Download PDF
Review  |  Open Access  |  5 May 2024

Re-energising the brain: glucose metabolism, Tau protein and memory in ageing and dementia

Views: 198 |  Downloads: 21 |  Cited:   0
Ageing Neur Dis 2024;4:7.
10.20517/and.2023.57 |  © The Author(s) 2024.
Author Information
Article Notes
Cite This Article


Memory naturally declines as we age, but the rapid loss of memory can be distressing for people living with Alzheimer’s disease (AD). How memories are formed and retrieved in the brain is not fully understood; it is thought to require plasticity to the synapses connecting neurons in a network of engram cells. Plasticity may occur either through changes to the volume and location of molecules and organelles within the synapse, or gross structural changes of synapses. Memory naturally declines as we age, as do many of the mechanisms required for learning and memory, such as changes in concentrations of the cytoskeletal structural protein Microtubule-Associated Protein Tau, reduced brain glucose metabolism, and sensitivities to insulin. The biggest risk factor for developing AD is ageing, yet only few studies try to reconcile the natural decline in functions we see with ageing with the dramatic impairment of these pathways in AD, such as Tau protein and energy homeostasis by neurons. This review will therefore explain the changes to metabolism, Tau protein, and memory impairment during ageing, and explore the latest research that links these processes to neurodegeneration seen in AD, and other Tauopathies. Understanding how ageing and dementia diverge may offer an important and underutilised avenue for therapeutic interventions to target metabolism in both “healthy” ageing and disease.


Alzheimer’s disease, Tau, ageing, metabolism, memory, glucose, lifestyle


Ageing is the strongest risk factor for dementia[1,2]. Episodic memory and many cognitive functions are known to decline progressively with ageing. Alzheimer’s disease (AD)-related cognitive decline occurs more rapidly from a critical age than in healthy ageing, whereas vascular dementia, primarily associated with major stroke, causes a rapid then steady decline[3]. Numerous processes are known to be affected by ageing, including glucose metabolism, insulin resistance[4], inflammation (termed “Inflammageing”)[5], protein translation[6,7], and protein concentrations such as that of AD-associated microtubule-associated protein Tau (Tau)[8,9].

As commonly quoted, despite accounting for 2% of body mass, the brain requires ~20% of the energy generated through oxidative metabolism[10]. Most of this energy is accounted for in regions of highly active neurons through synaptic function and restoration of neuronal membrane potentials[11]. Memory and problem-solving are therefore energetically expensive brain functions as they require temporally and spatially specific patterns of neuronal activity.

To understand how metabolism links to cognitive functions, it is important to know the pathways that neurons can use for energy. Neurons can perform the metabolism of glucose through mitochondrial oxidative phosphorylation (OXPHOS) or cytosolic aerobic glycolysis (nonoxidative metabolism of glucose despite the presence of abundant oxygen). OXPHOS is the most efficient pathway for producing energy in the form of 36 ATP, as compared to 2 ATP in aerobic glycolysis. A disadvantage of OXPHOS is associated with the free radical hypothesis, which suggests that reactive oxygen species from OXPHOS damage biomolecules and cause ageing[12,13]. Aerobic glycolysis has been shown to occur in neuronal somata to provide the energy required for neurons to function at rest or during neuronal activity, despite oxygen being available for OXPHOS[14,15]. Glycolysis is known to be required during high energy expenditure, such as long-term memory formation[16,17]. Traditionally, aerobic glycolysis was seen to compensate for the limited ATP production by rapid glucose metabolism. However, more recently, it is thought to produce metabolites for the building blocks of biosynthesis required for differentiation, and growth such as synaptic plasticity[18-20]. Neurovascular coupling allows neurons to control the vasodilation of blood vessels to maintain oxygen and glucose requirements. However, the limit of blood supply to the brain means that glucose stored as glycogen can also be metabolised for energy. Due to the storage of glycogen in astrocytes, the astrocyte-neuron lactate shuttle has been hypothesised. In response to glucose sensing, astrocytes can upregulate glycolysis into lactate, which can be shuttled from astrocytes to neurons. The use of this lactate is unknown, but it has been suggested to be metabolised through OXPHOS[21]. However, astrocytes also perform aerobic glycolysis, which is stimulated by glucose and glutamate uptake into astrocytes; this mechanism directly couples neuronal activity to aerobic glycolysis[22,23]. In addition, when blood glucose level is low, such as during intense exercise, fasting, or diabetes, ketone bodies can be metabolised for energy. Although controversial, “ketogenic diets” have been suggested for multiple neurological disorders and epilepsy, in particular to mimic fasting and reduce neuronal activity and lactate concentrations[24-26].

One hypothesis is that mitochondrial impairment may shift energy consumption from oxidative phosphorylation towards glycolysis or ketolysis[27]. Mitochondrial impairment, through numerous mechanisms, has been linked to many neurodegenerative conditions (for Review[28]). However, the shift towards aerobic glycolysis can be a cell proliferation process, or can occur in cancer in the presence of healthy mitochondria[29,30]. It therefore raises the question of how might alterations in energy metabolism influence memory impairment and pathology seen in neurodegeneration. This review will address two main aspects. First, it will delve into how metabolism may alter the function and homeostasis of Tau, a protein required for cytoskeletal structure[31], which has more recently been shown to bind with synaptic vesicles, mitochondria, and ribosomes[32]. In Taopathies such as AD and frontotemporal dementia, Tau forms pathological aggregates. Thus, understanding the links between metabolism and the physiological or pathological roles of Tau holds important therapeutic potential. Secondly, it will explore how metabolism and its influence on Tau protein can feed back to memory impairment. This review will therefore focus on how links established in the first aspect between metabolism and Tau could trigger the memory impairments observed in Tauopathies.


It has been debated whether Tau pathology causes metabolic deficits or metabolism can directly influence Tau pathology. During ageing, there is a progressive hypometabolism of glucose in the brain. Even greater glucose hypometabolism in the hippocampus can predict the progression to late-onset AD and mild cognitive impairment (MCI) compared with age-related cognitive impairment[33,34]. AD is characterised by decreased cortical[35] and hippocampal[33] glucose metabolism that is thought to reflect reduced synaptic activity[36]. Reduced cerebral glucose metabolism is also seen in young cognitively normal carriers of the late-onset genetic risk factor for AD, Apolipoprotein Ε4 (ApoE4). ApoE4 also exacerbates Tau-mediated pathology[37,38]. Figure 1 shows the relationship between glucose consumption and cognitive function with age; Tau Cerebrospinal fluid (CSF) concentration is superimposed[3,33,39,40]. In several studies, glucose hypometabolism follows a similar anatomical progression to the Braak stages of AD, and Tau pathology seen in Progressive Supranuclear Palsy and Corticobasal Degeneration[41-43]. However, it is noted that variations in the age of disease onset may have caused discrepancies between studies[44-47]. Furthermore, Tau pathology and glucose hypometabolism were shown to correlate with cognitive decline[48]. No correlation exists between amyloid-β pathology and cognitive impairments[49].

Re-energising the brain: glucose metabolism, Tau protein and memory in ageing and dementia

Figure 1. Glucose hypometabolism (purple; left axis) in the hippocampus has been shown to correlate with cognitive impairment (blue line; right axis) and can predict mild cognitive impairment and late-onset AD from age-related cognitive decline. Tau CSF concentration in AD is superimposed (dark blue) and has anatomical similarities to glucose hypometabolism, both of which can predict cognitive decline[3,33,39,40]. AG: Aerobic glycolysis; AD: Alzheimer’s disease; CSF: cerebrospinal fluid.

There is a direct link between glucose hypometabolism, or ischemia, and Tau pathology [Figure 2]. Glucose deprivation activates the environmental stress and inflammation sensing protein P38 mitogen-activated protein kinase (p38 MAPK), which phosphorylates Tau protein and can lead to hyperphosphorylation, loss of synaptic integrity, and ultimately cell apoptosis[50-53]. Agonists targeting a protein downstream of p38MAPK, Proliferator-activated receptor (PPAR)-δ/γ , are being investigated, but the efficacy cannot be determined as the recent phase 2 clinical trial was underpowered[54]. Reduced PPARδ and increased p-p38 MAPK were shown in rats with obesity, metabolic syndrome, and tissue hypertrophy, whereas increased PPAR activation can stimulate mitochondrial biogenesis and respiration[55,56].

Re-energising the brain: glucose metabolism, Tau protein and memory in ageing and dementia

Figure 2. A direct link between environmental stress, such as low glucose availability, and Tau is known to occur through the AMPK/p38MAPK pathway[50,53]. This pathway has been targeted for therapeutics for use in AD[54]. AMPK: AMP-activated protein kinase; p38MAPK: P38 mitogen-activated protein kinase; PPAR: p38MAPK, Proliferator-activated receptor; MSK1/2: mitogen- and stress-activated protein kinase; CREB: cAMP response element-binding protein; ER81: Ets transcription factor; AD: Alzheimer’s disease.


Different models of metabolic deficiency exist to explain protein pathology and memory impairment in AD. Models often refer to damaged mitochondria, or an imbalance between metabolism pathways due to limited oxygen supply. Models related to OXPHOS and aerobic glycolysis will be discussed.

Tau and OXPHOS

Numerous physical links between Tau and mitochondria have been made. Mutant Tau has been shown to impair mitochondrial axonal transport in AD mouse models and human induced pluripotent stem cells (iPSCs)[57,58]; human Tau (hTau) expression impairs mitochondrion fusion and fission in Drosophila and mouse neurons, and hTau mice[59,60]; hTau or mutant Tau reduces mitochondrial quality control through mitophagy in N2a cells and C. elegans neurons[61]; and mutant Tau directly reduces the mitochondrial membrane potential required for ATP-synthesis in triple transgenic mice[62], or iPSC-derived neurons from people with Tau mutation causing frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)[63].

The “inverse-Warburg effect” refers to a model based on the upregulation of glycolysis in the presence of oxygen (aerobic glycolysis) that occurs in cancer cells, known as the Warburg effect[29,64]. It is in part based on a negative correlation between the prevalence of cancer and AD[65,66]. However, the model suggests that upregulation of OXPHOS in neurons with impaired mitochondria to maintain adequate ATP levels leads to increased reactive oxygen species (ROS) and pathological ageing[64]. Mitochondrial impairment could occur from numerous factors including pathological proteins such as Tau, toxins, calorie surplus[67], or lipid metabolites[68]. In support of the model, although controversial, multiple studies suggest antioxidants, which reduce ROS, can have beneficial effects on Tau pathology and cognitive behavioural symptoms[69,70]. Antioxidant treatment increases lifespan and reduces hyperphosphorylated Tau, mitochondrial dysfunction, and oxidative stress induced in superoxide dismutase 2 knockout (SOD-/-) mice[71]. Conversely, OXPHOS downregulation has also been shown to occur in AD, with differences between OXPHOS gene regulation in MCI and AD, suggesting there may be changes to mitochondrial function as AD progresses[72-74].

ApoE4, required for forming complexes with lipids including cholesterol, is the strongest risk factor for late onset AD. ApoE4 reduces OXPHOS and increases aerobic glycolysis in astrocytes. ApoE4 causes lysosomal autophagic dysfunction, leading to damaged and high-ROS mitochondria accumulating in neurons[75].

It is therefore possible that any changes to OXPHOS regulation are not due to impaired mitochondria but instead to compensate for impaired aerobic glycolysis.

Tau and aerobic glycolysis

Whether aerobic glycolysis may be advantageous or detrimental to AD and Tau pathology is unclear. Lactate, a product of aerobic glycolysis, is known to be required for long-term memory and can potentiate NMDA receptor-mediated currents and induce transcription of synaptic plasticity-associated genes[16,76]. Lactate was also shown to be beneficial for memory function during normal ageing. However, increased lactate in APP/PS1 mice may indicate that impaired lactate processing pathways may contribute to cognitive decline in AD[77].

A shift from OXPHOS to aerobic glycolysis can be neuroprotective, leading to increased dendrite and axon growth in AD models[78], whereas reduced aerobic glycolysis has been linked to increased Tau deposition in preclinical AD[79]. In particular, glucagon-like peptide 1 (GLP-1), which shifts metabolism from OXPHOS to aerobic glycolysis, has been shown to increase cell viability during ischemia and hypoxia[80].

Increased aerobic glycolysis and impaired oxygen consumption occur in the brains of ApoE4 carriers[81-83]. This “Warburg like” endophenotype was shown to occur in young female ApoE4 carriers decades before AD symptom onset. Additionally, young female ApoE4 carriers showed decreases in resting energy expenditure and oxygen consumption, which was exaggerated following a dietary glucose challenge[81].

Aerobic glycolysis, which is associated with growth and development, gradually decreases with age, whereas mitochondrial OXPHOS remains relatively constant [Figure 1]. It is therefore possible that aged and impaired mitochondria in ApoE4 astrocytes could cause dramatic dysfunction later in life when the transition of metabolism in the brain shifts from aerobic glycolysis to OXPHOS.


Current therapeutics for AD do not target metabolism as a primary pathway, even though many lifestyle factors known to reduce the risk of AD inherently alter metabolism, such as diet and exercise.


Exercise has been stated to reduce the risk, and improve symptoms of AD through improved blood flow, lactate production, and Brain-derived neurotrophic factor (BDNF) secretion[84]. In one study, “moderate” physical activity, but not “light” or “vigorous” physical activity, was shown to upregulate cerebral glucose metabolism in adults at risk for AD[85]. However, other studies have found the benefits of high-intensity interval training in ameliorating AD-like pathology through the regulation of astrocytes[86]. Another study linked low-volume intense interval exercise to AMPK and p38 MAPK signalling, and increased expression of PPARγ activator protein[87,88]. Whether aerobic or anaerobic/high-intensity interval training offers overlapping of different protective effects against AD remains unclear. However, although clear links between exercise and reduced cognitive decline have been shown, the connection between exercise and protein pathology in humans is less clear[89]. In rodent AD models, exercise has also been shown to ameliorate Tau hyperphosphorylation, oxidative damage, and cognition[90,91]. Tau phosphorylation also occurs due to obesity. For instance, a 20-week high-fat diet in wild-type rats caused abnormal Tau phosphorylation in the cortex and hippocampus. However, this aberration was mitigated and memory performance concurrently improved after 8 weeks of exercise[92]. Some studies suggest that longer and/or higher-intensity exercise is more efficient in reducing Tau levels[93,94].

Ketone body metabolism

Diet is another lifestyle factor that has been linked to AD. Intermittent fasting and caloric restriction, ketogenic diets, and Mediterranean diets (MedDiets) have been studied with varying results. Fasting and ketogenic diets cause ketone bodies to be metabolised in place of glucose. Although ketone body metabolism has been shown to improve memory in MCI and promote brain health[95-97], studies have suggested that this is dependent on ApoE genotype. Ketogenic agents were shown to improve cognition in ApoE3 but not ApoE4 carriers[98,99]. In a AD mouse model, a ketone ester diet was shown to alleviate psychiatric and cognitive symptoms, as well as reduce hyperphosphorylated Tau[100], or restore exploratory behaviour[101]. It has been suggested that ketone body metabolism can compensate for dysfunctional glucose metabolism, but ketone metabolism requires functional mitochondria and may be impacted as mitochondrial damage progresses[25].

Mediterranean diet

The MedDiet has been suggested to reduce cognitive decline and risk of AD[102,103]. Numerous factors within this diet contribute to these benefits, such as antioxidants and cereals[104]. A recent study has shown the benefits of the MedDiet, specifically noting that green leafy vegetables were linked to a reduction in AD pathology, whereas higher consumption of fried and fast foods was associated with increased Tau pathology[105]. The importance of the MedDiet is underscored by its ability to decrease the risk of dementia, independent of genetic predisposition[103]. Although MedDiets are associated with lower postmortem AD pathology, this effect primarily pertains to β-amyloid load[105].

Lactate and pyruvate

Furthermore, the question arises as to whether lactate or pyruvate could be used as a therapeutic intervention. The “lactate shuttle” hypothesis has changed our perception of lactate as a waste molecule to a signalling molecule. Although thus far, ROS produced from OXPHOS have been associated with free radicals causing ageing, another hypothesis suggests that lactate causes ROS bursts that are important for signalling survival pathways and ER chaperones[106]. Lactate has therefore been discussed as a potential therapeutic avenue, and as the molecule responsible for the neuroprotective effects of exercise[107]. Some studies showed decreased CSF lactate in AD[108,109], whereas other studies suggest increased CSF lactate[110-112] or no change[113]. Liguori et al. (2015) found a negative correlation between CSF lactate and CSF Tau, with higher CSF lactate levels in mild compared to moderate-severe AD. They proposed a model in which Tau induces mitochondrial dysfunction, followed by impaired glycolytic metabolism. As Tau pathology advances in more severe AD cases, the increase in CSF lactate becomes less pronounced due to the greater impact on metabolism[112]. Similarly, Bonomi et al. (2021) identified a negative correlation between CSF lactate and Tau in AD, and suggested that low CSF lactate was “the advent” of Tau pathology[108]. Furthermore, elevated CSF lactate and cerebral Tau have been shown to co-occur following aneurysmal subarachnoid haemorrhage and are predictors of metabolic distress and poor long-term cognitive outcomes[114].

Pyruvate upregulation has also been suggested as a therapeutic avenue for dementia[115]. However, research outcomes regarding pyruvate levels in individuals with AD have been mixed, with some studies reporting increases[110,116] while others indicating decreases[117,118] in CSF. Systemic administration of pyruvate, but not lactate, has been demonstrated to mitigate ROS-induced pathology and improve spatial memory in a rat model of AD[119]. Conversely, in an AD mouse model, systemic pyruvate administration was found to increase glycogen stores and enhance spatial memory, yet it resulted in impaired performance in a passive avoidance task associated with fear memory. These paradoxical effects were attributed to pyruvate-induced heightened explorative behaviour[120]. Notably, pyruvate treatment has not exhibited reductions in Tau pathology, although there are limited studies investigating this relationship in AD[121] and investigating the differences observed in CSF lactate and pyruvate concentrations between several different studies.


This review has highlighted the importance of metabolism, and the changes to metabolism that occur inherently with ageing, and how these may exacerbate cognitive decline seen in dementia. Brain activity, particularly the activity-dependent functions required for learning and memory, functions at the limits of energy available to the brain both in terms of oxygen and glucose. Therefore, any perturbations, including damage to oxygen supply, genetics that decrease metabolic rate, or mitochondrial damage, can easily tip the balance into an energy deficit. Alongside the factors discussed in this review, gender is an important consideration in the onset of dementia. AD is known to be more prevalent in females; the reasons for this are unknown but may be due to hormones, or as has been suggested, women live longer but tend to be less physically active than men[122]. In addition, stress has been shown to cause divergent pathologies in the brains of male and female mice; furthermore, stress exerts a direct effect on metabolism, potentially to the extent that it can precipitate “stress-induced diabetes”[123,124].

This review has discussed how balances between OXPHOS and anaerobic glycolysis may impair normal brain function, but it provides limited discussion on ischemia. Ischemia is an important consideration as oxygen supply will determine the metabolic resources available during intensive neuronal activity. Tau protein is also known to be altered during ischemia events, such as stroke or cardiac arrest[125,126].

Metabolism and Tau pathology mutually influence the function of each other through the p38 MAPK pathway[50] and through the ability of Tau to alter mitochondria directly[57,61,62]. As such clear links are present between metabolism, cognitive dysfunction, and Tau pathology, OXPHOS and aerobic glycolysis are currently undervalued therapeutic avenues that could offer impactful treatment options for targeting Tau and amyloid-beta pathology alone. Metabolomics of dementia patients has been shown to reveal differences in disease-linked metabolites but has yet to be fully leveraged for diagnostic or treatment purposes[127-129].


Authors’ contributions

The author contributed solely to the article.

Availability of data and materials

Not applicable.

Financial support and sponsorship

This work was supported by the MRC Laboratory of Molecular Biology.

Conflicts of interest

The author declared that there are no conflicts of interest.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.


© The Author(s) 2024.


1. Daviglus ML, Bell CC, Berrettini W, et al. National Institutes of Health State-of-the-Science Conference statement: preventing alzheimer disease and cognitive decline. Ann Intern Med 2010;153:176-81.

2. Arvanitakis Z. The need to better understand aging and risk factors for dementia. Front Dement 2024;2:1346281.

3. Clouston SAP, Richmond LL, Scott SB, et al. Pattern recognition to objectively differentiate the etiology of cognitive decline: analysis of the impact of stroke and Alzheimer’s disease. Neuroepidemiology 2020;54:446-53.

4. Chang AM, Halter JB. Aging and insulin secretion. Am J Physiol Endocrinol Metab 2003;284:E7-12.

5. Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol 2018;15:505-22.

6. Webster GC, Webster SL. Decreased protein synthesis by microsomes from aging Drosophila melanogaster. Exp Gerontol 1979;14:343-8.

7. Ekstrom R, Liu DS, Richardson A. Changes in brain protein synthesis during the life span of male Fischer rats. Gerontology 1980;26:121-8.

8. Mukaetova-Ladinska EB, Harrington CR, Roth M, Wischik CM. Alterations in tau protein metabolism during normal aging. Dementia 1996;7:95-103.

9. Chiu MJ, Fan LY, Chen TF, Chen YF, Chieh JJ, Horng HE. Plasma tau levels in cognitively normal middle-aged and older adults. Front Aging Neurosci 2017;9:51.

10. Mink JW, Blumenschine RJ, Adams DB. Ratio of central nervous system to body metabolism in vertebrates: its constancy and functional basis. Am J Physiol 1981;241:R203-12.

11. Harris JJ, Jolivet R, Attwell D. Synaptic energy use and supply. Neuron 2012;75:762-77.

12. Harman D. Aging: a theory based on free radical and radiation chemistry. Sci Aging Knowl Environ 2002;2002:cp14.

13. Anik MI, Mahmud N, Masud AA, et al. Role of reactive oxygen species in aging and age-related diseases: a review. ACS Appl Bio Mater 2022;5:4028-54.

14. Wei Y, Miao Q, Zhang Q, et al. Aerobic glycolysis is the predominant means of glucose metabolism in neuronal somata, which protects against oxidative damage. Nat Neurosci 2023;26:2081-9.

15. Vaishnavi SN, Vlassenko AG, Rundle MM, Snyder AZ, Mintun MA, Raichle ME. Regional aerobic glycolysis in the human brain. Proc Natl Acad Sci U S A 2010;107:17757-62.

16. Descalzi G, Gao V, Steinman MQ, Suzuki A, Alberini CM. Lactate from astrocytes fuels learning-induced mRNA translation in excitatory and inhibitory neurons. Commun Biol 2019;2:247.

17. Brown AM, Ransom BR. Astrocyte glycogen as an emergency fuel under conditions of glucose deprivation or intense neural activity. Metab Brain Dis 2015;30:233-9.

18. Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009;324:1029-33.

19. Shannon BJ, Vaishnavi SN, Vlassenko AG, Shimony JS, Rutlin J, Raichle ME. Brain aerobic glycolysis and motor adaptation learning. Proc Natl Acad Sci U S A 2016;113:e3782-91.

20. Li D, Ding Z, Gui M, Hou Y, Xie K. Metabolic enhancement of glycolysis and mitochondrial respiration are essential for neuronal differentiation. Cell Reprogram 2020;22:291-9.

21. Goyal MS, Hawrylycz M, Miller JA, Snyder AZ, Raichle ME. Aerobic glycolysis in the human brain is associated with development and neotenous gene expression. Cell Metab 2014;19:49-57.

22. Pellerin L, Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A 1994;91:10625-9.

23. Horvat A, Muhič M, Smolič T, et al. Ca2+ as the prime trigger of aerobic glycolysis in astrocytes. Cell Calcium 2021;95:102368.

24. Ma W, Berg J, Yellen G. Ketogenic diet metabolites reduce firing in central neurons by opening K(ATP) channels. J Neurosci 2007;27:3618-25.

25. Ramezani M, Fernando M, Eslick S, et al. Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer’s disease. Front Neurosci 2023;17:1297984.

26. Ma S, Suzuki K. Keto-adaptation and endurance exercise capacity, fatigue recovery, and exercise-induced muscle and organ damage prevention: a narrative review. Sports 2019;7:40.

27. Klosinski LP, Yao J, Yin F, et al. White matter lipids as a ketogenic fuel supply in aging female brain: implications for Alzheimer’s disease. EBioMedicine 2015;2:1888-904.

28. Vodičková A, Koren SA, Wojtovich AP. Site-specific mitochondrial dysfunction in neurodegeneration. Mitochondrion 2022;64:1-18.

29. Warburg O. On the origin of cancer cells. Science 1956;123:309-14.

30. DeBerardinis RJ, Chandel NS. We need to talk about the Warburg effect. Nat Metab 2020;2:127-9.

31. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A 1975;72:1858-62.

32. Tracy TE, Madero-Pérez J, Swaney DL, et al. Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell 2022;185:712-28.e14.

33. Mosconi L, De Santi S, Li J, et al. Hippocampal hypometabolism predicts cognitive decline from normal aging. Neurobiol Aging 2008;29:676-92.

34. Hammond TC, Xing X, Wang C, et al. β-amyloid and tau drive early Alzheimer’s disease decline while glucose hypometabolism drives late decline. Commun Biol 2020;3:352.

35. Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 1997;42:85-94.

36. Rocher AB, Chapon F, Blaizot X, Baron JC, Chavoix C. Resting-state brain glucose utilization as measured by PET is directly related to regional synaptophysin levels: a study in baboons. Neuroimage 2003;20:1894-8.

37. Farfel JM, Yu L, De Jager PL, Schneider JA, Bennett DA. Association of APOE with tau-tangle pathology with and without β-amyloid. Neurobiol Aging 2016;37:19-25.

38. Shi Y, Yamada K, Liddelow SA, et al; Alzheimer’s Disease Neuroimaging Initiative. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 2017;549:523-7.

39. Goyal MS, Vlassenko AG, Blazey TM, et al. Loss of brain aerobic glycolysis in normal human aging. Cell Metab 2017;26:353-60.e3.

40. Petersen RC. Alzheimer’s disease: progress in prediction. Lancet Neurol 2010;9:4-5.

41. Dukart J, Mueller K, Villringer A, et al; Alzheimer’s Disease Neuroimaging Initiative. Relationship between imaging biomarkers, age, progression and symptom severity in Alzheimer’s disease. Neuroimage Clin 2013;3:84-94.

42. Beyer L, Meyer-Wilmes J, Schönecker S, et al. Clinical routine FDG-PET imaging of suspected progressive supranuclear palsy and corticobasal degeneration: a gatekeeper for subsequent tau-PET imaging? Front Neurol 2018;9:483.

43. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239-59.

44. Tahmasian M, Pasquini L, Scherr M, et al. The lower hippocampus global connectivity, the higher its local metabolism in Alzheimer disease. Neurology 2015;84:1956-63.

45. Apostolova I, Lange C, Mäurer A, et al; Alzheimer’s Disease Neuroimaging Initiative. Hypermetabolism in the hippocampal formation of cognitively impaired patients indicates detrimental maladaptation. Neurobiol Aging 2018;65:41-50.

46. Choi EJ, Son YD, Noh Y, Lee H, Kim YB, Park KH. Glucose hypometabolism in hippocampal subdivisions in Alzheimer’s disease: a pilot study using high-resolution 18F-FDG PET and 7.0-T MRI. J Clin Neurol 2018;14:158-64.

47. Chen Y, Wang J, Cui C, et al. Evaluating the association between brain atrophy, hypometabolism, and cognitive decline in Alzheimer’s disease: a PET/MRI study. Aging 2021;13:7228-46.

48. Baghel V, Tripathi M, Parida G, et al. In vivo assessment of tau deposition in Alzheimer disease and assessing its relationship to regional brain glucose metabolism and cognition. Clin Nucl Med 2019;44:e597-601.

49. Ackley SF, Zimmerman SC, Brenowitz WD, et al. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ 2021;372:n156.

50. Lauretti E, Praticò D. Glucose deprivation increases tau phosphorylation via P38 mitogen-activated protein kinase. Aging Cell 2015;14:1067-74.

51. Maphis N, Jiang S, Xu G, et al. Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology. Alzheimers Res Ther 2016;8:54.

52. Son SH, Lee NR, Gee MS, et al. Chemical knockdown of phosphorylated p38 mitogen-activated protein kinase (MAPK) as a novel approach for the treatment of Alzheimer’s disease. ACS Cent Sci 2023;9:417-26.

53. Coulthard LR, White DE, Jones DL, McDermott MF, Burchill SA. p38(MAPK): stress responses from molecular mechanisms to therapeutics. Trends Mol Med 2009;15:369-79.

54. Search results. Showing results for: T3D-959. Available from: [Last accessed on 30 Apr 2024].

55. Yan Z, Ni Y, Wang P, et al. Peroxisome proliferator-activated receptor delta protects against obesity-related glomerulopathy through the P38 MAPK pathway. Obesity 2013;21:538-45.

56. Fan M, Rhee J, St-Pierre J, et al. Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1alpha: modulation by p38 MAPK. Genes Dev 2004;18:278-89.

57. Combs B, Mueller RL, Morfini G, Brady ST, Kanaan NM. Tau and axonal transport misregulation in tauopathies. Adv Exp Med Biol 2019;1184:81-95.

58. Sabui A, Biswas M, Somvanshi PR, et al. Decreased anterograde transport coupled with sustained retrograde transport contributes to reduced axonal mitochondrial density in tauopathy neurons. Front Mol Neurosci 2022;15:927195.

59. DuBoff B, Götz J, Feany MB. Tau promotes neurodegeneration via DRP1 mislocalization in vivo. Neuron 2012;75:618-32.

60. Li XC, Hu Y, Wang ZH, et al. Human wild-type full-length tau accumulation disrupts mitochondrial dynamics and the functions via increasing mitofusins. Sci Rep 2016;6:24756.

61. Cummins N, Tweedie A, Zuryn S, Bertran-Gonzalez J, Götz J. Disease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria. EMBO J 2019;38:e99360.

62. Rhein V, Song X, Wiesner A, et al. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci U S A 2009;106:20057-62.

63. Esteras N, Rohrer JD, Hardy J, Wray S, Abramov AY. Mitochondrial hyperpolarization in iPSC-derived neurons from patients of FTDP-17 with 10+16 MAPT mutation leads to oxidative stress and neurodegeneration. Redox Biol 2017;12:410-22.

64. Demetrius LA, Simon DK. An inverse-Warburg effect and the origin of Alzheimer’s disease. Biogerontology 2012;13:583-94.

65. Harris RA, Tindale L, Cumming RC. Age-dependent metabolic dysregulation in cancer and Alzheimer’s disease. Biogerontology 2014;15:559-77.

66. Zhang X, Wu L, Swerdlow RH, Zhao L. Opposing effects of ApoE2 and ApoE4 on glycolytic metabolism in neuronal aging supports a warburg neuroprotective cascade against Alzheimer’s disease. Cells 2023;12:410.

67. Fisher-Wellman KH, Neufer PD. Linking mitochondrial bioenergetics to insulin resistance via redox biology. Trends Endocrinol Metab 2012;23:142-53.

68. Bonen A, Parolin ML, Steinberg GR, et al. Triacylglycerol accumulation in human obesity and type 2 diabetes is associated with increased rates of skeletal muscle fatty acid transport and increased sarcolemmal FAT/CD36. FASEB J 2004;18:1144-6.

69. Van der Jeugd A, Parra-Damas A, Baeta-Corral R, et al. Reversal of memory and neuropsychiatric symptoms and reduced tau pathology by selenium in 3xTg-AD mice. Sci Rep 2018;8:6431.

70. Wu, Zhe Ying, Gomez-Pinilla F. Vitamin E protects against oxidative damage and learning disability after mild traumatic brain injury in rats. Neurorehabil Neural Repair 2010;24:290-8.

71. Melov S, Adlard PA, Morten K, et al. Mitochondrial oxidative stress causes hyperphosphorylation of tau. PLoS One 2007;2:e536.

72. Chandrasekaran K, Hatanpää K, Brady DR, Rapoport SI. Evidence for physiological down-regulation of brain oxidative phosphorylation in Alzheimer’s disease. Exp Neurol 1996;142:80-8.

73. Manczak M, Park BS, Jung Y, Reddy PH. Differential expression of oxidative phosphorylation genes in patients with Alzheimer’s disease: implications for early mitochondrial dysfunction and oxidative damage. Neuromolecular Med 2004;5:147-62.

74. Mahapatra G, Gao Z, Bateman JR 3rd, et al. Blood-based bioenergetic profiling reveals differences in mitochondrial function associated with cognitive performance and Alzheimer’s disease. Alzheimers Dement 2023;19:1466-78.

75. Lee H, Cho S, Kim MJ, et al. ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes. Cell Rep 2023;42:113183.

76. Yang J, Ruchti E, Petit JM, et al. Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons. Proc Natl Acad Sci U S A 2014;111:12228-33.

77. Harris RA, Tindale L, Lone A, et al. Aerobic glycolysis in the frontal cortex correlates with memory performance in wild-type mice but not the APP/PS1 mouse model of cerebral amyloidosis. J Neurosci 2016;36:1871-8.

78. Zheng J, Xie Y, Ren L, et al. GLP-1 improves the supportive ability of astrocytes to neurons by promoting aerobic glycolysis in Alzheimer’s disease. Mol Metab 2021;47:101180.

79. Vlassenko AG, Gordon BA, Goyal MS, et al. Aerobic glycolysis and tau deposition in preclinical Alzheimer’s disease. Neurobiol Aging 2018;67:95-8.

80. Siraj MA, Mundil D, Beca S, et al. Cardioprotective GLP-1 metabolite prevents ischemic cardiac injury by inhibiting mitochondrial trifunctional protein-α. J Clin Invest 2020;130:1392-404.

81. Farmer BC, Williams HC, Devanney NA, et al. APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis. Mol Neurodegener 2021;16:62.

82. Cho S, Lee H, Seo J. Impact of genetic risk factors for Alzheimer’s disease on brain glucose metabolism. Mol Neurobiol 2021;58:2608-19.

83. Ercoli L, Siddarth P, Huang SC, et al. Perceived loss of memory ability and cerebral metabolic decline in persons with the apolipoprotein E-IV genetic risk for Alzheimer disease. Arch Gen Psychiatry 2006;63:442-8.

84. Grimm A. Impairments in brain bioenergetics in aging and Tau pathology: a chicken and egg situation? Cells 2021;10:2531.

85. Dougherty RJ, Schultz SA, Kirby TK, et al. Moderate physical activity is associated with cerebral glucose metabolism in adults at risk for Alzheimer’s disease. J Alzheimers Dis 2017;58:1089-97.

86. Feng S, Wu C, Zou P, et al. High-intensity interval training ameliorates Alzheimer’s disease-like pathology by regulating astrocyte phenotype-associated AQP4 polarization. Theranostics 2023;13:3434-50.

87. Gibala MJ, McGee SL, Garnham AP, Howlett KF, Snow RJ, Hargreaves M. Brief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1alpha in human skeletal muscle. J Appl Physiol 2009;106:929-34.

88. Gurd BJ, Menezes ES, Arhen BB, Islam H. Impacts of altered exercise volume, intensity, and duration on the activation of AMPK and CaMKII and increases in PGC-1α mRNA. Semin Cell Dev Biol 2023;143:17-27.

89. Frederiksen KS, Gjerum L, Waldemar G, Hasselbalch SG. Physical activity as a moderator of Alzheimer pathology: a systematic review of observational studies. Curr Alzheimer Res 2019;16:362-78.

90. Liu Y, Chu JMT, Yan T, et al. Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer’s disease mice. J Neuroinflammation 2020;17:4.

91. Wu C, Yang L, Tucker D, et al. Beneficial effects of exercise pretreatment in a sporadic Alzheimer’s rat model. Med Sci Sports Exerc 2018;50:945-56.

92. Jeong JH, Koo JH, Cho JY, Kang EB. Neuroprotective effect of treadmill exercise against blunted brain insulin signaling, NADPH oxidase, and Tau hyperphosphorylation in rats fed a high-fat diet. Brain Res Bull 2018;142:374-83.

93. Brown BM, Rainey-Smith SR, Dore V, et al. Self-reported physical activity is associated with Tau burden measured by positron emission tomography. J Alzheimers Dis 2018;63:1299-305.

94. Brown BM, Peiffer J, Rainey-Smith SR. Exploring the relationship between physical activity, beta-amyloid and tau: a narrative review. Ageing Res Rev 2019;50:9-18.

95. Pietrzak D, Kasperek K, Rękawek P, Piątkowska-Chmiel I. The therapeutic role of ketogenic diet in neurological disorders. Nutrients 2022;14:1952.

96. Lin AL, Zhang W, Gao X, Watts L. Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain. Neurobiol Aging 2015;36:2296-303.

97. Krikorian R, Shidler MD, Dangelo K, Couch SC, Benoit SC, Clegg DJ. Dietary ketosis enhances memory in mild cognitive impairment. Neurobiol Aging 2012;33:425.e19-27.

98. Reger MA, Henderson ST, Hale C, et al. Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging 2004;25:311-4.

99. Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab 2009;6:31.

100. Kashiwaya Y, Bergman C, Lee JH, et al. A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer’s disease. Neurobiol Aging 2013;34:1530-9.

101. Pawlosky RJ, Kashiwaya Y, King MT, Veech RL. A dietary ketone ester normalizes abnormal behavior in a mouse model of Alzheimer’s disease. Int J Mol Sci 2020;21:1044.

102. Limongi F, Siviero P, Bozanic A, Noale M, Veronese N, Maggi S. The effect of adherence to the mediterranean diet on late-life cognitive disorders: a systematic review. J Am Med Dir Assoc 2020;21:1402-9.

103. Shannon OM, Ranson JM, Gregory S, et al. Mediterranean diet adherence is associated with lower dementia risk, independent of genetic predisposition: findings from the UK Biobank prospective cohort study. BMC Med 2023;21:81.

104. Kang J, Jia T, Jiao Z, et al. Increased brain volume from higher cereal and lower coffee intake: shared genetic determinants and impacts on cognition and metabolism. Cereb Cortex 2022;32:5163-74.

105. Agarwal P, Leurgans SE, Agrawal S, et al. Association of mediterranean-DASH intervention for neurodegenerative delay and mediterranean diets with Alzheimer disease pathology. Neurology 2023;100:e2259-68.

106. Tauffenberger A, Fiumelli H, Almustafa S, Magistretti PJ. Lactate and pyruvate promote oxidative stress resistance through hormetic ROS signaling. Cell Death Dis 2019;10:653.

107. Huang Z, Zhang Y, Zhou R, Yang L, Pan H. Lactate as potential mediators for exercise-induced positive effects on neuroplasticity and cerebrovascular plasticity. Front Physiol 2021;12:656455.

108. Bonomi CG, De Lucia V, Mascolo AP, et al. Brain energy metabolism and neurodegeneration: hints from CSF lactate levels in dementias. Neurobiol Aging 2021;105:333-9.

109. Malm J, Kristensen B, Ekstedt J, Adolfsson R, Wester P. CSF monoamine metabolites, cholinesterases and lactate in the adult hydrocephalus syndrome (normal pressure hydrocephalus) related to CSF hydrodynamic parameters. J Neurol Neurosurg Psychiatry 1991;54:252-9.

110. Parnetti L, Gaiti A, Polidori MC, et al. Increased cerebrospinal fluid pyruvate levels in Alzheimer’s disease. Neurosci Lett 1995;199:231-3.

111. Redjems-Bennani N, Jeandel C, Lefebvre E, Blain H, Vidailhet M, Guéant JL. Abnormal substrate levels that depend upon mitochondrial function in cerebrospinal fluid from Alzheimer patients. Gerontology 1998;44:300-4.

112. Liguori C, Stefani A, Sancesario G, Sancesario GM, Marciani MG, Pierantozzi M. CSF lactate levels, τ proteins, cognitive decline: a dynamic relationship in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2015;86:655-9.

113. Zebhauser PT, Berthele A, Goldhardt O, et al. Cerebrospinal fluid lactate levels along the Alzheimer’s disease continuum and associations with blood-brain barrier integrity, age, cognition, and biomarkers. Alzheimers Res Ther 2022;14:61.

114. Helbok R, Schiefecker A, Delazer M, et al. Cerebral tau is elevated after aneurysmal subarachnoid haemorrhage and associated with brain metabolic distress and poor functional and cognitive long-term outcome. J Neurol Neurosurg Psychiatry 2015;86:79-86.

115. Xu D, Vincent A, González-Gutiérrez A, et al. A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer’s disease models. PLoS Genet 2023;19:e1010893.

116. de Geus MB, Leslie SN, Lam T, et al. Mass spectrometry in cerebrospinal fluid uncovers association of glycolysis biomarkers with Alzheimer’s disease in a large clinical sample. Sci Rep 2023;13:22406.

117. Bergau N, Maul S, Rujescu D, Simm A, Navarrete Santos A. Reduction of glycolysis intermediate concentrations in the cerebrospinal fluid of Alzheimer’s disease patients. Front Neurosci 2019;13:871.

118. Nielsen JE, Andreassen T, Gotfredsen CH, et al. Serum metabolic signatures for Alzheimer’s disease reveal alterations in amino acid composition: a validation study. Metabolomics 2024;20:12.

119. Wang X, Hu X, Yang Y, Takata T, Sakurai T. Systemic pyruvate administration markedly reduces neuronal death and cognitive impairment in a rat model of Alzheimer’s disease. Exp Neurol 2015;271:145-54.

120. Koivisto H, Leinonen H, Puurula M, et al. Corrigendum: Chronic pyruvate supplementation increases exploratory activity and brain energy reserves in young and middle-aged mice. Front Aging Neurosci 2017;9:67.

121. Isopi E, Granzotto A, Corona C, et al. Pyruvate prevents the development of age-dependent cognitive deficits in a mouse model of Alzheimer’s disease without reducing amyloid and tau pathology. Neurobiol Dis 2015;81:214-24.

122. Edwards ES, Sackett SC. Psychosocial variables related to why women are less active than men and related health implications. Clin Med Insights Womens Health 2016;9:47-56.

123. Edwards HM, Wallace CE, Gardiner WD, et al. Sex-dependent effects of acute stress on amyloid-β in male and female mice. Brain 2023;146:2268-74.

124. Sharma K, Akre S, Chakole S, Wanjari MB. Stress-induced diabetes: a review. Cureus 2022;14:e29142.

125. Chen X, Jiang H. Tau as a potential therapeutic target for ischemic stroke. Aging 2019;11:12827-43.

126. Randall J, Mörtberg E, Provuncher GK, et al. Tau proteins in serum predict neurological outcome after hypoxic brain injury from cardiac arrest: results of a pilot study. Resuscitation 2013;84:351-6.

127. Jiang Y, Zhu Z, Shi J, et al. Metabolomics in the development and progression of dementia: a systematic review. Front Neurosci 2019;13:343.

128. Zhang X, Hu W, Wang Y, et al. Plasma metabolomic profiles of dementia: a prospective study of 110,655 participants in the UK Biobank. BMC Med 2022;20:252.

129. Teruya T, Chen YJ, Kondoh H, Fukuji Y, Yanagida M. Whole-blood metabolomics of dementia patients reveal classes of disease-linked metabolites. Proc Natl Acad Sci U S A 2021;118:e2022857118.

Cite This Article

Export citation file: BibTeX | RIS

OAE Style

Robbins M. Re-energising the brain: glucose metabolism, Tau protein and memory in ageing and dementia. Ageing Neur Dis 2024;4:7.

AMA Style

Robbins M. Re-energising the brain: glucose metabolism, Tau protein and memory in ageing and dementia. Ageing and Neurodegenerative Diseases. 2024; 4(2): 7.

Chicago/Turabian Style

Miranda Robbins. 2024. "Re-energising the brain: glucose metabolism, Tau protein and memory in ageing and dementia" Ageing and Neurodegenerative Diseases. 4, no.2: 7.

ACS Style

Robbins, M. Re-energising the brain: glucose metabolism, Tau protein and memory in ageing and dementia. Ageing. Neur. Dis. 2024, 4, 7.

About This Article

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (, which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Data & Comments




Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at

Download PDF
Cite This Article 0 clicks
Like This Article 2 likes
Share This Article
Scan the QR code for reading!
See Updates
Ageing and Neurodegenerative Diseases
ISSN 2769-5301 (Online)


All published articles will be preserved here permanently:


All published articles will be preserved here permanently: