Copper/zinc superoxide dismutase 1 (SOD1) scavenges free radicals that may otherwise damage brain parenchyma. Impaired SOD1 activity drives Alzheimer's disease (AD) neuropathology in animal models and postmortem AD brains. Yet, it is unknown how cerebrospinal fluid (CSF) SOD1 is related in vivo to AD-relevant cognitive, neuroimaging, and CSF neurotoxic factors, and what potential mechanisms underlie these associations. We found that higher CSF SOD1 correlated with better global cognition scores, yet less gray matter (GM) and glucose metabolism in AD-sensitive parietal and frontal regions. Higher CSF SOD1 was also associated with more CSF total tau and phosphorylated tau-181, but not beta-amyloid 1–42. Through mediation analyses, higher total tau largely mitigated higher CSF SOD1 and better global cognition associations, and it fully accounted for less predicted regional GM but not glucose metabolism. Among participants who developed AD over 2 years or had AD at baseline, higher CSF SOD1 was initially related to more regional GM. This association became nonsignificant with full mediation via higher CSF total tau, through which higher CSF SOD1 predicted more total tau and in turn less GM. Our observations lead to the hypothesis that SOD1 antioxidation reflects tau but not amyloid accumulation, which may lead to pro-oxidant-based neurodegeneration and cognitive dysfunction. Antioxid. Redox Signal. 31, 572–578.

Background: Cognitive change is an important factor in understanding dementia. Estimating effects of exposures on cognitive change requires choosing an analytical timescale, typically time on study or current age. There is limited consensus regarding timescale choice in epidemiologic cognitive aging research. Methods: Using a coordinated analytic approach in 10 cohorts of older adults, we evaluated whether estimated effects of two exposures on memory change differed depending on timescale (time on study or current age). We modeled effects of apolipoprotein-E (APOE) ε4 genotype (a time-invariant exposure) and diabetes (a potentially time-varying/acquired exposure evaluated at baseline) using mixed-effects models with linear and nonlinear time specifications for both timescales. Results: Among APOE ε4 carriers, model-estimated memory scores at baseline (time on study timescale) or at each cohort’s median baseline age (current age timescale) were lower, and the average rate of decline was faster than among APOE ε4 noncarriers. Model-estimated memory scores at baseline or at median baseline age were generally similar across baseline diabetes status, with variability across cohorts in the diabetes-memory change association. In some cohorts, trends in diabetes-memory change associations differed in direction across timescales. Conclusions: Timescale was largely inconsequential for estimated effects of APOE genotype, but yielded differences in estimated diabetes effects, raising questions about the appropriate scale. The current age scale may be problematic because diabetes was measured heterogeneously in age across individuals, a common issue in aging cohorts. Our work demonstrates approaches to evaluate alternative timescales, including in multicohort analyses, and highlights potential implications for estimated exposure effects on cognitive change.

INTRODUCTION: “SuperAgers” are oldest-old adults (ages 80+) whose memory performance more closely resembles middle-aged adults. The present study examined APOE allele frequency in non-Hispanic Black (NHB) and non-Hispanic White (NHW) SuperAgers compared to controls and Alzheimer’s disease dementia cases. METHODS: In 18,080 participants from eight cohorts, harmonized clinical diagnostics and memory, executive function, and language domain scores were used to identify SuperAgers, cases, and controls across age-defined bins. RESULTS: NHW SuperAgers had significantly lower frequency of APOE- ε4 alleles and higher frequency of APOE -ε2 alleles compared to all cases and controls, including oldest-old controls. Similar patterns were found in a small yet substantial sample of NHB SuperAgers; however, not all comparisons with controls reached significance. DISCUSSION: We demonstrated strong evidence that APOE allele frequency relates to SuperAger status. Further research is needed with a larger sample of NHB SuperAgers to determine if mechanisms conferring resilience differ across race groups.