Hypotheses of Alzheimer’s Disease Pathogenesis

Liuhua Chen

Departments of Botany and Zoology, University of British Columbia, Vancouver, V6T 1Z1, Canada

Keywords:

Alzheimer’s Disease, Amyloid Aggregation, Tau, APP, Senile Plaque, NFT.

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia. The two hallmarks of AD are extracellular

senile plaques (SF) and intracellular neurofibrillary tangles (NFT). Numerous studies have been involved in

research for AD pathogenesis, proposing different hypotheses and theories to explain the occurrence of the

two hallmarks as well as AD onset. This paper will review three suppositions of AD pathogenesis, including

the amyloid cascade hypothesis, the APP metabolism impairment theory, and Tau hypothesis. The amyloid

cascade hypothesis is the mainstream hypothesis that suggests Aβ aggregation should predate all AD-related

pathological events. Amyloid precursor protein (APP) metabolism theory considers impaired metabolism of

APP to be a possible explanation for AD onset. Tau hypothesis, which is another major hypothesis for AD

pathogenesis, postulates that tau aggregation and NFT play an initiating role in AD onset. Many studies have

elucidated that Aβ aggregation may not cause AD; some of the AD researchers have shifted their research

focus to alternative hypotheses involving other biomarkers, such as tau and APP metabolites. However, the

role of Aβ should not be refuted as it interacts with so many AD pathological features. Research on Aβ should

be alongside explorations of other potential pathological causes of AD.

1 INTRODUCTION

Alzheimer’s disease (AD) is a progressive and

irreversible neurodegenerative disease that is

affecting millions of people in the world. AD is

categorized into two divisions based on the onset age.

Sporadic AD or late-onset AD is the most common

type of AD; it usually manifests after age 65. Familial

AD, also known as early-onset AD, occurs in people

younger than age 60. Both types of AD together

account for more than half of the dementia which is

recognized as a public health priority by WHO. In the

past, most of the early-staged dementia used to be

deemed as one of the normal consequences of aging,

overlooking AD onset. However, AD is not an

inevitable consequence of aging but an abnormal

neurological disorder that will cause more severe

cognitive impairment as the disease progresses.

Two hallmarks of AD are extracellular senile

plaques (SP) and intracellular neurofibrillary tangles

(NFT) within the central nervous system. There are

numerous studies on SP, NFT, and the relevant

metabolic processes to investigate AD pathologies;

however, different hypotheses have not yet unified to

provide a clear AD pathology because of the complex

nature of AD and the limitations of the hypotheses. It

is of importance to summarize and compare current

studies on AD pathogenesis in order to unravel the

full picture of AD mechanism. This paper reviews

several hypotheses of AD pathogenesis, including the

amyloid cascade hypothesis, APP metabolism theory,

and tau hypothesis, to serve as a concise summary of

the current progress in AD mechanism research.

2 AMYLOID CASCADE

HYPOTHESIS

The amyloid cascade hypothesis, also known as beta-

amyloid hypothesis, posits that SPs are amyloid

plaques, which are mainly composed of Aβ fibrils,

contribute to NFT and other neuronal alternations

associated with AD-induced dementia (Jack, Jr., et al.

2016, Bondi, Edmonds, and Salmon 2017) . For a

long time, Aβ aggregation was positioned as the

upstream cause of all the pathological changes in AD.

Aβ is a metabolic product of amyloid-beta precursor

protein (APP) which plays important role in neuronal

development, neurite outgrowth, as well as

intracellular trafficking in axons (Kametani, and

Hasegawa 2018). APP (Figure 1) has four cleavage

478

Chen, L.

Hypotheses of Alzheimer’s Disease Pathogenesis.

DOI: 10.5220/0011372500003438

In Proceedings of the 1st International Conference on Health Big Data and Intelligent Healthcare (ICHIH 2022), pages 478-483

ISBN: 978-989-758-596-8

sites (i.e. α, β, and two γ sites) respectively

recognized and cleaved by α-secretase, β-secretase,

and γ secretase. Aβ is produced by the cleavages of

APP by β-secretase and γ secretase. In accordance

with the two γ cleavage sites on APP, β-γ

combinatorial cleavage produces either Aβ40 or

Aβ42, depending on which γ site the secretase binds.

The research suggests that the elevated production

level of Aβ42 rather than Aβ40 leads to aggregation

of SP (Hillen 2019). Normally, Aβ is released out of

the neurons and degraded; however, in pathological

conditions, Aβ is accumulated to form extracellular

plaques. Moreover, Aβ exists in three forms, which

are soluble Aβ monomers, soluble Aβ oligomer, and

insoluble Aβ fibrils. The amyloid cascade hypothesis

considers amyloid plaques the aggregation of the

insoluble Aβ fibrils.

Figure 1. APP metabolism and the metabolic products. Four dark blue arrows are secretase recognition sites on APP; α, β,

and γ sites correspond to α-, β-, and γ-secretases respectively. P3 is produced by cleavage by α and γ secretase. Aβ is produced

by β and γ secretase. sAPPα and sAPPβ are produced by α-secretase and β-secretase cleavage respectively. AICD (APP

intracellular Domain) are C-terminal fragments that result from cleavage of γ secretase. Adapted from Kametani, F., &

Hasegawa, M. (2018). Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease. Front Neurosci,

12, 25. https://doi.org/10.3389/fnins.2018.00025.

The Amyloid cascade hypothesis initially

proposes a clear temporal order in the AD

pathogenesis, in which high-level aggregation of Aβ

is the causative agent of other pathological events

including NFT occurrence (Bondi, Edmonds, and

Salmon 2017, Hillen 2019). Cytotoxicity of Aβ

aggregation can directly cause neurodegeneration and

neuron loss (Kametani, and Hasegawa, Ohshima, et

al. 2018). Also, amyloid plaques can activate

microglia and astrocytes to release inflammatory

factors, causing neuron inflammation (Zhang, and

Zheng 2019). The activated microglia are phagocytic

towards synapses, resulting in synaptic impairment.

Combining the clinical examples that relate AD onset

to Aβ aggregation, β amyloid hypothesis is long

believed to primarily account for AD onset. However,

along with AD research advancing, amyloid cascade

hypothesis is challenged and disapproved by many

recent studies.

A lot of research, ranging from investigating Aβ

neurotoxicity to exploring the relationship between

AD and amyloid plaques, has validated that the

temporal ordering proposed in the amyloid cascade

hypothesis is wrong ((Kametani, and Hasegawa 2018,

Hillen 2019). Jack et al. have acknowledged that

temporal ordering of amyloid cascade hypothesis is

problematic. In terms of Aβ toxicity, several lines of

evidence have rejected that Aβ cytotoxicity causes

synapse loss or neurodegeneration (Bondi, Edmonds,

and Salmon 2017). Braak et al. directly refute the

temporal ordering of amyloid cascade hypothesis by

reporting that NFT is not a downstream event led by

amyloid plaques, and that tau aggregation,

components of NFT, precedes formation of amyloid

plaques. In addition, amyloid plaques are not always

related to AD as normal people could have more

extensive amyloid aggregation and same-aged AD

patients and normal people could have amyloid

plaques of the same density (Edison, et al. 2007). It

comes to a conclusion that amyloid plaque or senile

plaque aggregation is related to aging but may be

irrelevant to AD onset. Furthermore, the most

convincing evidence refusing amyloid cascade

hypothesis might be the devastating failure of all

Hypotheses of Alzheimer’s Disease Pathogenesis

479

clinical trials on AD therapeutics aiming to stop or

delay AD progress by eliminating or preventing Aβ

aggregation. β-secretase inhibitors that block the

cleavage of Aβ from APP should have reduced Aβ

production and aggregation; on the contrary, groups

treated with the β-secretase inhibitors show more

severe cognitive impairment than the control

(Knopman 2019). In conclusion, it is unlikely that

amyloid cascade hypothesis is a correct AD

pathogenic mechanism. Yet rejecting the amyloid

cascade hypothesis should not discontinue the

research on Aβ, Aβ aggregation might still be one of

the pathological events of AD onset.

3 APP METABOLISM

IMPAIRMENT THEORY

Amyloid-beta precursor protein (APP) metabolism,

also known as APP processing, generates several

downstream peptides that are found to be important

for neuron functionality. Some research suggest that

AD pathogenesis should be related to the impairment

of APP metabolism, where all the major APP

metabolites should be considered beside Aβ

aggregation (Bondi, Edmonds, and Salmon 2017,

Kametani, and Hasegawa 2018). APP gene locates on

chromosome 21 of which the trisomy form causes the

famous Down’s Syndrome. Patients of Down’s

Syndrome also exhibit AD-like symptoms such as

cognitive ability impairment, which could be caused

by the excess copies of APP gene and high amount of

APP metabolites including Aβ (Wilson, et al. 2019).

APP can be processed by three different

secretases (i.e. α-secretase, β-secretase, and γ

secretase) via four recognition sites (i.e. α, β, and two

γ sites) (Figure 1). In the non-amyloidogenic

pathway, APP is sequentially cleaved by α-secretase

and γ-secretase; in the amyloidogenic pathway, α-

secretase is substituted by β-secretase, generating Aβ.

In both pathways, γ-secretase cleaves to produce APP

intracellular domain (AICD). Evidence suggests that

α-secretase predominately cleaves more than 90% of

the APP while β-secretase only accounts for less than

10% of the APP cleavage (Kametani, and Hasegawa

2018). Accordingly, the major metabolites should be

sAPPα, p3, C99, and AICD while Aβ is supposed to

be in a small amount (Figure 1). In pathological

conditions, a large amount of Aβ is produced to form

amyloid aggregation, indicating that β cleavage is

more predominant than α cleavage. There is another

explanation for the prevalence of β cleavage.

Research on APP trafficking found that APP

primarily locates intracellularly, co-residing with β-

secretase whose activity is optimized by the acidic

endosomal environment, causing amyloidogenic

processing (Wang, et al. 2017). On the contrary, only

a small fraction of APP, localizing on the cell surface

where α-secretase is abundant, undergoes non-

amyloidogenic pathway. Given that β-secretase is

pivotal to Aβ generation, inhibiting β cleavage should

have ameliorated AD symptoms by reducing Aβ

production. However, experiment of β cleavage

inhibition, which aims to reduce Aβ aggregation,

even worsens cognitive impairment (Knopman

2019), implying that AD pathology is not limited to

amyloid plaques but APP metabolism as a whole.

Besides the notorious Aβ accumulation in the

amyloidogenic pathway, research has also

investigated the neuronal effects of other APP

metabolites (i.e. sAPPα, p3, C99, and AICD) of the

non-amyloidogenic pathway (Zhang, et al. 2011).

sAPPα

is considered to be neurotrophic (Zhang, and

Zheng 2019). P3 has long been classified as “non-

amyloidogenic”, so studies on APP metabolites

usually omit p3 and few studies focus on its

cytotoxicity. Nevertheless, Kuhn et al. and Kuhn and

Raskatov have revisited the function of p3; they

concluded that p3 is amyloidogenic and it may play a

role in amyloid plaque formation. Firstly, p3 contains

the amyloidogenic region in Aβ; secondly, p3 fibrils

facilitate the formation of Aβ fibrils that later

assemble to become amyloid plaques (Kuhn and

Raskatov 2020). Some researchers believe that Aβ

toxicity is due to the hydrophobicity of Aβ oligomers

(Hardy, and Selkoe 2002). P3 is almost entirely

hydrophobic, so it could have higher cytotoxicity than

Aβ (Wei, et al. 2002), which might eventually

contribute to neurodegeneration.

C99 and AICD are both C-terminal fragments

(CTF) of APP. CFT accumulation might be closely

related to AD onset. Stocking of CTF could induce

synaptic failure, abnormally phosphorylated tau

protein, and memory loss (Tamayev, et al. 2012) .

Additionally, the accumulation of CFT interferes the

normal function and morphology of mitochondria in

neurons (Vaillant-Beuchot, et al. 2021, Devi, et al.,

2006); specifically, CFT accumulation alters

mitochondria sizes, disorganize mitochondrial

cristae, and affects the mitophagy process.

Mitochondria are believed to be involved in AD

pathologies. Nevertheless, its role in the pathogenesis

is unclear. Some research proposes a primary

mitochondria hypothesis where mitochondria

disruption causing neuron dysfunction predates Aβ

accumulation. Meanwhile, some others studies

support a secondary mitochondria hypothesis in

ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare

480

which mitochondrial dysfunction is downstream of

Aβ aggregation (Devi, et al. 2006, Swerdlow 2018).

Summing the studies on APP metabolites, it is

clear that Aβ is not the only neurotoxic APP

metabolite that could potentially lead to

neurodegeneration. The impairment of APP

processing that alters the relative amount of various

APP metabolites should be considered as a whole to

explain AD onset.

4 TAU HYPOTHESIS

Tau is a microtubule-associated protein that is

responsible for the regulation of tubulin assemblies

and stabilization of neuronal microtubules in the

central nervous system. Normally, tau is only

moderately phosphorylated; hyperphosphorylated tau

fibrils form NFT, which is an AD hallmark. Tau’s

hypothesis suggests that tau in hyperphosphorylated

states form paired helical filaments and straight

filaments, both of which contribute to the formation

of intracellular NFT ((Kametani, and Hasegawa

2018, Muralidar, et al. 2020) . In tau hypothesis, Aβ

is a tau-induced downstream event.

Tau is cytotoxic as it negatively affects neuron

cytoskeletal structure, axonal transport, and

mitochondrial membrane integrity.

Hyperphosphorylated tau loses the ability to regulate

tubulin, which is pivotal for the neuron skeletal

system (Muralidar, et al. 2020). One of the most

important functions of tau is stabilizing the

microtubules in the axons. Normally, moderate

phosphorylated tau attaches to the microtubules in the

axons, allowing for the binding of motor molecules

that act as cargo for intracellular trafficking (Combs,

et al. 2019) (Figure 2a). Hyperphosphorylated tau

detaches from the microtubules (Figure 2b),

disaggregating the microtubules and thus disrupting

the axonal transport (Combs, et al. 2019, Arnsten, et

al. 2021); later, the detached tau assembles into NFT.

Disruption of axonal transport eventually contribute

to neurodegeneration. (Camilleri, Ghio) report that

accumulation of tau leads to mitochondrial organelle

swelling and loss of membrane potential, causing

mitochondrial defects

Figure 2. Stabilization of microtubules by tau protein. (a) In normal neurons, moderately phosphorylated tau (without P)

proteins associate to stabilize the microtubules, allowing for the binding of motor molecules. (b). Hyperphosphorylated tau

(with P) detach from microtubules, which then disaggregate microtubular structure. Motor molecules fail to bind to the

microtubules. Adapted from Muralidar, S., Ambi, S. V., Sekaran, S., Thirumalai, D., & Palaniappan, B. (2020). Role of tau

protein in Alzheimer's disease: The prime pathological player. Int J Biol Macromol, 163, 1599-1617.

Microtubules

Motor Molecules

Hypotheses of Alzheimer’s Disease Pathogenesis

481

The core proposition of tau hypothesis is that the

tau is the causative agent of AD and it is upstream of

Aβ plaques. Multiple studies have confirmed the

upstream tole of tau and verified tau-induced NFT

(Arnsten, et al. 2021) . Most importantly, the self-

propagating and aggregation-promoting

characteristics of tau can explain the staging and

progression of AD. Abnormally hyperphosphorylated

tau occurs in only a limited range of neurons, and they

can convert the normal tau into the

hyperphosphorylated states, increasing the total

amount of hyperphosphorylated tau and propagating

to a larger range of neurons (Nonaka, et al. 2010).

Moreover, aggregation of hyperphosphorylated tau

inhibits protein aggregation clearance, which in turn

protects tau aggregation from degradation (Keller,

Hanni, and Markesbery 2000), forming a viscous

cycle that enables for enlargement of

hyperphosphorylated tau aggregation. The nature of

the viscous cycle and self-propagation of tau might

explain the progression of AD clinically.

5 CONCLUSIONS

In summary, different hypotheses have not unified to

provide a clear AD pathology yet. A large amount of

evidence has rejected the amyloid cascade

hypothesis, especially the temporal ordering.

However, the role of Aβ should not be completely

refuted since it interacts with so many other

hypotheses for AD pathology. Some other

hypotheses, such as APP metabolism theory and Tau

hypothesis, seem to be valid explanations for AD. P3

and CTF, which are under-researched APP

metabolites, should be revisited for their

neurotoxicity, their relationship to SF and NFT, and

the relevance to AD onset. Also, as evidence

suggests, tau aggregation should be one of the pivotal

events in AD pathology that needs further

investigation. This review collates the above

hypotheses of AD pathogenesis and provides a clear

demonstration and comparison of the current

advances in AD research, which provide a wide

picture for AD mechanisms. To date, we have

witnessed an explosion of research into Alzheimer's

disease and the development of drugs at all levels, but

much remains to be done. As mentioned above, the

failure of clinical trials suggests that we should revisit

the role of beta-amyloid and reconsider other factors

involved in AD pathogenesis in future research.

ACKNOWLEDGMENTS

I would like to thank Jiaqiong Sun for providing

instructions on developing paper outlines and Min

Han for providing advice on editing. I would want to

express my gratitude to Dr. Kate Jeffery for offering

suggestions on literature research on Alzheimer’s

disease. Lastly, I would also like to thank my parents

and all of my friends for all the encouragement and

support all the time.

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