Sex differences in Alzheimer’s disease: metabolic reprogramming and therapeutic intervention
Authors: Lloyd A. Demetrius, Anne Eckert, Amandine Grimm
Journal: Trends in Endocrinology and Metabolism (2021)

The Amyloid Cascade Hypothesis has dominated the studies on the etiology of AD over the past 30 years Therapeutic interventions that this model involves have consistently failed until now.Age and gender are the two most salient risk factors for the origin and progression of sporadic AD. The effect of these two factors on the incidence of AD derives from age-related mitochondrial alterations and the hormonal changes affecting postmenopausal women.The MR Theory is a bioenergetic model of metabolic regulation in neurons and astrocytes during aging. It postulates that AD is the result of age-related bioenergetic dysregulation. The theory furnishes an understanding of certain phenomena that appear intractable in the conceptual framework of the Amyloid Cascade Hypothesis: the long prodromal phase of AD and the rapid transition to the pathological state. Studies on the sporadic form of Alzheimer's disease (AD) have revealed three classes of risk factor: age, genetics, and sex. These risk factors point to a metabolic dysregulation as the origin of AD. Adaptive alterations in cerebral metabolism are the rationale for the Metabolic Reprogramming (MR) Theory of the origin of AD. The theory contends that the progression toward AD involves three adaptive events: a hypermetabolic phase, a prolonged prodromal phase, and a metabolic collapse. This article exploits the MR Theory to elucidate the effect of hormonal changes on the origin and progression of AD in women. The theory invokes bioenergetic signatures of the menopausal transition to propose sex-specific diagnostic program and therapeutic strategies. Studies on the sporadic form of Alzheimer's disease (AD) have revealed three classes of risk factor: age, genetics, and sex. These risk factors point to a metabolic dysregulation as the origin of AD. Adaptive alterations in cerebral metabolism are the rationale for the Metabolic Reprogramming (MR) Theory of the origin of AD. The theory contends that the progression toward AD involves three adaptive events: a hypermetabolic phase, a prolonged prodromal phase, and a metabolic collapse. This article exploits the MR Theory to elucidate the effect of hormonal changes on the origin and progression of AD in women. The theory invokes bioenergetic signatures of the menopausal transition to propose sex-specific diagnostic program and therapeutic strategies. The sporadic form of AD is a neurodegenerative disorder with a multifactorial pathogenesis. Epidemiological and clinical studies have documented two classes of molecular signature that are identified with the disease: (i) bioenergetic: the critical features of this marker are metabolic defects and bioenergetic dysfunction in mitochondria, the energy-producing organelles. These abnormalities inhibit neuronal energy production and induce neuronal loss; and (ii) biochemical: the specific features of this class of signatures are misfolded proteins. These include the amyloid-β (Aβ) deposits that are the result of defective aggregation of the product of amyloid precursor protein (APP) processing, and the various intra- and extracellular neurofibrillary tangles characterized by the abnormally hyperphosphorylated tau protein. Epidemiological studies show that the biochemical signatures often contradict the clinical observations (reviewed in [1.Chételat G. et al.Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer's disease.NeuroImage Clin. 2013; 2: 356-365Crossref PubMed Scopus (229) Google Scholar]). Individuals with a high amyloid load are often cognitively intact and display no clinical manifestations of dementia [2.Nelson P.T. et al.Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature.J. Neuropathol. Exp. Neurol. 2012; 71: 362-381Crossref PubMed Scopus (1116) Google Scholar]. Consistently, a meta-analysis of antiamyloid drug clinical trials (pooled results from 14 randomized controlled trials) revealed that removal of brain amyloid plaques does not improve the cognitive functions of patients with AD [3.Ackley S.F. et al.Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis.BMJ. 2021; 372: n156Crossref PubMed Scopus (48) Google Scholar]. By sharp contrast, bioenergetic markers are highly correlated with the origin and progression of the disease (Figure 1) [4.Butterfield D.A. Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease.Nat. Rev. Neurosci. 2019; 20: 148-160Crossref PubMed Scopus (480) Google Scholar]. The support for a bioenergetics origin is further indicated by the correlation between reproductive history, hormonal changes, and the risk of AD in women [5.Gilsanz P. et al.Reproductive period and risk of dementia in a diverse cohort of health care members.Neurology. 2019; 92: e2005-e2014Crossref PubMed Scopus (38) Google Scholar]. These observations point to a disease origin with a critical metabolic component. The MR Theory [6.Demetrius L.A. et al.Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect.Front. Physiol. 2014; 5: 522PubMed Google Scholar,7.Demetrius L.A. Simon D.K. An inverse-Warburg effect and the origin of Alzheimer's disease.Biogerontology. 2012; 13: 583-594Crossref PubMed Scopus (58) Google Scholar,99.Demetrius L.A. Driver J. Alzheimer's as a metabolic disease.Biogerontology. 2013; : 641-649Crossref PubMed Scopus (71) Google Scholar], an analytic model of AD, derives from the study of the three main risk factors associated with the disease. These factors fall into three categories: (i) age: the disease has an average age of onset ~70 years. Moreover, the incidence of the disease increases exponentially with higher age; (ii) genetics: the incidence of the apolipoprotein ε4 (APOE4) allele. AD risk is increased threefold in APOE ε3/ε4 carriers, and 15-fold in APOE ε4/ε4 carriers [8.Sims R. et al.The multiplex model of the genetics of Alzheimer's disease.Nat. Neurosci. 2020; 23: 311-322Crossref PubMed Scopus (107) Google Scholar]; (iii) sex: the incidence of women among AD patients is two-thirds. The main risk factor which has been identified is the decline in sex-steroid hormones in post-menopausal women [9.Grimm A. et al.Alzheimer, mitochondria and gender.Neurosci. Biobehav. Rev. 2016; 67: 89-101Crossref PubMed Scopus (61) Google Scholar]. These three risk factors implicate metabolic dysregulation and bioenergetic deficits as critical elements in the etiology of the disease [9.Grimm A. et al.Alzheimer, mitochondria and gender.Neurosci. Biobehav. Rev. 2016; 67: 89-101Crossref PubMed Scopus (61) Google Scholar, 10.Grimm A. Eckert A. Brain aging and neurodegeneration: from a mitochondrial point of view.J. Neurochem. 2017; 143: 418-431Crossref PubMed Scopus (235) Google Scholar, 11.Yamazaki Y. et al.Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies.Nat. Rev. Neurol. 2019; 15: 501-518Crossref PubMed Scopus (292) Google Scholar]. In this article, we discuss the theoretical basis and empirical support for the MR Theory. We then exploit the theory to address two fundamental issues regarding the origin and progression of AD in women: (i) the formulation of AD diagnostic criteria based on metabolic changes in neurons due to the endocrine transition occurring at the menopause; and (ii) the development of therapeutic strategies to prevent the disease or to reduce its severity. The MR Theory is a bioenergetics model of metabolic regulation in neurons and astrocytes during the aging process (detailed explanation of the model reviewed in [6.Demetrius L.A. et al.Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect.Front. Physiol. 2014; 5: 522PubMed Google Scholar,7.Demetrius L.A. Simon D.K. An inverse-Warburg effect and the origin of Alzheimer's disease.Biogerontology. 2012; 13: 583-594Crossref PubMed Scopus (58) Google Scholar]). The theory is based on two fundamental properties of biological processes: energy and age. Energy is the prime determinant of neuronal viability. Defects in energy metabolism may lead to neuronal degeneration. Age is the decisive arbiter of the efficiency of energy production. Aging is associated with a decline in the activity of enzymes involved in metabolic regulation [10.Grimm A. Eckert A. Brain aging and neurodegeneration: from a mitochondrial point of view.J. Neurochem. 2017; 143: 418-431Crossref PubMed Scopus (235) Google Scholar]. The MR Theory is based on the effect of the process of aging on the interaction between two cell types: neurons, whose metabolism is driven by oxidative phosphorylation (OxPhos), and astrocytes, whose metabolic activity is determined primarily by glycolysis. Both cell types use glucose as an energy source. In astrocytes, a significant portion of the glucose is metabolized aerobically to lactate, which is released into the extracellular milieu. In neurons, glucose-derived and lactate-derived pyruvate are metabolized aerobically. The model proposes that, when some of the mitochondria in neurons become dysregulated during aging, the associated increased demand for energy is achieved by the action of two mechanisms: (i) the inverse Warburg effect (Box 1): the upregulation of OxPhos activity in some mitochondria of cortical neuronal cells. This mode of metabolic alteration is a compensatory action to maintain adequate production of energy and thereby mitigate the deficit induced by the age-related mitochondrial dysregulation; and (ii) the Warburg effect: the upregulation of glycolysis in the astrocytes, which are the nourishing cells in the brain. This process increases the activity of the astrocytic cells and, thus, enhances the production of lactate, which ensures an adequate energy source for the neurons.Box 1Inverse Warburg effect and Alzheimer's diseaseTheoretical basisOxPhos and glycolysis are the two modes of energy production in cells. The first is an electrical process the rate of which depends on the conductance of the mitochondrial membrane. The second is a chemical process the rate of which depends on the activity of the glycolytic enzymes. OxPhos generates up to 36 molecules of ATP upon complete oxidation of molecules of glucose, whereas glycolysis generates only two ATP molecules per molecule of glucose. The impairment of OxPhos due to the process of aging, for example, has a critical effect on the cellular metabolism. In non-neuronal cells, this effect elicits a compensatory shift to glycolysis. This shift from an electrical mode of energy production to a chemical mode is called the Warburg effect, for which empirical support is now well documented [69.Vander Heiden M.G. et al.Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (9348) Google Scholar]. The Warburg effect is also observed in stressed astrocytes that provide the energy source for neurons [70.Bouzier-Sore A.-K. Pellerin L. Unraveling the complex metabolic nature of astrocytes.Front. Cell. Neurosci. 2013; 7: 179Crossref PubMed Scopus (103) Google Scholar]. In contrast to cancer cells, neurons rely almost exclusively on OxPhos to generate the energy needed for cellular processes. Neurons, similar to differentiated postmitotic cells, are subject to continuous stress. These insults may be the result of mutations in the genes that regulate mitochondrial activity [10.Grimm A. Eckert A. Brain aging and neurodegeneration: from a mitochondrial point of view.J. Neurochem. 2017; 143: 418-431Crossref PubMed Scopus (235) Google Scholar]. We have proposed that, during aging, several mitochondria in certain neurons will become abnormally hypermetabolic, while a certain number will remain intact [7.Demetrius L.A. Simon D.K. An inverse-Warburg effect and the origin of Alzheimer's disease.Biogerontology. 2012; 13: 583-594Crossref PubMed Scopus (58) Google Scholar]. This is described by an increase in the metabolic activity of the neurons with an up-regulation in OxPhos: the inverse Warburg effect (Figure I).Empirical supportEvidence for the inverse Warburg effect has been documented in both patients with AD and AD animal models. Indeed, several independent studies highlighted a correlation between increased OxPhos and increased oxidative damages (see also Table 1 in the main text). Hypermetabolism detected in very early AD stages [23.Ashraf A. et al.Cortical hypermetabolism in MCI subjects: a compensatory mechanism?.Eur. J. Nucl. Med. Mol. Imaging. 2014; 42: 447-458Crossref PubMed Scopus (65) Google Scholar, 24.Blazhenets G. et al.Principal components analysis of brain metabolism predicts development of Alzheimer dementia.J. Nucl. Med. 2019; 60: 837-843Crossref PubMed Scopus (17) Google Scholar, 25.Cohen A.D. et al.Basal cerebral metabolism may modulate the cognitive effects of Aβ in mild cognitive impairment: an example of brain reserve.J. Neurosci. 2009; 29: 14770-14778Crossref PubMed Scopus (187) Google Scholar, 26.Willette A.A. et al.Insulin resistance predicts medial temporal hypermetabolism in mild cognitive impairment conversion to Alzheimer disease.Diabetes. 2015; 64: 1933-1940Crossref PubMed Scopus (72) Google Scholar,71.Haier R.J. et al.Temporal cortex hypermetabolism in Down syndrome prior to the onset of dementia.Neurology. 2003; 61: 1673-1679Crossref PubMed Scopus (55) Google Scholar] is likely linked to this increased OxPhos and may be a compensatory mechanism to sustain the higher energy needs of affected neurons.BiomarkerThe inverse Warburg effect (hypermetabolism in pre-AD brains) may be used as a marker for the early diagnosis of AD. Indeed, the three phases (hypermetabolism, stable metabolic phase, and hypometabolism) represent bioenergetic adaptations to age-related metabolic deregulation. The magnitude of changes in the hypermetabolic phase provides a measure of individual vulnerability to the disease. Hence, the inverse Warburg effect constitutes a bioenergetic marker for the later development of AD. Theoretical basis OxPhos and glycolysis are the two modes of energy production in cells. The first is an electrical process the rate of which depends on the conductance of the mitochondrial membrane. The second is a chemical process the rate of which depends on the activity of the glycolytic enzymes. OxPhos generates up to 36 molecules of ATP upon complete oxidation of molecules of glucose, whereas glycolysis generates only two ATP molecules per molecule of glucose. The impairment of OxPhos due to the process of aging, for example, has a critical effect on the cellular metabolism. In non-neuronal cells, this effect elicits a compensatory shift to glycolysis. This shift from an electrical mode of energy production to a chemical mode is called the Warburg effect, for which empirical support is now well documented [69.Vander Heiden M.G. et al.Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (9348) Google Scholar]. The Warburg effect is also observed in stressed astrocytes that provide the energy source for neurons [70.Bouzier-Sore A.-K. Pellerin L. Unraveling the complex metabolic nature of astrocytes.Front. Cell. Neurosci. 2013; 7: 179Crossref PubMed Scopus (103) Google Scholar]. In contrast to cancer cells, neurons rely almost exclusively on OxPhos to generate the energy needed for cellular processes. Neurons, similar to differentiated postmitotic cells, are subject to continuous stress. These insults may be the result of mutations in the genes that regulate mitochondrial activity [10.Grimm A. Eckert A. Brain aging and neurodegeneration: from a mitochondrial point of view.J. Neurochem. 2017; 143: 418-431Crossref PubMed Scopus (235) Google Scholar]. We have proposed that, during aging, several mitochondria in certain neurons will become abnormally hypermetabolic, while a certain number will remain intact [7.Demetrius L.A. Simon D.K. An inverse-Warburg effect and the origin of Alzheimer's disease.Biogerontology. 2012; 13: 583-594Crossref PubMed Scopus (58) Google Scholar]. This is described by an increase in the metabolic activity of the neurons with an up-regulation in OxPhos: the inverse Warburg effect (Figure I). Empirical support Evidence for the inverse Warburg effect has been documented in both patients with AD and AD animal models. Indeed, several independent studies highlighted a correlation between increased OxPhos and increased oxidative damages (see also Table 1 in the main text). Hypermetabolism detected in very early AD stages [23.Ashraf A. et al.Cortical hypermetabolism in MCI subjects: a compensatory mechanism?.Eur. J. Nucl. Med. Mol. Imaging. 2014; 42: 447-458Crossref PubMed Scopus (65) Google Scholar, 24.Blazhenets G. et al.Principal components analysis of brain metabolism predicts development of Alzheimer dementia.J. Nucl. Med. 2019; 60: 837-843Crossref PubMed Scopus (17) Google Scholar, 25.Cohen A.D. et al.Basal cerebral metabolism may modulate the cognitive effects of Aβ in mild cognitive impairment: an example of brain reserve.J. Neurosci. 2009; 29: 14770-14778Crossref PubMed Scopus (187) Google Scholar, 26.Willette A.A. et al.Insulin resistance predicts medial temporal hypermetabolism in mild cognitive impairment conversion to Alzheimer disease.Diabetes. 2015; 64: 1933-1940Crossref PubMed Scopus (72) Google Scholar,71.Haier R.J. et al.Temporal cortex hypermetabolism in Down syndrome prior to the onset of dementia.Neurology. 2003; 61: 1673-1679Crossref PubMed Scopus (55) Google Scholar] is likely linked to this increased OxPhos and may be a compensatory mechanism to sustain the higher energy needs of affected neurons. Biomarker The inverse Warburg effect (hypermetabolism in pre-AD brains) may be used as a marker for the early diagnosis of AD. Indeed, the three phases (hypermetabolism, stable metabolic phase, and hypometabolism) represent bioenergetic adaptations to age-related metabolic deregulation. The magnitude of changes in the hypermetabolic phase provides a measure of individual vulnerability to the disease. Hence, the inverse Warburg effect constitutes a bioenergetic marker for the later development of AD. The outcome of this metabolic reprogramming in neurons and astrocytes is the production of two types of neuronal population: Type 1: cells, primarily cortical neurons, with high OxPhos activity. Their mitochondrial population will be highly heterogeneous, with a few being hypermetabolic, and the large majority intact; and Type 2: cells with normal OxPhos activity. Their mitochondria will be relatively intact. The competition between these two types of neuron for the lactate generated by the astrocytes will result in the development of three distinct phases of metabolic activity in the neuronal population (Figure 2, Key figure): (i) a hypermetabolic phase, localized in the cortical regions; (ii) a metabolic homeostasis, quasi-equilibrium defined by the presence of neurons with upregulated OxPhos activity (Type 1) and neurons with standard OxPhos activity (Type 2); and (iii) a metabolic collapse, the rapid spread of metabolic abnormalities due to a change in the neuronal environment and the concomitant selective advantage of hypermetabolic neurons. Evidence of an inverse Warburg effect and hypermetabolism in AD animal models and patients with AD is summarized in Table 1. Indeed, an upregulation of genes involved in OxPhos, including subunits of the mitochondrial complexes I, III, IV, and V, was observed in the brain of AD transgenic mice (Tg2579 and PS1-A246E mutant mice) before the appearance of Aβ pathology and before AD-related cognitive deficits were observed [12.Reddy P.H. et al.Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease.Hum. Mol. Genet. 2004; 13: 1225-1240Crossref PubMed Scopus (257) Google Scholar,13.Strazielle C. et al.Regional brain metabolism with cytochrome c oxidase histochemistry in a PS1/A246E mouse model of autosomal dominant Alzheimer's disease: correlations with behavior and oxidative stress.Neurochem. Int. 2009; 55: 806-814Crossref PubMed Scopus (30) Google Scholar]. Mitochondrial abnormalities were associated with an increase in 8-hydroxyguanosine (8-OHG) level, a marker of oxidative damage [12.Reddy P.H. et al.Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease.Hum. Mol. Genet. 2004; 13: 1225-1240Crossref PubMed Scopus (257) Google Scholar,13.Strazielle C. et al.Regional brain metabolism with cytochrome c oxidase histochemistry in a PS1/A246E mouse model of autosomal dominant Alzheimer's disease: correlations with behavior and oxidative stress.Neurochem. Int. 2009; 55: 806-814Crossref PubMed Scopus (30) Google Scholar]. Strikingly, an increase in brain glucose uptake was also detected in different AD mouse models (Tg2579, APP/PS1, 5xTgAD, 3xTgAD) at early stages of the pathology [14.Luo F. et al.Characterization of 7- and 19-month-old Tg2576 mice using multimodal in vivo imaging: limitations as a translatable model of Alzheimer's disease.Neurobiol. Aging. 2012; 33: 933-944Crossref PubMed Scopus (60) Google Scholar, 15.Lebenberg J. et al.Automated indexation of metabolic changes in Alzheimer's mice using a voxel-wise approach combined to an MRI-based 3D digital atlas.2010: 5636-5639Google Scholar, 16.Poisnel G. et al.Increased regional cerebral glucose uptake in an APP/PS1 model of Alzheimer's disease.Neurobiol. Aging. 2012; 33: 1995-2005Crossref PubMed Scopus (84) Google Scholar, 17.Rojas S. et al.In vivo evaluation of amyloid deposition and brain glucose metabolism of 5XFAD mice using positron emission tomography.Neurobiol. Aging. 2013; 34: 1790-1798Crossref PubMed Scopus (54) Google Scholar, 18.Sancheti H. et al.Hypermetabolic state in the 7-month-old triple transgenic mouse model of Alzheimer's disease and the effect of lipoic acid: a 13C-NMR study.J. Cereb. Blood Flow Metab. 2014; 34: 1749-1760Crossref PubMed Scopus (28) Google Scholar].Table 1Evidence for an inverse Warburg effect and hypermetabolism in AD mouse models and patients with ADaAbbreviations: 2DG, 2-deoxyglucose; COX, cytochrome c oxidase (complex IV); FDG-PET, [18F] fluorodeoxyglucose positron emission tomography; hiPSC, human induced pluripotent stem cells; NMR, nuclear magnetic resonance; MRI, magnetic resonance imaging; n.i., not investigated; WT, wild-type.Animal model/humanMethodOrgan/tissue analyzedMain resultsRefsAnimal dataTg2576cDNA microarray techniques, northern blot, in situ hybridizationHippocampus (granule cells, pyramidal neurons), cerebral cortexUpregulation of genes involved in mitochondrial energy metabolism and apoptosis in 2-, 5-, and 18-month-old Tg2576 animal compared with WT[12.Reddy P.H. et al.Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease.Hum. Mol. Genet. 2004; 13: 1225-1240Crossref PubMed Scopus (257) Google Scholar]Brain glucose metabolism assessment using FDG-PETHippocampus, perirhinal cortex, entorhinal cortex, striatum, thalamus, cerebral cortexIncrease of glucose uptake in 7-month-old Tg2576 animals compared with WT[14.Luo F. et al.Characterization of 7- and 19-month-old Tg2576 mice using multimodal in vivo imaging: limitations as a translatable model of Alzheimer's disease.Neurobiol. Aging. 2012; 33: 933-944Crossref PubMed Scopus (60) Google Scholar]PS1-A246E mutant miceMeasure of COX activity in brainCortical area, striatum, forebrain cholinergic areas, limbic regions, thalamus, brainstemIncrease of COX activity in 12-month-old Tg animals compared with WT[13.Strazielle C. et al.Regional brain metabolism with cytochrome c oxidase histochemistry in a PS1/A246E mouse model of autosomal dominant Alzheimer's disease: correlations with behavior and oxidative stress.Neurochem. Int. 2009; 55: 806-814Crossref PubMed Scopus (30) Google Scholar]APP/PS1 miceBrain glucose metabolism assessment using FDG-PETCortex, hippocampus, striatumIncrease of glucose uptake in 6- and 12-month-old APP/PS1 animals compared with WT[16.Poisnel G. et al.Increased regional cerebral glucose uptake in an APP/PS1 model of Alzheimer's disease.Neurobiol. Aging. 2012; 33: 1995-2005Crossref PubMed Scopus (84) Google Scholar]Assessment of 2DG uptake in brain (voxel-wise approach using MRI-based digital atlas)Amygdala, anterior commissure, corpus callosum, cortex, hippocampus, olfactive bulb, striatumHigher glucose uptake in APP/PS1 mice than in PS1 mice[15.Lebenberg J. et al.Automated indexation of metabolic changes in Alzheimer's mice using a voxel-wise approach combined to an MRI-based 3D digital atlas.2010: 5636-5639Google Scholar]3xTgADAssessment of metabolic rate (O2 consumption, CO2 production, respiratory quotient) using calorimetry over 4 daysn.i. (global metabolic rate)Increase of metabolic rate and food intake in 12-month-old 3xTgAD mice despite weight loss compared with WT[90.Knight E.M. et al.Hypermetabolism in a triple-transgenic mouse model of Alzheimer's disease.Neurobiol. Aging. 2012; 33: 187-193Crossref PubMed Scopus (36) Google Scholar]Assessment of neuronal and astrocytic metabolism by intravenous infusion of [1-13C] glucose + [1,2-13C] acetate followed by 13C NMRWhole-brain analysis, neurons, astrocytesHypermetabolic state detected in both neurons and astrocytes of 7-month-old 3×TgAD mice compared with WT (increase in absolute levels of different 13C metabolites)[18.Sancheti H. et al.Hypermetabolic state in the 7-month-old triple transgenic mouse model of Alzheimer's disease and the effect of lipoic acid: a 13C-NMR study.J. Cereb. Blood Flow Metab. 2014; 34: 1749-1760Crossref PubMed Scopus (28) Google Scholar]5xTgADBrain glucose metabolism assessment using FDG-PETWhole-brain analysisIncrease in glucose uptake in 10-month-old 5xTgAD animals compared with WT[17.Rojas S. et al.In vivo evaluation of amyloid deposition and brain glucose metabolism of 5XFAD mice using positron emission tomography.Neurobiol. Aging. 2013; 34: 1790-1798Crossref PubMed Scopus (54) Google Scholar]Human dataSubjects with Down syndrome (DS) [N = 13, 35.4 years (range:0–65 years)]Patients with sporadic AD (N = 19, 76.6 years (range: 61.6–89.8 years)Old patients without dementia (N = 6, 74.3 years (range: 61.6–81.8 years)Postmortem brain immunohistochemistry for COX I and IV expressionHippocampusIncreased expression of COX I and IV in patients with DS or AD in nontangle-bearing neurons[19.Nagy Z. et al.Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology.Acta Neuropathol. 1999; 97: 346-354Crossref PubMed Scopus (75) Google Scholar]Patients with early AD (N = 6, 67–96 years)Diagnosed AD (N = 6, 69–82 years)Normal control subjects (N = 6, 68–90 years)Postmortem brain analysis (RT-qPCR and immunohistochemistry) of mitochondrial complex expressionFrontal cortexDownregulation of mitochondrial genes in complex I in both early and definite AD brains, but upregulation of complexes IV and V compared with control brains[22.Manczak M. et al.Differential Expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage.NeuroMolecular Med. 2004; 5: 147-162Crossref PubMed Scopus (286) Google Scholar]Patients with AD (N = 27, 57–93 years)Normal control subjects (N = 12, 54–85 years)In situ hybridization for analysis of mitochondrial DNA (mtDNA)Immunocytochemistry for COX I expressionHippocampusIncreased levels of mtDNA and COX I, but decreased number of total mitochondria per neuron in AD brains compared with age-matched control brains[20.Hirai K. et al.Mitochondrial abnormalities in Alzheimer's disease.J. Neurosci. 2001; 21: 3017-3023Crossref PubMed Google Scholar,21.Zhu X. et al.Mitochondrial abnormalities and oxidative imbalance in Alzheimer disease.J. Alzheimers Dis. 2006; 9: 147-153Crossref PubMed Scopus (143) Google Scholar]Patients with AD (N = 10, 79.9 ± 9 years)Normal control subjects (N = 9, 61.8 ± 15 years)Postmortem brain analysis of mitochondrial complex expressionWhole hippocampus and hippocampal pyramidal neuronsUpregulation of OxPhos genes (complexes I–IV) in whole hippocampus of patients with AD compared with controls, but downregulation of these genes in pyramidal neurons[91.Rice A.C. et al.Postmortem Alzheimer's disease hippocampi show oxidative phosphorylation gene expression opposite that of isolated pyramidal neurons.J. Alzheimers Dis. 2015; 45: 1051-1059Crossref PubMed Scopus (9) Google Scholar]hiPSCs derived from patients with AD (N = 5)Control subjects-derived IPSCs (n = 2)Gene expression analysis (OxPhos genes) in hiPSC-derived neuronshiPSC-derived neuronsUpregulation of OxPhos genes (complexes I, III, IV) in hiPSCs derived from patients with AD compared with controls[28.Birnbaum J.H. et al.Oxidative stress and altered mitochondrial protein expression in the absence of amyloid-β and tau pathology in iPSC-derived neurons from sporadic Alzheimer's disease patients.Stem Cell Res. 2018; 27: 121-130Crossref PubMed Scopus (75) Google Scholar]Middle-aged patients without dementia but with DS (N = 17, 41.4 ± 5.6 years)Patients with moderate AD (N = 10, 76.0 ± 6.7 years)Age-matched control subjects (N = 24)Glucose metabolic rate (GMR) determination using FDG-PETMultiple areas of inferior temporal cortex (including area of entorhinal cortex)GMR higher in DS group compared with matched controls; GMR lower in patients with AD compared with matched controls[71.Haier R.J. et al.Temporal cortex hypermetabolism in Down syndrome prior to the onset of dementia.Neurolog