Abstract Details

Title Metabolomic Interactions Between Alzheimer’s and Metabolic Diseases: Insights from the Nightingale–Mass General Brigham Biobank

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) S15 - Diagnostics, Mechanics, and Mortality of Alzheimer's Disease and Related Dementias (1:24 PM-1:36 PM)

Poster/Presentation
Number 003

Objective

To characterize how Alzheimer’s disease (AD) interacts metabolically with dyslipidemia (DL) and type 2 diabetes (T2D) and to evaluate the mediating role of APOE genotype using large-scale metabolomic data.

Background Neurodegenerative diseases often coexist with metabolic disorders, yet their biochemical overlap remains poorly defined. In this study, we investigated overlaps, main similarities and differences between significant metabolic alterations found in comorbidities such as DL and T2D, and metabolic alterations observed in AD.

Design/Methods We analyzed 249 metabolites quantified by Nightingale NMR metabolomics in 45,514 participants from the Mass General Brigham Biobank. Comprehensive linear interaction models (metabolite ~ AD + DL + T2D + interactions + covariates) were adjusted for age, sex, and APOE genotype. Bonferroni correction was applied using 24 principal components (α = 0.002). Visualization included volcano, Venn diagram, bubble, and UMAP plots; pathway enrichment identified altered metabolic routes.

Results Dyslipidemia showed specific metabolic changes, especially becoming more prominent by increased omega-3 fatty acids, reduced HDL size, and decreased ω6/ω3 ratio (792/996 significant associations). Alzheimer's disease demonstrated 72 synergistic AD:DL interactions with negative coefficients (β = –0.29 to –0.42) affecting LDL and VLDL particles, cholesteryl esters, and ApoB metabolism predominantly. In contrast, T2D displayed substantially different interaction profiles, specifically on amino acid and protein metabolism. When analyses were stratified by APOE genotype, APOE4 carriers exhibited stronger and more consistent lipid and fatty acid disturbances, whereas APOE2 carriers demonstrated partial reversal of these effects. Pathway enrichment detected disruptions in ammonia recycling, branched-chain amino acid degradation, phenylalanine/tyrosine metabolism, and ketone body pathways.

Conclusions

Alzheimer's disease demonstrates unique metabolic vulnerability to dyslipidemia, with additional T2D-related metabolic shifts and strong APOE-dependent changes. Metabolic overlaps and genotype-dependent differences across AD, DL, and T2D suggest that personalized, APOE-guided lipid and metabolic management strategies may improve understanding and treatment of neurodegeneration.

Authors/Disclosures
Ezgi Sila Toklucu PRESENTER	Miss Toklucu has nothing to disclose.
Haoqi Sun, PhD (Massachusetts General Hospital)	Dr. Sun has nothing to disclose.
Jessica Lasky Su, ScD	Dr. Lasky Su has nothing to disclose.
Elizabeth Karlson, MD	Dr. Karlson has nothing to disclose.
Can Zhang, MD, PhD	The institution of Dr. Zhang has received research support from NIH. The institution of Dr. Zhang has received research support from ADDF. The institution of Dr. Zhang has received research support from Cure Alzheimer's Fund. Dr. Zhang has received intellectual property interests from a discovery or technology relating to health care.

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