What do you call it?

Stuart Dombey

The Federal Drug Administration has given accelerated approval to aducanumab as a treatment for Alzheimer’s disease, while asking the manufacturer, Biogen, to conduct a phase 4 confirmatory trial. ‘There remains some uncertainty,’ according to the director of the FDA Center for Drug Evaluation and Research, ‘about the drug’s clinical benefit.’

‘Old age’, ‘senile dementia’, ‘cerebrovascular disease’ and ‘Alzheimer’s disease’ are all designations of a process of dementia that occurs in older people. The name has changed over time in subsequent editions of the International Classification of Diseases (ICD).

According to the Alzheimer’s Association about six million people in the United States have Alzheimer’s disease. The Centers for Disease Control and Prevention (CDC) report that 266,957 deaths in the US in 2018 were attributable to dementia as an underlying cause, 46 per cent of them due to Alzheimer’s. The cost of managing the disease runs into hundreds of billions of dollars per year. The annual list price of aducanumab is $56,000.

Alzheimer’s disease was first described in 1906 by Alois Alzheimer. Examining the brain of a 51-year-old woman who had died with dementia, he found neurofibrillary tangles (the deposition of tau protein in the neurons), amyloid plaques (the deposition of amyloid protein in clumps in the brain cortex) and cerebral atrophy. This suggested that Alzheimer’s was a distinct disease with a distinct pathology and for the next seventy years it described pre-senile dementia because it occurred in younger adults.

In 1975 the ninth edition of the ICD determined that ‘Alzheimer’s disease’ should also cover senile dementia – that is, dementia and memory loss in adults over the age of 65 – and this was strengthened in 1990 for the tenth edition of the ICD. Why the change was made is not clear to me, though it may have been a softening of the term ‘senile dementia’ which was becoming more common as life expectancy increased. But it raises the question of whether Alzheimer’s is describing a specific disease or a group of diseases that may have different pathologies.

According to the CDC there were no deaths from Alzheimer’s before 1979. There was then a rapid increase and since 2000 it has been the sixth most common cause of death in the US. Meanwhile there has been a dramatic reduction in deaths from cerebrovascular disease. As the CDC report says, ‘certification and coding rule changes can impact data analysis of component causes of dementia.’ Are we helping or confusing the treatment opportunities?

Psychiatric diseases are classified by the Diagnostic and Statistical Manual of Mental Diseases (DSM), now in its fifth edition. The diagnosis of Alzheimer’s disease in this classification is based on excluding all other possible neurological and systemic diseases that might have caused the memory loss. What is left is Alzheimer’s. The American Psychiatric Association has produced a practice guideline for the treatment of patients with Alzheimer’s and other dementias. It runs to 62 pages and is based on that definition. Does every newly referred person get the benefit of all the exclusionary tests before Alzheimer’s is diagnosed?

The most important part of diagnosis is to identify known treatable conditions. The potential overlaps with Alzheimer’s include Parkinson’s and Huntington’s. Normal pressure hydrocephalus is another condition that may be underdiagnosed. It was first described in 1965 as a build-up of cerebrospinal fluid (CSF), the normal fluid which surrounds the brain, causing brain shrinkage. It can be treated by withdrawing CSF by lumbar puncture or more permanently by inserting a shunt into the brain to allow the CSF to drain. There are several examples of people diagnosed with Alzheimer’s who have recovered after CSF is removed.

Another problem arises if clinical trials are undertaken for specific therapies that reduce amyloid plaque (aducamunab is one). If the diagnostic criteria are not settled, the population treated may not be homogeneous, which means a small potential benefit will be diluted by the subjects who are unable to benefit. This may have been the case with recent novel treatments. Solanezumab has been widely tested without success in improving the symptoms of Alzheimer’s. Verubecestat, another new oral agent, has also failed its recent trials. Could it be they were tested in too varied a group of people? Could a more specific population be helped by the new drugs? The greater the specificity of the trial population, the greater the chance of seeing an improvement (if it exists).

We have moved from the ancient point of view that memory loss and cognitive impairment are inevitable with aging, through ‘old age’ as a diagnosis, to Alzheimer’s disease as a blanket term for most cases of dementia. It seems time to move on to a more defined categorisation that looks more carefully at treatable opportunities, and provides more specific and homogeneous populations, based on clear measurements, for new drug studies that will allow improvements in treatment and a better understanding of the causes of memory loss. It is time for some new names.