1. Epidemiology and Global Health
  2. Neuroscience

Impact of social isolation on grey matter structure and cognitive functions: A population-based longitudinal neuroimaging study

  1. Laurenz Lammer  Is a corresponding author
  2. Frauke Beyer
  3. Melanie Luppa
  4. Christian Sanders
  5. Ronny Baber
  6. Christoph Engel
  7. Kerstin Wirkner
  8. Markus Loffler
  9. Steffi G Riedel-Heller
  10. Arno Villringer
  11. A Veronica Witte  Is a corresponding author
  1. Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Germany
  2. Clinic for Cognitive Neurology, University of Leipzig Medical Center, Germany
  3. CRC Obesity Mechanisms, Subproject A1, University of Leipzig, Germany
  4. Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Faculty of Medicine, Germany
  5. Department of Psychiatry and Psychotherapy, University of Leipzig Medical Centre, Germany
  6. Leipzig Research Center for Civilization Diseases (LIFE), University of Leipzig, Germany
  7. Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Germany
  8. Berlin School of Mind and Brain, Humboldt University of Berlin, Germany
https://doi.org/10.7554/eLife.83660
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Cite this article
  1. Laurenz Lammer
  2. Frauke Beyer
  3. Melanie Luppa
  4. Christian Sanders
  5. Ronny Baber
  6. Christoph Engel
  7. Kerstin Wirkner
  8. Markus Loffler
  9. Steffi G Riedel-Heller
  10. Arno Villringer
  11. A Veronica Witte
(2023)
Impact of social isolation on grey matter structure and cognitive functions: A population-based longitudinal neuroimaging study
eLife 12:e83660.
https://doi.org/10.7554/eLife.83660
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13 figures, 33 tables and 1 additional file

Figures

Figure 1
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Scatterplots with regression lines and 95% confidence intervals for model 1.

Asterisks show frequentist levels of significance. The first and second lines show values before and after FDR, respectively. ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05. LSNS, Lubben Social NEltwork ScaPie charts show Bayesian relative evidences. The green and black arc lengths represent the evidence in favour of the alternative and the null hypothesis, respectively.

Figure 2
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Forest plot of predictors’ effect sizes in model 1.

For the gender variable and the education variable being women and having at least a tertiary degree were coded as 0, respectively. Betas were standardized by the standard deviations of the dependent and independent variable. LSNS_base, baseline Lubben Social Network Scale; age_base, baseline age; LSNS_change, change in Lubben Social Network Scale; age_change, change in age.

Figure 3
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Forest plot of predictors’ effect sizes in model 2.

For the gender variable and the education variable being women and having at least a tertiary degree were coded as 0, respectively. Betas were standardized by the standard deviations of the dependent and independent variable. LSNS_base, baseline Lubben Social Network Scale; age_base, baseline age; LSNS_change, change in Lubben Social Network Scale; age_change, change in age.

Figure 4
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Whole-brain analysis of the effect of baseline social isolation on cortical thickness.

Unstandardized betas are the vertex-wise effect sizes of baseline social isolation in mm/point on the Lubben Social Network Scale corrected for baseline age, change in age, change in social isolation and gender. The first row shows the left hemisphere. Areas in which stronger isolation links to reduced thickness are marked in blue, the inverse in red. The right hemisphere is shown below. First and second columns show the lateral and medial views, respectively. The box on the right shows three clusters of lower cortical thickness associated with social isolation in the left hemisphere that remained significantly associated after FDR-correction and the F-value of each significant vertex. Significantly associated FDR-corrected clusters in the supramarginal gyrus and cuneus in the right hemisphere and further clusters in the left hemisphere are not highlighted.

Figure 5
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Whole-brain analysis of the effect of change in social isolation on cortical thickness.

Unstandardized betas are the vertex-wise effect sizes of change in social isolation in mm/point on the Lubben Social Network Scale corrected for baseline age, change in age, and baseline social isolation and gender. The first row shows the left hemisphere. Areas in which stronger isolation links to reduced thickness are marked in blue, the inverse in red. The right hemisphere is shown below. First and second columns show the lateral and medial views, respectively. The box on the right shows a cluster of lower cortical thickness associated with social isolation in the right middle frontal gyrus that was significant after FDR-correction and the F-value of each significant vertex.

Figure 6
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Flowchart of stepwise application of exclusion criteria.

Small rectangles show the number of participants fulfilling the respective criteria in total and for baseline and follow-up. The large box shows how many participants were excluded due to various exclusion criteria in total for baseline and follow-up. Missing control variables in model 2 were the Center for Epidemiological Studies Depression scores. LSNS, Lubben Social Network Scale; HCV, hippocampal volume; BL, baseline; FU, follow-up.

Appendix 1—figure 1
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Spaghetti plots of individuals’ developments in social isolation, hippocampal volume and cognitive functions over time.

Outliers in memory and processing speed with scores smaller than 5 are not depicted. LSNS, Lubben Social Network Scale; trend_, individual trend in respective ordinate axis variable development. Unit for hippocampal volume is mm3, unit for LSNS is points on the questionnaire and units for cognitive scores are deviations from the mean in standard deviations.

Appendix 1—figure 2
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Simplified plot of the bivariate latent change score models.

LSNS, Lubben Social Network Scale; HCV, hippocampal volume; BL, baseline; FU, follow up; Δ, change in. The blue arrows show our paths of interest.

Appendix 1—figure 3
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Directed acyclic graphs demonstrating the theoretical underpinnings of model 1 and 2.

In model 1 the additional risk factors are assumed to be mediators and do not have to be controlled for. In model 2 they are assumed to be confounders. Therefore, they have to be controlled for.

Appendix 1—figure 4
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Proportional missingness relative to social isolation.

(A) Histogram of Lubben Social Network Scale (LSNS) scores by individual observation. (B) Heatmap of proportional missingness of variables for different LSNS scores.

Appendix 1—figure 5
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Familywise error rates of frequentist and bayesian t-tests.
Appendix 1—figure 6
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Histogram of Bayes factors (BFs) with randomly simulated values for our predictors of interest.

The red lines show the traditional thresholds at 1/3 and 3.

Author response image 1
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Tables

Table 1
Descriptive statistics.
VariableBL, N = 1992FU, N = 1409
Gender (female)921 (46%)656 (47%)
Baseline age (years)67 (7) | 50 | 82 | 068 (7) | 50 | 84 | 0
Change in age (years)0.00 (0.00) | 0.00 | 0.00 | 05.89 (1.97) | 0.00 | 9.40 | 15
Baseline LSNS14.1 (5.2) | 0.0 | 30.0 | 18113.7 (5.1) | 0.0 | 30.0 | 20
Change in LSNS0.00 (0.00) | 0.00 | 0.00 | 00.39 (4.38) | –21.00 | 18.00 | 115
HCV (mm³)3671 (411) | 2022 | 4871 | 833487 (430) | 1,913 | 4579 | 665
BMI (kg/m²)27.9 (4.2) | 16.8 | 46.8 | 027.8 (3.7) | 18.1 | 46.5 | 0
Hypertension1219 (61%)830 (59%)
Diabetes367 (18%)239 (17%)
education255 (13%)153 (11%)
CESD10 (6) | 0 | 48 | 10410 (6) | 0 | 48 | 62
Memory (SD)0.03 (0.97) | –8.79 | 1.70 | 84–0.06 (1.04) | –5.84 | 1.64 | 314
Processing speed (SD)0.09 (0.92) | –7.80 | 1.73 | 12–0.14 (1.10) | –7.80 | 1.61 | 214
Executive functions (SD)0.12 (0.95) | –4.59 | 3.26 | 11–0.21 (1.04) | –4.43 | 3.29 | 210
TICS58 (27) | 0 | 166 | 148057 (27) | 0 | 146 | 938
Pandemic0 (0%)412 (31%)

  1. Values for categorical variables: n (%) yes; values for continuous variables: mean (SD) | minimum | maximum | n missing.

  2. HCV, right-left average hippocampal volume; BMI, body mass index; LSNS, Lubben Social Network Scale, calculated as 30 – LSNS to make larger values indicate greater social isolation; TICS, Trierer Inventar zum chroischen Stress; CESD, Center for Epidemiological Studies Depression Scale; SD, standard deviation; education, no tertiary education.

Table 2
Adjusted regression coefficients and measures of significance.
dvModelPredictorEstimate95% CIp-valueFDRBF
Hippo
campal volume		1LSNS_base–5.6−9.3,–20.0013**0.0034**18.95**
LSNS_change–4.7−8,–1.30.0035**0.0069**2.36
age_base-26.1-28.9, -23.2
age_change–26.8−29,–24.7
2LSNS_base–5.7−9.6,–1.80.0019**0.0078**14.93**
LSNS_change–4.5−8.1,–10.0066**0.0158*2.47
age_base–24.2−27.3,–21.2
age_change–26.8−29.2,–24.5
* p<0.05, BF >3** p<0.01, BF >10*** p<0.001, BF >30**** p<0.0001, BF >100

  1. The unit of effect sizes is mm³/point on the LSNS.

  2. full model1: dv~LSNS_base + LSNS_change + age_base + age_change + gender.

  3. full model 2: model 1 + hypertension + diabetes + education + BMI + CESD.

  4. dv, dependent variable; CI, confidence interval; FDR, q-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Table 3
Adjusted regression coefficients and measures of significance.
dvModelPredictorEstimate95% CIp-valueFDRBF
Executive functions1LSNS_base-0.028−0.037,–0.0198.0e-10****9.6e-09****1.4e+07****
LSNS_change–0.003–0.017, 0.0110.3420.41040.16
age_base–0.019−0.026,–0.012
age_change–0.050−0.061,–0.04
2LSNS_base–0.017−0.026,–0.0072e-04****0.0014**128.4****
LSNS_change0.001-0.013, 0.0160.57620.69140.13
age_base–0.014−0.021,–0.007
age_change-0.051−0.061,–0.04
Memory1LSNS_base-0.014−0.022,–0.0064e-04****0.0016**58.91***
LSNS_change-0.019−0.032,–0.0070.0014**0.0034**14.68**
age_base–0.035−0.042,–0.029
age_change-0.018-0.026, -0.009
2LSNS_base–0.008-0.016, 0.0010.0457*0.09141.23
LSNS_change–0.018−0.031,–0.0040.0047**0.0142*6.67*
age_base–0.033−0.04,–0.026
age_change-0.018-0.028, -0.009
Processing speed1LSNS_base–0.018−0.026,–0.011.9e-06****1.2e-05****8.2e+03****
LSNS_change–0.007–0.019, 0.0060.15850.23780.26
age_base–0.038−0.044,–0.032
age_change-0.038−0.047,–0.028
2LSNS_base–0.017−0.025,–0.0092.1e-05****3e-04****1.0e+03****
LSNS_change–0.008–0.021, 0.0050.12530.19810.53
age_base–0.036−0.042,–0.029
age_change-0.033−0.043,–0.024
* p<0.05, BF >3** p<0.01, BF >10*** p<0.001, BF >30**** p<0.0001, BF >100

  1. The unit of effect sizes is standard deviation/point on the LSNS.

  2. full model 1: dv~LSNS_base + LSNS_change + age_base + age_change + gender.

  3. full model 2: model 1 + hypertension + diabetes + education + BMI + CESD.

  4. dv, dependent variable; CI, confidence interval; FDR, q-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Table 4
FDR-corrected clusters of reduced cortical thickness significantly associated with social isolation.
POIHemisphereCortical regionMaximum p-valueSize (mm²)NVtxs
LSNS_baserhSupramarginal1.3e-0543.12114
LSNS_baserhCuneus2.8e-0528.0442
LSNS_changerhSuperior frontal1.4e-0643.8465
LSNS_baselhPrecuneus1.1e-06224.34504
LSNS_baselhPrecuneus1.2e-0541.7177
LSNS_baselhCuneus9.8e-0510.2115
LSNS_baselhPrecuneus1.1e-042.746
LSNS_baselhPrecentral1.1e-042.325
LSNS_baselhPosterior cingulate1.2e-040.662

  1. full model 1: cortical thickness ~ LSNS_base +LSNS_change +age_base +age_change +sex.

  2. POI, predictor of interest; NVtxs, Number of vertices constituting the cluster; LSNS_base, baseline social isolation; LSNS_change, change in social isolation; rh, right hemisphere; lh, left hemisphere.

Appendix 1—table 1
Descriptive statistics for further variables.
VariableBL, N = 1992FU, N = 1409
Married1,435 (72%) | 10768 (70%) | 306
Not working1,434 (73%) | 20887 (81%) | 309
Living alone426 (22%) | 13296 (27%) | 305
n in dwelling2 (1) | 1 | 11 | 132 (1) | 1 | 10 | 305
SES12.4 (3.3) | 4.5 | 21.0 | 1312.6 (3.3) | 4.5 | 21.0 | 8
Migration background332 (17%) | 10232 (17%) | 6
Global PSQI6 (3) | 0 | 19 | 5585 (3) | 0 | 14 | 1,110
Total weekly METs5,910 (5,829) | 0 | 38,880 | 1784,587 (5,994) | 0 | 49,500 | 1,055

  1. Values for categorical variables: n (%) yes, | n missing; values for continuous variables: mean (SD) | minimum | maximum | n missing.

  2. BL, baseline; FU, follow-up; not working, not gainfully employed due to other reasons than studies, military or other service; n in dwelling, number of persons living in the participants’ dwelling; SES, socioeconomic status; migration background, participant or at least one of the participants parents was not born in Germany; global PSQI, global score of the Pittsburgh Sleep Quality Index; total weekly METs, total weekly metabolic equivalents based on the International Physical Activity Questionnaire

Appendix 1—table 2
Regression coefficients and measures of significance.
Regression coefficients and measures of significance
dvPredictorEstimate95% CIp-valuen totaln indiv
LSNS_sumTICS0.008–0.005, 0.020.3652933794
LSNS_sumgender0.204-0.238, 0.6451.0e-28****31151921
LSNS_sumSES–0.377−0.442,–0.3125.1e-07****30991910
LSNS_sumnot working1.1250.686, 1.5651.2e-19****28121893
LSNS_sumn_dwell-1.605-1.95, -1.260.961628231899
LSNS_summigrat–0.015–0.605, 0.5762.5e-17****31031913
LSNS_summarried-1.951-2.399, -1.5029.3e-22****28251900
LSNS_sumlive alone2.3371.862, 2.8120.234428231899
LSNS_sumage_base0.0840.051, 0.1175.9e-07****31151921
LSNS_sumage_change0.0460.007, 0.0850.0207*31151921

  1. * p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001.

  2. dv, dependent variable; CI, confidence interval; n total, total number of observations; n indiv, number of participants; LSNS_sum, Lubben Social Network Scale sum score; SES, socioeconomic status; not working, not gainfully employed due to other reasons than studies, military or alternative service; n dwell, number of persons living in the participants' dwelling; migrat, migration background; live alone, participants living alone; TICS, sum score of the Trierer Inventar zum chronischen Stress (chronic stress questionnaire); age_base, age at baseline; age_change, change in age from baseline to follow-up.

Appendix 1—table 3
Comparison of LIFE-SES data with quintiles based on fully representative sample.
CategoryQuintileLIFE-Adult (%)
Low16.75
Middle215.36
322.01
423.82
High532.07

  1. Category, socioeconomic status category; LIFE-Adult (%), percentage of participants falling into the range of the quintile cut-off points based on a representative German sample.

Appendix 1—table 4
Adjusted regression coefficients and measures of significance of models without interaction terms.
dvModelPredictorEstimate95% CIp-valueFDRBFTotal nn individuals
Hippo
campal volume		1LSNS_base–5.616−9.281,–1.9510.0013**0.0034**18.95**16671306
LSNS_change–4.659−8.027,–1.2840.0035**0.0069**2.3616671306
age_base–26.079−28.932,–23.226   16671306
age_change–26.836−29.01,–24.668   16671306
gender–46.504−83.617,–9.392   16671306
2LSNS_base–5.697−9.56,–1.8330.0019**0.0078**14.93**15561226
LSNS_change-4.548−8.131,–0.9540.0066**0.0158*2.4715561226
age_base-24.246-27.292, -21.199   15561226
age_change-26.831−29.157,–24.513   15561226
gender–46.390−84.512,–8.269   15561226
BMI13.722-3.151, 30.599   15561226
CESD12.184-7.102, 31.47   15561226
diabetes–99.613−152.086,–47.131   15561226
education–93.450−155.942,–30.953   15561226
hypertension–21.182–61.555, 19.195   15561226
Executive functions1LSNS_base–0.028−0.037,–0.0198.0e-10****9.6e-09****1.4e+07****20481469
LSNS_change-0.003-0.017, 0.0110.3420.41040.1620481469
age_base–0.019−0.026,–0.012   20481469
age_change-0.050-0.061, -0.04   20481469
gender-0.084–0.176, 0.008   20481469
2LSNS_base-0.017-0.026, -0.0072e-04****0.0014**128.4****18931377
LSNS_change0.001–0.013, 0.0160.57620.69140.1318931377
age_base-0.014−0.021,–0.007   18931377
age_change–0.051−0.061,–0.04   18931377
gender-0.122−0.215,–0.028   18931377
BMI–0.074−0.121,–0.028   18931377
CESD-0.141−0.188,–0.094   18931377
diabetes-0.055-0.184, 0.074   18931377
education–0.331−0.489,–0.173   18931377
hypertension–0.097-0.196, 0.002   18931377
Memory1LSNS_base-0.014-0.022, -0.0064e-04****0.0016**58.91***19211408
LSNS_change–0.019−0.032,–0.0070.0014**0.0034**14.68**19211408
age_base-0.035−0.042,–0.029   19211408
age_change–0.018−0.026,–0.009   19211408
gender–0.381−0.465,–0.297   19211408
2LSNS_base-0.008-0.016, 0.0010.0457*0.09141.2317771315
LSNS_change–0.018−0.031,–0.0040.0047**0.0142*6.67*17771315
age_base-0.033−0.04,–0.026   17771315
age_change-0.018-0.028, -0.009   17771315
gender-0.421−0.507,–0.334   17771315
BMI-0.031-0.074, 0.012   17771315
CESD–0.120−0.164,–0.077   17771315
diabetes–0.038-0.155, 0.08   17771315
education–0.173−0.316,–0.031   17771315
hypertension0.017–0.074, 0.108   17771315
Processing speed1LSNS_base–0.018−0.026,–0.011.9e-06****1.2e-05****8.2e+03****20431470
LSNS_change–0.007–0.019, 0.0060.15850.23780.2620431470
age_base-0.038-0.044, -0.032   20431470
age_change-0.038−0.047,–0.028   20431470
gender-0.108−0.185,–0.031   20431470
2LSNS_base-0.017−0.025,–0.0092.1e-05****3e-04****1.0e+03****18881376
LSNS_change-0.008–0.021, 0.0050.12530.19810.5318881376
age_base–0.036−0.042,–0.029   18881376
age_change–0.033−0.043,–0.024   18881376
gender-0.124−0.204,–0.044   18881376
BMI-0.013-0.053, 0.028   18881376
CESD-0.027–0.067, 0.013   18881376
diabetes–0.005–0.115, 0.106   18881376
education–0.115–0.248, 0.017   18881376
hypertension-0.067-0.151, 0.018   18881376

  1. * p<0.05, BF >3; ** p<0.01, BF >10; *** p<0.001, BF >30; **** p<0.0001, BF >100.

  2. full model1: dv~LSNS_base+LSNS_change+age_base+age_change+gender.

  3. full model2: model1 + hypertension+diabetes+education+BMI+CESD.

  4. The unit of effect sizes on hippocampal volume and cognitive functions are mm³/point on the LSNS and standard deviation/point on the LSNS, respectively.

  5. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; BF, Bayes Factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Appendix 1—table 5
Adjusted regression coefficients and measures of significance of models with interaction term of baseline social isolation with change in age.
dvModelPredictorEstimate95% CIp-valueFDRBFTotal nn individuals
Hippo
campal volume		1LSNS_base*age_change–0.319–0.821, 0.1820.10630.18210.1616671306
LSNS_base–5.331−9.022,–1.6416671306
LSNS_change–5.570−9.227,–1.90916671306
age_base-26.052−28.905,–23.19916671306
age_change–22.528−29.639,–15.40916671306
gender–46.176−83.284,–9.06916671306
2LSNS_base*age_change–0.302-0.833, 0.2280.1320.19810.1515561226
LSNS_base–5.423−9.315,–1.53115561226
LSNS_change–5.369−9.23,–1.50315561226
age_base–24.219−27.266,–21.17315561226
age_change-22.738−30.287,–15.17915561226
gender–46.042−84.16,–7.92615561226
BMI13.544-3.326, 30.41715561226
CESD12.301-6.982, 31.58315561226
diabetes–99.378−151.839,–46.90715561226
education-93.471−155.947,–30.9915561226
hypertension–21.032–61.396, 19.33515561226
Executive functions1LSNS_base*age_change0.001–0.002, 0.0030.67390.67390.0820481469
LSNS_base–0.029−0.039,–0.01920481469
LSNS_change–0.002–0.017, 0.01420481469
age_base–0.019−0.026,–0.01220481469
age_change–0.057−0.09,–0.02520481469
gender-0.084–0.176, 0.00820481469
2LSNS_base*age_change0.001-0.001, 0.0030.77130.77130.0818931377
LSNS_base–0.018−0.028,–0.00818931377
LSNS_change0.004-0.012, 0.01918931377
age_base–0.014−0.021,–0.00718931377
age_change–0.063−0.097,–0.02918931377
gender–0.123−0.216,–0.02918931377
BMI-0.074-0.12, -0.02818931377
CESD–0.141−0.188,–0.09418931377
diabetes–0.056–0.185, 0.07318931377
education–0.331−0.488,–0.17318931377
hypertension-0.098–0.196, 0.00118931377
Memory1LSNS_base*age_change0.000–0.002, 0.0020.66950.67390.0719211408
LSNS_base-0.015−0.023,–0.00619211408
LSNS_change-0.018−0.032,–0.00519211408
age_base-0.035−0.042,–0.02919211408
age_change–0.024–0.052, 0.00519211408
gender–0.382−0.466,–0.29819211408
2LSNS_base*age_change0.001–0.001, 0.0030.72710.77130.0817771315
LSNS_base–0.008–0.018, 0.00117771315
LSNS_change–0.016−0.031, –0.00217771315
age_base-0.033–0.04, –0.02617771315
age_change-0.027–0.057, 0.00317771315
gender-0.421−0.507, –0.33517771315
BMI-0.031–0.074, 0.01117771315
CESD–0.120−0.164, –0.07717771315
diabetes–0.038–0.156, 0.0817771315
education–0.173−0.316, –0.03117771315
hypertension0.017-0.074, 0.10817771315
Processing speed1LSNS_base*age_change-0.001–0.003, 0.0010.23410.31220.1920431470
LSNS_base-0.017−0.025, –0.00920431470
LSNS_change–0.008–0.022, 0.00520431470
age_base–0.038−0.044, –0.03220431470
age_change–0.027–0.057, 0.00220431470
gender–0.107−0.185, –0.0320431470
2LSNS_base*age_change0.000–0.002, 0.0020.48560.64740.1118881376
LSNS_base–0.017−0.026, –0.00818881376
LSNS_change–0.008-0.022, 0.00618881376
age_base–0.036−0.042, –0.02918881376
age_change–0.033−0.063, 0.00318881376
gender–0.124−0.204, –0.04418881376
BMI–0.013–0.053, 0.02818881376
CESD–0.027–0.067, 0.01318881376
diabetes–0.004–0.115, 0.10618881376
education–0.115–0.248, 0.01718881376
hypertension–0.067–0.151, 0.01818881376

  1. full model1: dv~LSNS_base+LSNS_change+age_base+age_change+gender

  2. full model2: model1 +hypertension + diabetes +education + BMI +CESD

  3. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Appendix 1—table 6
Adjusted regression coefficients and measures of significance of models with interaction term of baseline social isolation with change in social isolation.
dvModelPredictorEstimate95% CIp-valueBFTotal nn individuals
Hippo
campal volume		1LSNS_base*LSNS_change0.14-0.51, 0.790.66460.0316671306
LSNS_base–5.62−9.29,–1.9616671306
LSNS_change–6.51–15.71, 2.6716671306
age_base–26.08−28.93,–23.2316671306
age_change–26.67−28.97,–24.3816671306
gender–46.44−83.55,–9.3316671306
2LSNS_base*LSNS_change0.18–0.5, 0.860.69850.0515561226
LSNS_base–5.70−9.57,–1.8415561226
LSNS_change–6.94–16.67, 2.7815561226
age_base–24.25−27.29,–21.215561226
age_change–26.63−29.08,–24.1915561226
gender–46.32−84.44,–8.2115561226
BMI13.78–3.1, 30.6515561226
CESD12.14–7.14, 31.4315561226
diabetes–99.48−151.96,–4715561226
education-93.43−155.91,–30.9315561226
hypertension-21.19–61.56, 19.1915561226

  1. full model1: dv~LSNS_base+LSNS_change+age_base+age_change+gender

  2. full model2: model1 + hypertension+diabetes+education+BMI+CESD

  3. dv, dependent variable; CI, confidence interval; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Appendix 1—table 7
Indirect effects of social isolation on hippocampal volume and cognitive functions.
MediatordvModelEstimateSEz-valuep-value
TICSHippo
campal volume		10.02910.74140.03930.5157
2–0.20591.0916–0.18860.4252
Hippo
campal volume		Executive functions1–0.00080.0012–0.65610.2559
2–0.00110.0013–0.80660.2099
Memory1–0.00080.0012–0.69450.2437
2–0.00140.0015–0.92450.1776
Processing speed1-0.00010.0005–0.24690.4025
2–0.00010.0007–0.16480.4345

  1. model1: corrected for baseline age, change in age and gender.

  2. model2: model1 + hypertension + diabetes +education + BMI +CESD.

  3. dv, dependent variable; SE, standard error; TICS, Trierer Inventar zum chronischen Stress (stress questionnaire).

Appendix 1—table 8
Adjusted regression coefficients and measures of significance of models controlling for Covid-pandemic.
dvModelPredictorEstimate95% CIp-valueFDRBFTotal nn individuals
Hippocampal volume1LSNS_base–5.617−9.285,–1.9490.0014**0.0027**19.38**16671306
LSNS_change–5.347−8.694,–1.9929e-04****0.0022**7.51*16671306
age_base–26.064−28.92,–23.209 16671306
age_change–24.528−27.14,–21.93 16671306
pandemic–48.811−80.321,–17.156 16671306
gender–45.254−82.41,–8.098 16671306
2LSNS_base–5.704−9.57,–1.8370.0019**0.0048**16.91**15561226
LSNS_change–5.268−8.836,–1.6870.002**0.0048**7.01*15561226
age_base-24.223−27.272,–21.174 15561226
age_change–24.606−27.382,–21.847 15561226
pandemic–48.519−82.488,–14.388 15561226
gender-44.976−83.143,–6.809 15561226
BMI13.485–3.334, 30.308 15561226
CESD12.444–6.859, 31.747 15561226
diabetes–99.503−152.012,–46.984 15561226
education–93.726−156.267,–31.179 15561226
hypertension–21.309–61.711, 19.097 15561226
Executive functions1LSNS_base-0.028−0.037,–0.0197.0e-10****8.4e-09****1.6e+07****20481469
LSNS_change–0.002–0.016, 0.0120.3950.4740.1620481469
age_base–0.019−0.026,–0.012 20481469
age_change–0.057−0.069,–0.044 20481469
pandemic0.116-0.013, 0.246 20481469
gender–0.086-0.178, 0.006 20481469
2LSNS_base–0.017−0.027,–0.0082e-04****0.0013**143.45****18931377
LSNS_change0.002–0.013, 0.0170.61540.73850.1418931377
age_base–0.014−0.021,–0.007 18931377
age_change-0.055−0.068,–0.043 18931377
pandemic0.091–0.044, 0.227 18931377
gender–0.124−0.217,–0.03 18931377
BMI–0.074−0.121,–0.028 18931377
CESD–0.141−0.188,–0.095 18931377
diabetes–0.055–0.184, 0.074 18931377
education-0.330−0.488,–0.172 18931377
hypertension–0.096–0.195, 0.002 18931377
Memory1LSNS_base–0.014−0.022,–0.0065e-04****0.0015**51.07***19211408
LSNS_change–0.021−0.034,–0.0095e-04****0.0015**43.05***19211408
age_base–0.035−0.042,–0.029 19211408
age_change–0.006-0.017, 0.004 19211408
pandemic–0.222−0.339,–0.103 19211408
gender–0.376−0.46,–0.292 19211408
2LSNS_base–0.007–0.016, 0.0010.0494*0.09871.3317771315
LSNS_change–0.020−0.034,–0.0070.0016**0.0048**16.7**17771315
age_base–0.033−0.04,–0.026 17771315
age_change–0.006–0.017, 0.005 17771315
pandemic–0.247−0.372,–0.122 17771315
gender–0.415−0.501,–0.328 17771315
BMI–0.031–0.074, 0.011 17771315
CESD-0.119−0.162,–0.075 17771315
diabetes–0.037–0.155, 0.081 17771315
education–0.176−0.318,–0.034 17771315
hypertension0.015–0.076, 0.106 17771315
Processing speed1LSNS_base–0.018−0.026,–0.012.0e-06****1.2e-05****8.6e+03****20431470
LSNS_change-0.007–0.019, 0.0060.15760.23640.2720431470
age_base–0.038−0.044,–0.032 20431470
age_change–0.037−0.049,–0.026 20431470
pandemic–0.005–0.123, 0.112 20431470
gender–0.108−0.185,–0.03 20431470
2LSNS_base–0.017−0.025,–0.0092.1e-05****3e-04****1.1e+03****18881376
LSNS_change-0.008–0.021, 0.0060.12760.19140.4118881376
age_base–0.036−0.042,–0.029 18881376
age_change–0.034−0.045,–0.022 18881376
pandemic0.009–0.112, 0.13 18881376
gender–0.124−0.205,–0.044 18881,376
BMI–0.013–0.053, 0.028 18881376
CESD-0.027–0.067, 0.013 18881,376
diabetes–0.005–0.115, 0.106 18881376
education–0.115–0.248, 0.017 18881376
hypertension–0.066–0.151, 0.018 18881376

  1. full model1: dv~LSNS_base +LSNS_change +age_base +age_change +gender.

  2. full model2: model1 +hypertension + diabetes +education + BMI +CESD.

  3. The unit of effect sizes on hippocampal volume and cognitive functions are mm³/point on the LSNS and standard deviation/point on the LSNS, respectively.

  4. * p<0.05, BF >3; ** p<0.01, BF >10; *** p<0.001, BF >30; **** p<0.0001, BF >100.

  5. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; pandemic, LSNS measurement taking place after initiation of lockdown measures in Germany; CESD, Center for Epidemiological Studies-Depression.

Appendix 1—table 9
Adjusted regression coefficients and measures of significance of models using fewer exclusion criteria.
dvModelPredictorEstimate95% CIp-valueFDRBFTotal nn individuals
Hippo
campal volume		1LSNS_base–5.362−9.037,–1.6870.0021**0.0051**12.35**16671309
LSNS_change–4.206−7.616,–0.7880.008**0.0137*1.1716671309
age_base-26.194−29.056,–23.333   16671309
age_change–26.655−28.851,–24.465   16671309
gender–46.466−83.665,–9.267   16671309
2LSNS_base–5.428−9.315,–1.5410.0031**0.0094**10.11**15561232
LSNS_change–4.368−8.04,–0.6860.01*0.0201*1.615561232
age_base–24.542−27.6,–21.486   15561232
age_change–26.819−29.198,–24.45   15561232
gender–48.740−86.973,–10.506   15561232
BMI10.301-6.446, 27.053   15561232
CESD12.673–6.798, 32.143   15561232
diabetes–96.009−148.633,–43.372   15561232
education–90.854−153.471,–28.23   15561232
hypertension–24.435-64.91, 16.046   15561232
Executive functions1LSNS_base-0.030-0.038, -0.0222.4e-13****2.8e-12****3.4e+10****25511756
LSNS_change–0.009–0.021, 0.0030.07760.11460.4925511756
age_base–0.018−0.024,–0.012   25511756
age_change-0.051−0.059,–0.042   25511756
gender-0.112−0.194,–0.03   25511756
2LSNS_base–0.019−0.027,–0.0115.6e-06****6.7e-05****3.8e+03****23651649
LSNS_change-0.005-0.018, 0.0070.1980.2640.323651649
age_base–0.011−0.018,–0.005   23651649
age_change–0.052−0.061,–0.043   23651649
gender–0.160−0.244,–0.077   23651649
BMI–0.052−0.093,–0.01   23651649
CESD-0.137−0.179,–0.095   23651649
diabetes-0.040-0.153, 0.073   23651649
education-0.315-0.45, -0.18   23651649
hypertension-0.102-0.191, -0.014   23651649
Memory1LSNS_base–0.014−0.021,–0.0062e-04****7e-04****120.88****24181697
LSNS_change–0.016−0.027,–0.0050.0017**0.0051**10.58**24181697
age_base–0.036−0.042,–0.03   24181697
age_change–0.024−0.031,–0.016   24181697
gender–0.383−0.459,–0.306   24181697
2LSNS_base-0.006–0.014, 0.0020.08180.14030.6822461590
LSNS_change–0.015−0.026,–0.0030.0057**0.0136*5.02*22461590
age_base–0.033−0.04,–0.027   22461590
age_change–0.025−0.034,–0.017   22461590
gender–0.429−0.508,–0.351   22461590
BMI–0.030-0.068, 0.009   22461590
CESD–0.133−0.172,–0.093   22461590
diabetes–0.067–0.172, 0.038   22461590
education-0.148−0.272,–0.023   22461590
hypertension0.032–0.052, 0.115   22461590
Processing speed1LSNS_base–0.016−0.023,–0.0091.9e-06****1.1e-05****7.7e+03****25521749
LSNS_change-0.014−0.025,–0.0030.0047**0.0093**4.61*25521749
age_base–0.038−0.044,–0.033   25521749
age_change–0.037−0.045,–0.029   25521749
gender–0.096−0.163,–0.028   25521749
2LSNS_base–0.013−0.02,–0.0062e-04****0.0011**162.63****23661640
LSNS_change–0.016−0.027,–0.0050.0023**0.0092**10.97**23661640
age_base–0.036−0.041,–0.03   23661640
age_change–0.036−0.044,–0.028   23661640
gender–0.116−0.186,–0.045   23661640
BMI–0.021–0.056, 0.014   23661640
CESD–0.037−0.073,–0.002   23661640
diabetes–0.025–0.121, 0.07   23661640
education–0.172−0.284,–0.06   23661640
hypertension–0.049–0.123, 0.026   23661640

  1. full model1: dv~LSNS_base +LSNS_change +age_base +age_change +gender.

  2. full model2: model1 +hypertension + diabetes +education + BMI +CESD.

  3. The unit of effect sizes on hippocampal volume and cognitive functions are mm³/point on the LSNS and standard deviation/point on the LSNS, respectively.

  4. * p<0.05, BF >3; ** p<0.01, BF >10; *** p<0.001, BF >30; **** p<0.0001, BF >100.

  5. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Appendix 1—table 10
Adjusted regression coefficients and measures of significance of models including only participants with data for both timepoints.
dvModelPredictorEstimate95% CIp-valueFDRBFTotal nn individuals
Hippo
campal volume		1mean LSNS–7.344−11.754,–2.9346e-04****0.0022**40.15***1281920
LSNS within–4.584−7.955,–1.2070.0039**0.0118*2.861281920
mean age–26.691−30.087,–23.295   1281920
age within–26.052−28.219,–23.877   1281920
gender–41.688–84.828, 1.452   1281920
2mean LSNS–7.216−11.815,–2.6170.0011**0.0064**26.85**1210880
LSNS within–4.401−7.981,–0.8070.0082**0.0245*2.11210880
mean age–25.319−28.9,–21.739   1210880
age within–25.990−28.309,–23.662   1210880
gender–41.693–85.905, 2.519   1210880
BMI11.325–7.727, 30.38   1210880
CESD4.825–17.285, 26.933   1,210880
diabetes–94.690−157.099,–32.268   1,210880
education–83.335−159.602,–7.057   1,210880
hypertension–23.297–69.476, 22.882   1,210880
Executive functions1mean LSNS–0.029−0.039,–0.0188.4e-08****1.0e-06****1.8e+05****1,6311,052
LSNS within0.000–0.016, 0.0150.49880.540.111,6311,052
mean age–0.014−0.022,–0.006   1,6311,052
age within–0.053−0.064,–0.043   1,6311,052
gender–0.004–0.109, 0.102   1,6311,052
2mean LSNS–0.018−0.029,–0.0076e-04****0.0064**55.52***1,5181,002
LSNS within0.002–0.014, 0.0180.57790.63040.111,5181,002
mean age–0.007–0.016, 0.001   1,5181,002
age within–0.052−0.063,–0.041   1,5181,002
gender–0.051–0.158, 0.057   1,5181,002
BMI–0.059−0.113,–0.005   1,5181,002
CESD–0.147−0.2,–0.094   1,5181,002
diabetes–0.169−0.321,–0.018   1,5181,002
education–0.290−0.477,–0.103   1,5181,002
hypertension–0.123−0.235,–0.011   1,5181,002
Memory1mean LSNS–0.009–0.019, 00.0292*0.05851.631,5391,026
LSNS within–0.015−0.029,–0.0020.0147*0.0353*1.891,5391,026
mean age–0.031−0.039,–0.024   1,5391,026
age within–0.018−0.027,–0.009   1,5391,026
gender–0.351−0.446,–0.256   1,5391,026
2mean LSNS–0.005–0.015, 0.0050.18070.30820.521,436974
LSNS within–0.013–0.027, 0.0010.0365*0.08771.151,436974
mean age–0.027−0.035,–0.02   1,436974
age within–0.017−0.027,–0.008   1,436974
gender–0.397−0.493,–0.301   1,436974
BMI0.005–0.044, 0.053   1,436974
CESD–0.122−0.17,–0.075   1,436974
diabetes–0.079–0.215, 0.056   1,436974
education–0.166–0.333, 0.001   1,436974
hypertension0.006–0.094, 0.107   1,436974
Processing speed1mean LSNS–0.016−0.025,–0.0073e-04****0.0017**88.66***1,6251,052
LSNS within–0.005–0.019, 0.010.26280.35050.171,6251,052
mean age–0.039−0.046,–0.032   1,6251,052
age within–0.038−0.047,–0.028   1,6251,052
gender–0.100−0.191,–0.009   1,6251,052
2mean LSNS–0.014−0.024,–0.0050.0017**0.0066**23.31**1,5131,001
LSNS within–0.006–0.021, 0.0080.20550.30820.351,5131,001
mean age–0.038−0.045,–0.03   1,5131,001
age within–0.033−0.043,–0.023   1,5131,001
gender–0.115−0.209,–0.021   1,5131,001
BMI–0.016–0.064, 0.032   1,5131,001
CESD–0.039–0.085, 0.007   1,5131,001
diabetes0.041–0.091, 0.173   1,5131,001
education0.033–0.13, 0.196   1,5131,001
hypertension–0.070–0.168, 0.028   15131,001

  1. full model1: dv~LSNS_base+LSNS_change+age_base+age_change+gender

  2. full model2: model1 + hypertension+diabetes+education+BMI+CESD

  3. The unit of effect sizes on hippocampal volume and cognitive functions are mm³/point on the LSNS and standard deviation/point on the LSNS, respectively.

  4. * p<0.05, BF >3; ** p<0.01, BF >10; *** p<0.001, BF >30; **** p<0.0001, BF >100.

  5. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Appendix 1—table 11
Adjusted regression coefficients and measures of significance of models using a systolic blood pressure of 140 as a cut-off for hypertension.
dvModelPredictorEstimate95% CIp-valueFDRBFTotal nn individuals
Hippo
campal volume		1LSNS_base–5.616−9.281,–1.9510.0013**0.0034**18.34**16671306
LSNS_change–4.659−8.027,–1.2840.0035**0.0069**2.316671306
age_base-26.079-28.932, -23.226   16671306
age_change-26.836-29.01, -24.668   16671306
gender-46.504-83.617, -9.392   16671306
2LSNS_base–5.814−9.679,–1.9480.0016**0.0065**19.34**15561226
LSNS_change–4.564−8.148,–0.9710.0064**0.0154*2.6915561226
age_base–24.531−27.577,–21.486   15561226
age_change–26.822−29.148,–24.504   15561226
gender–46.179−84.385,–7.974   15561226
BMI12.505–4.264, 29.277   15561226
CESD11.135–8.105, 30.375   15561226
diabetes–101.939−154.404,–49.466   15561226
education–83.250−145.334,–21.16   15561226
hypertension–9.769-51.307, 31.773   15561226
Executive functions1LSNS_base–0.028−0.037,–0.0198.0e-10****9.6e-09****1.4e+07****20481469
LSNS_change–0.003–0.017, 0.0110.3420.41040.1620481469
age_base–0.019−0.026,–0.012   20481469
age_change-0.050−0.061,–0.04   20481469
gender-0.084–0.176, 0.008   20481469
2LSNS_base-0.017−0.027,–0.0082e-04****0.0013**132.13****18931377
LSNS_change0.001-0.013, 0.0160.5740.68880.1218931377
age_base–0.013−0.021,–0.006   18931377
age_change–0.051−0.062,–0.04   18931377
gender–0.119−0.212,–0.025   18931377
BMI–0.074−0.12,–0.028   18931377
CESD–0.142−0.189,–0.095   18931377
diabetes–0.052-0.181, 0.077   18931377
education–0.354−0.51,–0.198   18931377
hypertension-0.127−0.229,–0.025   18931377
Memory1LSNS_base–0.014−0.022,–0.0064e-04****0.0016**58.04***19211408
LSNS_change-0.019-0.032, -0.0070.0014**0.0034**14.76**19211408
age_base–0.035−0.042,–0.029   19211408
age_change-0.018−0.026,–0.009   19211408
gender–0.381−0.465,–0.297   19211408
2LSNS_base–0.007–0.016, 0.0010.0475*0.09511.1817771315
LSNS_change-0.018-0.031, -0.0040.0047**0.0141*6.8*17771315
age_base–0.032−0.039,–0.025   17771315
age_change–0.018−0.028,–0.009   17771315
gender–0.420−0.507,–0.334   17771315
BMI–0.029–0.071, 0.014   17771315
CESD–0.119−0.162,–0.075   17771315
diabetes-0.033-0.151, 0.084   17771315
education-0.198-0.339, -0.057   17771315
hypertension–0.015-0.109, 0.079   17771315
Processing speed1LSNS_base–0.018−0.026,–0.011.9e-06****1.2e-05****8.1e+03****20431470
LSNS_change–0.007-0.019, 0.0060.15850.23780.2520431470
age_base–0.038−0.044,–0.032   20431470
age_change–0.038−0.047,–0.028   20431470
gender–0.108−0.185,–0.031   20431470
2LSNS_base–0.017−0.025,–0.0091.9e-05****2e-04****1.1e+03****18881376
LSNS_change–0.008–0.021, 0.0050.12380.19730.4818881376
age_base–0.037−0.043,–0.03   18881376
age_change–0.033−0.043,–0.024   18881376
gender–0.125−0.206,–0.045   18881376
BMI–0.018-0.057, 0.022   18881376
CESD–0.030-0.07, 0.01   18881376
diabetes–0.011-0.121, 0.099   18881376
education–0.105-0.237, 0.026   18881376
hypertension–0.019–0.106, 0.069   18881376
* p<0.05, BF >3; ** p<0.01, BF >10; *** p<0.001, BF >30; **** p<0.0001, BF >100.

  1. full model1: dv~LSNS_base+LSNS_change+age_base+age_change+gender

  2. full model2: model1 + hypertension+diabetes+education+BMI+CESD

  3. The unit of effect sizes on hippocampal volume and cognitive functions are mm³/point on the LSNS and standard deviation/point on the LSNS, respectively.

  4. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Appendix 1—table 12
Adjusted regression coefficients and measures of significance of models using an MMST score of 27 as cut-off for inclusion.
dvModelPredictorEstimate95% CIp-valueFDRBFTotal nn individuals
Hippo
campal volume		1LSNS_base-6.811-10.548, -3.0752e-04****7e-04****123.9****15791235
LSNS_change–4.755−8.191,–1.3140.0034**0.0069**2.9115791235
age_base-25.045−27.923,–22.167   15791235
age_change–26.913−29.146,–24.689   15791235
gender-44.363−81.921,–6.805   15791235
2LSNS_base–6.992−10.919,–3.0642e-04****0.0017**121.62****14761159
LSNS_change–4.563−8.184,–0.9330.0069**0.0173*3.04*14761159
age_base–23.204−26.261,–20.147   14761159
age_change–26.882−29.251,–24.525   14761159
gender–42.353−80.94,–3.767   14761159
BMI15.149–2.009, 32.309   14761159
CESD13.511–6.205, 33.227   14761159
diabetes–101.214−154.93,–47.492   14761159
education–90.005−154.773,–25.23   14761159
hypertension–27.620–68.265, 13.025   14761159
Executive functions1LSNS_base-0.026−0.035,–0.0164.3e-08****5.2e-07****3.3e+05****19511397
LSNS_change–0.002-0.016, 0.0120.38670.46410.1519511397
age_base–0.017−0.024,–0.01   19511397
age_change–0.055−0.065,–0.044   19511397
gender–0.083–0.177, 0.011   19511397
2LSNS_base–0.016−0.026,–0.0075e-04****0.0021**64.25***18081310
LSNS_change0.002-0.012, 0.0170.62080.7110.1218081310
age_base–0.013−0.021,–0.006   18081310
age_change–0.054−0.064,–0.043   18081310
gender–0.113−0.209,–0.016   18081310
BMI–0.059−0.107,–0.011   18081310
CESD–0.130−0.179,–0.082   18081310
diabetes–0.033–0.168, 0.101   18081310
education-0.261−0.426,–0.096   18081310
hypertension-0.109−0.21,–0.007   18081310
Memory1LSNS_base–0.013−0.021,–0.0040.0015**0.0046**17.75**18281336
LSNS_change-0.019-0.032, -0.0060.0022**0.0054**9.93*18281336
age_base–0.035−0.042,–0.028   18281336
age_change–0.023−0.032,–0.014   18281336
gender-0.376−0.461,–0.291   18281336
2LSNS_base-0.007-0.016, 0.0020.06380.12760.9716941247
LSNS_change–0.017−0.031,–0.0030.0072**0.0173*6.68*16941247
age_base–0.032−0.039,–0.025   16941247
age_change–0.023−0.033,–0.014   16941247
gender-0.415-0.502, -0.328   16941247
BMI-0.028–0.072, 0.016   16941247
CESD–0.120−0.164,–0.076   16941247
diabetes–0.007–0.127, 0.113   16941247
education-0.116–0.262, 0.029   16941247
hypertension0.002–0.089, 0.094   16941247
Processing speed1LSNS_base–0.016−0.024,–0.0083.4e-05****2e-04****561.09****19451392
LSNS_change–0.006–0.019, 0.0070.1660.22950.2519451392
age_base–0.038−0.044,–0.032   19451392
age_change–0.040−0.049,–0.03   19451392
gender–0.106−0.186,–0.026   19451392
2LSNS_base–0.015−0.023,–0.0063e-04****0.0017**118.91****18021303
LSNS_change–0.007–0.02, 0.0060.15230.25710.3918021303
age_base–0.036−0.043,–0.03   18021303
age_change–0.035−0.045,–0.025   18021303
gender–0.122−0.205,–0.039   18021303
BMI0.002–0.04, 0.044   18021303
CESD–0.027–0.068, 0.015   18021303
diabetes–0.017–0.132, 0.097   18021303
education-0.104–0.243, 0.035   18021303
hypertension–0.042–0.129, 0.044   18021303

  1. full model1: dv~LSNS_base+LSNS_change+age_base+age_change+gender

  2. full model2: model1 + hypertension+diabetes+education+BMI+CESD

  3. The unit of effect sizes on hippocampal volume and cognitive functions are mm³/point on the LSNS and standard deviation/point on the LSNS, respectively.

  4. * p<0.05, BF >3; ** p<0.01, BF >10; *** p<0.001, BF >30; **** p<0.0001, BF >100.

  5. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Appendix 1—table 13
Adjusted regression coefficients and measures of significance of models controlling for physical activity.
dvModelPredictorEstimate95% CIp-valueFDRBFTotal nn individuals
Hippo
campal volume		2ipaq-12.253–27.485, 2.86   12501141
2LSNS_base-5.887−9.939,–1.8340.0022**0.0067**17.64**12501141
2LSNS_change-9.057-14.719, -3.3120.0011**0.0042**11.47**12501141
2age_base–23.367−26.536,–20.199   12501141
2age_change–27.978−31.859,–24.157   12501141
2gender–36.998–76.761, 2.76   12501141
2BMI16.826–1.735, 35.382   12501141
2CESD11.892-8.516, 32.3   12501141
2diabetes-113.206-168.435, -57.981   12501141
2education-97.882-164.736, -31.03   12501141
2hypertension-16.735–58.972, 25.495   12501141
Executive functions2ipaq–0.035–0.083, 0.013   13921249
2LSNS_base–0.018−0.028,–0.0074e-04***0.0024**87.51***13921249
2LSNS_change0.002-0.026, 0.0290.54830.7310.1713921249
2age_base–0.012−0.02,–0.004   13921249
2age_change–0.050−0.068,–0.031   13921249
2gender–0.149−0.251,–0.047   13921249
2BMI-0.068−0.119,–0.018   13921249
2CESD–0.150−0.202,–0.098   13921249
2diabetes-0.038–0.18, 0.103   13921249
2education-0.275-0.45, -0.099   13921249
2hypertension–0.072–0.18, 0.037   13921249
Memory2ipaq–0.023-0.066, 0.021   13421211
2LSNS_base-0.007-0.016, 0.0020.07350.17650.9513421211
2LSNS_change–0.013–0.037, 0.010.13420.26830.4713421211
2age_base-0.032−0.039,–0.024   13421211
2age_change0.001–0.016, 0.017   13421211
2gender–0.406−0.5,–0.312   13421211
2BMI-0.032–0.079, 0.014   13421211
2CESD-0.119-0.167, -0.071   13421211
2diabetes-0.066–0.194, 0.063   13421211
2education-0.154-0.312, 0.004   13421211
2hypertension0.012–0.087, 0.111   13421211
Processing speed2ipaq-0.041−0.081,–0.001   13921252
2LSNS_base–0.015−0.023,–0.0063e-04***0.0024**107.46****13921252
2LSNS_change–0.011–0.036, 0.0130.18690.28040.4813921252
2age_base–0.033−0.04,–0.027   13921252
2age_change–0.036−0.053,–0.019   13921252
2gender-0.117-0.202, -0.033   13921252
2BMI-0.015–0.057, 0.027   13921252
2CESD-0.011–0.054, 0.032   13921252
2diabetes-0.029-0.146, 0.087   13921252
2education–0.058–0.201, 0.084   13921252
2hypertension–0.057–0.147, 0.032   13921252

  1. full model1: dv~LSNS_base +LSNS_change +age_base +age_change +gender.

  2. full model2: model1 +hypertension + diabetes +education + BMI +CESD.

  3. The unit of effect sizes on hippocampal volume and cognitive functions are mm³/point on the LSNS and standard deviation/point on the LSNS, respectively.

  4. * p<0.05, BF >3; ** p<0.01, BF >10; *** p<0.001, BF >30; **** p<0.0001, BF >100.

  5. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; ipaq; total METs/week based on the International Physical Activity Questionnaire; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Appendix 1—table 14
Adjusted regression coefficients and measures of significance of models controlling for sleep quality.
dvModelPredictorEstimate95% CIp-valueFDRBFTotal nn individuals
Hippo
campal volume		2psqi-11.915-30.746, 6.993 1019912
2LSNS_base-4.588−9.086,–0.090.0228*0.05482.391019912
2LSNS_change-1.302-7.72, 5.1430.34510.46010.131019912
2age_base-21.787−25.361,–18.213 1019912
2age_change-27.975−32.159,–23.815 1019912
2gender–42.342-86.176, 1.482 1019912
2BMI10.944–9.704, 31.591 1019912
2CESD32.2959.313, 55.285 1019912
2diabetes–105.790−166.428,–45.135 1019912
2education–170.384−252.271,–88.503 1019912
2hypertension–15.415–61.357, 30.533 1019912
Executive functions2psqi0.024–0.034, 0.082 1112987
2LSNS_base–0.018−0.03,–0.0070.0011**0.0133*38.25***1112987
2LSNS_change-0.011–0.039, 0.0180.23030.34550.41112987
2age_base–0.004-0.013, 0.006 1112987
2age_change–0.051−0.07,–0.032 1112987
2gender–0.199−0.314,–0.083 1112987
2BMI–0.065−0.122,–0.009 1112987
2CESD-0.150−0.21,–0.09 1112987
2diabetes-0.154-0.311, 0.003 1112987
2education-0.273−0.49,–0.057 1112987
2hypertension–0.058–0.178, 0.062 1112987
Memory2psqi–0.005–0.056, 0.046 1066940
2LSNS_base-0.008-0.018, 0.0030.06920.13841.061066940
2LSNS_change–0.031−0.056,–0.0070.0059**0.0237*6.91*1066940
2age_base–0.031−0.04,–0.023 1066940
2age_change–0.030−0.047,–0.014 1066940
2gender-0.482−0.585,–0.379 1066940
2BMI–0.010-0.06, 0.041 1066940
2CESD–0.111−0.165,–0.057 1066940
2diabetes–0.087–0.225, 0.052 1066940
2education–0.092–0.282, 0.097 1066940
2hypertension0.054–0.053, 0.162 1066940
Processing speed2psqi-0.057−0.103,–0.01 1114986
2LSNS_base–0.013−0.023,–0.0040.003**0.0179*15.38**1114986
2LSNS_change-0.025-0.048, -0.0020.0158*0.0475*4.08*1114986
2age_base–0.031−0.039,–0.024 1114986
2age_change-0.024−0.04,–0.008 1114986
2gender–0.163−0.256,–0.07 1114986
2BMI–0.009–0.054, 0.037 1114986
2CESD0.018–0.03, 0.066 1114986
2diabetes-0.059-0.185, 0.067 1114986
2education0.003-0.168, 0.174 1114986
2hypertension–0.005-0.101, 0.092 1114986

  1. full model1: dv~LSNS_base+LSNS_change+age_base+age_change+gender

  2. full model2: model1 + hypertension+diabetes+education+BMI+CESD

  3. The unit of effect sizes on hippocampal volume and cognitive functions are mm³/point on the LSNS and standard deviation/point on the LSNS, respectively.

  4. * p<0.05, BF >3; ** p<0.01, BF >10; *** p<0.001, BF >30; **** p<0.0001, BF >100.

  5. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; psqi, global Pittsburgh Sleep Quality Index score; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Appendix 1—table 15
Adjusted regression coefficients and measures of significance of models using cognitive scores standardized using the baseline mean.
dvModelPredictorEstimate95% CIp-valueFDRBFTotal nn individuals
Executive functions1LSNS_base–0.028−0.037,–0.0198.4e-10****1.0e-08****1.3e+07****20471468
LSNS_change–0.002–0.017, 0.0120.36810.44170.1520471468
age_base-0.017-0.024, -0.01   20471468
age_change-0.050−0.06,–0.04   20471468
gender-0.073–0.164, 0.018   20471468
2LSNS_base-0.017−0.026,–0.0072e-04****0.0015**111.14****18921376
LSNS_change0.002–0.013, 0.0170.61120.73350.1318921376
age_base–0.012−0.02,–0.005   18921376
age_change-0.050−0.061,–0.04   18921376
gender-0.111−0.204,–0.018   18921376
BMI–0.072−0.119,–0.026   18921376
CESD–0.139−0.185,–0.092   18921376
diabetes-0.059–0.187, 0.07   18921376
education–0.349−0.504,–0.193   18921376
hypertension–0.101−0.199,–0.003   18921376
Memory1LSNS_base–0.014−0.022,–0.0064e-04****0.0016**58.49***19201407
LSNS_change–0.019−0.032,–0.0060.0018**0.0044**11.45**19201407
age_base-0.035−0.042,–0.029   19201407
age_change–0.017−0.026,–0.008   19201407
gender–0.378−0.462,–0.295   19201407
2LSNS_base–0.007–0.016, 0.0010.0479*0.09571.2117761314
LSNS_change–0.017−0.031,–0.0040.0062**0.0148*5.51*17761314
age_base–0.032−0.039,–0.025   17761314
age_change–0.018−0.028,–0.009   17761314
gender–0.419−0.505,–0.333   17761314
BMI–0.031–0.074, 0.012   17761314
CESD–0.119−0.162,–0.076   17761314
diabetes–0.037-0.155, 0.08   17761314
education–0.197−0.338,–0.055   17761314
hypertension0.015–0.076, 0.106   17761314
Processing speed1LSNS_base–0.018−0.026,–0.011.9e-06****1.2e-05****8.1e+03****20421469
LSNS_change–0.006–0.019, 0.0060.16110.24160.2620421469
age_base–0.038−0.044,–0.032   20421469
age_change–0.038−0.047,–0.028   20421469
gender–0.108−0.185,–0.03   20421469
2LSNS_base–0.017−0.025,–0.0092.0e-05****2e-04****1.3e+03****18871375
LSNS_change–0.008–0.021, 0.0060.12790.19870.4418871375
age_base–0.036−0.042,–0.029   18871375
age_change–0.033−0.043,–0.024   18871375
gender–0.124−0.204,–0.043   18871375
BMI–0.013-0.053, 0.028   18871375
CESD–0.027-0.067, 0.013   18871375
diabetes–0.005–0.115, 0.105   18871375
education–0.103–0.235, 0.029   18871375
hypertension–0.067–0.152, 0.017   18871375

  1. full model1: dv~LSNS_base +LSNS_change +age_base +age_change +gender.

  2. full model2: model1 +hypertension + diabetes +education + BMI +CESD.

  3. The unit of effect sizes on hippocampal volume and cognitive functions are mm³/point on the LSNS and standard deviation/point on the LSNS, respectively.

  4. * P<0.05, BF >3; ** p<0.01, BF >10; *** p<0.001, BF >30; **** p<0.0001, BF >100.

  5. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Appendix 1—table 16
Adjusted regression coefficients and measures of significance of models without interaction terms coding social isolation dichotomously.
dvModelPredictorEstimate95% CIp-valueFDRBFTotal nn individuals
Hippo
campal volume		1LSNS_base–84.196−132.116,–36.273e-04****0.0012**65.9***16671306
LSNS_change-39.200−76.322,–2.1290.0193*0.0462*0.6416671306
age_base–26.126−28.968,–23.285   16671306
age_change–26.947−29.131,–24.77   16671306
gender–44.575−81.629,–7.521   16671306
2LSNS_base–81.625−131.358,–31.8847e-04****0.004**43.8***15561226
LSNS_change–38.922–77.936, 0.0260.0252*0.1010.7115561226
age_base–24.310−27.348,–21.272   15561226
age_change–26.905−29.243,–24.575   15561226
gender–44.492−82.58,–6.406   15561226
BMI14.402–2.476, 31.281   15561226
CESD10.096–8.894, 29.085   15561226
diabetes–97.865−150.283,–45.437   15561226
education–95.626−157.878,–33.368   15561226
hypertension-22.042–62.348, 18.267   15561226
Executive functions1LSNS_base–0.224−0.347,–0.1012e-04****0.0011**153.03****20481469
LSNS_change–0.065-0.219, 0.0880.20120.24150.2720481469
age_base–0.020−0.027,–0.013   20481469
age_change–0.050−0.06,–0.04   20481469
gender–0.077–0.17, 0.016   20481469
2LSNS_base–0.107–0.232, 0.0180.0461*0.13831.3218931377
LSNS_change0.023-0.137, 0.1830.61250.66820.1118931377
age_base–0.015−0.022,–0.007   18931377
age_change–0.051−0.061,–0.04   18931377
gender–0.121−0.215,–0.027   18931377
BMI–0.076−0.123,–0.03   18931377
CESD-0.154−0.2,–0.108   18931377
diabetes-0.054–0.184, 0.076   18931377
education–0.348−0.506,–0.19   18931377
hypertension–0.098–0.197, 0.001   18931377
Memory1LSNS_base–0.128−0.239,–0.0170.012*0.036*2.7919211408
LSNS_change–0.117-0.255, 0.0210.048*0.0960.6719211408
age_base–0.036−0.043,–0.029   19211408
age_change–0.018−0.027,–0.009   19211408
gender–0.379−0.463,–0.295   19211408
2LSNS_base–0.060–0.175, 0.0550.15370.2050.4417771315
LSNS_change-0.086–0.231, 0.0590.12220.2050.4117771315
age_base–0.033−0.04,–0.026   17771315
age_change–0.019−0.028,–0.009   17771315
gender–0.421−0.507,–0.335   17771315
BMI–0.031–0.074, 0.012   17771315
CESD–0.126−0.169,–0.083   17771315
diabetes-0.037–0.155, 0.081   17771315
education–0.179−0.321,–0.037   17771315
hypertension0.016–0.075, 0.107   17771315
Processing speed1LSNS_base–0.254−0.357,–0.1517.0e-07****8.4e-06****2.1e+04****20431470
LSNS_change–0.089–0.23, 0.0510.10610.14140.3520431470
age_base–0.038−0.044,–0.032   20431470
age_change–0.038−0.047,–0.028   20431470
gender–0.103−0.18,–0.025   20431470
2LSNS_base–0.238−0.344,–0.1316.6e-06****7.9e-05****3.8e+03****18881376
LSNS_change-0.101–0.245, 0.0440.08610.17220.6218881376
age_base–0.036−0.042,–0.03   18881376
age_change–0.033−0.043,–0.024   18881376
gender–0.119−0.199,–0.039   18881376
BMI–0.013–0.053, 0.027   18881376
CESD–0.033-0.073, 0.006   18881376
diabetes–0.001–0.112, 0.109   18881376
education–0.122–0.254, 0.01   18881376
hypertension–0.067–0.151, 0.018   18881376

  1. full model1: dv~LSNS_base +LSNS_change +age_base +age_change +gender.

  2. full model2: model1 +hypertension + diabetes +education + BMI +CESD.

  3. The unit of effect sizes on hippocampal volume and cognitive functions are mm³/point on the LSNS and standard deviation/point on the LSNS, respectively.

  4. * p<0.05, BF >3; ** p<0.01, BF >10; *** p<0.001, BF >30; **** p<0.0001, BF >100.

  5. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Appendix 1—table 17
Adjusted regression coefficients and measures of significance of models with interaction term of baseline social isolation with change in age coding social isolation dichotomously.
dvModelPredictorEstimate95% CIp-valueFDRBFTotal nn individuals
Hippo
campal volume		1LSNS_base*age_change–5.548-13.179, 2.0570.07660.13120.2216671306
LSNS_base–80.584−128.741,–32.42816671306
LSNS_change–54.052−96.412,–11.81316671306
age_base–26.085−28.926,–23.24416671306
age_change–26.202−28.609,–23.79716671306
gender–44.416−81.456,–7.37716671306
2LSNS_base*age_change–5.693-13.731, 2.3050.08170.17220.2815561226
LSNS_base–77.832−127.826,–27.83915561226
LSNS_change–54.295−98.952,–9.8115561226
age_base–24.257−27.294,–21.2215561226
age_change–26.109−28.697,–23.52515561226
gender–44.285−82.353,–6.21915561226
BMI14.474–2.392, 31.34315561226
CESD10.297–8.685, 29.27715561226
diabetes–98.022−150.411,–45.62215561226
education–95.589−157.807,–33.36515561226
hypertension-22.260–62.545, 18.02815561226
Executive functions1LSNS_base*age_change0.008–0.025, 0.0410.68610.68610.0820481469
LSNS_base–0.234−0.363,–0.10520481469
LSNS_change–0.046–0.218, 0.12620481469
age_base–0.020−0.027,–0.01320481469
age_change–0.051−0.063,–0.0420481469
gender–0.078–0.17, 0.01520481469
2LSNS_base*age_change0.012–0.022, 0.0460.75330.75330.118931377
LSNS_base-0.121–0.253, 0.0118931377
LSNS_change0.052–0.128, 0.23218931377
age_base–0.015−0.022,–0.00718931377
age_change–0.053−0.064,–0.04118931377
gender-0.122−0.216,–0.02718931377
BMI-0.076-0.123, -0.02918931377
CESD–0.154−0.201,–0.10818931377
diabetes–0.055–0.185, 0.07518931377
education–0.348−0.506,–0.1918931377
hypertension–0.097-0.197, 0.00218931377
Memory1LSNS_base*age_change-0.004–0.034, 0.0260.39080.42640.1219211408
LSNS_base–0.124−0.239,–0.00819211408
LSNS_change-0.126-0.281, 0.02719211408
age_base–0.036−0.042,–0.02919211408
age_change–0.017−0.027,–0.00719211408
gender–0.379−0.463,–0.29519211408
2LSNS_base*age_change0.002–0.029, 0.0340.56020.66820.1117771315
LSNS_base-0.062–0.182, 0.05717771315
LSNS_change-0.080-0.244, 0.08317771315
age_base-0.033-0.04, -0.02617771315
age_change-0.019-0.03, -0.00817771315
gender–0.421−0.507,–0.33517771315
BMI–0.031–0.074, 0.01217771315
CESD–0.126−0.169,–0.08317771315
diabetes–0.037–0.155, 0.08117771315
education–0.179−0.321,–0.03717771315
hypertension0.016–0.075, 0.10717771315
Processing speed1LSNS_base*age_change–0.020-0.05, 0.010.09320.13990.4220431470
LSNS_base–0.229−0.338,–0.1220431470
LSNS_change–0.136–0.293, 0.0220431470
age_base–0.038−0.044,–0.03220431470
age_change–0.035−0.045,–0.02420431470
gender–0.102−0.179,–0.02520431470
2LSNS_base*age_change-0.017–0.047, 0.0140.14340.2050.3918881376
LSNS_base–0.218−0.331,–0.10618881376
LSNS_change–0.141-0.303, 0.02218881376
age_base–0.036−0.042,–0.02918881376
age_change–0.031−0.041,–0.0218881376
gender–0.118−0.198,–0.03818881376
BMI-0.013–0.053, 0.02718881376
CESD–0.033–0.072, 0.00718881376
diabetes0.000–0.11, 0.1118881376
education–0.122–0.254, 0.0118881376
hypertension–0.068–0.152, 0.01718881376

  1. full model1: dv~LSNS_base +LSNS_change +age_base +age_change +gender.

  2. full model2: model1 +hypertension + diabetes +education + BMI +CESD.

  3. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Appendix 1—table 18
Adjusted regression coefficients and measures of significance of models with interaction term of baseline social isolation with change in social isolation coding social isolation dichotomously.
dvModelPredictorEstimate95% CIp-valueBFTotal nn individuals
Hippo
campal volume		1LSNS_base*LSNS_change88.306.68, 170.140.98280.0116671306
LSNS_base–81.55−129.51,–33.5916671306
LSNS_change–73.96−123.04,–25.0216671306
age_base-26.07-28.91, -23.2316671306
age_change-26.01-28.35, -23.6716671306
gender-44.60-81.64, -7.5716671306
2LSNS_base*LSNS_change80.69–5.28, 166.930.96690.0315561226
LSNS_base–79.16−128.94,–29.3815561226
LSNS_change–70.92−122.76,–19.2615561226
age_base–24.26−27.3,–21.2315561226
age_change–26.01−28.53,–23.515561226
gender–44.46−82.53,–6.3915561226
BMI14.26–2.6, 31.1215561226
CESD10.14–8.84, 29.1215561226
diabetes-96.81-149.22, -44.415561226
education–95.85−158.07,–33.6215561226
hypertension-22.07–62.35, 18.2215561226

  1. full model1: dv~LSNS_base +LSNS_change +age_base +age_change +gender.

  2. full model2: model1 +hypertension + diabetes +education + BMI +CESD

  3. dv, dependent variable; CI, confidence interval; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression

Appendix 1—table 19
Adjusted regression coefficients and measures of significance of models with interaction of baseline social isolation with dichotomously coded social isolation.
dvModelPredictorEstimate95% CIp-valueFDRBFTotal nn individuals
Hippo
campal volume		1LSNS_base:LSNS_cut2.250–6.458, 10.9630.69380.89050.1616671306
LSNS_cut–71.797-236.505, 92.59516671306
LSNS_base–4.417-8.954, 0.12116671306
LSNS_change–3.100-6.926, 0.74616671306
age_base–26.018−28.869,–23.16716671306
age_change-26.635−28.876,–24.416671306
gender–46.137−83.249,–9.02616671306
2LSNS_base:LSNS_cut2.285-6.996, 11.5740.68540.89050.0715561226
LSNS_cut–72.191-248.895, 104.11915561226
LSNS_base-4.504–9.251, 0.24215561226
LSNS_change–2.989-7.062, 1.10915561226
age_base-24.193−27.238,–21.14915561226
age_change-26.615-29.017, -24.2215561226
gender–45.963−84.1,–7.82915561226
BMI13.651–3.22, 30.52515561226
CESD11.931–7.334, 31.19815561226
diabetes–98.801−151.224,–46.37115561226
education–94.113−156.541,–31.67815561226
hypertension–21.159-61.488, 19.17315561226
Executive functions1LSNS_base:LSNS_cut0.017-0.01, 0.0450.89050.89050.0520481469
LSNS_cut–0.298–0.845, 0.24920481469
LSNS_base-0.033-0.045, -0.0220481469
LSNS_change–0.002-0.019, 0.01420481469
age_base–0.019−0.026,–0.01220481469
age_change–0.049−0.059,–0.03820481469
gender–0.088–0.18, 0.00520481469
2LSNS_base:LSNS_cut0.016–0.013, 0.0460.85770.89050.118931377
LSNS_cut-0.234-0.819, 0.35118931377
LSNS_base-0.023-0.036, -0.0118931377
LSNS_change0.000-0.017, 0.01618931377
age_base–0.014−0.021,–0.00618931377
age_change–0.049−0.06,–0.03918931377
gender-0.127−0.221,–0.03418931377
BMI–0.075−0.122,–0.02918931377
CESD–0.141−0.187,–0.09418931377
diabetes–0.055–0.184, 0.07418931377
education–0.332−0.489,–0.17418931377
hypertension–0.097–0.195, 0.00218931377
Memory1LSNS_base:LSNS_cut0.003–0.022, 0.0290.59680.89050.119211408
LSNS_cut–0.044–0.545, 0.45719211408
LSNS_base–0.016−0.027,–0.00419211408
LSNS_change–0.020−0.035,–0.00519211408
age_base-0.035−0.042,–0.02919211408
age_change-0.017−0.026,–0.00819211408
gender-0.382−0.466,–0.29819211408
2LSNS_base:LSNS_cut-0.001–0.028, 0.0270.47880.89050.1617771315
LSNS_cut0.043–0.501, 0.58717771315
LSNS_base–0.009–0.021, 0.00317771315
LSNS_change–0.020−0.035,–0.00417771315
age_base-0.033-0.04, -0.02617771315
age_change–0.018−0.028,–0.00917771315
gender–0.421−0.507,–0.33517771315
BMI–0.031-0.074, 0.01217771315
CESD–0.120−0.164,–0.07717771315
diabetes–0.038-0.156, 0.0817771315
education–0.173−0.315,–0.03117771315
hypertension0.017–0.074, 0.10817771315
Processing speed1LSNS_base:LSNS_cut–0.005–0.03, 0.020.34850.89050.1720431470
LSNS_cut–0.028–0.521, 0.46520431470
LSNS_base–0.011–0.022, 020431470
LSNS_change–0.001–0.016, 0.01420431470
age_base–0.038−0.044,–0.03220431470
age_change–0.038−0.047,–0.02820431470
gender–0.104−0.182,–0.02720431470
2LSNS_base:LSNS_cut–0.005–0.032, 0.0210.34060.89050.218881376
LSNS_cut–0.017-0.538, 0.50318881376
LSNS_base–0.010–0.021, 0.00218881376
LSNS_change-0.002–0.017, 0.01318881376
age_base–0.036−0.042,–0.02918881376
age_change–0.034−0.043,–0.02418881376
gender–0.119−0.2,–0.03918881376
BMI–0.012–0.052, 0.02818881376
CESD–0.028–0.068, 0.01218881376
diabetes–0.004-0.114, 0.10618881376
education–0.115–0.248, 0.01718881376
hypertension–0.066–0.151, 0.01818881376
* p<0.05, BF >3; ** p<0.01, BF >10; *** p<0.001, BF >30; **** p<0.0001, BF >100.

  1. full model1: dv~LSNS_base+LSNS_change+age_base+age_change+gender

  2. full model2: model1 + hypertension+diabetes+education+BMI+CESD

  3. The unit of effect sizes on hippocampal volume and cognitive functions are mm³/point on the LSNS and standard deviation/point on the LSNS, respectively.

  4. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression

Appendix 1—table 20
Adjusted regression coefficients and measures of significance of models with interaction of change in social isolation with dichotomously coded social isolation.
dvModelPredictorEstimate95% CIp-valueFDRBFTotal nn individuals
Hippo
campal volume		1LSNS_change:LSNS_cut–0.930–9.602, 7.760.41670.45470.0116671306
LSNS_cut–28.481-70.048, 12.89316671306
LSNS_base–4.055-8.326, 0.21616671306
LSNS_change–3.107–7.124, 0.92616671306
age_base–26.031−28.882,–23.1816671306
age_change-26.718-28.955, -24.48916671306
gender–45.786−82.874,–8.70116671306
2LSNS_change:LSNS_cut–0.531–9.699, 8.6520.45470.45470.0815561226
LSNS_cut-28.795–71.993, 14.19815561226
LSNS_base-4.120-8.611, 0.3715561226
LSNS_change–3.056-7.347, 1.25815561226
age_base–24.213−27.257,–21.16915561226
age_change–26.727−29.127,–24.33615561226
gender–45.537−83.637,–7.4415561226
BMI13.763-3.103, 30.63315561226
CESD11.997-7.275, 31.26915561226
diabetes–98.822−151.25,–46.38515561226
education-93.862-156.289, -31.42915561226
hypertension–21.270-61.601, 19.06415561226
Executive functions1LSNS_change:LSNS_cut–0.035−0.067,–0.0030.1650.45472.3220481469
LSNS_cut0.088–0.06, 0.23620481469
LSNS_base–0.032−0.044,–0.0220481469
LSNS_change0.004–0.014, 0.02120481469
age_base–0.019−0.026,–0.01220481469
age_change–0.047−0.058,–0.03720481469
gender–0.086–0.178, 0.00620481469
2LSNS_change:LSNS_cut–0.023–0.057, 0.0120.09920.45470.6318931377
LSNS_cut0.108–0.043, 0.25918931377
LSNS_base–0.022−0.035,–0.0118931377
LSNS_change0.003–0.016, 0.02118931377
age_base–0.014−0.021,–0.00618931377
age_change–0.049−0.06,–0.03818931377
gender–0.125−0.219,–0.03118931377
BMI–0.075−0.121,–0.02918931377
CESD–0.140−0.187,–0.09318931377
diabetes–0.056–0.185, 0.07318931377
education-0.331-0.489, -0.17418931377
hypertension-0.097–0.196, 0.00118931377
Memory1LSNS_change:LSNS_cut–0.015–0.044, 0.0150.36740.45470.2819211408
LSNS_cut0.040–0.094, 0.17319211408
LSNS_base–0.016−0.027,–0.00519211408
LSNS_change-0.017-0.033, -0.00119211408
age_base–0.035−0.042,–0.02919211408
age_change–0.016−0.026,–0.00719211408
gender–0.382−0.466,–0.29819211408
2LSNS_change:LSNS_cut-0.002-0.034, 0.030.45050.45470.1617771315
LSNS_cut0.032-0.106, 0.16917771315
LSNS_base-0.009–0.021, 0.00217771315
LSNS_change-0.019-0.036, -0.00217771315
age_base-0.033-0.04, -0.02617771315
age_change–0.018−0.028,–0.00817771315
gender–0.421−0.508,–0.33517771315
BMI–0.032-0.074, 0.01117771315
CESD-0.120−0.164,–0.07717771315
diabetes–0.038-0.156, 0.0817771315
education–0.173−0.315,–0.03117771315
hypertension0.017-0.074, 0.10817771315
Processing speed1LSNS_change:LSNS_cut-0.005-0.034, 0.0240.31460.45470.1520431470
LSNS_cut–0.116–0.246, 0.01420431470
LSNS_base–0.012−0.022,–0.00220431470
LSNS_change0.001–0.015, 0.01720431470
age_base–0.038−0.044,–0.03220431470
age_change-0.037−0.047,–0.02720431470
gender-0.105−0.183,–0.02820431470
2LSNS_change:LSNS_cut–0.002–0.033, 0.0290.45070.45470.1518881376
LSNS_cut–0.120-0.252, 0.01218881376
LSNS_base–0.010–0.021, 018881376
LSNS_change–0.001–0.017, 0.01518881376
age_base–0.036−0.042,–0.02918881376
age_change–0.033−0.043,–0.02318881376
gender–0.121−0.201,–0.0418881376
BMI–0.012–0.052, 0.02818881376
CESD–0.028–0.068, 0.01218881376
diabetes–0.004–0.114, 0.10618881376
education–0.116–0.249, 0.01618881376
hypertension–0.066–0.151, 0.01818881376

  1. full model1: dv~LSNS_base+LSNS_change+age_base+age_change+gender

  2. full model2: model1 + hypertension+diabetes+education+BMI+CESD

  3. The unit of effect sizes on hippocampal volume and cognitive functions are mm³/point on the LSNS and standard deviation/point on the LSNS, respectively.

  4. * p<0.05, BF >3; ** p<0.01, BF >10; *** p<0.001, BF >30; **** p<0.0001, BF >100.

  5. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; BF, Bayes factor in favour of alternative hypothesis; total n, total number of observations; n individuals, number of participants; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression.

Appendix 1—table 21
Adjusted regression coefficients and measures of significance of models stratified by gender.
dvModelGenderPredictorEstimate95% CIp-valueFDRTotal nn individuals
Hippo
campal volume		1FemaleLSNS_base–7.904−13.243,–2.5650.0019**0.01136203571821
LSNS_change–1.774–5.926, 2.3910.20080.30123866746821
LSNS_base*age_change–0.379-0.997, 0.2380.11420.22831958503821
LSNS_base*LSNS_change-0.245-1.039, 0.5490.2722821.00000000000641
1MaleLSNS_base–4.188-9.231, 0.8560.05180.10361941628846
LSNS_change–6.954−12.13,–1.7630.0044**0.01330355028846
LSNS_base*age_change–0.182–0.96, 0.5940.32270.43024443281846
LSNS_base*LSNS_change0.653-0.367, 1.680.895846.00000000000665
2FemaleLSNS_base-10.046−15.757,–4.3343e-04****0.00356326264757
LSNS_change–0.904–5.303, 3.5150.34330.51492077295757
LSNS_base*age_change-0.349-1.004, 0.3050.14760.29523685430757
LSNS_base*LSNS_change–0.108-0.94, 0.7230.3988757.00000000000595
2MaleLSNS_base-2.798–8.072, 2.4770.14910.29813938291799
LSNS_change-7.481−12.964,–1.9760.004**0.02377229139799
LSNS_base*age_change–0.203–1.019, 0.6080.31140.47285051084799
LSNS_base*LSNS_change0.683–0.385, 1.7550.8949799.00000000000631
Executive functions1FemaleLSNS_base–0.033−0.046,–0.0191.1e-06****0.00001324504994
LSNS_change–0.012-0.032, 0.0090.13620.23354595086994
LSNS_base*age_change0.001–0.003, 0.0040.63470.63469552193994
1MaleLSNS_base–0.024−0.037,–0.0125.9e-05****0.000351244091,054
LSNS_change0.004–0.015, 0.0240.67450.735790507821,054
LSNS_base*age_change0.001-0.002, 0.0040.66290.735790507821,054
2FemaleLSNS_base–0.020−0.035,–0.0060.0025**0.01480365447904
LSNS_change–0.001-0.023, 0.020.45420.54501865266904
LSNS_base*age_change0.001-0.002, 0.0050.76670.76666321855904
2MaleLSNS_base-0.015−0.028,–0.0020.0122*0.04879051790989
LSNS_change0.004–0.016, 0.0250.66130.72350282272989
LSNS_base*age_change0.001-0.002, 0.0040.66320.72350282272989
Memory1FemaleLSNS_base-0.010-0.022, 0.0010.0428*0.10263106694926
LSNS_change–0.024−0.041,–0.0060.004**0.01584355921926
LSNS_base*age_change0.000–0.003, 0.0020.41350.45108055271926
1MaleLSNS_base–0.017−0.028,–0.0050.0026**0.01044641225995
LSNS_change–0.015-0.034, 0.0030.05020.10361941628995
LSNS_base*age_change0.001-0.002, 0.0040.80580.80583563356995
2FemaleLSNS_base-0.005–0.017, 0.0080.23490.40271104563843
LSNS_change–0.023−0.041,–0.0050.0072**0.02874128134843
LSNS_base*age_change0.000-0.003, 0.0030.40730.54304918017843
2MaleLSNS_base-0.009–0.021, 0.0030.07580.21377460911934
LSNS_change–0.014–0.033, 0.0060.08910.21377460911934
LSNS_base*age_change0.002-0.001, 0.0050.84090.84087211792934
Processing speed1FemaleLSNS_base–0.014−0.026,–0.0020.0112*0.03374550604991
LSNS_change-0.007–0.025, 0.0120.24340.32450988520991
LSNS_base*age_change–0.001-0.004, 0.0020.34950.41941795284991
1MaleLSNS_base–0.022−0.032,–0.0121.2e-05****0.000144763321,052
LSNS_change–0.005-0.023, 0.0120.270.404939169791,052
LSNS_base*age_change–0.001-0.004, 0.0020.26650.404939169791,052
2FemaleLSNS_base–0.012–0.025, 0.0010.0346*0.10389307138903
LSNS_change–0.016–0.035, 0.0030.05280.12678399573903
LSNS_base*age_change0.001–0.002, 0.0040.66530.72576997994903
2MaleLSNS_base–0.020−0.031,–0.018.1e-05****0.00097014826985
LSNS_change0.000–0.018, 0.0190.51190.68246828507985
LSNS_base*age_change–0.001-0.004, 0.0020.31520.47285051084985

  1. full model1: dv~LSNS_base+LSNS_change+age_base+age_change.

  2. full model2: model1 + hypertension+diabetes+education+BMI+CESD.

  3. The unit of effect sizes on hippocampal volume and cognitive functions for non-interaction models are mm³/point on the LSNS and standard deviation/point on the LSNS, respectively. For interaction models the unit in the denominator is multiplied by year or point on the LSNS.

  4. * p<0.05; ** p<0.01; *** p<0.001; **** p<0.0001.

  5. dv, dependent variable; CI, confidence interval; FDR, p-values after FDR-correction; LSNS_base, baseline Lubben Social Network Score; LSNS_change, change in Lubben Social Network Score; CESD, Center for Epidemiological Studies-Depression full model1: dv~LSNS_base +LSNS_change +age_base +age_change full model2: model1 +hypertension + diabetes +education + BMI +CESD

Appendix 1—table 22
Relevant regressions of bivariate latent change score models.
dvPredictorEstimateSEp-valueq-valuen
ΔHCVLSNS_base0.0010.0040.5710.5901536
ΔLSNSHCV_base–0.1990.1680.1180.1231536
ΔEFLSNS_base–0.0140.0070.024*0.0941536
ΔLSNSEF_base–0.1880.1610.1210.1231536
ΔMemoLSNS_base0.0010.0060.590.5901536
ΔLSNSMemo_base-0.3030.1650.033*0.1231536
ΔPSLSNS_base-0.0070.0070.1770.3541536
ΔLSNSPS_base–0.2020.1740.1230.1231536

  1. * p<0.05.

  2. dv, dependent variable; SE, standard error; n, number of participants; _base, baseline score of; Δ, change in; LSNS, Lubben Social Network Score; HCV, hippocampal volume; EF, executive functions; Memo, memory performance; PS, processing speed.

Appendix 1—table 23
Fit indices of mediation analyses of model 1.
Fit index311ok?411aok?411bok?411cok?
chisq0.7334.6750.6070.215
df1.0001.0001.0001.000
p-value0.392Good fit0.031Acceptable fit0.436Good fit0.643Good fit
chisq/df0.733Good fit4.675Unacceptable fit0.607Good fit0.215Good fit
rmsea0.000Good fit0.049Good fit0.000Good fit0.000Good fit
rmsea_lower0.0000.0120.0000.000
rmsea_upper0.0640.0970.0620.052
srmr0.009Good fit0.006Good fit0.002Good fit0.001Good fit
nnfi1.005Unacceptable fit0.946Unacceptable fit1.006Unacceptable fit1.018Unacceptable fit
cfi1.000Good fit0.996Good fit1.000Good fit1.000Good fit

  1. 311: indirect effect of social isolation on hippocampal volume via chronic stress.

  2. 411a: indirect effect of social isolation on executive functions via hippocampal volume.

  3. 411b: indirect effect of social isolation on memory via hippocampal volume.

  4. 411c: indirect effect of social isolation on processing speed via hippocampal volume.

  5. chisq, chi squared; df, degrees of freedom

Appendix 1—table 24
Fit indices of mediation analyses of model 2.
Fit index312ok?412aok?412bok?412cok?
chisq1.2430.2115.2380.395
df5.0001.0001.0001.000
p-value0.941Good fit0.646Good fit0.022Acceptable fit0.530Good fit
chisq/df0.249Good fit0.211Good fit5.238Unacceptable fit0.395Good fit
rmsea0.000Good fit0.000Good fit0.053Acceptable fit0.000Good fit
rmsea_lower0.0000.0000.0160.000
rmsea_upper0.0070.0520.1000.058
srmr0.007Good fit0.001Good fit0.004Good fit0.001Good fit
nnfi1.023Unacceptable fit1.011Unacceptable fit0.896Unacceptable fit1.015Unacceptable fit
cfi1.000Good fit1.000Good fit0.996Good fit1.000Good fit

  1. 312: indirect effect of social isolation on hippocampal volume via chronic stress.

  2. 412a: indirect effect of social isolation on executive functions via hippocampal volume.

  3. 412b: indirect effect of social isolation on memory via hippocampal volume.

  4. 412c: indirect effect of social isolation on processing speed via hippocampal volume.

  5. chisq, chi squared; df, degrees of freedom

Appendix 1—table 25
Simulated Bayes factors above the threshold of 3.

BFA0, sided Bayes factor in favour of the alternative hypothesis; FWER, familywise error rate if the threshold would be set just below BFA0. In the simulation with randomly simulated values for our predictors of interest, 14 BFs exceeded the standard threshold of three. Given a family size of 12 tests, a threshold of 10.75 would maintain the FWER below 5%.

BFA0FWER in %n
15.7441.181
13.6342.362
13.1393.513
10.9264.664
10.6325.795
9.1966.916
8.7288.027
8.5109.128
7.74910.209
7.19111.2810
6.08112.3411
4.74613.3912
4.04414.4213
4.00315.4514
Appendix 1—table 26
Results of power simulation of Bayes factors.

BFA0b, sided Bayes factor in favour of the alternative hypothesis of baseline social isolation; BFA0c, sided Bayes factor in favour of the alternative hypothesis of change in social isolation; n, number of simulations in the category; model 1, model with reduced number of control variables; model 2, model with full number of control variables; effect, effect size per point in the Lubben Social Network Scale in years of baseline age.

Percentages of Bayes factors giving moderate or stronger evidence in favour of the alternative hypothesis (>3), giving anecdotal evidence (3 ≥ BF ≥ 1/3) and giving moderate or stronger evidence in favour of the null hypothesis (< 1/3).

CategoryBFA0b > 3 in %3 ≥ BFA0b ≥ 1/3 in %BFA0b<1/3 in %BFA0c>3 in %3 ≥ BFA0c ≥ 1/3 in %BFA0c<1/3 in %n
Overall44.2331.4124.3628.8530.4540.71312
Model 145.5130.1324.3630.1330.1339.74156
Model 242.9532.6924.3627.5630.7741.67156
Effect = 0.19.6238.4651.925.7724.0470.19104
Effect = 0.237.5044.2318.2721.1539.4239.42104
Effect = 0.585.5811.542.8859.6227.8812.50104
Appendix 1—table 27
Results of power simulation of Bayes factors with adjusted thresholds for a family of 12 tests.

BFA0b, sided Bayes factor in favour of the alternative hypothesis of baseline social isolation; BFA0c, sided Bayes factor in favour of the alternative hypothesis of change in social isolation; n, number of simulations in the category; model 1, model with reduced number of control variables; model 2, model with full number of control variables; effect, effect size per point in the Lubben Social Network Scale in years of baseline age. Percentages of Bayes factors giving moderate or stronger evidence in favour of the alternative hypothesis (>10.75), giving anecdotal evidence (10.75 ≥ BF ≥ 1/3) and giving moderate or stronger evidence in favour of the null hypothesis (<1/3).

CategoryBFA0b>10.75 in %10.75 ≥ BFA0 b ≥ 1/3 in %BFA0b<1/3 in %BFA0c>10.75 in %10.75 ≥ BFA0 c ≥ 1/3 in %BFA0c<1/3 in %n
Overall37.1838.4624.3620.8338.4640.71312
Model 138.4637.1824.3621.7938.4639.74156
Model 235.9039.7424.3619.8738.4641.67156
Effect = 0.15.7742.3151.920.9628.8570.19104
Effect = 0.224.0457.6918.2714.4246.1539.42104
Effect = 0.581.7315.382.8847.1240.3812.50104
Author response table 1
Adjusted regression coefficients and measures of significance of models for sleep quality and physical activity
dvPredictorEstimate95% CIp-valuetotal nn individuals
Hippocampal Volumepsqi-5.764-23.6, 12.1440.26311,081968
age_base-25.040-28.409, -21.6721,081968
age_change-28.033-32.052, -24.0221,081968
gender-39.143-82.377, 4.0771,081968
Hippocampal Volumeipaq-10.785-25.642, 3.9680.07611,3271,210
age_base-25.567-28.549, -22.5851,3271,210
age_change-27.248-31.086, -23.4591,3271,210
gender-37.001-75.962, 1.9561,3271,210
Executive Functionspsqi-0.040-0.095, 0.0150.0761,1791,046
age_base-0.008-0.017, 0.0011,1791,046
age_change-0.053-0.071, -0.0341,1791,046
gender-0.197-0.312, -0.0821,1791,046
Executive Functionsipaq-0.031-0.078, 0.0170.10541,4781,325
age_base-0.017-0.025, -0.011,4781,325
age_change-0.052-0.07, -0.0331,4781,325
gender-0.126-0.227, -0.0241,4781,325
Memorypsqi-0.030-0.078, 0.0180.10871,1341,000
age_base-0.032-0.04, -0.0241,1341,000
age_change-0.032-0.048, -0.0171,1341,000
gender-0.470-0.571, -0.3691,1341,000
Memoryipaq-0.015-0.058, 0.0280.2461,288
age_base-0.035-0.042, -0.0281,4291,288
age_change0.002-0.014, 0.0171,4291,288
gender-0.378-0.469, -0.2861,4291,288
Processing Speedpsqi-0.056-0.099, -0.0120.0059**1,1801,044
age_base-0.032-0.039, -0.0251,1801,044
age_change-0.027-0.042, -0.0111,1801,044
gender-0.160-0.25, -0.071,1801,044
Processing Speedipaq-0.031-0.071, 0.0090.06231,4781,328
age_base-0.036-0.042, -0.031,4781,328
age_change-0.038-0.055, -0.0221,4781,328
gender-0.120-0.202, -0.0371,4781,328
Author response table 2
start timeabsolute nproportion of participants
before 82560.043163
08-095370.090541
09-109290.156635
10-1110630.179228
11-1212040.203001
12-1310000.168606
13-146090.102681
after 143330.056146

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  1. Laurenz Lammer
  2. Frauke Beyer
  3. Melanie Luppa
  4. Christian Sanders
  5. Ronny Baber
  6. Christoph Engel
  7. Kerstin Wirkner
  8. Markus Loffler
  9. Steffi G Riedel-Heller
  10. Arno Villringer
  11. A Veronica Witte
(2023)
Impact of social isolation on grey matter structure and cognitive functions: A population-based longitudinal neuroimaging study
eLife 12:e83660.
https://doi.org/10.7554/eLife.83660