INTRODUCTION: Loneliness has a rising public health impact, but research involving neuropathology and representative cohorts has been limited. METHODS: Inverse odds of selection weights were generalized from the autopsy sample of Rush Alzheimer's Disease Center cohorts (N = 680; 89 ± 9 years old; 25% dementia) to the US-representative Health and Retirement Study (N = 8469; 76 ± 7 years old; 5% dementia) to extend external validity. Regressions tested cross-sectional associations between loneliness and (1) Alzheimer's disease (AD) and cerebrovascular pathology; (2) five cognitive domains; and (3) relationships between pathology and cognition, adjusting for depression. RESULTS: In weighted models, greater loneliness was associated with microinfarcts, lower episodic and working memory in the absence of AD pathology, lower working memory in the absence of infarcts, a stronger association of infarcts with lower episodic memory, and a stronger association of microinfarcts with lower working and semantic memory. DISCUSSION: Loneliness may relate to AD through multiple pathways involving cerebrovascular pathology and cognitive reserve. HIGHLIGHTS: Loneliness was associated with worse cognition in five domains. Loneliness was associated with the presence of microinfarcts. Loneliness moderated cognition-neuropathology associations. Transportability methods can provide insight into selection bias.

2nd Faculty of Medicine Charles University Prague Prague Czech

Department of Biometry and Data Management Leibniz Institute for Prevention Research and Epidemiology BIPS Bremen Germany

Department of Epidemiology Boston University Boston Massachusetts USA

Department of Integrative Biology and Physiology College of Life Sciences University of California Los Angeles Los Angeles California USA

Department of Neurology and Neurological Sciences Stanford University School of Medicine Stanford California USA

Department of Neurology Columbia University New York New York USA

Department of Psychology and Gerontology Institute Georgia State University Atlanta Georgia USA

Department of Psychology University of Michigan Ann Arbor Michigan USA

General Internal Medicine School of Medicine University of Washington Seattle Washington USA

Rush Alzheimer's Disease Center Rush University Medical Center Chicago Illinois USA

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Manly JJ, Jones RN, Langa KM, et al. Estimating the prevalence of dementia and mild cognitive impairment in the US: The 2016 Health and Retirement Study Harmonized Cognitive Assessment Protocol Project. JAMA Neurol. 2022;79(12):1242‐1249. PubMed PMC

Kalaria RN, Maestre GE, Arizaga R, et al. Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol. 2008;7:812‐826. PubMed PMC

Thal DR, Rub U, Orantes M, Braak H. Phases of A beta‐deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58:1791‐1800. PubMed

Braak H, Braak E. Neuropathological stageing of Alzheimer‐related changes. Acta Neuropathologica. 1991;82:239‐259. PubMed

Jack CR Jr, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010;9:119‐128. PubMed PMC

Jack CR Jr, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12:207‐216. PubMed PMC

Jack CR Jr, Bennett DA, Blennow K, et al. A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016;87:539‐547. 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;14:535‐562. PubMed PMC

Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396:413‐446. PubMed PMC

Stern Y, Arenaza‐Urquijo EM, Bartrés‐Faz D, et al. Whitepaper: defining and investigating cognitive reserve, brain reserve, and brain maintenance. Alzheimers Dement. 2020;16:1305‐1311. PubMed PMC

Stern Y, Albert M, Barnes CA, Cabeza R, Pascual‐Leone A, Rapp PR. A framework for concepts of reserve and resilience in aging. Neurobiol Aging. 2023;124:100‐103. PubMed PMC

Hampel H, Cummings J, Blennow K, Gao P, Jack CR, Vergallo A. Developing the ATX (N) classification for use across the Alzheimer disease continuum. Nat Rev Neurol. 2021;17(9):580‐589. PubMed

Wilson RS, Krueger KR, Arnold SE, et al. Loneliness and risk of Alzheimer disease. Arch Gen Psychiatry. 2007;64:234‐240. PubMed

Bennett DA, Arnold SE, Valenzuela MJ, Brayne C, Schneider JA. Cognitive and social lifestyle: links with neuropathology and cognition in late life. Acta Neuropathol. 2014;127:137‐150. PubMed PMC

Sharifian N, Zaheed AB, Morris EP, et al. Social network characteristics moderate associations between cortical thickness and cognitive functioning in older adults. Alzheimers Dement. 2022;18:339‐347. PubMed PMC

Office of the Surgeon General (OSG) . Our epidemic of loneliness and isolation: the us surgeon general's advisory on the healing effects of social connection and community. 2023. PubMed

Fried L, Prohaska T, Burholt V, et al. A unified approach to loneliness. Lancet. 2020;395(10218):114. PubMed

Prohaska T, Burholt V, Burns A, et al. Consensus statement: loneliness in older adults, the 21st century social determinant of health? BMJ Open. 2020;10:e034967. PubMed PMC

Shafighi K, Villeneuve S, Rosa Neto P, et al. Social isolation is linked to classical risk factors of Alzheimer's disease‐related dementias. PLoS One. 2023;18:e0280471. PubMed PMC

Sundström A, Adolfsson AN, Nordin M, Adolfsson R. Loneliness increases the risk of all‐cause dementia and Alzheimer's disease. J Gerontol B Psychol Sci Soc Sci. 2020;75:919‐926. PubMed PMC

Ren Y, Savadlou A, Park S, Siska P, Epp JR, Sargin D. The impact of loneliness and social isolation on the development of cognitive decline and Alzheimer's Disease. Front Neuroendocrinol. 2023;69:101061. PubMed

Hawkley LC, Cacioppo JT. Loneliness matters: a theoretical and empirical review of consequences and mechanisms. Ann Behav Med. 2010;40:218‐227. PubMed PMC

Kannan VD, Veazie P. US trends in social isolation, social engagement, and companionship⎯ nationally and by age, sex, race/ethnicity, family income, and work hours, 2003‐2020. SSM Popul Health. 2023;21:101331. PubMed PMC

Holt‐Lunstad J, Robles TF, Sbarra DA. Advancing social connection as a public health priority in the United States. Am Psychol. 2017;72:517. PubMed PMC

Valtorta NK, Kanaan M, Gilbody S, Ronzi S, Hanratty B. Loneliness and social isolation as risk factors for coronary heart disease and stroke: systematic review and meta‐analysis of longitudinal observational studies. Heart. 2016;102:1009‐1016. PubMed PMC

Smith RW, Barnes I, Green J, Reeves GK, Beral V, Floud S. Social isolation and risk of heart disease and stroke: analysis of two large UK prospective studies. Lancet Public Health. 2021;6:e232‐e239. PubMed PMC

Gorji MH, Fatahian A, Farsavian A. The impact of perceived and objective social isolation on hospital readmission in patients with heart failure: a systematic review and meta‐analysis of observational studies. Gen Hosp Psychiatry. 2019;60:27‐36. PubMed

Manemann SM, Chamberlain AM, Roger VL, et al. Perceived social isolation and outcomes in patients with heart failure. J Am Heart Assoc. 2018;7:e008069. PubMed PMC

Lazzari C, Rabottini M. COVID‐19, loneliness, social isolation and risk of dementia in older people: a systematic review and meta‐analysis of the relevant literature. Int J Psychiatry Clin Pract. 2022;26:196‐207. PubMed

Fortmann AL, Gallo LC. Social support and nocturnal blood pressure dipping: a systematic review. Am J Hypertens. 2013;26:302‐310. PubMed PMC

Teoh AN, Hilmert C. Social support as a comfort or an encouragement: a systematic review on the contrasting effects of social support on cardiovascular reactivity. Br J Health Psychol. 2018;23:1040‐1065. PubMed

Li H, Xia N. The role of oxidative stress in cardiovascular disease caused by social isolation and loneliness. Redox Biol. 2020;37:101585. PubMed PMC

Yang YC, Boen C, Gerken K, Li T, Schorpp K, Harris KM. Social relationships and physiological determinants of longevity across the human life span. Proc Natl Acad Sci U S A. 2016;113:578‐583. PubMed PMC

Schneider JA, Aggarwal NT, Barnes L, Boyle P, Bennett DA. The neuropathology of older persons with and without dementia from community versus clinic cohorts. J Alzheimers Dis. 2009;18:691‐701. PubMed PMC

Hayes‐Larson E, Mobley TM, Mungas D, et al. Accounting for lack of representation in dementia research: generalizing KHANDLE study findings on the prevalence of cognitive impairment to the California older population. Alzheimers Dement. 2022;18(11):2209‐2217. PubMed PMC

Westreich D, Edwards JK, Lesko CR, Stuart E, Cole SR. Transportability of trial results using inverse odds of sampling weights. Am J Epidemiol. 2017;186:1010‐1014. PubMed PMC

Bennett DA, Buchman AS, Boyle PA, Barnes LL, Wilson RS, Schneider JA. Religious orders study and rush memory and aging project. J Alzheimers Dis. 2018;64:S161‐S189. PubMed PMC

Barnes LL, Shah RC, Aggarwal NT, Bennett DA, Schneider JA. The Minority Aging Research Study: ongoing efforts to obtain brain donation in African Americans without dementia. Curr Alzheimer Res. 2012;9:734‐745. PubMed PMC

Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. The National Institute on aging, and reagan institute working group on diagnostic criteria for the neuropathological assessment of Alzheimer's Disease. Neurobiol Aging. 1997;18:S1‐S2. PubMed

Bennett D, Schneider J, Arvanitakis Z, et al. Neuropathology of older persons without cognitive impairment from two community‐based studies. Neurology. 2006;66:1837‐1844. PubMed

Schneider J, Bienias J, Wilson R, Berry‐Kravis E, Evans D, Bennett DA. The apolipoprotein E ε4 allele increases the odds of chronic cerebral infarction detected at autopsy in older persons. Stroke. 2005;36:954‐959. PubMed

Arvanitakis Z, Leurgans SE, Barnes LL, Bennett DA, Schneider JA. Microinfarct pathology, dementia, and cognitive systems. Stroke. 2011;42:722‐727. PubMed PMC

Wilson RS, Boyle PA, Yu L, et al. Temporal course and pathologic basis of unawareness of memory loss in dementia. Neurology. 2015;85:984‐991. PubMed PMC

Laing KK, Simoes S, Baena‐Caldas GP, et al. Cerebrovascular disease promotes tau pathology in Alzheimer's disease. Brain Commun. 2020. PubMed PMC

Sonnega A, Faul JD, Ofstedal MB, Langa KM, Phillips JW, Weir DR. Cohort profile: the health and retirement study (HRS). Int J Epidemiol. 2014;43:576‐585. PubMed PMC

Sutin AR, Luchetti M, Aschwanden D, Zhu X, Stephan Y, Terracciano A. Loneliness and risk of all‐cause, Alzheimer's, vascular, and frontotemporal dementia: a prospective study of 492,322 individuals over 15 years. Int Psychogeriatr. 2023;35:283‐292. PubMed PMC

Bennett DA, Schneider JA, Tang Y, Arnold SE, Wilson RS. The effect of social networks on the relation between Alzheimer's disease pathology and level of cognitive function in old people: a longitudinal cohort study. Lancet Neurol. 2006;5:406‐412. PubMed

Bugallo‐Carrera C, Dosil‐Díaz C, Anido‐Rifón L, Pacheco‐Lorenzo M, Fernández‐Iglesias MJ, Gandoy‐Crego MJ. A systematic review evaluating loneliness assessment instruments in older adults. Front Psychol. 2023;14:1101462. PubMed PMC

Lou M. Social isolation, loneliness, and depressive symptoms: a twelve‐year population study of temporal dynamics. J Gerontol B Psychol Sci Soc Sci. 2023;78:280‐290. PubMed PMC

Latimer CS, Keene CD, Flanagan ME, et al. Resistance to Alzheimer disease neuropathologic changes and apparent cognitive resilience in the Nun and Honolulu‐Asia Aging Studies. J Neuropathol Exp Neurol. 2017;76:458‐466. PubMed PMC

SantaCruz KS, Sonnen JA, Pezhouh MK, et al. Alzheimer disease pathology in subjects without dementia in 2 studies of aging: the Nun Study and the Adult Changes in Thought Study. J Neuropathol Exp Neurol. 2011;70:832‐840. PubMed PMC

Sonnen JA, Santa Cruz K, Hemmy LS, et al. Ecology of the aging human brain. Arch Neurol. 2011;68:1049‐1056. PubMed PMC

Knox SS, Uvnäs‐Moberg K. Social isolation and cardiovascular disease: an atherosclerotic pathway? Psychoneuroendocrinology. 1998;23:877‐890. PubMed

Donovan NJ, Okereke OI, Vannini P, et al. Association of higher cortical amyloid burden with loneliness in cognitively normal older adults. JAMA Psychiatry. 2016;73:1230‐1237. PubMed PMC

Biddle KD, d'Oleire Uquillas F, Jacobs HIL, et al. Social engagement and amyloid‐β‐related cognitive decline in cognitively normal older adults. Am J Geriatr Psychiatry. 2019;27:1247‐1256. PubMed PMC

d'Oleire Uquillas F, Jacobs HI, Biddle KD, et al. Regional tau pathology and loneliness in cognitively normal older adults. Transl Psychiatry. 2018;8:282. PubMed PMC

Englund EJD, Disorders GC. Neuropathology of white matter changes in Alzheimer's disease and vascular dementia. Dement Geriatr Cogn Disord. 1998;9:6‐12. PubMed

Salinas J, Beiser AS, Samra JK, et al. Association of loneliness with 10‐year dementia risk and early markers of vulnerability for neurocognitive decline. Neurology. 2022;98:e1337‐e1348. PubMed PMC

Lao PJ, Gutierrez J, Keator D, et al. Alzheimer‐related cerebrovascular disease in down syndrome. Ann Neurol. 2020;88:1165‐1177. PubMed PMC

Lee S, Viqar F, Zimmerman ME, et al. White matter hyperintensities are a core feature of Alzheimer's disease: evidence from the dominantly inherited Alzheimer network. Ann Neurol. 2016;79:929‐939. PubMed PMC

Shen C, Rolls ET, Cheng W, et al. Associations of social isolation and loneliness with later dementia. Neurology. 2022;99:e164‐e175. PubMed

Zhang Y, Tatewaki Y, Liu Y, et al. Perceived social isolation is correlated with brain structure and cognitive trajectory in Alzheimer's disease. Geroscience. 2022;44:1563‐1574. PubMed PMC

Lara E, Martín‐María N, De la Torre‐Luque A, et al. Does loneliness contribute to mild cognitive impairment and dementia? A systematic review and meta‐analysis of longitudinal studies. Ageing Res Rev. 2019;52:7‐16. PubMed

Piolatto M, Bianchi F, Rota M, Marengoni A, Akbaritabar A, Squazzoni F. The effect of social relationships on cognitive decline in older adults: an updated systematic review and meta‐analysis of longitudinal cohort studies. BMC Public Health. 2022;22:278. PubMed PMC

Wang S, Molassiotis A, Guo C, Leung ISH, Leung AYM. Association between social integration and risk of dementia: a systematic review and meta‐analysis of longitudinal studies. J Am Geriatr Soc. 2023;71:632‐645. PubMed

Qiao L, Wang G, Tang Z, et al. Association between loneliness and dementia risk: a systematic review and meta‐analysis of cohort studies. Front Hum Neurosci. 2022;16:899814. PubMed PMC

Alexopoulos GS, Meyers BS, Young RC, Campbell S, Silbersweig D, Charlson M. 'Vascular Depression' hypothesis. Arch Gen Psychiatry. 1997;54:915‐922. PubMed

Taylor WD, Aizenstein HJ, Alexopoulos GS. The vascular depression hypothesis: mechanisms linking vascular disease with depression. Mol Psychiatry. 2013;18:963‐974. PubMed PMC

Hill CV, Pérez‐Stable EJ, Anderson NA, Bernard MA. The National Institute on Aging health disparities research framework. Ethn Dis. 2015;25:245. PubMed PMC