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. 2022 Dec 8:13:957308.
doi: 10.3389/fpsyg.2022.957308. eCollection 2022.

Midlife occupational cognitive requirements protect cognitive function in old age by increasing cognitive reserve

Luca Kleineidam  1   2 , Steffen Wolfsgruber  2 , Anne-Sophie Weyrauch  1 , Linn E Zulka  1   3 , Simon Forstmeier  4 , Sandra Roeske  2 , Hendrik van den Bussche  5 , Hanna Kaduszkiewicz  5   6 , Birgitt Wiese  7 , Siegfried Weyerer  8 , Jochen Werle  8 , Angela Fuchs  9 , Michael Pentzek  9 , Christian Brettschneider  10 , Hans-Helmut König  10 , Dagmar Weeg  11 , Horst Bickel  11 , Melanie Luppa  12 , Francisca S Rodriguez  2   12 , Silka Dawn Freiesleben  13   14   15 , Selin Erdogan  13   14   15 , Chantal Unterfeld  13   16 , Oliver Peters  13   14   15 , Eike J Spruth  13   17 , Slawek Altenstein  13   17 , Andrea Lohse  17 , Josef Priller  11   13   17   18 , Klaus Fliessbach  1   2 , Xenia Kobeleva  2 , Anja Schneider  1   2 , Claudia Bartels  19 , Björn H Schott  19   20   21 , Jens Wiltfang  19   20   22 , Franziska Maier  23 , Wenzel Glanz  24 , Enise I Incesoy  24   25 , Michaela Butryn  24 , Emrah Düzel  24   25 , Katharina Buerger  26   27 , Daniel Janowitz  27 , Michael Ewers  26   27 , Boris-Stephan Rauchmann  28 , Robert Perneczky  26   28   29   30   31 , Ingo Kilimann  32   33 , Doreen Görß  33 , Stefan Teipel  32   33 , Christoph Laske  34   35 , Matthias H J Munk  34   36 , Annika Spottke  2   37 , Nina Roy  2 , Frederic Brosseron  2 , Michael T Heneka  1   2 , Alfredo Ramirez  1   2   38   39   40 , Renat Yakupov  24 , Martin Scherer  5 , Wolfgang Maier  1 , Frank Jessen  2   23   38 , Steffi G Riedel-Heller  12 , Michael Wagner  1   2
Affiliations

Midlife occupational cognitive requirements protect cognitive function in old age by increasing cognitive reserve

Luca Kleineidam et al. Front Psychol. .

Abstract

Introduction: Several lifestyle factors promote protection against Alzheimer's disease (AD) throughout a person's lifespan. Although such protective effects have been described for occupational cognitive requirements (OCR) in midlife, it is currently unknown whether they are conveyed by brain maintenance (BM), brain reserve (BR), or cognitive reserve (CR) or a combination of them.

Methods: We systematically derived hypotheses for these resilience concepts and tested them in the population-based AgeCoDe cohort and memory clinic-based AD high-risk DELCODE study. The OCR score (OCRS) was measured using job activities based on the O*NET occupational classification system. Four sets of analyses were conducted: (1) the interaction of OCR and APOE-ε4 with regard to cognitive decline (N = 2,369, AgeCoDe), (2) association with differentially shaped retrospective trajectories before the onset of dementia of the Alzheimer's type (DAT; N = 474, AgeCoDe), (3) cross-sectional interaction of the OCR and cerebrospinal fluid (CSF) AD biomarkers and brain structural measures regarding memory function (N = 873, DELCODE), and (4) cross-sectional and longitudinal association of OCR with CSF AD biomarkers and brain structural measures (N = 873, DELCODE).

Results: Regarding (1), higher OCRS was associated with a reduced association of APOE-ε4 with cognitive decline (mean follow-up = 6.03 years), consistent with CR and BR. Regarding (2), high OCRS was associated with a later onset but subsequently stronger cognitive decline in individuals converting to DAT, consistent with CR. Regarding (3), higher OCRS was associated with a weaker association of the CSF Aβ42/40 ratio and hippocampal volume with memory function, consistent with CR. Regarding (4), OCR was not associated with the levels or changes in CSF AD biomarkers (mean follow-up = 2.61 years). We found a cross-sectional, age-independent association of OCRS with some MRI markers, but no association with 1-year-change. OCR was not associated with the intracranial volume. These results are not completely consistent with those of BR or BM.

Discussion: Our results support the link between OCR and CR. Promoting and seeking complex and stimulating work conditions in midlife could therefore contribute to increased resistance to pathologies in old age and might complement prevention measures aimed at reducing pathology.

Keywords: Alzheimer's disease; brain maintenance; brain reserve; cognitive reserve; mid-life cognitive demands; occupation.

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Conflict of interest statement

ME receives research funding and consulting fees from Eli Lilly and Company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
(A) Hypotheses for CR regarding the relationship of the OCRS and CSF AD biomarkers with cognition. (B) Hypotheses for BR regarding the relationship of the OCRS and CSF AD biomarkers with cognition. (C) Hypotheses for BM regarding the relationship of the OCRS w OCRS and CSF AD biomarkers with cognition. (D) Hypotheses for CR regarding the relationship of the OCRS and brain structure with cognition. (E) Hypotheses for BR regarding the relationship of the OCRS and brain structure with cognition. (F) Hypotheses for BM regarding the relationship of the OCRS and brain structure with cognition. (G) Hypotheses for CR regarding the relationship of the OCRS with longitudinal change in markers of pathology. (H) Hypotheses for BR regarding the relationship of the OCRS with longitudinal change in markers of pathology. (I) Hypotheses for BM regarding the relationship of the OCRS with longitudinal change in markers of pathology. (J) Hypotheses for CR regarding the relationship of the OCRS and APOE with cognitive decline in general population-based cohorts. (K) Hypotheses for BR regarding the relationship of the OCRS and APOE with cognitive decline in general population-based cohorts. (L) Hypotheses for BM regarding the relationship of the OCRS and APOE with cognitive decline in general population-based cohorts. (M) Hypotheses for CR regarding the relationship of the OCRS with cognitive decline prior to the onset of dementia of the Alzheimer's type (DAT). (N) Hypotheses for BR regarding the relationship of the OCRS with cognitive decline prior to the onset of dementia of the Alzheimer's type (DAT). (O) Hypotheses for BM regarding the relationship of the OCRS with cognitive decline prior to the onset of dementia of the Alzheimer's type (DAT). OCRS, occupational cognitive requirement score; APOE−+4, apolipoprotein E +4 allele; CSF, cerebrospinal fluid; CR, cognitive reserve; BM, brain maintenance; BR, brain reserve.
Figure 2
Figure 2
Flowchart of sample selection. APOE, apolipoprotein E; CSF, cerebrospinal fluid; DAT, dementia of the Alzheimer's type; OCRS, occupational cognitive requirement score.
Figure 3
Figure 3
Interaction effects of OCRS with Aβ42/40 ratio and hippocampal volume regarding cross-sectional memory function. (A) Predicted memory factor scores depending on Aβ42/40 ratio in individuals with either low (25th percentile, orange line) or high (75th percentile, blue line) OCRS levels. Shaded areas indicate 95% confidence intervals. (B) Marginal effects of the Aβ42/40 ratio depending on OCRS levels. Bars indicate 95% confidence intervals. Marginal effects indicate the change in the memory factor when the Aβ42/40 ratio increases by one standard deviation. It is computed as the sum of the coefficients of the Aβ42/40 ratio and the Aβ42/40 ratio*OCRS interaction term. Blue dots and bars correspond to the predicted trajectory for individuals with high OCRS (blue line) in plot (A). Orange dots and bars correspond to the predicted trajectory for individuals with low OCRS (orange line) in plot (A). Marginal effects indicate that effects of Aβ42/40 ratio on memory function are stronger at lower levels of the OCRS. (C) Predicted memory factor scores depending on the averaged left and right hippocampal volume in individuals with either low (25th percentile, orange line) or high (75th percentile, blue line) OCRS levels. Shaded areas indicate 95% confidence intervals. (D) Marginal effects of the hippocampal volume depending on OCRS levels. Bars indicate 95% confidence intervals. Interpretation analogous to (B), that is, marginal effects indicate that the effects of hippocampal volume on memory function are stronger at lower levels of the OCRS. Abeta ratio, cerebrospinal fluid Aβ42/Aβ42 ratio; OCRS, occupational cognitive requirement score.
Figure 4
Figure 4
Predicted trajectories of cognitive decline in AgeCoDe depending on OCRS and APOE-ε4. (A) Predicted trajectories in MMSE for APOE-ε4 carrier and non-carrier with either low (25th percentile) or high (75th percentile) OCRS levels. Shaded areas indicate 95% confidence intervals. While APOE-ε4 is generally associated with a stronger cognitive decline (steeper slope for dotted compared to straight lines), this difference is larger in individuals with low OCRS (orange lines) compared to high OCRS (blue lines). (B) Differences in MMSE between APOE-ε carrier and non-carrier at different time points for individuals with either low (25th percentile) or high (75th percentile) OCRS levels. Bars indicate 95% confidence intervals. Differences are presented on the scale of the latent variable in the latent process mixed models (Proust-Lima et al., 2011), not on the scale of the observed variable (i.e., the MMSE). Differences are generally lower (i.e., closer to zero) for individuals with high (blue line) as compared to low (orange line) OCRS values. APOE-e4, apolipoprotein E ε4 allele; MMSE, Mini-Mental-State-Examination; OCRS, occupational cognitive requirement score.
Figure 5
Figure 5
Predicted trajectories of cognitive decline in AgeCoDe before DAT onset depending on OCRS. (A) Predicted trajectories in the normalized MMSE (normMMSE) (Philipps et al., 2014) relative to the onset of DAT for individuals with either low (25th percentile) or high (75th percentile) OCRS levels. The normalized MMSE has a range of 0 to 100. Shaded areas indicate 95% confidence intervals. Individuals with high OCRS (blue line) show stable cognitive function for a longer period than individuals with low OCRS (orange line). However, they decline stronger after the onset of deterioration. Both groups show equal levels of performance at dementia onset. Afterward, high OCRS is associated with slightly lower levels of cognitive function. (B) Predicted differences of individuals with high (75th percentile) or low OCRS (25th percentile) compared to individuals with median OCRS values at different time points relative to DAT onset. Bars indicate 95% confidence intervals. Differences are computed from the sum of OCRS smooth terms [ti(OCRS) in the mgcv package] and OCRS and time tensor product interaction terms [ti(time,OCRS) in the mgcv package]. While high OCRS (blue line) shows an increasingly protective association with cognitive function until ~5 years before dementia onset, this association diminishes and predicted cognition is even lower than in individuals with low OCRS (orange line) after DAT onset. DAT, dementia of the Alzheimer's type; normMMSE, normalized Mini-Mental-State-Examination; OCRS, occupational cognitive requirement score.
Figure 6
Figure 6
Graphical illustrations of hypothesis test results for CR, BM, and BR. In the graphical illustrations of hypotheses (right side), black arrows linking boxes indicate expected association, red dashed arrows indicate associations inconsistent with the predictions by the respective resilience concept, and gray dotted arrows indicate no expectation regarding association by the respective resilience concept. Arrows pointing toward other arrows indicate an expected statistical interaction effect. In the bottom row, plots on the left illustrate the typical development of cognition over time. Bold arrows indicate the alignment of time to the onset of dementia (horizontal black line) that is a shift along the x-axis. In the graphical illustrations of empirical results (left side), black arrows indicate supported associations while red arrows indicate non-significant associations not supported by our data. OCRS, occupational cognitive requirement score; APOE-ε4, apolipoprotein E ε4 allele; CSF, cerebrospinal fluid; CR, cognitive reserve; BM, brain maintenance; BR, brain reserve.
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