Study flow diagram.

All participants included in the present study were concurrently enrolled in the MemAID clinical trial of intranasal insulin. Only data included in the longitudinal analysis are shown and were drawn from visits at baseline, 25 weeks, and 48 weeks. Additional assessments which were performed as part of the MemAID trial have been previously published (Novak, et al., Journal of Neurology 2022) and are not shown in the figure. INI: intranasal insulin; MMSE: Mini mental state examination; WHODAS: World Health Organization Disability Assessment Schedule 2.0; GDS: Geriatric Depression Scale. (TIF)</p

Longitudinal mediation analysis models.

A mediation analysis was performed to measure the extent to which depressive symptoms on the Geriatric depression scale (GDS) exacerbate the effects of (a) cognition, (b) gait speed, and (c) medical comorbidities on disability over 48 weeks. To investigate possible causality, the models used values from each independent variable at baseline, depressive symptoms at 25 weeks, and disability at 48 weeks. Coefficients for Direct pathways (w) and Indirect pathways (x and y) are shown. The “w” pathway represents the direct effect of each independent variable on disability, independent from the effect attributable to mediation by GDS. The “x” pathway represents the effect of each independent variable on GDS. The “y” pathway represents the effect of GDS on disability. The “z” coefficient represents the total effect, including both the Direct and Indirect pathways. The percent Indirect effect was calculated as % Indirect effect = (x*y)/z. Depressive symptoms accounted for 24–51% of the effect of each independent variable on disability in these longitudinal models.</p

CONSORT diagram.

Participant flow of the Memory Advancement with Intranasal insulin (MemAID) participants and relationship with this prospective cohort study. All 223 participants who completed screening and baseline assessments were included in the cross-sectional analyses. Of these, 66 did not complete the MemAID study (either withdrew from the study, were terminated by the investigator, or were lost to follow-up), and one completed the MemAID study but was missing data for the week 48 WHODAS. Therefore, the remaining 155 participants were included in the longitudinal analysis of this prospective cohort.</p

S1 Appendix -

Cross-sectional mediation analysis. Evaluation of baseline data showed that the mediation effects seen in the longitudinal analysis were already present at baseline. Post-hoc T2DM Subgroup analysis. The group of participants with T2DM showed more disability than controls, however, markers of diabetes severity were not related to greater disability. (DOCX)</p

Mediation effect of depression on the relationship between gait speed, cognition, and medical comorbidities on disability.

Mediation effect of depression on the relationship between gait speed, cognition, and medical comorbidities on disability.</p

Demographics and clinical variables.

Demographics and clinical variables.</p

Change in depressive symptoms predicts change in disability over 48 weeks.

Worsening depressive symptoms on GDS (baseline to Mid-Study) were related to increasing disability on WHODAS (baseline to week 48) (p<0.001). Forty-six participants experienced worsening of both GDS and WHODAS, while 24 participants experienced improvement on both measures. A 10-point increase in GDS corresponds to conversion from no depression to mild depression. WHODAS 2.0 Complex score ranges from 0 to 100, with each 10-point increasing corresponding to a 10% increase in overall disability.</p

Association between cognition, gait and comorbidities and disability at baseline.

a: Greater disability on the World Health Organization Disability Assessment Schedule 2.0 (WHODAS) was associated with higher depression scores on the Geriatric Depression Scale (GDS, pb: More disability was associated with worse cognition on Mini-Mental State Examination (MMSE, p = 0.027). c: More disability was associated with slower gait speed during normal walk (NW, pd: More disability was associated with medical comorbidities on the Charlson Comorbidity Index total points (CCI, p<0.001).</p

Longitudinal depressive symptoms.

Mean depressive symptoms over the duration of the study are shown. At the group level, depressive symptoms were stable between baseline, Mid-study (week 25), and end of the study (week 48). GDS: Geriatric Depression Scale. (TIF)</p