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Alzheimer's disease pathway

Learn about the prominent hypotheses behind the complex biochemistry of Alzheimer's disease with our downloadable pathway poster.
Last edited Mon 15 Apr 2024

Alzheimer’s disease (AD) is the most common form of dementia, thought to affect approximately 50 million people worldwide1. Despite its prevalence, the actual cause of and mechanisms behind AD symptoms – progressive loss of cognitive function caused by neuron and synapse loss– remain surprisingly elusive.

AD has been identified as a proteopathy, or protein misfolding disease. The most widely held hypothesis for the origin of AD symptoms is that they are caused by an accumulation and aggregation of amyloid beta (Aβ) in the brain; AD symptoms are caused by the breakdown of the cytoskeleton, leading to cell death, and mechanisms have been proposed that link Aβ to this process.

Aβ is a small peptide generated from the proteolytic cleavage of the transmembrane protein amyloid-beta precursor protein (APP) by beta secretase and gamma secretase. Aβ monomers can aggregate to form oligomers, which further aggregate to form protofibrils. These undergo a significant conformational change to form insoluble, beta sheet-dominated fibrils and finally senile plaques that deposit outside neurons.

As well as Aβ, tau, another misfolding protein, is also associated with the development of AD symptoms. Tau normally acts to stabilize the cytoskeleton, but aggregates when hyperphosphorylated to form paired helical filaments and subsequently neurofibrillary tangles. When aggregated, tau’s protective effect on the cytoskeleton disappears, leading to cytoskeleton breakdown. Neuroinflammation is also thought to be central to disease development, explored further in our poster. The overall AD cascade is very complex, especially as many research questions remain unanswered. 

Alzheimer's disease pathway


What to expect

Our Alzheimer’s disease poster explores the complex signaling cascades behind the accumulation of amyloid beta and tau, and explores their association with cytoskeleton breakdown, cell death, and ultimately with disease symptoms.

The tau hypothesis

The tau hypothesis suggests that the paired helical filaments and neurofibrillary tangles formed by aggregated tau precede Aβ plaque formation and are the true cause of AD symptoms. This is supported by the existence of non-AD “tauopathies”, such as frontotemporal dementia, where neurofibrillary tangles have been observed. However, drugs that target tau hyperphosphorylation, such as Tideglusib, an inhibitor of glycogen synthase kinase 3, have shown no significant clinical benefit2.

The amyloid cascade

The amyloid hypothesis—the idea that AD development is truly caused by mature Aβ fibrils and senile plaques—is the most widely accepted by researchers. However, this remains a subject of active debate, as there is no conclusive evidence that supports a causative mechanism, and, like tau, drugs targeting amyloid plaques have not demonstrated significant clinical improvement. A variation of the amyloid hypothesis, that Aβ oligomers are truly cytotoxic species, has gained traction in recent years.

Regardless of the specific Aβ causative agent, the amyloid cascade hypothesis centers around disrupted calcium signaling. It is thought that Aβ, either in its oligomeric form or as larger aggregated species, increases the concentration of calcium ions within neurons. Intracellular calcium is associated with apoptosis, Aβ deposition, tau hyperphosphorylation, and abnormal synaptic plasticity3, so is thought to contribute to AD symptom development by causing cell death, as well as contributing to further Aβ and tau aggregation.

Excess intracellular calcium can cause dysregulation of the calcium-dependent proteolytic enzyme calpain, which can cause various pathogenic effects within the cell. Calpain can itself destroy elements of the cytoskeleton (which in turn can cause greater calcium influx), and can also lead to the dysregulation of cyclin-dependent kinase 5 (cdk5) by cleaving its regulators, p35 and p39. Cdk5 drives the phosphorylation of APP and tau, causing greater aggregation of Aβ and tau.

As well as acting via calpain, calcium can cause the accumulation of reactive oxygen species within the cell. Oxidative stress is now thought to be vital in the development of AD. It causes oxidative damage to both nuclear and mitochondrial DNA, as well as further accumulation of Aβ and tau via the activation of intermediary kinases.

Alzheimer’s disease is ultimately driven by complex, interconnecting cascades that proliferate themselves and each other in positive feedback loops. Research continues to shed light on these processes, identifying new potential therapeutic targets that may lessen the impact of this disease..



Lovestone, S., Boada, M., Dubois, B., et al. A phase II trial of tideglusib in Alzheimer's disease IOS Press (45),75-88 (2015)


Ge, M., Zhang, J., Chen, S., et al. Role of calcium homeostasis in Alzheimer's disease Neuropsychiatric disease and treatment 18 ,487-498 (2022)