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Metabolic Mechanisms Underlying Low Circulating Lactate and Pyruvate in Subjects With Alzheimer’s Disease Volume 13 - Issue 4

Manuela Verri*, Roberto Aquilani, Daniela Buonocore and Maurizia Dossena

  • Dipartimento di Biologia e Biotecnologie “Lazzaro Spallanzani”, Università degli Studi di Pavia, Via Ferrata, 9-27100 Pavia (PV), Italy

Received: January 23, 2019;   Published: January 29, 2019

*Corresponding author: Manuela Verri, Dipartimento di Biologia e Biotecnologie “Lazzaro Spallanzani”, Università degli Studi di Pavia, Via Ferrata, 9-27100 Pavia (PV), Italy

DOI: 10.26717/BJSTR.2019.13.002449

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Subjects with Alzheimer’s disease (AD) may have low levels of circulating lactate and pyruvate but normal plasma ketone bodies (KBs, β-hydroxybutyrate and acetoacetate). In this paper, we point out the underlying mechanisms for the above findings. Low lactate and pyruvate may be accounted for by abnormalities in glycolytic and aerobic pathways, such as reduced glycogen store and/or decreased levels of glucose transport, decreased phosphofructokinase activity, and increases in oxidatively modified glycolytic enzymes. The fact that patients had normal levels of KBs suggests that they were not starving and that their dietary intakes were normal. There are potentially two negative practical consequences of these metabolic abnormalities: reduced residual physical performance and lower provision of energy substrates to several organs including the heart.

Keywords: Alzheimer’s Disease; Plasma Lactate; Pyruvate; Ketone Bodies

Abbreviations: AD: Alzheimer’s Disease; β-AP: β-Amyloid Peptide; KBs: Ketone Bodies; TCA: Tricarboxylic Chain Acid


In a recent investigation by our group, subjects with Alzheimer’s disease (AD) exhibited low plasma lactate and pyruvate concentrations, indicating altered skeletal muscle metabolic energy-generating pathways. This was particularly evident in subjects with a longer diagnosis time (> 5 years). However, the plasma concentrations of ketone bodies (KBs, β-hydroxybutyrate and acetoacetate) were normal [1]. In the present article we point out the metabolic mechanisms underlying both the deficit in circulating lactate and pyruvate, and normal KB concentrations. This could potentially be important for clinical practice in the non-pharmacological treatment of the disease.

Potential Mechanisms Underlying Altered Circulating Lactate and Pyruvate Levels

Abnormalities in glucose breakdown both through the glycolytic and aerobic pathways may account for the changes in plasma lactate and pyruvate. With respect to glycolysis, several steps might be interrupted in the muscles of AD subjects. For example, a reduction in myocyte glucose availability may occur following reduced glycogen store, as a consequence of the activation of the enzyme glycogen synthase kinase 3 β [2] in AD patients. This enzyme inhibits the enzyme glycogen synthase which normally catalyses the synthesis of glycogen. Moreover, other potential glycolytic defects may be decreased levels of glucose transport [3], decreased phosphofructokinase activity [4] (which catalyses the irreversible phosphorylation of fructose-6-phosphate to fructose-1,6 bisphosphate), and increases in oxidatively modified glycolytic enzymes including enolase [5] (which catalyses the conversion of 2-phosphoglycerate to phosphoenolpyruvate). These enzyme defects have been described in neurons. However, in the light of the results of our previous study [1], we postulate that they might also be present in the skeletal muscle of the AD patients in our study..

Our hypothesis may be supported by two factors. Firstly, neurons and myocytes produce energy using the same enzyme activities. Secondly, the pathogenic β-AP, which is present in skeletal muscle [6], also exerts its toxicity on the production of pyruvate through glycolysis [7].

The fact that muscle hypometabolism depends on the diagnosis time of the disease suggests that the deterioration of the glycolytic pathway for energy production is progressive. The low plasma pyruvate level in subjects with a longer diagnosis time does not only mean reduced synthesis through glycolysis but also impaired utilisation of an important glucose by-product in mitochondrial reactions for aerobic energy generation. Some of the muscle pyruvate may be transaminated to the gluconeogenic amino acid alanine. We cannot exclude the possibility that impaired energy provision to extramuscular tissues from low pyruvate may be compensated for by partial transformation of the pyruvate into alanine, one of the most important gluconeogenic amino acids. In any case, low plasma pyruvate means reduced liver availability of an important metabolite for energy production and other metabolic processes. Low/blocked mitochondrial utilisation of pyruvate impairs mitochondrial efficiency in energy production. This could be catastrophic for AD subjects, should they have intrinsic mitochondrial defects that have been reported in other body cells such as the dysregulated tricarboxylic chain acid (TCA) cycle [8] and changes in oxidative phosphorylation systems [9]. This has been experimentally demonstrated both in brain and peripheral cells such as fibroblasts [10] and platelets [11].

Plausible Explanations For Normal Circulating KBs

With respect to KBs, the normal plasma concentrations, an expression of a normal liver ketogenesis, may be due to the fact that the AD subjects were not starving and their dietary intakes, including fat ingestion and plasma glucose, were normal. We cannot exclude the possibility that skeletal muscle may partly contribute to normal plasma levels of KBs. Indeed, muscle tissue can synthesise KBs from Acetyl-CoA via direct deacylation [12]. This can occur whenever the release of free fatty acids by adipose tissue is higher than the fatty acid oxidation capacity of the muscle [12].

Potential Implications For Clinical Practice

Altered glucose metabolism might have a negative impact on the efficacy of physical rehabilitation that aims to maximise activities of daily living, function and mobility and reduce peripheral fatigue and the risk of injuries and falls. Moreover, this energy deficit can have unfavourable effects on the performance of physical activities, for example deambulation, in which the integrated metabolic work of vital visceral organs requires prompt adequate extra-energy availability. All these aspects involving the relationship between energy metabolism and complex physical activities of daily living, which have an impact on the quality of life of AD patients, should be investigated further. Another negative effect of altered glucose metabolism may be the impairment of several organs. Low plasma lactate, especially if associated with concomitant low pyruvate, reduces the rate of liver and kidney glucose production (gluconeogenesis). In this condition, the brain and the cells with obligatory anaerobic metabolism (red cells, leukocytes and kidney medulla) receive less glucose. Reduced gluconeogenesis aggravates brain glucose hypometabolism [13], which leads to a progression of synaptic dysfunction [14].

The low levels of lactate in AD patients cause its reduced utilisation as a fuel in the heart, since the myocardium normally uses circulating lactate as an important energy source. One practical consequence of our study [1] is that an adequate nutrition intake by subjects with a longer diagnosis time of AD may not be enough to ensure normal metabolic pathways of glucose breakdown. Consequently, nutrition intakes of AD subjects should be monitored in order to ensure that there is at least adequate peripheral availability of nutrients. Another potential consequence for clinical practice is that AD subjects with muscle hypometabolism may increase muscle amino acid release from protein breakdown to ensure adequate gluconeogenesis processes. This requires a wellplanned investigation.


The previous study [1] and the underlying metabolic alterations pointed out here suggest a need for future investigations to address whether and how to limit altered energy metabolism that could help to improve physical performance in AD subjects.


Verri M. and Aquilani R. contributed equally to this work.


  1. Verri M, Aquilani R, Ricevuti G, Rondanelli M, Ghitti M, et al. (2018) Plasma energy substrates at two stages of Alzheimer’s disease in humans. Int J Immunopathol Pharmacol 32: 1-7.
  2. Terracciano C, Nogalska A, Engel WK, Askanas V (2010) In AbetaPPoverexpressing cultured human muscle fibers proteasome inhibition enhances phosphorylation of AbetaPP751 and GSK3beta activation: effects mitigated by lithium and apparently relevant to sporadic inclusion-body myositis. J Neurochem 112(2): 389-396.
  3. Liu Y, Liu F, Iqbal K, Grundke-Iqbal I, Gong CX (2008) Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease. FEBS Lett 582(2): 359-364.
  4. Bigl M, Apelt J, Eschrich K, Schliebs R (2003) Cortical glucose metabolism is altered in aged transgenic Tg2576 mice that demonstrate Alzheimer plaque pathology. J Neural Transm (Vienna) 110(1): 77-94.
  5. Butterfield DA, Lange ML (2009) Multifunctional roles of enolase in Alzheimer’s disease brain: beyond altered glucose metabolism. J Neurochem 111(4): 915-933.
  6. Kuo YM, Kokjohn TA, Watson MD, Woods AS, Cotter RJ, et al. (2000) Elevated abeta42 in skeletal muscle of Alzheimer disease patients suggests peripheral alterations of AbetaPP metabolism. Am J Pathol 156(3): 797-805.
  7. Pereira C, Santos MS, Oliveira C (1999) Involvement of oxidative stress on the impairment of energy metabolism induced by A beta peptides on PC12 cells: protection by antioxidants. Neurobiol Dis 6(3): 209-219.
  8. Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE (2005) Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol 57 (5): 695-703.
  9. Moreira PI, Cardoso SM, Pereira CM, Santos MS, Oliveira CR (2009) Mitochondria as a therapeutic target in Alzheimer’s disease and diabetes. CNS Neurol Disord Drug Targets 8 (6): 492-511.
  10. Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, et al. (2002) Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer’s disease. Neurobiol Aging 23(3): 371-376.
  11. Cardoso SM, Proença MT, Santos S, Santana I, Oliveira CR (2004) Cytochrome c oxidase is decreased in Alzheimer’s disease platelets. Neurobiol Aging 25(1): 105-110.
  12. Scofield RF, Schumann WC, Kumaran K, Landau BR (1983) Ketone body production in diabetic ketosis by other than liver. Metabolism 32(10): 1009-1012.
  13. Mosconi L, Pupi A, De Leon MJ (2008) Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci 1147: 180-195.
  14. Mosconi L, De Santi S, Li J, Tsui WH, Li Y, et al. (2008) Hippocampal hypometabolism predicts cognitive decline from normal aging. Neurobiol Aging 29(5): 676-692.