Summary: Researchers report that enhancing the brain’s ability to convert glucose into usable energy may reduce risk factors and delay the onset of Alzheimer’s disease in people who carry high-risk genes.
Source: SfN
The strongest genetic risk factor for Alzheimer’s disease may interfere with the brain’s ability to turn its primary fuel into usable energy, according to a study in female mice published in the Journal of Neuroscience. The findings suggest that therapies aimed at improving brain energy conversion in carriers of the risk gene could lower risk or postpone disease onset.
Human apolipoprotein E (ApoE) exists in three common isoforms. About 20 percent of people produce ApoE4, which raises the risk of developing Alzheimer’s disease; the more rare ApoE2 is associated with apparent protection, while ApoE3 is the most common isoform and considered neutral with respect to Alzheimer’s risk.
In this study, Liqin Zhao and colleagues examined how the three human ApoE isoforms—ApoE2, ApoE3 and ApoE4—affect key biochemical pathways that convert glucose and ketone bodies into cellular energy. Using female mice genetically engineered to express each human ApoE variant, the researchers measured expression and activity of genes and enzymes involved in glucose transport, glycolysis, mitochondrial respiration and ketone body utilization. Their results reveal distinct differences in how brains with each ApoE isoform manage energy, providing a potential explanation for their varying impacts on Alzheimer’s disease risk.
Key findings:
- Brains expressing ApoE4 showed deficiencies in using glucose, the brain’s primary fuel. These deficiencies were linked to lower expression and activity of facilitated glucose transporters and hexokinases—the gateway enzymes that begin glucose metabolism.
- ApoE2-expressing brains displayed the most robust profile for glucose uptake and metabolism, consistent with the protective association of ApoE2 against Alzheimer’s disease.
- For ketone body uptake and metabolism—the brain’s secondary energy source—ApoE2 and ApoE4 brains were similarly robust, while ApoE3 brains were relatively deficient.
- Pathway analysis implicated the PPAR-γ/PGC-1α signaling pathway: it appeared activated in ApoE2 brains and inhibited in ApoE4 brains. Increasing PGC-1α expression improved glycolysis and mitochondrial respiration in ApoE4 tissue, suggesting a targetable mechanism.
These findings indicate that hexokinase activity in the cytosol is a critical point where ApoE genotypes differentially influence glucose metabolism. Reduced hexokinase function in ApoE4 carriers may underlie impaired brain glucose utilization and increased vulnerability to Alzheimer’s disease. Conversely, the energetic resilience observed in ApoE2 brains may help protect against disease development.
Therapeutic implications
The study suggests several possible strategies to reduce risk or delay symptoms in people with high-risk ApoE genotypes. Approaches that boost cytosolic glucose metabolism—such as supplying glucose-metabolizing intermediates like pyruvate—or that activate the PPAR-γ/PGC-1α pathway could help restore energy balance in ApoE4 carriers. The fact that ApoE4 brains can compensate by using ketone bodies highlights the potential of metabolic interventions, including dietary or pharmacological strategies that increase ketone availability, to support brain energy needs and preserve synaptic function.
By improving bioenergetic capacity, such interventions could enhance synaptic activity and resilience, potentially lowering the likelihood of developing Alzheimer’s disease or delaying the clinical onset of symptoms.
Funding and source
Funding for this research was provided by the NIH/National Institute on Aging, the NIH/National Institute of General Medical Sciences, and the University of Kansas. Source: David Barnstone, SfN. Publisher: NeuroscienceNews.com. Original research: Long Wu, Xin Zhang and Liqin Zhao, “Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer’s Disease Risk Reduction and Early Intervention,” Journal of Neuroscience. doi: 10.1523/JNEUROSCI.2262-17.2018
Abstract (summary)
The three human ApoE isoforms—ApoE2, ApoE3 and ApoE4—differentially affect brain energy metabolism, an early and significant disturbance in preclinical Alzheimer’s disease. In female human ApoE gene-targeted replacement mice, expression profiles of 43 genes involved in glucose and ketone body transport and metabolism revealed that ApoE2 brains exhibit the most robust glucose metabolism, while ApoE4 brains show the greatest deficits in glucose uptake and processing. Differences were most notable in facilitated glucose transporters and hexokinases. For ketone body metabolism, ApoE2 and ApoE4 brains were similarly robust, with ApoE3 showing relative deficiency. Pathway analysis suggested divergent regulation of the PPAR-γ/PGC-1α pathway across isoforms; overexpressing PGC-1α alleviated ApoE4-associated deficits in glycolysis and mitochondrial respiration. These results support the idea that ApoE isoforms modulate brain bioenergetics in ways that likely contribute to their distinct impacts on Alzheimer’s disease risk.
Significance statement
Hexokinase emerges as a central cytosolic regulator of glucose metabolism that is differentially affected by ApoE genotype. Addressing cytosolic glucose metabolic deficits—potentially by providing metabolite intermediates such as pyruvate or by targeting PGC-1α signaling—may offer therapeutic benefit for ApoE4 carriers and help reduce Alzheimer’s disease risk or delay its clinical onset.