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Perhaps the most brutal decisions in writing a feature article, particularly a narrative-driven piece, concern what to leave out. Having decided to tell a story conveying the complexity of Alzheimer’s disease and the paradoxically tantalising prospect of a ‘simple’ solution to it, I knew that too much detail would impede my already convoluted narrative. But Alzheimer’s disease is complicated, and so here are a few of the intricacies I’ve read about and discussed with scientists since spring 2013 when I started researching the piece.

ApoE and other genes

One thread that got cut was the story of a gene called apolipoprotein E (ApoE), whose importance hangs on the distinction between early- and late-onset Alzheimer’s disease. Early onset of dementia (before the age of 65) was one of the original defining characteristics of the disease. But researchers then found the hallmarks of Alzheimer’s (amyloid plaques and tau tangles) in the brains of older people who had ‘senile dementia’, which occurs later in life. At first, they called such cases ‘senile dementia of the Alzheimer’s type’. Then, from the 1970s, when Alzheimer’s disease was more broadly defined, these cases were just called Alzheimer’s disease, but a distinction remains between early- and late-onset disease, and the extent to which the two share the same causes (and treatments) is still uncertain.

Only about 1 per cent of cases of Alzheimer’s disease today are early-onset. Yet the first genes to be associated with the disease were all discovered in families with strong histories of early-onset Alzheimer’s. The role these genes play in late-onset Alzheimer’s is not particularly clear – it is assumed that the findings can be extrapolated to the late-onset form of the disease since they have such similar neuropathology. There are many genes specifically associated with late-onset Alzheimer’s disease – ApoE being the first to have been identified – but they are not as revelatory as the early-onset genes, which all have a direct link to amyloid beta production. Instead, they present a murkier picture of several slightly perturbed networks – harder to tease out and harder to target with drug treatments.

ApoE was associated with Alzheimer’s disease in 1993 and it remains the most significant gene in late-onset disease. There are three forms of ApoE in people that affect the relative risk of developing Alzheimer’s. The most common form is called ApoE3, and most people have two copies of it in their genome (one copy inherited from each parent). In about a quarter of the population, one of the ApoE copies comes in a form called ApoE4 – these people are about three times more likely to get Alzheimer’s disease than if both copies were plain ApoE3. In the rarer case of having two copies of ApoE4 (2 or 3 per cent of the population), the risk jumps to about eight times.

There is another form of ApoE, however, called ApoE2 – and studies suggest that having a copy of this form actually protects people from Alzheimer’s disease, which offers an intriguing angle for developing potential treatments. However, it is still not clear exactly how the different forms of ApoE affect progression of the disease. We do know that the protein produced by the ApoE gene can bind to amyloid beta, and studies have shown that ApoE4 is associated with the brain being less able to remove amyloid beta, so perhaps ApoE4 is a defective form. Unfortunately, boosting expression of ApoE proteins in the hope of improving the clearance of amyloid beta has not worked in mouse studies.

Over the years, some 20 or so other genes have also been associated with the risk of developing late-onset Alzheimer’s disease. Each has variant forms that are fairly common in the general population, and seem to have only a small effect on disease risk. But as an October 2013 blog post by Alzheimer’s Research UK says, “The value of identifying these new Alzheimer’s risk genes does not lie in their potential to identify people at risk or aid diagnosis… The true potential comes from understanding what all of these genes do and from that, highlighting new avenues for investigation to understand what is causing or driving Alzheimer’s.”

And new avenues we certainly have found. Biological processes implicated by these common, low-risk genes include the immune system and inflammation, the control of cell movement, the transport of molecules between cells, cell-to-cell communication, and the cellular scaffolding that helps maintain structure and direct the transport of cargo within cells.

Unfolding mysteries

ApoE didn’t first catch researchers’ eyes as a dementia-associated gene. Interest in it began thanks to its association with cardiovascular disease. It is intriguing that the same gene should crop up in relation to heart disease and dementia, especially as the same lifestyle factors are suggested to reduce the risk of both: physical exercise, a balanced diet, not smoking, and keeping your blood pressure and cholesterol levels down. This suggests there may be a common mechanism involved – perhaps it is some fundamental process that works less well as we age, but the most sensitive parts of the body are our blood vessels and brain cells, so they are the first to suffer.

How exactly Alzheimer’s disease relates to ageing is a matter of debate. Some of the researchers I interviewed think it’s an inevitable consequence of ageing that would hit us all if we lived long enough. Others think it is a distinct disease, a form of dementia quite unlike the gentler decline in mental faculties that generally comes with getting older. It is an interesting question, and one that perhaps will only become answerable when we have a better understanding of all types of neurodegeneration.

The hallmarks of Alzheimer’s disease at a cellular level are clumps of two abnormally folded proteins, amyloid beta and tau. Other neurodegenerative diseases involve similar accumulations of misfolded proteins. Each protein is produced as a string of amino acids, but the way the string is folded determines its final structure and function. Mistakes in folding lead to malfunctions. In frontotemporal lobe dementia, the second most common type of dementia after Alzheimer’s, around half of cases display faulty tau, while others have different malfunctioning proteins, such as TDP-43 and ubiquitin. Lewy body dementia, closely linked to Parkinson’s disease (itself associated with the build-up of a protein called alpha-synuclein), has characteristic clumps of alpha-synuclein and ubiquitin.

And in prion diseases, most famously Creutzfeldt–Jakob Disease (CJD), one prion protein misfolds, which gives it the power to make other prion proteins misfold in the same way, and so it spreads through the brain, causing damage as it goes. Recent research has suggested that misfolded tau also has the potential to self-propagate, which may add weight to its importance in Alzheimer’s disease and certain other dementias.

However, research published in October 2013 suggested it might just be possible to target the mechanisms that deal with misfolded proteins using a drug that would stop them from damaging and killing brain cells. Modifying this process with a drug may have unwanted effects, but it certainly offers hope of a new approach to tackling these diseases. It’ll be worth keeping an eye on this work to see if it lives up to its early promise.

Where are we now?

One of the starting-points for writing my piece was the failure in 2012 and 2013 of a clutch of clinical trials of drugs developed on the basis that amyloid beta was the key protein in Alzheimer’s disease. I appreciate that translating results from the lab into drugs that help people is incredibly hard, but it got me wondering: did these failures point to a bigger problem with the dominant theory of Alzheimer’s disease, the amyloid hypothesis? Of course, there are still a number of amyloid-based drugs in development and many researchers will tell you that we are making good progress, in both our basic understanding of the disease and the drugs that will next come out of the pipeline.

But as an example of a different approach, I focused on Claude Wischik, who is dismissive of the role of amyloid beta in Alzheimer’s disease. His company TauRx has started a trial of a drug that purportedly dissolves tau tangles instead. My decision to tell this story was not to dismiss other ongoing efforts in Alzheimer’s research, but because it may well be the next major phase III trial to report results. And for me, it clearly highlighted that different scientists are pursuing quite divergent paths through the labyrinth of Alzheimer’s.

Since filing my piece, I’ve read that a much earlier ‘amyloid-based’ treatment, which was thought to have caused dangerous inflammation in patients who participated in trials, might be brought back thanks to work at Southampton University. And as mentioned in the main article, one of the more recently ‘failed’ amyloid drugs is already being re-tested to check on the possibility that it could, in fact, help patients at an early stage of disease.

It is not all about the drugs, either. Great advances are being made in imaging, for example, that will enable scientists to track the build-up of amyloid beta and tau in people’s brains, allowing a much more definitive analysis of the proteins’ association with dementia than ever before. Of course, until the results are announced, it is impossible to say how any of these studies will fit into the long and tortuous story of Alzheimer’s disease.

What all this shows is that we should not underestimate the complexity of the problem of Alzheimer’s disease. Although a ‘simple’ solution is not precluded, even after a century of research, it will be no simple task to find it.

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