Fungus – is it the real ‘Dementor’ in Alzheimer’s disease?


Isn’t it heartbreaking when your favourite grandmother forgets your name or goes blank on seeing your face? One cannot fathom as to how the Alzheimer’s disease (AD) can completely impair the cognitive functions of our very intelligent brain leaving us with a million unanswered questions!

Several theories including the extracellular deposition of β-amyloid plaques, intracellular formation of neurofibrillary tangles of tau proteins, autoimmune degeneration and inflammatory damage have been well researched, yet in vain. We have still been lurking in the dark regarding the aetiology of the disease and the right medicine to target the same. But, a dedicated team of scientists from the Autonomous University of Madrid, Spain, may have revealed the debilitating secret by showing evidence of a fungal infection in the brain of AD patients!

The research team headed by Dr. Luis Carrasco compared the central nervous system (CNS) tissue samples of 11 patients who had lived with Alzheimer’s disease and compared them to 11 healthy people who had died at a similar age. Using the immunohistochemistry technique, mixed fungal species were detected from the different regions of CNS of all AD patients, as opposed to normal subjects where no fungal cells were present. Both intracellular and extracellular regions of neurons showed the presence of fungal hyphae which coincided with the presence of the AD associated Tau protein.

Immunohistochemistry analysis of CNS sections from patient AD1 using different anti-fungal antibodies.  DAPI appears in blue, anti-S. racemosum are shown in green and human neurofilament in red.
Immunohistochemistry analysis of CNS sections from patient AD1 using different anti-fungal
antibodies. DAPI appears in blue, anti-S. racemosum are shown in green and human neurofilament in red.

“The fact that we find this in 100 percent of AD patients [tested] but no controls makes me optimistic that this is significant,” said Carrasco.

Simply put, they found evidence of fungal cells in nerve cells in several regions of the brain that become damaged in Alzheimer’s disease.

They also found evidence of fungus in the cells that make up blood vessels, in people who had lived with Alzheimer’s disease, compared to those who did not have the disease. Vascular pathologies such as cerebral amyloid angiopathy, microinfarcts, haemorrhages and microvascular degeneration are commonly seen in AD patients due to plaques formed by the deposition of amyloid β protein. The researchers implicated fungal infection in the blood vessels in the formation of the amyloid deposits.

In order to corroborate the results obtained through immunohistochemistry, frozen CNS samples were subjected to a sensitive PCR technique to obtain greater amounts of fungal DNA followed by sequencing analysis. Also, the fungal protein was detected through proteomic analysis. These techniques together confirmed the presence of mixed fungal species which was linked by the researchers to the diversity of symptoms seen in AD.

Although it was earlier proposed that AD might have a microbial aetiology, this is for the first time that compelling evidence was provided through CNS tissue samples. The researchers have proposed several new theories through which fungal infections can be correlated to AD aetiology. They have suspected that a chronic infection might be stimulating the synthesis of Aβ peptide in brain since the peptide has potent antimicrobial activity. Aβ peptide in turn leads to amyloid deposition in the CNS.

In another study it was it was proposed that chitin-like polysaccharides arising from neural cells participate in the amyloidogenic process. The current research team claims otherwise by explaining that chitin is also a fungal cell wall component and triggers the production of ‘Chitinase’, a chitin degrading enzyme found at high levels in the cerebrospinal fluid (CSF) of AD patients. Researchers Ala et al and Hoffmann et al have previously demonstrated that antifungal treatment in two AD patients could even reverse the clinical symptoms.

The researchers stress upon the fact that the symptoms of AD are reflective of the fungal infection theory. The disease has a slow progression and shows signs of inflammation indicative of the chronic nature of fungal infections which trigger production of inflammatory cytokines. Also, one fungal infection can recruit another fungal species and thus lead to multiple fungal species infesting the tissue. The blood vessels can also be targeted by the fungus to thrive on oxygen. Last but not the least, genetic predisposition to Alzheimer’s can actually be a tendency to acquire fungal infections.

In conclusion, the study cannot determine whether fungus is the causative agent in Alzheimer’s disease or whether it just worsens the symptoms as mentioned by several sceptics. But, it definitely lays the ground for further research related to the role of microbial infection in the aetiology of AD. In a press release, Carrasco exclaimed with conviction that “I believe this opens a new direction for research.”

Dr Laura Phipps, Science Communications Manager at Alzheimer’s Research UK, said: “While this very small study suggests that fungal cells may be present in the brains of people with Alzheimer’s, we cannot conclude from this work that such infections cause or increase the risk of the disease. Without a corresponding medical history, we do not know whether the fungal infection occurred before or after the onset of Alzheimer’s disease, or whether this group of people had an increased risk of fungal infection due to other health complications. This study is a snapshot of the brain after death – we would need to see larger studies, following people with fungal infections for extended periods of time, to better understand whether there is a relationship between such infections and Alzheimer’s disease.

If fungus is really the culprit, we already have a wide array of anti-fungal drugs in our kitty to conquer the dementia!

Original Article: Nature