ALZHEIMER’S DISEASE/PARKINSON’S DISEASE 2015
12TH INTERNATIONAL CONFERENCE
NICE, FRANCE, 18–22 MARCH 2015
I was fortunate to attend this conference that is held every second year in one of the European cities on progress in research concerning Alzheimer’s disease and Parkinson’s disease. This year the meeting was in the lovely French city of Nice on the French Riviera. The next conference will be held in 2017 in Vienna.
The most notable presentation at the meeting with direct clinical relevance was evidence of the beneficial clinical effect on cognition of a new monoclonal antibody aducanumab for the treatment of early Alzheimer’s disease.
The results were from a promising phase 1b randomized study of aducanumab – a monoclonal antibody being developed by Biogen Idec Inc with the hope that it will modulate the course of Alzheimer’s disease (AD). The compound targets aggregated beta-amyloid and was tested in 166 patients in the early phases of Alzheimer’s disease. Learning from the disappointing results of previous trials testing monoclonal antibodies in Alzheimer’s disease, the investigators enrolled patients very early in the disease course – those with either prodromal or mild Alzheimer’s disease. Using florbetapir PET scans, they also ensured that enrolled patients had a significant amyloid burden.
On the basis of before-and-after PET findings, the drug was found to reduce amyloid plaque burden in the brain as early as six months out from initiating therapy and also at one year. Furthermore, aducanumab treatment was associated with a slowing of cognitive decline. The primary safety and tolerability signals were amyloid-related imaging abnormalities–edema (ARIA-E), the incidence of which did significantly increase with treatment, especially in ApoE ε4 carriers. However, the compound was deemed safe and tolerable enough based on the findings that the investigators plan to move directly to a phase 3 worldwide trial.
This monoclonal antibody was developed in an interesting way. Very healthy elderly individuals (‘super elderly’) were asked to provide blood samples. These blood samples were then treated to isolate the lymphocyte element. Lymphocytes were then stimulated and plasma cells were obtained. The plasma cells were then provoked to express all the antibodies that these elderly individuals had developed over their lifetime.
The theory here was that healthy elderly people might produce antibodies against certain toxic proteins and other substances that are implicated in the causes of neurodegenerative disease. In this way they protect themselves against developing these conditions.
It was found that plasma cells of these elderly individuals produced monoclonal antibodies against beta-amyloid proteins. Aggregated beta-amyloid is accumulated in plaques and in the walls of blood vessels in the brain of individuals with Alzheimer’s disease.
The monoclonal antibody against beta-amyloid was then produced. This antibody was injected into subjects in the trial on a monthly basis for a period of six months. Subjects were randomised to placebo or aducanumab.
Beta-amyloid clearance was demonstrated by repeated amyloid PET brain scans and also by measurements of CSF indexes of beta-amyloid. The doses of aducanumab in this study were 1mg, 3mg, 6mg and 10 mg per kilogram.
Those on placebo continued to accumulate beta-amyloid in the brain and their cognitive condition declined. Those on aducanumab gradually cleared amyloid from the brain and their cognitive performance either stayed the same or improved. The clearance of amyloid and the improvement of cognitive performance was dose dependent. The higher the dose of aducanumab per kilogram the greater the clearance of beta-amyloid and the greater the improvement in cognitive performance.
This study is the first evidence that a drug that reduces beta-amyloid load in the brain has a beneficial effect on cognitive function. The results of the study support to some degree the amyloid theory of the pathology involved in Alzheimer’s disease.
Multi-target approach to Alzheimer’ disease
Beta-amyloid is only one target of therapeutic interventions that may be successful in the treatment of Alzheimer’s disease. However, 30% of healthy elderly individuals have beta-amyloid pathology so beta-amyloid deposition is not the only explanation of sporadic or late onset Alzheimer’s disease. Other theories of Alzheimer’s disease pathophysiology implicate altered inflammatory processes, abnormal autoimmune modulation, microvascular disease, and genetic aberrations (particularly in younger onset cases). For example, beta-amyloid protein can be thought to be a form of an antimicrobial agent. It condenses around infection in the brain. This suggest that Alzheimer’s disease can be viewed in part as an immunologic disorder with an underlying immunologic disturbance affected by susceptibility genes (risk genes) that are involved in distorting the immune processes. It is likely that a multi-target therapeutic approach to Alzheimer’s disease will be required. This will mirror the situation with other chronic neurodegenerative diseases and chronic infections. For example the treatment of AIDS requires numerous antiviral agents to gain control of this infection.
Reverse translational medicine
The method used to develop the monoclonal antibody aducanumab is novel. The process is called reverse translational medicine. ‘Super healthy’ older individuals are selected, immune lymphocytes harvested and they are induced to switch to plasma cells and the antibodies expressed by these plasma cells are identified. As mentioned earlier, some antibodies have been found that act against amyloid-beta 40 and 42 variants. Other antibodies identified have shown action against tau and other pathological proteins found in Alzheimer’s disease and other neurodegenerative conditions such as frontotemporal dementia, corticobasal degeneration, motor neurone disease and Parkinson’s disease. It is possible that this form of reverse translational medicine will lead to a number of agents that may be of benefit in the treatment of these neurodegenerative diseases which at the moment have little in the way of effective treatment options.
Amyloid-related imaging abnormalities (ARIA)
The main concerning adverse effect of aducanumab (and other monoclonal antibody treatments) is amyloid-related imagining abnormalities (ARIA). There are two types of ARIA. There is the hemorrhagic type (ARIA-H) and the edematous type (ARIA-E). ARIA-H is due to the effect of clearing beta-amyloid protein from the endothelium of the walls of microvascular blood vessels in the brain. ARIA-E is most likely an inflammatory reaction to the loss of beta-amyloid protein in the Alzheimer’s disease plaques. The development if ARIA is dose dependent. This means there will need to be a balance achieved between the dose of monoclonal antibody that is effective for removing beta-amyloid and improving cognitive performance in patients versus the dose that causes ARIA effects. This balance is something that will be addressed in future studies.
Beta-amyloid pathophysiology in younger versus older-onset Alzheimer’s disease
Studies of individuals with late onset Alzheimer’s disease (over the age of 65) suggest that late onset disease is due to impaired clearance of beta-amyloid deposits in the brain. There is not an overproduction but the clearance of the beta-amyloid is defective. In early onset Alzheimer’s disease, particularly of the inherited type, the problem is overproduction of beta-amyloid and accumulation of this abnormal protein in the brain of these individuals – clearance does not seem to be effected.
Hippocampal and precuneus volume and beta-amyloid
Hippocampal volume and precuneus volume of individuals is associated with age. The older the individual the smaller the volume of these two regions of the brain. The size of these regions is also associated with global atrophy and total intracranial volume. Individuals with greater global atrophy have smaller hippocampal and precuneus volumes and individuals with greater total intracranial volume have larger hippocampal and precuneus regions. However, precuneus volume is most associated with these variables when the ApoE ε4 status is controlled.
CSF beta-amyloid 42 levels are inversely associated with PET measures of amyloid deposition. This association is strongest with PET measures of amyloid deposition in the precuneus region when ApoE ε4 status is controlled.
In selecting individuals for clinical trials researches will need to be aware of differences in CSF beta-amyloid markers and PET amyloid present in both patient and control subjects in order to be able to match placebo and active drug groups. It is important to note that beta-amyloid 40 is as important a pathological protein as beta-amyloid 42 in Alzheimer’s disease.
Brain imaging studies that have measured cerebral blood flow and beta-amyloid deposition longitudinally have observed that areas of higher cerebral blood flow measured in certain parts of the cortex in younger individuals are regions that are susceptible to increased amyloid deposition in later life and that these regions are associated with increased deposition of beta-amyloid in individuals who develop Alzheimer’s disease.
Hemosiderin deposits in the brain mark cerebral microbleeds. These deposits are identified by T2 images and SWI sequences on MRI scan. These microbleeds are also called amyloid angiopathy or hypertensive arteriopathy. Cerebral microbleeds are correlated with dementia and stroke. Cerebral microbleeds are associated with CSF biomarkers and they have a negative correlation with CSF beta-amyloid 42.
Current CSF biomarkers are beta-amyloid 40 and 42, total tau (t-tau: this marker reflects overall neuronal cell death) and phosphorylated tau (p-tau: reflects the amount of Alzheimer tangle pathology).
Additional CSF markers to consider in neurodegenerative disease include YKL-40, and neurogranin (in CSF this is associated with Alzheimer’s disease and mild cognitive impairment).
We have now possibly reached the stage where the measurement of CSF biomarkers are needed for the diagnosis, staging, prognosis and progressive monitoring of patients with Alzheimer’s disease.
In the future it is likely that the diagnosis of Alzheimer’s disease will move from clinical features to biomarkers. Unfortunately the methods used to measure CSF biomarkers remain unreliable. A major world standardisation procedure needs to take place so that measurement of CSF markers can be trusted.
Chronic traumatic encephalopathy
Chronic traumatic encephalopathy (CTE) is now classified as an acquired form of frontotemporal dementia. This condition is seen in people participating in sports where they are exposed to repeated concussive injuries.
There was a report of a new drug called fasudil. This drug is thought to improve neuronal survival and may be beneficial in the treatment of Alzheimer’s disease, frontotemporal dementia and other neurodegenerative conditions.
Genetic aspects of Alzheimer’s disease
Genetic aspects of Alzheimer’s disease were covered at this meeting. 5-10% of Alzheimer’s disease is the early onset form coming on between the ages of 45–65 years. 60% of early onset Alzheimer’s disease has a positive family history. Gene alterations identified with this early onset group include the amyloid precursor protein (APP), presenilin 1 gene (PSEN1), and the presenilin 2 gene (PSEN2). These are all autosomal dominant genes.
There are now nineteen identified susceptibility genes for Alzheimer’s disease. Three of these are causal genes – they have a large effect size. Others confer genetic risk or predisposition – they are of small effect size. Nine of these genes are implicated in adaptive and innate immunity – again raising the possibility of disturbed immune processes being an etiological factor.
A combination of ApoE ε4 status plus presence of any of these nineteen susceptibility genes predicts 97% of Alzheimer’s disease cases. Both ApoE ε4 and ApoE ε2 variance are associated with Alzheimer’s disease risk, however the ApoE ε4 carrier status drives the Alzheimer’s disease phenotype.
The ApoE ε4 gene is associated with an increased risk of Alzheimer’s disease. An individual with one ApoE ε4 allele has a three to four times the background risk of Alzheimer’s disease. An individual with two ApoE ε4 alleles has an eight times background risk of Alzheimer’s disease.
If the ApoE ε4 genotype is present and there is a clinical picture of amnesic Alzheimer’s disease then most likely 98% of individuals will have significant beta-amyloid protein burden in the brain. If the individual has Alzheimer’s disease at a clinical level but is ApoE ε4 negative only 50% of these individuals are likely to have amyloid-beta in the brain. The other 50% have other forms of pathology; possibly hippocampal sclerosis, frontotemporal dementia amnesic variant, vascular dementia or other conditions.
It is now feasible to test individuals with a genetic coding test for fifteen susceptibility genes to identify genetic causes of Alzheimer’s disease, frontotemporal dementia, motor neurone disease, Parkinson’s disease and Lewy body disease.
Finally, brain-derived neurotrophic factor (BDNF) is a gene that also has an influence on cognitive decline over time. Individuals who are positive for the 66 Met polymorphism allele of this gene (compared to the Val allele) are more likely to develop beta-amyloid related memory decline over time and develop hippocampal atrophy. The combination of BDNF 66 Met and an ApoE ε4 genotype confers a strong genetic risk for the development of Alzheimer’s disease.
Clinical forms of Alzheimer’s disease and frontotemporal dementia
There are a number of frontotemporal dementia types and these have expanded recently. There is the behavioural version, the language version (semantic dementia or progressive non-fluent aphasia), the motor version (motor neurone disease), and now the amnesic version that can look like classic Alzheimer’s disease. This amnesic version is sometimes called hippocampal sclerosis but it is not differentiable from Alzheimer’s disease on CT or MRI scans with regard to the hippocampal structures. Individuals who present with a clinical picture of Alzheimer’s disease but do not have beta-amyloid pathology are suspected to have non-amyloid pathology (SNAP).
We now also have a number of different Alzheimer’s disease types or presentations. There is the ‘classic’ amnesic version where episodic memory is the most affected initially. There is also the frontal version with behavioural disturbance predominant. There is a language version characterized by logopenia. There is a posterior cortical atrophy presentation that involves difficulties with visuospatial skills and visual problems and cortical blindness.
Much more work needs to be done with these types of frontotemporal dementia and Alzheimer’s disease with investigations including amyloid and tau PET and CSF studies to identify different pathophysiological mechanisms underlying these conditions.
The frontal presentation of Alzheimer’s disease can be difficult to distinguish from the behavioural version of frontotemporal dementia, and the amnesic version of frontotemporal dementia can be difficult to distinguish from classic Alzheimer’s disease.
However, investigations can help with the differential diagnosis. While frontal Alzheimer’s disease and behavioural type frontotemporal dementia might share similar regional frontal atrophy on MRI scan and frontal hypometabolism on FDG PET scan, and amnesic frontotemporal dementia and ‘classic’ Alzheimer’s disease might share medial temporal lobe atrophy on MRI scan and temporal hypometabolism on FDG PET scan, a PET amyloid scan plus CSF markers could discriminate individuals with Alzheimer’s disease from frontotemporal dementia. Individuals with Alzheimer’s disease will have a CSF pattern of reduced amyloid-beta 42 and increases in total tau and phosphorylated tau levels, and a positive PET scan for beta-amyloid deposition. These findings would not be expected in frontotemporal dementia.
Implications for practice
The development of specific disease-modifying drugs for Alzheimer’s disease will force changes to clinical diagnostic practice. It is likely these monoclonal antibodies directed at removing beta-amyloid from brain will be very expensive. Therefore only patients with a demonstrated loading of brain amyloid will justify the expense of these medications. It will be important to identify suitable patient candidates for these treatments. To do this PET amyloid scans and CSF protein levels of beta-amyloid 42 and t-tau and p-tau will be required in clinical practice – not just in research studies.
The spectrum of Alzheimer’s disease and treatment possibilities
The conference canvassed the spectrum of Alzheimer’s disease. The spectrum runs from cognitively normal individuals with cerebral deposits of beta-amyloid (now known as preclinical Alzheimer’s disease), through to prodromal Alzheimer’s disease (mild cognitive impairment of an amnesic type due to Alzheimer’s disease), through to Alzheimer’s disease dementia of varying severity. For the future understanding of Alzheimer’s disease and for determining treatments that might be effective in preventing progression it will be important to diagnose preclinical and prodromal stages of Alzheimer’s disease.
By the time beta-amyloid has built up a substantial presence in the brain it may be too late for effective treatment. Tau abnormalities come later in the course of Alzheimer’s disease and are more strongly associated with rapid cognitive decline and disease progression and neurodegeneration. It is possible that it may be better to target tau and its associated pathological processes in the treatment of individuals who suffer symptomatic Alzheimer’s disease and have developed clear cognitive impairment.
However, it is likely that a combination of treatment with drugs that clear or diminish the production of beta-amyloid, as well as drugs that affect tau production and clearance will be needed for the treatment of amyloid-related disease in the future.
For the clearance of beta-amyloid protein, monoclonal antibodies will be needed. Perhaps active immunisation with vaccines may have a role here too, both for clearance of beta-amyloid and tau protein.
Secretase inhibitors will be needed to block the production of beta-amyloid in both patients with established late onset disease and in particular with individuals with early onset Alzheimer’s disease. These drugs are base inhibitors and the Merck pharmaceutical company is involved in studies of these drugs.
A plan of combined treatment in Alzheimer’s disease would be to reduce production of beta-amyloid, stabilise toxic forms of this protein in the brain, increase the clearance of beta-amyloid, reduce inflammation due to the removal of amyloid (which shows as development of ARIAs on MRI scans) – perhaps with the use of anti-inflammatory drugs such as Etanercept, as well as reducing the production, stabilising toxic forms and enhancing the clearance of abnormal tau proteins.
Finally it is worth noting that if an individual has little in the way of beta-amyloid protein in the brain at age 70 then it is unlikely this person will accumulate this protein over the next thirty years. This means that an individual at this age is likely to be Alzheimer’s free for the remainder of his or her lifespan.
The conference reviewed Parkinson’s disease pathology. The abnormality in Parkinson’s disease is the abnormal deposition of another misfolded protein: alpha-synuclein protein. This is a fibril and is bigger than a monomer. The monomeric alpha-synuclein is the normal form of this protein but in Parkinson’s disease the protein is deformed into a fibril or larger sized configuration than the monomer. Using monoclonal antibodies that bind to the abnormal forms of alpha-synuclein and thereby clear the brain of this protein may advance the treatment of Parkinson’s disease. A new passive humanised antibody for attacking alpha-synuclein is PRX002. Early studies of this antibody are being trialed in Parkinson’s disease and Lewy body dementia. A phase 1 trial of reducing alpha-synuclein in serum was 98% successful.
I left this meeting with a sense of excitement and hope for the future. I saw the first evidence of a disease-modifying agent that produces a dose related improvement of cognitive performance in individuals with early stage Alzheimer’s disease. This development alongside many of the other important findings reported suggest that new windows of understanding and treatment initiatives are opening on Alzheimer’s disease, Parkinson’s disease and related neurodegenerative conditions. While this meeting does not have a strong clinical focus I would recommend that all professionals interested in the field of Alzheimer’s disease and Parkinson’s disease make an attempt to get to the next meeting in 2017 to be informed of progress made on the many exciting fronts explored at AD/PD 2015.