A recent study published in PNAS has revealed a distinct trajectory for brain aging, characterized by critical transition points. The research, led by Dr. Lilianne R. Mujica-Parodi from Stony Brook University, provides new insights into effective timings for interventions aimed at preventing cognitive decline.
The team studied functional communication between brain regions in over 19,300 individuals across four datasets. They found that brain networks degrade following an S-shaped curve with clear transition points. This contrasts with the previously assumed late-life clinical onset or gradual linear decline. The effect begins around age 44, peaks at age 67, and plateaus by age 90.
Dr. Mujica-Parodi stated, “Understanding exactly when and how brain aging accelerates gives us strategic timepoints for intervention.” She further explained that midlife represents a window where neurons are metabolically stressed but still viable, allowing alternative fuels to restore function before irreversible damage occurs.
The study identified neuronal insulin resistance as a primary driver of this trajectory. Metabolic changes were found to precede vascular and inflammatory ones. Gene expression analyses implicated the insulin-dependent glucose transporter GLUT4 and the lipid transport protein APOE in these patterns but also highlighted the potential protective role of the neuronal ketone transporter MCT2.
An interventional study was conducted comparing glucose and ketones administered to 101 participants at various stages along the aging trajectory. The results showed that ketones stabilized deteriorating brain networks more effectively than glucose during midlife metabolic stress but had reduced impact in older adults.
These findings suggest a paradigm shift in preventing age-related cognitive decline and neurodegenerative diseases like Alzheimer’s. Current treatments often target symptoms too late; this research indicates that starting metabolic interventions in one’s 40s might be more effective.
Botond Antal, PhD, emphasized the potential of identifying at-risk individuals through neurometabolic markers for early intervention: “Rather than waiting for cognitive symptoms...we can potentially identify people at risk...and intervene during this critical window.”
From a public health perspective, these insights could lead to new screening guidelines and preventive strategies to delay cognitive aging significantly.
The study was funded by the W.M. Keck Foundation and the NSF Brain Research through Advancing Neurotechnologies (BRAIN) Initiative and involved collaboration among scientists from Stony Brook University, Massachusetts General Hospital, Mayo Clinic, Oxford University, and Memorial Sloan Kettering.