Alzheimer’s Disease – Hypotheses Old and New – Part One

Nov 7, 2017 | Trends

The Discovery of Alzheimer’s Disease

The Alzheimer’s story began when the German physician Dr. Aloysius Alzheimer reported distinctive plaques and neurofibrillary tangles in the brains of deceased individuals in a series of case study reports, published in the early 1900’s. Alzheimer originally coined these features as presenile dementia, and the disease was later renamed by his supervisor, the German psychiatrist, Emil Kraepelin.

Today, Alzheimer’s disease (AD) is recognized as a serious neurodegenerative disorder, and the leading cause of dementia among elderly people. AD is well characterized from a clinical perspective, with classical features such as: cognitive decline, progressive dementia, neuroinflammation and neuronal death.

No Cure Without Cause

Although AD can develop in all age groups, the vast majority of cases occur in the elderly (late-onset). While AD is not considered to be a normal part of the aging process, increasing age is a well-known risk factor, and the likelihood of developing AD increases significantly after the age of 65.

Unfortunately, despite more than 100 years of research since Alzheimer’s findings, including the development of numerous disease models, the aetiology of AD remains elusive. This fact makes it very challenging, if not impossible, to develop preventative and curative treatments for this devastating disease, which affects a staggering 46 million people worldwide, according to a recent estimate.

The Multi-Billion Dollar Question

Experts within the AD field believe that most cases manifest through an array of genetic, lifestyle and environmentally-induced brain changes that occur over time. The brain plaques and tangles discovered by Alzheimer represent the two hallmark pathological features of the disease. This puts brain changes at the centre of most AD hypotheses and attempts to study human-derived models of AD. But what actually triggers these plaques and tangles to develop? Let’s have a look at some of the major hypotheses surrounding AD aetiology, past and present.

Hypothesis 1: The Amyloid Cascade Hypothesis

The plaques discovered by Alzheimer were later revealed to comprise clumps of amyloid beta peptides (Aβ). This observation eventually led to the amyloid cascade hypothesis (ACH). In simple terms, the hypothesis dictates that the accumulation of Aβ plaques triggers a change in a transport protein called tau, a microtubule-associated protein that is essential for the transport of nutrients and other materials throughout the long extensions of brain cells. These events eventually lead to the death of cortical neurons, and the symptoms seen in AD sufferers.

Plaques, Twists and Tangles – an Endless Cycle of Destruction

Aβ accumulation damages brain tissue in a number of ways:

  • Aggregates of Aβ form plaques throughout the brain and its vasculature, acting as synaptotoxins that ultimately cause synapse failure.
  • Aβ interacts with the signalling pathway that regulates tau phosphorylation and function.
  • Accumulation of Aβ plaques outside the brain leads to hyperphosphorylation of tau, causing it to twist into abnormal tangles within brain cells, and impeding its transport function.
  • The synaptotoxic nature of the Aβ plaques prevents proteasomal degradation of hyperphosphorylated tau, further fuelling the vicious cascade of events that eventually destroy the brain.

The ACH has dominated the Alzheimer’s field since the early ‘90s. Not surprisingly, Aβ, tau and associated signaling pathways are seen as important therapeutic targets for AD. However, clinical testing of several drugs in the past few years aimed at reducing Aβ production or aggregation have failed to provide the expected therapeutic effects, calling this hypothesis into question.

Hypothesis 2: Neurotransmitter Loss

The discovery that the number of acetylcholine-producing cells is reduced in AD led to the development of several cholinesterase-inhibiting drugs e.g., donepezil, which was originally marketed as Aricept® in the mid ’90s. Such treatments are symptomatic at best, and don’t benefit everyone. At times, patients’ symptoms will actually get worsen with donepezil. This raises the question of whether the loss of these cells is simply an effect rather than a cause of AD. The levels of another neurotransmitter serotonin are also reduced in AD, but similarly to acetylcholine, scientists don’t yet know whether this is a cause or an effect of the disease.

Hypothesis 3: Alzheimer’s is in the Genes!

Most cases of late-onset AD are sporadic, and are likely to involve both environmental and genetic risk factors. Inheritance of the ε4 allele of the apolipoprotein E gene is the most well-known genetic risk factor, with 40-80 % of sufferers possessing at least one APOEε4 allele.

In rare cases, AD has an early-onset, and these cases are caused by an inherited familial mutation(s). These familial forms exhibit autosomal dominant inheritance, and account for about 0.1% of all AD cases.

Although there is strong evidence for genetically acquired AD, genetic abnormalities only account for about 5 % of all cases of AD. The remaining cases are sporadic.

Hypothesis 4: The Old Age Phenomenon

It is no secret that the aging process is associated with a number of brain changes, such as tissue loss and synapse degeneration, resulting in insufficient neurotransmission. Plaques and tangles are also known to develop in cognitively normal older adults. However, these changes are more frequently observed in individuals with advanced vascular disease, suggesting that reduced blood flow to brain cells may contribute to the development of AD.

The fact that most cognitively normal older adults show no such changes also suggests that AD is much more than just normal aging of the brain.

A Century Old Story Continues

In the 100 years since Alzheimer described the disease, countless hypotheses have emerged concerning its aetiology. We have covered only a few of the canonical hypotheses in this article. Stay tuned for our next article where we will touch upon some of the more controversial hypotheses!

Further Reading:

An account on the discovery of Alzheimer’s Disease.

A comprehensive review article on the possible causes of AD.

Alzheimer’s disease drug development pipeline: 2017.

Article by Karen O’Hanlon Cohrt PhD. Contact Karen at 

Karen O’Hanlon Cohrt is a Science Writer with a PhD in biotechnology from Maynooth University, Ireland (2011). After her PhD,  Karen moved to Denmark and held postdoctoral positions in mycology and later in human cell cycle regulation, before moving to the world of drug discovery. Her broad research background provides the technical know-how to support scientists in diverse areas, and this in combination with her passion for writing helps her to keep abreast of exciting research developments as they unfold. Follow Karen on Twitter @KarenOHCohrt. Karen has been a science writer since 2014; you can find her other work on her portfolio.