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Alzheimer Disease: An Update on Pathobiology and Treatment Strategies


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Pretty good summary.

Published September, 2019


"Infectious Hypothesis

Multiple recent studies have revived interest in a long-standing hypothesis that there may be an underlying infectious basis for AD. Dating back to 1991, studies have demonstrated the presence of herpesvirus in brains of patients with AD, as well as within amyloid plaques (Carbone et al., 2014; Jamieson et al., 1991, 1992; Wozniak et al., 2009). A recent systems-level molecular network analysis of preclinical AD brain identified a set of network driver genes noted to be enriched for viral-susceptibility genes. Follow-up analyses in AD brain specimens found detectable human herpesvirus (HHV)-6 and herpes simplex virus (HSV)-1 DNA in three separate cohorts and identified many putative viral-host interactions that regulate gene networks pertinent to AD biology, including innate immunity and APP processing (Readhead et al., 2018). Ab exhibits characteristics of an antimicrobial peptide. Synthetic and AD-brain-derived Ab peptide fibrils significantly inhibit the growth of Gram-positive and Gram-negative bacteria, fungus (Soscia et al., 2010), and herpesvirus, while additionally inhibiting the entry of herpesvirus into cells (Bourgade et al., 2015). Ab also forms fibrils that entrap bacteria and fungal cells, leading to agglutination in vitro (Kumar et al., 2016; Spitzer et al., 2016). The presence of Ab in brain parenchyma is linked with protection against infectious bacterial encephalomyelitis experimentally induced by intracerebral inoculation with Salmonella enterica typhimurium bacteria in 4-week-old 5xFAD mice. 5xFAD mice survived longer with less severe disease than WT mice, while APP KO mice had slightly increased mortality compared to WT mice.

At sites of bacterial deposition in the brain, significant Ab deposition was also noted. (Kumar et al., 2016). Similarly, presence of parenchymal Ab in 5xFAD mice results in decreased mortality following direct intracerebral HSV inoculation. Areas of brain parenchyma containing deposits of HSV-1 infection also demonstrated increased Ab deposition (Eimer et al., 2018). These experiments have led to the antimicrobial protection hypothesis of AD that suggests intracerebral infection by certain pathogens may induce Ab fibrillization as an antimicrobial defense mechanism, leading to amyloid seeding and deposition and thereby initiating the amyloid cascade. (Moir et al., 2018). In support of this theory, HSV-1 viral particles have recently been shown to directly catalyze the fibrillization of Ab42 in vitro by nucleating aggregation via contact with the viral surface (Ezzat et al., 2019). Two recent Taiwanese-based nationwide, matched-control, retrospective cohort studies have evaluated the association of (Cell 179, October 3, 2019 321) HSV and varicella zoster virus (VZV) infection with risk of dementia. One study demonstrated a significantly increased risk of developing all-cause dementia (3-fold increase) in patients greater than 50 years of age following a new HSV infection. This risk was nearly eliminated in patients who received antiherpetic treatment (Tzeng et al., 2018). A second study demonstrated a very slight increased risk of developing all-cause dementia after zoster infection (HR 1.12). Again, a significant decrease in dementia risk was observed in patients that received antiherpetic treatment (HR 0.47) (Chen et al., 2018).

The results of these studies will need to be replicated, ideally in a large prospective, longitudinal, observational cohort study, before accepting herpesvirus infection as a bona fide risk factor for AD or related dementias. Another recent study suggests that periodontal infections may contribute to AD pathogenesis. In this study, periodontal bacterial proteins (gingipains) and DNA were identified in human AD brain. Oral infection of WT mice with Porphyromsonas gingivalis resulted in elevated intraparenchymal Ab levels, and inhibition of gingipain activity led to reduced intracerebral bacterial burden, decreased Ab levels, and reduced neuroinflammation (Dominy et al., 2019). Based on these results, a phase 2/3 double-blind, randomized control trial testing use of gingipain inhibitor COR388 is underway in mild-to-moderate AD (ClinicalTrials. gov, ID# NCT03823404)."

Edited by MikeHerp
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Hey @MikeHerp that’s all pretty old hat stuff now, recent years have continued the genetic, ageing, amyloid theory that blows all the others out of the water. Infectious theory represents maybe 1% of research effort these days.

Here’s an excellent piece of research that explains an exciting new find surrounding amyloid kinks.


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2 minutes ago, vzhe said:

Reminder: You can block @WilsoInAus and make your experience on this forum a lot better. Instructions in my signature.

But why would want that? To tell people how they should think without challenge and the full truth?

What did you think of the paper I linked?

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10 hours ago, vzhe said:

Reminder: You can block @WilsoInAus and make your experience on this forum a lot better. Instructions in my signature.

Thanks, yeah, I'm keeping it in mind.  

On 10/10/2019 at 5:49 AM, WilsoInAus said:

Hey @MikeHerp that’s all pretty old hat stuff now


"Published September, 2019" 

Read the first sentence: "Multiple recent studies have revived interest in a long-standing hypothesis that there may be an underlying infectious basis for AD..." 

Edited by MikeHerp
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      Yes, but every married person who I found out about that has this waited 6-8 months into the relationship to disclose it. But maybe you're right. If I had told her 6-7 months in, she'd still have Googled it and flipped out, and maybe it would have been harder then. I don't know. I don't see myself going through this level of pain and rejection so easily next time. I really don't. I'm taking the meds. I use protection. It's been almost a decade since I've had it so I'm not worried about shedding or passing it on so easily. British studies confirm that the first 2 years are the most contagious and we're passed that. I'm just over this. I've never been in so much emotional pain in my life.
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