Saturday, May 22, 2021

What's new in Alzheimer's disease?

Dementia is a huge and growing problem. An estimated 50 million people around the world suffer dementia, with Alzheimer’s disease the most common cause. It is estimated that some six million Americans are living with Alzheimer’s disease. The impact on the person with dementia is exceeded by the impact on their family, as the enormous care-giving needs are rarely covered by health insurance.

While there are genetic factors (particularly the APOE4 allele) that increase one’s risk of developing AD, and a rare familial form that occurs in younger people, the major risk factor is age. While rare in young adults, dementia occurs in some 10% of adults over 80. Thus, as we live longer, the incidence of AD will inevitably rise. The diagnosis of AD remains clinical. While all primary care clinicians should be able to detect dementia, a specialist should be consulted at least once to confirm the diagnosis and try to distinguish AD from other less common causes of dementia.

In 2021, the laboratory plays little role in routine care. After a new diagnosis of dementia, both serum vitamin B12 levels and a test of thyroid function such as TSH should be done. While uncommon, both B12 deficiency and an underactive thyroid can cause dementia and are easily treated. Some form of brain imaging should also be done to look for uncommon but surgically treatable conditions.

There is a growing interest in new diagnostic tools including advanced brain imaging techniques such as PET scans and measuring specific proteins in the spinal fluid, but Medicare does not pay for these expensive tests and their use is generally confined to clinical trials. On the horizon are blood tests that may confirm a diagnosis of AD.

To date, treatment of AD has largely been limited to a class of drugs called cholinesterase inhibitors that improve transmission of nerve impulses. The first, donepezil (Aricept), was approved by the FDA in 1996 and was soon followed by rivastigmine and galantamine. A different type of medication, memantine, targets glutamate, another “neurotransmitter.” None of these drugs cure AD but they do slightly improve symptoms and will often allow the sufferer to be able to avoid the need for nursing home care for several months longer.

Despite immense amounts of research, no new drugs for AD have been approved since 2003. Many promising candidates showed no benefit or even worsening. Recently there has been an explosion of research on a new class of drugs called monoclonal antibodies that target the pathologic markers of AD in the brain: proteins called tau and amyloid-beta.

This post was prompted by a full page ad in the Wall Street Journal from the Alzheimer’s Association calling on the FDA to approve one of these new agents, aducanumab, based on a trial reporting a 22% reduction in decline compared to placebo. I also found a more recent trial of another monoclonal antibody, donanemab, that also reported positive results.

Delving into these trials showed several factors that gave me pause. The first was the very small group that were entered into the trials after screening. The donanemab study began with 1955 people 60 to 85 with mild dementia, but entry required specific findings on PET imaging and in the end, only 272 were entered into the trial. The generalizability of the study was thus clearly limited when thinking of the broad group of people suffering dementia. Secondly, while there was a “statistically significant” difference in a score evaluating AD severity, the absolute difference was only 3.2 points on a score that ranged from 0 to 144. Hardly a “miracle.”

The data on aducanumab similarly showed an absolute difference of 0.39 on a different scoring system that ranged from 0 to 18, and this was in one of two studies, the other showing no benefit. Almost 1% of the patients receiving aducanumab had major side effects.

This class of drugs clearly warrant further study, but delaying their approval for general use seems prudent. While they have been shown to be of some modest benefit in a carefully selected subset of patients, FDA approval would almost certainly lead to an explosion of use in patients who were not studied in the trials and who might as likely be harmed as helped.

In the interim, some lifestyle changes have been shown beneficial and are both safe and free: regular aerobic exercise (walking), diet rich in leafy greens and flavanols (berries, nuts), staying socially active and trying to learn new things.

We should also be pressuring the federal government to do more to assist caregivers and improve payment for such things as adult day care and home health aides.

I am optimistic that within a few years, we will have both better and less invasive ways to diagnose Alzheimer’s disease and better treatments.

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