Microbial infections in the brain can lead to cognitive impairment, including dementia. Such infections are suspected to also lead to Alzheimer’s Disease in some patients – including the loss of memory and cognitive skills that are hallmarks of the disease – yet a causal link has yet to be confirmed. Now an international group of researchers has embarked on the Alzheimer’s Pathobiome Initiative to develop pilot studies that look for infections in dementia and Alzheimer’s patients, with the eventual aim of finding out whether giving infected patients anti-microbial drugs prior to the onset of symptoms slows or prevents disease symptoms.
The path forward is outlined in a recently published perspective article in the journal Alzheimer’s & Dementia in which researchers from Drexel’s College of Medicine, Intracell Research Group and other institutions, including clinicians, neurologists, molecular biologists and other scientists, seek to find better tests to identify and characterize central nervous system infections in patients with mild cognitive impairment and Alzheimer’s disease, as well as those at risk of disease, with the ultimate goal of better understanding any role that microbes or infections may play in development of some patients’ disease.
The authors outline the need to secure bio-samples and critically evaluate various detection methods in brains and other tissues of deceased patients first. This will ensure the least invasive methods are used in subsequent studies of living patients with neurodegenerative diseases. The group’s current insights were garnered from past research into chronic meningitis, tertiary syphilis, and various genetic conditions that trigger excess beta-amyloid production, together with the realization that the A-beta peptide (the precursor of beta amyloid) is a powerful antimicrobial peptide combined with case reports that show some success with antimicrobial therapy for the treatment of infection-based cognitive disorders.
There are many risk factors linked to onset and progression of Alzheimer’s disease and other dementias, including genetics, sleep, lifestyle and other factors. Yet researchers in the new initiative say investment in efforts to prevent and treat these neurodegenerative diseases has been disproportionately dominated for decades by clinical trials of low-performing drugs that attack two attributes linked with the condition – the protein beta-amyloid resulting in plaques – and tangles, fibers in the form of the tau protein.
These two attributes, along with broken connections between neurons in the brain, are associated with the destruction of healthy nerve cells and are seen as key markers of Alzheimer’s disease, but over the past decade, researchers from the initiative say a relatively new idea of infections as the cause and main factor fueling the progression of Alzheimer’s dementia, and related conditions in many patients is picking up steam.
“There’s so much potential for data collection from sequencing techniques, bioinformatic tools and AI to detect infectious agents of concern and develop tailored antimicrobial therapies for patients to slow the pace of symptoms or stop further mental deficits,” said co-author Garth Ehrlich, PhD, a professor of microbiology and immunology in the College of Medicine. “We know infections cause some types of dementia in human patients and in animal models; moreover, we and others have identified a diverse set of microbes in the brains of Alzheimer’s patients. Now we’re embarking on establishing verified standards for better data collection and for better detection of any infectious elements in patients so we can get them to better antimicrobial therapeutics faster.”
The authors outline in the paper the amyloid beta “cascade hypothesis,” data suggesting that, upon real or perceived infection, the body’s defenses produce inflammation and the a-beta peptide (precursor of beta amyloid) in the brain that plays a surprisingly helpful antimicrobial role, trapping and inactivating bacteria, fungi and viruses, and protecting cells from infection. When this immune response fails, likely due to microbial biofilm formation, according to this hypothesis, long-term inflammation and neurodegeneration results.
This work, which will take place at Drexel and other institutions, includes possibly using cerebral spinal fluid, blood and brain tissue samples from deceased Alzheimer’s patients to “map” their pathobiome, to understand whether more than one microorganism or pathogen in multiple brain regions can cause more than one type of disease. The investigative teams will evaluate this by examining multiple samples from each patient, looking at the pathobiome, composition and number of microbes.
“The research community is working collaboratively to create consensus on the most important questions for this research,” said Ehrlich. “What tissues to look at, extraction methods for DNA & RNA, the most accurate and cost-effective sequencing and bioinformatic techniques, and so on. These range-finding experiments will be used to create the foundation for a multi-site international study to determine correlations between specific microbiomes and measures of cognition in the brains of healthy, mild cognitive impairment and Alzheimer’s disease patients.”
There is no cure available to the estimated 6.7 million Americans struggling with Alzheimer’s – a number that is expected to nearly double by 2050. This translates to one in three seniors dying with Alzheimer’s or another dementia. Beyond the physical cost is a significant financial cost: more than 11 million Americans provide unpaid care for people afflicted with the disease, and costs of treating patients with these diseases costs taxpayers an estimated $345 billion annually, according to the Alzheimer’s Association.
Seeing this need, The National Institutes of Health increased funding for dementia and Alzheimer’s research in recent years, currently dedicating a $3.7 billion annual budget for diagnosis and drug development, along with other studies into other possible therapies.