**3. Histopathological brain changes in AD**

Autopsy studies examining the incidence of neuropathological lesions and clinical symptoms reveal that AD often occurs in conjunction with other pathologies, specifically, vascular and Lewy body dementias. The overlap of pathologies suggests the existence of common patho‐ physiological mechanisms [19].

In AD brains, many cellular and molecular changes coincide with changes in the proteins and genes implicated. The two primary lesions associated with AD are NFTs and the senile plaques first described by Alois Alzheimer. Graeber and co‐workers explained in 1998 that the tissue sections of cerebral cortex from Auguste D had numerous NFTs and many amyloid plaques, especially in the upper cortical layer of the brain [20]. In this tissue, NFTs can be seen as accumulations of abnormally phosphorylated tau protein within the perikaryal cytoplasm of cortical neurons, and senile plaques consist of a central core of amyloid‐β (Aβ), a 4‐kD peptide, surrounded by abnormally configured neuronal processes or neurites; the neurites are localized similarly in animal models such as the PDAPP first model, which develops plaques and cognitive deficits similar to those in humans [13].

These histopathological features start in the temporal lobe and extend to the Meynert nucleus that projects to the hippocampus and to the frontal, parietal and occipital cortices, all of which have important roles in the control of cognitive functions; gradually, these lesions destroy a person's memory and ability to learn, to reason, to communicate and to carry out daily activities [21, 22]. The first histopathological lesion is the intracellular NFT, which consists largely of twisted, hyperphosphorylated filaments of the microtubule‐associated protein tau. The second lesion type is the extracellular plaque of differently sized, small amyloid peptides called Aβ that are derived via sequential proteolytic cleavages of APP [23]. The two types of lesions seem to form independently, with tangles appearing first [24]. Affected regions typically exhibit synaptic and neuronal loss, with cholinergic and glutamatergic neurons being the most affected [25], as well as inflammation, gliosis, oxidative stress and neuronal dystrophy [8].

#### **3.1. Brain atrophy and traumatic brain injury**

New technologies based on structural and functional neuroimaging and on the biochemical analysis of cerebrospinal fluid have established interesting correlates of intracerebral amyloi‐ dosis in individuals with mild, pre‐dementia symptoms.

Whole brain volume changes are used as surrogate markers for AD neuropathology in clinical studies; the extent to which these changes can be attributed to pathological features of AD in the aging brain may be established using other signs of brain atrophy in patients showing cognitive impairment [26]. The relationship between pathology and brain atrophy is not simple and linear; neither is the distinction between normal aging and the disease, which is a complicated issue. Aging, dementia diagnosis and AD pathologies closely correlate with enlargement of the brain ventricles but not with reduced total brain volume. Ventricle enlargement may be a response to various conditions and reflect changes in both white and gray matter of the brain, and may be related to cerebrovascular disease and AD. Clinically, brain atrophy in AD patients precedes symptoms. Researchers have proposed using brain atrophy as a surrogate marker for pathology in clinical trials and longitudinal studies. For example, decreased hippocampal volume is considered an acceptable marker in people with mild cognitive impairment (MCI) and at early stages of AD.

It is well established that AD leads to nerve cell death and tissue loss throughout the brain. As more neurons die, more brain regions are affected and over time, the brain shrinks dramatically leading to functional impairment. The atrophy pattern involves white matter and largely spares the isocortex and hippocampus, which is different from that reported in AD patients [27]. The atrophy of the medial temporal lobe, including the entorhinal cortex, amygdala and hippocampus, is closely related to impairment for forming new memories. The hippocampus in AD patients may lose 3–4% of its volume in a year, whereas average loss in a normal brain is less than 1%. Thus, these hippocampal alterations are one of the best‐established signs of AD. Furthermore, the hippocampus is more susceptible to reduced blood flow, which occurs in cortical amyloid angiopathy.

Some studies evaluating brain atrophy in the transgenic PDAPP mouse model found a reduction in hippocampal volume and severe atrophy or agenesis of fiber tracts, fornix and corpus callosum [28–30]. ApoE ε4 is associated with increased risk of sporadic AD and of conversion from mild cognitive impairment to AD. ApoE ε4 also plays an important role in brain atrophy and memory impairment by modulating amyloid production and deposition [31].

Microglia is the innate immune cell in the brain that, as a result of brain injury like infection or traumatic injury, produces cytokines and may remain primed in a state where a second stimulus produces an exaggerated activation (hyper‐reactivity). This response may be triggered by traumatic brain injury, infection or aging [32, 33], which are risk factors for developing AD. Hyper‐activated microglia is importantly involved in this process [33–35].

#### **3.2. Neuronal and synaptic loss**

[21, 22]. The first histopathological lesion is the intracellular NFT, which consists largely of twisted, hyperphosphorylated filaments of the microtubule‐associated protein tau. The second lesion type is the extracellular plaque of differently sized, small amyloid peptides called Aβ that are derived via sequential proteolytic cleavages of APP [23]. The two types of lesions seem to form independently, with tangles appearing first [24]. Affected regions typically exhibit synaptic and neuronal loss, with cholinergic and glutamatergic neurons being the most affected [25], as well as inflammation, gliosis, oxidative stress and neuronal dystrophy [8].

New technologies based on structural and functional neuroimaging and on the biochemical analysis of cerebrospinal fluid have established interesting correlates of intracerebral amyloi‐

Whole brain volume changes are used as surrogate markers for AD neuropathology in clinical studies; the extent to which these changes can be attributed to pathological features of AD in the aging brain may be established using other signs of brain atrophy in patients showing cognitive impairment [26]. The relationship between pathology and brain atrophy is not simple and linear; neither is the distinction between normal aging and the disease, which is a complicated issue. Aging, dementia diagnosis and AD pathologies closely correlate with enlargement of the brain ventricles but not with reduced total brain volume. Ventricle enlargement may be a response to various conditions and reflect changes in both white and gray matter of the brain, and may be related to cerebrovascular disease and AD. Clinically, brain atrophy in AD patients precedes symptoms. Researchers have proposed using brain atrophy as a surrogate marker for pathology in clinical trials and longitudinal studies. For example, decreased hippocampal volume is considered an acceptable marker in people with

It is well established that AD leads to nerve cell death and tissue loss throughout the brain. As more neurons die, more brain regions are affected and over time, the brain shrinks dramatically leading to functional impairment. The atrophy pattern involves white matter and largely spares the isocortex and hippocampus, which is different from that reported in AD patients [27]. The atrophy of the medial temporal lobe, including the entorhinal cortex, amygdala and hippocampus, is closely related to impairment for forming new memories. The hippocampus in AD patients may lose 3–4% of its volume in a year, whereas average loss in a normal brain is less than 1%. Thus, these hippocampal alterations are one of the best‐established signs of AD. Furthermore, the hippocampus is more susceptible to reduced blood flow, which occurs

Some studies evaluating brain atrophy in the transgenic PDAPP mouse model found a reduction in hippocampal volume and severe atrophy or agenesis of fiber tracts, fornix and corpus callosum [28–30]. ApoE ε4 is associated with increased risk of sporadic AD and of conversion from mild cognitive impairment to AD. ApoE ε4 also plays an important role in brain atrophy and memory impairment by modulating amyloid production and deposition

**3.1. Brain atrophy and traumatic brain injury**

194 Update on Dementia

dosis in individuals with mild, pre‐dementia symptoms.

mild cognitive impairment (MCI) and at early stages of AD.

in cortical amyloid angiopathy.

[31].

Extracellular accumulation of Aβ protein and intracellular accumulation of tau in brain tissues have been described in animal models of AD, as well as in some mechanical stress‐based diseases with different mechanisms, such as traumatic brain injury, arterial hypertension and normal pressure hydrocephalus.

Numerous studies dealing with AD have shown evidence for synaptic dysfunction, which correlates with cognitive decline along with an abundance of plaques or tangles [36]. Synapse abnormalities in AD brain tissue were first described by Gonatas and colleagues [37]. Quan‐ titative ultrastructural and immunohistochemical *postmortem* studies of brain samples from patients with MCI to early‐mild AD confirmed previous results that synapse loss was an early structural finding that correlated with AD severity. These studies showed a marked loss of synaptic proteins, such as synaptophysin, SV2 and p65, in the brains of AD patients [38–41]. Numerous factors have been associated with increased risk of AD: diabetes, hypertension, smoking, obesity and dyslipidemia [3].

Dysfunction of synaptic communication in cortical and hippocampal networks has been suggested as one of the neuropathological hallmarks of the early stages of AD and has been increasingly referred to as a "synaptopathy", in which the soluble oligomeric Aβ peptide plays a pivotal role in disrupting synaptic function and, thus, in neuronal network activity [42, 43]. In addition, high levels of soluble Aβ oligomers show a strong correlation with synaptic dysfunction, which contributes to neurodegeneration. This reflects the loss or damage to synapses that occurs as the disease progresses, which in turn produces functional degeneration of specific neuronal circuits and consequent aberrant activity in neural networks; however, the exact mechanisms are still unknown. One possibility is the immediate‐early gene Arc/Arg3.1 (early‐expression activity‐regulated cytoskeletal gene, here referred to as Arc), one of the genes known to be vital for memory consolidation and synaptic plasticity. Also, the mapping of Arc expression patterns in brain networks has been extensively used as a marker of memory‐ relevant neuronal activity history. A recent study by Morin et al. proposes that in 3xTg‐AD mice, intraneuronal Aβ expression in the hippocampus could increase unspecific neuronal activation and subsequent Arc protein expression, which might impair further memory‐ stabilizing processes [44]. Understanding the link between intracellular Aβ and Arc/Arg3.1 protein function should help disentangle the molecular and cellular mechanisms underlying episodic memory deficits during the early phases of AD and could clarify the role of disrupted hippocampal excitability in memory retrieval deficits occurring in early‐stage AD‐like pathology.

#### **3.3. Synaptopathy**

Activated Arc/Arg3.1 is targeted to the post‐synaptic density of synaptically active dendritic spines where it associates with polysomes. Arc interacts with endophilin 2/3 and dynamin, contributing to α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate (AMPA) type gluta‐ mate receptor (AMPAR) modulation by enhancing receptor endocytosis. The Arc‐endosome also traffics APP and physically associates with PS 1, thereby increasing the amount of activity‐ dependent Aβ [45]. This may be a positive feedback mechanism in which removal of the AMPAR from the synapse will produce a significant loss of dendritic spines and synaptic activity, resulting in synaptic failure similar to that observed in AD. Activity of the *N*‐methyl‐ D‐aspartate receptor (NMDAR) in the hippocampus is also known to be crucial for long‐term spatial memory formation and to play a role in AD pathogenesis. The NMDAR is localized at synaptic and extra‐synaptic sites where it has diverse functions, from modulating memory strength to neurotoxicity and neuroprotection, and one of the components of the NMDAR‐ associated signaling complex is Arc/Arg3.1. Other postsynaptic elements are the lipid rafts (subdomains of the plasma membrane that contain high concentrations of cholesterol and glycosphingolipids), which are involved in cell signaling and with the NMDAR complex. Thus, physiological and pathological events such as ischemia and spatial learning can induce movements of NMDAR signaling complexes between the postsynaptic density and lipid raft subdomains. Synaptopathy and lipid raft disruption may be related to the onset of episodic memory deficits during the early stages of AD [46–48]. In order to analyze this possibility, studies have been initiated to determine the content of NMDA and AMPA receptors as well as Arc/Arg3.1 levels in the lipid raft microdomains of the 3xTg‐AD murine model of AD at the pre‐plaque stage and to understand perturbations in neurons, which may help to explain the synaptic plasticity deficits and long‐term memory impairments observed in AD models.
