We here posit that measurements of midlife cognition can be instructive in understanding cognitive disorders. Even though molecular events signal possible onset of cognitive disorders decades prior to their clinical diagnoses, cognition and its possible early changes in midlife remain poorly understood. We characterize midlife cognition in a cognitively healthy population-based sample using the Cogstate Brief Battery and test for associations with cardiovascular, adiposity-related, lifestyle-associated, and psychosocial variables. Learning and working memory showed significant variability and vulnerability to psychosocial influences in midlife. Furthermore, midlife aging significantly and progressively increased prevalence of suboptimal cognitive performance. Our findings suggest that physiological changes in cognition, measured with simple tests suitable for use in everyday clinical setting, may signal already in midlife the first clinical manifestations of the presymptomatic biologically defined cognitive disorders. This pilot study calls for longitudinal studies investigating midlife cognition to identify clinical correlates of biologically defined cognitive disorders.

Department of Global Health and Population Harvard TH Chan School of Public Health Harvard University Boston Massachusetts USA

Division of Alzheimer's Disease and Memory Disorders Program Department of Neurology Barrow Neurological Institute Phoenix Arizona USA

Division of Neurology University Medical Centre Ljubljana Slovenia

Division of Preventive Cardiology Department of Cardiovascular Medicine Mayo Clinic Rochester Minnesota USA

Kardiovize Study International Clinical Research Centre St Anne's University Hospital Brno Czech Republic

Translational Aging and Neuroscience Program Centre for Translational Medicine International Clinical Research Centre St Anne's University Hospital Brno Czech Republic

Translational Aging and Neuroscience Program Mayo Clinic Rochester Minnesota USA

Zobrazit více v PubMed

Rosenbaum RS, Stuss DT, Levine B, et al. Theory of mind is independent of episodic memory. Science. 2007;318(5854):1257. PubMed

Hofmann W, Schmeichel BJ, Baddeley AD. Executive functions and self‐regulation. Trends Cogn Sci. 2012;16(3):174‐180. PubMed

McGaugh JL. Making lasting memories: remembering the significant. Proc Natl Acad Sci U S A, 2013;110:10402‐10407. Suppl 2. PubMed PMC

Kopelman MD. Disorders of memory. Brain. 2002;125:2152‐2190. Pt 10. PubMed

Collins AG, Frank MJ. Cognitive control over learning: creating, clustering, and generalizing task‐set structure. Psychol Rev. 2013;120(1):190‐229. PubMed PMC

De Zeeuw CI, Hoebeek FE, Bosman LW, et al. Spatiotemporal firing patterns in the cerebellum. Nat Rev Neurosci. 2011;12(6):327‐344. PubMed

Moran JM, Jolly E, Mitchell JP. Social‐cognitive deficits in normal aging. J Neurosci. 2012;32(16):5553‐5561. PubMed PMC

Reiter AMF, Diaconescu AO, Eppinger B, et al. Human aging alters social inference about others' changing intentions. Neurobiol Aging. 2021;103:98‐108. PubMed

Beker N, Ganz A, Hulsman M, et al. Association of cognitive function trajectories in centenarians with postmortem neuropathology, physical health, and other risk factors for cognitive decline. JAMA Netw Open. 2021;4(1):e2031654. PubMed PMC

Cohen RA, Marsiske MM, Smith GE. Neuropsychology of aging. Handb Clin Neurol. 2019;167:149‐180. PubMed

Katzman R. Editorial: the prevalence and malignancy of Alzheimer's disease. A major killer. Arch Neurol. 1976;33(4):217‐218. PubMed

Jessen F, Amariglio RE, van Boxtel M, et al. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease. Alzheimers Dement. 2014;10(6):844‐852. PubMed PMC

Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56(3):303‐308. PubMed

Reisberg B, Ferris SH, de Leon MJ, et al. The global deterioration scale for assessment of primary degenerative dementia. Am J Psychiatry. 1982;139(9):1136‐1139. PubMed

Jessen F, Amariglio RE, Buckley RF, et al. The characterisation of subjective cognitive decline. Lancet Neurol. 2020;19(3):271‐278. PubMed PMC

Cacciamani F, Sambati L, Houot M, et al. Awareness of cognitive decline trajectories in asymptomatic individuals at risk for AD. Alzheimers Res Ther. 2020;12(1):129. PubMed PMC

Folstein MF, Folstein SE, McHugh PR. Mini‐mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189‐198. PubMed

Nasreddine ZS, Phillips NA, Bédirian V, et al. The montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695‐699. PubMed

Mioshi E, Dawson K, Mitchell J, et al. The Addenbrooke's cognitive examination revised (ACE‐R): a brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry. 2006;21(11):1078‐1085. PubMed

Bachman DL, Wolf PA, Linn R, et al. Prevalence of dementia and probable senile dementia of the Alzheimer's type in the Framingham Study. Neurology. 1992;42(1):115‐119. PubMed

Engelhart MJ, Geerlings MI, Meijer J, et al. Inflammatory proteins in plasma and the risk of dementia: the rotterdam study. Arch Neurol. 2004;61(5):668‐672. PubMed

Caselli RJ, Dueck AC, Osborne D, et al. Longitudinal modeling of age‐related memory decline and the APOE epsilon4 effect. N Engl J Med. 2009;361(3):255‐263. PubMed PMC

Sheinerman KS, Tsivinsky VG, Crawford F, et al. Plasma microRNA biomarkers for detection of mild cognitive impairment. Aging (Albany NY). 2012;4(9):590‐605. PubMed PMC

Crum RM, Anthony JC, Bassett SS, et al. Population‐based norms for the mini‐mental state examination by age and educational level. JAMA. 1993;269(18):2386‐2391. PubMed

Ihle‐Hansen H, Vigen T, Berge T, et al. Montreal Cognitive assessment in a 63‐ to 65‐year‐old Norwegian Cohort from the general population: data from the akershus cardiac examination 1950 Study. Dement Geriatr Cogn Dis Extra. 2017;7(3):318‐327. PubMed PMC

Mathuranath PS, Nestor PJ, Berrios GE, et al. A brief cognitive test battery to differentiate Alzheimer's disease and frontotemporal dementia. Neurology. 2000;55(11):1613‐1620. PubMed

Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012;367(9):795‐804. PubMed PMC

Jack CR Jr, Bennett DA, Blennow K, et al. NIA‐AA Research Framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535‐562. PubMed PMC

Kiselica AMI. Alzheimer's disease neuroimaging, empirically defining the preclinical stages of the Alzheimer's continuum in the Alzheimer's disease neuroimaging initiative. Psychogeriatrics. 2021. PubMed PMC

O'Shea DM, Thomas KR, Asken B, et al. Adding cognition to AT(N) models improves prediction of cognitive and functional decline. Alzheimers Dement (Amst). 2021;13(1):e12174. PubMed PMC

Tavares TP, Mitchell DGV, Coleman KK, et al. Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration. J Neurol Neurosurg Psychiatry. 2020;91(9):975‐984. PubMed PMC

O'Connor A, Pavisic I, Ryan NS, et al. Quantitative detection and staging of presymptomatic cognitive decline in familial Alzheimer's disease: a retrospective cohort analysis. Alzheimers Res Ther. 2020;12(1):126. PubMed PMC

Thai C, Lim YY, Villemagne VL, et al. Amyloid‐Related memory decline in preclinical Alzheimer's disease is dependent on APOE epsilon4 and is detectable over 18‐Months. PLoS One. 2015;10(10):e0139082. PubMed PMC

Lim YY, Pietrzak RH, Bourgeat P, et al. Relationships between performance on the cogstate brief battery, neurodegeneration, and Abeta accumulation in cognitively normal older adults and adults with MCI. Arch Clin Neuropsychol. 2015;30(1):49‐58. PubMed

Braak H, Thal DR, Ghebremedhin E, et al. Stages of the pathologic process in Alzheimer's disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011;70(11):960‐969. PubMed

Movsisyan NK, Vinciguerra M, Lopez‐Jimenez F, et al. Kardiovize Brno 2030, a prospective cardiovascular health study in Central Europe: methods, baseline findings and future directions. Eur J Prev Cardiol. 2018;25(1):54‐64. PubMed

Kuiper JS, Oude Voshaar RC, Verhoeven FEA, et al. Comparison of cognitive functioning as measured by the Ruff Figural Fluency Test and the CogState computerized battery within the LifeLines Cohort Study. BMC Psychol. 2017;5(1):15. PubMed PMC

Shah T, Verdile G, Sohrabi H, et al. A combination of physical activity and computerized brain training improves verbal memory and increases cerebral glucose metabolism in the elderly. Transl Psychiatry. 2014;4:e487. PubMed PMC

Ashford MT, Ashford MT, Jin C, et al. Effects of sex, race, ethnicity, and education on online aging research participation. Alzheimers Dement (N Y). 2020;6(1):e12028. PubMed PMC

Papp KV, Rentz DM, Maruff P, et al. The Computerized cognitive composite (C3) in an Alzheimer's disease secondary prevention trial. J Prev Alzheimers Dis. 2021;8(1):59‐67. PubMed PMC

Cysique LA, Maruff P, Darby D, et al. The assessment of cognitive function in advanced HIV‐1 infection and AIDS dementia complex using a new computerised cognitive test battery. Arch Clin Neuropsychol. 2006;21(2):185‐194. PubMed

Fredrickson J, Maruff P, Woodward M, et al. Evaluation of the usability of a brief computerized cognitive screening test in older people for epidemiological studies. Neuroepidemiology. 2010;34(2):65‐75. PubMed

Maruff P, Lim YY, Darby D, et al. Clinical utility of the cogstate brief battery in identifying cognitive impairment in mild cognitive impairment and Alzheimer's disease. BMC Psychol. 2013;1(1):30. PubMed PMC

Darby DG, Pietrzak RH, Fredrickson J, et al. Intraindividual cognitive decline using a brief computerized cognitive screening test. Alzheimers Dement. 2012;8(2):95‐104. PubMed

Medina‐Inojosa JR, Vinciguerra M, Maugeri A, et al. Prevalence of ideal cardiovascular health in a Central European community: results from the Kardiovize Brno 2030 Project. Eur J Prev Cardiol. 2020;27(4):441‐443. PubMed

Maugeri A, Hlinomaz O, Agodi A, et al. Is drinking alcohol really linked to cardiovascular health? Evidence from the Kardiovize 2030 Project. Nutrients. 2020;12(9). PubMed PMC

Pavlovska I, Mechanick JI, Maranhao Neto GA, et al. Arterial stiffness and cardiometabolic‐based chronic disease: the Kardiovize Study. Endocr Pract. 2021. PubMed

Gonzalez‐Rivas JP, Mechanick JI, Infante‐Garcia MM, et al. The prevalence of dysglycemia‐based chronic disease in a European Population ‐ a New paradigm to address diabetes burden: a kardiovize study. Endocr Pract. 2021;27(5):455‐462. PubMed

Baumgart M, Snyder HM, Carrillo MC, et al. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population‐based perspective. Alzheimers Dement. 2015;11(6):718‐726. PubMed

Zokaei N, Husain M. Working memory in Alzheimer's Disease and Parkinson's disease. Curr Top Behav Neurosci. 2019;41:325‐344. PubMed

Quiroz YT, Budson AE, Celone K, et al. Hippocampal hyperactivation in presymptomatic familial Alzheimer's disease. Ann Neurol. 2010;68(6):865‐875. PubMed PMC

Varela C, Kumar S, Yang JY, et al. Anatomical substrates for direct interactions between hippocampus, medial prefrontal cortex, and the thalamic nucleus reuniens. Brain Struct Funct. 2014;219(3):911‐929. PubMed PMC

Briggs RG, Khan AB, Chakraborty AR, et al. Anatomy and white matter connections of the superior frontal gyrus. Clin Anat. 2020;33(6):823‐832. PubMed

Masters CL, et al. Alzheimer's disease. Nat Rev Dis Primers. 2015;1:15056. PubMed

Ballard C, et al. Alzheimer's disease. Lancet. 2011;377(9770):1019‐1031. PubMed

Fernandez‐Baizan C, Diaz‐Caceres E, Arias JL, et al. Egocentric and allocentric spatial memory in healthy aging: performance on real‐world tasks. Braz J Med Biol Res. 2019;52(4):e8041. PubMed PMC

Vonk JMJ, Higby E, Nikolaev A, et al. Demographic effects on longitudinal semantic processing, working memory, and cognitive speed. J Gerontol B Psychol Sci Soc Sci. 2020;75(9):1850‐1862. PubMed PMC

Korkki SM, Richter FR, Jeyarathnarajah P, et al. Healthy ageing reduces the precision of episodic memory retrieval. Psychol Aging. 2020;35(1):124‐142. PubMed

Beath N, Moxley K, Subramaney U, et al. Validation of the Montreal cognitive assessment against the RBANS in a healthy South African cohort. S Afr J Psychiatr. 2018;24:1304. PubMed PMC

Mazerolle M, Régner I, Barber SJ, et al. Negative aging stereotypes impair performance on brief cognitive tests used to screen for predementia. J Gerontol B Psychol Sci Soc Sci. 2017;72(6):932‐936. PubMed PMC

Gluhm S, Goldstein J, Loc K, et al. Cognitive performance on the mini‐mental state examination and the montreal cognitive assessment across the healthy adult lifespan. Cogn Behav Neurol. 2013;26(1):1‐5. PubMed PMC

Roalf DR, Moberg PJ, Xie SX, et al. Comparative accuracies of two common screening instruments for classification of Alzheimer's disease, mild cognitive impairment, and healthy aging. Alzheimers Dement. 2013;9(5):529‐537. PubMed PMC

Kesse‐Guyot E, Andreeva VA, Lassale C, et al. Clustering of midlife lifestyle behaviors and subsequent cognitive function: a longitudinal study. Am J Public Health. 2014;104(11):e170‐7. PubMed PMC

Gross AL, Lu H, Meoni L, et al. Physical activity in midlife is not associated with cognitive health in later life among cognitively normal older adults. J Alzheimers Dis. 2017;59(4):1349‐1358. PubMed

van Vliet P, van de Water W, de Craen AJ, et al. The influence of age on the association between cholesterol and cognitive function. Exp Gerontol. 2009;44(1‐2):112‐122. PubMed

Stella F, Radanovic M, Balthazar ML, et al. Neuropsychiatric symptoms in the prodromal stages of dementia. Curr Opin Psychiatry. 2014;27(3):230‐235. PubMed

Zufferey V, Gunten AV, Kherif F. Interactions between personality, depression, anxiety and cognition to understand early stage of Alzheimer's disease. Curr Top Med Chem. 2020;20(9):782‐791. PubMed

Lim YY, Ellis KA, Harrington K, et al. Use of the cogstate brief battery in the assessment of Alzheimer's disease related cognitive impairment in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. J Clin Exp Neuropsychol. 2012;34(4):345‐358. PubMed

Singh‐Manoux A, Akbaraly TN, Marmot M, et al. Persistent depressive symptoms and cognitive function in late midlife: the Whitehall II study. J Clin Psychiatry. 2010;71(10):1379‐1385. PubMed PMC

Petkus AJ, Reynolds CA, Wetherell JL, et al. Temporal dynamics of cognitive performance and anxiety across older adulthood. Psychol Aging. 2017;32(3):278‐292. PubMed PMC

Krell‐Roesch J, Syrjanen JA, Rakusa M, et al. Association of cortical and subcortical beta‐amyloid with standardized measures of depressive and anxiety symptoms in adults without dementia. J Neuropsychiatry Clin Neurosci. 2021;33(1):64‐71. PubMed PMC

Krell‐Roesch J, Vassilaki M, Mielke MM, et al. Cortical beta‐amyloid burden, neuropsychiatric symptoms, and cognitive status: the mayo clinic study of aging. Transl Psychiatry. 2019;9(1):123. PubMed PMC

Ng KP, Chiew H, Rosa‐Neto P, et al. Associations of AT(N) biomarkers with neuropsychiatric symptoms in preclinical Alzheimer's disease and cognitively unimpaired individuals. Transl Neurodegener. 2021;10(1):11. PubMed PMC

Unterrainer J, Michal M, Rahm B, et al. Association of Type D personality with cognitive functioning in individuals with and without cardiovascular disease ‐ The Gutenberg Health Study. Int J Cardiol. 2016;214:256‐261. PubMed

Toussaint LL, Shields GS, Green E, et al. Hostility, forgiveness, and cognitive impairment over 10 years in a national sample of American adults. Health Psychol. 2018;37(12):1102‐1106. PubMed PMC

Stefler D, Prina M, Wu YT, et al. Socioeconomic inequalities in physical and cognitive functioning: cross‐sectional evidence from 37 cohorts across 28 countries in the ATHLOS project. J Epidemiol Community Health. 2021. PubMed

Miao C, Ning H, Zhong VW, et al. Cardiovascular health score and the risk of cardiovascular diseases. PLoS One. 2015;10(7):e0131537. PubMed PMC

de Groot E, van Leuven SI, Duivenvoorden R, et al. Measurement of carotid intima‐media thickness to assess progression and regression of atherosclerosis. Nat Clin Pract Cardiovasc Med. 2008;5(5):280‐288. PubMed

Garvey WT, Garber AJ, Mechanick JI, et al. American association of clinical endocrinologists and american college of endocrinology consensus conference on obesity: building an evidence base for comprehensive action. Endocr Pract. 2014;20(9):956‐976. PubMed

Mechanick JI, Hurley DL, Garvey WT. Adiposity‐Based chronic disease as a new diagnostic term: the american association of clinical endocrinologists and American College of Endocrinology Position Statement. Endocr Pract. 2017;23(3):372‐378. PubMed

Craig CL, Marshall AL, Sjöström M, et al. International physical activity questionnaire: 12‐country reliability and validity. Med Sci Sports Exerc. 2003;35(8):1381‐1395. PubMed

Cole SR. Assessment of differential item functioning in the perceived stress scale‐10. J Epidemiol Community Health. 1999;53(5):319‐320. PubMed PMC

Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The fifth joint task force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J. 2012;33(13):1635‐1701. PubMed

Kroenke K, Spitzer RL, Williams JB. The PHQ‐9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606‐613. PubMed PMC

Sloan JA, Aaronson N, Cappelleri JC, et al. Assessing the clinical significance of single items relative to summated scores. Mayo Clin Proc. 2002;77(5):479‐487. PubMed