Cognitive reserve (CR) may reduce the risk of dementia. We summarized the effect of CR on progression to mild cognitive impairment (MCI) or dementia in studies accounting for Alzheimer's disease (AD)-related structural pathology and biomarkers. Literature search was conducted in Web of Science, PubMed, Embase, and PsycINFO. Relevant articles were longitudinal, in English, and investigating MCI or dementia incidence. Meta-analysis was conducted on nine articles, four measuring CR as cognitive residual of neuropathology and five as composite psychosocial proxies (e.g., education). High CR was related to a 47% reduced relative risk of MCI or dementia (pooled-hazard ratio: 0.53 [0.35, 0.81]), with residual-based CR reducing risk by 62% and proxy-based CR by 48%. CR protects against MCI and dementia progression above and beyond the effect of AD-related structural pathology and biomarkers. The finding that proxy-based measures of CR rivaled residual-based measures in terms of effect on dementia incidence underscores the importance of early- and mid-life factors in preventing dementia later.

Department of Neurology 2nd Medical Faculty and Motol University Hospital Charles University Prague Czech Republic

Department of Neurology University of Southern California Los Angeles CA USA

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

School of Aging Studies University of South Florida Tampa FL USA

Zobrazit více v PubMed

Albert M, Zhu Y, Moghekar A, Mori S, Miller MI, Soldan A, et al. Predicting progression from normal cognition to mild cognitive impairment for individuals at 5 years. Brain. 2018;141(3):877–887. doi: 10.1093/brain/awx365. PubMed DOI PMC

Allegri RF, Taragano FE, Krupitzki H, Serrano CM, Dillon C, Sarasola D, et al. Role of cognitive reserve in progression from mild cognitive impairment to dementia. Dementia & Neuropsychologia. 2010;4(1):28–34. doi: 10.1590/S1980-57642010DN40100005. PubMed DOI PMC

Andel R, Crowe M, Pedersen NL, Mortimer J, Crimmins E, Johansson B, et al. Complexity of work and risk of Alzheimer's disease: A population-based study of Swedish twins. The Journals of Gerontology: Series B. 2005;60(5):P251–P258. doi: 10.1093/geronb/60.5.p251. PubMed DOI

Arenaza-Urquijo EM, Vemuri P. Resistance vs resilience to Alzheimer disease: Clarifying terminology for preclinical studies. Neurology. 2018;90(15):695–703. doi: 10.1212/wnl.0000000000005303. PubMed DOI PMC

Arenaza-Urquijo EM, Vemuri P. Improving the resistance and resilience framework for aging and dementia studies. Alzheimer's Research & Therapy. 2020;12(1):1–4. doi: 10.1186/s13195-020-00609-2. PubMed DOI PMC

Association A. 2019 Alzheimer’s Disease Facts and Figures. Alzheimers & Dementia. 2019;15(3):321–387. doi: 10.1016/j.jalz.2019.01.010. DOI

Bartres-Faz D, Arenaza-Urquijo EM. Structural and functional imaging correlates of cognitive and brain reserve hypotheses in healthy and pathological aging. Brain Topography. 2011;24(3–4):340–357. doi: 10.1007/s10548-011-0195-9. PubMed DOI

Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. American Journal of Public Health. 1998;88(9):1337–1342. doi: 10.2105/ajph.88.9.1337. PubMed DOI PMC

Cabeza R, Albert M, Belleville S, Craik FIM, Duarte A, Grady CL, et al. Maintenance, reserve and compensation: The cognitive neuroscience of healthy ageing. Nature Reviews Neuroscience. 2018;19(11):701–710. doi: 10.1038/s41583-018-0068-2. PubMed DOI PMC

Clouston SAP, Glymour MM, Terrera GM. Educational inequalities in aging-related declines in fluid cognition and the onset of cognitive pathology. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. 2015;1(3):303–310. doi: 10.1016/j.dadm.2015.06.001. PubMed DOI PMC

Dekhtyar S, Marseglia A, Xu W, Darin-Mattsson A, Wang HX, Fratiglioni L. Genetic risk of dementia mitigated by cognitive reserve: A cohort study. Annals of Neurology. 2019;86(1):68–78. doi: 10.1002/ana.25501. PubMed DOI PMC

Dekhtyar S, Wang HX, Scott K, Goodman A, Koupil I, Herlitz A. A life-course study of cognitive reserve in dementia–From childhood to old age. The American Journal of Geriatric Psychiatry. 2015;23(9):885–896. doi: 10.1016/j.jagp.2015.02.002. PubMed DOI

Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56(2):455–463. doi: 10.1111/j.0006-341x.2000.00455.x. PubMed DOI

Garibotto V, Borroni B, Kalbe E, Herholz K, Salmon E, Holtoff V, et al. Education and occupation as proxies for reserve in aMCI converters and AD: FDG-PET evidence. Neurology. 2008;71(17):1342–1349. doi: 10.1212/01.wnl.0000327670.62378.c0. PubMed DOI

Henneman WJP, Sluimer JD, Barnes J, van der Flier WM, Sluimer IC, Fox NC, et al. Hippocampal atrophy rates in Alzheimer disease: Added value over whole brain volume measures. Neurology. 2009;72(11):999–1007. doi: 10.1212/01.wnl.0000344568.09360.31. PubMed DOI PMC

Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine. 2002;21(11):1539–1558. doi: 10.1002/sim.1186. PubMed DOI

Hoenig MC, Bischof GN, Hammes J, Faber J, Fliessbach K, van Eimeren T, et al. Tau pathology and cognitive reserve in Alzheimer's disease. Neurobiology of Aging. 2017;57:1–7. doi: 10.1016/j.neurobiolaging.2017.05.004. PubMed DOI

Hohman TJ, McLaren DG, Mormino EC, Gifford KA, Libon DJ, Jefferson AL. Asymptomatic Alzheimer disease: Defining resilience. Neurology. 2016;87(23):2443–2450. doi: 10.1212/WNL.0000000000003397. PubMed DOI PMC

Jack CR, Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research framework: Toward a biological definition of Alzheimer's disease. Alzheimer's & Dementia. 2018;14(4):535–562. doi: 10.1016/j.jalz.2018.02.018. PubMed DOI PMC

Jones RN, Manly J, Glymour MM, Rentz DM, Jefferson AL, Stern Y. Conceptual and measurement challenges in research on cognitive reserve. Journal of the International Neuropsychological Society. 2011;17(4):593–601. doi: 10.1017/S1355617710001748. PubMed DOI PMC

Karp A, Kareholt I, Qiu C, Bellander T, Winblad B, Fratiglioni L. Relation of education and occupation-based socioeconomic status to incident Alzheimer's disease. American Journal of Epidemiology. 2004;159(2):175–183. doi: 10.1093/aje/kwh018. PubMed DOI

Kröger E, Andel R, Lindsay J, Benounissa Z, Verreault R, Laurin D. Is complexity of work associated with risk of dementia? The Canadian Study of Health and Aging. American Journal of Epidemiology. 2008;167(7):820–830. doi: 10.1093/aje/kwm382. PubMed DOI

Lockhart SN, DeCarli C. Structural imaging measures of brain aging. Neuropsychology Review. 2014;24(3):271–289. doi: 10.1007/s11065-014-9268-3. PubMed DOI PMC

Lopez ME, Turrero A, Cuesta P, Lopez-Sanz D, Bruna R, Marcos A, et al. Searching for primary predictors of conversion from mild cognitive impairment to Alzheimer's disease: A multivariate follow-up study. Journal of Alzheimer's Disease. 2016;52(1):133–143. doi: 10.3233/jad-151034. PubMed DOI

Marioni RE, Valenzuela MJ, van den Hout A, Brayne C, Matthews FE. Active cognitive lifestyle is associated with positive cognitive health transitions and compression of morbidity from age sixty-five. PLoS ONE. 2012;7(12):1–6. doi: 10.1371/journal.pone.0050940. PubMed DOI PMC

Mazzeo S, Padiglioni S, Bagnoli S, Bracco L, Nacmias B, Sorbi S, et al. The dual role of cognitive reserve in subjective cognitive decline and mild cognitive impairment: A 7-year follow-up study. Journal of Neurology. 2019;266(2):487–497. doi: 10.1007/s00415-018-9164-5. PubMed DOI

Menardi A, Pascual-Leone A, Fried PJ, Santarnecchi E. The role of cognitive reserve in Alzheimer's disease and aging: A multi-modal imaging review. Journal of Alzheimer's Disease. 2018;66(4):1341–1362. doi: 10.3233/jad-180549. PubMed DOI PMC

Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6(7):1–6. doi: 10.1371/journal.pmed.1000097. PubMed DOI PMC

Myung W, Lee C, Park JH, Woo SY, Kim S, Kim S, et al. Occupational attainment as risk factor for progression from mild cognitive impairment to Alzheimer's disease: A CREDOS study. Journal of Alzheimer's Disease. 2017;55(1):283–292. doi: 10.3233/jad-160257. PubMed DOI

Nilsson J, Lövdén M. Naming is not explaining: Future directions for the "cognitive reserve" and "brain maintenance" theories. Alzheimer's Research & Therapy. 2018;10(1):1–7. doi: 10.1186/s13195-018-0365-z. PubMed DOI PMC

Oschwald J, Guye S, Liem F, Rast P, Willis S, Röcke C, et al. Brain structure and cognitive ability in healthy aging: A review on longitudinal correlated change. Reviews in the Neurosciences. 2019;31(1):1–57. doi: 10.1515/revneuro-2018-0096. PubMed DOI PMC

Osone A, Arai R, Hakamada R, Shimoda K. Impact of cognitive reserve on the progression of mild cognitive impairment to Alzheimer's disease in Japan. Geriatrics & Gerontology International. 2015;15(4):428–434. doi: 10.1111/ggi.12292. PubMed DOI PMC

Osone A, Arai R, Hakamada R, Shimoda K. Cognitive and brain reserve in conversion and reversion in patients with mild cognitive impairment over 12 months of follow-up. Journal of Clinical and Experimental Neuropsychology. 2016;38(10):1084–1093. doi: 10.1080/13803395.2016.1191620. PubMed DOI

Petkus AJ, Resnick SM, Rapp SR, Espeland MA, Gatz M, Widaman KF, et al. General and domain-specific cognitive reserve, mild cognitive impairment, and dementia risk in older women. Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2019;5:118–128. doi: 10.1016/j.trci.2019.02.003. PubMed DOI PMC

Pettigrew C, Soldan A, Li S, Lu Y, Wang MC, Selnes OA, et al. Relationship of cognitive reserve and APOE status to the emergence of clinical symptoms in preclinical Alzheimer's disease. Cognitive Neuroscience. 2013;4(3–4):136–142. doi: 10.1080/17588928.2013.831820. PubMed DOI PMC

Pettigrew C, Soldan A, Zhu YX, Wang MC, Brown T, Miller M, et al. Cognitive reserve and cortical thickness in preclinical Alzheimer's disease. Brain Imaging and Behavior. 2017;11(2):357–367. doi: 10.1007/s11682-016-9581-y. PubMed DOI PMC

Pyun J-M, Park YH, Kim H-R, Suh J, Kang MJ, Kim BJ, et al. Posterior atrophy predicts time to dementia in patients with amyloid-positive mild cognitive impairment. Alzheimer's Research & Therapy. 2017;9(1):1–9. doi: 10.1186/s13195-017-0326-y. PubMed DOI PMC

Reed BR, Mungas D, Farias ST, Harvey D, Beckett L, Widaman K, et al. Measuring cognitive reserve based on the decomposition of episodic memory variance. Brain. 2010;133(8):2196–2209. doi: 10.1093/brain/awq154. PubMed DOI PMC

Rentz DM, Mormino EC, Papp KV, Betensky RA, Sperling RA, Johnson KA. Cognitive resilience in clinical and preclinical Alzheimer's disease: The association of amyloid and tau burden on cognitive performance. Brain Imaging and Behavior. 2017;11(2):383–390. doi: 10.1007/s11682-016-9640-4. PubMed DOI PMC

Roe CM, Fagan AM, Williams MM, Ghoshal N, Aeschleman M, Grant EA, et al. Improving CSF biomarker accuracy in predicting prevalent and incident Alzheimer disease. Neurology. 2011;76(6):501–510. doi: 10.1212/WNL.0b013e31820af900. PubMed DOI PMC

Soldan A, Pettigrew C, Albert M. Evaluating cognitive reserve through the prism of preclinical Alzheimer disease. Psychiatric Clinics of North America. 2018;41(1):65–77. doi: 10.1016/j.psc.2017.10.006. PubMed DOI PMC

Soldan A, Pettigrew C, Li SS, Wang MC, Moghekar A, Selnes OA, et al. Relationship of cognitive reserve and cerebrospinal fluid biomarkers to the emergence of clinical symptoms in preclinical Alzheimer's disease. Neurobiology of Aging. 2013;34(12):2827–2834. doi: 10.1016/j.neurobiolaging.2013.06.017. PubMed DOI PMC

Soldan A, Pettigrew C, Lu Y, Wang MC, Selnes O, Albert M, et al. Relationship of medial temporal lobe atrophy, APOE genotype, and cognitive reserve in preclinical Alzheimer's disease. Human Brain Mapping. 2015;36(7):2826–2841. doi: 10.1002/hbm.22810. PubMed DOI PMC

Sorensen, A., Blazhenets, G., Rucker, G., Schiller, F., Meyer, P. T., & Frings, L. (2019). Prognosis of conversion of mild cognitive impairment to Alzheimer's dementia by voxel-wise Cox regression based on FDG PET data. Neuroimage: Clinical, 21, 1–8. 10.1016/j.nicl.2018.101637. PubMed PMC

Stern Y. What is cognitive reserve? Theory and research application of the reserve concept. Journal of the International Neuropsychological Society. 2002;8(3):448–460. doi: 10.1017/S1355617702813248. PubMed DOI

Stern Y. Cognitive reserve. Neuropsychologia. 2009;47(10):2015–2028. doi: 10.1016/j.neuropsychologia.2009.03.004. PubMed DOI PMC

Stern Y. Cognitive reserve in ageing and Alzheimer's disease. Lancet Neurology. 2012;11(11):1006–1012. doi: 10.1016/s1474-4422(12)70191-6. PubMed DOI PMC

Stern Y, Arenaza-Urquijo EM, Bartrés-Faz D, Belleville S, Cantilon M, Chetelat G, et al. Whitepaper: Defining and investigating cognitive reserve, brain reserve, and brain maintenance. Alzheimer's & Dementia. 2020;16(9):1305–1311. doi: 10.1016/j.jalz.2018.07.219. PubMed DOI PMC

Tokuchi R, Hishikawa N, Kurata T, Sato K, Kono S, Yamashita T, et al. Clinical and demographic predictors of mild cognitive impairment for converting to Alzheimer's disease and reverting to normal cognition. Journal of the Neurological Sciences. 2014;346(1–2):288–292. doi: 10.1016/j.jns.2014.09.012. PubMed DOI

Udeh-Momoh CT, Su B, Evans S, Zheng B, Sindi S, Tzoulaki I, et al. Cortisol, amyloid-β, and reserve predicts Alzheimer's disease progression for cognitively normal older adults. Journal of Alzheimer's Disease. 2019;70(2):551–560. doi: 10.3233/JAD-181030. PubMed DOI

van Loenhoud AC, van der Flier WM, Wink AM, Dicks E, Groot C, Twisk J, et al. Cognitive reserve and clinical progression in Alzheimer disease: A paradoxical relationship. Neurology. 2019;93(4):e334–e346. doi: 10.1212/wnl.0000000000007821. PubMed DOI PMC

van Loenhoud AC, Wink AM, Groot C, Verfaillie SCJ, Twisk J, Barkhof F, et al. A neuroimaging approach to capture cognitive reserve: Application to Alzheimer's disease. Human Brain Mapping. 2017;38(9):4703–4715. doi: 10.1002/hbm.23695. PubMed DOI PMC

Vemuri P, Weigand SD, Knopman DS, Kantarci K, Boeve BF, Petersen RC, et al. Time-to-event voxel-based techniques to assess regional atrophy associated with MCI risk of progression to AD. Neuroimage. 2011;54(2):985–991. doi: 10.1016/j.neuroimage.2010.09.004. PubMed DOI PMC

Wang Y, Du Y, Li J, Qiu C. Lifespan intellectual factors, genetic susceptibility, and cognitive phenotypes in aging: Implications for interventions. Frontiers in Aging Neuroscience. 2019;11:1–11. doi: 10.3389/fnagi.2019.00129. PubMed DOI PMC

Wells, G. A., Shea, B., O’Connell, D., Peterson, J., Welch, V., Losos, M., et al. (2019). The Newcastle-Ottawa Scale (NOS) for assessing quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 18 March 2020.

Xu H, Yang R, Qi X, Dintica C, Song R, Bennett DA, et al. Association of lifespan cognitive reserve indicator with dementia risk in the presence of brain pathologies. JAMA Neurology. 2019;76(10):1184–1191. doi: 10.1001/jamaneurol.2019.2455. PubMed DOI PMC

Zahodne LB, Manly JJ, Brickman AM, Narkhede A, Griffith EY, Guzman VA, et al. Is residual memory variance a valid method for quantifying cognitive reserve? A longitudinal application. Neuropsychologia. 2015;77:260–266. doi: 10.1016/j.neuropsychologia.2015.09.009. PubMed DOI PMC

Zahodne LB, Manly JJ, Brickman AM, Siedlecki KL, Decarli C, Stern Y. Quantifying cognitive reserve in older adults by decomposing episodic memory variance: Replication and extension. Journal of the International Neuropsychological Society. 2013;19(8):854–862. doi: 10.1017/s1355617713000738. PubMed DOI PMC

Zissimopoulos J, Crimmins E, St Clair P. The value of delaying Alzheimer's disease onset. Forum for Health Economics & Policy. 2014;18(1):25–39. doi: 10.1515/fhep-2014-0013. PubMed DOI PMC

Cognitive reserve, neuropathology, and progression towards Alzheimer's disease