Could Altered Evoked Pain Responsiveness Be a Phenotypic Biomarker for Alzheimer’s Disease Risk? A Cross-Sectional Analysis of Cognitively Healthy Individuals

Abstract

Background: This study evaluated whether the apolipoprotein ɛ4 (APOE4) allele, a genetic marker associated with increased risk of developing late-onset Alzheimer’s disease (AD), was associated with differences in evoked pain responsiveness in cognitively healthy subjects. Objective: The aim was to determine whether individuals at increased risk of late-onset AD based on APOE allele genotype differ phenotypically in their response to experimentally-induced painful stimuli compared to those who do not have at least one copy of the ɛ4 allele. Methods: Forty-nine cognitively healthy subjects aged 30–89 years old with the APOE4 allele (n = 12) and without (n = 37) were assessed for group differences in pain thresholds and affective (unpleasantness) responses to experimentally-induced thermal pain stimuli. Results: Statistically significant main effects of APOE4 status were observed for both the temperature at which three different pain intensity percepts were reached (p = 0.040) and the level of unpleasantness associated with each (p = 0.014). APOE4 positive participants displayed lower overall pain sensitivity than those who were APOE4 negative and also greater overall levels of pain unpleasantness regardless of intensity level. Conclusion: Cognitively healthy APOE4 carriers at increased risk of late-onset AD demonstrated reduced thermal pain sensitivity but greater unpleasantness to thermal pain stimuli relative to individuals at lower risk of late-onset AD. These results suggest that altered evoked pain perception could potentially be used as a phenotypic biomarker of late-onset AD risk prior to disease onset. Additional studies of this issue may be warranted.

Preserved Thermal Pain in 3xTg-AD Mice With Increased Sensory-Discriminative Pain Sensitivity in Females but Affective-Emotional Dimension in Males as Early Sex-Specific AD-Phenotype Biomarkers

“…Finally, the most recent report in humans shows that cognitively healthy apolipoprotein E4 (APOE4) carriers, with a demonstrated increased risk of late-onset AD, displayed lower overall pain sensitivity non-carriers but greater unpleasantness to thermal pain stimuli. This association of APOE4 allele status with an altered response to pain in a cognitively healthy sample of adults suggests that thermal evoked pain testing could serve as a potential phenotypic biomarker of individuals at increased risk for AD (Romano et al, 2021 ). The present work on the preserved withdrawal response in the 3xTg-AD mice since young age mimicks asymptomatic stages of disease agrees with this clinical finding and proposes sex-specific phenotypic biomarkers sensory-discriminative dimension in the female sex and affective-emotional in males.…”