**5. Hypotheses explaining AD**

because it has been suggested to affect both Aβ and NFT pathology in AD. ApoE is a 34‐kDa lipid‐binding protein that functions in the transport of triglycerides and cholesterol in multiple tissues by interacting with lipoprotein receptors on target cells; these functions are particularly critical for the central nervous system where ApoE transport of cholesterol is important for the maintenance of myelin and neuronal membranes [60]. Polymorphism of the ApoE gene has been implicated in many chronic cardiovascular (myocardial infarction, hypertension, coronary heart) and neuronal diseases. The ApoE ε4 genotype not only is a risk factor for cardiovascular disease but also it combines synergistically with age, atherosclerosis, peripheral

The ApoE gene is expressed most highly in the liver and brain; genome‐wide association studies have confirmed the ε4 allele of ApoE as the strongest genetic risk factor for AD [67, 68], because over 60% of persons with AD harbor at least one ApoE‐ε4 allele, and recent data indicate complex interactions between age, ApoE genotype and gender [61]. In reference [69], Dowell et al. used NMR to study two age groups: a young group (average age, 21 years) and a mid‐age group (average age, 50 years); they reported that there are regional white matter brain volume and cortical thickness differences between genotype groups at each age. They raised the possibility that an over‐engagement with these regions by e4+ individuals in youth may have a neurogenic effect that is observable later in life. According to a genome‐wide association study of cerebrospinal fluid (CSF) from AD subjects, several single nucleotide polymorphisms (SNPs) in the ApoE gene region of the brain were also associated with phosphorylated tau (p tau) elevated levels in the CSF. When cerebrospinal fluid levels of Aβ 1–42 were analyzed together with tau/ p tau, a significant correlation was found with SNPs of the ApoE gene. ApoE is also a crucial regulator of the innate immune system, which promotes pro‐inflammatory responses

In 2002, Colton et al. demonstrated that ApoE regulates the production of nitric oxide (NO), a critical cytoactive factor released by active macrophages. Thus, due to greater NO production, ApoE4 carriers characteristically have high levels of oxidative/nitrosative stress and a higher incidence of AD, a mechanism that explains the genetic association between ApoE4 and human

Besides the accumulation of soluble and toxic Aβ‐aggregates, tau accumulation causes oxidative stress and mitochondrial dysfunction, and it is linked to the initiation of the tau cascade. The tauopathies are a group of degenerative diseases with histopathology character‐ ized by filamentary inclusions composed of tau protein in neurons (NFT pathology). These are abundant in many neurodegenerative diseases, including AD, Pick's disease, argyrophilic grain disease and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17) [72]. In AD, the presence of neurofibrillary tangles (NFT) composed of tau is prominent, and their density correlates with neuronal loss and clinical severity [72, 74]. Dystrophic neurites are all sites of accumulation of pathological paired helical filaments (PHFs) that appear to be central to neurofibrillary degeneration of neuropathology and that contain

vascular disease or type‐2 diabetes to increase the risk of AD [62–66].

that could exacerbate AD pathogenesis [70].

diseases [71].

198 Update on Dementia

**4.4. Tau accumulation**

#### **5.1. Developmental origins of health and adult disease in dementia**

Today, an increasing number of epidemiological, clinical and experimental studies suggest an association between toxicant and drug exposure during the perinatal period and the development of metabolic‐related diseases and neurotoxicity later in life. A study called 'The developmental origins of health and adult disease' (DOHaD) addressed fundamental issues in the emerging areas of lifetime neurotoxicity testing, differential vulnerable periods of exposure, non‐monotonic dose‐response effects and neurotoxic risk assessment. Neurotoxicity during central nervous system development results in permanent changes.

The DOHaD hypothesis proposes an association of early fetal environment with adult size, later ischemic heart disease, hypertension, metabolism, diabetes and insulin resistance, which are risk factors for dementia, obesity and deficits in behavior and learning [89–91]. Aβ‐derived diffusible ligands (ADDL) also contribute to insulin deficits and insulin resistance in the brain of AD patients, and ADDL levels can be used to diagnose AD [92].

The brain of patients with AD has deficits in cerebral glucose utilization due to insulin/IGF resistance associated with increased oxidative stress, DNA damage, reactive oxygen species and mitochondrial dysfunction. The consequences of insulin and IGF resistance in the brain compromise neuronal survival, energy production, gene expression, and cerebral plasticity [93]. Thus, inhibition of insulin/IGF signaling mediates AD neurodegeneration by an increase in activity of kinases which phosphorylate tau; accumulation of AβPP – Aβ; mitochondrial dysfunction; generation of reactive oxygen and nitrogen species, oxidative and endoplasmic reticulum stress, and signaling through pro‐inflammatory and pro‐apoptotic cascades [93, 94].

Since Hoyer [95] proposed that the deficits in cerebral glucose utilization and energy metab‐ olism worsen with progression in cognitive impairment. In addition, Steen et al. proposed that chronic deficits in insulin signaling mediate the pathogenesis of AD [96]. Additionally, AD could be regarded as a brain disorder that has composite features of type 1 (insulin deficiency) and type 2 (insulin resistance) diabetes. Thus, AD could be referred to as "type 3 diabetes", because both molecular and biochemical consequence overlap with type 1 and type 2 diabetes [94, 97]. Recently, experimental studies consider that glucose hypometabolism is an early and persistent sign of AD because brains present features of impaired insulin signaling, a model using intracerebroventricular streptozotocin injections (icv STZ model) to generate sporadic AD that emulates the AD characteristics of Aβ deposits on the wall of meningeal and cortical blood vessels, mitochondrial abnormalities and oxidative stress [98].

#### **5.2. Mitochondria, aging and AD**

A major risk factor in patients who progress to dementia is aging, which is characterized by defects in energy metabolism and mitochondrial function. Mitochondrial dysfunction is a hallmark of aging, and it plays a central role not only in Alzheimer's but also in Parkinson's disease [99]; it causes the accumulation of soluble and toxic Aβ‐aggregates and oxidative stress, and it is linked to the initiation of the tau cascade. In addition, signaling from the nucleus to mitochondria may be crucial for the regulation of mitochondrial function and aging, possibly contributing to the development of age‐associated diseases such as AD. Mitochondria not only play a central role in metabolic pathways, they also regulate cell fate through crosstalk between autophagy and apoptosis. Macroautophagy (autophagy) and apoptosis are intimately interconnected and determine whether cells survive or die [100].

On the other hand, genes define a baseline mitochondrial function, where maternal mtDNA contributes more, and environmental factors determine the rate of mitochondrial function, with less durability producing faster brain aging. Mitochondrial function influences AD, APP expression and processing and Aß accumulation [101, 102]. Also in familiar AD (FAD), the impaired mitochondrial function is caused by PS (either PS 1 or PS 2) mutations, but about 10% are inherited, most of the cases are sporadic AD (SAD). Both FAD and SAD share the features of accumulated extra and intracellular Aβ plaques, as well as intracellular NFTs and cell atrophy and cell death, suggesting a common pathogenic origin on the basis of the intracellular Ca2+‐homeostasis disruption tested in a mutant PS with a mitochondrial dysfunc‐ tion with potential cell death [103]. Xie et al. used APP/PS1 transgenic mice to study the temporal relationship among Aβ plaque deposition, oxidative stress, and cell death, identified Aβ as the mediator of oxidative stress and subsequent neurodegeneration. Oxidative stress began in neurites and was followed by the appearance of Aβ plaques in the surrounding tissue ultimately leading to oxidation in neuronal soma, but the oxidized neurites survived for several weeks. The oxidation in neuronal soma was associated with caspase‐dependent apoptosis [104]. In addition, intermediate cellular players, including astrocytes or microglia, responded to amyloid deposits with chemokine or cytokine signaling which, in turn, led to oxidation in neurites.

The Glutamate (Glu) and mitochondria have a relationship in oxidative stress that underlies AD; Glu is an important neurotransmitter in neurons and glial cells, and is strongly dependent on calcium homeostasis and mitochondrial function [105]. Mitochondrial deficits occur early in AD, even before plaque formation [106]. Decreased expression of cytochrome c oxidase (COX) and pyruvate dehydrogenase (PDH) has also been detected in postmortem brain tissue of patients with AD, as well as in animal models. Substances used to maintain brain metabolism in the 3xTg‐AD mouse model, such as icariin active component of the traditional Chinese herbal medicine *Epimedium*, could modulate neuronal cell activity, preserve mitochondria and functional synaptic proteins, inhibit Abfix expression and improve cognitive functions in AD mice [107].

#### **5.3. Nutrition and AD**

exposure, non‐monotonic dose‐response effects and neurotoxic risk assessment. Neurotoxicity

The DOHaD hypothesis proposes an association of early fetal environment with adult size, later ischemic heart disease, hypertension, metabolism, diabetes and insulin resistance, which are risk factors for dementia, obesity and deficits in behavior and learning [89–91]. Aβ‐derived diffusible ligands (ADDL) also contribute to insulin deficits and insulin resistance in the brain

The brain of patients with AD has deficits in cerebral glucose utilization due to insulin/IGF resistance associated with increased oxidative stress, DNA damage, reactive oxygen species and mitochondrial dysfunction. The consequences of insulin and IGF resistance in the brain compromise neuronal survival, energy production, gene expression, and cerebral plasticity [93]. Thus, inhibition of insulin/IGF signaling mediates AD neurodegeneration by an increase in activity of kinases which phosphorylate tau; accumulation of AβPP – Aβ; mitochondrial dysfunction; generation of reactive oxygen and nitrogen species, oxidative and endoplasmic reticulum stress, and signaling through pro‐inflammatory and pro‐apoptotic cascades [93, 94].

Since Hoyer [95] proposed that the deficits in cerebral glucose utilization and energy metab‐ olism worsen with progression in cognitive impairment. In addition, Steen et al. proposed that chronic deficits in insulin signaling mediate the pathogenesis of AD [96]. Additionally, AD could be regarded as a brain disorder that has composite features of type 1 (insulin deficiency) and type 2 (insulin resistance) diabetes. Thus, AD could be referred to as "type 3 diabetes", because both molecular and biochemical consequence overlap with type 1 and type 2 diabetes [94, 97]. Recently, experimental studies consider that glucose hypometabolism is an early and persistent sign of AD because brains present features of impaired insulin signaling, a model using intracerebroventricular streptozotocin injections (icv STZ model) to generate sporadic AD that emulates the AD characteristics of Aβ deposits on the wall of meningeal and cortical

A major risk factor in patients who progress to dementia is aging, which is characterized by defects in energy metabolism and mitochondrial function. Mitochondrial dysfunction is a hallmark of aging, and it plays a central role not only in Alzheimer's but also in Parkinson's disease [99]; it causes the accumulation of soluble and toxic Aβ‐aggregates and oxidative stress, and it is linked to the initiation of the tau cascade. In addition, signaling from the nucleus to mitochondria may be crucial for the regulation of mitochondrial function and aging, possibly contributing to the development of age‐associated diseases such as AD. Mitochondria not only play a central role in metabolic pathways, they also regulate cell fate through crosstalk between autophagy and apoptosis. Macroautophagy (autophagy) and apoptosis are intimately

On the other hand, genes define a baseline mitochondrial function, where maternal mtDNA contributes more, and environmental factors determine the rate of mitochondrial function, with less durability producing faster brain aging. Mitochondrial function influences AD, APP

during central nervous system development results in permanent changes.

of AD patients, and ADDL levels can be used to diagnose AD [92].

blood vessels, mitochondrial abnormalities and oxidative stress [98].

interconnected and determine whether cells survive or die [100].

**5.2. Mitochondria, aging and AD**

200 Update on Dementia

Genetic and environmental factors are particularly important for the sporadic form of AD. Diets rich in saturated fatty acids and alcohol but deficient in antioxidants and vitamins appear to promote the onset of the disease. In contrast, diets rich in antioxidants, vitamins B6, B12 and folate, unsaturated fatty acids, and fish suppress its onset [108]. During the last decade, many investigations have shown metabolic disturbances (obesity and metabolic syndrome) to be risk factors for the development of dementias and even AD [109]. Obesity is related to vascular diseases, and there is increasing evidence linking vascular risk factors to dementia and AD [109]. Instead of exploring the effect of its subcomponents, several studies have assessed the relationship between metabolic syndrome as a whole and the risk of AD or cognitive decline [111–113]. The cellular mechanisms involved in the AD associated with metabolic alterations are now becoming more understandable. It is well known that an optimal supply of nutrients is necessary to maintain normal functioning of the brain. Thus, the impact of poor nutrition (overweight, obesity) on the development of AD and the importance of good nutrition as a preventive strategy to reduce the incidence of dementias and AD are clear.

Malnutrition is associated with increased morbidity and mortality in patients with AD, with sleep disturbances, psychological problems, immobility, falls and increased hospitalization risk [114]. Normal human aging is also associated with vitamin deficiencies. One study in an Alzheimer transgenic mouse (VCT2+/‐APP/PSEN1) found decreased ascorbic acid and increased oxidative stress in the brain as well as for Alzheimer's disease [115].

Antioxidant nutrients may help to protect these affected brain regions. Plasma vitamin C levels are lower in subjects with dementia compared to controls, supporting the free radical theory of oxidative neuronal damage [116]. Despite years of scientific, medical and clinical advances in this area, much work remains to discover specific nutritional interventions for the preven‐ tion of AD. Promising agents such as vitamins, energy substrates, flavonoids, lipids and modified diets functioning as antioxidants, metabolic enhancers, immune modulators and direct disease‐modifying agents await further investigation [117].

#### **5.4. Malnutrition and senescence hypothesis of AD progression**

It is well known that adequate nutrition is an important factor in order to maintain cognitive function, particularly during aging. Malnutrition is among the risk factors for developing mild cognitive impairment and AD in which a cognitive decline is correlated with synaptic loss. The synapses are part of the neuronal membrane and are continuously being remodeled; therefore, ensuring the availability of sufficient levels of nutritional precursors (i.e., uridine monophosphate, choline and omega‐3 fatty acids) to make the phospholipids required to build neuronal membranes may reduce synaptic degeneration in AD. Also, B‐vitamins, phospholi‐ pids and other micronutrients act as cofactors to enhance the supply of precursors required to make neuronal membranes and synapses. Vitamin D has a role in brain physiology as well, for instance, by promoting neurotransmission, neurogenesis, synaptogenesis, amyloid clearance and preventing neuronal death [118].

Undernutrition during early life results in deficits in the spatial learning capacity of the animals [118], as shown by a wide variety of behavioral tests, and it is known to cause changes in the developing brain that affect the morphology, particularly in the granule cells of the dentate gyrus [120–122]. Prenatal malnutrition and chronic malnutrition in the aged rats cause abnormal mitochondrial, swollen Golgi membrane system, increase in multivesicular bodies and lypofuscine density in neurons of the hippocampus [123]. Since the mitochondrion is responsible for the production of ATP, its dysfunction induces a senescence response [124]. Furthermore, mitochondrial autophagocytosis is believed to be a major contributor to lipo‐ fuscin formation [125]. Autophagocytosis of mitochondria is also prominent in AD, because the accumulated autophagic vacuoles in dystrophic neurites contribute to the local production of Aβ within plaques, and the generalized increase in autophagy in the neuropil could be a significant source of Aβ overproduction in the AD brain. Thus, a link between mitochondrial dysfunction/oxidative stress and autophagy has been reported to occur in AD [126]. In addition, lipofuscin can be used as a biomarker to detect senescence [127], since it is one of the "age pigments", autofluorescent cell products from lysosomes that diverge in number and size among brain regions.

The increase in lipid components is possibly due to modifications in neuronal metabolism with age [128]. In Ref. [129], Giacone et al. proposed the "lipofuscin hypothesis of AD", in which the first step in the genesis of senile plaques is the release of lipofuscin free into the neuropil, where it cannot be rapidly degraded due to its biochemical characteristics. Therefore, the lipofuscin may persist in the extracellular milieu, giving rise to a focal impairment that can initiate the senile plaque and serving as a source of Aβ oligomers for a prolonged period of time. This idea is supported by the hydrophobic and insoluble characteristics of lipofuscin, which mimic those of substances that are the most effective in inducing an innate immune response [130]; the rate of lipofuscin formation is also closely related to oxidative stress [131].

#### **5.5. Senescence hypothesis and microglial aging**

Malnutrition is associated with increased morbidity and mortality in patients with AD, with sleep disturbances, psychological problems, immobility, falls and increased hospitalization risk [114]. Normal human aging is also associated with vitamin deficiencies. One study in an Alzheimer transgenic mouse (VCT2+/‐APP/PSEN1) found decreased ascorbic acid and

Antioxidant nutrients may help to protect these affected brain regions. Plasma vitamin C levels are lower in subjects with dementia compared to controls, supporting the free radical theory of oxidative neuronal damage [116]. Despite years of scientific, medical and clinical advances in this area, much work remains to discover specific nutritional interventions for the preven‐ tion of AD. Promising agents such as vitamins, energy substrates, flavonoids, lipids and modified diets functioning as antioxidants, metabolic enhancers, immune modulators and

It is well known that adequate nutrition is an important factor in order to maintain cognitive function, particularly during aging. Malnutrition is among the risk factors for developing mild cognitive impairment and AD in which a cognitive decline is correlated with synaptic loss. The synapses are part of the neuronal membrane and are continuously being remodeled; therefore, ensuring the availability of sufficient levels of nutritional precursors (i.e., uridine monophosphate, choline and omega‐3 fatty acids) to make the phospholipids required to build neuronal membranes may reduce synaptic degeneration in AD. Also, B‐vitamins, phospholi‐ pids and other micronutrients act as cofactors to enhance the supply of precursors required to make neuronal membranes and synapses. Vitamin D has a role in brain physiology as well, for instance, by promoting neurotransmission, neurogenesis, synaptogenesis, amyloid

Undernutrition during early life results in deficits in the spatial learning capacity of the animals [118], as shown by a wide variety of behavioral tests, and it is known to cause changes in the developing brain that affect the morphology, particularly in the granule cells of the dentate gyrus [120–122]. Prenatal malnutrition and chronic malnutrition in the aged rats cause abnormal mitochondrial, swollen Golgi membrane system, increase in multivesicular bodies and lypofuscine density in neurons of the hippocampus [123]. Since the mitochondrion is responsible for the production of ATP, its dysfunction induces a senescence response [124]. Furthermore, mitochondrial autophagocytosis is believed to be a major contributor to lipo‐ fuscin formation [125]. Autophagocytosis of mitochondria is also prominent in AD, because the accumulated autophagic vacuoles in dystrophic neurites contribute to the local production of Aβ within plaques, and the generalized increase in autophagy in the neuropil could be a significant source of Aβ overproduction in the AD brain. Thus, a link between mitochondrial dysfunction/oxidative stress and autophagy has been reported to occur in AD [126]. In addition, lipofuscin can be used as a biomarker to detect senescence [127], since it is one of the "age pigments", autofluorescent cell products from lysosomes that diverge in number and size

increased oxidative stress in the brain as well as for Alzheimer's disease [115].

direct disease‐modifying agents await further investigation [117].

**5.4. Malnutrition and senescence hypothesis of AD progression**

clearance and preventing neuronal death [118].

among brain regions.

202 Update on Dementia

Cellular senescence is a terminal phase of mitotic cells characterized by permanent cell‐cycle arrest; it can be induced by a variety of stressors, including reactive oxygen species. One hypothesis is that senescent cells contribute to aging by altering cells and its secretory phenotype, as well as to the development of age‐associated diseases such as AD [132].

It has been suggested that neuroinflammation, mediated by the brain's innate immune system, contributes to AD neuropathology and exacerbates the course of the disease. Some studies found that a systemic immune challenge during late gestation predisposes mice to develop AD‐like neuropathology during aging when there are elevated levels of inflammatory cytokines and hippocampal amyloid precursor protein (APP), altered tau phosphorylation and missorting to somatodendritic compartments. All these effects produced significant impair‐ ments in working memory in old age [34]. Also, AD and brain aging share common molecular changes, and AD could be a form of accelerated brain aging. In addition, in AD senescent mechanisms are present in all cells, including glia and neurons. Evidence indicates that vascular impairment is a fundamental contributor to AD pathology, and platelets are generally considered a key element because they represent the link between Aβ deposition, peripheral inflammation and endothelial senescence. AD is superimposed onto the normal process of aging and one important facet of aging is the accumulation of senescent cells that lose the ability to proliferate, and also release cytokines and proteases, collectively known as the senescence‐associated secretory phenotype, which contribute to the chronic inflammatory environment seen in the old age [133]. In brain, astrocytes clearly play a role in modulating neuronal function and survival in health but in disease are senescent [134]. Also, human astrocyte lines expressing the toxic form of Aβ rapidly reached a senescent state in vitro [135].

In the other hand, observations suggest that chronic systemic inflammation induces in middle‐ aged rats intense neuroinflammation evoked by senescent‐type microglia and may contrib‐ ute to the initiation and progression of AD, resulting in cognitive impairment. Also, with chronic inflammatory bone disorders, pro‐inflammatory blood cells and bacterial compo‐ nents including lipopolysaccharides (LPS), activate the receptors localized on the surface of leptomeningeal cells, which in turn activate brain‐resident microglia to evoke neuroinflam‐ mation [136]. Furthermore, the maternal immune response predisposes the offspring to develop neuropsychiatric disorders and can prime microglia cells to produce high levels of cytokines with a second stimulus [137]. Prenatal immune activation of offspring changes the

integrity of the gastrointestinal barrier [138], which probably increases exposure to antigens with pathogen‐associated molecular patterns, such as LPS. Exposure to Poly (I:C) on the late gestational day can alter cognitive performance in the adult or aged animals [34, 139]. High‐ fat diets can also cause metabolic endotoxemia (an increased LPS concentration in plasma from microbiota in the gut) with a pro‐inflammatory response [140]. This gut microbiota LPS accelerates aging, with an increase in the concentration of pro‐inflammatory cytokines and of protein 16 (p16), which is a senescence biomarker in the colon [141]. The senescent cells produce chemokines, cytokines, growth and differentiation factors and matrix‐remodeling enzymes, collectively known as the senescence‐associated secretory phenotype [142, 143], which can contribute to tissue dysfunction [142] as Alzheimer's diseases [144]. The possible mechanism is that chronic systemic inflammatory challenges induce differential age‐depend‐ ent microglial responses. Microglia are the resident immune cells in the brain, providing its first line of defense and initiating the release of pro‐inflammatory mediators to trigger neuroinflammation in response to autoimmune injury, infection, ischemia, toxic insults and trauma. They recognize a broad spectrum of molecular targets, such as glycolipids, lipopro‐ teins, nucleotides, abnormally processed peptides, modified or aggregated proteins (i.e., Aβ), inflammatory cytokines, and damaged neurons, which are the strongest inducers of micro‐ glia activation [145]. In Ref. [99], Wu et al. propose a strong relationship between nutrients, microglia, aging and brain based on the concept of "microglia ageing." This concept consid‐ ers microglia as the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. Senescent microglia display morphological changes: fewer and shorter processes, increased soma volume, and formation of spheroid swellings, collectively refer‐ red to as "dystrophic microglia." Furthermore, inflammation induces oxidative stress and DNA damage, leading to the overproduction of reactive oxygen species, including macro‐ phages and microglia and promoting aging. Therefore, providing early treatment of inflam‐ matory disorders and controlling microglia aging, may delay the onset and limit the severity and/or progression of AD [136].

Animal models are used to test changes in microglia. For example, in adult APP/PS1 mice, exercise enhances memory test performance and is associated with increased numbers of cholinergic and serotoninergic neurons, and reduced Aβ levels and microglia activation [146]. Dietary restriction also appears to attenuate age‐related activation of microglia, resulting in beneficial effects on neurodegeneration and cognitive decline [147]. Dietary restriction suppresses LPS‐induced secretion of inflammatory cytokines, and shifts hypothalamic signaling pathways to an anti‐inflammatory bias [148].

#### **5.6. β‐Amyloidopathy and neuroinflammation in the pathogenesis of age‐related AD**

The study of the aging organism allowed selection of a group of neurodegenerative diseases which have a similar mechanism of pathogenesis, including the pathological processes of protein aggregation and deposition in nerve tissue. The AD pathogenesis in β‐amyloidopathy is a manifestation of proteinopathy leading to cytotoxicity, neurodegeneration and the development of pathological apoptosis activated by the formation of intracellular Aβ [166].

Proteinopathy‐induced cell senescence is caused by the accumulation of misfolded proteins and activation of the innate immune system, with the production of pro‐inflammatory cytokines, chemokines and oxidative stress that trigger chronic inflammation and ultimately, senescence. Components of SASP and proteinopathy can induces more senescent cells. These cells are resistant to apoptosis, but can die by autophagy. Senescent cells can be the link between Aß and secondary proteinopathies such as tau, α‐synuclein and TDP‐43 [149]. Indirect evidence that infection could be a cause of AD has been reported, and it was suggested that invasion by a virus could cause activation of microglia and pericytes and ultimately, amyloid deposition [150].

Systemic infections and persistent neuroinflammation are risk factors for developing AD [151]. Mice injected on gestational day 17 with poly I:C (a mimic of virus exposure) show, at 15 months, an increase in APP and its proteolytic fragments, hyperphosphorylation of tau without NFTs and the absence of significant Aβ accumulation, but these parameters have not yet been determined in aged mice [34]. Indirect evidence that infection could be a cause of AD has been reported by Wisniewski et al., who suggested that invasion by a virus could cause activation of microglia and pericytes and ultimately, amyloid deposition [152].

The infectious hypothesis is suggested by the altered blood‐brain barrier and the activation of neuroinflammation in the brain, which could decrease Aß peptide clearance. For example, infection by *Helicobacter pylori* is acquired during childhood and often persists for life, inducing a chronic gastric inflammation that remains asymptomatic but can induce systemic inflam‐ mation and increase homocysteine levels, contributing to the risk of AD. In animal models of AD (5xFAD), in which glutamate excitotoxicity through NMDA receptors involves neuroin‐ flammation, however, apart from Aβ reductions, improvements were no longer observed in the 5xFAD model during advanced stages of the disease, which may reflect the limited efficacy of memantine in clinical settings [153].

#### **5.7. Amyloid cascade hypothesis**

integrity of the gastrointestinal barrier [138], which probably increases exposure to antigens with pathogen‐associated molecular patterns, such as LPS. Exposure to Poly (I:C) on the late gestational day can alter cognitive performance in the adult or aged animals [34, 139]. High‐ fat diets can also cause metabolic endotoxemia (an increased LPS concentration in plasma from microbiota in the gut) with a pro‐inflammatory response [140]. This gut microbiota LPS accelerates aging, with an increase in the concentration of pro‐inflammatory cytokines and of protein 16 (p16), which is a senescence biomarker in the colon [141]. The senescent cells produce chemokines, cytokines, growth and differentiation factors and matrix‐remodeling enzymes, collectively known as the senescence‐associated secretory phenotype [142, 143], which can contribute to tissue dysfunction [142] as Alzheimer's diseases [144]. The possible mechanism is that chronic systemic inflammatory challenges induce differential age‐depend‐ ent microglial responses. Microglia are the resident immune cells in the brain, providing its first line of defense and initiating the release of pro‐inflammatory mediators to trigger neuroinflammation in response to autoimmune injury, infection, ischemia, toxic insults and trauma. They recognize a broad spectrum of molecular targets, such as glycolipids, lipopro‐ teins, nucleotides, abnormally processed peptides, modified or aggregated proteins (i.e., Aβ), inflammatory cytokines, and damaged neurons, which are the strongest inducers of micro‐ glia activation [145]. In Ref. [99], Wu et al. propose a strong relationship between nutrients, microglia, aging and brain based on the concept of "microglia ageing." This concept consid‐ ers microglia as the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. Senescent microglia display morphological changes: fewer and shorter processes, increased soma volume, and formation of spheroid swellings, collectively refer‐ red to as "dystrophic microglia." Furthermore, inflammation induces oxidative stress and DNA damage, leading to the overproduction of reactive oxygen species, including macro‐ phages and microglia and promoting aging. Therefore, providing early treatment of inflam‐ matory disorders and controlling microglia aging, may delay the onset and limit the severity

Animal models are used to test changes in microglia. For example, in adult APP/PS1 mice, exercise enhances memory test performance and is associated with increased numbers of cholinergic and serotoninergic neurons, and reduced Aβ levels and microglia activation [146]. Dietary restriction also appears to attenuate age‐related activation of microglia, resulting in beneficial effects on neurodegeneration and cognitive decline [147]. Dietary restriction suppresses LPS‐induced secretion of inflammatory cytokines, and shifts hypothalamic

**5.6. β‐Amyloidopathy and neuroinflammation in the pathogenesis of age‐related AD**

The study of the aging organism allowed selection of a group of neurodegenerative diseases which have a similar mechanism of pathogenesis, including the pathological processes of protein aggregation and deposition in nerve tissue. The AD pathogenesis in β‐amyloidopathy is a manifestation of proteinopathy leading to cytotoxicity, neurodegeneration and the development of pathological apoptosis activated by the formation of intracellular Aβ [166].

and/or progression of AD [136].

204 Update on Dementia

signaling pathways to an anti‐inflammatory bias [148].

The amyloid cascade hypothesis postulates that memory deficits are caused by increased brain levels of Aβ peptide, which are derived from the larger amyloid precursor protein (APP) by sequential proteolytic processing [154]. This hypothesis is a neuron‐centric, linear and quantitative model postulating direct cause and consequences in a cascade initiated by Abfix deposition and leading progressively to Tau pathology, synaptic dysfunction, inflammation, neuronal loss and ultimately, to dementia. Earlier AD mouse models have generated a wealth of information that has significantly improved our knowledge about AD; however, the amyloid cascade hypothesis remains controversial, because the majority of these models are based on transgenic overexpression of APP in combinations with different familial AD‐ associated mutations in APP or PS 1. Overexpression of APP generates elevated Aβ levels to mimic the Aβ amyloidosis of AD brains, but concomitant with this it produces non‐physio‐ logical effects and a number of undesirable side effects. One strategy is to introduce mutations into the mouse APP gene and new models (APPNL‐F and APPNLG‐F) that develop robust Aβ amyloidosis, which induces synaptic degeneration and memory impairments [155].

The quantitative aspects of the hypothesis imply that reducing the number of Aβ‐plaques or the concentration of Aβ‐oligomers should be sufficient to halt progression of AD. Thus, a minor increase in the Aβ42:Aβ<sup>40</sup> ratio stabilizes toxic oligomeric species with intermediate conformations. The toxic impact of these Abfix species on the synapse but can spread into cells, producing neuronal death; Kuperstein et al. [156], suggest that there is a dynamic equilibrium between toxic and non‐toxic intermediates.

In addition, it is well known that diffusible Aβ oligomers are the major toxic agents in AD, and both monomers and oligomers are important for the early diagnosis of dementia because they are potential predictors for the progression of AD and are useful to evaluate new drugs against AD [157, 158].

A quarter to a third of older people has amyloid burdens without symptoms of dementia [159]. Various APP transgenic mice do not have all the characteristics of AD: they exhibit little or no neuron loss and not all of them develop cognitive impairments, even if for three‐quarters of their lives they have deposits of amyloid, suggesting that Aβ alone is not sufficient. Thus, they are a model of asymptomatic AD [159, 160].
