Changes in brain aerobic glycolysis reflect aging-related pathologies in Alzheimer’s

In a recent study published in the journal Proceedings of the National Academy of Sciences, researchers explore aerobic glycolysis (AG) in the brain and its resilience during Alzheimer’s disease (AD).

Study: Brain aerobic glycolysis and resilience in Alzheimer disease. Image Credit: Atthapon Raksthaput / Shutterstock.com

The role of glucose in the brain

In a healthy brain, glucose is the primary source of energy for mitochondrial respiration. However, a fraction of young people’s resting glucose intake exceeds what would be predicted from oxygen consumption rates.

Some studies indicate that AG in the brain may enhance neurite outgrowth, learning, myelination, as well as reduce oxidative stress and microglial activity. However, the function of this excess utilization of glucose remains unknown.

AD also impacts AG in the human brain. In fact, early AD is related to a large decline in glucose consumption rates in comparison to a lesser shift in oxygen consumption.

About the study

In the present study, researchers examine regional brain AG among AD patients to quantify AG, as well as oxygen and glucose metabolism, in patients further characterized by amyloid imaging and cognitive tests.

From the Knight Alzheimer Disease Research Center (ADRC) and Washington University community, a total of 285 individuals between 25 and 92 years of age were recruited. All individuals underwent positron emission tomography (PET) and magnetic resonance imaging (MRI) for registration, as well as segmentation of brain structure.

Awake and eyes-closed subjects underwent 8F-FDG, 15O-O2, 15O-HO2, and 15O-CO PET scans that were subsequently processed to generate regional maps of AG (GI), the cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF), and total cerebral metabolic rate of glucose (CMRGlc). In addition to obtaining blood radioactivity counts, venous specimens were collected for plasma glucose measurement prior to and midway through the scan.

For each PET assessment and metabolic estimate (GI, CBF, CMRO2, and CMRGlc), a “youthful pattern” was described according to its association with average regional values. These values reflected gray matter assessed in a distinct but re-processed dataset consisting of a group of young and healthy adults between 20 and 34 years of age in the N33 cohort. The N33 cohort was used to determine the youthful trend related to each metabolic characteristic.

Furthermore, the severity of white matter hyperintensities (WMH) was assessed by manually segmenting intensity thresholds in regions of high signal intensity on individual fluid-attenuated inversion recovery (FLAIR) scans.

Study findings

Between 2013 and 2021, 353 multi-tracer metabolic PET scans were performed on 285 adult patients. For all metabolic metrics, young individuals from the Aging Metabolism & Brain Resilience (AMBR) study group maintained their youthful patterns. This youthful pattern varied with increasing age for all metabolic measures, with increasing inter-individual variability among trends of brain metabolism, particularly for GI.

When adjusting for amyloid status and age, the female sex was associated with an elevated youthful GI index. This pattern was also observed in the youthful CMRO2 index, but not to the same extent for the youthful CBF and CMRGlc indices.

Further study revealed a significant interaction between gender and age, wherein the youthful GI index decreased more rapidly for men than women as they aged. Considering these results, age and gender were included as factors in subsequent analyses.

Cognitive impairment, which was determined by the Clinical Dementia Rating® (CDR®) sum of boxes, was significantly associated with the male gender, age, and amyloid positivity. Controlling for age, gender, and amyloid status, cognitive impairment was also strongly related to reduced youthful GI and CMRGlc indices. A reduction in youthful GI was also related to AD and cognitive impairment in amyloid-positive people when adjusting for age and gender.

Neither the youthful CBF nor CMRO2 indices were significantly related to cognitive impairment. Thus, early cognitive impairment appears to be related to specific alterations in glycolysis.

Amyloid positivity among cognitively intact individuals was correlated with a higher youthful GI index. This finding indicates that the retention of AG in the typically glycolytic regions of the youth brain was coupled with asymptomatic brain amyloid detection.

In the superior frontal, caudal middle frontal, superior parietal, entorhinal, and medial orbitofrontal cortices, the GI index decreased with age. These age-related alterations corresponded to locations with the highest GI among young and healthy persons.

AD status was also linked with significantly decreased GI in the inferior temporal, rostral middle frontal, inferior parietal, middle temporal, precuneus, and lateral orbitofrontal cortices when age and gender were adjusted.

Significant WMH was associated with decreased total gray matter glycolysis among older persons. When controlling for age, gender, and amyloid status, global WMH volumes were significantly related to a lower youthful GI index.

Conclusions

The study findings showed that a preserved/increased youthful pattern of brain AG is related to early asymptomatic pathology of brain amyloid; however, the loss of this trend indicated cognitive impairment in AD patients. WMH was found to be a factor that decreased gray matter AG.

Further investigation into the methods through which AG is maintained or lost in the aged brain could uncover new avenues for enhancing the brain’s resistance to disease.