*4.1.2 Aβ clearance*

*Geriatric Medicine and Gerontology*

strategies will be reviewed.

brils and fibrils [44, 45].

monomer, oligomer and fibril [46].

*4.1.1 Reducing Aβ production*

**4.1 Amyloid-focused ongoing clinical trials**

treatment strategies aiming at the prevention of and/or clearance of pathological Aβ and tau. Neurotransmitter-based strategies and others, such as combatting against oxidative stress or neuroinflammation are generally classified as "symptomatic treatments". In this section, current disease-modifying and symptomatic treatment

According to the amyloid cascade hypothesis, AD begins with the accumulation of Aβ, years before its clinical onset. APP is a transmembrane protein whose physiological function is not completely understood. In a healthy brain, APP is metabolized by three proteolytic enzymes, namely α, β and γ secretases [43]. Proximally, γ-secretase cleaves the protein in its membrane-spanning domain solely by itself, forming an intracellular carboxy-terminal fragment (CTF), which is probably pro-plastic by translocating into the neuronal nucleus and playing a role in pro-plastic signaling. However distally, APP is cleaved alternatively, either by α-secretase or by β-secretase (BACE) on its two different sites in the extracellular domain close to the amino terminal of APP. The former cleavage is nonamyloidogenic since it produces an inert peptide called p3 in the mid-segment and another one, which is called sAPPα containing the N-terminus and probably having some neurotrophic functions. However, the latter cleavage is amyloidogenic, since it produces the anti-plastic and deposition-prone Aβ fragment in the mid-segment and sAPPβ in the N-terminus. The resulting Aβ will either be cleared by lysosomal-proteasomal mechanisms or will oligomerize and start to induce its pathophysiological functions. Now it is known that soluble oligomers of Aβ are more toxic than its more downstream moieties that are insoluble protofi-

Therefore, current studies aim to agonize α-secretase activity (ADAM10 activators), inhibit β-secretase (BACE inhibitors), and inhibit or modulate γ-secretase (GSIs and GSMs). Also enhancing clearance of Aβ with active or passive immunotherapies or prevention of aggregation of APs are the treatment focuses of ongoing trials. Monoclonal antibodies bind different epitopes which are N-terminal, C-terminal or mid-domain of Aβ and different conformations of Aβ which are

Two secretases, namely α and γ are seemingly no longer the focus of drug development efforts for AD, as a result of many failures in clinical trials and concerns that their interaction with other substrates may trigger diseases like cancer. Specific ADAM10 activators that will act only in the brain thus preventing its potential role in breast cancer is yet to be developed [47] In a recent review it was stated that "the future of γ-secretase inhibition as an AD treatment strategy may depend on the development of GSMs, which aim to cause a shift from Aβ1-42 species toward the shorter and less pathogenic forms of Aβ, while also sparing

β-Secretase is an aspartic acid protease belongs to the pepsin family. β-Site APP cleaving enzyme 1 (BACE1) plays role in Aβ production. BACE1 inhibition strategies do not share the same concerns for interfering with the other secretases. Therefore BACE1 inhibition is one of the strategies to interfere with amyloid cascade. There are ongoing trials with E 2609 (NCT03036280, NCT02956486), CNP520 (NCT02565511, NCT03131453) and JNJ-54861911 (NCT02569398,

**90**

Notch" [48].

NCT01760005) [49].

The first experience of active vaccine trial was with AN1792 and ended occurrence of T-cell mediated meningoencephalitis [50]. Now the only ongoing active vaccine trial is CAD-106 that generates anti-Aβ antibodies to N-terminus [51, 52].

Crenezumab is a humanized IgG4 monoclonal antibody (mAb) that binds the mid-domain of the Aβ peptide (residues 13–24) and binds multiple conformations of Aβ (monomers, oligomers, fibrils) [53, 54]. Patients with mild to moderate Alzheimer Disease and also Preclinical Presenilin1 (PSEN1) E280A Mutation Carriers are involved in ongoing trials of Crenezumab (NCT03491150, NCT03114657, NCT02353598, NCT01998841, NCT02670083).

Gantenerumab is a first fully human IgG1 mAb binds an N-terminal [3–12] and central [18–27] amino acids of the Aβ peptide. It binds monomers weaker than oligomers and fibrils [46]. Gantenerumab is being evaluated in phase 2 and 3 trials in individuals with prodromal and early AD and individuals at risk for and with early-stage autosomal-dominant AD (NCT02051608, NCT03444870, NCT03443973, NCT01224106, NCT01760005) [46, 55, 56].

Aducanumab is a fully human IgG1 mAb binds the N-terminus (residues 3–6) of Aβ peptide. It recognizes oligomers and fibrils but it does not react to the monomers [18]. Ongoing Aducanumab trials involve prodromal, early and mild AD patients (NCT03639987, NCT02484547, NCT02477800, NCT01677572) [46, 57].

Solanezumab is a humanized IgG1 mAb, binds the mid-domain of Aβ (residues 16–26). It specifically recognizes monomers [58]. There are two ongoing prevention trials with solanezumab (NCT01760005, NCT02008357).

#### *4.1.3 Other anti-amyloidogenic compounds*

In addition to abovementioned strategies, there are some other anti-amyloidogenic compounds with diverse mechanisms. ALZT-OP1 prevents Aβ aggregation and neuroinflammation and is being evaluated in phase III clinical trial (NCT02547818) [59]. Posiphen is another anti-amyloidogenic drug that currently in phase I/II clinical trial (NCT02925650) [60].

Update of selected anti-Alzheimer's disease drugs in clinical trials including anti-amyloid strategies are summarized in **Table 2**.

#### **4.2 Tau-focused ongoing clinical trials**

Tau is a microtubule-associated protein (MAP) in neurons which regulates the axonal transport [63]. Although tau pathology proved to be more correlated with clinical symptoms than amyloid mechanisms, tau-based therapeutic strategies are relatively new. Beta-folded oligomers of abnormal phosphorylation of tau are the main component of NFTs. Post-translational modifications such as phosphorylation, acetylation and truncation play a major role in tau function [64]. Modulating tau phosphorylation, targeting other tau post-translational modifications, microtubule stabilizers, tau aggregation inhibitors, anti-tau immunotherapy are the mechanisms targeted by clinical trials. Current clinical trials focusing on tau are summarized in **Table 3**.

#### *4.2.1 Targeting tau-post-translational modifications*

Salsalate is a nonsteroidal anti-inflammatory drug that has been shown to inhibit acetyltransferase p300-induced tau acetylation in frontotemporal dementia (FTD) mouse model [75]. There is a phase I clinical trial in patients with prodromal to mild


**93**

**Target**

**Drug name**

**Study title** A Study of Crenezumab Versus Placebo in Preclinical Presenilin1 (PSEN1) E280A Mutation Carriers to Evaluate Efficacy and Safety in the Treatment of Autosomal-Dominant Alzheimer's Disease, Including a Placebo-Treated Non-Carrier Cohort [27]

CREAD Study: A Study of Crenezumab Versus

Placebo to Evaluate the Efficacy and Safety in

Participants with Prodromal to Mild Alzheimer's

A Study of Gantenerumab in Participants with Mild

Passive

Phase III Phase III

Phase II

•

Washington University

NCT01760005

School of Medicine,

Eli Lilly and Company,

Hoffmann-La Roche

(and 5 more)

Phase III

Hoffmann-La Roche

NCT01224106

Hoffmann-La Roche

NCT02051608

immunotherapy

Alzheimer Disease

A Study of Gantenerumab in Participants with

Prodromal Alzheimer's Disease [56]

Dominantly Inherited Alzheimer Network Trial:

An Opportunity to Prevent Dementia. A Study

of Potential Disease Modifying Treatments in

Individuals at Risk for or With a Type of Early Onset

Alzheimer's Disease Caused by a Genetic Mutation.

A Study of Aducanumab in Participants with Mild

Passive

Phase II

Biogen

NCT03639987

immunotherapy

(against aggregated

Aβ)

Cognitive Impairment Due to Alzheimer's Disease or

With Mild Alzheimer's Disease Dementia to Evaluate

the Safety of Continued Dosing in Participants

with Asymptomatic Amyloid-Related Imaging

221AD302 Phase 3 Study of Aducanumab (BIIB037)

Phase III

Biogen

NCT02484547

in Early Alzheimer's Disease (EMERGE) [46]

Abnormalities

(DIAN-TU) [55]

Aducanumab

Disease [20]

Gantenerumab

**Therapy type**

**Trial status** Phase II

• • Institute

•

National Institute on

Aging (NIA)

Phase III

AC Immune SA,

NCT02670083

Genentech, Hoffmann-La

Roche

Banner Alzheimer's

Genentech, Inc.

NCT01998841

**Company**

**Clinical trial identifier**

*Future Treatment of Alzheimer Disease DOI: http://dx.doi.org/10.5772/intechopen.85096*

#### *Geriatric Medicine and Gerontology*


#### *Future Treatment of Alzheimer Disease DOI: http://dx.doi.org/10.5772/intechopen.85096*

*Geriatric Medicine and Gerontology*

**92**

**Target** BACE inhibitor

E2609

A 24 Month Study to Evaluate the Efficacy and Safety

of E2609 in Subjects with Early Alzheimer's Disease\_

(MissionAD2)

A 24-Month Study to Evaluate the Efficacy and

Small molecule

Phase III

Biogen, Eisai Co., Ltd.

NCT02956486

Safety of E2609 in Subjects with Early Alzheimer's

Disease\_ (MissionAD2)

A Study of CAD106 and CNP520 Versus Placebo

Small molecule

Phase II/III

Amgen, Inc., Novartis

NCT02565511

Pharmaceuticals

Corporation

in Participants at Risk for the Onset of Clinical

Symptoms of Alzheimer's Disease

A Study of CNP520 Versus Placebo in Participants

Small molecule

Phase II/III

Amgen, Inc., Novartis

NCT03131453

Pharmaceuticals

Corporation

at Risk for the Onset of Clinical Symptoms of

Alzheimer's Disease

JNJ-54861911 [49]

An Efficacy and Safety Study of Atabecestat in

Small molecule

Phase II/III

Janssen, Shionogi Pharma

NCT02569398

Participants Who Are Asymptomatic at Risk for

Developing Alzheimer's Dementia (EARLY)

Dominantly Inherited Alzheimer Network Trial:

Small molecule

Phase II/III

Janssen, Shionogi Pharma

NCT01760005

An Opportunity to Prevent Dementia. A Study

of Potential Disease Modifying Treatments in

Individuals at Risk for or With a Type of Early Onset

Alzheimer's Disease Caused by a Genetic Mutation.

A Study of CAD106 and CNP520 Versus Placebo

Active

Phase II/III

Novartis Pharmaceuticals

NCT02565511

Corporation

immunotherapy

in Participants at Risk for the Onset of Clinical

Symptoms of Alzheimer's Disease

An Open-Label Crenezumab Study in Patients with

A Study of Crenezumab Versus Placebo to Evaluate

the Efficacy and Safety in Participants with

Prodromal to Mild Alzheimer's Disease (CREAD 2)

Passive

Phase III Phase III

Hoffmann-La Roche

NCT03114657

Hoffmann-La Roche

NCT03491150

immunotherapy

Alzheimer's Disease

Crenezumab

Aβ clearance

CAD106 [49, 61]

CNP520 [49]

Elenbecestat [49]

**Drug name**

**Study title**

**Therapy type** Small molecule

Phase III

Biogen, Eisai Co., Ltd.

NCT03036280

**Trial** 

**Company**

**Clinical trial** 

**identifier**

**status**


*Geriatric Medicine and Gerontology*

**Table 2.**

**95**

**Target** Lisin acetylation inhibitor

c-Abl inhibitor

Microtubule stabilizers Tau aggregation inhibitors

TRX-0237 [67, 68]

Nicotinamide

Anti-Tau immunoteraphies

AADvac-1 [67]

24 Months Safety and Efficacy Study of AADvac1 in Patients with Mild Alzheimer's Disease

A study comparing the safety and effects of a new compound, ACI-35 with

placebo in patients with mild to moderate Alzheimer's disease

Study of Intravenous Immunoglobulin in Amnestic Mild Cognitive

A Study to Evaluate Albumin and Immunoglobulin in Alzheimer's disease

A Study to Evaluate the Efficacy and Safety of ABBV-8E12 in Subjects with

Active

Phase II

Instituto Grifols, S.A./

NCT01561053

Grifols Biologicals Inc.

Phase III

immunotherapy

Passive

Phase II

AbbVie

NCT02880956

Immunotherapy

ACI-35 [19] IvIg [69–71] ABBV-8E12

[72, 73]

RO 7105705 [74]

**Table 3.**

*Current clinical trials focusing on tau.*

Early Alzheimer's Disease

An Extension Study of ABBV-8E12 in Early Alzheimer's Disease

A Study to Evaluate the Efficacy and Safety of RO7105705 in Patients with

Prodromal to Mild Alzheimer's Disease

Passive

Phase II

AbbVie

NCT03712787

Immunotheraphy

Passive

Phase II

Genentech, Inc

NCT03289143

Immunotheraphy

Impairment

TPI-287

Nilotinib [66]

Salsalate [65]

Salsalate in Patients Mild to Moderate Alzheimer's Disease

Impact of Nilotinib on Safety, Biomarkers and Clinical Outcomes in Mild to Moderate Alzheimer's Disease

A Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy Study of TPI-287 in Alzheimer's Disease

Safety and Efficacy of TRx0237 in Subjects with Early Alzheimer's Disease

Nicotinamide as an Early Alzheimer's Disease Treatment (NEAT)

Lysosomal acidification Active immunotherapy

Phase II

Axon Neuroscience SE

NCT02579252

Active

Phase I

AC Immune SA, Janssen

ISRCTN13033912

immunotherapy

Active

Phase II •

Sutter Health

NCT01300728

immunotherapy

Phase II •

University of California, Irvine

NCT03061474

Small molecule

Phase II-III •

TauRx Therapeutics Ltd

NCT03446001

Small molecule

c-Abl inhibitor Small molecule

Phase I

Cortice Biosciences

NCT01966666

Phase II

Georgetown University

NCT02947893

Phase I

Adam Boxer

NCT03277573

**Drug name**

**Study title**

**Therapy type**

**Trial status**

**Company/sponsor**

**Clinical trial identifier**

*Future Treatment of Alzheimer Disease DOI: http://dx.doi.org/10.5772/intechopen.85096*

*Update of selected anti-Alzheimer's disease drugs in clinical trials including anti-amyloid strategies.*

#### *Future Treatment of Alzheimer Disease DOI: http://dx.doi.org/10.5772/intechopen.85096*

*Geriatric Medicine and Gerontology*

NCT02477800

**94**

**Target**

**Drug name**

**Study title** 21AD301 Phase 3 Study of Aducanumab (BIIB037) in

Early Alzheimer's Disease (ENGAGE) [46]

Multiple Dose Study of Aducanumab (BIIB037)

(Recombinant, Fully Human Anti-Aβ IgG1 mAb)

in Participants with Prodromal or Mild Alzheimer's

Disease (PRIME) [57]

Dominantly Inherited Alzheimer Network Trial:

Passive

Phase II

•

Washington University

NCT01760005

School of Medicine

• •

Hoffmann-La Roche

(and 5 more)

Phase III

• •

Alzheimer's Therapeutic

Research Institute

Phase III

Phase I

•

QR Pharma Inc.

NCT02925650

Phase II

•

Alzheimer's Disease

Cooperative Study

(ADCS)

AZTherapies, Inc.

NCT02547818

Eli Lilly and Company

NCT02008357

Eli Lilly and Company

Phase III

immunotherapy

(against Aβ3–12 and

Aβ18–27)

An Opportunity to Prevent Dementia. A Study

of Potential Disease Modifying Treatments in

Individuals at Risk for or With a Type of Early Onset

Alzheimer's Disease Caused by a Genetic Mutation.

Clinical Trial of Solanezumab for Older Individuals

Who May be at Risk for Memory Loss [62]

Other Antiamyloidogenic

ALZT-OP1 [59]

Safety and Efficacy Study of ALZT-OP1 in Subjects

with Evidence of Early Alzheimer's Disease

(COGNITE)

Compounds

Posiphen® [60]

Safety, Tolerability, PK and PD of Posiphen®

in Subjects with Early Alzheimer's Disease

(DISCOVER)

**Table 2.**

*Update of selected anti-Alzheimer's disease drugs in clinical trials including anti-amyloid strategies.*

(DIAN-TU) [55]

Solanezumab

**Therapy type**

**Trial** 

**Company**

**Clinical trial** 

**identifier**

**status**

Phase III

Phase I

Biogen

NCT01677572

Biogen


**Table 3.** *Current clinical trials focusing on tau.* AD (NCT03277573). Nilotinib is a c-Abl tyrosine kinase inhibitor used in patients with leukemia [76]. It is thought to clean tau by inducing autophagy. It is being evaluated in a phase II clinical trial in patients with mild to moderate AD (NCT02947893).

### *4.2.2 Microtubule stabilizers*

TPI-287 is a small molecule that stabilizes microtubules. It is tested in a phase I clinical trial in AD patients [77].

### *4.2.3 Tau aggregation inhibitors*

LMT-X or named as TRx0237 is a second generation formulation of methylene blue that targets tau accumulation [77]. There is a phase II/III clinical trial in patients with early AD (NCT03446001) [67, 68]. Nicotinamide is the precursor of coenzyme Nicotinamide adenine dinucleotide prevents phosphorylation of tau in mice. A phase II study in mild-to-moderate Alzheimer's disease is currently ongoing (NCT03061474).

### *4.2.4 Active immunotherapy*

There are three active immunotherapy agents being evaluated in ongoing trials. AADvac-1 contains synthetic tau peptide spanning residues 294–305 derived from a naturally occurring truncated and misfolded tau protein coupled to keyhole limpet hemocyanin and aluminum hydroxide as adjuvant [77]. A phase II clinical trial in subjects with mild AD is ongoing (NCT02579252) [78]. ACI-35 is a synthetic peptide spanning the human protein tau sequence 393–408, phosphorylated at S396 and S404 [72]. A phase I clinical trial in subjects with mild to moderate AD is ongoing (ISRCTN13033912) [19]. Intravenous immunoglobulin (IVIg) is a human plasma-derived product consisting of polyclonal serum IgG used as anti-inflammatory and immunomodulatory therapy for various neurological diseases [73]. There are phase II and III studies in subjects with mild cognitive impairment and AD (NCT01300728, NCT01561053) [69, 70].

#### *4.2.5 Passive immunotherapy*

ABBV-8E12 is a humanized anti-tau monoclonal antibody. There are two studies with ABBV-8E12 in patients with early AD (NCT02880956, NCT03712787) [72, 73]. Another passive immunotherapy agent R07105705 is an anti-tau antibody [39]. It is being evaluated in patients with prodromal to mild AD (NCT03289143) [74].

#### **4.3 Other ongoing clinical trials**

Riluzole, a sodium channel blocker, is used as a disease-modifying drug for amyotrophic lateral sclerosis [79]. It lowers extracellular glutamate levels, inhibits presynaptic glutamate release and induces glutamate transporter activity. Riluzole is being evaluated in a Phase II clinical trial in patients with mild AD (NCT01703117) [79–82].

LMA11A-31 is a small molecule prevents synaptic dysfunction, spine loss, neurite degeneration, microglial activation, and cognitive deficits in animal models [83, 84]. A phase I/II trial with mild to moderate AD patients is ongoing (NCT03069014) [85]. AD is thought to be linked with viral infections [86, 87]. Therefore a phase II trial is ongoing in mild AD patients who test positive for serum antibodies for herpes simplex virus 1 or 2, with valacyclovir (NCT03282916). Lifestyle interventions, management of metabolic and cardiovascular risk factors,

**97**

**Target** Glutaminergic Neurotrophins and Their Receptor-

based Therapies

Therapies Targeted at

Valacyclovir [85]

Disease

Anti-viral Therapy in Alzheimer's

Neuroinflammation and Oxidative

Stress

Therapies and Interventions for AD

Insulin (Humulin R®

The Study of Nasal Insulin in the Fight

Against Forgetfulness (SNIFF)

U-100) [85]

Prevention

**Table 4.**

*Other strategies of Alzheimer's disease treatment.*

LM11A-31-BHS [85]

Study of LM11A-31-BHS in Mild–

moderate AD Patients

Phase I Phase II

• •

National Institute on

Aging (NIA)

Phase II

New York State

NCT03282916

Psychiatric Institute

National Institutes of

Health (NIH)

National Institute on

Aging (NIA)

Phase II

NCT01767909

Phase III

PharmatrophiX Inc.

NCT03069014

**Drug name** Riluzole [79–82]

Riluzole in Mild Alzheimer's Disease

Small molecule

Phase II

Sanofi

**Study title**

**Therapy type**

**Trial status**

**Company**

**Clinical trial identifier** NCT01703117

*Future Treatment of Alzheimer Disease DOI: http://dx.doi.org/10.5772/intechopen.85096*



### *Future Treatment of Alzheimer Disease DOI: http://dx.doi.org/10.5772/intechopen.85096*

*Geriatric Medicine and Gerontology*

*4.2.2 Microtubule stabilizers*

clinical trial in AD patients [77].

*4.2.3 Tau aggregation inhibitors*

(NCT03061474).

*4.2.4 Active immunotherapy*

(NCT01300728, NCT01561053) [69, 70].

*4.2.5 Passive immunotherapy*

**4.3 Other ongoing clinical trials**

AD (NCT03277573). Nilotinib is a c-Abl tyrosine kinase inhibitor used in patients with leukemia [76]. It is thought to clean tau by inducing autophagy. It is being evaluated in a phase II clinical trial in patients with mild to moderate AD (NCT02947893).

TPI-287 is a small molecule that stabilizes microtubules. It is tested in a phase I

LMT-X or named as TRx0237 is a second generation formulation of methylene

There are three active immunotherapy agents being evaluated in ongoing trials. AADvac-1 contains synthetic tau peptide spanning residues 294–305 derived from a naturally occurring truncated and misfolded tau protein coupled to keyhole limpet hemocyanin and aluminum hydroxide as adjuvant [77]. A phase II clinical trial in subjects with mild AD is ongoing (NCT02579252) [78]. ACI-35 is a synthetic peptide spanning the human protein tau sequence 393–408, phosphorylated at S396 and S404 [72]. A phase I clinical trial in subjects with mild to moderate AD is ongoing (ISRCTN13033912) [19]. Intravenous immunoglobulin (IVIg) is a human plasma-derived product consisting of polyclonal serum IgG used as anti-inflammatory and immunomodulatory therapy for various neurological diseases [73]. There are phase II and III studies in subjects with mild cognitive impairment and AD

ABBV-8E12 is a humanized anti-tau monoclonal antibody. There are two studies with ABBV-8E12 in patients with early AD (NCT02880956, NCT03712787) [72, 73]. Another passive immunotherapy agent R07105705 is an anti-tau antibody [39]. It is being evaluated in patients with prodromal to mild AD (NCT03289143) [74].

Riluzole, a sodium channel blocker, is used as a disease-modifying drug for amyotrophic lateral sclerosis [79]. It lowers extracellular glutamate levels, inhibits presynaptic glutamate release and induces glutamate transporter activity. Riluzole is being evaluated in a Phase II clinical trial in patients with mild AD (NCT01703117) [79–82]. LMA11A-31 is a small molecule prevents synaptic dysfunction, spine loss, neurite degeneration, microglial activation, and cognitive deficits in animal models [83, 84]. A phase I/II trial with mild to moderate AD patients is ongoing (NCT03069014) [85]. AD is thought to be linked with viral infections [86, 87]. Therefore a phase II trial is ongoing in mild AD patients who test positive for serum antibodies for herpes simplex virus 1 or 2, with valacyclovir (NCT03282916). Lifestyle interventions, management of metabolic and cardiovascular risk factors,

blue that targets tau accumulation [77]. There is a phase II/III clinical trial in patients with early AD (NCT03446001) [67, 68]. Nicotinamide is the precursor of coenzyme Nicotinamide adenine dinucleotide prevents phosphorylation of tau in mice. A phase II study in mild-to-moderate Alzheimer's disease is currently ongoing

**96**

exercise and diet are the focuses for primary prevention of AD (NCT01767909, NCT03249688) [88–92].

Deep brain stimulation is a novel therapeutic strategy for AD. One trial is ongoing in patients with mild AD (NCT03622905). Other strategies of Alzheimer's disease treatment are summarized in **Table 4**.

#### **5. Gene and stem cell therapy in Alzheimer disease**

#### **5.1 Genetics of Alzheimer's disease**

Both age and family history are important risk factors for AD. The risk of developing AD increases for one who has a first-degree relative with AD when compared to the general population. AD can be grouped into two subtypes with respect to age of onset. Most of the AD cases (>95%) are late-onset AD (sporadic/LOAD) (above age 65) that is considered to be multifactorial [93]. Many susceptibility genes for LOAD have been defined thanks to genome-wide association studies (GWAS) and several other sequencing analyzes. For instance, one of the well-studied genetic risk factors for LOAD is an alteration in Apolipoprotein E (APOE) coded by the gene localized to 19q13 [94]. APOE is a multifunctional protein which serves a number of functions in neuronal activities. In brain tissue, there are three main isoforms that are diversified by each other by different one amino acid, which are APOEε2 (Cys112, Cys158), APOEε3 (Cys112, Arg158) and APOEε4 (Arg112, Arg158). The differences between these three APOE isoforms have a significant impact on the structure and function of APOE at molecular and cellular levels. Therefore, those are thought as associated with neuropathological conditions [95].

Early onset AD (Familial/EOAD) represent <5% of all cases of AD. APP (Amyloid beta (A4) precursor protein), PSEN1 (Presenilin 1), and PSEN2 (Presenilin 2) genes mutations are exclusively considered as a basis for EOAD in most cases [94]. APP, a transmembrane protein in neuron cells, is cleaved by β-secretase and γ-secretase, respectively, to produce β-amyloids (Aβ) and some other side products [96]. Since neurotoxic consequences of altered Aβ ratios like neurodegeneration resulting from aberrant synaptic function take place in brain, APP mutations have continuously been investigated. Yet, only approximately 15% of EOAD could be enlightened by dominant APP gene mutations [97].

Another protein that is strictly associated with the progression of AD is PSEN1 as it is the principal component of γ-secretase complex. Since neurotoxic fragments are formed by proteolytic function of γ-secretase on APP, PSEN1 gene mutations give rise to abnormal activity of the proteolytic enzyme leading to abnormal or longer Aβ fragments and, therefore this contributes to development of EOAD [95]. More than 180 autosomal dominant PSEN1 mutations associated with AD have been reported, which makes PSEN1 significantly important protein in the occurrence of EOAD [98]. Disease-causing PSEN1 gene mutations, showing complete penetrance, accounts for majority of EOAD (approximately 80%) and these mutations are defined as the most common cause of the disease [99]. Lastly, the gene PSEN2 is also coding for one subunit of γ-secretase, the aspartyl protease generates Aβ. Missense mutations are reported in PSEN2, which are rarely genetic basis of EOAD [100]. In total, as mentioned in Zou's review article in 2013, majority of the diseasecausing mutations identified for the EOAD have been reported in PSEN1 gene (approximately 78%), followed by APP mutations (17%) then with rare PSEN2 gene mutations (approximately 5%) [94].

Technological advances in sequencing methods over the past decade allow researchers to investigate AD thoroughly, especially genetic fundamentals of the

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*Future Treatment of Alzheimer Disease DOI: http://dx.doi.org/10.5772/intechopen.85096*

**5.2 Gene therapy for AD**

NCT00876863) [103].

**5.3 Stem cell treatment for AD**

*5.3.1 Embryonic stem cells (ESCs)*

in rodent models [106, 107].

disease. Since high-throughput sequencing provides a large number of polymorphisms in numerous subjects, new several genes associated with AD risk have been emerged and reported [96]. Accordingly, genome-wide association studies (GWAS) about AD increased, which consequently suggests new gene therapy strategies.

Discovering risk loci by GWAS studies may help to enlighten the biological mechanisms underlying AD because the reported genes might have been target for medicines, thereby this issue promises further investigation in order to improve gene therapy strategies and thus precision medicine concept for AD [101].

Over time, gene delivery of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), APOE, ECE (endothelin-converting enzyme) have been investigated in several animal models of AD. Endothelin-converting enzyme (ECE) is protease involved in the degradation of Aβ peptides. Intracranial administration of five recombinant adeno-associated viral vector (rAAV) containing the ECE-1 synthetic gene showed reduced Aβ in the anterior cortex and hippocampus in APP-PS1 transgenic mice. Use of AAV vector encoding anti-Aβ Ab in Tg2576 mice results in a significant decrease in Aβ level in the brain of subjects. These results

The first clinical trial using Adeno-Associated Virus delivery of NGF has been accomplished and the results indicate amelioration of AD pathogenesis. Clinical trials were conducted using CERE-110 that is an AAV2/2 vector containing full length NGF transgene for the treatment of AD patients. These trials confirmed that AAV2- NGF delivery was well tolerated with a high level of safety and no systemic toxicity but did not affect clinical outcomes or selected AD biomarkers (NCT00087789,

Stem cells (SCs) are continuously capable of self-renewing and differentiating into specialized cells. Accordingly, SC therapy is surely becoming a promising strategy in the treatment of neurodegenerative diseases including AD owing to the capacity of SCs to migrate and reach areas of the brain. SCs are classified into four groups; embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs),

ESCs, called as pluripotent, are derived from the inner cell mass of blastocyst because they have the ability to develop cell types from the ectoderm, mesoderm, and endoderm germ layers [105]. ESCs may an excellent cell replacement therapy approaches for transplantation in AD [104]. In vitro studies have been successful to differentiate ESCs into specific neuronal cell types like dopaminergic neurons and these studies show that the role of ESCs and their derivatives reduce AD pathology

Several studies reveal that ESC-derived NSCs can be safely transplanted without tumorigenesis despite the fact that undifferentiated ESCs have risks of tumor formation, transplantation rejection and immune responses [106, 108, 109]. Experiments conducted on human ESCs have been able to generate dopaminergic neurons, spinal motor neurons and astroglial cells [110]. Some studies demonstrated use of retinoic acid (RA) induce direct differentiation of human ESCs into basal forebrain cholinergic neurons (BFCNs). Tang et al. showed that ESC-derived

support its use for the prevention and treatment of AD [102].

mesenchymal stem cell, and neural stem cells [104].

disease. Since high-throughput sequencing provides a large number of polymorphisms in numerous subjects, new several genes associated with AD risk have been emerged and reported [96]. Accordingly, genome-wide association studies (GWAS) about AD increased, which consequently suggests new gene therapy strategies.
