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A longitudinal study of late-life psychosis and incident dementia and the potential effects of race and cognition

Nature Mental Health volume 1, pages 273–283 (2023)Cite this article

Subjects

Abstract

Later-life psychotic symptoms are meaningful and are associated with adverse outcomes. Psychosis is an important domain in mild behavioural impairment (MBI), a syndrome that incorporates later-life emergent and persistent neuropsychiatric symptoms (NPS) in dementia-free individuals into dementia prognostication. However, MBI-psychosis-associated risk and its interaction with race has not been well quantified. Here we determined risk of incident dementia in dementia-free participants with MBI-psychosis and effect modification by race as an important factor in assessing the risk of psychosis. Data for participants with normal cognition (NC) or mild cognitive impairment (MCI) from the National Alzheimer Coordinating Centre were used. Participants with neurodevelopmental, neurological and/or longstanding psychiatric disorders were excluded. MBI-psychosis was defined by persistence of delusions and hallucinations across two consecutive visits. Kaplan–Meier curves of ten-year dementia-free survival were generated for MBI-psychosis versus no NPS before dementia diagnosis. Cox proportional hazard models were implemented to assess relative incidence rates, adjusted for cognitive status, age, sex, education, race and APOE-ε4 status. Interaction terms were included for relevant demographic variables. Similar secondary analyses utilized MBI-no-psychosis as reference. The sample consisted of 3,704 no-NPS (age = 72.8 ± 9.9; 62.7% female; 13.4% MCI) and 66 MBI-psychosis (age = 75.2 ± 9.8; 53% female; 72.7% MCI) participants. For MBI-psychosis, in reference to no NPS, the hazard ratio (HR) for incident dementia was 3.76 (CI: 2.53–5.58, p < 0.001), while for conventionally captured psychosis, the HR was 1.92 (CI: 1.58–2.33, p < 0.001). Interaction analyses revealed that in NC, those with MBI-psychosis had a 9.96-fold greater incidence of dementia than those with no NPS (CI: 3.65–27.22, p < 0.001). In MCI, the MBI-psychosis-associated dementia incidence was 3.38-fold greater than no-NPS (CI: 2.22–5.15, p < 0.001). Furthermore, MBI-psychosis-associated dementia incidence in Black participants was 7.44-fold greater than no NPS (CI: 3.54–15.65, p < 0.001), while in white participants, it was 3.18-fold greater (CI: 1.94–5.2, p < 0.001). In a secondary analysis, compared with MBI-no-psychosis (n = 2,260), MBI-psychosis had a 2.47-fold greater incidence of dementia (CI: 1.69–3.59, p < 0.001). Although psychosis is an infrequently endorsed MBI domain, when present it is associated with substantial risk for dementia. HRs differed between cognitive strata, and these differences were significantly greater when MBI-psychosis emerged in NC as opposed to MCI, emphasizing the importance of cognitive assessment at the time of symptom emergence. In addition, the relationship between MBI-psychosis and incident dementia was stronger in Black participants than in white participants. The emergence of persistent psychotic symptoms in older adults is clinically meaningful, and MBI-psychosis identifies a high-risk group for precision medicine approaches to dementia prevention.

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Fig. 1: KM curve of dementia-free survival and adjusted HR for incident dementia over ten years stratified by NPS groups.
Fig. 2: Forest plot of adjusted HRs for incident dementia across the strata of the interaction.
Fig. 3

Data availability

Data are available from NACC upon submission of a data access request (https://naccdata.org/requesting-data/data-request-process).

Code availability

Custom R codes are available online (https://github.com/mghahrem/psychosis_and_incidentdementia).

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Acknowledgements

The NACC database is funded by NIA/NIH grant U24 AG072122. NACC data are contributed by the NIA-funded ADRCs: P30 AG019610 (PI E. Reiman), P30 AG013846 (PI N. Kowall), P50 AG008702 (PI S. Small), P50 AG025688 (PI A. Levey), P50 AG047266 (PI T. Golde), P30 AG010133 (PI A. Saykin), P50 AG005146 (PI M. Albert), P50 AG005134 (PI B. Hyman), P50 AG016574 (PI R. Petersen), P50 AG005138 (PI M. Sano), P30 AG008051 (PI T. Wisniewski), P30 AG013854 (PI R. Vassar), P30 AG008017 (PI J. Kaye), P30 AG010161 (PI D. Bennett), P50 AG047366 (PI V. Henderson), P30 AG010129 (PI C. DeCarli), P50 AG016573 (PI F. LaFerla), P50 AG005131 (PI J. Brewer), P50 AG023501 (PI B. Miller), P30 AG035982 (PI R. Swerdlow), P30 AG028383 (PI L. Van Eldik), P30 AG053760 (PI H. Paulson), P30 AG010124 (PI J. Trojanowski), P50 AG005133 (PI O. Lopez), P50 AG005142 (PI H. Chui), P30 AG012300 (PI R. Rosenberg), P30 AG049638 (PI S. Craft), P50 AG005136 (PI T. Grabowski), P50 AG033514 (PI S. Asthana), P50 AG005681 (PI J. Morris), P50 AG047270 (PI S. Strittmatter). Z.I. is supported by the Canadian Institutes of Health Research (BCA2633). M.G. is supported by an award from the Mathison Centre for Mental Health, Research & Education at the University of Calgary, Canada. This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

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Authors and Affiliations

  1. Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Zahinoor Ismail, Maryam Ghahremani & M. Amlish Munir

  2. Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Zahinoor Ismail, Maryam Ghahremani, M. Amlish Munir & Eric E. Smith

  3. Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Zahinoor Ismail & Eric E. Smith

  4. Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Zahinoor Ismail & Eric E. Smith

  5. O’Brien Institute for Public Health, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Zahinoor Ismail

  6. Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK

    Zahinoor Ismail & Byron Creese

  7. Keenan Research Centre for Biomedical Science, St Michaels Hospital, Toronto, Ontario, Canada

    Corinne E. Fischer

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Contributions

Z.I. and M.G. had major roles in study design and conception, data preparation, statistical analysis and interpretation, and drafting and revision of the manuscript. M.A.M., C.E.F., E.E.S. and B.C. contributed to drafting and revision of the manuscript and interpretation of the data.

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Correspondence to Zahinoor Ismail.

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Z.I. has received honoraria from Otsuka/Lundbeck outside the submitted work. His institution has received payment in lieu from Acadia, Biogen and Roche. The remaining authors declare no competing interests.

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Ismail, Z., Ghahremani, M., Amlish Munir, M. et al. A longitudinal study of late-life psychosis and incident dementia and the potential effects of race and cognition. Nat. Mental Health 1, 273–283 (2023). https://doi.org/10.1038/s44220-023-00043-x

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