Perspectives on Alzheimer’s Disease

Examining multiple theoretical frameworks for understanding Alzheimer’s disease, from amyloid cascade hypothesis to tau pathology and their implications for treatment.

Essays
Neuroscience
Uni
Author

Federico D’Agostino

Published

Thursday, the 12th of December, 2019

Introduction

Alzheimer’s disease (AD) should need no introduction. It is a neurodegenerative disorder with a prevalence of 10-30% in the population over 65 years of age (Kawas et al., 2000), causing devastating effects both subjectively, on patients’ and caregivers’ lives, and objectively, on national healthcare costs.

First observed and reported by Dr Alois Alzheimer in 1906 (Sahyouni, Verma & Chen, 2016, p. 121), the hallmark features in the pathophysiology of the disease are Amyloid plaques and neurofibrillary tangles (NFTs). The former are accumulations of insoluble forms of the amyloid-β (Aβ) protein in the extracellular space, while the latter are aggregations of anomalous hyperphosphorylated forms of the microtubule protein tau in intracellular spaces.

Both these features have historically been associated with the widespread neurodegeneration seen in the disease, progressing through neuronal cell death and eventually leading to cortical atrophy (Figure 1).

The progression of Alzheimer’s disease. (2015, July 2). Retrieved 2 December 2019, from the BrightFocus Foundation website: [https://www.brightfocus.org/alzheimers-disease/infographic/progression-alzheimers-disease](https://www.brightfocus.org/alzheimers-disease/infographic/progression-alzheimers-disease)

Figure 1. The progression of Alzheimer’s disease. (2015, July 2). Retrieved 2 December 2019, from the BrightFocus Foundation website: https://www.brightfocus.org/alzheimers-disease/infographic/progression-alzheimers-disease

The disease usually first spreads from the hippocampus and the temporal lobes to areas of the neocortex. Notably, the clinical phase of the disease is preceded by a largely asymptomatic phase that is thought to last as long as two decades (Villemagne et al., 2013), during which amyloid starts accumulating but cognitive impairment is mild if at all present. The clinical duration of Alzheimer’s is of 8-10 years, with patients usually dying for complications associated with the disease (in two-thirds of patients this is pneumonia due to cough reflex suppression. Sahyouni, Verma & Chen, 2016, p. 93-94), after having largely lost cognitive functions, self-sufficiency and memories of loved ones.

As the world population ages, the threat represented by the disease grows in importance. In this essay, I am going to discuss the prominent theories of the causes of Alzheimer’s, to see in what direction this vital research area is headed.

The amyloid cascade hypothesis

The amyloid-β peptide is a metabolic product of the amyloid precursor protein (APP), which is a transmembrane glycoprotein thought to have some roles in synaptic plasticity (Masters et al., 2015). APP can be cleaved following two pathways; when cleaved successively by β- and γ-secretase, Aβ is released. Aβ peptides can be generated at various lengths. The most abundant form, Aβ1-40 is sufficiently soluble to be usually cleared before depositing. On the other hand, Aβ1-42 (and more rarely Aβ1-43) fragments are less soluble and can readily aggregate to build from toxic oligomers (Benilova, Karran & De Strooper, 2012) to, ultimately, plaques.

The idea that accumulation of Aβ is a key event in the pathogenesis of Alzheimer’s is known as the “amyloid cascade hypothesis” (Hardy & Higgins, 1992), and for many years has been the leading theoretical framework used by researchers to understand the disease. Aβ overproduction or lack of clearance is thought to evoke a cascade of responses which ultimately leads to neuronal loss and dementia (Figure 2). Specifically, the cytotoxic effects of Aβ are now thought to be mediated mainly by Aβ1-42 oligomers, which are associated, among other things, with calcium dyshomeostasis, mitochondrial damage (Waldemar & Burns, 2017, p. 11-12), decrease in synaptic density and tau hyperphosphorylation (Selkoe & Hardy, 2016).

Evidence supporting the hypothesis comes mainly from genetic studies. The APP gene is located on chromosome 21. Since it has been observed that individuals with Down syndrome all typically get AD by 35 years of age (Wisniewski, Wisniewski & Wen, 1985), this suggests that it might be due to the Aβ overproduction caused by APP overexpression. This has been corroborated by various further studies (Prasher et al., 1998; Rovelet-Lecrux et al., 2006).

Mutation in the genes coding for presenilin 1 and 2, parts of the γ-secretase complex cleaving APP, have also been strongly linked with AD, specifically with increased production of Aβ1-42 oligomers (Kumar-Singh et al., 2006).

Chain of major pathogenic developments leading to Alzheimer's, according to the amyloid cascade hypothesis. The blue arrow underlines the fact that oligomers are now thought to have direct effects on neurites’ damage. Original figure from Selkoe & Hardy, 2016.

Figure 2. Chain of major pathogenic developments leading to Alzheimer’s, according to the amyloid cascade hypothesis. The blue arrow underlines the fact that oligomers are now thought to have direct effects on neurites’ damage. Original figure from Selkoe & Hardy, 2016.

Furthermore, an APP missense mutation has been identified that alters Aβ production and properties (Jonsson et al., 2012). This mutation has been found to be protective against plaque formation, AD development and even age-related decline in cognitive functions.

Challenging the amyloid cascade hypothesis

The merit of the hypothesis has been to generate testable predictions along the years and to focus the efforts of research (Hardy, 2009), but recent evidence now suggests it might be time for a change in paradigm.

To begin with, large clinical trials of many different drugs trying to tackle Aβ production, aggregation or clearance have failed to show benefits in patients with mild to moderate AD (Panza et al., 2019).

The current effort is directed more towards Aβ oligomers, but some observe that brains in which plaques are present must have been exposed to oligomers for a long time (Panza et al., 2019). This is problematic when we consider that amyloid plaques can be observed in cognitively healthy individuals (Herrup, 2015).

What is more, research is starting to appreciate the physiological roles of amyloid-β. It appears in fact that brain amyloid levels are raised in an impressive variety of conditions, from traumatic brain injury (Marklund et al., 2014) to sleep deprivation (Ju et al., 2017). Aβ could serve a broad role in modulating synaptic function (Brothers, Gosztyla & Robinson, 2018), and its secretion might represent the brain’s attempt to mitigate neuronal damage (Panza et al., 2019). A better appreciation of the physiological roles of Aβ might come to explain why γ-secretase inhibitors ended up worsening AD symptoms in some clinical trials (Doody et al., 2013).

However, at this point in the discussion – parallel to what happened for some time in the research world – we have lost focus of another key player: the microtubule protein tau.

The role of tau

A key passage in the amyloid cascade hypothesis is the alleged link between Aβ and tau.

Tau stabilizes microtubules and enables axonal transport in healthy neurons. Cycles of tau phosphorylation and de-phosphorylation allow the movements of cargo containing substances such as nutrients and neurotransmitters along the axon. However, if tau becomes abnormally phosphorylated, it can start to accumulate inside the neuron and form NFTs, with disrupting effects (Waldemar & Burns, 2017, p. 12-13).

Unlike amyloid, tau alone is sufficient to cause neurodegeneration and is involved in a wide spectrum of diseases, from frontotemporal dementia to Pick’s disease, aptly referred to as tauopathies (Kovacs, 2018, Chapter 25). Even in AD, the advance of neurodegeneration correlates much more strongly with tau rather than Aβ pathology (Ossenkoppele et al., 2016).

A question to address remains: is tau degeneration just a more proximal cause, with Aβ upstream in the cascade?

A complex interaction

Determining the nature of the interaction between Aβ and tau is perhaps the biggest challenge that research on AD has faced and will continue to face. Evidence is, to say the least, disorienting.

On the one hand, we have a series of studies suggesting that Aβ is upstream of tau in the disease pathology. Those are summarised in Table 1.

Table 1. Reproduced from Bloom, 2014.

Table 1. Reproduced from Bloom, 2014.

On the other hand, there is the puzzling finding that Aβ and tau accumulation originates in different areas of the brain (van der Kant, Goldstein & Ossenkoppele, 2019). The former in the association cortices and the latter in the trans-entorhinal cortex. This has been termed the “spatial paradox” and is shown in Figure 3.

Progression of Aβ and tau pathology in AD, from an overview of data coming from PET and neuropathology studies. Notably, the initial accumulating regions are different, which may seem inconsistent with the cascade hypothesis. Original figure and adapted caption from van der Kant, Goldstein & Ossenkoppele, 2019.

Figure 3. Progression of Aβ and tau pathology in AD, from an overview of data coming from PET and neuropathology studies. Notably, the initial accumulating regions are different, which may seem inconsistent with the cascade hypothesis. Original figure and adapted caption from van der Kant, Goldstein & Ossenkoppele, 2019.

This might be explained by the discovery of some independent regulators of both Aβ and tau pathology: the lipid metabolism, the endocytic system and the brain immune system (van der Kant, Goldstein & Ossenkoppele, 2019).

Interestingly, however, tau does not seem to be able to spread alone to neocortical regions in the absence of Aβ pathology (Jack et al., 2018). On the light of this, researchers are now inclined to conclude that Alzheimer’s disease is an Aβ or APP facilitated tauopathy (Kametani & Hasegawa, 2018; van der Kant, Goldstein & Ossenkoppele, 2019).

However, to put the amyloid cascade hypothesis to a final test, researchers should include tau PET measures in clinical trials of Aβ-targeting drugs, since tau monitorization has not been efficient in the past (Figure 4).

Testing the amyloid-cascade hypothesis in clinical trials combining Aβ-removing therapies and tau PET. (1) This scenario might be the ultimate proof of the cascade hypothesis. (2) This result would provide evidence that Aβ drives tau pathology, though will not find a cure, indicating that something is still missing in our understanding. (3) This result would support the dual-stream hypothesis, also indicating that some mechanism acts upstream of both Aβ and tau. The use of both Aβ and tau targeting therapies might then result in a cure. (4) This outcome would also fit the dual cascade hypothesis, and perhaps a tau hypothesis, indicating that Aβ has no effect on degeneration. Original figure from van der Kant, Goldstein & Ossenkoppele, 2019.

Figure 4. Testing the amyloid-cascade hypothesis in clinical trials combining Aβ-removing therapies and tau PET. (1) This scenario might be the ultimate proof of the cascade hypothesis. (2) This result would provide evidence that Aβ drives tau pathology, though will not find a cure, indicating that something is still missing in our understanding. (3) This result would support the dual-stream hypothesis, also indicating that some mechanism acts upstream of both Aβ and tau. The use of both Aβ and tau targeting therapies might then result in a cure. (4) This outcome would also fit the dual cascade hypothesis, and perhaps a tau hypothesis, indicating that Aβ has no effect on degeneration. Original figure from van der Kant, Goldstein & Ossenkoppele, 2019.

Conclusion

Almost 30 years after the formulation of the amyloid cascade hypothesis, the research framework on Alzheimer’s disease is impressively multifaceted. The focus on amyloid is now beginning to gradually shift towards new promising approaches directed against other elements of the disease, such as CNS inflammation, brain insulin resistance and tau aggregation (Panza et al., 2019).

Pursuing alternative hypotheses is a key motor in scientific discovery, and in a field as serious and complex as this, with countless open questions remaining, it is almost an imperative.

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