Knopman, David S.

Abstract Although APOE ε4 is an established risk factor for dementia, it is unclear whether it is associated with elevated risk or earlier symptom onset. Longitudinal study of 10,400 white-race individuals in the ARIC cohort followed from age 60 to incident dementia diagnosis, death, or censoring. All-cause dementia was defined using standardized algorithms incorporating longitudinal cognitive change, proxy report, and hospital or death certificate dementia codes. Death was ascertained via the National Death Index and death certificates. We used a parametric mixture of generalized gamma distributions to simultaneously estimate the distribution of event times and the proportion of individuals who experience each outcome (i.e., dementia and its competing risk, dementia-free death) by APOE ε4 status (≥ 1 allele vs. no alleles). Age-adjustment was through use of age as the time scale. APOE ε4 carrier status was associated with a doubling of the overall frequency of dementia incidence to 25% compared to 13% (p < 0.001) in non- ε4 carriers. The distributions of time to dementia was modified by APOE ε4 status (p=0.007): median time to dementia onset among APOE ε4 carriers was 81.9 years compared to 83.3 years in non-APOE ε4 carriers (p = 0.005). No differences in results were found by sex. APOE ε4 carrier status is associated with both elevated risk and earlier time to dementia onset. These findings clarify the causal role of APOE in dementia etiology, could help better identify at-risk subgroups, and may help facilitate better research recruitment.

BACKGROUND: We evaluated the hypothesis that the rate of postoperative decline in global cognition is greater in older adults exposed to general anesthesia with nitrous oxide (N 2 O) compared to general anesthesia without N 2 O. METHODS: Longitudinal measures of cognitive function were analyzed in nondemented adults, 70–91 years of age, enrolled in the Mayo Clinic Study of Aging. Linear mixed-effects models with time-varying covariates assessed the relationship between exposure to surgery with general anesthesia (surgery/GA) with or without N 2 O and the rate of long-term cognitive changes. Global cognition and domain-specific cognitive outcomes were defined using z scores, which measure how far an observation is, in standard deviations, from the unimpaired population mean. RESULTS: The analysis included 1819 participants: 280 exposed to GA without N 2 O following enrollment and before censoring during follow-up (median [interquartile range {IQR}] follow-up of 5.4 [3.9–7.9] years); 256 exposed to GA with N 2 O (follow-up 5.6 [4.0–7.9] years); and 1283 not exposed to surgery/GA (follow-up 4.1 [2.5–6.4] years). The slope of the global cognitive z score was significantly more negative following exposure to surgery/GA after enrollment (change in slope of −0.062 [95% confidence interval {CI}, −0.085 to −0.039] for GA without N 2 O, and −0.058 [95% CI, −0.080 to −0.035] for GA with N 2 O, both P < .001). The change in slope following exposure to surgery/GA did not differ between those exposed to anesthesia without versus with N 2 O (estimated difference −0.004 [95% CI, −0.035 to 0.026], P = .783). CONCLUSIONS: Exposure to surgery/GA is associated with a small, but statistically significant decline in cognitive z scores. Cognitive decline did not differ between anesthetics with and without N 2 O. This finding provides evidence that the use of N 2 O in older adults does not need to be avoided because of concerns related to decline in cognition.

Abstract Introduction Three cerebrospinal fluid (CSF) markers of neurodegeneration (N) (neurofilament light [NfL], total‐tau [T‐tau], and neurogranin [Ng]) have been proposed under the AT(N) scheme of the National Institute on Aging–Alzheimer's Association Research Framework. Methods We examined, in a community‐based population (N = 777, aged 50–95) (1) what variables were associated with each of the CSF (N) markers, and (2) whether the variables associated with each marker differed by increased brain amyloid. CSF T‐tau was measured with an automated electrochemiluminescence Elecsys immunoassay; NfL and Ng were measured with in‐house enzyme‐linked immunosorbent assays. Results Multiple variables were differentially associated with CSF NfL and T‐tau levels, but not Ng. Most associations were attenuated after adjustment for age and sex. T‐tau had the strongest association with cognition in the presence of amyloidosis, followed by Ng. Variables associations with NfL did not differ by amyloid status. Discussion Understanding factors that influence CSF (N) markers will assist in the interpretation and utility of these markers in clinical practice.