progress towards earlier diagnosis and effective

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Prita R Asih‡,1,2, Pratishtha Chatterjee‡,1,3,4, Giuseppe Verdile1,3,5, Veer B Gupta1,4, ... REVIEW Asih, Chatterjee, Verdile, Gupta, Trengove & Martins.
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Clearing the amyloid in Alzheimer’s: progress towards earlier diagnosis and effective treatments – an update for clinicians Prita R Asih‡,1,2, Pratishtha Chatterjee‡,1,3,4, Giuseppe Verdile1,3,5, Veer B Gupta1,4, Robert D Trengove2 & Ralph N Martins*,1,3,4

Practice points

Brain pathology in Alzheimer’s disease ●●

The accumulation of aggregates of the β-amyloid (Aβ) peptide and abnormally phosphorylated tau protein in the brain are hallmark characteristics of Alzheimer’s disease (AD).

Risk factors for AD & their impact on Aβ accumulation in AD ●●

Health authorities should place greater emphasis on education concerning healthy diets, regular cardiovascular exercise and brain-stimulating exercises to help reduce the risk of AD.

Preclinical diagnosis of AD ●●

The Aβ peptide is being tested extensively for use as a biomarker of AD.

●●

Brain PET using an Aβ-specific dye, 11C PiB, is proving to be highly useful in preclinical diagnosis of AD in clinical trials, but this technology is not practical for routine diagnosis.

AD biomarkers in body fluids & other tissues ●●

CSF levels of specific forms of Aβ and tau are almost as useful as PiB-PET in diagnosis of AD, but again routine CSF testing is not ideal.

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Recent studies of plasma biomarkers including forms of Aβ are encouraging, but a panel of plasma biomarkers is still in the development phase.

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Potential diagnostic eye tests have emerged recently, and all appear quite promising; further testing will determine specificity and how early pathology can be detected.

Anti-amyloid therapy (drugs) ●●

AD drug trials have not been successful, partly due to the need to apply such drugs at preclinical stages, and preclinical diagnostic methods are clearly still mostly being developed.

Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia 2 Separation Science & Metabolomics Laboratory, Murdoch University, Murdoch, WA 6150, Australia 3 School of Psychiatry & Clinical Neurosciences, University of Western Australia, Crawley, WA 6009, Australia 4 The Cooperative Research Centre for Mental Health, Australia 5 School of Biomedical Sciences, Curtin University, Bentley, WA 6102, Australia *Author for correspondence: Tel.: +61 8 93474200; Fax: +61 93474299; [email protected] ‡ Authors contributed equally 1

10.2217/NMT.14.29 © 2014 Future Medicine Ltd

Neurodegener. Dis. Manag. (2014) 4(5), 363–378

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ISSN 1758-2024

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Review  Asih, Chatterjee, Verdile, Gupta, Trengove & Martins SUMMARY A beta (Aβ or β-amyloid) is a key molecule in Alzheimer’s disease (AD) pathogenesis. According to the ‘amyloid hypothesis’, the gradual accumulation of Aβ triggers events which results in neuronal loss in regions of the brain involved with memory and learning. Diverse agents have been developed to reduce brain Aβ accumulation or to enhance its clearance. Some have progressed to human trials, however all have failed to improve cognition in patients. This has led researchers to question whether Aβ is really the problem. However, the trials have been targeting end stages of AD, by which stage extensive irreversible neuronal damage has already occurred. Intervention is required preclinically, therefore preclinical AD biomarkers are needed. In this regard, amyloid imaging and cerebrospinal fluid biomarkers are leading the way, with plasma biomarkers and eye tests also being investigated. This review covers the current state of knowledge of Aβ as an early diagnostic biomarker and as a therapeutic target in AD. KEYWORDS 

• amyloid • anti-amyloid drug • biomarkers • CSF • lifestyle • PET amyloid

imaging plasma biomarkers • retinal photography • Type 2 diabetes

Introduction Alzheimer’s disease (AD) is a complex, progressive neurodegenerative disease for which there is currently no cure, preventative therapy or effective treatment. It is the most common cause of dementia, and it has been estimated that by 2050, one in every 85 individuals will be living with the disease [1] , thus impacting healthcare systems and economies worldwide. Most individuals die within 7 years of diagnosis, and less than 3% live more than 14 years [2] . While the majority of AD cases are sporadic, less than 3% of AD cases are familial autosomal dominant (FAD). The affected members of each FAD family carry a mutation in one of three genes, and these mutations are dominant, in other words, possession of one of these disease-causing mutations means the person will definitely be afflicted with the disease. Brain pathology in AD Some of the major clinical symptoms of AD are memory loss, disorientation and paranoia. However, there are other causes of dementia, and currently a definite diagnosis can only be obtained from an autopsy or brain biopsy, and more recently brain amyloid imaging to confirm the presence of the specific pathological hallmarks of this debilitating disease. These pathological hallmarks include: ●● Amyloid plaques ●● Neurofibrilliary tangles (NFT) ●● Cerebral amyloid angiopathy (CAA) ●● Widespread neuronal loss and brain atrophy.

This pathology was first characterized by Dr Alois Alzheimer just over 100 years ago. The amyloid plaques and CAA, as the names suggest, primarily comprise a protein called b-amyloid or A beta (Aβ).

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●●Amyloid plaques

The deposition of amyloid (senile) plaques is possibly the defining hallmark of AD; these plaques are progressively accumulated in brain regions involved in memory and learning. They consist mostly of extracellular deposits of Aβ – long fibrils and small oligomers of insoluble protein aggregates which accumulate to form amyloid – so named originally because it was thought these large insoluble aggregates were composed of complex sugars, but in fact turned out to be mostly protein. There are about 20 different small peptides that can aggregate into amyloid, however, Aβ amyloid has probably been the most e­xtensively investigated and is exclusively linked to AD. As depicted in Figure 1, it is thought that the accumulation of Aβ begins decades before the clinical symptoms of AD arise. Based on the degree of Aβ aggregation, amyloid plaques can be classified as either diffuse plaques or compact plaques. Diffuse plaques are immature plaques which comprise less aggregated Aβ and are free of reactive glial cells and damaged neurites (neuritic dystrophy). On the other hand, compact plaques are formed from diffuse plaque clusters giving rise to a core of heavily aggregated Aβ fibrils. The core of compact plaques are surrounded by neuritic dystrophy and reactive glial cells and astrocytes. Both diffuse and compact plaques are present in an intermingled state in the cerebral cortex of AD patients. It was originally thought that the large highly insoluble Aβ plaques were the toxic principle of AD, however, it is now believed that the Aβ toxicity is the result of nonspecific interaction between small soluble Aβ oligomers with plasma membranes [3] . This hypothesis may explain the lack of correlation between the number of insoluble amyloid plaques and the level of cognitive impairment. Moreover, the brain levels of soluble Aβ oligomers appear to

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Review  Asih, Chatterjee, Verdile, Gupta, Trengove & Martins SUMMARY A beta (Aβ or β-amyloid) is a key molecule in Alzheimer’s disease (AD) pathogenesis. According to the ‘amyloid hypothesis’, the gradual accumulation of Aβ triggers events which results in neuronal loss in regions of the brain involved with memory and learning. Diverse agents have been developed to reduce brain Aβ accumulation or to enhance its clearance. Some have progressed to human trials, however all have failed to improve cognition in patients. This has led researchers to question whether Aβ is really the problem. However, the trials have been targeting end stages of AD, by which stage extensive irreversible neuronal damage has already occurred. Intervention is required preclinically, therefore preclinical AD biomarkers are needed. In this regard, amyloid imaging and cerebrospinal fluid biomarkers are leading the way, with plasma biomarkers and eye tests also being investigated. This review covers the current state of knowledge of Aβ as an early diagnostic biomarker and as a therapeutic target in AD. KEYWORDS 

• amyloid • anti-amyloid drug • biomarkers • CSF • lifestyle • PET amyloid

imaging plasma biomarkers • retinal photography • Type 2 diabetes

Introduction Alzheimer’s disease (AD) is a complex, progressive neurodegenerative disease for which there is currently no cure, preventative therapy or effective treatment. It is the most common cause of dementia, and it has been estimated that by 2050, one in every 85 individuals will be living with the disease [1] , thus impacting healthcare systems and economies worldwide. Most individuals die within 7 years of diagnosis, and less than 3% live more than 14 years [2] . While the majority of AD cases are sporadic, less than 3% of AD cases are familial autosomal dominant (FAD). The affected members of each FAD family carry a mutation in one of three genes, and these mutations are dominant, in other words, possession of one of these disease-causing mutations means the person will definitely be afflicted with the disease. Brain pathology in AD Some of the major clinical symptoms of AD are memory loss, disorientation and paranoia. However, there are other causes of dementia, and currently a definite diagnosis can only be obtained from an autopsy or brain biopsy, and more recently brain amyloid imaging to confirm the presence of the specific pathological hallmarks of this debilitating disease. These pathological hallmarks include: ●● Amyloid plaques ●● Neurofibrilliary tangles (NFT) ●● Cerebral amyloid angiopathy (CAA) ●● Widespread neuronal loss and brain atrophy.

This pathology was first characterized by Dr Alois Alzheimer just over 100 years ago. The amyloid plaques and CAA, as the names suggest, primarily comprise a protein called b-amyloid or A beta (Aβ).

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●●Amyloid plaques

The deposition of amyloid (senile) plaques is possibly the defining hallmark of AD; these plaques are progressively accumulated in brain regions involved in memory and learning. They consist mostly of extracellular deposits of Aβ – long fibrils and small oligomers of insoluble protein aggregates which accumulate to form amyloid – so named originally because it was thought these large insoluble aggregates were composed of complex sugars, but in fact turned out to be mostly protein. There are about 20 different small peptides that can aggregate into amyloid, however, Aβ amyloid has probably been the most e­xtensively investigated and is exclusively linked to AD. As depicted in Figure 1, it is thought that the accumulation of Aβ begins decades before the clinical symptoms of AD arise. Based on the degree of Aβ aggregation, amyloid plaques can be classified as either diffuse plaques or compact plaques. Diffuse plaques are immature plaques which comprise less aggregated Aβ and are free of reactive glial cells and damaged neurites (neuritic dystrophy). On the other hand, compact plaques are formed from diffuse plaque clusters giving rise to a core of heavily aggregated Aβ fibrils. The core of compact plaques are surrounded by neuritic dystrophy and reactive glial cells and astrocytes. Both diffuse and compact plaques are present in an intermingled state in the cerebral cortex of AD patients. It was originally thought that the large highly insoluble Aβ plaques were the toxic principle of AD, however, it is now believed that the Aβ toxicity is the result of nonspecific interaction between small soluble Aβ oligomers with plasma membranes [3] . This hypothesis may explain the lack of correlation between the number of insoluble amyloid plaques and the level of cognitive impairment. Moreover, the brain levels of soluble Aβ oligomers appear to

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Clearing the amyloid in Alzheimer’s: progress towards earlier diagnosis & effective treatments 

Familial AD

Sporadic AD

(Rare form) caused by mutations in APP, presenilin-1, or presenilin-2 genes, which causes lifelong abnormally high Aβ production

(Common form) caused by high Aβ production and/or failure of Aβ clearance mechanisms

Review

Time

Toxic Aβ oligomer levels

Toxicity of Aβ to synapses

Oxidative stress

Microglial and astrocytic activation

One decade

Aβ amyloid deposition (relatively inert deposits in the brain) Progressive neuritic and synaptic injury

Two decades Altered neuron enzyme (kinase/phosphatase) activities (leads to neurofibrillary tangle formation inside neurons

Neuronal dysfunction and cell death

Dementia

Three decades

Figure 1. Flow diagram of how abnormally high levels of β-amyloid are thought to cause synaptic damage, oxidative stress, cell death and eventually dementia. Pathogenesis is thought to be slow – it may take 20–30 years before symptoms appear, by which stage extensive damage has already occurred in the brain. Aβ: β-amyloid; AD: Alzheimer’s disease.

correlate better with severity of cognitive impairment than the highly insoluble plaques. This finding could potentially m­odify the design of therapeutic approaches for AD. ●●Aβ is toxic

The Aβ peptide is one of the breakdown products of a much larger protein called the amyloid precursor protein (APP). APP is found in most tissues in the body, and Aβ is a normal product, however it is thought that in AD too much Aβ is produced, and/or the normal mechanisms for getting rid of Aβ malfunction, causing a toxic accumulation of the peptide. While several lengths of Aβ peptides exist, Aβ40 (40 amino acids long) is the most common form, whereas

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Aβ42, which is not as common, has been reported to be the most pathogenic. Aβ is hydrophobic in nature, and it is notorious for its properties to aggregate (Aβ42 more so than Aβ40). Aβ aggregates firstly into small soluble oligo­ mers, and these small aggregates are believed to be the most toxic form of Aβ [4] . ●●The Aβ hypothesis

Although extensively explored, the properties of Aβ and its role in AD development are yet to be fully elucidated. Several hypotheses have been formulated around the pathogenesis of AD. Some of these include the oxidative stress hypothesis, the cholinergic hypothesis, calcium hypothesis and the tau hypothesis; however the

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Review  Asih, Chatterjee, Verdile, Gupta, Trengove & Martins most widely studied hypothesis is the amyloid hypothesis. Here, the accumulation of Aβ, or more likely the Aβ oligomers, is thought to play a pivotal role in neuronal loss or dysfunction through a cascade of events that include the generation of free radicals, mitochondrial oxidative damage and inflammatory processes [5] . ●●Cerebral amyloid angiopathy

Cerebral amyloid angiopathy is characterized by the accumulation of Aβ in the cortical and leptomeningeal vessel walls. AD is linked to an increase in total Aβ levels, or an increase in the amount of Aβ42, thus increasing the Aβ42:Aβ40 ratio (or both). CAA however, appears to be linked particularly strongly to situations where total Aβ increases. For example, CAA is the main feature in people carrying specific rare mutations within the Aβ sequence of APP, at amino acid residue 693 of APP, which cause an increase in total Aβ production [6] . CAA is also prominent in Down Syndrome, which is caused by trisomy 21, and chromosome 21 is where the APP gene is located, thus resulting in Down Syndrome patients having three instead of two copies of the APP gene, and thus increasing the overall Aβ levels [7] . It has been hypothesized that Aβ produced in the brain can be degraded in the brain, or is transported via a perivascular drainage pathway to the blood vessel wall [8] . An overproduction of Aβ or an impaired clearance of Aβ at this stage is likely to result in Aβ polymerization, thus promoting CAA formation. Brain hemorrhage or stroke, ischemic brain lesions and dementia are some of the symptoms associated with CAA [9] . ●●Neurofibrilliary tangles

Tau is a protein used inside cells to provide stability to microtubule structures, and tau protein is normally phosphorylated. Neurofibrilliary tangles primarily comprise tau protein, however this is abnormally hyperphosphorylated tau. Hyperphosphorylation of tau adversely affects its biological function: it prevents tau from providing stability to microtubule structures, and instead encourages tau to aggregate into paired helical filaments resulting in aggregates, giving the appearance of intra-neuronal tangled threads under the microscope, hence the name neurofibrilliary tangles. Recent studies have shown that tau influences Aβ’s toxic properties, and conversely, that Aβ can increase the production of NFT by activating enzymes that promote tau

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phosphorylation [10] , therefore it would appear that Aβ and NFT can act synergistically in the development of AD. Many years ago, post-mortem studies of AD brains found that NFT levels correlated better than plaque numbers with AD symptom severity, leading researchers to think that NFT might be more important in causing AD symptoms. This led to ‘competition’ between Aβ plaque and NFT researchers trying to establish which pathology is more important in disease pathogenesis. More recent studies however, suggest that disease severity correlates well with the levels of smaller soluble Aβ aggregates and amyloid plaques. Nevertheless, the brain amyloid deposition and NFT neuropathology develop for two to three decades before symptoms appear, and the rate of Aβ deposition and NFT formation may change considerably over these two to three decades, which probably explains why the level of pathology does not correlate well with disease severity. The level of synaptic loss and death of neurons are more strongly associated with disease severity than the levels of the more easily detectable plaques and NFT [11] . On this topic, one should also mention the concepts of ‘brain reserve’ and ‘cognitive reserve’. Some people might have a greater number of brain cells (brain reserve) or a greater number of connections between these brain cells (cognitive reserve) than others, implying that a greater amount of AD-related pathology can occur in such people before they reach a critical point below which symptoms of AD surface [12] . This is believed to be another reason why the level of AD pathology does not always reflect the severity of symptoms. Furthermore, keeping mentally fit by maintaining challenging cognitive activity is believed to protect against AD: a recent study found that more frequent cognitive activity throughout life is associated with slower late-life cognitive decline, which is consistent with the cognitive reserve hypothesis [13] . Aβ & its production As mentioned earlier, Aβ is a small protein which is generated via the normal enzymatic processing of its ‘parent’ molecule APP. Although Aβ protein fragments of various lengths can be generated, the majority are of 40 or 42 amino acids in length. The Aβ42 fragments have greater tendency than Aβ40 to aggregate to form small soluble aggregates (called ‘oligomers’) in the brain, however both lengths of Aβ aggregate, and then

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Clearing the amyloid in Alzheimer’s: progress towards earlier diagnosis & effective treatments  form larger insoluble aggregates (called ‘fibrils’) which eventually deposit as amyloid plaques. The APP molecule is a transmembrane protein which spans from the intracellular domain through the cell membrane to the extracellular space. The APP molecule is a transmembrane protein which spans from the extracellular domain through the cell membrane into the cell cytosol (see Figure 2). It is cleaved by enzymes known as ‘secretases’ by two pathways: the nonamyloidogenic and the amyloidogenic pathways. In the non-amyloidogenic pathway, the first cut is carried out by the α-secretase enzyme, which cuts within the Aβ sequence of APP, precluding Aβ formation. In the amyloidogenic pathway, APP is first cut by the β-cut APP-cleaving enzyme (BACE) then by the gamma (γ)-secretase enzyme to generate the Aβ peptide. The genetic mutations that have been shown to cause FAD occur in the gene for the parent molecule APP near the secretase cleavage sites, or else in the genes for essential components (the presenilins proteins) of the γ-secretase enzyme. Regardless of which of these three genes is affected, the mutations cause changes

APP processing that will produce Aβ (amyloidogenic pathway)

in the processing of APP, which result in an increase in total Aβ production, or an increase in the Aβ42:Aβ40 ratio. It is due to the extensive studies of FAD families and the mutations in each of these families that researchers formulated the amyloid hypothesis described in Figure 1 that an increase in Aβ levels, either due to increased production (particularly the more toxic Aβ42 form) as in these FAD cases, or a reduction in Aβ clearance from the brain which may occur in the more common sporadic form of AD, is enough to induce the development of AD [14] . In support of this, a recent study found another mutation to have the opposite effect – an APP mutation (A673T) was found to be protective against AD pathogenesis and, importantly, the mutation in this case reduced Aβ levels [15] . ●●Aβ production versus Aβ clearance

According to the Aβ hypothesis, an excess of Aβ promotes the aggregation of oligomers, then the toxic effects of these Aβ oligomers starts (or exacerbates) a cycle of damage caused by oxidative stress, inflammation and further Aβ production,

APP processing that prevents Aβ production (non-amyloidogenic pathway)

Whole APP showing portion that is Aβ sequence



β-secretase (BACE) cut Step 1

Review

Intracellular

Extracellular

Whole APP Aβ

Cell membrane Step 1

γ-secretase cut that releases Aβ Step 2



α-secretase cut in middle of Ab sequence so no Ab is produced Step 2

γ-secretase cut but no Aβ produced

Figure 2. Amyloidogenic and non-amyloidogenic pathways for processing amyloid precursor protein. Aβ: Amyloid-β; Ab: Antibody; APP: Amyloid precursor protein; BACE: β-cut APP-cleaving enzyme.

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Review  Asih, Chatterjee, Verdile, Gupta, Trengove & Martins to result in AD pathology. The excessive levels of Aβ can occur via overproduction, as has been found in the FAD mutation families, or it can occur via a reduced clearance of Aβ from the brain, which is believed to be the main problem in the more common sporadic form of AD. Alternatively, sporadic AD may be a combination of both. Recently however, direct evidence for reduced clearance (and not increased production) of Aβ from the CNS of AD patients has been provided [16] . Aβ can be cleared from the brain by several mechanisms [17] . First, there are enzymes that degrade Aβ, such as insulin-degrading enzyme (IDE) or neprilysin, another enzyme that breaks down small peptides [18] . Aβ can also bind to large complexes that function mostly in lipid transport around the body and in the brain – the lipoproteins. Lipoproteins consist of lipids (fats and cholesterol, along with small amounts of lipid-soluble steroid hormones and vitamin D, for example) and proteins known as apolipoproteins. These complexes transport lipids from cell to cell, by attaching to specific cell receptors then being internalized or by transporting components across into the bloodstream. If Aβ is transported into the bloodstream, it is likely to be degraded by the liver, kidney or proteases in the blood [19] . Aβ’s half-life once in the periphery is known to be short, and this fast clearance of Aβ forms the basis of the peripheral sink hypothesis – which states that increasing the transfer of Aβ to the periphery will reduce the risk of AD. ●●Targeting the secretases to reduce Aβ

production

Improving the clearance of Aβ from the brain, or reducing the production of Aβ in the first place, are both targets of pharmaceutical companies that are aiming to reduce the incidence of AD. The essential roles that the secretase enzymes play in Aβ production has made them pharmacological targets for developing inhibitors or modulators of enzyme activity, aimed at lowering Aβ levels and thus preventing Aβ oligomer-induced toxicity. However, these enzymes have other roles in the cell, and reducing or preventing their function altogether has proven to cause harmful side effects. Therefore, it has been difficult to develop safe and specific drugs that reduce Aβ production (discussed further below). Efforts are now being made to elucidate the structure and activity of these enzymes

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to a greater extent, in the hope to develop more specific inhibitors or modulators of activity. Risk factors for AD & their impact on Aβ accumulation in AD ●●Aging

Advancing age is the most conspicuous risk factor for AD. Once over the age of 65 years, the risk for developing AD doubles every 5 years, such that the incidence of dementia over the age of 85 years is around 40%. Improvements in certain aspects of medicine have increased lifespans around the world, however this has caused an increase in the incidence of currently untreatable neurodegenerative conditions such as AD, due to aging being a risk factor for such conditions. Brain scans of aging people corroborate the concept of aging as a risk factor, as both people with AD and many people without AD (possibly presymptomatic stages of AD) have agedependent increases in levels of amyloid in their brains [20] . At the same time, there appears to be an increased vulnerability to fibrillar Aβ, and a differential change towards producing more insoluble Aβ42 in aging brains [21] , this may be related to an age-related increase in free radicalinduced oxidative stress activating astrocytes and microglia. These free radicals contribute to lipid oxidation and inflammatory responses, and the Aβ accumulation at synapses may cause impaired neurotransmission due to synaptic damage, resulting in cognitive decline [22] . Aβ accumulation also appears to damage mitochondria – the powerhouses of cells – ­contributing to brain cell malfunction [22] . Post-mortem studies of the brains of people who had no symptoms of dementia sometimes show significant amyloid deposition [23] , in fact, Aβ deposition has been identified in one-third of the normal aging population. However, as we have mentioned previously (see Figure 1), the accumulation of brain amyloid begins decades before the onset of clinical symptoms, implying these subjects most likely were in a p­resymptomatic stage of AD. ●●Apolipoprotein allele

Apolipoprotein (apoE), a plasma and brain apolipoprotein, plays a central role in lipid metabolism, and has been found in amyloid plaques and NFT in AD. Lipoprotein-bound ApoE binds to Aβ, and plays a major role in Aβ clearance and transport in the brain, as the lipoproteins then bind to cell surface receptors such as the

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Clearing the amyloid in Alzheimer’s: progress towards earlier diagnosis & effective treatments  low-density lipoprotein receptor (LDLR) and the lipoprotein receptor-related protein [24] . Such receptors help transport Aβ into cells for degradation, or transport across the blood brain barrier into the bloodstream, and a deficiency in this transport system will increase brain Aβ load (transport in the other direction from the blood to brain uses the receptor for advanced glycation end products, which is unrelated to lipoprotein receptor-related protein) [25] . APOE has three alleles (APOE ε2, ε3 and ε4, with slightly different genetic sequences to each other) which mean the three proteins differ in the amino acid residues at positions 112 and 158 of the protein sequence. APOE first gained interest in AD as a susceptibility gene. Although only about 15% of people in the general population have an APOE ε4 allele, about 50% of patients who have late onset (sporadic) AD are carriers of an E4 allele of APOE, indicating APOE ε4 carriers are at greater risk of developing AD [26] . APOE ε4 alleles, especially if homozygous, have been shown to propel the onset of AD by 5–10 years whereas APOE ε2 and APOE ε3 alleles have a slightly beneficial or no effect, respectively. Several reasons for why APOE ε4 may increase the risk of AD have been proposed. First, ApoE binds to Aβ, and studies have shown that this binding might accelerate Aβ aggregation. More recently, the binding of ApoE to Aβ has been shown to be necessary to help Aβ clearance, either by brain cells or via transfer to the periphery, and ApoE proteins possess an apoE-Aβ binding efficiency in the order of ε2>ε3>ε4 [19,27–28] . This results in the least efficient Aβ clearance by the ApoE ε4 protein. Whether this mechanism is due to the interaction between ApoE and aggregated Aβ still needs further study, as in vitro studies have been inconsistent. ●●Type 2 diabetes

Type 2 diabetes is a well-known risk factor for AD that involves both insulin resistance and dysregulation of glucose metabolism [29] . Aβ degradation is influenced by insulin via IDE which has been associated with AD severity, and the decreased insulin sensitivity in the brain in AD has led to the concept of ‘Type 3 diabetes’ (or diabetes of the brain). A considerable number of studies both in animal models and humans have demonstrated the link between diabetes and cognitive impairment in general [30] . Specific to AD, the link between diabetes and AD has been observed [31] as well as with vascular dementia

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Review

[32,33] . The metabolic disturbances associated with

Type 2 diabetes correlate with the accumulation of Aβ and with reduced CNS insulin and insulin signaling, reduced cerebral volume as well as hippocampal atrophy. Deficits in insulin signaling may cause or indicate a loss of protection against Aβ-mediated neurotoxicity, for example, insulin resistance has been linked to Aβ oligomers attaching to cell membranes and removing insulin receptors [34] . Insulin resistance also promotes NFT formation, as insulin signaling is closely involved in the pathway that regulates tau phosphorylation. Drugs for the management of diabetes (thiazolidinediones or incretin hormone analogues) have been shown to reduce Aβ pathology and to attenuate cognitive deficits in AD transgenic mouse models [35,36] ; however, their efficacy in the presence of a chronic diabetic phenotype has not been assessed. Intranasal insulin has been trialled recently, and has shown promise as a treatment for AD, as memory performance and metabolic integrity of the brain are improved in patients with mild cognitive impairment (MCI). Such insulin treatment has also been shown to reduce synapse vulnerability to Aβ [37] . Currently, the TOMORROW multi-site prevention trial sponsored by Takeda is investigating the significance of the insulin-sensitizing drug Pioglitazone in preventing cognitive decline. ●●Lifestyle

Differences in lifestyle have been observed to influence Aβ deposition in the brain and thus the risk of developing AD. We have shown that exercise significantly impacts Aβ deposition in the brain. The AIBL study of aging cohort showed that participants who undertook increased physical activity exhibited reduced Aβ brain load. In this AIBL study, intensity rather than the amount of exercise was found to be more relevant when assessing improvements, according to comprehensive neuropsychological testing [38] . Another study of a 24 week physical exercise intervention in elderly people with minor memory problems found the exercise improved mental function, based on Alzheimer Disease Assessment Scale – Cognitive Subscale scores over 18 months [39] . We have also demonstrated that adherence to a Mediterranean diet is associated with reduced risk of Alzheimer’s and correlates with reduced brain Aβ load. Other studies have shown that a healthy diet, including Mediterranean diet, are all associated with a lower risk of AD [40] . Other dietary aspects for which there is evidence of a reduced risk of AD include

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Review  Asih, Chatterjee, Verdile, Gupta, Trengove & Martins dietary supplementation with a selection of antioxidants (but not individual antioxidants), B vitamins, polyphenols and polyunsaturated fatty acids; furthermore, in general, a high consumption of fish, fruits, vegetables, coffee, and light-tomoderate alcohol also has been shown to reduce the risk of AD [41] . Lifestyle changes to improve diet and exercise habits are a clear and obvious recommendation to give to people who have cardiovascular disease, Type 2 diabetes, hypertension or insulin resistance, as changing to a healthier diet would reduce symptoms of these conditions as well as reduce the risk of AD. Preclinical diagnosis of AD Looking back at Figure 1, by the time AD symptoms surface, the characteristics of AD including synaptic damage, neuronal death as well as NFT and amyloid deposition have been developing for years in the brain. For the foreseeable future, these changes are irreversible, therefore to make the most of any disease-delaying or preventative therapy, people at risk of developing AD, or people in the early preclinical stages of AD need to be identified as early as possible. This would provide a window of opportunity for therapy before much neuronal damage has occurred, thereby increasing therapeutic efficacy. Currently, the histopathological hallmarks of AD only allow for a post-mortem confirmatory diagnosis of AD. However, noteworthy progress has been made towards identifying a set of AD-specific biomarkers in biological fluids such as CSF and blood. These biomarkers have been established on the basic findings of sequestration and elevation of Aβ in the brain and as a result, a decline in cerebrospinal fluid amyloid concentrations; therefore creating an inverse relationship between brain amyloid load and CSF Aβ concentrations [42] . AD biomarkers in body fluids Aβ peptides are produced continuously by most cells in the body, they circulate in blood and can traverse to the CSF and brain through the bloodbrain barrier, although as mentioned earlier, Aβ peptides have a short half-life in the periphery. In the plasma and CSF of cognitively normal individuals, Aβ40 levels are greater than Aβ42 levels by about 1.5–10-fold, respectively [43] . ●●CSF biomarkers

Levels of Aβ and tau have been investigated in CSF to determine if levels differ at the various

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stages of disease, and whether they can be used for diagnosis. Several CSF measures appear to be highly promising, in particular Aβ42; total tau (T-tau) protein, reflecting axonal damage; and phosphorylated tau (P-tau), reflecting NFT pathology [44] . In the CSF of individuals with MCI who convert to AD, Aβ42 levels decrease [45], and this is believed to reflect an increase in brain Aβ42 accumulation in an aggregated form. This characteristic feature of Aβ42 can distinguish AD from healthy controls and has been demonstrated in at least 40 studies [46] . However, changes in CSF Aβ levels are not specific to AD, as Aβ changes have been found also in the CSF of patients with Parkinson’s disease, Creutzfeld–Jakob disease, and dementia with Lewy bodies. This is why a combination of Aβ42, t-tau and p-tau181 are used as a CSF AD signature [47,48] and levels of these biomarkers at the MCI stage have been tested for sensitivity and specificity when predicting conversion to AD, and one study, for example, produced a sensitivity of 75% and specificity of 96% [49] . Nevertheless, there are some challenges in standardization of CSF assay measurements that need to be met in order to minimize the sources of analytical variability. Although declining CSF Aβ concentrations and increases in the tau biomarkers mentioned above can be employed as AD biomarkers, and many studies have shown that these biomarkers are quite reliable [45,50] ; the invasive sampling procedure limits its application in routine clinical practice, therefore considerable research has been focused on blood biomarkers. However in CSF studies, Aβ is one of the gold standards of AD biomarkers, as evidenced by the DIAN studies of familial AD [51] . ●●Aβ in the brain – advances in imaging

studies

MRI and CT scans have been available for many years to help with the diagnosis of AD, they can measure the shrinkage of the brain, and help rule out brain tumors, hydrocephalus and stroke, for example. A PET scan using the chemical tracer 18 F-fluorodeoxyglucose (FDG) can indicate brain regional glucose usage. Alzheimer’s has a typical pattern of low glucose usage in certain areas of the brain, yet this sort of scanning is only about 80% accurate on its own. With respect to Aβ, abnormal brain amyloid depostion has been observed in these imaging studies prior to signs of neurodegeneration such as aberrant glucose metabolism in AD pathology [52] . This structural MRI and hypometabolism on FDG-PET

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Clearing the amyloid in Alzheimer’s: progress towards earlier diagnosis & effective treatments  are considered to be topographical imaging biomarkers (neurodegenerative measurement) which are less specific for AD diagnosis than the relatively new pathophysiological imaging biomarkers that is much more specific for AD [53] as described below. Thus, a combination of FDG-PET, other biomarkers and routine tests is more useful, and improves the prediction of MCI to AD considerably [54] . Since the first human study in 2004, amyloid imaging has shifted the paradigm to suggesting that Aβ may be a good target for prevention as it has been shown that amyloid plaques begin to accumulate 15–20 years before clinical symptoms arise. Imaging not only serves as a diagnostic marker for AD, but also provides us a window to test the amyloid hypothesis. It has also provided a new platform for patient selection and therapeutic monitoring in clinical trials. The most frequently used amyloid imaging agent, 11C PiB, is an amyloid binding PET tracer (a thioflavin-T amyloid dye) that has been reported to bind fibrillar Aβ, diffuse plaques and amyloid cores [55] . PiB-PET is a marker of Aβ deposition measurement, hence falls under the category of pathophysiological imaging biomarkers [53] . There is no detectable binding to soluble Aβ forms or neurofibrillary tangles at ligand concentrations of ∼1 nM [56,57] . The uptake of PiB in vivo, using PET, has been reported to be highly correlated with brain amyloid burden, post-mortem [58] . A recent study has shown a correlation between increased PiB uptake and the development of AD in 5 years time [59] . Similarly, longitudinal cognitive decline has been found to correlate with levels of fibrillar Aβ, as measured by PiB-PET [60] . In addition, several studies have observed PiB uptake can be predicted from CSF Aβ42 levels [61] , and the pattern of Aβ deposition in FAD has been found to differ from that in sporadic AD, with higher striatal and somewhat lower cortical PiB retention in FAD [62] . Therefore, 11C PiB PET is considered a highly valuable biomarker for AD since it allows visualization and quantification of amyloid deposits in vivo. To supplement visual interpretation of amyloid plaques in the brain, standardized uptake values ratio has been used as the most frequent normalization for PiB. This computes the ratio of PiB retention in the whole brain to that in the cerebellum [63] . For example, brain amyloid standardized uptake values ratios of the frontal, superior parietal, lateral temporal, lateral occipital, anterior and posterior cingulate regions from AIBL imaging

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data in conjunction with CSF Aβ concentrations have proven to be potential early biomarkers and useful for the differential d­iagnosis of AD [64] . The AIBL study has been instrumental in demonstrating that Aβ starts to build up in the brain at least 20 years before the onset of clinical symptoms. Amyloid imaging results from AIBL have shown that elevated PiB binding is associated with MCI, that greater levels are seen in AD, and that the highest are in APOE ε4 carriers with AD. However, healthy people from age 60–69 years also show PiB binding with increasing age, with this effect seen most strongly in APOE ε4 carriers [65] . These findings show that amyloid deposition increases with advancing age, even without apparent cognitive deficits – most likely preclinical stages of AD. Thus, it appears inevitable that a cognitively normal individual with advanced amyloid deposition will progress to becoming cognitively impaired with age. Although not a technique for mass screening due to cost and the requirement of highly specialized equipment, this technique is proving to be highly valuable as it facilitates the identification of subjects in early stages of Aβ deposition, for the purposes of trialling and monitoring the effectiveness of preventative therapies and treatments [56] . Findings from the DIAN cohort have also shown that brain amyloid deposition starts to occur approximately two decades prior to clinical manifestations [66] . The DIAN cohort comprises individuals who are the offspring of biological parents carrying an FAD mutation. These offspring have a 50% chance of inheriting the mutation and have an expected age at onset (AAO) for clinical symptom manifestation, as recorded from their parents’ AAO. Elevated brain amyloid load represented by 11C PiB PET imaging in mutation carriers compared with the non-carriers was observed approximately 20 years prior to their AAO [66] . Additionally, CSF Aβ42 levels declined in mutation carriers 15 years prior to their AAO. These findings show Aβ metabolism is altered almost 2 decades prior to symptom onset. Additionally, blood plasma Aβ42 levels (see below) were also altered almost a decade prior to expected symptom onset [66] . As we have already mentioned, it is becoming increasingly important that amyloid imaging and quantifying Aβ burden not only serves as an early biomarker and for classification of AD, but also as a potential predictor of anti-amyloid treatment response. In addition, advancement of pathophysiological imaging biomarkers like PiB-PET

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Review  Asih, Chatterjee, Verdile, Gupta, Trengove & Martins will potentially improve the specificity of AD diagnosis. Future challenges will be to combine amyloid imaging biomarkers with CSF and blood biomarkers to most efficiently facilitate early diagnosis and ultimately for the development of AD treatments. In addition, other imaging agents targeted at the cholinergic system, NFT (such as FDDNP), microglial activation and inflammation (such as TSPO ligands) and other tracers are in development, and will contribute to our basic understanding of AD. ●●Aβ in plasma

Ideally plasma biomarkers would be used if possible, as blood collection is cheap and less invasive than CSF sampling. Studies have attempted to elucidate Aβ metabolism in AD and whether blood Aβ levels change during the course of the disease. The AIBL study compared plasma Aβ levels to Aβ load derived from PiB-PET. An inverse correlation was observed and lower Aβ42 levels as well as lower Aβ42:Aβ40 ratios were shown in AD [50] . After follow-up for 36 months, the AIBL study suggested that longitudinal plasma Aβ is a potential biomarker for presymptomatic AD [67] . Another recent study has shown that Aβ40 levels in plasma can distinguish AD from normal control subjects [68] . Complicating issues in measuring plasma Aβ levels have been highlighted in studies which showed that plasma levels of both Aβ forms depend on APOE allele status, yet the ratio Aβ42:Aβ40 was unaffected by APOE allele status [69] , and another recent study which found that plasma Aβ could be found in three plasma compartments (free in plasma, in plasma matrix, or in the cellular pellet) and that the free Aβ was influenced by diastolic blood pressure [70] . Overall, the literature on the validity of plasma Aβ alone as an appropriate AD biomarker has been inconsistent. Plasma Aβ levels have been considered to be a powerful biomarker in the DIAN study that has recruited patients with FAD, yet it has not been successful in identifying sporadic AD. These differences can be partly explained by the cause of Aβ accumulation in the first place; in FAD, Aβ accumulation in the brain is caused by a mutation leading to an overproduction, whereas the cause in sporadic AD is less clear, most likely due to decreased clearance, and likely to be complicated by genetic and environmental factors. There are several reasons that could account for the lack of consistency in plasma Aβ studies. Plasma contains very low levels of Aβ, and the current technology is not developed enough

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to detect very low levels, or to distinguish easily between the different conformations of Aβ [71] . Furthermore, differences in blood collection methods and Aβ assays will have influenced results; daily fluctuations in blood Aβ levels have been shown to occur, and blood Aβ levels are influenced by Aβ carrier proteins such as albumin, levels of which may fluctuate. Fortunately however, a number of other blood biomarkers are showing promise, including markers in peripheral cells such as platelets and leukocytes. Other studies indicate that peripheral inflammatory markers can help in dementia diagnosis [72,73] and it is expected that a panel of these biomarkers together with Aβ will eventually form the basis of a diagnostic blood test in the future [74] . The search for preventative or diseasemodifying drugs for AD ●●Current treatments for AD

At present, only five prescription drugs have been approved by the US FDA and EMA, and these only address symptoms, not the underlying disease. Four are acetylcholinesterase inhibitors (AChEI) such as Tacrine (‘Cognex’ – but no longer used due to serious side effects), Rivastigmine (‘Exelon’), Galantamine (‘Razadyne’), and Donepezil (‘Aricept’) and the fifth is an NMDA antagonist, Memantine. These are all drugs that target neurotransmitter deficits that occur relatively late in the disease process. Notably, the drugs can only stabilize the cognitive function of individuals with AD for up to 1 year by counteracting the functional consequences of lost cholinergic neurons and they can only modestly alleviate the symptoms, and do not stop disease progression [75,76] . However, even though these benefits are relatively short-lived, the improved quality of life for patients is greatly appreciated by family member and carers. ●●Problems translating studies from animal

studies to human clinical trials

Ever since the creation of the first APP transgenic mouse with AD-like pathology in 1995, animal models have provided valuable information in defining the mechanisms involved in AD pathology and have played a significant role in e­valuating novel therapeutic drugs. The brains of AD transgenic mice develop Aβ plaques with similar structures and patterns to those found in a human brain afflicted with AD [77] . Diffuse plaques comprising mainly Aβ42 develop into a dense core, and then incorporate

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Clearing the amyloid in Alzheimer’s: progress towards earlier diagnosis & effective treatments  Aβ40 as well as numerous other non-Aβ components in an age-dependent manner [78] . Aβ plaques only develop in the majority of the animals in mid–late adulthood despite constant Aβ production. Furthermore, as observed in humans, the amount of Aβ plaque deposition does not correlate well with cognitive decline [79] , but c­orrelates instead with levels of soluble Aβ species [80] . Most current animal models of AD are derived from the genetics of familial AD and may not be representative of sporadic AD, there is also no single model that can encompass the whole spectrum of AD. However, each animal model has provided an understanding of certain important aspects that could not have been investigated in humans. For example, in the most widely studied Tg2576 mouse model, increased Aβ42 is known to accelerate plaque formation whereas high Aβ40 levels delay it [81] . In addition, much of the evidence of the involvement of Aβ oligomers and their toxicity has been provided from studies of transgenic animal models. All drugs investigated in clinical trials will have had initial studies performed in such animal models of AD. Considerable therapies and interventions in reducing Aβ pathophysiology have proven to be successful to some degree in animal models, but have universally failed when evaluated in human clinical trials. These discrepancies most likely reflect the fact that the mouse models do not capture all the aspects of the human disease, they also brings into question the validity of animal models in drug and therapy investigations. The answer to these issues might be that mouse studies have primarily targeted the amyloid pathology, and not addressed the extensive neuronal loss. Despite developing neuronal dysfunction and cognitive deficits, most animal models do not develop extensive neuronal loss, even when more than one FAD mutations are expressed, or when both plaques and tangles are produced [82] . Reasons for this disparity between mice models and what occurs in the human condition are not known. Possible reasons include: ●● AD is a slow progressive disease that can not

be modeled in mice that have short lifespans; ●● There are other triggers of neurotoxicity that

are present in humans but not mice; or ●● Mice neurons are more resistant to Aβ toxic

insults than human neurons. It should also be stressed that transgenic mice model FAD mutations, and do not model the

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more common sporadic AD, which is associated with genetic and environmental risk factors. Another issue concerns the timing of treatment: many trials in the past have involved people already with advanced clinical AD, yet anti-amyloid treatments (for example) are not likely to be effective in humans for whom the pathology has already destroyed a large number of neurons. Clinical trials aimed at slowing the disease process are now testing potential treatments in presymptomatic subjects at high risk of AD, for example people with MCI. The advances in imaging and biomarker techniques in providing preclinical diagnosis are slowly making it possible to test potential treatments at much earlier stages of illness, thus optimizing the potential effectiveness of the treatments. There are other, possibly more relevant, larger animal models (i.e., nonhuman primates), however ethical considerations, expense and logistics in housing and maintenance, prevents them being used routinely. Thus, despite their failings, rodent models are still the most suitable and commonly used model in initial stages of preclinical evaluation of AD therapeutics. Anti-amyloid therapy (drugs) Since 1998, more than 100 compounds have failed in AD clinical trials [83] , in fact despite over 1000 trials in people with mild-to-moderate Alzheimer’s dementia [84] , so far none have improved cognition. These failures in anti-Aβ treatments that reached Phase III clinical trials include Tarenflurbil (Flurizan) which acts by lowering Aβ42 [85] , Bapineuzumab, a monoclonal anti-amyloid antibody which failed to improve cognitive functions in two major trials, despite Aβ plaque and phosphorylated tau-lowering effects in CSF [86] , Tramiprosate (Alzhemed), an anti-aggregation agent which had a clinical outcome that was difficult to interpret [87] and intravenous immunoglobulin (IVIG) that employed multiple antibodies against Aβ [88] . Another approach which also targets Aβ directly involves γ-secretase inhibitors. If γ-secretase can be prevented from cleaving APP in the first place, there will be no Aβ. However, this approach also had a striking failure recently in Phase III clinical trial of semagacestat, as it caused adverse side effects and a worsening of disease symptoms [89] . γ-Secretase has several other substrates in addition to APP; one such substrate being Notch. Therefore, trials of γ-secretase inhbitors affected Notch signalling, leading to skin

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Review  Asih, Chatterjee, Verdile, Gupta, Trengove & Martins tumors and alterations in lymphopoiesis and intestinal cells, as observed both in experimental animals and in humans [90,91] . Considering the difficulties in designing appropriate inhibitors of γ-secretase, many researchers are turning their attention to inhibitors of BACE as this enzyme is said to have fewer substrates, enhancing the feasibility of designing specific Aβ-lowering agents [92] . However recent trials from Lilly were halted due to issues surrounding liver toxicity. Despite this, Merck is continuing with their BACE inhibitor in clinical trials. The recently completed Phase I trial for Merck’s BACE inhibitor (MK-8931) reported an impressive 80–90% reduction in CSF Aβ40 and Aβ42 levels in healthy people who received the inhibitor. Such a reduction in the pathogenic Aβ42 species is beneficial, but an equivalent reduction in Aβ40 may lead to physiological consequences as it appears to have a number of biological functions. Developing specific Aβ42 lowering agents would be a better alternative, and as such targeting the final stage of generating Aβ performed by γ-secretase would offer a more appropriate strategy, yet as we have seen above, γ-secretase influences many other cell processes. Thus, in order for this approach to be successful highly selective drugs need to be designed. Improving the removal of Aβ by immunotherapy is one of the more extensively studied approaches in Aβ-targeted therapy. Both active and passive anti-Aβ immunotherapies have been shown to effectively reduce Aβ accumulation and prevent downstream pathology in preclinical models. Among passive immunotherapy, the use of monoclonal antibodies such as Bapineuzumab and Solanezumab have not been successful in large Phase III clinical trials [93] . Several new monoclonal antibodies have been developed and are now being tested in on going Phase II and III clinical trials, such as gantenerumab and crenezumab [94,95] . With respect of active Aβ immunotherapy, several second-generation Aβ vaccines are also under clinical testing. Following AN1792, an Elan–Wyeth vaccine that had the disastrous side effect of massive T-cell activation, secondgeneration active immunotherapies have shown promising results in terms of antibody response and safety. A novel vaccine EB101, which consists of Aβ42 peptides in a lipid adjuvant containing sphingosine-1-phosphate (a lipid thought to play a role in immune cell trafficking) has been trialled in mice genetically engineered to have aspects of AD. EB101 was shown to reduce the deposition of Aβ plaques and reduce inflammation in the

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brain in these mice [96] . Future directions of antiamyloid therapy should be addressed on humanized monoclonal antibodies (derived from human sequence) targeting the right Aβ species and are given at the earliest stage of AD. These are promising results, but the vaccine needs to be investigated further in animal models before being considered for clinical trials. Due to disappointing findings so far from anti-Aβ immunotherapies, immunotherapies have also focused on tau protein as an attractive target, especially once cognitive dysfunction is already evident. Various active and passive tau immunotherapies are ongoing in clinical setting such as TauRx and TRx0237. In comparison, to Aβ immunotherapy, tau immunotherapy is not as advanced, but preclinical data do support its development into clinical trials [97] . One important mechanism suggested for the removal of extracellular Aβ involves the uptake of Aβ or its aggregates into cells, followed by degradation, known as autophagy. In neurodegenerative diseases, autophagy is considered to be important in the removal of aggregated or misfolded proteins such as those seen in AD, Parkinson’s disease and Huntington’s disease. The autophagy pathway appears to be deficient in the AD brain and is a pathway that can contribute to Aβ generation [98,99] and the accumulation of Aβ aggregates [100,101] . Enhancing this pathway has been suggested as an appropriate therapeutic approach for AD, and we have previously shown that enhancing autophagy and the removal of Aβ aggregates is an underlying mechanism of action for the trialled drug, Latrepirdine [101–103] . It is clear from these trials that a greater understanding of the biological pathways that such drugs are targeting is required. In fact, this knowledge should be used initially in both preclinical (cell cultures and animal) and human studies to test any drugs for safety. Finally, it is a matter of great importance to inform the public and government that the failed clinical trials of amyloid-based therapies do not necessarily mean that the past 2 decades of amyloid-driven research are wasted. By establishing a comprehensive peer review, all clinical trial data will be available to facilitate a learning platform in order to improve translational findings in search of ‘the silver bullet’ for AD [104] . The fact that AD pathology progressively develops for at least 2 decades prior to the manifestation of its clinical symptoms implies that drugs that reduce Aβ accumulation early in the

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Clearing the amyloid in Alzheimer’s: progress towards earlier diagnosis & effective treatments  disease process are likely to be effective. This preclinical approach involving disease-modifying drugs that target Aβ accumulation have recently commenced testing in Phase III prevention trials for both autosomal dominant AD and the more sporadic form of AD. All previous and currently ongoing AD clinical trials involve cohorts of symptomatic individuals, thus who have already progressed to an irreversible stage of neuronal loss, where disease-modifying drugs are not likely to be that effective. Recently, the secondary preventative trial of anti-amyloid treatment in asymptomatic AD, named the A4 Trial, has been designed for the elderly (aged 65–85 years) who have normal cognitive function but may be at risk for developing AD, as assessed by PET imaging for brain amyloid burden. This study is designed to evaluate the effectiveness and safety of potential drugs for AD, with the monoclonal antibody, Solanezumab, chosen as the first drug to be evaluated in 1000 people 70 years of age and above. Although not as relevant to sporadic AD, the DIAN study is currently undergoing Phase II trials for Gantenerumab (225 mg subcutaneously every 4 weeks) and Solanezumab (400 mg intravenous infusion every 4 weeks). Individuals who are carriers of an AD-causing mutation, or are biological offspring or siblings of an AD-causing mutation carrier are being recruited. The latter type of recruits have a 50% chance of inheriting the mutation. If the widely accepted amyloid hypothesis is correct, anti-amyloid drug treatment should be administered at a stage when Aβ first begins to accumulate (or earlier!), at the start of the amyloid cascade and before neuronal damage begins. Therefore, in the not too distant future, anti-­ amyloid therapy will hopefully be directed at removing insoluble Aβ deposits as well as reducing soluble smaller aggregates of Aβ directly in susceptible individuals, to get the best disease-modifying outcome.

Review

the human lens, and found a twofold difference between AD and healthy control subjects [105] . Yet another study has investigated the retinal nerve fiber layer thickness in patients with early stages of AD and compared with healthy controls, using spectral domain optical coherence tomography. This study found the mean superior quadrant retinal nerve fiber layer thickness to be significantly lower in AD (p