List of Contributors xv

1 Current Understanding of Alzheimer’s Disease and Other Neurodegenerative Diseases, and the Potential Role of Diet and Lifestyle in Reducing the Risks of Alzheimer’s Disease and Cognitive Decline 1
Charles S. Brennan, Margaret A. Brennan, W.M.A.D. Binosha Fernando and Ralph N. Martins

References 7

2 Alzheimer’s Disease and Other Neurodegenerative Diseases 9
Stephanie J. Fuller, Hamid R. Sohrabi, Kathryn G. Goozee, Anoop Sankaranarayanan and Ralph N. Martins

2.1 Introduction 9

2.2 Alzheimer’s Disease 9

2.2.1 Pathology 9

2.2.2 Symptoms 10

2.2.3 Incidence 11

2.2.4 Onset and Risk Factors 12

2.2.5 Treatment 12

2.2.6 Potential for AD Prevention 13

2.3 Frontotemporal Lobe Dementia 13

2.3.1 Neuropathology and Causes 14

2.3.2 Treatment 15

2.3.3 Diagnosis and Clinical Overlap with Other Diseases 15

2.4 Vascular Dementia 16

2.4.1 Symptoms and Diagnosis 16

2.4.2 Causes and Risk Factors 16

2.4.3 Prevention and Treatment 17

2.4.4 Dementia with Lewy Bodies 18

2.4.5 Causes 18

2.4.6 Symptoms 18

2.4.7 Diagnosis of DLB 18

2.4.7.1 Clinical Approach to Dementias 19

2.5 Parkinson’s Disease 19

2.5.1 Onset 22

2.5.2 Causes and Risk Factors 22

2.5.3 Incidence 22

2.5.4 Pathology 22

2.5.5 Treatment 23

2.6 Huntington’s Disease 24

2.6.1 Genetics of the Disease 24

2.6.2 Incidence and Prevalence 25

2.6.3 Pathology 25

2.6.4 Treatment 26

2.7 Motor Neuron Diseases 27

2.7.1 Amyotrophic Lateral Sclerosis 27

2.7.2 Spinal Muscular Atrophy 27

2.7.3 Hereditary Spastic Paraplegia 27

2.7.4 Onset of MND and Differential Diagnosis 28

2.7.5 Incidence, Causes, and Risk Factors 28

2.7.6 Pathology 29

2.7.7 Treatment 30

2.8 Prion Diseases 30

2.8.1 Causes 31

2.8.2 Symptoms and Diagnosis 31

2.8.3 Treatment 32

2.8.4 Differential Diagnosis of the Various Types of Dementia 32

2.8.5 DLB Treatment 33

2.9 Summary 33

References 34

3 Current and Developing Methods for Diagnosing Alzheimer’s Disease 43
Stephanie J. Fuller, Nicholas Carrigan, Hamid R. Sohrabi and Ralph N. Martins

3.1 Introduction 43

3.2 Classical Post-Mortem Diagnosis 43

3.2.1 Plaques 44

3.2.2 Neurofibrillary Tangles (NFT) 44

3.2.3 Cerebral Amyloid Angiopathy (CAA) 44

3.2.4 Glial Responses 45

3.2.5 Brain Shrinkage 45

3.2.6 Loss of Synapses and Neurons 45

3.3 Clinical Diagnosis 45

3.3.1 Initial Assessment/Screening Tools 47

3.3.1.1 Mini-Mental State Examination (MMSE) 47

3.3.1.2 Montreal Cognitive Assessment (MoCA) 47

3.3.1.3 Clinical Dementia Rating (CDR) 47

3.3.1.4 Clock Drawing 48

3.3.1.5 Seven-Minute Screen 48

3.3.1.6 Alzheimer’s Disease Assessment Scale (ADAS-Cog) 48

3.3.1.7 Psychogeriatric Assessment Scales (PAS) 48

3.3.1.8 Dementia Rating Scale (DRS) 49

3.3.1.9 Mini-Cog 49

3.3.1.10 Rowland Universal Dementia Assessment Scale (RUDAS) 49

3.3.1.11 The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Neuropsychological Battery (nb) and Other Tests 49

3.4 Brain Imaging in the Diagnosis of Alzheimer’s Disease and Other Dementias 51

3.4.1 Imaging Tests in AD Diagnosis: Established Tests 51

3.4.1.1 Computed Tomography (CT) 51

3.4.1.2 Electroencephalography (EEG) 51

3.4.1.3 Magnetic Resonance Imaging (MRI), for the Assessment of Morphological Changes, and the Detection of Stroke 52

3.4.1.4 Positron Emission Tomography (PET) 52

3.4.1.5 FDG-PET 52

3.4.2 Imaging Tests in AD Diagnosis: More Recently Developed Tests 52

3.4.2.1 MRI for Measuring Regional Blood Flow 53

3.4.2.2 Single Photon Emission Computed Tomography (SPECT) Scan 54

3.4.2.3 PiB-PET 54

3.4.3 The Rapidly Evolving Diagnostic Criteria 55

3.4.4 CSF Biomarkers of AD 56

3.4.4.1 Aβ, Tau, and AβPP-Related Biomarkers 56

3.4.4.2 Other Potential CSF Protein Biomarkers 57

3.4.4.3 Potential Lipid Biomarkers in the CSF 58

3.4.5 Blood Biomarkers of AD 60

3.4.5.1 Aβ Peptides in Plasma 60

3.4.5.2 Other Potential Blood Biomarkers 62

3.4.5.3 Blood Proteins 62

3.4.6 Blood Lipids 64

3.4.7 Metabolites 65

3.4.8 Blood Platelets 66

3.4.9 Genetic Risk Factors 67

3.4.10 The Eye as a Window to the Brain 68

3.4.11 miRNA Tests 69

3.5 Conclusions 71

References 72

4 The Link Between Diabetes, Glucose Control, and Alzheimer’s Disease and Neurodegenerative Diseases 89
Giuseppe Verdile, Paul E. Fraser and Ralph N.Martins

4.1 Introduction 89

4.2 The Impact of Type 2 Diabetes on the Brain 90

4.3 Evidence from Cell Culture, Animal, and Clinical Studies 93

4.3.1 CNS Insulin Signalling and Disruptions in AD 93

4.3.2 The Accumulation of Aβ Is Associated with Impaired Insulin Signalling 94

4.3.3 Insulin Resistance Promotes the Accumulation of Aβ 95

4.3.4 Impairments in Insulin Signalling Can Induce Hyperphosphorylation of Tau 96

4.3.5 Type 2 Diabetes and Neuroinflammation 96

4.3.6 Oxidative Stress and Mitochondrial Dysfunction in T2D and AD 97

4.3.7 Targeting Type 2 Diabetes to Slow Down Progression/Prevent Neurodegeneration and Cognitive Decline 99

4.4 Conclusions 103

References 103

5 Diet and Nutrition, and their Influence on Alzheimer’s Disease and other Neurodegenerative Diseases 117
Stephanie R. Rainey-Smith, Rhona Creegan, Stephanie J. Fuller, Michele L. Callisaya and Velandai Srikanth

5.1 Introduction 117

5.2 Dietary Patterns 118

5.3 Key Macronutrients 119

5.3.1 Dietary Fatty Acids 119

5.3.2 Cholesterol 120

5.3.3 Polyunsaturated Fatty Acids 121

5.3.4 Dietary Carbohydrates 122

5.4 Key Micronutrients 124

5.4.1 Water Soluble Vitamins 125

5.4.1.1 B Vitamins 125

5.4.2 Fat Soluble Vitamins 128

5.4.2.1 Vitamin A (Retinol, Retinal, and Retinoic Acid) 128

5.4.2.2 Vitamin D 129

5.4.2.3 Vitamin E 130

5.4.3 Dietary Minerals 131

5.4.3.1 Selenium 131

5.4.3.2 Manganese 132

5.4.3.3 Zinc, Iron, Copper, and Calcium 132

5.5 Conclusion 134

References 135

6 Carbohydrate and Protein Metabolism: Influences on Cognition and Alzheimer’s Disease 149
W.M.A.D. Binosha Fernando, Veer B. Gupta, Vijay Jayasena, Charles S. Brennan and Ralph N.Martins

6.1 Carbohydrates 149

6.1.1 Carbohydrate Digestion 149

6.1.2 Glucose Ingestion and Use 151

6.1.3 Glucose and Insulin, Insulin Resistance, and Type 2 Diabetes (Short Summary) 151

6.1.4 Relative Intake of Carbohydrate and Its Impacts on Neurodegenerative Disease Risk 152

6.1.5 Ketogenic Diets 154

6.1.6 Glucose and Its Effects on Cognition 154

6.1.7 Possible Mechanisms Related to Memory Enhancement with Glucose 157

6.1.7.1 Glucose and the Hippocampus 158

6.1.7.2 Glucose Availability in Brain Cells 158

6.1.7.3 Glucose and the Central Cholinergic System 159

6.1.7.4 ATP-Regulated Potassium (K-ATP) Channels and Brain Control of Glucose Homeostasis 159

6.1.7.5 Effects of High Fructose Diets 160

6.1.7.6 Sucrose 161

6.2 Proteins 161

6.2.1 Protein Metabolism in General 162

6.2.2 Links Between Specific Amino Acids and Brain Function 163

6.2.2.1 Tryptophan 163

6.2.2.2 Tyrosine 164

6.2.3 Clinical Studies of Protein Supplementation 165

6.2.4 Links Between Loss of Protein Function and Neurodegeneration 167

6.2.5 Clearance Mechanisms Associated with Proteinopathies Involved in Neurodegeneration 168

6.2.6 Role of Protein Crosslinking and Inflammation in Neurodegeneration and AD 170

6.3 Conclusion 171

References 171

7 Fat and Lipid Metabolism and the Involvement of Apolipoprotein E in Alzheimer’s Disease 189
Eugene Hone, Florence Lim and Ian J. Martins

7.1 Introduction 189

7.2 Alzheimer’s Disease 189

7.3 Cholesterol and Lipid Metabolism 190

7.3.1 Cholesterol Synthesis and Metabolism 190

7.3.2 Oxysterols 191

7.3.2.1 Oxysterols in AD 191

7.3.3 Pathways of Dietary (Exogenous) Lipid Homeostasis 192

7.3.4 Pathways of Endogenous Lipid Homeostasis 193

7.3.5 Peripheral Clearance of Lipoproteins and Reverse Cholesterol Transport 195

7.3.5.1 Lipoproteins in the CNS 197

7.4 Apolipoprotein E Alleles and Isoforms 197

7.4.1 ApoE in the Brain 198

7.4.2 Apolipoprotein E and Alzheimer’s Disease 198

7.4.2.1 ApoE Binding to Aβ 199

7.4.2.2 ApoE in the Cellular Clearance of Aβ 200

7.4.2.3 ApoE and Antioxidant Properties 201

7.4.2.4 ApoE and Tissue Transglutaminase 201

7.4.2.5 Apolipoprotein J (Clusterin, CLU) 202

7.5 LRP-1 in the Brain and Its Role in Aβ Clearance 203

7.5.1 LDL, HDL, and AD 203

7.5.2 Statins, Cholesterol, and AD 204

7.6 The Role of Lipid Rafts in Neurodegenerative Diseases 205

7.7 Changes to Glycerophospholipids in Alzheimer’s Disease 206

7.7.1 Omega-3 and Omega-6 Fatty Acids 207

7.7.1.1 Omega-3 Fatty Acids, Modern Diets, and Health Implications 208

7.8 Sphingolipids 208

7.8.1 Ceramides 208

7.8.2 Sulfatides 209

7.8.3 Gangliosides 209

7.9 Conclusions 210

References 210

8 Inflammation in Alzheimer’s Disease, and Prevention with Antioxidants and Phenolic Compounds –What Are the Most Promising Candidates? 233
Matthew J. Sharman, Giuseppe Verdile, Shanmugam Kirubakaran and Gerald Münch

8.1 Introduction 233

8.2 Inflammation and the Immune Response in AD 233

8.2.1 The Role of Microglia and Astrocytes in Chronic Inflammation in AD 233

8.3 Oxidative Stress 236

8.3.1 Advanced Glycation End Products 237

8.3.2 Involvement of the Complement System in AD 238

8.3.3 Involvement of Cytokines and Chemokines in Inflammation 239

8.3.4 Inflammation – Susceptibility to Aβ Deposition or Aggregation 240

8.3.5 Inflammation Can Influence AβPP Metabolism and Aβ Clearance Directly 241

8.4 Current Medications for AD 242

8.4.1 Current Medications – Acetylcholinesterase Inhibitors and Memantine 242

8.5 Disease Modification and Treatment Approaches 243

8.5.1 Non-Steroidal Anti-Inflammatory Drugs (NSAID) 243

8.6 Some Anti-inflammatory Foods, Supplements, and Newly Developed Drugs for the Treatment of AD 244

8.6.1 Cinnamon/Cinnamaldehyde 244

8.6.2 (−)Epigallocatechin-3-Gallate (EGCG) and Other Green Tea Polyphenols 245

8.6.3 Curcumin 247

8.6.4 Other Polyphenolic Antioxidants 248

8.6.5 Omega-3 (n-3) Essential Fatty Acids 249

8.6.6 Lipoic Acid 250

8.7 Conclusion 253

References 253

9 Cognitive Impairments in Alzheimer’s Disease and Other Neurodegenerative Diseases 267
Hamid R. Sohrabi and Michael Weinborn

9.1 Introduction 267

9.2 Dementia due to Alzheimer’s Disease 268

9.2.1 Subjective Cognitive Decline [4] and Mild Cognitive Impairment (MCI) 268

9.2.2 Memory Impairments in AD 271

9.2.2.1 Episodic Memory 271

9.2.2.2 Semantic Memory 272

9.2.2.3 Prospective Memory (PM) 272

9.2.3 Attention and Executive Dysfunction in AD 273

9.2.4 Language 274

9.2.5 Visuospatial Abilities 276

9.2.6 Dementia with Lewy Bodies and Parkinson’s Disease with Dementia 276

9.2.7 Vascular Dementia 277

9.2.8 Frontotemporal Dementia 279

9.3 Conclusions 281

References 282

10 Animal Models of Alzheimer’s Disease 291
Prashant Bharadwaj

10.1 Introduction 291

10.2 Transgenic Mouse Models 292

10.3 Knock-in AD Mice Models 296

10.4 Non-Transgenic and Other Mammalian Animal Models 297

10.5 Drug Development and Translational Issues 298

10.6 Correlations Between Animal Models of AD and Human AD 300

10.7 Experimental Design and Reporting 301

10.8 The Future of Animal Models in AD 302

References 303

11 The Products of Fermentation and Their Effects on Metabolism, Alzheimer’s Disease, and Other Neurodegenerative Diseases: Role of Short-Chain Fatty Acids (SCFA) 311
W.M.A.D Binosha Fernando, Charles S. Brennan and Ralph N.Martins

11.1 Introduction 311

11.2 Fermentable Substrates and Short-Chain Fatty Acids 312

11.2.1 Colonic Microflora and Fermentation 313

11.2.1.1 Probiotics and Prebiotics 313

11.2.2 Propionic Acid (PPA) 315

11.2.3 Acetic Acid 315

11.2.4 Butyric Acid 315

11.2.5 Short-Chain Fatty Acids and Free Fatty-Acid Receptor Signalling 316

11.2.6 Short-Chain Fatty Acids and Energy Intake 316

11.2.7 Short-Chain Fatty Acids and Energy Expenditure 319

11.2.8 Regulation of Fatty-Acid Metabolism by SCFA 320

11.2.9 Effect of Short-Chain Fatty Acids on Glucose Regulation 320

11.2.10 Regulation of Cholesterol Metabolism by Short-Chain Fatty Acids 321

11.2.11 Regulation of Inflammation by Short-Chain Fatty Acids 322

11.2.12 Short-Chain Fatty Acids and Neuroprotection 324

11.3 Conclusions 325

References 326

12 Hormonal Expression Associated with Alzheimer’s Disease and Neurodegenerative Diseases 335
Giuseppe Verdile, Anna M. Barron and Ralph N. Martins

12.1 The Hypothalamic–Pituitary–Gonadal (HPG) Axis 335

12.1.1 Dysregulation of the HPG Axis During Ageing 336

12.2 Roles for Sex Steroids and Gonadotropins in the Neurodegenerative Process in AD 339

12.2.1 Sex Steroids Modulate Aβ Accumulation 340

12.2.2 Sex Steroids and Oxidative Stress 342

12.2.3 Sex Steroids and Inflammation 344

12.2.4 Testosterone and Diabetes 346

12.2.5 A Role for Gonadotropins in AD Pathogenesis 347

12.3 Hormone-based Therapies 349

12.3.1 The Oestrogens 349

12.3.2 Testosterone Therapy 350

12.3.3 Selective Oestrogen or Androgen Receptor Modulators (SERM or SARM) 352

12.3.4 Gonadotropin-Lowering Agents 354

12.4 Conclusions 355

References 355

13 The Link Between Exercise and Mediation of Alzheimer’s Disease and Neurodegenerative Diseases 371
Belinda Brown and Tejal M. Shah

13.1 Introduction 371

13.2 Physical Activity Promotes Health and Well-being 372

13.3 Neuroplasticity 372

13.4 The Link Between Physical Activity and Cognition Across the Human Lifespan 373

13.4.1 Childhood 373

13.4.2 Adulthood and Midlife 374

13.4.3 Older Adults 375

13.5 Physical Activity Reduces the Risk of Dementia and AD 376

13.6 Mechanisms Underlying the Relationship Between Exercise and Brain Health 376

13.6.1 Evidence from Molecular and Cellular Research 377

13.6.2 Neurotrophins 378

13.6.3 Hormonal Pathways 379

13.6.4 Cardiovascular and Metabolic Mechanisms 380

13.6.5 Evidence from Neuroimaging Studies 380

13.7 The Effect of Genetics on the Relationship Between Exercise and Brain Health 381

13.8 Future Directions 382

References 382

Contents xiii

14 Current and Prospective Treatments for Alzheimer’s Disease (and Other Neurodegenerative Diseases) 391
Steve Pedrini, Mike Morici and Ralph N. Martins

14.1 Introduction 391

14.2 Current and Potential Medical Treatments 391

14.2.1 Treatments That Influence Neurotransmission 391

14.2.1.1 Cholinergic System 391

14.2.1.2 Other Neurotransmitters 396

14.2.2 Cholesterol-Lowering Medications 399

14.2.3 Immunotherapy 400

14.2.3.1 Active Immunotherapy (Aβ) 401

14.2.3.2 Active Immunotherapy (tau) 402

14.2.3.3 Passive Immunotherapy (Aβ) 402

14.2.3.4 Passive Immunotherapy (tau) 404

14.2.4 Targeting the Aβ-Producing Pathway 405

14.2.4.1 α-Secretase 406

14.2.4.2 β-Secretase 406

14.2.4.3 γ-Secretase 407

14.2.5 Other Compounds Affecting Aβ 408

14.2.6 Other Compounds Affecting Tau 410

14.2.7 Inflammatory Targets 411

14.3 Conclusions 412

References 412

15 The Role of Genetics in Alzheimer’s Disease and Parkinson’s Disease 443
Tenielle Porter, Aleksandra K. Gozt, Francis L. Mastaglia and Simon M. Laws

15.1 Introduction 443

15.2 Genetics of Alzheimer’s Disease 444

15.3 Autosomal Dominant AD (ADAD) 445

15.3.1 Understanding the Importance of APP and the Presenilins in AD 445

15.4 Amyloid Precursor Protein (APP) 447

15.5 Presenilin 1 (PSEN1) 447

15.6 Presenilin 2 (PSEN2) 448

15.7 Genetic Contributions to Sporadic Late-Onset AD (LOAD) 449

15.8 Cholesterol Metabolism 449

15.8.1 Apolipoprotein E (APOE) 449

15.8.2 Clusterin (CLU) 452

15.8.3 ATP-Binding Cassette Transporter A7 (ABCA7) 453

15.9 Immune Response 454

15.9.1 Complement Receptor 1 (CR1) 454

15.9.2 CD33(Myeloid Cell Surface Antigen CD33; Sialic Acid-Binding Immunoglobulin-Like Lectin 3) 455

15.9.3 Membrane Spanning 4 Domains, Subfamily A (MS4A) 456

15.9.4 Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) 456

15.9.5 Further Genetic Associations Implicating the Immune Response 457

15.10 Endocytosis 458

15.10.1 Bridging Integrator 1 (BIN1) 459

15.10.2 Phosphatidylinositol Binding Clathrin Assembly Lymphoid Myeloid Protein (PICALM) 460

15.10.3 CD2-Associated Protein (CD2AP) 461

15.10.4 Further Genetic Associations Implicating Endocytosis 462

15.10.5 Variants in APP and Genes for APP-Metabolising Proteins 463

15.10.6 Further Mechanisms Implicated Through Genetic Associations 464

15.11 Genetics of Parkinson’s Disease 465

15.12 Monogenic forms of PD 466

15.12.1 Autosomal Dominant Forms 466

15.12.1.1 PARK 1 (SNCA) 466

15.12.1.2 PARK 8 (LRRK2) 467

15.12.1.3 PARK 11 (GIGYF2) 468

15.12.1.4 PARK 17 (VPS35) 468

15.12.1.5 PARK 18 (EIF4G1) 468

15.12.2 Autosomal Recessive Forms 469

15.12.2.1 PARK 2 (PRKN) 469

15.12.2.2 PARK 6 (PINK 1) 469

15.12.2.3 PARK 7 (DJ-1) 470

15.12.2.4 PARK 9 (ATP13A2) 470

15.12.2.5 PARK 14 (PLA2G6) 470

15.12.2.6 PARK 15 (FBXO7) 471

15.12.3 Genetic Contributions to Late-Onset Sporadic PD (LOPD) 471

15.12.4 Common Variants in PD Genes 471

15.12.5 Glucocerebrosidase (GBA) 472

15.12.6 Immune-Inflammatory Genes 472

15.12.7 Mitochondrial DNA Variants 473

15.13 Conclusion 473

References 474

Final Thoughts Regarding Alzheimer’s Disease, Diet, and Health 499
Charles S. Brennan, Margaret A. Brennan, W.M.A.D. Binosha Fernando, Stephanie J. Fuller and Ralph N.Martins

List of Abbreviations 503

Index 511