https://www.medpagetoday.com/meetingcoverage/aaic/81065

Does Alzheimer’s Disease Stem From Infection?

Scientists debate, and one company targets gingivitis bacterium to slow Alzheimer’s progression

LOS ANGELES — Is there an infectious link to Alzheimer’s disease?

That’s a question of debate, and opinion was divided at the 2019 Alzheimer’s Association International Conference (AAIC) now underway here.

“Ideas in this area of research are still evolving; there is now growing evidence that microbes such as bacteria and viruses may play a role in degenerative brain diseases such as Alzheimer’s,” said Maria Carillo, PhD, chief science officer of the Alzheimer’s Association.

New research suggests infectious agents may be triggering immune reactions related to plaques and tangles and that loss of cognitive function in Alzheimer’s disease may stem from several different disease processes in the brain, not just one, she added.

A common virus coupled with a genetic factor — namely herpes simplexvirus 1 (HSV-1) and the APOE4 gene — can create a major risk for Alzheimer’s disease, noted Ruth Itzhaki, PhD, of the University of Manchester in England. The viral concept of Alzheimer’s proposes that HSV-1 in the brain of APOE4 carriers accounts a high percentage of Alzheimer’s cases. It postulates that HSV-1 travels to the brain earlier in life and establishes a latent infection that, when activated, “leads to viral damage in infected cells and viral-induced inflammation,” she said.

Recent studies have found an increased abundance of human herpesvirus6A (HHV-6A), HHV-7, HHV-6B, and HSV-1 in post-mortem Alzheimer’s disease brains, said Ben Readhead, MBBS, of Arizona State University in Tempe.

“These findings indicate that these species are capable of perturbing host cellular networks that are central to the pathogenesis of Alzheimer’s disease and offer testable hypotheses to guide further evaluation of the pathogen hypothesis of Alzheimer’s,” Readhead noted.

But associations seen in laboratory and epidemiological studies do not demonstrate causality, “and in fact, reverse causation must be considered more likely,” said Todd Golde, MD, PhD, of the University of Florida in Gainesville.

While neurodegeneration or other states “may very well enable slight reactivation of latent viruses present in many human brains” and there’s strong evidence that an additional hit from an infection can impair cognition, there’s no evidence for causality, he observed. “Trying to pin an infectious origin of Alzheimer’s disease on a virus or a bacteria may distract the field from more impactful research,” he said.

And open questions still need to be answered, said Michael Heneka, MD, PhD, of University Hospital Bonn in Germany. “The precise time point in the pathogenesis of Alzheimer’s at which bacteria may enter the brain needs to be determined, since these phenomena may present just late-stage events,” he said. “Furthermore, it remains elusive how bacteria would overcome the intrinsic innate immune defense of microglia that usually shield the brain from such invasion.”

One group looking for a causal link is testing whether targeting Porphyromonas gingivalis bacteria can slow or halt the progression of Alzheimer’s disease. In the GAIN trial, researchers from the biotech company Cortexyme are studying COR388 — an oral agent that inhibits gingipain proteases secreted by P. gingivalis, the culprit behind degenerative gum disease — in people with mild to moderate Alzheimer’s disease.

Earlier research identified the bacterium in brains and cerebrospinal fluid of people with Alzheimer’s disease, said Michael Detke, MD, PhD, Cortexyme’s chief medical officer, who reviewed the science behind the study at AAIC. Moreover, levels of gingipain proteases correlate with tau and ubiquitin pathology, Detke told MedPage Today.

Studies of wild type mice showed that oral infection with P. gingivalis invaded the brain and led to plaques, inflammation, and the loss of hippocampal neurons — effects which were blocked when the animals received COR388.

The drug was rapidly absorbed and well-tolerated in a phase I study of 24 older healthy volunteers. A smaller study of nine people with Alzheimer’s disease — six taking COR388 and three taking placebo – showed patients treated with the drug trended toward better memory scores and exhibited improvements in verbal skills, using more prepositions in their speech patterns over 28 days.

People taking COR388 also had reduced protein fragmentation and roughly 30% lower levels of inflammation, Detke said. The phase II/III GAIN trial in 570 Alzheimer’s patients in the U.S. and Europe is underway, with ADAS-Cog11 change at 48 weeks as the primary endpoint. Top-line results are expected late in 2021.

Itzhaki and Readhead reported no disclosures. Heneka reported relationships with IFM Therapeutics, Alector, Schering, Pfizer, Novartis, Roche, Abbvie, and Biogen, and is a co-inventor on patents and patent applications relating to Alzheimer’s diagnostics and therapeutics. Golde reported relationships with ProMIS Neuroscience, Eli Lilly, Novartis, Bristol Myers Squib, Abbvie, Lundbeck, Biogen, and Pfizer; he is a co-inventor on multiple patents and patent applications relating to Alzheimer’s therapeutics. Detke is an employee of Cortexyme.

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For more: https://madisonarealymesupportgroup.com/2019/04/09/the-diagnosis-is-alzheimers-but-thats-probably-not-the-only-problem/

https://madisonarealymesupportgroup.com/2019/03/09/researchers-identify-herpes-1-chlamydia-pneumoniae-several-types-of-spirochaete-as-major-causes-of-alzheimers/

https://madisonarealymesupportgroup.com/2017/01/18/a-bug-for-alzheimers/

https://madisonarealymesupportgroup.com/2016/06/09/alzheimers-byproduct-of-infection/

https://madisonarealymesupportgroup.com/2016/11/17/antibiotics-and-alzheimers/

https://madisonarealymesupportgroup.com/2016/06/03/borrelia-hiding-in-worms-causing-chronic-brain-diseases/

https://madisonarealymesupportgroup.com/2018/03/25/a-brief-history-of-neuroborreliosis-research-dementia-an-inside-look-at-two researchers/https://madisonarealymesupportgroup.com/2016/11/17/alzheimers-lyme