Randomized trial of n‐3 PUFA for cerebral white matter hyperintensities, medial temporal lobe atrophy and white matter integrity in older non‐demented adults: Per‐protocol and ApoE stratified results. (31st December 2021)

• Record Type: Journal Article
• Authors: Bowman, Gene L; Murchison, Charles F; Silbert, Lisa C; Dodge, Hiroko H; Hagen, Kirsten; Lahna, David; Harris, William S; Kaye, Jeffrey A; Quinn, Joseph F; Shinto, Lynne
• Is Part Of: Alzheimer's & dementia. Volume 17(2021)Supplement 10
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12-31
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.055682
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Blood levels of marine n‐3 PUFA (20:5; 22:6) are inversely associated with cerebral white matter lesion volume (WML), suggesting that n‐3 may offer one approach to reduce this major vascular contributor to cognitive impairment and dementia. This trial determined whether n‐3 slows WML progression and sustains white matter integrity over 3‐years in older non‐demented adults with suboptimum n‐3 status and WML (NCT01953705). Methods: Double‐blind, placebo‐controlled trial in non‐demented adults age 75 and older with plasma omega‐3 (20:5 + 22:6) < 110 ug/mL and total WML ≥ 5 cm3. Participants were randomized to 1.65 g of n‐3 (975 mg‐20:5, 675 mg‐22:6) or placebo. Primary outcome was the annual WML progression with biomarker‐based ITT, per‐protocol (PP) and APOE4 stratified analysis. Total brain, medial temporal lobe, and diffusion tensor imaging (DTI) of white matter integrity were secondary outcomes. Linear mixed‐effects models were used. Result: 102 participants randomized (51 per group; mean age 81; 60% female, 28% APOE4 +), 78 completed 3‐year visit (39 per group). Under mITT, annual WML change was 1.34 cm3 (95%CI: 0.80‐1.88) vs. 1.19 (0.64‐1.74) (p = 0.303) and annual DTI fractional anisotropy (FA) change was ‐0.002718 vs ‐0.001352 (p = 0.069) in the placebo and active, respectively. PPA comparing participants with study exit plasma omega‐3 ≤ 110 ug/mL vs above this threshold exhibited WML change of 1.71 cm 3 vs. 0.99 (p = 0.026) and DTI radial diffusivity change of 5.412e06 mm2/sec vs. 3.143e06 (p = 0.047). No effects on WML were observed by APOE genotype (e4 p = 0.196; non‐carriers p = 0.785), however, e4 carriers on placebo had annual DTI FA change of ‐0.005 vs. ‐0.002 in the active arm (p = 0.037). Conclusion: Omega‐3 did not slow total WML progression in all randomized participants; however, those that superseded the plasma n‐3 threshold established in preliminary studies (110 ug/mL) had 50% and 43% reduction in annual WML and annual DTI RD progression, respectively. These results highlight responders and macro‐and microscopic structural features sensitive to omega‐3 that warrant more extensive studies powered to detect cognitive effects and dementia incidence. NIH‐National Institute on Aging R01 AG043398 (GLB).