Brain glucose hypometabolism precedes cognitive decline in Alzheimer's disease, however its role in determining long-term cognitive trajectories remains under studied in current literature in a clear manner. We investigated whether baseline brain glucose metabolism predicts cognitive decline rates and disease conversion risk in a large longitudinal cohort.

We analyzed 4,732 participants (1,685 with longitudinal cognitive data) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with fluorodeoxyglucose positron emission tomography (FDG-PET), Mini-Mental State Examination (MMSE), and Alzheimer's Disease Assessment Scale (ADAS) measurements over ten years. Mixed-effects models investigated time × brain glucose metabolism interactions on cognitive decline. Cross-validation assessed predictive accuracy for mild cognitive impairment and Alzheimer's disease conversion.

Brain glucose metabolism was found to modulate the cognitive decline rates (time × FDG interaction: MMSE β = 0.746, P-value <0.001; ADAS β = −1.595, P-value <0.001). High versus low glucose metabolism demonstrated 1.49 MMSE points/year and 3.19 ADAS points/year protection. Among cognitively normal participants, low glucose metabolism increased Alzheimer's disease conversion risk four-fold (incidence rate ratio = 3.79, 95%CI: 2.94–4.88). Predictive models achieved high accuracy for Alzheimer's disease conversion (AUC = 0.826) with good calibration (Brier score = 0.092). High-metabolism individuals showed essentially stable cognition over ten years follow-up duration as evident in the ADNI dataset.

We found that brain glucose metabolism is a notable determinant of cognitive decline progression, especially for Alzheimer’s disease risk, providing quantifiable metabolic protection against decline. Our results demonstrate brain glucose hypometabolic findings from baseline FDG-PET as a precision biomarker for therapeutic stratification and support further interventions for cognitive preservation for further research, validation and development purposes that should be further evaluated and investigated in further clinical trials that may lead to better preventive and therapeutic benefits for cognitive functions preservation and prevention of cognitive decline process in high-risk individuals.