, Inc; Totowa, New Jersey: 2000.
    1. Sperling R.A., Aisen P.S., Beckett L.A., Bennett D.A., Craft S., Fagan A.M. Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging and the Alzheimer's Association workgroup. Alzheimers Dement. 2011;7:280–292.
    1. Albert M.S., Dekosky S.T., Dickson D., Dubois B., Feldman H.H., Fox N.C. The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:270–279.
    1. McKhann G.M., Knopman D.S., Chertkow H., Hyman B.T., Jack C.R., Jr., Kawas C.H. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging and the Alzheimer's Association workgroup. Alzheimers Dement. 2011;7:263–269.
    1. Wagner M., Wolf S., Reischies F.M., Daerr M., Wolfsgruber S., Jessen F. Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease. Neurology. 2012;78:379–386.
    1. Doraiswamy P.M., Sperling R.A., Johnson K., Reiman E.M., Wong T.Z., Sabbagh M.N. Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study. Mol Psychiatry. 2014;19:1044–1051.
    1. Lim Y.Y., Maruff P., Pietrzak R.H., Ames D., Ellis K.A., Harrington K. Effect of amyloid on memory and non-memory decline from preclinical to clinical Alzheimer's disease. Brain. 2014;137:221–231.
    1. Petersen R.C., Wiste H.J., Weigand S.D., Rocca W.A., Roberts R.O., Mielke M.M. Association of elevated amyloid levels with cognition and biomarkers in cognitively normal people from the community. JAMA Neurol. 2016;73:85–92.
    1. Burnham S.C., Bourgeat P., Dore V., Savage G., Brown B., Laws S. Clinical and cognitive trajectories in cognitively healthy elderly individuals with suspected non-Alzheimer's disease pathophysiology (SNAP) or Alzheimer's disease pathology: a longitudinal study. Lancet Neurol. 2016;15:1044–1053.
    1. Mormino E.C., Papp K.V. Cognitive decline in preclinical stage 2 Alzheimer disease and implications for prevention trials. JAMA Neurol. 2016;73:640–642.
    1. Soldan A., Pettigrew C., Cai Q., Wang M.C., Moghekar A.R., O'Brien R.J. Hypothetical preclinical Alzheimer disease groups and longitudinal cognitive change. JAMA Neurol. 2016;73:698–705.
    1. Mormino E.C., Papp K.V., Schultz A.P., Hanseeuw B.J., Munro C.E., Jaimes S.Y. Alzheimer's Association International Conference; Toronto, Canada: 2016. AB+ clinically normal participants with elevated tau show greatest decline in the preclinical Alzheimer's disease cognitive composite; p. P333.
    1. Jack C.R., Jr., Wiste H.J., Weigand S.D., Knopman D.S., Mielke M.M., Vemuri P. Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings. Brain. 2015;138(Pt 12):3747–3759.
    1. Alexopoulos P., Kriett L., Haller B., Klupp E., Gray K., Grimmer T. Limited agreement between biomarkers of neuronal injury at different stages of Alzheimer's disease. Alzheimers Dement. 2014;10:684–689.
    1. Caroli A., Prestia A., Wade S., Chen K., Ayutyanont N., Landau S.M. Alzheimer disease biomarkers as outcome measures for clinical trials in MCI. Alzheimer Dis Assoc Disord. 2015;29:101–109.
    1. Chetelat G. Alzheimer disease: Abeta-independent processes-rethinking preclinical AD. Nat Rev Neurol. 2013;9:123–124.
    1. Chetelat G., Desgranges B., Landeau B., Mezenge F., Poline J.B., de la Sayette V. Direct voxel-based comparison between grey matter hypometabolism and atrophy in Alzheimer's disease. Brain. 2008;131(Pt 1):60–71.
    1. Toledo J.B., Weiner M.W., Wolk D.A., Da X., Chen K., Arnold S.E. Neuronal injury biomarkers and prognosis in ADNI subjects with normal cognition. Acta Neuropathol Commun. 2014;2:26.
    1. Wirth M., Madison C.M., Rabinovici G.D., Oh H., Landau S.M., Jagust W.J. Alzheimer's disease neurodegenerative biomarkers are associated with decreased cognitive function but not beta-amyloid in cognitively normal older individuals. J Neurosci. 2013;33:5553–5563.
    1. Mormino E.C., Betensky R.A., Hedden T., Schultz A.P., Ward A., Huijbers W. Amyloid and APOE ε4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology. 2014;82:1760–1767.
    1. Amariglio R.E., Mormino E.C., Pietras A.C., Marshall G.A., Vannini P., Johnson K.A. Subjective cognitive concerns, amyloid-beta, and neurodegeneration in clinically normal elderly. Neurology. 2015;85:56–62.
    1. Samieri C., Proust-Lima C., Glymour M M., Okereke O.I., Amariglio R.E., Sperling R.A. Subjective cognitive concerns, episodic memory, and the APOE ε4 allele. Alzheimers Dement. 2014;10:752–759.e1.
    1. Food and Drug Administration . 2013. Draft Guidance for Industry. Alzheimer's disease: Developing drugs for the treatment of early stage disease. Available at.
    1. Vassar R., Kuhn P.H., Haass C., Kennedy M.E., Rajendran L., Wong P.C. Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects. J Neurochem. 2014;130:4–28.
    1. Ayutyanont N., Langbaum J.B., Hendrix S.B., Chen K., Fleisher A.S., Friesenhahn M. The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers. J Clin Psychiatry. 2014;75:652–660.
    1. Langbaum J.B., Hendrix S.B., Ayutyanont N., Chen K., Fleisher A.S., Shah R.C. An empirically derived composite cognitive test score with improved power to track and evaluate treatments for preclinical Alzheimer's disease. Alzheimers Dement. 2014;10:666–674.
    1. Sperling R.A., Rentz D.M., Johnson K.A., Karlawish J., Donohue M., Salmon D.P. The A4 study: stopping AD before symptoms begin? Sci Transl Med. 2014;6:228fs13.
    1. Hassenstab J. Paper presented at ADPD meeting, April 2017; reference to be added. 2017.
    1. Hassenstab J, Hagen C, Han B, Lim YY, Maruff P, Mielke MM, et al. Reliability and reproducibility of cognitive composites for Alzheimer's disease secondary prevention trials: The power PACC. Paper presented at ADPD 2017; Vienna, Austria.
    1. Ritchie K., Ropacki M., Albala B., Harrison J., Kaye J., Kramer J. Recommended cognitive outcomes in preclinical Alzheimer's disease: Consensus statement from the European Prevention of Alzheimer's Dementia project. Alzheimers Dement. 2017;13:186–195.
    1. Mortamais M., Ash J.A., Harrison J., Kaye J., Kramer J., Randolph C. Detecting cognitive changes in preclinical Alzheimer's disease: A review of its feasibility. Alzheimers Dement. 2017;13:468–492.
    1. Farias S.T., Chou E., Harvey D.J., Mungas D., Reed B., DeCarli C. Longitudinal trajectories of everyday function by diagnostic status. Psychol Aging. 2013;28:1070–1075.
    1. Marshall G.A., Amariglio R.E., Sperling R.A., Rentz D.M. Activities of daily living: where do they fit in the diagnosis of Alzheimer's disease? Neurodegener Dis Manag. 2012;2:483–491.
    1. Sikkes S.A., Visser P.J., Knol D.L., de Lange-de Klerk E.S., Tsolaki M., Frisoni G.B. Do instrumental activities of daily living predict dementia at 1- and 2-year follow-up? Findings from the Development of Screening guidelines and diagnostic Criteria for Predementia Alzheimer's disease study. J Am Geriatr Soc. 2011;59:2273–2281.
    1. Goldberg T.E., Koppel J., Keehlisen L., Christen E., Dreses-Werringloer U., Conejero-Goldberg C. Performance-based measures of everyday function in mild cognitive impairment. Am J Psychiatry. 2010;167:845–853.
    1. Gomar J.J., Harvey P.D., Bobes-Bascaran M.T., Davies P., Goldberg T.E. Development and cross-validation of the UPSA short form for the performance-based functional assessment of patients with mild cognitive impairment and Alzheimer disease. Am J Geriatr Psychiatry. 2011;19:915–922.
    1. Kirchberg B.C., Cohen J.R., Adelsky M.B., Buthorn J.J., Gomar J.J., Gordon M. Semantic distance abnormalities in mild cognitive impairment: their nature and relationship to function. Am J Psychiatry. 2012;169:1275–1283.
    1. Sousa A., Gomar J.J., Ragland J.D., Conejero-Goldberg C., Buthorn J., Keehlisen L. The relational and item-specific encoding task in mild cognitive impairment and Alzheimer disease. Dement Geriatr Cogn Disord. 2016;42:265–277.
    1. Marshall G.A., Dekhtyar M., Bruno J.M., Jethwani K., Amariglio R.E., Johnson K.A. The Harvard Automated Phone Task: new performance-based activities of daily living tests for early Alzheimer's disease. J Prev Alzheimers Dis. 2015;2:242–253.
    1. Triebel K.L., Martin R., Griffith H.R., Marceaux J., Okonkwo O.C., Harrell L. Declining financial capacity in mild cognitive impairment: A 1-year longitudinal study. Neurology. 2009;73:928–934.
    1. Farias S.T., Mungas D., Reed B.R., Cahn-Weiner D., Jagust W., Baynes K. The measurement of everyday cognition (ECog): scale development and psychometric properties. Neuropsychology. 2008;22:531–544.
    1. Rueda A.D., Lau K.M., Saito N., Harvey D., Risacher S.L., Aisen P.S. Self-rated and informant-rated everyday function in comparison to objective markers of Alzheimer's disease. Alzheimers Dement. 2015;11:1080–1089.
    1. Farias S.T., Park L.Q., Harvey D.J., Simon C., Reed B.R., Carmichael O. Everyday cognition in older adults: associations with neuropsychological performance and structural brain imaging. J Int Neuropsychol Soc. 2013;19:430–441.
    1. Lau K.M., Parikh M., Harvey D.J., Huang C.J., Farias S.T. Early cognitively based functional limitations predict loss of independence in instrumental activities of daily living in older adults. J Int Neuropsychol Soc. 2015;21:688–698.
    1. Farias S.T., Lau K., Harvey D., Denny K.G., Barba C., Mefford A.N. Early functional limitations in cognitively normal older adults predict diagnostic conversion to mild cognitive impairment. J Am Geriatr Soc. 2017;65:1152–1158.
    1. Weber M.T., Mapstone M., Staskiewicz J., Maki P.M. Reconciling subjective memory complaints with objective memory performance in the menopausal transition. Menopause. 2012;19:735–741.
    1. Sikkes S.A., Hooghiemstra A.M., Pijnenburg Y.A., Scheltens P. AAIC; Toronto, CA: 2016. The past, present, and future of instrumental activities of daily living assessments in Alzheimer's disease; p. P372. Alzheimer's & Dementia; 2016.
    1. Sikkes S.A., de Lange-de Klerk E.S., Pijnenburg Y.A., Gillissen F., Romkes R., Knol D.L. A new informant-based questionnaire for instrumental activities of daily living in dementia. Alzheimers Dement. 2012;8:536–543.
    1. Koster N., Knol D.L., Uitdehaag B.M., Scheltens P., Sikkes S.A. The sensitivity to change over time of the Amsterdam IADL Questionnaire(©) Alzheimers Dement. 2015;11:1231–1240.
    1. Jutten R.J., Peeters C.F.W., Leijdesdorff S.M.J., Visser P.J., Maier A.B., Terwee C.B. Detecting functional decline from normal aging to dementia: Development and validation of a short version of the Amsterdam IADL Questionnaire. Alzheimers Dement (Amst) 2017;8:26–35.
    1. Jack C.R., Jr., Knopman D.S., Weigand S.D., Wiste H.J., Vemuri P., Lowe V. An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease. Ann Neurol. 2012;71:765–775.
    1. Jack C.R., Jr., Knopman D.S., Chetelat G., Dickson D., Fagan A.M., Frisoni G.B. Suspected non-Alzheimer disease pathophysiology–concept and controversy. Nat Rev Neurol. 2016;12:117–124.
    1. Reiman E.M., Langbaum J.B., Fleisher A.S., Caselli R.J., Chen K., Ayutyanont N. Alzheimer's Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J Alzheimers Dis. 2011;26(Suppl 3):321–329.
    1. Mills S.M., Mallmann J., Santacruz A.M., Fuqua A., Carril M., Aisen P.S. Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial. Rev Neurol (Paris) 2013;169:737–743.
    1. Roses A.D., Saunders A.M., Lutz M.W., Zhang N., Hariri A.R., Asin K.E. New applications of disease genetics and pharmacogenetics to drug development. Curr Opin Pharmacol. 2014;14:81–89.
    1. Ropacki M. Placeholder of clinical meaningfulness paper in press. 2017.
    1. Jutten R.J., Harrison J., de Jong F.J., Aleman A., Ritchie C.W., Scheltens P. A composite measure of cognitive and functional progression in Alzheimer's disease: Design of the Capturing Changes in Cognition study. Alzheimers Dement (N Y) 2017;3:130–138.
    1. European Medicines Agency . (CHMP) CfMPfHU. 2016. Draft guideline on the clinical investigation of medicines for the treatment of Alzheimer's disease and other dementia. EMA: London, United Kingdom. Available at: .
    1. Rogalski E., Sridhar J., Rader B., Martersteck A., Chen K., Cobia D. Aphasic variant of Alzheimer disease: Clinical, anatomic, and genetic features. Neurology. 2016;87:1337–1343.
    1. Albers M.W., Gilmore G.C., Kaye J., Murphy C., Wingfield A., Bennett D.A. At the interface of sensory and motor dysfunctions and Alzheimer's disease. Alzheimers Dement. 2015;11:70–98.
    1. Barnes L.L., Mendes de Leon C.F., Wilson R.S., Bienias J.L., Evans D.A. Social resources and cognitive decline in a population of older African Americans and whites. Neurology. 2004;63:2322–2326.
    1. Beauchet O., Allali G., Launay C., Herrmann F.R., Annweiler C. Gait variability at fast-pace walking speed: a biomarker of mild cognitive impairment? J Nutr Health Aging. 2013;17:235–239.
    1. Buracchio T., Dodge H.H., Howieson D., Wasserman D., Kaye J. The trajectory of gait speed preceding mild cognitive impairment. Arch Neurol. 2010;67:980–986.
    1. Gras L.Z., Kanaan S.F., McDowd J.M., Colgrove Y.M., Burns J., Pohl P.S. Balance and gait of adults with very mild Alzheimer disease. J Geriatr Phys Ther. 2015;38:1–7.
    1. Montero-Odasso M., Casas A., Hansen K.T., Bilski P., Gutmanis I., Wells J.L. Quantitative gait analysis under dual-task in older people with mild cognitive impairment: a reliability study. J Neuroeng Rehabil. 2009;6:35.
    1. Uhlmann R.F., Larson E.B., Rees T.S., Koepsell T.D., Duckert L.G. Relationship of hearing impairment to dementia and cognitive dysfunction in older adults. JAMA. 1989;261:1916–1919.
    1. Wilson R.S., Schneider J.A., Arnold S.E., Tang Y., Boyle P.A., Bennett D.A. Olfactory identification and incidence of mild cognitive impairment in older age. Arch Gen Psychiatry. 2007;64:802–808.
    1. Yan J.H., Rountree S., Massman P., Doody R.S., Li H. Alzheimer's disease and mild cognitive impairment deteriorate fine movement control. J Psychiatr Res. 2008;42:1203–1212.
    1. Karlawish J., Langa K.M. Unfinished Business in Preventing Alzheimer Disease. JAMA Intern Med. 2016;176:1739–1740.

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