Table 4 Causal mediation analysis of sociodemographic or clinical characteristic exposures and cognitive reserve metric mediators, in the Strong Heart Study/cerebrovascular disease and its consequences in American Indians (CDCAI) sub-cohort at Visit 1 (2010–2013), on composite cognitive test scores (Z-scale), defined at CDCAI Visit 2 (2017–2019)

Mediator	Exposure	Total effect beta (95% CI)	Direct effect beta (95% CI)	Indirect effect beta (95% CI)	Proportion mediated (95% CI)	P value
WAIS-Brain	Education	0.39 (0.26, 0.51)	0.29 (0.15, 0.43)	0.09 (0.03, 0.16)	0.24 (0.05, 0.44)	0.014
	Depression		0.38 (0.25, 0.51)	0.01 (−0.01, 0.04)	0.04 (−0.03, 0.10)	0.260
	Diabetes		0.38 (0.26, 0.51)	0.0 (−0.01, 0.01)	0.0 (−0.01, 0.01)	0.984
COWA-WMH	Education	0.43 (0.29, 0.56)	0.37 (0.22, 0.51)	0.06 (0.00, 0.12)	0.15 (0.00, 0.29)	0.045
	Depression		0.41 (0.28, 0.55)	0.01 (0.00, 0.03)	0.02 (−0.02, 0.06)	0.374
	Diabetes		0.42 (0.29, 0.56)	0.00 (−0.01, 0.02)	0.01 (−0.02, 0.04)	0.552
CVLT-Hipp	Education	0.40 (0.27, 0.52)	0.39 (0.28, 0.51)	0.01 (−0.03, 0.04)	0.02 (−0.07, 0.10)	0.679
	Depression		0.40 (0.27, 0.53)	−0.01 (−0.03, 0.01)	^a	^a
	Diabetes		0.40 (0.27, 0.52)	0.0 (−0.01, 0.01)	0.0 (−0.02, 0.03)	0.676

^aWhen direct and indirect coefficient signs are opposite (one positive, one negative), the interpretation of proportion mediated is unclear.
Numbers included in analysis: WAIS-Brain both Visit 1 and Visit 2 n = 298, COWA-WMH both Visit 1 and Visit 2 n = 298. Model-directed acyclic flows include exposure (e.g., diabetes at Visit 1), mediator (metric of cognitive reserve, e.g., WAIS-Brain volume, at Visit 1), and outcome (e.g., composite cognitive score at Visit 2). Total effect is an association of exposure to outcome (direct + indirect); direct = excljuding effect of mediator, indirect = effect via mediator. Assumes causality. Direct effect is the association of exposure (diabetes or depression) on outcome (composite cognitive test score) without the mediator (cognitive reserve); indirect effect is the effect of exposure on outcome estimated to function through the mediator.
Terms defined: Weschler Adult Intelligence Scale Digit Symbol Coding Test (WAIS DSST) over brain volume as percent intracranial volume (WAIS-Brain), (middle) residuals of Controlled Oral Word Association f/a/s test (COWA) over white matter hypointensities volume (MRI T1 sequence) as percent intracranial volume (COWA-WMH), and (bottom) residuals of California Verbal Learning Test version II short form long delay free recall test (CVLT LF) over hippocampus volume as percent intracranial volume (CVLT-Hipp).

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