Road to dementia?

Alzheimer's Disease is a substantial global heath problem, with over 26 million sufferers worldwide in 2006, that is predicted to grow substantially, with 1 in 85 people forecast to be affected by 2050 (Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer's disease. Alzheimer's and Dementia (2007) 3:186–91). Yet despite decades of research the fundamental molecular mechanisms that lead to the development of dementia remain poorly understood. Although we know that accumulations of amyloid plaques are the direct cause of the decline in cognitive function, we remain much less clear why amyloid builds up in the brains of some individuals faster than others.

As a result, treatments for Alzheimer's Disease are largely ineffective. The two classes of approved drugs, the acetlycholinesterase inhibitors (such as Aricept™ donepezil, Razadyne™ galantamine and Excelon™ rivastigmine) and the NMDA receptor antagonists (various branded forms of memantine) treat the cognative decline associated with dementia but do not halt the progression of the disease. There are currently no medicines with a label that includes delaying or halting the course of Alzheimer's Disease.

Initial clinical studies using inhibitors of the secretase enzymes that process the amyloid precursor to yield the insoluble peptides that are the major components of the plaques have reported disappointing results, suggesting that we need to understand more about the mechanisms that initiate plaque formation.

Our hypothesis for the development of Alzheimer's Disease stemmed from our studies of ApoE-deficient mice. ApoE is a fascinating protein: it is a component of lipoprotein particles that play a key role in regulating cholesterol transport around the body. But in 2004, we discovered an alternative function for this protein: regulating the clearance of apoptotic cell debris (Grainger DJ, Reckless J, McKilligin E. Apolipoprotein E modulates clearance of apoptotic bodies in vitro and in vivo, resulting in a systemic proinflammatory state in apolipoprotein E-deficient mice. J Immunol. (2004) 173:6366-75). This provided an intriguing new mechanism to explain the development of Alzheimer's Disease, since genotype at the ApoE locus is strongly linked to the risk of developing Alzheimer's Disease. The high risk alleles encode variants of the ApoE protein that are less effective at stimulating the clearance of cell debris. As a result, individuals with less effective debris clearance would see an accumulation of debris that in turn stimulates a chronic pro-inflammatory state. This, we proposed, may underlie the development of the amyloid plaques.

A major thread in support of this hypothesis was the old observation that following major head injuries, such as those sustained in road traffic accidents, there was a high risk of a rapidly progressive dementia in the months after the initial injury had apparently healed. In our model, this initial injury led to a massive production of cell debris that overwhelms the normal capacity for debris clearance, seeding the substrate for plaque development and hence dementia.

In the last month, three new studies suggest that indeed this same mechanism may underlie the majority of later onset Alzhemier's Disease as well. In a small post mortem study accepted for Brain Pathology, Crawford and colleagues show that individuals who had recovered from head trauma have substantial deposits of beta amyloid and tau protein in their brains, in marked contrast to individuals free from all head injuries (doi: 10.1111/j.1750-3639.2011.00513.x). More intriguingly still, two studies reported at the International Alzheimer's Conference in Paris at the end of July, found substantial increases in the risk of Alzheimer's Disease among individuals with a history of milder head injury. Among 281,000 US soldiers, the rate of Alzheimer's was 15.3% among those who had suffered at least one head injury, compared with 6.8% among ex-soldiers who had not. The lead investigator, Kristine Yaffe at the San Francisco Veterans Association Medical Centre said "This issue is important, because head injury is very common – 1.7million people in the United States suffer head injury each year".

The third study looked at dementia rates in adults who had played American football when they were younger – a sport that results in repeated knocks to the head despite the impressive protective gear the players wear. Among 500 ex-players over the age of 55, the rate of cognitive impairment indicative of dementia was almost triple the rate found in Americans of the same age who had not played football.

All in all, the accumulation of new data strongly suggests that our model of an inflammatory origin for plaque dementia, resulting from a failure to clear cell debris sufficiently quickly is a very important pathway in the development of Alzheimer's Disease in the general population, as well as in severe traumatic brain injury.

What does the mean for new therapeutic options? Over the last five years, we have been searching for analogs of apoE protein that can stimulate cell debris clearance systemically. We believe that these drugs could be useful to prevent dementia after traumatic brain injury, but also to prevent or slow the progress of Alzheimer's Disease. The new data provides a further strong impetus for developing these compounds further.

And the utility of ApoE mimetic drugs may not be limited to neurodegenerative conditions. We have found that failure to clear cell debris, at least in rodents, contributes to the development of autoimmune conditions. ApoE mimetics may very well also find uses therefore in the treatment of diseases such as systemic lupus erythrematosis (SLE).

It has taken almost a decade since we performed the first studies that showed a role for ApoE in regulating cell debris clearance, but the latest raft of data suggests the process we discovered is potentially even more important than we had imagined, and represents the best hope for real 'disease modifying' drugs for neurodegeneration in the next decade.