Key Points
Question
What cortical proteins are associated with cognitive resilience among community-dwelling older persons?
Finding
This study leveraged data from 391 community-dwelling older
persons to conduct a proteome-wide association analysis of the human
dorsolateral prefrontal cortex. Eight cortical proteins were identified
in association with cognitive resilience, of which a higher level of
NRN1, ACTN4, EPHX4, RPH3A, SGTB, CPLX1, and SH3GL1 and a lower level of
UBA1 were associated with greater resilience.
Meaning
Identifying these cortical proteins provides a complementary
approach to developing novel therapeutics for the treatment and
prevention of Alzheimer disease and related dementias.
Importance
Identifying genes and proteins for cognitive resilience (ie,
targets that may be associated with slowing or preventing cognitive
decline regardless of the presence, number, or combination of common
neuropathologic conditions) provides a complementary approach to
developing novel therapeutics for the treatment and prevention of
Alzheimer disease and related dementias.
Objective
To identify proteins associated with cognitive resilience via a
proteome-wide association study of the human dorsolateral prefrontal
cortex.
Design, Setting, and Participants
This study used data from 391 community-dwelling older persons
who participated in the Religious Orders Study and the Rush Memory and
Aging Project. The Religious Orders Study began enrollment January 1,
1994, and the Rush Memory and Aging Project began enrollment September
1, 1997, and data were collected and analyzed through October 23, 2019.
Exposures
Participants had undergone annual detailed clinical
examinations, postmortem evaluations, and tandem mass tag proteomics
analyses.
Main Outcomes and Measures
The outcome of cognitive resilience was defined as a
longitudinal change in cognition over time after controlling for common
age-related neuropathologic indices, including Alzheimer disease, Lewy
bodies, transactive response DNA-binding protein 43, hippocampal
sclerosis, infarcts, and vessel diseases. More than 8000 high abundance
proteins were quantified from frozen dorsolateral prefrontal cortex
tissue using tandem mass tag and liquid chromatography-mass
spectrometry.
Results
There were 391 participants (273 women); their mean (SD) age
was 79.7 (6.7) years at baseline and 89.2 (6.5) years at death. Eight
cortical proteins were identified in association with cognitive
resilience: a higher level of NRN1 (estimate, 0.140; SE, 0.024;
P = 7.35 × 10
−9), ACTN4 (estimate, 0.321; SE, 0.065;
P = 9.94 × 10
−7), EPHX4 (estimate, 0.198; SE, 0.042;
P = 2.13 × 10
−6), RPH3A (estimate, 0.148; SE, 0.031;
P = 2.58 × 10
−6), SGTB (estimate, 0.211; SE, 0.045;
P = 3.28 × 10
−6), CPLX1 (estimate, 0.136; SE, 0.029;
P = 4.06 × 10
−6), and SH3GL1 (estimate, 0.179; SE, 0.039;
P = 4.21 × 10
−6) and a lower level of UBA1 (estimate, −0.366; SE, 0.076;
P = 1.43 × 10
−6) were associated with greater resilience.
Conclusions and Relevance
These protein signals may represent novel targets for the maintenance of cognition in old age.
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