The Genetic Basis of AD Incidence and Treatment

Yiying Zhu

BSc Biomedical Sciences, Division of Biosciences, University College London, Gower Street, London, WC1E 6BT, U.K.

Keywords: Neurosciences, Alzheimer’s Disease, Transgenic Mouse, Gene Therapy.

Abstract: Alzheimer’s disease (AD) is caused by neuron death and is one of the diseases that cannot be cured under

current medical technology. This review provides a summary of the relationship between the expression of

three common AD-related gene variants (APP, PSEN1 and PSEN2) and the formation of abnormal Aβ and

tau proteins aggregations (plaques and tangles). The possibility of using gene therapy to cure AD is also stated

in this review. During research, several recent papers about gene-related AD are viewed. In those papers,

researchers did experiment on transgenic mice and matched the results with markers of human AD to confirm

that investigated gene variants are AD-related. However, mouse models cannot represent whole human AD

characteristics, symptoms like language deficits cannot be investigated on mouse models. Furthermore,

researches show that gene therapy such as overexpression of PGC-1α can eliminate AD-like symptoms in

transgenic mouse models. It illustrates the potential of treating AD by using this type of gene therapy.

Importantly, genetic technology is still under exploration before the safe application of gene therapy on

humans due to possible unknown consequences of editing human genes.

1 INTRODUCTION

Among aged people, AD is a common

neurodegenerative disease. It is mainly represented

by cognitive impairment and memory loss led by

death of nerve cells and diminished synapses. In order

to reduce the suffering of both AD patients and their

families, lots of researchers are trying to know more

about the pathogenesis of AD and find out effective

therapies. According to known information, carriers

of some mutant genes are more possible to develop

AD (Jeong 2017). Reviewing previous papers aims to

list the most common gene variants, which were

confirmed to be able to enhance AD incidence, and

show the pathways they use. For example, gene

mutations might cause abnormal proteins production

to disturb both transmission and survival of neurons

(Thal, Fändrich 2015). During investigation on

curing AD, it is nonnegligible that the commonly

used AD therapies are only for AD symptoms

attenuation but do not have real therapeutic effects.

However, as gene mutations can cause AD, editing

specific gene is possible to treat AD and it has been

proofed feasible on mouse models (Katsouri, Lim,

Blondrath, Eleftheriadou, Lombardero, Birch,

Mirzaei, Irvine, Mazarakis, Sastre 2016). The

therapeutic effects on mouse models show that it is

worth to keep an eye on how gene therapy can cure

human AD without causing unwanted side effects. As

there are too many differences between mice and

humans, future investigations can focus more on

other primates which are closer to humans than

rodents.

2 BASIC INFORMATION ABOUT

ALZHEIMER’S DISEASE

The degeneration of neurons and their connections in

the AD brain is mostly due to accumulation of two

misfolded proteins in the brain: amyloid β-peptide

(Aβ) and tau-protein (an accessory protein of

microtubule). In AD brains, Aβ aggregate to form

intercellular plaques; tau-proteins which do not

correctly attach to microtubule make intracellular

twisted fibres (tangles) (Thal, Fändrich 2015). Aβ

oligomers (intermediate before forming fibril from

Aβ peptides) disturb synaptic plasticity so they can

cause long-term depression and further synapse loss

(Jeong 2017). In addition, the extracellular Aβ

plaques reduce diffusion among cells, therefore result

in decayed neurons communication (Gendron,

Petrucelli 2009). Tau filaments inside cells cause

neurons death because they can displace the location

Zhu, Y.

The Genetic Basis of AD Incidence and Treatment.

DOI: 10.5220/0011368900003438

In Proceedings of the 1st International Conference on Health Big Data and Intelligent Healthcare (ICHIH 2022), pages 325-331

ISBN: 978-989-758-596-8

325

and reduce the number of organelles, disturb cellular

homeostasis and impair microtubule dynamics (Thal,

Fändrich 2015). Except for the two proteins, neuron

degeneration can also arise from several other factors,

for instance, chronic inflammation by dysfunctional

glial cells and reduced cerebral vascular blood flow

(https://www.nia.nih.gov/health/what-happens-

brain-alzheimers-disease).

Brain shrinking caused by neurodegeneration

with a specific pathway is an important characteristic

of AD. The entorhinal cortex and the hippocampus,

which are significant brain regions about memory,

are usually the starting points of it. Then, it slowly

spreads into medial parietal, lateral temporal and

frontal regions. Finally, the whole cerebral cortex can

be affected by atrophy, the patients cannot handle

daily tasks (Fjell, McEvoy, Holland, Dale, Walhovd

2014).

Researchers believe that there are various risk

factors that are responsible for the pathogenesis of

AD, such as, age, genetic inheritance, exposure to

aluminium, traumatic brain injury, vascular diseases

(A Armstrong 2019). Although family history is not

the most prominent risk factor of AD, understanding

the mechanisms of the gene mutations that are related

to the neurons degeneration and finding out the

suitable genetic treatments can be effective in

delaying and curing AD.

3 GENETIC EFFECT ON

INCIDENCE OFAD

3.1 Early-onset Familial AD

Early-onset familial AD(EOFAD) usually happens

under 65-year-old and has high heredity, which is

about 92-100%. EOFADs that follow Mendelian

inheritance occupy about 10-15% of all EOFADs and

are confirmed to be associated with mutations on

APP (Amyloid protein precursor), PSEN1

(Presenilin-1) and PSEN2 (Presenilin-2) genes

(duplications and missense) (Ayodele, Rogaeva,

Kurup, Beecham, Reitz, 2021). These mutations have

a similar effect, which is increased Aβ42 to Aβ40

ratio. Because Aβ42 is more prone to aggregation,

plaques are more possible to be formed (Tanzi 2012).

APP is the gene that is mapped into chromosome

21, which codes for amyloid precursor protein (APP)

(Tanzi 2012). Both 40 and 42 amino acids long Aβs

(Aβ40 and Aβ42) can be produced by proteolytic

processing of APP by β-secretase and γ-secretase

(Jeong 2017). In Nilsson and colleagues’ APP knock-

in mouse models, as figure 1 shows, 2 clinical

mutations are introduced to mice APP genes. The

Swedish mutation (KM670/671NL) increases β-

cleavage so enhance total Aβ production and the

Beyreuther/Iberian (I716F) mutation increases γ-

cleavage to increase Aβ42/Aβ40 ratio. Observation

shows formation of plaques that mainly contained

Aβ42 appears at the age of 6 months. In addition,

microglia and astrocytes also accumulated near the

plaques. These observations in APP mutant mice are

consistent with the pathology that can be found in the

human AD brains. The abnormal Aβ accumulation

later reduced synaptic plasticity and led to memory

impairment in the 18 months old transgenic mice,

which also match the symptom of AD (Nilsson, Saito,

Saido 2014).

PSEN1 gene locates on chromosome 14 and

codes PS1 protein, which comprises the γ-secretase

catalytic site (Tanzi 2012, Sasaguri, Nagata,

Sekiguchi, Fujioka, Matsuba, Hashimoto, Sato,

Kurup, Yokota, Saido 2018). In the analysis of

PSEN1-P436S and PSEN1-P117L transgenic mice,

results show that these mutations induce abnormal

cleavage activity of γ-secretase and increase

Aβ42/Aβ40 ratio (Sasaguri, Nagata, Sekiguchi,

Fujioka, Matsuba, Hashimoto, Sato, Kurup, Yokota,

Saido 2018). The reason is that changes in PS1

protein can affect the conformation of catalytic

component of γ-secretase and eventually change its

activity.

Only a single PSEN1 mutation might be

Figure 1: Different mutations and their effects (Nilsson, Saito, Saido 2014).

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Figure 2. Sequential changes of biomarkers of AD over time (Grøntvedt, Schröder, Sando, White, Bråthen, Doeller 2018)

insufficient to observe all AD characteristics such as

change in behaviors on transgenic mice (Sasaguri,

Nagata, Sekiguchi, Fujioka, Matsuba, Hashimoto,

Sato, Kurup, Yokota, Saido 2018). Nevertheless,

figure 2 illustrates that the abnormal rising Aβ level

is an important biomarker for AD which shows up

first (Grøntvedt, Schröder, Sando, White, Bråthen,

Doeller 2018). The observation on PSEN1 gene

mutant mice is consistent with the biomarker so

PSEN1 mutations can be proofed to be AD-related.

PSEN2 is mapped on chromosome 1 (Tanzi

2012). Similar to PSEN1 mutations, mutant PSEN2

gene also raises Aβ42 level by altering γ-secretase

activity (Giau, Bagyinszky, Youn, An SSA, Kim

2019). It might be even harder to investigate the

influence of mutant PSEN2 individually because its

expression is about 10 folds lower than that of PSEN1

in the brain (Ayodele, Rogaeva, Kurup, Beecham,

Reitz 2021). However, researches show that PSEN2

mutation can accelerate Aβ accumulation and

memory impairment in transgenic mice with APP

mutation. In Fedeli and colleagues’ experiment, to

introduce PSEN2 mutation into APP mutant mouse,

they cross PSEN2 mutant female (N1411) with

Swedish APP mutant male which expresses

humanized Aβ sequence (Tg2576). The double

mutant mouse shows early Aβ aggregation at 2-3

months of age ( 6 months in Tg2576 mice), and also

early impaired learning and memory function at 4-5

months of age (7-8 months in Tg2576 mice) (Toda,

Noda, Ito, Maeda, Shimizu 2011). The observations

fit human AD biomarker and symptoms respectively.

The rest 85-90% EOFADs do not follow

Mendelian inheritance and are caused by other

unknown gene mutations. They are believed to be

induced by undentified or mixed genetic variants

(Ayodele, Rogaeva, Kurup, Beecham, Reitz 2021). It

might be helpful in developing gene therapy of AD if

more AD-related gene variants can be discovered in

the future.

3.2 Late-onset Familial AD

Late-onset sporadic AD (LOSAD) patients are

usually more than 65 years old. Unlike EOFAD,

LOSAD does not have a particular mode of

transmission so weaker familial clustering (Tanzi

2012). APOE gene on chromosome 17 is popular

while studying AD since it is considered the most

common gene that is related to AD (Safieh, Korczyn,

Michaelson 2019). It codes for apolipoprotein E

(apoE protein), a lipid binding and transporting

carrier protein, which is important for the cholesterol

transport in and out the central nervous system

(CNS), Aβ binding, clearance and synaptic function

in the brain (Theendakara, Peters-Libeu, Bredesen,

Rao 2018, Dorey, Chang, Liu, Yang, Zhang 2014).

There are 3 types of alleles of APOE gene, APOE ε4,

APOE ε3 and APOE ε2 (sequence from high to low

risk of developing AD) (Theendakara, Peters-Libeu,

Bredesen, Rao 2018). APOE4 allele is considered as

a significant risk factor of LOSAD (Jeong 2017).

First, APOE4 can increase Aβ deposition in the

brain. In Youmans and colleagues’ mouse models,

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327

They cross female mice, which have five familial

AD-related gene muations, with male homozygous

APOE2-, APOE3- and APOE4- mice to produce

EFAD mice. The results indicate that E4FAD mice

have higher Aβ42 levels and plaque deposition than

both E2FAD and E3FAD mice (Youmans, Tai,

Nwabuisi-Heath, Jungbauer, Kanekiyo, Gan, Kim,

Eimer, Estus, Rebeck, Weeber, Bu, Yu, Ladu 2012).

According to figure 3, APOE4 gene have these effects

by increasing production and reduce loss of Aβ

(Dorey, Chang, Liu, Yang, Zhang 2014). APOE4

protein alters γ-cleavage on APP gene to enhance

Aβ42 production, therefore following plaque

deposition as well. Additionally, APOE4 carriers

have reduced elimination of Aβ because: It impairs

degradation of Aβ; it can not cross the blood brain

barrier effectively; APOE3 can form complex with

Aβ to stop fibrillation but APOE4 cannot (Safieh,

Korczyn, Michaelson 2019).

Figure 3. comparison of interaction between APOE gene alleles and Aβ (Dorey, Chang, Liu, Yang, Zhang, 2014)

In addition, APOE4 gene can interact with tau-

protein to increase risk of AD as well (Safieh,

Korczyn, Michaelson 2019). In Shi and colleagues’

investigation, tau transgenic mice (P301S) are treated

by human APOE knock-in or APOE knock out. The

comparison among observations in P301S/E2,

P301S/E3, P301S/E4 and P301S/KO mice shows that

P301S/E4 mice have higher tau level in the brain,

which might results from weak autophagy-mediated

tau clearance caused by APOE4 (Shi 2017).

Additionally, APOE protein can affect the

hyperphosphorylation of tau. APOE3 protein can

bind tau effectively to prevent accumulation while

APOE4 protein cannot; APOE4 protein is stronger in

escaping secretion so it can stay in cytoplasm to

phosphorylate tau to greater extent through both

direct and indirect interaction (Safieh, Korczyn,

Michaelson 2019). The P301S/E4 mice are shown to

have greater hyperphosphorylated tau (ptau) covered

area (Shi 2017). Since neurofibrillary tangles are

mainly constituted by hyperphosphorylated tau and

can directly lead to neurodegeneration, APOE4

significantly raises the risk of developing AD.

There are still problems with AD-related gene

mutations investigations. As scientists cannot do

transgenic experiments on human, and also AD

patients might be affected by various other factors

like different lifestyles, the variables cannot be

controlled strictly while investigating relationship

between mutant genes and the incidence of AD. In

addition, although mouse models are a quite useful

tool, it is impossible to present AD symptoms on

functions beyond rodents’ memory system including

language and episodic memory on them. It is also

important to know that human AD is not only decided

by a single gene mutation, it might comes from the

combination of several mutations and even some

environmental factors. In this case, it is difficult to

present all of these on mouse models. Nevertheless,

the experimental results are still meaningful after

bringing the biomarkers for human AD and other AD-

like symptoms on the transgenic mice together.

Hence, the screening of AD-related genes can be a

reference while evaluating the AD onset possibility of

a person, and also help to make a judgment on

whether early treatment is needed or not. People

should also understand that having AD-related genes

does not mean that they will develop AD for sure,

those genes only means their possibility of having AD

is higher.

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4 TREATMENT OF AD

The treatment of AD is usually a hot topic among

researchers who are interested in AD. Nowadays, a

common drug for AD patients is Tacrine. Because

acetylcholine is an important neurotransmitters in the

brain and it is broken down by acetylcholinesterase.

These drugs can increase acetylcholine level in

synapses by inhibiting acetylcholinesterase activity.

Therefore the loss of neurons in AD brains can be

offset by the increased activity of survived neurons.

However, these drugs can only attenuate the

symptoms of AD but have no curative effect since

they are not reducing the plaques and tangles, neurons

keep degenerating and AD keeps getting worse.

In order to cure AD, the death of neurons should

be stopped, so the plaques and tangles which cause

this must be eliminated. Hence, both reducing the

formation and increasing the clearance of plaques and

tangles should be considered. In this case, gene

therapy might be the most efficient way to achieve the

aim because proteins are coded by DNA. By editing

patients’ DNA, increasing the expression of proteins

which can inhibit the formation or promote the

clearance of key AD proteins, might be able to

decrease or even remove the plaques and tangles in

AD brain. Gene therapy of AD is proofed feasible on

mouse models. Katsouri and colleagues found that

overexpression of PPARγ coactivator-1α (PGC-1α)

gene can reduce the secreted level of insoluble Aβ by

reducing the transcription of β-secretase through co-

activating nuclear peroxisome proliferator activated

receptor-γ (PPARγ) and other transcription factors

(Katsouri, Parr, Bogdanovic, Willem, Sastre, 2011).

To investigate the therapeutic effect of PGC-1α gene

on AD patients, they inject human PGC-1α (hPGC-

1α) gene to hippocampus and cortex of APP23

transgenic mice. The result shows that selectively

inducing hPGC-1α gene to specific brain regions can

reduce Aβ aggregation, β-secretase expression and

neuroinflammation; improve the spatial and

recognition memory of these mice; provide some

neuroprotective effects. However, this therapy has no

effect on wild-type mice (Katsouri, Lim, Blondrath,

Eleftheriadou, Lombardero, Birch, Mirzaei, Irvine,

Mazarakis, Sastre 2016).

To provide the treatment on humans, there is still

such a long way to go because there might be

unpredictable consequences on editing human gene.

Nevertheless, the PGC-1α gene therapy can be an

inspiration for future research direction since it

effectively reduces neurons degeneration in mouse

models, which shows the potential of gene therapy to

be applied in early AD treatment. Unfortunately, for

late AD patients who have great extent of neurons

degeneration, nearly fully impaired memory and

cognition, gene therapy like PGC-1α overexpression

is not useful because it aims to stop neurons

degeneration but not generating new neurons.

Producing new neurons is another aspect of treating

AD, which might be related to stem cell therapy and

still need lots of effort on the methods to unfrozen the

differentiation of stem cells.

5 CONCLUSIONS

For now, what people know is that AD is an

irreversible disease, which means patients’ symptoms

worsen gradually until they die as recent medical

technology is not able to stop AD effectively.

Therefore, more researches on both the pathogenesis

and treatment of AD are necessary for finding

effective precautions and therapies of AD. This

review only talks about AD pathogenesis which is

related to genes but there are lots of other non-

negligible factors can cause AD such as age and

lifestyle. The reason of focusing on gene is that gene

screening can help early prevention or even early

treatment if already diagnosed as AD. Except for the

four most common genes discussed, there are still lots

of other suspectable gene mutations might affect AD

pathogenesis but they appear fewer and are less

understood. If more AD-related genetic variants can

be confirmed, there can be more target for AD gene

therapy researches no matter direct or indirect.

Currently, gene therapy is still in the laboratory stage

and cannot be applied on humans. Because the gap

between researches on animals and humans is large,

and also the knowledge about human gene is still

insufficient. People are not capable to take the risk of

developing possible unknown side effects by editing

human gene nowadays. Importantly, ethic problems

on genetic therapy should not be neglected as well.

Hence, scientists still have loads of tasks like

discovery and elimination of unwanted side effects

before actual application of gene therapy on human.

To achieve the goal, it is more helpful to do

experiments on other primates such as monkeys

because their brain structures are much more similar

to human brains than rodents. This might be the

general direction of researching gene therapy in the

future. After all, gene therapy has the potential to stop

and even cure AD, people will understand more about

human gene and finally apply safe and effective gene

therapy on AD treatment in the future.

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329

ACKNOWLEDGMENTS

Thanks Prof. Kate Jeffery of University College

London and Gongting Wang as the teaching assistant

very much for passing on their knowledge of

neurosciences patiently to me. Their lessons gave me

the chance to learn basic knowledge about brain

science and understand common useful experimental

methods. My curiosity and interest on Alzheimer’s

diseases come from their lessons as well. They

provided me general direction of writing this review

and removed my doubts with patience. Also thanks to

Min Han for guiding me during writing this review,

her advice helps a lot in making this review clearer.

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