Theories of Alzheimer's Disease
Research into the potential causes of Alzheimer’s disease has been frustrating. A number of processes are believed to contribute to the cognitive decline observed in Alzheimer’s disease. Brain deterioration in Alzheimer’s disease is thought to begin decades before symptoms become evident. Outlined below are several factors postulated to contribute to Alzheimer’s disease; each also represents a potential therapeutic target (Luan 2012; Teng 2012).
A prominent finding in Alzheimer’s disease is that senile plaques, which are comprised of “clumps” of the protein fragment amyloid beta, accumulate and cause cellular damage in key areas of the brain, especially the hippocampus, which is involved in memory consolidation and spatial navigation (Biasutti 2012). Aggregates of amyloid beta have been shown to contribute to oxidative damage, excitotoxicity, inflammation, cell death, and formation of neurofibrillary tangles (NFTs) (see below) (Massoud 2010). However, therapies aimed solely at reducing amyloid beta have proven disappointing, suggesting a more complex process is involved (Marchesi 2012; Schmitz 2004; Holmes 2008).
Neurons contain a cellular skeleton made up of microtubules, secured in place by specialized proteins called tau. In Alzheimer’s disease, microtubules disintegrate and tau proteins “clump” together to form aggregates called neurofibrillary tangles or NFTs. NFTs function much the same as amyloid beta aggregates in that they initiate several process that lead to cellular dysfunction and death. Whether amyloid beta or NFTs arise first in Alzheimer’s disease is unclear, and this remains a heavily debated topic within the scientific community (Massoud 2010; Crespo-Biel 2012).
A theory once widely advocated, but which has proved to be disappointing at addressing underlying disease progression, is the cholinergic hypothesis. This view suggests that Alzheimer’s disease is the consequence of insufficient synthesis of the neurotransmitter acetylcholine, which is fundamental in many aspects of cognition (Munoz-torrero 2008; Nieoullon 2010).
Clinical trials have shown medications that support acetylcholine signaling reduce symptoms, but do not reverse or halt the disease. Therefore, inadequate cholinergic neurotransmission is now viewed as a consequence of generalized brain deterioration observed in Alzheimer’s disease, rather than a direct cause. Nonetheless, drugs that modulate acetylcholine signaling are still a mainstay of symptomatic management of Alzheimer’s disease (Munoz-torrero 2008; Nieoullon 2010).
Oxidative stress is a process in which highly reactive molecules called free radicals damage cellular structures. Free radicals are byproducts of normal metabolism, but during states of metabolic abnormality such as mitochondrial dysfunction (see below), they are created more rapidly and in greater quantity. In the case of Alzheimer’s disease, oxidative stress both facilitates some of the damage caused by amyloid beta and spurs its formation (Dong-gyu 2010; Hampel 2011).
Oxidative stress propagates Alzheimer’s disease via another route as well. As neurons become damaged, free iron accumulates on their surfaces and within nearby cells called microglia. Free iron causes radical formation and drives oxidative stress (Mandel 2006).
The inflammatory process appears to play an important role in the development of Alzheimer's disease (AD). When high levels of amyloid beta accumulate in the brain, it activates the body’s immune response, resulting in inflammation that damages neurons (Salminen 2009). Part of the inflammatory response to amyloid beta appears to be facilitated by tumor necrosis factor-alpha (TNF-α) (Tobinick 2008a). TNF-α is a pro-inflammatory cytokine that is often found in high levels in serum and cerebral spinal fluid (CSF) of Alzheimer’s patients; it represents a potential target for novel Alzheimer’s disease therapies (Culpan 2011; Ardebili 2011; Tobinick 2008a).
Mitochondria are the energy power plants of cells; they generate energy in the form of adenosine triphosphate (ATP), which is necessary for cellular function. Mitochondrial dysfunction has been implicated in many age-related diseases, including Alzheimer’s disease (Chen 2011). One line of evidence that supports a link between Alzheimer’s disease and mitochondrial dysfunction is the finding that ApoE4, a genetic variant associated with Alzheimer’s disease and amyloid beta deposition within the brain, seems to play a role in disrupting mitochondrial respiratory chain function (Caselli 2012; Chen 2011; Polvikoski 1995).
Dysfunctional mitochondria are important mediators of amyloid beta toxicity (Leuner 2012). Mitochondrial dysfunction contributes to an increased burden of oxidative stress as well, which itself is another mediator of amyloid beta toxicity. Mitochondrial dysfunction and oxidative stress then drive the formation of additional amyloid beta, creating a vicious, self-propagating cycle that ultimately leads to neuron death (Leuner 2012).
Glutamate is the most abundant excitatory neurotransmitter in the brain and is necessary for normal brain function. However, too much glutamatergic neurotransmission can be toxic to neurons, a phenomenon known as “excitotoxicity”. Excitotoxicity is thought to contribute to neuronal degeneration in Alzheimer’s disease because it is promoted by amyloid beta, neurofibrillary tangles, mitochondrial dysfunction, and oxidative stress among other factors (Danysz 2012).
Glutamate excitotoxicity is the result of over activation of N-methyl-D-aspartate (NMDA) receptors. Therefore, modulating this receptor is a way to lessen some of the damaging effects of excess glutamate signaling. The FDA has approved memantine (e.g., Namenda®), an NMDA receptor blocker, for the treatment of moderate to severe Alzheimer’s disease (Danysz 2012).
Loss of Sex Hormones
Evidence suggests that age-related loss of sex hormones – estrogen in women and testosterone in men – may contribute to Alzheimer’s disease. Although the specific mechanisms are unclear, sex hormones appear to protect the brain against the development of Alzheimer’s disease (Vest 2012; Barron 2012). For example, declining estrogen and testosterone levels seem to be associated with increased amyloid beta and tau abnormalities (Overk 2012).
An intriguing theory that remains largely unappreciated by the medical community is that chronic infection with a variety of pathogenic bacteria and/ or viruses may contribute to the development of Alzheimer’s disease. Research indicates that some common pathogens are consistently detected in the brains of Alzheimer’s patients. For example, a comprehensive analysis of studies found that Spirochetes, a family of bacteria, was detected in about 90% of Alzheimer’s patients and was virtually absent in healthy age-matched controls. Further statistical evaluation revealed a high probability of a causal relationship between Spirochetes infection and Alzheimer’s disease (Miklossy 2011).
Spirochetes and other bacteria can linger in the brain and drive inflammation and the formation of amyloid beta and neurofibrillary tangles, all of which are hallmarks of Alzheimer’s disease (Miklossy 2011). Moreover, laboratory studies indicate that amyloid beta is an antimicrobial peptide, suggesting its formation could be an adaptive response to infectious organisms (Soscia 2010). These and other findings have led some researchers to hypothesize that “…early intervention against infection may delay or even prevent the future development of [Alzheimer’s disease]” (Honjo 2009).
A recent article published in Science Advances provides intriguing evidence that Alzheimer’s disease could be caused, in part, by infection with Porphyromonas gingivalis,a keystone pathogen of chronic periodontitis and significant risk factor for developing amyloid beta plaques, dementia, and Alzheimer’s disease. P. gingivalis produces virulence factors called gingipains—proteases essential for its survival and pathogenicity. The authors hypothesized that gingipains promote neuronal damage in Alzheimer’s patients and may contribute to the pathogenesis of Alzheimer’s disease.
The scientists began by studying and comparing brain tissue samples from Alzheimer’s disease patients and neurologically normal controls. They found that the gingipain load was significantly higher in Alzheimer’s disease samples than in controls, indicating gingipain load is correlated with Alzheimer’s disease diagnosis and disease markers. Interestingly, the scientists found a portion of the “healthy” brains were infected as well indicating that “… brain infection with P. gingivalis is not a result of poor dental care following the onset of dementia or a consequence of late-stage disease, but an early event that can explain the pathology found in middle-aged individuals before cognitive decline.”
In addition to identifying P. gingivalis in the brains and cerebrospinal fluid of Alzheimer’s disease patients, they also developed potent small molecule gingipain inhibitors which protected neurons from P. gingivalis-induced cell death. Mouse studies also showed the inhibitors could protect against neurodegeneration caused by P. gingivalis infection and provided direct evidence that oral infection with P. gingivalis can result in brain infiltration, increases in the conventional Alzheimer’s disease biomarker Aβ1-42, and neurodegeneration. COR388, an analog of the most potent inhibitor with better oral bioavailability and central nervous system penetration, was shown to treat an existing brain P. gingivalis infection and reduce bacterial load, Aβ1-42 levels, and tumor necrosis factor-α levels (Dominy 2019).
These findings offer compelling evidence that P. gingivalis infection and gingipains in the brain play an important role in the pathogenesis of Alzheimer’s disease. Furthermore, it demonstrates that oral administration of a small molecule gingipain inhibitor is effective for blocking gingipain-induced neurodegeneration and reducing bacterial load in mouse brains.
Ask the Scientist – Herpesviruses and Alzheimer’s Disease
Prof. Ruth Itzhaki is Professor Emeritus of Molecular Neurobiology at University of Manchester and Honorary Research Fellow at the University of Oxford.
- Hi, Professor Itzhaki. Thank you for taking time out of your day to share your thoughts with us. Would you tell us a little bit about your background and training?
I graduated in Physics and then did an MSc and then a PhD in Biophysics (on different research topics), all University of London degrees. Subsequently, I was involved in research on the structure of chromatin, then on carcinogen effects on chromatin and more recently, on Alzheimer's disease, starting work on a possible role of a virus in the disease way back in 1989.
- You’ve been studying the association between herpesviruses and Alzheimer’s disease and dementia for quite some time. Why were you drawn to this area of study?
Little was understood at the time I started and even the name of the disease was almost unknown to the public. Also, it was a challenge which appealed to me—and the possibility that a virus might be involved fascinated me. Another reason was that my father unfortunately had a type of dementia (probably Lewy Body dementia), so I was glad to work on a related topic.
- Given that you’ve clearly been persistent in studying this topic, how has your understanding of the potential link between herpesviruses and Alzheimer’s disease changed over the years as you’ve examined this link more closely?
It started as a vague though quite reasonable possibility but has now become a probability, particularly about 10 years ago when other labs started working on the topic—so I was no longer alone!
- Your work is considered controversial by some in the field of Alzheimer’s disease research . What key items still need to be addressed that make the work you’re doing important?
I agree that it is considered controversial but as our opponents, though virulently hostile, never produce any arguments against the HSV1-Alzheimer’s disease concept, the results could hardly be called controversial (as controversy by definition needs both pro and con arguments!). As for key items, I think they are to: (a) set up a clinical trial to investigate the effect of anti-herpes antiviral treatment of Alzheimer’s disease patients; (b) find if one or more microbes are involved in any one brain; (c) repeat the Taiwan studies; (d) determine the critical pathways by which the virus and APOE-e4 are involved in the development of the disease; and (e) develop a vaccine specifically against HSV1.
- Do you personally believe that herpesviruses are causally linked to Alzheimer’s disease?
- If so, what key pieces of evidence have been most convincing from your perspective?
- If you are of the opinion that the relationship is probably correlational and not causal, what evidence do you believe is the strongest indicator that the link is probably not causal?
The population epidemiological studies in Taiwan provide good evidence that HSV1 is a risk factor for Alzheimer’s disease and that anti-herpes antivirals would target the virus very effectively. All previous studies, reported in over 150 refereed publications, although important show only associations between virus and the disease, not whether the virus is a cause. The Taiwan studies are the first to provide evidence that the virus is a cause, so I regard them as key work. However, of course they need to be replicated in other countries.
- Do you believe that antiviral therapies could have a role in the prevention or treatment of Alzheimer’s disease in some cases? If so, what key features would help select patients most likely to benefit?
Yes, judging by all the research carried out, treatment should have a major effect. Prevention would be even better, but no vaccine is yet available and the apparent prevention shown by antiviral treatment in the Taiwan studies is very hard to explain (though I and Prof R. Lathe suggested a speculative explanation in our article in J. Alzheimer's Disease, 2018). For treatment, patients would be selected who have mild disease, who definitely harbour the virus (shown by seropositivity to it) and who, preferably, are carriers of the type 4 allele (form) of the APOE gene.
- Do you think any particular dietary, lifestyle, or environmental factors modulate the relationship between herpesvirus and Alzheimer’s disease. If so, what factors do you think exert the most influence?
Unfortunately, there is really no information about these factors in relation to herpesviruses and Alzheimer’s disease, but exercise and a good diet seem important in any case.
- The immune system does a pretty good job keeping HSV1 at bay in younger, healthy people. Do you think that age-related immune senescence is an important factor that may allow HSV1 to escape immune control and potentially contribute to Alzheimer’s disease in aging people?
- If so, do you think taking steps to maintain healthy immune function with advancing age might help keep HSV1 at bay and maintain brain health?
Yes, I think it is the decline in the immune system that allows virus entry into the brain, and keeps it latent (ie, dormant) there, at least part of the time. Possibly, virus entry might be prevented by treating seropositive people who have an APOE-e4 allele in early middle age with anti-herpes antivirals—but this is very speculative—as mentioned in my recent review in Frontiers in Aging Neuroscience, 2018.