Alzheimer’s Disease Failing Hypothesis: Why are we unable to identify the true cause?

Named after the famed German scientist, Alois Alzheimer in 1906, the world has since then witnessed millions of dollars being poured into research on the deadly degenerative disease, in an attempt to locate the true cause of this curse.

However, efforts have been more or less futile as the data is highly inconclusive.

Alzheimer’s disease affects about 6% of individuals above the age of 65, worldwide, which is the typical age where the symptoms of Alzheimer’s usually begin. We mention symptoms and not the underlying disease itself because it is believed that the disease actually begins decades before the symptoms first become apparent.

This is in contrast to early onset Alzheimer’s which accounts for nearly 5% of all cases.

The Alzheimer’s Association’s annual  facts and figures report suggests that, as of 2019, there are believed to be nearly 5.8 million Americans currently living with Alzheimer’s and this number is only projected to go up in the coming years. Nearly 200,000 of these are individuals who are younger than 65 and suffer from early onset Alzheimer’s.

Alzheimer’s is estimated to account for 70% of the cases of dementia worldwide.

Today, let us look at some of the hypothesis circulating within the medical community that attempt to pinpoint the cause of the disease and the supposed evidence that supports said hypothesis.



It is prudent to mention that in a small subset of people suffering from Alzheimer’s (Less than 5 percent), genetic differences have been confirmed to play a part in bringing about the onset of the disease.

Twin and family studies have tried to place the genetic heritability of AD and found that it ranges from 49% to 79%. Early onset familial Alzheimer’s disease accounts for about 0.1% of all cases and is due to familial forms of autosomal dominant inheritance.



This hypothesis states that the primary cause of Alzheimer’s disease is the accumulation and deposition of oligomeric or fibrillar amyloid β (Aβ) peptide. This concept has been the foundation upon which decades of AD research has been established, in an attempt to develop Aβ targeting drugs.

Needless to say, there has been no success as of now.

The crux of the hypothesis is as follows. The peptide Aβ is removed from the cell with the help of β- and γ-secretase and quickly disintegrated. However, in older individuals or Alzheimer’s sufferers, the peptide Aβ is not broken down but rather accumulated. This results in the formation of Aβ amyloid fibrils which ultimately develop into senile plaque. The resulting symptoms are neurotoxicity which leads to the degeneration and death of neurons and induction of tau pathology.



This hypothesis has plenty going in its favor.

Chromosome 21 contains the APP gene. In early onset familial Alzheimer’s disease, the APP gene has been discovered to have genetic mutations. This was considered to lend compelling support for the Aβ hypothesis.

These mutations are found near β-secretase and γ-secretase cleavage sites, which facilitate the excision and degradation of the Aβ peptide. This results in a marked increase in Aβ or Aβ42 to be exact.


The pathogenesis of Alzheimer’s disease was investigated by experimentations on identical mice and the results were as follows.

The mice were genetically modified hence Aβ was produced in the brain.  As expected, this led to formation of senile plaques. However, there was no accumulation of tau or any observable nerve cell death.

These results were in direct contradiction to the Aβ hypothesis.  It led researchers to conclude that accumulation of Aβ fibrils outside the cell body is not cytotoxic by itself, considering all physiological conditions are normal.

It was also proposed, that in actuality it was the oligomers or multimers that were the major toxic agents.


Chromosome 17 in human cells contains the tau gene, responsible for the manufacture of the Tau Protein that regulates the stability of tubulin assemblies.

The tau hypothesis states that the main cause Alzheimer’s disease is due to tau and not Aβ. Studies found the accumulation of 3R and 4R tau in human brains affected with AD. The studies suggested that induction of tau pathology might be linked to the wrong sorting of tau in neurofibrillary tangles, otherwise known as NFT’s.

PET studies show that spatial patterns of tau tracer binding have a close correlation with neurodegeneration patterns in patients.

A further study of APP and PS mutations in familial AD suggest that Alzheimer’s is most likely triggered by drastic changes in APP metabolism rather than simply Aβ accumulation and that the progression of the disease is most likely linked to tau pathology.

These findings seem to go against the very fundamentals of Alzheimer’s research for the past twenty years. While the data is not absolutely conclusive, it’s apparent that this new hypothesis has a lot to offer in terms of possible treatment breakthroughs since all previous attempts to develop drugs that targeted the Aβ amyloid fibrils, have been unsuccessful.

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