Tackling the Causes of Alzheimer's Disease

The following is an essay by Dr. Denise Harold from the MRC Centre for Neuropsychiatric Genetics and Genomics at Cardiff University and relates to the sciSCREEN following a screening of Robot and Frank.

Set in the near future, the film “Robot and Frank” deals with how Frank and his family deal with his decline into dementia. With only the options of robot care or being placed in the ‘Brain Centre’ available to Frank, clearly in this future, a cure or an effective treatment for dementia has not yet been developed. Unfortunately, this is a major problem that we’re facing right now, with 35 million dementia sufferers worldwide, and as a result of increasing longevity, this figure is set to double every 20 years.

Accounting for 50-70% of all cases, Alzheimer’s disease (AD) is the most common form of dementia. Although it’s not specified in the film, Frank may well suffer from AD; there appears to have been a gradual onset of his symptoms, a progressive decline in his memory, and he’s having difficulties with activities of daily living. While there are approved drug treatments available for AD, such as the cholinesterase inhibitors, these unfortunately aren’t disease-modifying; they treat the symptoms rather than the cause of the disease. At best, an AD patient might expect a 6-12 month delay in the worsening of symptoms. There are a number of ongoing drug trials that are aiming to target what many see as central to Alzheimer’s disease, namely the toxic β-amyloid peptide that accumulates in the brains of patient’s with AD. Unfortunately, the results from these aren’t too promising. Some of the trials have shown a reduction in β-amyloid but unfortunately without any corresponding improvement in symptoms. Others have had unmanageable side effects, and some have even worsened the condition.

One possibility as to why these drugs aren’t proving effective may be that they’re being administered when the disease is already manifest. So for example, even though Frank appears to be in the early stages of disease in terms of symptoms, he’s likely had pathological changes occurring in his brain for 10-15 years previously. Many believe that for the current round of trial drugs to be effective, they will need to be applied pre-symptomatically, and in fact, one such trial has recently been approved and should be taking place soon. The drug, solanezumab, is the first β-amyloid clearing drug to be tested in older people thought to be in the pre-symptomatic stage of Alzheimer’s; the trial will enrol 1,000 people of at least 70 years of age with evidence of β-amyloid in their brains, but who do not show clinical symptoms of the disease. Although conducting such trials in apparently healthy individuals is a risky prospect, a comment on the Alzheimer’s Research Forum  indicates there is certainly a demand for this type of approach: “I am the daughter of a 97-year-old father with Alzheimer's. All of his eight siblings' deaths were from Alzheimer's. His 94-year-old half-sister and he are left alone with the disease. My three sisters, brother, and I are all deathly afraid that we already are seeing the beginnings of it! I would be a participant in this study in a heartbeat”; post by Judy Eggerling, on the announcement of the Solanezumab A4 Prevention Trial.

However, another possibility as to why these trial drugs aren’t successful may be that there are other pathological mechanisms at work other than the accumulation of β-amyloid. If we can find these triggering mechanisms of disease, this may help us develop more effective drug treatments. In order to achieve this, we need to look at factors that cause AD, rather than looking at the end results of the disease process. A number of factors have been identified that may affect whether or not you’re likely to get AD, including a number of environmental factors such as diet, levels of physical activity, whether you suffer from hypertension/high cholesterol in mid-life, etc. However, one factor that we can’t control has a very strong impact on disease susceptibility: our genetic makeup.

There are rare mutations in three genes related to β-amyloid biology (the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2)), that directly cause Alzheimer’s disease. Frank is very unlikely to have had one of these mutations, as they usually result in disease that manifests between the ages of 40 and 60; these mutations account for ~1% of AD cases. Frank likely suffers from the much more common late-onset AD, which usually occurs after the age of 60-65. Identifying genes that influence late-onset AD is complicated by the fact that individually, they usually have only a small effect on the likelihood of developing disease, i.e. while they increase risk of the disease it is certainly possible to have a particular disease-associated genetic variant and not develop disease, or conversely, to develop disease without the disease-associated genetic variant. This means that we have to perform very large studies, typically looking at thousands of AD patients and thousands of healthy control individuals, trying to find genetic variants that differ in frequency between the two groups.

The AD genetics group at Cardiff University, headed by Professor Julie Williams, has been involved in a number of large collaborations with other AD researchers from around the world. This has culminated in the International Genomics of Alzheimer’s Project (IGAP), involving 25,580 AD patients and 48,958 healthy individuals, and as a result, over 20 genes influencing AD risk have been identified in the past 4 years. As previously mentioned, these genes individually have only a small effect on disease risk, but they act cumulatively, such that the combination of many disease-associated genetic variants and environmental risk factors will cause a person to develop Alzheimer’s. However we have many, many more genes yet to identify before we would for example, be able to predict whether or not someone will develop disease based on their genetic profile. However, we are starting to see a pattern in the types of genes indentified. For example many of the disease-associated genes play a role in immunity, and as chronic inflammation is present in the AD brain, this is very disease relevant. Similarly, many of the genes identified so far are involved in cholesterol metabolism, and we’ve previously seen that depletion of membrane cholesterol in neuronal cells affects the processing of β-amyloid. We hope that as we identify more and more genes involved in AD, we’ll start to get a more complete picture of the pathogenic mechanisms that lead to disease, and this will hopefully aid in the development of more effective drug treatments. These treatments aren’t going to be developed today, or tomorrow, but we really have cause to hope that sufficient advances will have been made in 20-30 years time, such that a story like Frank’s would have a much more optimistic outcome.