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Folia Neuropathologica
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Review article
What causes alzheimer’s disease?

Richard A. Armstrong

Folia Neuropathol 2013; 51 (3): 169-188
Article file
- What causes.pdf  [0.25 MB]
 
 

Introduction

Ever since the first description of pre-senile dementia by Alois Alzheimer in 1907 [5], the presence of cognitive impairment together with the formation of senile plaques (SP) and neurofibrillary tangles (NFT) have been regarded as the defining clinico-pathological features of Alzheimer’s disease (AD) [13,103,126]. The term AD was first used in 1910 by Kraepelin based on the clinical and pathological description of Alzheimer’s original cases. Of the two cases described by Alzheimer, however, both had numerous SP, but only one had significant numbers of NFT [76], thus identifying the pathological heterogeneity characteristic of AD [4], and creating difficulties in establishing a single theory as to its cause.

Many theories as to the cause of AD have consequently been proposed. It is not the intention to discuss every theory but to concentrate on those most likely to be involved. Hence, the theories are discussed in eight categories: (1) acceleration of aging, (2) degeneration of anatomical pathways, including the cholinergic and cortico-cortical pathways, (3 environmental factors such as exposure to aluminium, head injury, and malnutrition, (4) genetic factors including mutations of amyloid precursor protein (APP) and presenilin (PSEN) genes, and allelic variation in apolipoprotein E (Apo E), (5) a metabolic disorder resulting from mitochondrial dysfunction, (6) vascular factors such as a compromised blood brain barrier, (7) immune system dysfunction, and (8) infectious agents. This review discusses the evidence for and against each of these hypotheses and develops a general theory as to the cause of AD. The implications of this theory are considered with reference to future research and treatment of AD.

Theories based on aging

That AD may be an accelerated form of natural aging is based on the observation that the many pathological changes in AD are similar to those present in normal aging apart from their severity [156]. Hence, in cognitively normal brain, there is an age-related reduction in brain volume and weight, enlargement of ventricles, and loss of synapses and dendrites in selected areas [94]. Accompanying these changes are the characteristic pathological features of AD, including SP and NFT [6]. Hence, in 60 normal elderly cases [117], 32/60 had no SP, although 30/60 were younger than 65 years, 13/60 had SP in the hippocampus, mainly in sector CA1 and the subiculum, and 12/60 had SP in temporal cortex comprising mainly the ‘primitive/mature’ and ‘burnt-out’ types of plaque. It was concluded that it was not possible to distinguish early-stage AD from normal aging at post-mortem [117]. Similarly, SP have been observed in 60% of normal elderly cases, albeit at lower density than in AD [37]. Moreover, Arrigada et al. [29] reported SP in most normal individuals greater than 55 years of age and concluded that there could be a ‘continuum’ of pathological change from elderly non-demented brains, early stage AD, to advanced AD [16].

The density of neuritic plaques (NP), which in-corporate dystrophic neurites (DN), and SP with a distinct ‘core’ (‘classic’ plaques), may not be significantly different in AD and aging [36]. A greater vascular involvement in the formation of SP has been observed in aging than in AD [36]. Hence, SP have been observed in the frontal and temporal cortex in 15/20 patients with critical stenosis, most often in the depths of the gyri [180]. Alterations in cerebral perfusion may therefore play a role in SP formation and SP may not always be causally related to dementia. A further study of non-demented patients with critical coronary artery disease suggested that some patients had similar densities of SP to AD, numbers of SP being directly proportional to the duration of arterial disease [181]. In addition, there may a close link between ischaemic brain episodes and sporadic cases of AD (SAD) suggesting that neovascular factors could aggravate the progression of the disease [150,151].

The most important molecular constituent of the SP is β-amyloid (Aβ [72], an approximately 4 kDa peptide arising by constitutive cleavage of a trans-membrane amyloid precursor protein (APP) [79]. Three subtypes of Aβ deposit are commonly observed in AD, viz., diffuse, primitive, and classic deposits [11,55]. Studies of Aβ deposition have also demonstrated a clear overlap between AD and normal aging. Hence, Aβ deposits were present in non-demented individuals greater than 60 years but were rare before this age [118]. After 60 years of age, Aβ deposits were present in a variety of diseases as a result of aging, especially in the temporal cortex, thus blurring the distinction between AD and related disorders [118]. In 14 non-demented elderly cases, Aβ deposits were present in the temporal lobe in 8/14, but only in cortical gyri, the CA sectors of the hippocampus and dentate gyrus being spared [9]. Moreover, there was a considerable variation in the density of deposits in control cases and a significant overlap with AD. The pattern of clustering of Aβ deposits was also similar in control and AD cases, i.e., in cortical gyri, deposits were aggregated into clusters regularly distributed parallel to the pia mater, suggesting a similar pathogenesis [9]. In a further study of centenarians [56], Aβ deposits were recorded in the parahippocampal gyrus (PHG) of patients, whether demented or not, but the hippocampus was unaffected, suggesting a little relationship between lesion density and severity of mental deficits.

Whether NFT occur as a result of normal aging is more controversial. The most important constituent of the paired helical filaments (PHF) and straight filaments which comprise cellular NFT in AD is the microtubule-associated protein (MAP) tau. Some studies suggest that the majority of cognitively normal individuals have minimal tau-immunoreactive NFT [105] and also less astrocytosis and microglial reaction [51]. By contrast, Bouras et al. [40] found that all non-demented cases had NFT in lamina II of the entorhinal cortex (EC) and in sector CA1 of the hippocampus. Moreover, in non-demented individuals, NFT were more numerous in the medial temporal lobe and in cortical association areas when a memory deficit was present suggesting NFT could be the pathological substrate for memory loss in non-demented as well as demented cases [82]. In the me-dial temporal lobe, the perforant path appears to be sensitive to tau-immunoreactive pathology in AD and these changes are distinct from those seen in normal aging even in the oldest individuals [67].

Two further aging processes may be involved in AD. First, an age-related breakdown of myelin [33], although other studies suggest that myelin loss occurs late in AD and is secondary to neuronal degeneration [43]. Second, the loss of cells in the locus caeruleus (LC), which provides noradrenaline to the cortex via terminal varicosities, and stimulates microglia to suppress production of Aβ [87]. Tau-immunoreactive NFT appear early in the LC in aging, mild cognitive impairment (MCI), and in AD apparently forming a continuum [80]. Loss of cells in the LC may therefore induce an age-related impairment of the blood brain barrier, thus implicating vascular factors in AD.

These studies suggest that the differences between AD and the normal elderly are largely quantitative rather than qualitative and there may be a ‘continuum’ of pathological change connecting these cases [17]. Nevertheless, the distribution of the pathology may differ in AD and control brain, being more localised to areas of the temporal lobe in aging and with a more extensive spread into the hippocampus and cortical association areas in AD [53,129,139]. An important question, therefore, is whether AD is an exacerbation of normal aging resulting from enhanced spread of the pathology along anatomical pathways.

Theories based on the degeneration of anatomical pathways

Cholinergic hypothesis



A specific degeneration of the cholinergic neurotransmitter system was one of the earliest theories as to the cause of AD [148]. Several studies prior to 1980 showed significant losses of acetylcholine in the AD brain [41]. Subsequent studies also showed reductions of choline acetyltransferase (CAT), values in the cerebral cortex being 30-50% of those of controls [175], and in levels of acetylcholinesterase (ACHE) especially late in the disease [148]. In the cerebral cortex, there were correlations between the density of SP and levels of CAT, and in the hippocampus between the density of NFT and CAT [147,148]. Moreover, loss of neurons was reported in the nucleus basalis of Meynert (nBM), a site of diffuse cholinergic projection to the cortex [202], and it was suggested that cortical SP may develop on the axon terminals of nBM cells [194]. Hence, AD was considered as the ‘cholinergic’ analogue of Parkinson’s disease (PD); as in the latter, there was degeneration of dopamine neurons originating in the substantia nigra, together with their cortical projections.

Rosser and Mountjoy [163], however, cautioned against extrapolating data from neurotransmitter system studies obtained post mortem as significant changes often occur at the extremes of life. In addition, it became clear that several neurotransmitter-specific neurons contribute neurites to SP [186] and that multiple neurotransmitter deficits were common in AD [46]. Hence, Bowen [42] found increased 5-hydroxytryptamine (5-HT) turnover in AD and suggested that this was due to a selective loss of cortical 5-HT neurons and the subsequent denervation of ascending projections. Hence, although degeneration of the cholinergic system undoubtedly occurs in AD, it is only a part of a more widespread neuronal degeneration affecting many anatomical pathways.



Cortico-cortical pathways



Several lines of evidence suggest degeneration of anatomical pathways connecting different parts of the cerebral cortex occurs in AD [53,139]. A major feature of the anatomical structure of the cerebral cortex is the replicated local neural circuit represented by ‘columns’ or ‘modules’ [130]. The diameter of individual cortical modules varies between 500 m and 1000 m, depending on the region, and there are specific connections between ordered sets of columns [90,130]. First, there is a reciprocal projection between a specific cortical area and a dorsal thalamic nucleus. Second, there are inputs to the cortex from generalised regulatory systems, e.g., from the basal forebrain, such as the nBM, and monoaminergic nuclei of the brain stem such as the LC. Consequently, the cortex is interlaced by clusters of fine noradrenergic fibres which repeat at 30-40 m intervals. Third, homologous neocortical areas, with the exception of the striate cortex and primary somatosensory cortex, are reciprocally connected in both hemispheres via commissures, both the commissural and ipsilateral association fibres terminating in vertically oriented columns 200-500 m in width, alternating in a regular sequence with zones of comparable width free of such connections. Fourth, within a hemisphere, different regions are connected by fibres of the short and long cortico-cortical projections [53,90]. The cells of origin of these projections are also clustered and occur in bands approximately 500-1000 m in width [90].

A number of studies suggest that AD is linked to degeneration of these cortical pathways. First, Scheff and Price [168] measured loss of synaptophysin reactivity in the cortex in AD and related it to synapse loss in the temporal lobe, while Wakabayashi et al. [198] found a decrease in the synaptic marker SP6 in all regions of the AD brain. Second, Pearson et al. [139] studied the distribution of NFT in AD and observed they were located in the cell bodies that give rise to the cortico-cortical pathways, SP developing at their terminals and collateral branches. It was suggested that the disease could spread via these pathways in the orthograde and/or retrograde direction. This pattern of spread was also observed by Hiorns et al. [90] who concluded that in AD, severely affected regions were interconnected by cortico-cortical pathways. The most explicit description of this hypothesis, however, is by De Lacoste and White [53] in which the authors describe AD as a ‘disconnection syndrome’, characterised by disruption of all afferent/efferent connections between the hippocampus, cortex, and the rest of the brain. Hence, if cortico-cortical projections are selectively vulnerable, the pathology may spread in a stepwise fashion via these connections, SP arising from the distal axonal projections of degenerating NFT-bearing neurons [53,139]. In support of this hypothesis, Roberts et al. [160] postulated that regions of the medial temporal lobe are affected first, especially laminae II pre- neurons of the EC, followed by association areas, and then the primary sensory areas. EC neurons exhibit high levels of APP, which is converted into Aβat the synaptic terminal resulting in loss of synaptic connectivity [160]. Several studies also suggest that NFT in AD exhibit a spatial pattern consistent with their development in relation to the cortico-cortical pathways [25]. Hoesen and Solodkin [91], for example, showed that NFT selectively damage strips of the cortex and hippocampus, columns of NFT exhibiting a regular periodicity repeating every 80-120 m and representing 4-5 cell diameters, and with a spacing of 300 m. With a greater duration of disease, NFT gradually filled up these columns giving rise to clusters of NFT of increasing size, a result also reported by Armstrong [8].



Cell to cell transfer of pathogenic proteins



One of the first studies to suggest that the degeneration in AD could spread across normal synaptic projections, and involve the transfer of substances between neurons, was by Saper et al. [165]. More recent research confirms these ideas and suggests that pathogenic proteins, including tau, -synuclein, the disease form of prion protein (PrPsc), and Aβ may be secreted from cells, enter other cells, and seed small intracellular aggregates within these cells [73,184] (Fig. 1). Hence, tau and Aβ could exit cells via exocytosis or secretion and enter a new cell by endocytosis or by interactions with membrane lipids. Transfer may also occur via tunnelling nanotubes (TNT) which connect various neurons [184]. For example, if tau spreads from cell to cell in the cortex, the resulting NFT may exhibit a spatial pattern which reflects this spread. Previous studies have suggested non-random distributions of NCI in the cerebral cortex of various disorders, the inclusions often exhibiting a distinct clustering pattern consistent with their spread via the cortico-cortical pathways [25].

Theories based on environmental factors

Many environmental factors have been linked to AD, but most studies relate to three such variables, viz., exposure to aluminium (Al), effect of head trauma, and the influence of diet and malnutrition.



Aluminium



Much of the evidence that Al is a cause of AD is circumstantial and controversial [21]. Epidemiological studies [77,120,133] have found little correlation between environmental Al and AD. In addition, out of 13 studies, in which gross brain tissue has been analysed for Al, 9/13 found enhanced levels in AD brain, while 4/13 found no significant differences compared with control brains [34]. The significance of enhanced Al levels in brain is also unclear since damaged brains may accumulate Al [21]. The presence of Al may also be linked to the formation of SP and NFT. Studies have either reported [61], or not reported [109], Al in association with the cores of classic Aβ deposits, but it is not clear whether this type of SP is especially frequent in AD [18]. Al has also been detected in pyramidal neurons containing NFT [142,143]. It has been suggested that Al can bind to DNA and affect processing of cytoskeletal proteins resulting in the formation of NFT. Nevertheless, there is little evidence that Al can bind significantly to DNA [57,120]. In addition, patients with renal failure, exposed to high concentrations of Al, do not develop cellular NFT [142]. Furthermore, whether or not exposure of experimental animals [52] or cell cultures [171] to Al results in NFT formation has been controversial. Experimentally induced cytoskeletal change usually results in the formation of straight 10 nm filaments, unlike the majority of NFT, which are composed of 20-24 nm twisted filaments [190], and which have a different molecular composition in AD [81]. Finally, neuropsychological conditions, which arise from acute exposure to Al, such as dialysis dementia [7] or bladder irrigation [131], in which a 1% alum solution is used to treat haemorrhagic cystitis, probably have little significance apart from demonstrating that Al in acute doses can be neurotoxic.



Head injury



Head trauma results in a primary injury which frequently spreads via inflammatory cytokines to initially unaffected regions, thus amplifying the original injury due to the activation of microglia and central nervous system immune cells [71]. Several observations suggest a link between head injury and AD. In survivors of the head injury, APP is observed in neuronal perikarya and in DN surrounding Aβ deposits, as in AD [68]. The formation of Aβ from APP occurs within the synaptic terminal fold of axons, the presence of glia not being necessary for this conversion. Hence, the production of APP may be a component of the brain’s response to neuronal injury [68]. Subsequently, it was shown that specific neurons in the medial temporal lobe secreted large quantities of APP and that there were more APP-immunoreactive neurons in these areas in head injury patients [124]. Hence, an increased expression of APP in head trauma cases may be an acute phase response to neuronal injury [161], the overexpression of APP leading to the deposition of Aβ. Several acute phase proteins are localised within Aβ deposits in AD including amyloid-P, complement factors, and -antichymotrypsin [98]. Furthermore, Regland and Gottfries [154] proposed that APP maintains cell function by supporting neuronal growth and survival. The possible neurotrophic action of APP is supported by the observation that it shares structural features with the precursor for the epidermal growth factor [154]. NFT may also be a part of the neurons response to injury [205]. These studies suggest that the formation of pathological proteins as a result of brain injury is one method by which AD pathology develops and is then propagated within the brain by cell to cell transfer.



Diet and malnutrition



Abalan [1] was one of the first authors to propose that AD could be caused by malnutrition. This hypothesis is based on clinical observation of AD patients who often exhibit emaciation and cachexia, urinary tract infections, terminal bronchopneumonia, and low triceps skinfold. Low serum albumin, iron, folate, tryptophan, vitamin B12, and low cerebral metabolism of glucose and oxygen may also be present. These symptoms suggest a protein calorie malnutrition syndrome in AD which could result in the development of NFT due to chronic nutritional deficiencies of calcium and magnesium. A problem with this type of hypothesis, however, is in determining cause and effect, as malnutrition could be a consequence of the disease resulting from the mental state of the patient [1]. A more direct demonstration of a link between diet and AD has been reported by Sparks et al. [182] in which deposition of Aβ was induced in rabbits fed with high levels of dietary cholesterol. In addition, McCaddon and Kelly [121] found in a human family carrying a mutation of the APP gene (APP717, Val-Glycine), that individuals with AD had a greater vitamin B12 deficiency, compared with unaffected members. It was concluded that this link was unlikely to be secondary and to be a consequence of impaired dietary intake. A B12 deficiency could then result in a reduction of monoamine transmitters and in cholinergic activity.

Theories based on genetics

In the 1990s, strong evidence emerged of the connection between familial AD (FAD) and specific genetic factors. Hence, small numbers of cases were linked to APP mutations [48,74] and a larger subgroup to PSEN1/2 mutations [112,173], while others genes are currently unidentified [179]. In addition, allelic variation in the Apo E locus on chromosome 19 was identified as a significant risk factor, especially in late-onset AD [185].

APP

A variety of Aβ peptides are formed as a result of secretase cleavage of APP [79]. The most common of these peptides is Aβ42, found largely in discrete Aβ deposits, whereas the more soluble Aβ40 is also found in association with blood vessels [125] and may develop later in the disease [54]. In addition, mutations of APP within the Aβ coding region may result in the deposition of Aβ38 in vessel walls, especially in those cases with extensive cerebral amyloid angiopathy (CAA) [128]. Causation of AD could also be attributable to early soluble peptide oligomers [69], which vary with the type of mutant, thus providing a genetic basis for variations in pathogenesis among FAD cases. The discovery of Aβ led to the formulation of the ‘Amyloid Cascade Hypothesis’ (ACH), the most influential model of the molecular pathology of AD developed over the last 25 years [84] (Fig. 2). Essentially, the ACH proposes that the deposition of Aβ peptides is the initial pathological event in AD leading to the formation of SP and NFT, and then to cell death and dementia, both SP and NFT acquiring several additional proteins during their formation, such as Apo E, ubiquitin, and complement [14].

Evidence in support of the ACH comes from several sources. First, experiments using transgenic mice expressing high levels of APP result in Aβ deposition, synaptic loss, and gliosis [66]. Second, FAD caused by APP717 (valine–isoleucine) mutation have significant numbers of NFT thus supporting a link between APP and the cytoskeleton [110]. Third, cases linked to PSEN1 have greater numbers of SP and NFT compared with cases of sporadic AD (SAD) suggesting that PSEN1 may also increase tau deposition [172].

There are two main problems regarding the ACH as originally formulated. First, as demonstrated in head injury patients, SP and NFT may be reactive products resulting from cellular neurodegeneration rather than being its cause [27]. The results of animal experiments also suggest that the formation of Aβ could be a reactive process. Experimental lesions that damage the nucleus basalis in rat brain elevate APP synthesis in the cerebral cortex suggesting that the production of APP is a specific response to loss of functional innervation [199]. In addition, chemical lesions of the nucleus basalis using N-methyl-D-aspartate (NMDA) elevate APP synthesis in cortical polysomes [199] and, in areas of brain damaged by kainite [101], APP695 was recorded in DN near to the lesion. Intrathecal or intraparenchymal injections of a toxin also induced APP in hippocampal neurons subsequent to neuronal damage [97].

Lesion experiments may also induce pathological changes leading to NFT. Denervation of the dopamine pathways and septal lesions which affect both the cholinergic system and -aminobutyric acid (GABA) neurons projecting to the dentate gyrus, for example, result in loss of dendritic microtubule associated protein 2 (MAP2) and tau-immunoreactivity in dentate gyrus granule cells [193]. Hence, denervation may cause transsynaptic changes in dentate gyrus neurons which represent a precursor stage to NFT.

The second objection to the ACH is that there is no generally accepted mechanism to explain how Aβ deposition leads to NFT [59]. There have been several attempts to establish such a mechanism but none have become universally accepted. First, Aβ may promote the formation of intracellular tau, although the mechanism of this interaction was uncertain [70]. Second, there may be a synergistic interaction between NFT and Aβ [136,177]. Third, when foetal rat hippocampal and human cortical neurons were treated with Aβ, fibrillar forms of Aβ could apparently induce tau phosphorylation. Hence, amyloid fibril formation might alter the phosphorylation state of tau resulting in the loss of microtubule binding capacity.

Studies have also suggested that SP and NFT occur in distinct but independently distributed patterns in AD [19,93]. Studies of the spatial patterns of SP and NFT show them to be clustered, the clusters often being regularly distributed parallel to the pia mater [8]. Clusters of SP and NFT, however, are frequently distributed independently of each other, i.e., neither in nor out of phase, which would not support a direct pathogenic link between them. In addition, SP and NFT may be separated in the brain both in space and in time [119]: in the entorhinal cortex, for example, NFT may precede the appearance of SP [59]. Perez et al. [140], however, showed that Aβ25-35 could result in tau aggregation and that a decrease in Aβ aggregation was induced by tau peptides. Hence, aggregation of tau may be correlated with disassembly of Aβ which could explain the lack of spatial correlation of the SP and NFT [19].

In transgenic experiments [13], the presence of APP mutations alone or in combination with PSEN1 can induce Aβ deposits in normal brain. Apart from evidence of hyperphosphorylated tau in DN associated with the plaques, these mutations do not appear to induce tau pathology or a significant inflammatory response. Hence, the presence of tau transgenes in the form of a triple model appears to be necessary to completely replicate AD pathology [13]. Hence, the ACH as originally formulated does not appear to provide a complete explanation for AD.

PSEN genes

The most common type of FAD is linked to mutations of the PSEN genes [112,173] and the effect of these mutations is also assumed, albeit more indirectly, to lead to the enhanced deposition of Aβ [79]. Full length PSEN is composed of nine trans-membrane domains located on the endoplasmic reticulum membrane. Endoproteolytic cleavage of PSEN and assembly into -secretase complex is followed by transport to the cell surface, thus potentially influencing APP processing [92]. Hence, mutant PSEN1 could enhance 42-specific--secretase cleavage of normal APP resulting in increased deposition of amyloid-forming species [188]. PSEN may also act through loss of function by a reduction in -secretase activity [206].

PSEN, however, may have a variety of other functions. The PSEN1 gene may be involved in notch signalling [183] and therefore important in cell differentiation. PSEN1/2 genes may also be involved via the perturbation of cellular calcium homeostasis [207] or in interactions with the transcriptional coactivator cAMP-response element binding (CREB-binding) protein which plays a key role in regulating gene expression [64]. PSEN1 may also mediate neuroprotective functions by ephrin-B [32] and a decline in such protection could be involved in AD.

Apo E

An allelic variation in Apo E has been identified as a major risk factor in late-onset AD, individuals with AD having 2-3 times the frequency of allele 4 compared with cognitively normal individuals [185]. In addition, allele 4 may accelerate the development of AD pathology within the aging brain [137] and hence, is often associated with an earlier disease onset [75].

The relationship between the deposition of Aβ and Apo E genotype has been controversial. The majority of studies, however, report increased amyloid deposition in individuals expressing allele 4 [35,38,152]. In addition, the clustering pattern of NP may reflect the degeneration of specific cortico-cortical and cortico-hippocampal pathways [10]. Cellular NFT often occur in regularly distributed clusters along the cortex [8] and NP may develop on the dendrites and axon terminals of NFT containing cells [53,139]. Individuals expressing allele 4 are associated with the development of NP in smaller and denser clusters compared with the other Apo E genotypes, which may reflect a more specific pattern of neurodegeneration [22].



Other genes



APP and PSEN1/2 genes together account for less than 5% of cases of AD [78,90]. Late-onset AD (LO-AD) is likely to be a multifactorial disease with the potential involvement of multiple genes. Hence, genome wide studies have revealed genes on chromosomes 6, 9, 10, 11, 12, 14, 18, 19, and the X chromosome could be involved in AD [44,176] with the

most compelling case for a gene on chromosome 12 [138]. Further studies map this locus to 12q13, a region which encompasses the vitamin D receptor (VDR) gene [200]. This gene is a major mediator of the activity of vitamin D and insufficiency of this vitamin has been implicated as a risk factor for AD. In addition, the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene has been implicated in LO-AD [3]. A major problem with postulating genetic factors as the cause of AD, however, is the similarity of FAD and SAD phenotypes [49,134] and therefore, no specific gene mutation is an essential condition to generate the AD phenotype.

Theories based on mitochondrial dysfunction

Theories that AD may be due to mitochondrial dysfunction have a long history [39] and rely on several lines of evidence. First, an early change in AD is the presence of swollen and distorted mitochondria accompanied by a decline in the cerebral metabolic rate [39]. Second, there may be a deficiency of several enzymes involved in carbohydrate utilization in AD including such mitochondrial markers as phosphofructokinase (PFK) and pyruvate dehydrogenase [39]. Third, part of the familial aggregation of AD may be accounted for by excess maternal versus paternal inheritance, consistent with mitochondrial inheritance. Hence, genomic analysis of 1007 individuals suggested that possession of specific haplotypes could reduce the risk of AD, and therefore, there is a possibility of haplotypes that would increase the risk [159]. The possibility of a genetic origin of mitochondrial dysfunction in AD has led to the formulation of the ‘mitochondrial cascade hypothesis’ (MCH) in which it is the mitochondrial dysfunction that is the root cause of the events leading to the ACH [189]. Nevertheless, it is possible that mitochondrial dysfunction is a further consequence of the ACH [189]. Fourth, ‘adaptor protein evolutionarily conserved signalling intermediate in Toll pathway’ (ECSIT) is a protein which may act as a molecular sensor, ascertaining cell homeostasis in response to oxidative damage by Aβ[178]. Protective molecules could then be specifically activated in response and this failure could result in severe mitochondrial damage, promote apoptosis, and result in synaptic dysfunction and neuronal death [178].

Theories based on blood brain barrier dysfunction

The involvement of the cerebral blood vessels in the pathogenesis of AD has been controversial [30]. Some studies have found spatial correlations between Aβdeposits and blood vessels suggesting that degeneration of blood vessels or diffusion of substances from vessels could be involved in the formation of Aβ deposits [127,145,146]. By contrast, other studies conclude that the spatial correlations observed between Aβ deposits and blood vessels are fortuitous and arise because of the presence of high densities of capillary profiles and Aβ [102,115]. In the cerebral cortex of cases of SAD, however, of the three Aβ deposit subtypes, only the classic Aβ deposits exhibited a consistent spatial relationship with blood vessels [15,23]. Classic deposits were clustered specifically around larger blood vessel profiles, such as the vertically penetrating arterioles, the number of classic deposits declining exponentially with distance from the vessels [15].

A number of factors could explain the correlation between Aβ deposits and blood vessels in AD (Fig. 3). First, Aβ could develop in association with the basement membranes or smooth muscle of blood vessel walls [145,204]. Tian et al. [192] found that blood vessels underwent degenerative changes in AD accompanied by Aβdeposition and loss of smooth muscle cells. Second, Aβ could be released by axon terminals or reactive glial cells juxtaposed to vessel walls [96]. Attems et al. [30], for example, found that Aβ42 was deposited within the glia limitans rather than the capillary walls. Third, diffusion could occur from degenerating arterioles or from clusters of capillaries surrounding the larger blood vessels. Blood vessels with collapsed or degenerated endothelia are evident in more than 90% of AD cases [100] and occur concurrently with Aβ deposition. The integrity of the brain microvasculature may be related to neuronal degeneration and especially to age-related cell losses in the LC [87,116]. In AD transgenic mice, deposition of Aβ in blood vessels is associated with endothelial cell activation and apoptosis [170], which could encourage diffusion. Endothelial cell injury could also depend on duration of dementia [192].

If diffusion is involved in the pathogenesis of the classic Aβ deposits, then various plasma proteins may be implicated. Amyloid fibrils have been observed projecting directly from blood vessels towards classic-type deposits [196] suggesting that Aβ itself could diffuse from blood vessels. However, most Aβdeposited in the cortex is likely to be of neuronal origin [4,12]. A number of other plasma proteins could be involved including amyloid-P, -antichymotrypsin, antitrypsin, antithrombin III as well as complement factors [96,97] and Apo E [165]. The mRNAs of these proteins, however, is found in brain tissue suggesting that they are made in situ [97]. The likely exception is amyloid-P since the liver is the only tissue of the body which exhibits its mRNA [97]. Plasma proteins, such as amyloid-P, may act as ‘molecular chaperones’ and be involved in the aggregation of Aβ to form plaque amyloid. Hence, secondary damage to cerebral vessels as a result of Aβ deposition from neurons could result in the leakage of plasma proteins from the larger diameter blood vessels. These proteins could then enhance the condensation of already formed Aβ to form a solid amyloid core resulting in the observed pattern of dispersion of classic deposits around blood vessels.

Fifth, deposition of Aβ around the larger blood vessels could be a result of impaired drainage. Extracellular fluid is drained from the brain to the cervical lymph nodes via the perivascular channels [191] and therefore, Aβ around vessels could be attributable to overloading of this system. Such a process could also lead to enhanced deposition of Aβ in the immediate vicinity of the blood vessel and a negative exponential distribution of amyloid deposits. Sixth, another function of Aβ may be to serve as an acute response to vessel damage and to seal vascular leakage [106].

Vascular pathology may also be involved in the pathogenesis of Aβ deposits in FAD. Hence, plasma Aβ may be increased in FAD as well as in SAD [187]. In addition, a proportion of FAD cases exhibit CAA similar to that observed in SAD, viz., the deposition of Aβ in and around the major blood vessels. Mutations of the APP gene within the Aβregion are often associated with familial CAA [174] while APP mutations outside the Aβ region result in a pathology deficient in Aβ40, and with lower levels of CAA [108]. In addition, possession of one or more ApoE 4 alleles significantly increases the risk of AD, and could also be linked to vascular pathology. In transgenic mice, for example, ApoE markedly promotes CAA associated vessel damage [65].

Theories based on immunology

There are several lines of evidence supporting the presence of immune system dysfunction in AD [123,132,162]. Complement proteins associated with the ‘classical’ pathway [123], brain reactive antibodies [132], immunoglobulins [62,95], circulating immune complexes (CIC) in peripheral tissue and cerebral blood vessels [86], helper/inducer and cytotoxic/suppressor T-cells [123], and abundant reactive microglia [123] have all been observed in AD. Complement system proteins may act as pattern recognition molecules mediating the uptake of Aβ by glial cells which express complement receptors [195]. Significant alterations in the major histocompatibility locus (MHC) antigens have also been demonstrated [197] suggesting either increased resistance or susceptibility to an antigen in AD [50,88]. These immune reactions could be a response to the pathological processes of AD and especially to the deposition of Aβ. However, of more interest is whether immune reactions to an environmental antigen could be a cause of AD.

Studies suggest that exposure to metals can in-duce an immune response in peripheral tissues [20]. First, mercury can induce antibodies against renal antigens and inhibit RT6+ T-cells [107]. Second, exposure to cobalt, Al [21], tin, zirconium, and beryllium have been associated with lung inflammatory disease [63]. Lymphocyte transformation, an increase in T-cells, and the development of a granulomatous pneumonitis have been observed in these disorders [63]. Third, Al phosphate and hydroxide are used as vaccine adjuvants [83], i.e., they enhance the immune response to an antigen [60]. Adjuvants containing Al can activate complement proteins [153], prime helper T-cells for IgE production [104] and induce antibody [155]. Since many metals can be absorbed into the brain [34], it is possible that a metal-induced immune activation could occur in brain and contribute to the pathogenesis of AD.

The essential features of a possible hypothesis have been proposed by Sartvetnick and Fox [166] (Fig. 4). The immune system can respond to antigens expressed by the major histocompatibility complex (MHC) pathway expressed in non-immune cells, MHC-antigen complexes on the cell surface then initiating a T-cell response. Hence, metals entering cells via transferrin receptors or directly could bind to peptide fragments and result in the production of CD4+ cells [122] which recognise peptide fragments taken up by macrophages and other cells. Potentially pathogenic metals such as Al could therefore be taken up into antigen-presenting cells in the brain resulting in an immune response. This is unlikely to occur in neurons or in astrocytes directly, as they do not express MHC antigens [123], but could occur in microglia or capillary endothelial cells which do express these antigens. The result could be the production of CD4+ T-cells which infiltrate the neuropil as a consequence of disruption of the blood brain barrier, and cluster around antigen-presenting cells. T-cells release lymphokines, such as interferon-gamma (ITN-), which activate microglia [201] resulting in the formation of free radicals and an oxidative attack, which can damage adjacent neurons. In addition, the pro-inflammatory cytokine IL-15 is produced by activated blood monocytes, macrophages, dendritic cells, and activated glia, and can cause T-cell proliferation and induction of cytolytic effector cells resulting in the formation of immunoglobulins [157]. These processes could result in an increase in APP and PHF-tau and the formation of Aβ SP, and NFT due to loss of synaptic connections. Nevertheless, even if a metal such as Al enters neurons, there is little evidence that it reacts with MHC proteins in human brain cells and no evidence linking variations in MHC antigens in AD and susceptibility to metal-induced immunity. Moreover, there is also doubt as to the degree to which effector CD4+ T-cells can enter the neuropil. In addition, there is no evidence that such a process results in Aβ deposits, SP, or NFT. The most obvious immune response observed in histological preparations of AD brain is the presence of microglia associated with mature Aβ deposits [119,135], which supports the hypothesis that the immune reactions are likely to occur as a response to the production of Aβ.

A further immunological factor in AD involves the action of peptidyl-arginine deiminases (PAD), enzymes which catalyse a post-translational reaction termed ‘citrullination’ by converting arginine to citrulline [2]. A selective expression of PAD2 and PAD4 in astrocytes and neurons respectively results in a citrullinated protein expression in the hippocampus and cerebral cortex. Hence, neuronal loss in AD could result from the loss of cellular contents, including citrullinated proteins, resulting in an auto-immune response and the production of auto-antibodies [2].

Theories based on infectious agents

Indirect evidence that infection could be a cause of AD has been reported by Wisniewski et al. [203] who suggested that invasion by a virus could cause activation of microglia and pericytes and ultimately, amyloid deposition. In addition, Libikova et al. [113] suggested that the virus herpes simplex (HSV), to which antibodies may be observed in the cerebral spinal fluid (CSF) in AD, could induce abnormal protein formation and result in PHF and NFT. This type of theory has been given further credibility by observations of marked structural and biochemical alterations in regions associated with olfaction, most notably the olfactory bulb and EC [58]. The olfactory system is a possible point of entry into the brain for an infectious agent or protein [117]. Hence, experimentally introduced viruses into body cavities and organs often result in high titres of the virus in olfactory epithelium, olfactory bulb, and other brain regions. Nevertheless, it is unlikely that HSV is the responsible virus, as it does not typically enter the brain via the olfactory system [164].

Recent research on cell to cell transfer of pathogenic proteins has re-established interest in infectious agents as a cause of AD and related neurodegenerative diseases [73,184]. The similarity in the properties of Aβ and PrPsc in AD and Creutzfeldt-Jakob disease (CJD), respectively [26], has also contributed to this debate. Such cell to cell transfer raises the possibility, first proposed by Braak and colleagues [85], that in PD, a pathogenic agent introduced via ingestion and/or inhalation, may transfer along axons to basal areas of brain, the brain stem, and then to the cerebral cortex. Hence, in PD, -synuclein could be the target of the unknown agent causing protein misfolding and subsequent spread via connecting cells (Fig. 1). -Synuclein taken up from the extracellular space can induce aggregation of other -synuclein proteins in recipient cells. By analogy with PrPsc, nucleation or seeding activity of -synuclein may result in a core of transferred -synuclein surrounded by additional layers of cytoplasmic -synuclein contributed by the host cell. Aβ and tau may also have these properties and therefore, cell to cell transfer of an externally acquired infectious agent or protein could be involved in AD.

Discussion

Consideration of the theories



Many theories have been advanced as to the cause of AD and the objective of this section is to select those, which on the basis of the evidence, are most likely to be involved and then to assemble them into a plausible theory. Any theory of AD would need to explain a number of key observations: (1) the heterogeneity characteristic of AD, (2) the overlap between AD and aging, (3) the similarity of FAD and SAD, (4) that Aβ and tau may be reactive proteins, (5) that some cases of AD have few SP and/or NFT, (6) that the pathology is spatially related to cerebral blood vessels, and (7) the immunological responses.

One of the major problems in assessing the validity of any theory is that it is not clear whether it is a primary or secondary event. The theories which have had the most longevity and impact are the cholinergic hypothesis and the ACH. Both are involved in the pathogenesis of AD, but do not provide a complete theory. Hence, there is evidence of cholinergic dysfunction in AD, but only as part of a multi-system degeneration. In addition, the ACH has two problems, viz., SP and NFT may be reactive rather than causal [27], and there is no accepted mechanism to explain how Aβ leads to NFT. Hence, the cholinergic hypothesis is unlikely to be the primary cause of AD and the ACH in its present form requires modification to be included in a general theory.

Of the remaining theories, interest in Al and other metals as a cause of AD has declined, although there is some evidence that Al could accumulate in the brain, interact with processes that result in Aβ deposition and tau formation [20], and that metals may cause an immune reaction in brain. In addition, hypotheses derived from the study of malnutrition and head injury, suggest that these are likely to be risk factors for AD rather than primary causes. Immunological changes and mitochondrial dysfunction in AD are also likely to be reactions to earlier pathological processes such as the formation of abnormal proteins.

By contrast, there is a clear connection between AD and normal aging [158], all features of AD can be observed to some degree in a cognitively normal brain. An important aspect of aging is age-related decline in LC neurons, and its effects on the blood brain barrier could play a role in the disease [87,116]. In addition, there is strong evidence that degeneration of specific anatomical pathways and the spread of the pathology by cell to cell transfer is important in AD.



A possible theory



It is hypothesised first, that the primary factor in AD is an age-dependent breakdown of anatomical systems and pathways within the brain and the consequence loss of synapses [47] (Fig. 5). The extent of

this aging effect, which begins early in life, is mediated by the degree of lifetime stress (the ‘allostatic load’). The brain is the ultimate mediator of stress-related mortality through hormonal changes resulting in hypertension, glucose intolerance, cardiovascular disease, and immunological problems [47]. The consequence is gradual synaptic disconnection,

neuronal degeneration, and the upregulation of ge-nes determining various reactive and breakdown products such as Aβ and tau [27,149,154,199]. These changes are most manifest initially in the EC which has a high proportion of APP reactive cells. In addition, cell losses in the LC may begin to affect the integrity of the blood brain barrier resulting in the release of proteins with chaperone-type activity. Second, in small numbers of families, specific APP or PSEN mutations directly influence the outcome of this age-related degeneration by determining the solubility and/or toxicity of the molecular product. Cells have mechanisms to protect against the accumulation of misfolded and aggregated proteins including the ubiquitin system and the phagosome-lysosome system. Neuronal degeneration in individuals with specific mutations results in the rapid formation of pathogenic Aβ and tau, and then phases of ‘secondary’ neurodegeneration, which overwhelms the protection systems. Early onset FAD is the consequence of this process. Once initiated, Aβ and tau are then likely to be propagated through the brain via cell to cell transfer from their origin in the medial temporal lobe to the hippocampus and cerebral cortex.

By contrast, in individuals without a specific genetic mutation, but where more complex genetic, e.g. Apo E, and environmental risk factors are present, the outcome of age-related loss of synapses is mainly soluble and smaller quantities of insoluble proteins which are degraded by the cellular protection systems and do not significantly accumulate to form SP and NFT. With advancing age, however, the protective systems become ess effective resulting inslowly accumulating quantities of Aβ and tau. The result of these insidious processes is that the cellular protection systems do not become overwhelmed until much later in life, the consequence being late onset SAD. Subsequently, there are a number of responses to neurodegeneration including a further disruption of the blood brain barrier, an immunological response, and mitochondrial dysfunction which could initiate phases of secondary degeneration. Disease heterogeneity [24] is attributable to variations in the pathways of spread of the pathology from its origin in the medial temporal lobe.



Predictions of the theory



The theory suggests that it is aging and the diseases associated with aging that provide the trigger initiating the cascade of events leading to AD, rather than the initial deposition of Aβ and makes a number of predictions. First, the hypothesis predicts that significant signs of neuronal degeneration in AD should precede those of Aβ deposition and that the effect of Aβ is secondary rather than primary in causing neurodegeneration. Second, that the pathogeneses of SP and NFT are not directly linked and the two lesions essentially arise independently. Third, in transgenic experiments, the effect of the transgene will be age-dependent. In a model which incorporates an APP: V717I mutation, for example, there was an age-related loss of pyramidal neurons in the hippocampus CA sectors including at sites devoid of plaque deposition [169] consistent with this prediction.



Implications



First, the theory suggests that AD is not a disease linked primarily to defective genes but a complex syndrome dependant on the rate of aging and indirectly influenced by genetic risk factors and the environment. Second, the hypothesis questions whether the presence, distribution, and molecular determinants of SP and/or NFT should continue to play an important role in pathological diagnosis. Hence, if SP/NFT are the products of brain degeneration and not its cause, they will represent relatively late stages in pathogenesis and there may be cases of AD that are difficult to classify because they may have insufficient numbers of SP and NFT or exhibit early developmental stages of these pathologies. In addition, if SP and NFT represent the consequences of specific types of neurodegeneration [11] rather than being characteristic of AD, then many cases may show combinations of pathological features, i.e., there will be a considerable degree of overlap between different disorders. Numerous examples of such cases have been reported in the literature, e.g., dementia with Lewy bodies (DLB) with associated AD pathology, Creutzfeldt-Jakob disease (CJD) with AD, Pick’s disease (PkD) with AD, and these cases are often difficult to classify [17,28]. Third, should significant effort continue to be devoted to immunotherapy and other treatments designed to remove Aβ from the brain? Such treatments could limit the degree of secondary degeneration induced by Aβ. Nevertheless, Aβ might be beneficial to the nervous system by promoting neurogenesis [114] and having a range of other protective functions [111]. In addition, excessive removal of Aβ could reduce chelation within the brain and result in enhanced oxidative stress [31].

Conclusions

Many theories have been advanced as to the cause of AD including those based on: (1) aging,

(2) degeneration of anatomical pathways, (3) environmental factors, (4) genetic factors, (5) mitochondrial dysfunction, (6) vascular factors, (7) immune system dysfunction, and (8) infectious agents. It is proposed that AD is a multifactorial disorder in which external and internal factors act together to increase the rate of normal aging (‘allostatic load’). The consequent degeneration of neural pathways and blood vessels results in the formation of abnormally aggregated proteins such as β-amyloid and tau which then spread, via cell to cell transfer, from the medial temporal lobe to affect association areas of brain and then the primary sensory areas. Variation in the pathways of spread leads to the disease heterogeneity characteristic of AD.

References

 1. Abalan F. Alzheimer’s disease and malnutrition: a new aetiological hypothesis. Med Hypoth 1984; 15: 385-393.

 2. Acharya NK, Nagele EP, Han M, Coretti NJ, DeMarshall C, Kosciuk MC, Boulos PA, Nagele RG. Neuronal PAD4 expression and protein citrullination: Possible role in production of autoantibodies associated with neurodegenerative disease. J Autoimmune 2012; 38: 369-380.

 3. Allen M, Cox C,Belbin O, Ma L, Bisceglio GD, Wilcox SL, Howell CC, Hunter TA, Culley O, Walker LP, Carrasquillo MM, Dickson DW, Petersen RC, Graff-Radford NR, Younkin SG, Ertekin-Taner N. Association and heterogeneity at the GAPDH locus in Alzheimer’s disease. Neurobiol Aging 2012; 33: DOI: 10.1016/j.neurobiolaging.2010.08.002.

 4. Allsop D, Haga S, Ikeda S, Mann D, Ishii T. Early senile plaques in Down’s syndrome brains show a close relationship with cell bodies of neurons. Neuropath Appl Neurobiol 1989; 15: 531-542.

 5. Alzheimer A. On a peculiar disease of the cerebral cortex. Allgemeine Zeitschrift fur Psychiatrie und Psychish-Gerichtlich Medicin 1907; 64: 146-148.

 6. Anderton BH. Ageing of the brain. Mech Ageing Dev 2002; 123: 811-817.

 7. Arieff AI. Aluminium and the pathogenesis of dialysis encephalopathy. Am J Kidney Dis 1985; 6: 317-321.

 8. Armstrong RA. Is the clustering of neurofibrillary tangles in Alzheimer’s patients related to the cells of origin of specific cortico-cortical projections? Neurosci Lett 1993; 160: 57-60.

 9. Armstrong RA. Beta-amyloid deposition in the medial temporal lobe in elderly non-demented brains and in Alzheimer’s disease. Dementia 1995; 6: 121-125.

10. Armstrong RA. Are neuritic plaques in Alzheimer’s disease related to cellular neurofibrillary tangles? Alz Res 1996; 2: 69-71.

11. Armstrong RA. β-amyloid plaques: stages in life history or independent origin? Dement Geriatr Cogn Disord 1998; 9: 227-238.

12. Armstrong RA. Diffuse β-amyloid (Aβ) deposits and neurons: in situ secretion or diffusion of Aβ? Alz Rep 2001; 3: 289-294.

13. Armstrong RA. Plaques and tangles and the pathogenesis of Alzheimer’s disease. Folia Neuropathol 2006; 44: 1-11.

14. Armstrong RA. The molecular biology of senile plaques and neurofibrillary tangles in Alzheimer’s disease. Folia Neuropathol 2009; 47: 289-299.

15. Armstrong RA. Spatial patterns of β-amyloid (Aβ) deposits in familial and sporadic Alzheimer’s disease. Folia Neuropathol 2011; 49: 153-161.

16. Armstrong RA. β-amyloid (Aβ) deposition in cognitively normal brain, dementia with Lewy bodies, and Alzheimer’s disease: a study using principal components analysis (PCA). Folia Neuropathol 2012; 50: 130-139.

17. Armstrong RA. On the classification of neurodegenerative disorders: discrete entities, overlap or continuum? Folia Neuropathol 2012; 50: 201-218.

18. Armstrong RA, Myers D, Smith CUM. The spatial patterns of β/A4 deposit subtypes in Alzheimer’s disease. Acta Neuropathol 1993; 86: 36-41.

19. Armstrong RA, Myers D, Smith CUM. The spatial patterns of plaques and tangles in Alzheimer’s disease do not support the ‘Cascade hypothesis’. Dementia 1993; 4: 16-20.

20. Armstrong RA, Winsper SJ, Blair JA. Hypothesis: is Alzheimer’s disease a metal-induced immune disorder? Neurodegen 1995; 4: 107-111.

21. Armstrong RA, Winsper SJ, Blair JA. Aluminium and Alzheimer’s disease: Review of possible pathogenic mechanisms. Dementia 1996; 7: 1-9.

22. Armstrong RA, Cairns NJ, Lantos PL. The spatial pattern of β-amyloid (Aβ) deposits in Alzheimer’s disease patients is related to apolipoprotein genotype. Neurosci Res Communs 1998; 22: 99-106.

23. Armstrong RA, Cairns NJ, Lantos PL. Spatial distribution of diffuse, primitive, and classic amyloid-b deposits and blood vessels in the upper laminae of the frontal cortex in Alzheimer’s disease. Alz Dis Assoc Disord 1998; 12: 378-383.

24. Armstrong RA, Nochlin D, Bird TD. Neuropathological heterogeneity in Alzheimer’s disease: A study of 80 cases using principal components analysis. Neuropathol 2000; 20: 31-37.

25. Armstrong RA, Lantos PL, Cairns NJ. What does the study of spatial patterns of pathological lesions tell us about the pathogenesis of neurodegenerative disorders. Neuropathol 2001; 21: 1-12.

26. Armstrong RA, Lantos PL, Cairns NJ. The spatial patterns of prion protein deposits in Creutzfeldt-Jakob disease: comparison with b-amyloid deposits in Alzheimer’s disease. Neurosci Lett 2001; 298: 53-56.

27. Armstrong RA, Cairns NJ, Lantos PL. Are pathological lesions in neurodegenerative disorders the cause or the effect of the degeneration? Neuropathol 2002; 22: 114-127.

28. Armstrong RA, Lantos PL, Cairns NJ. Overlap between neurodegenerative disorders. Neuropathol 2005; 25: 111-124.

29. Arriagada PV, Marzloff K, Hyman BT. Distribution of Alzheimer-type pathologic changes in non-demented elderly individuals matches the pattern in Alzheimer’s disease. Neurology 1992; 42: 1681-1688.

30. Attems J, Lintner F, Jellinger K. Amyloid beta peptide 1-42 highly correlates with capillary cerebral amyloid angiopathy and Alzheimer disease pathology. Acta Neuropathol 2004; 107: 283-291.

31. Atwood CS, Obrenovitch ME, Liu T, Chan H, Perry G, Smith MA, Martins RN. Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-β. Brain Res Rev 2004; 43: 1-6.

32. Barthet G, Dunys J, Shao ZP, Xuan Z, Ren YM, Xu JD, Arbez N, Mauger G, Bruban J, Georgakopoulos A, Shioi J, Robakis NK. Presenilin mediates neuroprotective functions of ephrin-B and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors. Neurobiol Aging 2013; 34: 499-510.

33. Bartzokis G. Alzheimer’s disease as homeostatic response to age-related myelin breakdown. Neurobiol Aging 2011; 32: 1341-1371.

34. Basun H, Forssell LG, Wellerberg L, Winblad B. Metals and trace elements in plasma and cerebralspinal fluid in normal ageing and Alzheimer’s disease. J Neural Transm 1991; 4: 231-258.

35. Beffert U, Poirier J. Apolipoprotein E, plaques, tangles and cholinergic dysfunction in Alzheimer’s disease. Ann NY Acad Sci 1996; 777: 166-174.

36. Bell MA, Ball MJ. Neuritic plaques and vessels of visual cortex in aging and Alzheimer’s dementia. Neurobiol Aging 1990; 11: 359-370.

37. Bergeron C, Ranalli PJ, Miceli PN. Amyloid angiopathy in Alzheimer’s disease. Can J Neurol Sci 1987; 14: 564-569.

38. Berr C, Hauw JJ, Delaere P, Duyckaerts C, Amouyel P. Apolipoprotein E allele e4 is linked to increased deposition of the amyloid-β-peptide (Aβ) in cases with or without Alzheimer’s disease. Neurosci Lett 1994; 178: 221-224.

39. Blass JP, Zemcov A. Alzheimer’s disease- a metabolic systems degeneration. Neurochem Pathol 1984; 2: 103-114.

40. Bouras C, Hof PR, Morrison JH. Neurofibrillary tangle densities in the hippocamal formation in a non-demented population define subgroups of patients with differential early pathologic changes. Neurosci Lett 1993; 153: 131-135.

41. Bowen DM, Davison AN. Biochemical changes in the cholinergic system of the aging brain and in senile dementia. Psychol Med 1980; 10: 315.

42. Bowen DM. The biochemistry of cortical and subcortical neurons in Alzheimer’s disease. In: Glenner GG and Wurtman RJ (eds.) Advancing Frontiers in Alzheimer’s Disease Research. University of Texas Press, Austin 1987, pp. 11-26.

43. Brun A. An overview of light and electron microscopic changes. In: Reisberg B (ed.). Alzheimer’s disease. The Standard reference. Macmillan, London and New York 1983, pp. 37-45.

44. Burns LC, Minster RL, Demirci FY, Barmada MM, Ganguli M, Lopez OL, DeKosky ST, Kamboh MI. Replication study of genome-waide associated SNPs with late-onset Alzheimer’s disease. Am J Med Genet B Neuropsych Genet 2011; 156B: 507-512.

45. Busciglio J, Lorenzo A, Yeh J, Yankner BA. β-amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 1995; 14: 879-888.

46. Carlsson A. Changes in neurotransmitter systems in the aging brain and in Alzheimer’s disease. In: Reisberg B (ed.). Alzheimer’s disease. The Standard reference. Macmillan, London and New York 1983, pp. 100-105.

47. Carroll BJ. Ageing, stress and the brain. Endocrine Facets of Ageing, Novartis Foundation Symposium 2002; 242: 26-36.

48. Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani, L, Goate A, Rossor M, Rocques P, Hardy J, Mullan M. Early onset Alzheimer’s disease caused by mutations at codon 717 of the b-amyloid precursor protein gene. Nature 1991; 353: 844-846.

49. Chui HC, Teng EL, Henderson VW, Moy AC. Clinical subtypes of dementia of the Alzheimer type. Neurology 1985; 35: 1544-1550.

50. Cohen D, Eisdorfer C, Walford R. Histocompatibility antigens (HLA) and patterns of cognitive loss in dementia of the Alzheimer type. Neurobiol Aging 1982; 2: 277-280.

51. Coria F, Moreno A, Rubio I, Garcia MA, Morato E, Major F. The cellular pathology associated with Alzheimer β-amyloid deposits in non-demented aged individuals. Neuropath Appl Neurobiol 1993; 19: 261-268.

52. Crapper DR, Karlik S, de Boni U. Aluminium and other metals in senile (Alzheimer) dementia. Aging (NY) 1978; 7: 471-489.

53. De Lacoste M, White CL III. The role of cortical connectivity in Alzheimer’s disease pathogenesis: a review and model system. Neurobiol Aging 1993; 14: 1-16.

54. Delacourte A, Sergeant N, Champain D, Wattez A, Maurage CA, Lebert F, Pasquier F, David JP. Nonoverlapping but synergetic tau and amyloid precursor protein pathologies in sporadic Alzheimer’s disease. Neurology 2002; 59: 398-407.

55. Delaere P, Duyckaerts C, He Y, Piette F, Hauw J. Subtypes and differential laminar distributions of β/A4 deposits in Alzheimer’s disease: relationship with the intellectual status of 26 cases. Acta Neuropathol 1991; 81: 328-335.

56. Delaere P, He Y, Fayet G, Duyckaerts C, Hauw J. βA4 deposits are constant in the brains of the oldest old: an immunocytochemical study of 20 French Centenarians. Neurobiol Aging 1993; 14: 191-194.

57. Dobson CB, Templer J, Day JP, Itzhaki RF. Aluminium and Alzheimer’s disease: Sites of aluminium-binding in human neuroblastoma cells. Biochem Soc Trans 1993; 21: P32.

58. Doty RL, Reyes PF, Gregor T. Presence of both odor identification and detection deficits in Alzheimer’s disease. Brain Res Bull 1987; 18: 597-600.

59. Duyckaerts C. Looking for the link between plaques and tangles. Neurobiol Aging 2004; 25: 735-739.

60. Edelman R. Vaccine adjuvants. Rev Inf Dis 1980; 2: 370-383.

61. Edwardson JA, Klinowski J, Oakley AE, Perry RH, Candy JM. Aluminosilicates and the ageing brain: Implications for the pathogenesis of Alzheimer’s disease. Ciba Found Symp 1986; 121: 160-179.

62. Eikelenboom P, Stam FC. Immunoglobulins and complement factors in senile plaques. Acta Neuropathol 1982; 57: 239-242.

63. Epstein PE, Dauber JH, Rossman MD, Daniele RP. Bronchoalveolar lavage in a patient with chronic berylliosis: evidence for hypersensitivity pneumonitis. Ann Int Med 1982; 57: 213-216.

64. Francis YI, Stephanou A, Latchman DS. CREB-binding protein activation by presenilin 1 but not by its M146L mutant. Neuroreport 2006; 17: 917-921.

65. Fryer JD, Taylor JW, DeMattos RB, Bates KR, Paul SM, Parsadamian M, Holtzman DM. Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice. J Neurosci 2003; 23: 7889-7896.

66. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, Hagopian S, Johnson-Wood K, Khan K, Lee M, Lechowitz P, Lieberberg I, Little S, Masliah E, McConlogue M, Montoya-Zavala M, Mucke L, Paganini L, Penniman E, Power M, Schenk D, Seubert P, Snyder B, Soriano F, Tan H, Vitale J, Wadsworth S, Wolozin B, Zhao J. Alzheimer-type neuropathology in transgenic mice overexpressing V717F b-amyloid precursor protein. Nature 1995; 373: 523-527.

67. Garcia-Sierra F, Hauw JJ, Duyckaerts C, Wischik CM, Luna-Munoz J, Mena R. The extent of neurofibrillary pathology in perforant pathway neurons is the key determinant of dementia in the very old. Acta Neuropathol 2000; 100: 29-35.

68. Gentleman SM, Nash MJ, Sweeting CJ, Graham DI, Roberts GW. β-amyloid precusor protein (βAPP) as a marker for axonal injury after head injury. Neurosci Lett 1993; 160: 139-144.

69. Gessel MM, Bernstein S, Kemper M, Teplow DB, Bowers MT. Familial Alzheimer’s disease mutations differentially alter amyloiod beta protein oligomerization. ACS Chem Neurosci 2012; 3: 909-918.

70. Giasson BI, Lee VM, Trojanowski JQ. Interactions of amyloidogenic proteins. Neuromol Med 2003; 4: 49-58.

71. Giunta B, Obregon D, Velisetty R, Sanberg PR, Borlongan CV, Tan J. The immunology of traumatic brain injury: a prime target for Alzheimer’s disease prevention. J Neuroinflamm 2012; 9: DOI: 10.1186/1742-2094-9-185.

72. Glenner GG, Wong CW. Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 1984; 122: 1131-1135.

73. Goedert M, Clavaguera F, Tolnay M. The propagation of prion-like protein inclusions in neurodegenerative diseases. TINS 2010; 33: 317-325.

74. Goate R, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M and Hardy J. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991; 349: 704-706.

75. Gomez-Isla T, West HL, Rebeck GW, Harr SD, Growdon JH, Locascio JJ, Perls TT, Lipsitz LA, Hyman BT. Clinical and pathological correlates of apolipoprotein E e4 in Alzheimer’s disease. Anns Neurol 1996; 39: 62-70.

76. Graeber MB, Kosel S, Egensperger R, Banati RB, Muller U, Bise K, Hoff P, Moller HJ, Fujisawa K and Mehraein P. Rediscovery of the case described by Alois Alzheimer in 1911: historical, histological and molecular genetic analysis. Neurogenetics 1997; 1: 73-80.

77. Graves AB, White E, Koepsell TD, Reifler BV, van Belle G, Larson EB. The association between aluminium containing products and Alzheimer’s disease. J Clin Epidemiol 1990; 43: 35-44.

78. Grazini M, Prabas J, Silva F, Oliveira S, Santana I, Oliveira C. Genetic basis of Alzheimer’s dementia: role of mitochondrial DNA mutations. Genes, Brain, and Behaviour 2006; 5 (suppl 2): 92-107.

79. Greenberg BD. The COOH-terminus of the Alzheimer amyloid Ab peptide: Differences in length influence the process of amyloid deposition in Alzheimer brain, and tell us something about relationships among parenchymal and vessel-asssociated amyloid deposits. Amyloid 1995; 21: 195-203.

80. Grudzien A, Shaw P, Wientraub S, Bigio E, Mash DC, Mesulam MM. The locus caeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging 2007; 28: 327-335.

81. Grunde-Iqbal I, Wang GP, Iqbal K, Wisniewski HM. Alzheimer’s paired helical filaments: identification of polypeptides with monoclonal antibodies. Acta Neuropathol 1985; 68: 279-283.

82. Guillozet AL, Weintraub S, Mash DC, Mesulam MM. Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 2003; 60: 729-736.

83. Gupta RK, Relyveld EH, Lindblad EB, Bizzini B, Ben-Efraim S, Gupta KG. Adjuvants – a balance between toxicity and adjuvanticity. Vaccine 1993; 11: 293-306.

84. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992; 256: 184-185.

85. Hawkes CH, Del Tredici K, Braak H. Parkinson’s disease: a dual hit hypothesis. Neuropathol Appl Neurobiol 2007; 33: 599-614.

86. Heinonen O, Syrjanen S, Soininen H, Talasmenii S, Kaski M, Mantyjarvi R, Syrjanen K, Riekkinen P. Circulating immune complexes in sera from patients with Alzheimer’s disease, multi-infarct dementia, and Down’s syndrome. Neurosci Lett 1993; 149: 67-70.

87. Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Oziniek L, Terivel D, Jardanhazi-Kurutz D, Walter J, Kirchoff F, Hanisch UK, Kummer MP. Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial function through norepinephrine. Proc Natl Acad Sci USA 2010; 107: 6058-6063.

88. Henschke PJ, Bell DA, Cape RDT. Alzheimer’s disease and HLA. Tissue Antigens 1978; 12: 132-135.

90. Hiorns RW, Neal JW, Pearson RCA, Powell TPS. Clustering of ipsilateral cortico-cortical projection neurons to area 7 in the rhesus monkey. Proc R Soc London 1991; 246: 1-9.

90. Hoenicka J. Genes in Alzheimer’s disease. Revista de Neurolgia 2006; 42: 302-305.

91. Hoesen GW, Solodkin A. Some modular features of temporal cortex in humans as revealed by pathological changes in Alzheimer’s disease. Cerebral Cortex 1993; 3: 465-475.

92. Honarnejad K, Herms J. Presenilins: role in calcium homeostasis. Int J Biochem Cell Biol 2012; 44: 1983-1986.

93. Hyman BT, Tanzi RE. Amyloid, dementia and Alzheimer’s disease. Curr Opin Neurol Neurosurg 1992; 5: 88-93.

94. Imhof A, Kovari E, von Gunten A, Gold G, Rivara CB, Herrmann FR, Hof PR, Bouras C and Glannakopoulos P. Morphological substrates of cognitive decline in nonagenarians and centenarians: a new paradigm? J Neurol Sci 2007; 257: 72-79.

95. Ishii T, Haga S. Immuno-electron microscopic localisation of immunoglobulins in amyloid fibrils of senile plaques. Acta Neuropathol 1976; 20: 372-378.

96. Kalaria R. The blood-brain barrier and cerebral microcirculation in Alzheimer disease. Cerebrovasc Brain Met Rev 1992; 4: 226-260.

97. Kalaria R, Kroon S, Perry G. Serum proteins and the blood-brain barrier in the pathogenesis of Alzheimer’s disease. In: Nicolini M, Zatta PF, Corain B (eds.). Alzheimer’s disease and related disorders. Advances in Biosciences 87. Pergamon Press 1993, pp. 281-282.

98. Kalaria RN, Perry G. Amyloid P component and other acute-phase proteins associated with cerebellar Aβ deposits in Alzheimer’s disease. Brain Res 1993; 631: 151-155.

99. Kalaria RN, Bhatt SU, Perry G, Lust WD. The amyloid precursor protein in ischaemic brain injury and chronic hypoperfusion. Proc 7th Inter Study Group on Pharm Mem Dis Assoc with Aging 1993; 291-294.

100. Kalaria R, Hedera P. Differential degeneration of the cerebral microvasculature in Alzheimer’s disease. Neuroreport 1995; 6: 477-480.

101. Kawarabayashi T, Shoji M, Harigaya Y, Yamaguchi H, Hirai S. Expression of amyloid precursor protein in early stage of brain damage. Brain Res 1991; 563: 334-338.

102. Kawai M, Kalaria R, Harik S, Perry G. The relationship of amyloid plaques to cerebral capillaries in Alzheimer’s disease. Am J Pathol 1990; 137: 1435-1446.

103. Khatchaturian ZS. Diagnosis of Alzheimer’s disease. Arch Neurol 1985; 42: 1097-1005.

104. Kishimoto T, Ishizaka K. Regulation of antibody responses in vitro VI. Carrier-specific helper cells for IgG and IgF antibody responses. J Immunol 1973; 111: 720-732.

105. Knopman DS, Parisi JE, Salviati A, Floriach-Robert M, Boeve BF, Ivnik RJ, Smith GE, Dickson DW, Johnson KA, Petersen LE, McDonald WC, Braak H, Petersen RC. Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 2003; 62: 1087-1095.

106. Kokjohn TA, Maarouf CL, Roher AE. Is Alzheimer’s disease amyloidosis the result of a repair mechanism gone wrong? Alzheimers Dement 2012; 8: 574-583.

107. Kosuda LL, Greiner DL, Bigazzi PE. Mercury-induced renal autoimmunity: changes in RT6+ T-lymphocytes of susceptible and resistant rats. Environ Health Persp 1993; 101: 178-185.

108. Kumar-Singh S. Cerebral amyloid angiopathy: pathogenic mechanism and link to dense amyloid plaques. Genes Brain Behav 2008; 7: 67-82.

109. Landsberg JP, McDonald B, Watt F. Absence of aluminium in neuritic plaque cores in Alzheimer’s disease. Nature 1992; 360: 65-68.

110. Lantos PL, Luthert PJ, Hanger D, Anderton BH, Mullan M, Rossor R. Familial Alzheimer’s disease with the amyloid precursor protein position 717 mutation and sporadic Alzheimer’s disease have the same cytoskeletal pathology. Neurosci Lett 1992; 137: 221-224.

111. Lee HG, Casadesus G, Zhu X, Takeda A, Perry G, Smith MA. Challenging the amyloid cascade hypothesis: senile plaques and amyloid-beta as protective adaptations to Alzheimer’s disease. Ann NY Acad Sci 2004; 1019: 1-4

112. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu C, Paul D, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu Y, Guenette SY, Galas D, Nemens E, Wijsman EM, Bird TD, Schellenberg GD, Tanzi RE. Candidate gene for chromosome 1 familial Alzheimer’s disease locus. Science 1995; 269: 973-977.

113. Libikova H, Pogady J, Weidermann V. Search for herpetic antibodies in CSF in senile dementia and mental retardation. Acta Virol 1975; 19: 493-495.

114. Lopez-Toledano MA, Shelanski ML. Neurogenic effect of beta-amyloid peptide in the development of neural stem cells. J Neurosci 2004; 24: 5439-5444.

115. Luthert P, Williams J. A quantitative study of the coincidence of blood vessels and A4 protein deposits in Alzheimer’s disease. Neurosci Lett 1991; 126: 110-112.

116. Mann DMA. The neuropathology of Alzheimer’s disease: a review with pathogenetic, aetiological, and therapeutic considerations. Mech Ageing Dev 1985; 31: 213-255.

117. Mann DMA, Tucker CM, Yates PO. Topographic distribution of senile plaques, neurofibrillary tangles in the brains of non demented persons of different age. Neuropath App Neurobiol 1987; 13: 123-139.

118. Mann DMA, Jones D. Deposition of amyloid A4 protein within the brains of persons with dementing disorders other than Alzheimer’s disease and Down’s syndrome. Neurosci Lett 1990; 109: 68-75.

119. Mann DMA, Younis N, Jones D, Stoddart RW. The time course of pathological events in Down’s syndrome with particular reference to the involvement of microglial cells and deposits of β/A4. Neurodegen 1992; 1: 201-215.

120. Martyn CN. The epidemiology of Alzheimer’s disease in relation to aluminium. Ciba Found Symp 1992; 169: 69-79.

121. McCaddon A, Kelly CL. Familial Alzheimer’s disease and vitamin B12 deficiency. Age Ageing 1994; 23: 334-337.

122. McCoy KL, Noone M, Inman JK, Stutzman R. Exogenous antigens internalized through transferrin receptors activate CD4+ T cells. J Immunol 1993; 150: 1691-1704.

123. McGeer PL, McGeer EG, Kawamata T, Yamada T, Akiyama H. Reactions of the immune system in chronic degenerative neurological diseases. Can J Neurol Sci 1991; 18: 376-379.

124. McKenzie JE, Gentleman SM, Roberts GW, Graham DI, Royston MC. Increased numbers of beta APP-immunoreactive neurons in the entorhinal cortex after head injury. Neuroreport 1994; 6: 161-164.

125. Miller DL, Papayannopoulos IA, Styles J, Bobin SA, Lin YY, Biemann K, Igbal K. Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer’s disease. Arch Biochem Biophys 1993; 301: 41-52.

126. Mirra SS, Heyman A, McKeel, D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L. The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 1991; 41: 479-486.

127. Miyakawa T, Katsuragi S, Yamashita K, Ohuchi K. Morphological study of amyloid fibrils and preamyloid deposits in the brain with Alzheimer’s disease. Acta Neuropathol 1992; 83: 340-346.

128. Moro ML, Giaccone G, Lombardi R, Indaco A, Uggetti A, Morbin M, Saccucci S, Di Fede G, Catania M, Walsh DM, Denmarchi A, Rozemuller A, Bogdanovic N, Bugiani F, Ghetti B, Tagliavini F. APP mutations in the A beta coding region are associated with abundant cerebral deposition of A beta 38. Acta Neuropathol 2012; 124: 809-821.

129. Morrison JH, Hof PR. Changes in cortical circuits during aging. Clin Neurosci Res 2007; 5: 294-304.

130. Mountcastle VB. An organizing principle for cerebral function: The unit module and the distributed system. In: The Neurosciences. 4th Study Program. Ed FO Schmitt and FG Worden 1979, pp. 21-42.

131. Murphy CP, Cox RI, Harden EA, Stevens DA, Heize MM, Herzig RH. Encephalopathy and seizures induced by intravesical alum irrigations. Bone Marrow Transpl 1992; 10: 383-385.

132. Nandy K. Immunological factors. In: Reisberg B (ed.). Alzheimer’s disease. The Standard reference. Macmillan, London and New York 1983, pp. 135-138.

133. Neri LC, Hewitt D. Aluminium, Alzheimer’s disease and drinking water. Lancet 1991; 338: 390.

134. Nochlin D, Van belle G, Bird TD, Sumi SM. Comparison of the severity of neuropathologic changes in familial and sporadic Alzheimer’s disease. Alz Dis Assoc Dis 1993; 7: 212-222.

135. Ohgami T, Kitamoto T, Shin RW, Kaneko Y, Ogomori K, Tateishi J. Increased senile plaques withouit microglia in Alzheimer’s disease. Acta Neuropathol 1991; 81: 242-247.

136. Oyama F, Shimada H, Oyama R, Titani K, Ihara Y. β-amyloid protein precursor and tau mRNA levels versus β-amyloid plaque and NFT in the aged human brain. J Neurochem 1993; 60: 1658-1664.

137. Oyama F, Shimada H, Oyama R, Ihara Y. Apolipoprotein E genotype, Alzheimer pathologies and related gene expression in the age population. Mol Brain Res 1995; 29: 92-98.

138. Panja F, Colacicco A, D’Introno A, Capurso C, Liaci M, Capurso S, Capurso A, Solfrizzi V. Candidate genes for late-onset Alzheimer’s disease: focus on chromosome 12. Mech Ageing Dev 2006; 127: 36-47.

139. Pearson RCA, Esiri MM, Hiorns RW, Wilcock GK, Powell TPS. Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer’s disease. Proc Natl Acad Sci USA 1985; 82: 4531-4534.

140. Perez P, Cuadros R, Benitez MJ, Jimeniz JS. Interaction of Alzheimer’s disease Aβ peptide 25-35 with tau protein and with a tau peptide containing the microtubule binding domain. J Alz Dis 2004; 6: 461-470.

141. Perl DP. Relationship of Aluminium to Alzheimer’s disease. Environ Health Perspect 1985; 63: 149-153.

142. Perl DP, Brody AR. Alzheimer’s disease: X-ray spectrometric evidence of aluminium accumulation in neurofibrillaty tangle-bearing neurons. Science 1980; 208: 297-299.

143. Perl DP, Pendlebury WW. Aluminium neurotoxicity: Potential role in the pathogenesis of neurofibrillary tangle formation. Can J Neurol Sci 1986; 13: 441-445.

144. Perlmutter L. Microvascular pathology and vascular basement membrane components in Alzheimer’s disease. Mol Neurobiol 1994; 9: 33-40.

145. Perlmutter L, Chui C. Microangiopathy, the vascular basement membrane and Alzheimer’s disease: A review. Brain Res Bull 1990; 24: 677-686.

146. Perlmutter L, Chui C, Saperia D, Athanikar J. Microangiopathy and the colocalisation of heparan sulfate proteoglycan with amyloid in senile plaques of Alzheimer’s disease. Brain Res 1990; 508: 9-11.

147. Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J 1978; 2: 1457-1459.

148. Perry EK, Perry RH. The cholinergic system in Alzheimer’s disease. In: Roberts PJ (ed.). Biochemistry of dementia. Wiley, New York 1980, pp. 135-183.

149. Perry G, Siedlak SL, Richey P, Kawai M, Cras P, Kalaria RN, Galloway PG, Scardina JM, Cordell B, Greenberg BD, Ledbetter SR, Gambetti P. Association of heparan sulfate proteoglycan with the neurofibrillary tangles of Alzheimer’s disease. J Neurol 1991; 11: 3679-3683.

150. Pluta R, Jabloński M, Czuczwar SJ. Postischemic dementia with Alzheimer phenotype: selectively vulnerable versus resistant areas of the brain and neurodegeneration versus β-amyloid peptide. Folia Neuropathol 2012; 50: 101-109.

151. Pluta R, Kocki J, Maciejewski R, Ulamek-Koziol M, Jabloński M, Bogucka-Kocka A, Czuczwar SJ. Ischemia signalling to Alzheinmer-related genes. Folia Neuropathol 2012; 50: 322-329.

152. Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinisto L, Halonen P, Kontula K. Apolipoprotein E, dementia and cortical deposition of β-amyloid protein. New Engl J Med 1995; 333: 1242-1247.

153. Ramanathan VD, Badenoch-Jones P, Turk JL Complement activation by aluminium and zirconium compounds. Immunol 1979; 37: 881-888.

154. Regland B, Gottfries CG. The role of amyloid β-protein in Alzheimer’s disease. Lancet 1992; 340: 467-469.

155. Reiotella R, Orasy Z. Reagenic antibody production in different mouse strains. Immunol 1969; 17: 45-54.

156. Reisberg B. Alzheimer’s disease. The Standard reference. Macmillan, London, New York 1983.

157. Rentzos M, Rombos A. The role of IL-15 in central nervous system disorders. Acta Neurol Scand 2012; 125: 77-82.

158. Richartz-Salzburger E, Stransky E, Laske C, Kohler N. Premature immunosenescence: a pathogenic factor in Alzheimer’s disease. Nervenarzt 2010; 81: 837-843.

159. Ridge PG, Maxwell TJ, Corcoran CD, Norton MC, Tschanz JT, O’Brien E, Kerber RA, Cawthorn RM, Munger RG, Kauwe JSK. Mitochondrial genomic analysis of late-onset Alzheimer’s disease reveals protective haplogroups H6A1A/H6A1B: The Cache County study on memory and aging. Plos One 2012; 7: article e45134.

160. Roberts GW, Nash M, Ince PG, Roystan MC, Gentleman SM. On the origin of Alzheimer’s disease: a hypothesis. NeuroReport 1993; 4: 7-9.

161. Roberts GW, Gentleman SM, Lynch A, Murray L, Landon M, Graham DI. β-amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer’s disease. J Neurol Neurosurg Psychiatr 1994; 57: 419-425.

162. Rogers J, Luber-Narod J. Immuno actions in nervous system: brief review with special emphasis on Alzheimer’s disease. Drugs Dev Res 1988; 15: 227-235.

163. Rossor M, Mountjoy CQ. Post-mortem neurochemical changes in Alzheimer’s disease compared with normal ageing. Can J Neurol Sci 1986; 13: 499-502.

164. Salazar AM, Brown P, Gajdusek DC, Gibbs CJ. Relation to Creutzfeldt-Jakob disease and other unconventional virus diseases. In: Reisberg B (ed.). Alzheimer’s disease. The Standard reference. Macmillan, London, New York 1983, pp. 311-318.

165. Saper CB, Wainer BH, German DC. Axonal and transneural transport in the transmission of neurological disease: potential role in system degenerations including Alzheimer’s disease. Neuroscience 1987; 23: 389-398.

166. Sarvetnick N, Fox HS. Interferon-gamma and the sexual dimorphism of auto-immunity. Mole Biol Med 1990; 7: 323-331.

167. Saunders A, Strittmater W, Schmechel D, St. George-Hyslop P, Pericak-Vance M, Joo S, Rose B, Gasella J, Crapper-MacLachan D, Albersts M, Hulette C, Crain B, Goldgaber D, Roses A. Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 1993; 43: 1467-1472.

168. Scheff SW, Price DA. Synapse loss in the temporal lobe in Alzheimer’s disease. Ann Neurol 1993; 33: 190-199.

169. Schmitz C, Rutten BP, Pielen A, Schafer S, Wirths O, Tremp G, Czech C, Blanchard V, Multhaup G, Rezaie P, Korr H, Stenbusch HW, Pradier L, Bayer TA. Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer’s disease. Am J Pathol 2004; 164: 1495-1502.

170. Schultheiss C, Blechert B, Gaertner F, Drecoli E, Mueller J, Weber G, Drzezga A, Essler M. Angiogenesis in a transgenic model of Alzheimer’s disease. J Vasc Dis 2006; 43: 568.

171. Seil FJ, Lampert PW, Katzo I. Neurofibrillary spheroids induced by aluminium phosphate in dorsal root ganglia neurons in vitro. J Neuropathol Exp Neurol 1969; 28: 74.

172. Shepherd CE, Gregory GC, Vickers JC, Brooks WS, Kwok JB, Schofield PR, Kril JJ, Halliday GM. Positional effects of presenilin-1 mutations on tau phosphorylation in cortical plaques. Neurobiol Dis 2004; 15: 115-119.

173. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Moulese MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sauseau P, Polinski RJ, Wasco RJ, Dasilva HAR, Haines JL, Pericak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM and St George-Hyslop PH. Cloning of a gene bearing missense mutations in early onset familial Alzheimer’s disease. Nature 1993; 375: 754-760.

174. Shin Y, Cho HS, Fukumoto H, Shimizu T, Shirasawa T, Greenberg SM, Rebeck GW A beta species, including IsoAsp23 Abeta, in Iowa-type familial cerebral amyloid angiopathy. Acta Neuropathol 2003; 105: 252-258.

175. Sims NR, Bowen DM. Changes in choline acetyltransferase and in acetylcholine synthesis. In: Reisberg B (ed.). Alzheimer’s Disease: The Standard reference. MacMillan, London, New York 1983, pp. 37-45.

176. Sillen A, Forsell C, Lilius L, Axwlman K, Bjork B, Onkamo P, Kere J, Winblad B, Graff C. Genome scan on Swedish Alzheimer disease families. Mol Psychiatry 2006; 11: 182-186.

177. Smith MA, Siedlak SL, Richey PL, Mulvihill P, Ghiso J, Frangione B, Tagliavini F, Giaccone G, Bugiani O, Praprotnik D, Kalaria RN, Perry G. Tau protein directly interacts with the amyoid beta-protein precusor: implications for Alzheimer’s disease. Nat Med 1995; 1: 365-369.

178. Soler-Lopez M, Badiola N, Zanzoni A, Aloy P. Towards Alzheimer’s root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction. Bioessays 2012; 34: 532-541.

179. Sorbi S, Forteo P, Tedde A, Cellini E, Ciantelli M, Bagnoli S, Nacmias B. Genetic risk factors in familial Alzheimer’s disease. Mech Aging Dev 2001; 122: 1951-1960.

180. Sparks DL, Hunsaker JC, Scheff SW, Kryscio RJ, Henson JL, Markesbery WR. Cortical senile plaques in coronary artery disease, aging and Alzheimer’s disease. Neurobiol Aging 1990; 11: 601-607.

181. Sparks DL, Huaichen L, Scheff SW, Coyne CM, Hunsaker JC. Temporal sequence of plaque formation in the cerebral cortex of non-dented individuals. J Neuropath Exp Neurol 1993; 52: 135-142.

182. Sparks DL, Scheff SW, Hunsaker JC, Liu H, Landers T, Gross DR. Induction of Alzheimer-like β-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol 1994; 126: 88-94.

183. Steiner H, Capell A, Leimer U, Haass C. Genes and mechanisms involved in beta-amyloid generation and Alzheimer’s disease. Eur Arch Psych and Clin Neurol 1999; 249: 266-270.

184. Steiner JA, Angot E, Brunden P. A deadly spread: cellular mechanisms of -synuclein transfer. Cell Death Differ 2011; 18: 1425-1433.

185. Strittmatter WJ, Wiesgraber KH, Huang DY, Dong LM, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D and Roses D. Binding of human apolipoprotein E to synthetic amyloid-β-peptide: isoform specific effects and implications for late-onset Alzheimer’s disease. Proc Natl Acad Sci 1993; 90: 8098-8102.

186. Struble RG, Powers RE, Casanova MF, Kitt CA, Brown EC, Price DL. Neuropeptidergic systems in plaques of Alzheimer’s disease. J Neuropath Exp Neurol 1987; 46: 567-584.

187. Su GC, Arendash GW, Kalaria RN, Bjugstad KB, Mullan M. Intravascular infusions of soluble beta-amyloid compromise the blood brain barrier, activate central nervous system glial cells and induce peripheral hemorrhage. Brain Res 1999; 818: 105-117.

188. Sudoh S, Kawamura Y, Sato K. Wang R, Saido TC, Oyama F, Sakaki Y, Komano H, Yanagisawa K. Presenilin-1 mutations linked to FAD increase the intracellular levels of amyloid beta protein 1-42 and its n-terminally truncated variant(s) which are generated at distinct sites. J Neurochem 1998; 71: 1535-1543.

189. Swerdlow RH. Mitochondria and cell bioenergetics: increasingly recognised components and a possible etiologic cause of Alzheimer’s disease. Antiox Redux Sign 2012; 16: 1434-1463.

190. Terry RD, Pena C. Experimental production of neurofibrillary degeneration. J Neuropathol Exp Neurol 1965; 24: 200-210.

191. Thal D, Larionov S, Abramowski D, Wiederhold K, van Dooren T, Yamaguchi H, Haass C, van Leuven F, Staufenbiel M, Capetillo-Zarate E. Occurrence and co-localization of amyloid beta-protein and apolipoprotein E in perivascular drainage channels of wild-type and APP-transgenic mice. Neurobiol Aging 2006; 28: 1221-1230.

192. Tian J, Shi J, Smallman R, Iwatsubo T, Mann D. Relationships in Alzheimer’s disease between the extent of A beta deposition in cerebral blood vessel walls, as cerebral amyloid angiopathy, and the amount of cerebrovascular smooth muscle cells and collagen. Neuropathol Appl Neurobiol 2006; 32: 332-340.

193. Torack RM, Miller JW. Immunoreactive changes resulting from dopaminergic denervation of the dentate gyrus of the rat hippocampal formation. Neurosci Lett 1994; 169: 9-12.

194. Ulrich J, Meir-Ruge W, Probst A, Meier E, Ipsen S. Senile plaques: staining for acetylcholinesterase and A4 protein: a comparative study in the hippocampus and entorhinal cortex. Acta Neuropathol 1990; 80: 624-628.

195. Veerhuis R. Histological and direct evidence for the role of complement in the neuroinflammation of Alzheimer’s disease. Curr Alz Res 2011; 8: 34-58.

196. Vuia O. Paraproteinosis and amyloidosis of the cerebral vessels and senile plaques. J Neurol Sci 1978; 39: 37-46.

197. Walford RL, Fortoul T. Histocompatibility locus antigens in Alzheimer’s disease. In: Reisberg B (ed.). Alzheimer’s disease. The Standard reference. Macmillan, London, New York 1983, pp. 166-169.

198. Wakabayashi K, Honer WG, Masliah E. Synapse alterations in the hippocampal entorhinal formation in Alzheimer’s disease with and without Lewy body dementia. Brain Res 1994; 667: 24-32.

199. Wallace WC, Bragin V, Robakis NK, Sambamurti K, Vanderputten D, Merril CR, Davis KL, Santucci AC Haroutunian V. Increased biosynthesis of Alzheimer amyloid precursor protein in the cerebral cortex of rats with lesions of the nucleus basalis of Meynert. Mol Brain Res 1991; 10: 173-178.

200. Wang LY, Hara K, Van Baaren JM, Price JC, Beecham GW, Gallins PJ, Whitehead PL, Wang GF, Lu CR, Slifer MA, Zuchner S, Martin ER, Mash D, Haines JL, Pericak-Vance MA, Gilbert JR. Vitamin D receptor and Alzheimer’s disease: a genetic and functional study. Neurobiol Aging 2012; 33: 1844.e1-9, doi: 10.1016/j.neurobiolaging.2011.12.038.

201. Weiss G, Fuchs D, Hausen A, Reibnegger C, Werner ER, Werner-Felmayer G, Semenitz E, Dierich MP, Wachter H. Neopterin modulates toxicity mediated by reactive oxygen and chloride species. FEBS 1993; 321: 89-92.

202. Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR. Alzheimer’s disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Arch Neurol 1981; 10: 122-126.

203. Wisniewski HM, Moretz RC, Lossinsky AS. Evidence for the induction of localised amyloid deposits and neuritic plaques by an infectious agent. Ann Neurol 1981; 10: 517-522.

204. Wisniewski HM, Wegiel J. β-amyloid formation by myocytes of leptomeningeal vessels. Acta Neuropathol 1994; 87: 223-241.

205. Wisniewski T, Ghiso J, Frangione B. Alzheimer’s disease and soluble Aβ. Neurobiol Aging 1994; 15: 143-152.

206. Wolfe MS. Processive proteolysis by gamma-secretase and the mechanism of Alzheimer’s disease. Biol Chem 2012; 393: 899-905.

207. Zatti G, Burgo A, Giacomello M, Barbiero L, Ghidoni R, Sinigaglia C, Florean C, Bagnoli S, Binetti G, Sorbi S, Pizzo P, Fasolata C. Presenilin mutations linked to familial Alzheimer’s disease reduce endoplasmic reticulum and Golgi apparatus calcium levels. Cell Calcium 2006; 39: 539-550.
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