Abstract 063: Higher Visit-to-Visit Variability in Fasting Glucose and HbA1c is Associated with Decline in Global Cognitive Performance: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Schaich Christopher L , Bancks Michael , Hayden Kathleen , Ding Jingzhong , Rapp Steve , Bertoni Alain G , Fitzpatrick Annette L , Heckbert Susan R , Hughes Timothy M , Mongraw-chaffin Morgana 
Published: April 2022

Background:
Higher visit-to-visit variability in fasting glucose (GV) and HbA1c (A1cV), indicating worse glycemic control, is associated with incident dementia in adults with type 2 diabetes (T2D). Few studies have investigated the relationship of GV and A1cV with cognitive decline in the general population.

Hypothesis:
Higher visit-to-visit GV and A1cV are associated with decline in global cognitive performance.

Methods:
Fasting glucose (FG) was measured in MESA participants at Exam 1 (2000-02) and each of 5 follow-up exams, and HbA1c was measured at Exam 2 (2002-04), Exam 5 (2010-12), and Exam 6 (2016-18). Global cognitive performance was assessed by the Cognitive Abilities Screening Instrument (CASI; scored 0-100) at Exam 5 and re-administered to a subset at Exam 6. We calculated GV and A1cV as the SD (SD
GV
; SD
A1c
), coefficient of variation (CV
GV
; CV
A1c
), and average real variability (ARV
GV
; ARV
A1c
), and defined global cognitive decline as a ≥1 race/ethnicity-specific SD decrease in CASI score from Exam 5 to Exam 6 (-5.9 to -8.2 points across 4 races/ethnicities). We report the CASI point-change and relative odds of decline (OR) from Exam 5 to Exam 6 (95% CI) associated with continuous log
2
-normalized and highest quartile (Q4 vs. quartiles 1-3 for potential floor effects) of GV and A1cV from inverse probability of censor-weighted linear and logistic regression adjusted for Exam 5 CASI score, age, sex, race/ethnicity, education, vascular risk factors, and
APOE
ε4 status.

Results:
A total of 1834 Exam 6 participants (aged 73±8 years; 47% men; 43% White; 7% with T2D at Exam 1; 13% with incident T2D over follow-up) had ≥3 FG measurements and repeat CASI data. The overall 6-year mean (SD) change in CASI was +0.1 (6.6) points. Q4 of SD
GV
, CV
GV
, and ARV
GV
was associated with 0.8 (0.1, 1.5), 0.9 (0.2, 1.6), and 0.7 (0.03, 1.4) point decreases in CASI, respectively, and Q4 of CV
GV
was associated with higher odds of global cognitive decline (OR = 1.5 [1.1, 2.1]); continuous GV indices were not associated with CASI change. Associations with SD
GV
and CV
GV
were driven by participants with incident T2D (interaction
P
<0.01 for change and odds of decline). In 1175 participants with 3 HbA1c measurements, a 2-fold increment in ARV
A1c
was associated with a 0.5 (0.1, 0.9) point decrease in CASI. However, in participants with incident T2D, 2-fold increments in SD
A1c
, CV
A1c
, and ARV
A1c
were associated with 1.3 (0.2, 2.4), 1.4 (0.2, 2.6), and 1.8 (0.6, 3.0) point decreases in CASI, respectively, and a 2-fold increment in ARV
A1c
was associated with greater odds of decline (OR = 2.1 [1.1, 3.8]) (interaction
P
all <0.01). There were no associations with Q4 of A1cV indices. Associations did not differ by sex, race/ethnicity, or Exam 1 T2D status.

Conclusions:
Poor glycemic control over 14-16 years is associated with modest cognitive decline over the subsequent 6-8 years, particularly among adults at high risk for T2D during mid- to late-life.