Table 1.
Longitudinal studies of the association between CR and AD biomarkers among individuals with normal cognition at baseline
| Study | Outcome Variable(s) | AD Biomarkers | CR Measures | Mean Clinical Follow-Up Time in Years (SD) | Number of Cognitively Normal Subjects at Baseline | Baseline CR Biomarker Association | CR Associated with Delayed Clinical Progression/Better Cognitive Performance Accounting for Baseline Biomarker Levels | Longitudinal CR-Biomarker Association | Relationship Between Biomarker and Clinical/Cognitive Outcome Modified by CR |
|---|---|---|---|---|---|---|---|---|---|
| Soldan et al,31 2013 | Time to onset of clinical symptom of MCI; change in AD biomarkers | CSF Aβ1-42, t-tau, p-tau | Composite score (education, NART-IQ, WAIS-R vocabulary) | 8.0 (3.4), max = 17 | 239 53 progressed |
No | Yes Delayed clinical progression |
No | Yes, for CSF t-tau and p-tau. |
| Pettigrew et al,30 2017 | Time to onset of clinical symptom of MCI | Cortical thickness in AD-vulnerable regions | Composite score (education, NART-IQ, WAIS-R vocabulary) | 11.8 (3.6) max = 20 | 232 48 progressed |
No | Yes Delayed clinical progression |
– | Yes, for those who progressed 7+ y after baseline only. |
| Roe et al,33 2011 | Time to CDR ≥0.5; change in CDR-SB, Short Blessed Test, MMSE | CSF Aβ1-42, t-tau, p-tau | Education | 3.3 (2.0) | 197 26 progressed |
– | Yes, delayed clinical progression after accounting for Aβ1-42, but not significant among those with low tau/p-tau; significant among those with high tau/p-tau | – | Yes, among those with high tau or p-tau and low education, WBV was associated with faster progression. In low tau/p-tau group, neither education nor WBV associated with progression. Similar results obtained for CDR-SB and Blessed Test, but not for MMSE. |
| Roe et al,34 2011 | Time to CDR ≥0.5 | CSF Aβ1-42, t-tau, p-tau | Education, occupational attainment (6 levels) | 3.2 (1.6) | 213 14 progressed |
– | Yes Delayed clinical progression |
– | – |
| Soldan et al,32 2015 | Time to onset of clinical symptom of MCI; change in AD biomarkers | Volumes of hippocampus, entorhinal cortex, amygdala; entorhinal cortex thickness | Composite score (education, NART-IQ, WAIS-R vocabulary) | 11.1 (3.6), max = 18 | 245 57 progressed |
No | Yes Delayed clinical progression |
No | Yes, for left entorhinal cortex volume only. |
| Udeh-Momoh et al,35 2019 | Time to progression to MCI and AD dementia | CSF Aβ1-42; CSF cortisol | Composite score (education, IQ, occupation, intracranial volume) | Median = 7, max = 10 | 91 19 progressed to MCI, 10 progressed to AD dementia |
No | No | – | Yes, among those with abnormal CSF Aβ1-42 and high cortisol, higher CR score was associated with reduced risk of progression; remained significant when other biomarkers were covaried (eg, CSF t-tau). |
| Soldan, et al,18 2017 | Change in cognitive composite Z score | Composite Z score (CSF Aβ1-42, p-tau, entorhinal cortex thickness, hippocampal volume, cortical thickness in AD-vulnerable regions) | Composite score (education, NART-IQ, WAIS-R vocabulary) | 12.1 (4.2) max = 20 | 303 with clinical/cognitive data; 170 with baseline biomarker data | No | Yes, better baseline cognitive performance and faster decline after MCI symptom onset | – | No. |
| Vemuri et al,36 2015 | Change in cognitive composite Z score | Cortical PiB-PET (dichotomous); white matter hyperintensity volume, brain infarcts on fluid-attenuated inversion recovery-MRI (dichotomous) | Education/occupation score and self-reported mid/late life cognitive activity score | 2.7 | 393 | No | Yes, better baseline cognitive performance, but no difference in slope | – | No. |
| Wolf et al,37 2019 | Change in memory composite score, ADAS-Cog, CDR-SB | CSF Aβ1-42 | Education | 2.6 (2.4), max = 10 | 276 | – | – | – | Yes, those with high education showed reduced amyloid-related cognitive decline; effects remained significant when other biomarkers were covaried (CSF t-tau, p-tau, FDG-PET, ventricular volume). |
| Suo et al,39 2012 | Change in hippocampal volume | Hippocampal volume, whole-brain volume (VBM) | LEQ | 2–3, max = 3 | 151 | Yes, midlife LEQ/occupational complexity and bilateral hippocampus, and left amygdala | – | Yes, high supervisory experiences associated with less hippocampal atrophy (N = 91) | – |
| Lo & Jagust,38 2013 | Change in AD biomarkers | CSF Aβ1-42, t-tau, p-tau, FDG-PET metabolism in 5 AD-vulnerable regions, hippocampal volume | Education (tertiles), occupation (3 levels), NART errors (tertiles) | 2–3, max = 3 | 229; 35 (CSF) 103 (FDG) 228 (HCV) | No | – | Yes, higher CR associated with less decline in CSF Aβ1-42. | – |
| Walters et al,40 2018 | Change in AD biomarkers | Cortical thickness in PCC and entorhinal cortex; PiB-PET and FDG-PET metabolism in PCC and precuneus | Intellectual activity throughout life | 3 (1), max = 3.5 | 70 | Yes, intellectual activity and FDG-PET | Yes, better baseline cognitive performance, but no difference in slope | No | – |
| Pettigrew et al,50 in press | Change in AD biomarkers | CSF Aβ1-42, t-tau, p-tau, medial temporal lobe composite Z score, cortical thickness in AD-vulnerable regions; white hyperintensity volume | Composite score (education, NART-IQ, WAIS-R vocabulary) | 2.7 (2.6), max = 8.3 | 271 (CSF) 288 (MTL) 251 (AD-vulnerable regions) 277 (WMH) |
Yes, CR composite and WMH volume | – | No | – |
Abbreviations: ADAS-Cog, alzheimer’s disease assessment scale-cognition sub-scale; CDR-SB, clinical dementia rating-sum of boxes; LEQ, lifetime experiences questionnaire; MMSE, mini-mental state examination; PCS, posterior cingulate cortex.