Using the NIA-AA Research Framework to stratify Cognitive Normal Older Adults with Obstructive Sleep Apnea
Authors List
Bubu OM*, Turner A, Kaur SS, Ramos-Cejudo J, Valkanova E, Mbah AK, White P, Azad D, Kovbasyuk Z, Cesar O, Wahab A, Jacobs T, Kam K, Mullins AE, Parekh A, Rapoport DM, Ayappa I, Jean-Louis G, de Leon MJ, Masurkar AV, Varga AW, Osorio RS*
Background
Obstructive Sleep Apnea (OSA) increases Alzheimer’s disease (AD) risk and is associated with both established and novel plasma AD biomarkers, even in clinically normal (NL) older-adults. Clearly establishing which OSA individuals are at heightened risk to develop AD is critical. Using the NIA-AA Research
Framework, we aimed to characterize risk profiles of cognitively normal (NL) older-adults with OSA by examining the interactive effects of OSA, Aβ, PTau & T-tau (ATN), on prospective cognitive decline.
Methods
Longitudinal study utilizing data from 167 community-dwelling NL older-adults participating in NYU studies on memory, sleep and aging. Subjects had baseline CSF AD biomarker data and at least two follow-up clinical and neuropsychological data. OSA was defined using AHI4%. Using the NIA-AA Research Framework, data-driven, clinically relevant thresholds for CSF-Aβ42 (≤375pg/ml), P-tau (≥53.7pg/ml) and T-tau (≥367 pg/ml) indicated ATN status respectively. Twenty-four participants with suspected non-AD pathologic change defined as A-T+ were excluded leaving 143 for the analysis. Main outcome was the annual rate-of-change in global cognition (calculated as an average composite Z-score of episodic memory, language and executive
function). Linear mixed-effects models with random intercept and slope were used to assess associations between ATN characterized OSA subjects, and longitudinal changes in global cognition controlling for age-atbaseline, sex, APOE4-status, years-of-education, and their interactions with time.
Results
Of the 143 participants, 91 (63.8%) were women. The mean (SD) age was 69.6 (7.3) years and follow up time was 4.73 (3.45) years. Sixteen subjects (11.2%) were OSA+/A+/T-, and 21 (14.7%) were OSA-/A+/T-. Ninety-two (64.3%) had normal AD biomarkers (OSA+/A-/T- [n=45] and OSA-/A-/T- [N=47]). Aβ and T-tau were each associated with significant faster rate-of-decline in global cognition (β = −0.066, 95%CI, −0.088, −0.046; and β = −0.043, 95%CI, −0.060, −0.028; P < .01 for both). OSA and P-tau were not associated with significant faster rate-of-decline in global cognition (β = −0.035, 95%CI, −0.088, 0.018, P = .071, P for trend = .02; and β = −0.008, 95%CI, −0.024, 0.008; P = .433). The interaction of OSA, Aβ, P-tau and T-tau with time was significant (−0.033, 95%CI, −0.048, −0.018; P <.001) suggesting a synergistic effect.
Characterization of OSA/ATN groups’ risk estimates via post hoc analyses showed both OSA+/A+/TN+ and OSA+/A+/TN subjects with the highest risk of prospective cognitive decline ((β = −0.042, 95%CI, −0.063, −0.019; P < .001, relative to OSA-/A+/T+ and OSA-/A+/T- participants). OSA+/A-/T- participants did not show any significant cognitive change over time.
Conclusion
OSA and Aβ demonstrate synergism related to cognitive decline that might be independent of tau deposition, thus, placing OSA patients with evidence of AD pathologic change at heightened risk of prospective cognitive decline. Clinical trials aimed at preventing AD in a population of elderly OSA cognitive normal individuals should target persons with Alzheimer’s pathologic change.
Funding: NIH/NIA/NHLBI (L30-AG064670, K23AG068534, CIRAD P30AG059303 Pilot, R01HL118624, R21AG049348, R21AG055002, R01AG056031, R01AG022374, R21AG059179, R01AG056682, R01AG056531, K07AG05268503), Alzheimer’s Association [AARG-D- 21-848397], BrightFocus Foundation [A2022033S]
Bubu OM*, Turner A, Kaur SS, Ramos-Cejudo J, Valkanova E, Mbah AK, White P, Azad D, Kovbasyuk Z, Cesar O, Wahab A, Jacobs T, Kam K, Mullins AE, Parekh A, Rapoport DM, Ayappa I, Jean-Louis G, de Leon MJ, Masurkar AV, Varga AW, Osorio RS*
Background
Obstructive Sleep Apnea (OSA) increases Alzheimer’s disease (AD) risk and is associated with both established and novel plasma AD biomarkers, even in clinically normal (NL) older-adults. Clearly establishing which OSA individuals are at heightened risk to develop AD is critical. Using the NIA-AA Research
Framework, we aimed to characterize risk profiles of cognitively normal (NL) older-adults with OSA by examining the interactive effects of OSA, Aβ, PTau & T-tau (ATN), on prospective cognitive decline.
Methods
Longitudinal study utilizing data from 167 community-dwelling NL older-adults participating in NYU studies on memory, sleep and aging. Subjects had baseline CSF AD biomarker data and at least two follow-up clinical and neuropsychological data. OSA was defined using AHI4%. Using the NIA-AA Research Framework, data-driven, clinically relevant thresholds for CSF-Aβ42 (≤375pg/ml), P-tau (≥53.7pg/ml) and T-tau (≥367 pg/ml) indicated ATN status respectively. Twenty-four participants with suspected non-AD pathologic change defined as A-T+ were excluded leaving 143 for the analysis. Main outcome was the annual rate-of-change in global cognition (calculated as an average composite Z-score of episodic memory, language and executive
function). Linear mixed-effects models with random intercept and slope were used to assess associations between ATN characterized OSA subjects, and longitudinal changes in global cognition controlling for age-atbaseline, sex, APOE4-status, years-of-education, and their interactions with time.
Results
Of the 143 participants, 91 (63.8%) were women. The mean (SD) age was 69.6 (7.3) years and follow up time was 4.73 (3.45) years. Sixteen subjects (11.2%) were OSA+/A+/T-, and 21 (14.7%) were OSA-/A+/T-. Ninety-two (64.3%) had normal AD biomarkers (OSA+/A-/T- [n=45] and OSA-/A-/T- [N=47]). Aβ and T-tau were each associated with significant faster rate-of-decline in global cognition (β = −0.066, 95%CI, −0.088, −0.046; and β = −0.043, 95%CI, −0.060, −0.028; P < .01 for both). OSA and P-tau were not associated with significant faster rate-of-decline in global cognition (β = −0.035, 95%CI, −0.088, 0.018, P = .071, P for trend = .02; and β = −0.008, 95%CI, −0.024, 0.008; P = .433). The interaction of OSA, Aβ, P-tau and T-tau with time was significant (−0.033, 95%CI, −0.048, −0.018; P <.001) suggesting a synergistic effect.
Characterization of OSA/ATN groups’ risk estimates via post hoc analyses showed both OSA+/A+/TN+ and OSA+/A+/TN subjects with the highest risk of prospective cognitive decline ((β = −0.042, 95%CI, −0.063, −0.019; P < .001, relative to OSA-/A+/T+ and OSA-/A+/T- participants). OSA+/A-/T- participants did not show any significant cognitive change over time.
Conclusion
OSA and Aβ demonstrate synergism related to cognitive decline that might be independent of tau deposition, thus, placing OSA patients with evidence of AD pathologic change at heightened risk of prospective cognitive decline. Clinical trials aimed at preventing AD in a population of elderly OSA cognitive normal individuals should target persons with Alzheimer’s pathologic change.
Funding: NIH/NIA/NHLBI (L30-AG064670, K23AG068534, CIRAD P30AG059303 Pilot, R01HL118624, R21AG049348, R21AG055002, R01AG056031, R01AG022374, R21AG059179, R01AG056682, R01AG056531, K07AG05268503), Alzheimer’s Association [AARG-D- 21-848397], BrightFocus Foundation [A2022033S]
