Alzheimers: Future treatment Flashcards
Amyloid based targets for A.D. therapy?
- Production. Inhibiting cleavage enzymes (BACE-1 or gamma secretase inhibitors)
- Aggregation. Amyloid vaccination
- Breakdown. Protease activators?
- Microglial activation. TFG-1a, NSAIDs
- Clearance. Statins (neprisylin enhancers)
What are some clinical trial designs for investigating disease modifying therapies?
- Randomised withdrawal. (Ethical issues)
-
Staggered start. Preffered to randomised withdrawal due to ethics.
These first two compare slope divergence over time to assess whether effect is symptomatic or disease modifying. - Biomarkers. Must be used along with other measures of improvement
- Imaging. E.g. hippocamapl atrophy. Almost should be used with other measures
- Clinical milestones.
What pathologies of AD might a disease modifying strategy target?
- Cell loss
- Synapse loss
- Tangle formation
- Plaque formation
- Ab deposition
- Inflammation
What are the causes of cell death in AD.
- Amyloidosis
- Tangles
- Inflammation
- Trophic factor withdrawal
- Excitotoxicity
- Reduced energy supply
All of these factors converge to cause cell death - therefore targeting any one factor may be inadequate to provide disease modifcation.
Genetic mice models of AD (value and limitation)
Value:
Test genetic contribution to aetiology
Recapitulate some features of human disease
Allow examination of evolution of pathology and disease mechanisms.
Examine influence of other genes/products
Test novel therapies
Limitations:
Do not recapitulate several important features such as cell death, tangles and NT dysfunction.
Predictive value unknown
Tau based targets for A.D. therapy
- Microtubule stabilisers
- Tau kinase inhibitors
- Autophagy enhancers
- Tau assembly inhibitors
- HPS90 inhibitors
Emerging disease modifying treatments
- NSAIDs. Anti-inflammatory mechanisms
- Gonadotrophin releasing hormone agonist (GnRH)
- NGF transfer (gene/cell Tx)
- Cannabinoid (CB2) agonists
Evidence for the toxicity of AB monomers/oligomers
- Amyloid beta applied to neurons in vivo dampens LTP, causes mitochondrial dysfunction and oxidative stress.
- Amyloid injections cause transient congitive impairments in mice
- Soluble AB shows a stronger correlation with congitive impairment than plaque formation, which only correlates with severe cognitive impairment
- Plaques are insoluble and relatively inert compared to AB
- AB binds to a host of cell surface receptors suhc as NMDA and RAGE, through which deleterious effects could be mediated (excitotoxicity, NFkb mediated inflammation).
It has been proposed that AB oligomers are the cause of neural dysfunction, neurodegeneration and cognitive decline in AD, and that plaques are a protective mechanisms to sequester the oligomers.
However, mice models of AD that produce high levels of AB oligomers and subsequent pathology do not show cell death. Furthermore, AB reducing therapies such as solanezumab and verubecestat failed to attentuate disease progression in AD despite significantly reducing CSF levels of AB.
Cause/effect condundurm (chronochemistry of AD).
Evidence against the amyloid beta cascade hypothesis.
- Pharmacological: Several amyloid targeting therapies have failed to improve congitive symptoms or slow decline despite successful removal of amyloid e.g., verubecestat, solanezumab. This has been used to imply that there could be AD without plauqes - however this doesn’t consider that the downstream effects of plaques might be required for AD.
- Neurobiological:
- Individuals can show extensive AB pathology whilst remaining symptom free
- AB plauqes does not show Braak staging, and it does not correlate with cognitive decline (although AB-42 does correlate with decline).
- Amyloid pathology found to a lesser extent in areas associated with memory and is preceded by Tau pathology. Only in advanced stages in the neocortex is there a linear progession of AB followed by p-tau. This goes against amyloid cascade hypotheses, which place tau several steps down-stream of AB.
- **Genetic:
- **APP/presenelin familial mutations only account for a very small number of cases.
- There are also no identified mutations in alpha or beta secretase that alter the risk of Alzheimer’s disease.
- Non-familial Alzheimer’s disease (LOAD) has not yet identified risk factor genes involved in APP or AB.
- GWAS meta-analysis have revealed several more susceptability loci for Alzheimer’s disease, many of which have no clear links to the amyloid cascade hypothesis
Difficulties in studying/treating oxidative stress
The central component of oxidative stress is the unpaired electron, which rapidly reacts with cellular compartments. The production and effect reactive oxygen species cannot be easily studied in in-vitro mdoels - not least in living humans with Alzheimer’s. Studied molecules (i.e., carbonyalted proteins, DNA damage) are usually several steps removed from what would be the target of antioxidants.
Theories of RNA damage have recently emerged - however this is not disease specific, not least gene specific.
Developing disease modifying therapies is compounded by their chemical-state-dependent property, meaning that molecules can be pro or anti oxidant depending on their environment.
Theories of mitochondrial dysfunction are more tractable and targetable routes for disease modifying therapies.
Failed disease modifying alzheimer’s therapies
- Immunisation. There are still drugs in trial, but the majority had no effect and some (active immunisation) proved to be fatal due to inflammation of the brain.
- Gamma secretase inhibitors. Discontinued due to high toxicity and limited efficacy
- BACE-1 inhibitors. While still many in trial, verubecestat failed for futility.
- RAGE inhibitors
- Antioxidants
- Tau aggregation inhibitors. These failed due to lack of effect - however for a small subset of patients who recieved no other medication, it showed mild efficacy. Results need to be repeated with a larger group as there were only 82 in this subset.
- nicotonic ACh agonist. Showed gastrointestinal toxicity, and ultimately failed to meet end points.
https://www.tandfonline.com/doi/pdf/10.1080/13543784.2017.1323868?needAccess=true
read
Implications of the definition A.D.
It currently depends on the presence of amyloid. If it is the case that it is not dependent on amyloid, then we may have people without AD in the samples, and people with AD in the control groups - particularly if amyloidosis is used to allocate members.
