More than 5 million Americans suffer from Alzheimer’s disease, a devastating neurodegenerative process resulting in loss of memory, dementia and inability to lead an independent life. Because of the aging population, it is estimated that 13 million people will have clinical signs of Alzheimer’s disease in 2050, and the cost of care is expected to increase from $172 billion per year today to a trillion dollars in 2050. Because of this huge prevalence and the devastating effect on the individual and their families, there has been a very energetic effort to understand the disease and develop drugs to slow or stop the degenerative progression. Alzheimer’s disease develops slowly over years or even decades, and so the absolute cause is difficult to ascertain. The most commonly accepted hypothesis is that there is abnormal or excessive breakdown of a normal protein, called amyloid precursor protein (APP) in the brain, and the breakdown products are deposited as amyloid-beta (A-beta) plaques causing death of neurons in the brain. It is absolutely known that Alzheimer’s patients have huge excess of A-beta in their brains, but it is still not absolutely understood if this is the cause of the dementia, or a result of some other process. Research supporting the hypothesis that A-beta is the cause rests on the ability to cure mouse models of Alzheimer’s with processes that remove the A-beta plaques. In addition, there are people with genetic predispositions to deposit abnormal amount of A-beta, and they always develop Alzheimer’s disease. A very interesting study recently published in the journal Nature (1) identified people with the genetic predisposition for Alzheimer’s disease who had a second mutation that prevented the excessive APP from being cleaved to the pathogenic A-beta and were protected from developing Alzheimer’s. These findings seem to support the hypothesis that A-beta deposition in the brain is responsible for Alzheimer’s disease.
By 1999 studies had shown that giving mice with A-beta plaques in their brains antibodies against A-beta cleared the plaques from their brains. This has led to enormous efforts in academic laboratories and biopharmaceutical research units to develop anti-A-beta antibodies to use in Alzheimer’s patients, thinking the antibodies would remove the plaques and if not reverse the disease at least stop it’s progression. The most advanced of these studies were reported this year. This Examiner reported on a very small study looking at use of intra-venous immunoglobulins at very high doses in 4 patients, and the results were encouraging but still quite preliminary, and would not be useful for treatment of the 5 million Alzheimer’s sufferers. With hopes of much more widespread therapeutic application, Pfizer and Jansen AI developed bapineuzimab, an anti-A-beta1-5 antibody that binds plaques better than soluble A-beta. Four very large studies were initiated throughout the world in a large number of mild to moderate Alzheimer’s patients with and without genetic mutations predisposing to Alzheimer’s disease. All these studies were recently terminated when results showed that although Ab plaques were reduced by treatment with the antibody, after a year and a half of treatment there was absolutely no change in the mental decline of the patients. Lilly was meanwhile developing solanezumab, an anti A-beta13-28 antibody that would recognize shortened A-beta that would be missed by bapineuzimab and also bound to soluble Ab as well as plaques. But, unfortunately the results of clinical trials were recently announced and although Lilly is scrounging to reassess the data and try to come up with something hopeful, there was essentially no difference in mental decline between treated and untreated patients. Why would this be?
This week in the New England Journal of Medicine, a large group of researchers and neurologists who call themselves the “Dominantly Inherited Alzheimer’s Network” or DIAN, reported a very interesting study that may help to explain these negative results (2). They analyzed 128 patients with an autosomal dominant genetic defect that caused excessive A-beta plaques and Alzheimer’s disease in successive generations. The age of onset of signs of dementia in this group of people is quite closely predicted by the age of onset of signs in their parents. They normalized the group by calling the age of onset of clinical signs of dementia in the parent time “0” and the age of onset of the offspring minus the parent the time before clinical signs. For example, if the parent started showing signs of dementia at age 45, and the patient in question is 20 at the time of the examination, this is deemed -25 years, or 25 years until the expected onset of clinical signs. They measured memory and a battery of cognitive tests well accepted to monitor onset and progression of Alzheimer’s. They also looked at the brain using MRI and positron-emission tomography (PET) to look at brain atrophy and identify deposition of A-beta plaques. And, they took blood and cerebrospinal fluid (CSF) to look at circulation concentrations of A-beta in the blood and the brain. They found very interesting, perhaps a bit disheartening, results, but they may help explain the negative results with the anti-A-beta antibodies.
As long as 25 years before the expected onset of clinical signs of dementia, levels of A-beta in the CSF of patients started to change. PET scans showed increases in A-beta plaques in the brains of patients 15 years before expected onset of dementia along with increases in brain atrophy. The careful tests of memory and cognitive impairment showed decreases 5 years before the expected onset of dementia.
In patients with genetic predispositions to Alzheimer’s including patients with homozygous APOE ε4, or Down’s syndrome patients, who all get Alzheimer’s in their middle age, should treatment with the anti-Ab antibodies begin as teenagers? Will one day we treat Alzheimer’s prevention much as we now treat cardiovascular disease prevention by administration of statins for years or decades? Now, the authors of the New England Journal article state multiple times that these people in this study with Dominantly Inherited Alzheimer’s may be different than the patients with much more common sporadic age associated Alzheimer’s disease, but the results clearly demonstrate that initiation of the processes occur decades prior to dementia. Clearly starting treatment at time “0” in this study would have been way too late to change the progression of neurodegeneration that had been going on for 25 years!
So, there may not be a “golden bullet” anytime soon in the future. Disease modification of Alzheimer’s is going to require the ability to detect changes predictive of eventual decline and initiation of treatment decades before the clinical changes become apparent. Evidently, we still have a long way to go.
1. Jonsson T, Atwal JK, Steinberg S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature July 11 (Epub ahead of print) 2012.
2. Bateman, R.J., Xiong, C., Benzinger, T.L.S. et al. Clinical and Biomarker Changes in Dominantly Inherited Alzheimer’s Disease. New Engl J Med 367: 795-804. 2012.