Is Alois Alzheimer Still Waiting?

Lee Stein, MD

A fifty-one-year-old female presented to her physician's office with complaints of short-term memory loss and altered behavioral symptoms. After gradual but progressive decline, the patient died five years later of Alzheimer's disease. Her physician, Dr. Alois Alzheimer, in 1906, had no adequate medication to alter the progressive nature of this disease. Little has changed in the subsequent 114 years.

During the latter portion of the 20th century and early 21st century, there have been substantial advances in the treatment of Neurologic disease. Advancements have particularly been noted in multiple sclerosis, Parkinson's disease, epilepsy, ALS, headache, and have resulted in effective forms of treatment.

Also, notable in the past 20 years has been substantial progress in defining the pathophysiology and neurogenetics of Alzheimer's, but treatment for the degenerative aspects of this disease is still lacking.

Alzheimer's is a neurodegenerative disease consisting of behavioral and cognitive changes impairing social, functional and occupational endeavors and activities of daily living. No cure or treatment to slow progression has been uncovered. There are over 6 million Americans with the diagnosis of Alzheimer's today. Numbers are expected to rise to 13.8 million by 2050. A long preclinical phase is suspected, followed by a chronic progressive course. Amyloid plaques and neurofibrillary tangles develop in the cerebral cortex and deep brain structures. It is also suspected that this preclinical period may extend for years prior to onset of symptoms. Clinical symptomatology includes memory loss, decrease in language skills, changes in personality, judgement, mood and agitation.

Diagnosis is typically made with review of history, exam, and clinical exclusion of alternate etiologies. MRI and PET scans can be helpful in establishment of diagnosis. Checking spinal fluid levels of Tau and Amyloid can also be helpful, but rarely utilized outside of the research setting. A recent serum study has been developed which can detect Tau protein. FDA approved medications are available for symptomatic improvement only and have no effect on long term prognosis. Psychotropic medications have been utilized for treatment of depression, anxiety, agitation and hallucinations.

Numerous Alzheimer clinical trials for disease modifying therapy have been performed with almost 100 percent failure. These trials have increasingly focused on patients with mild, moderate or prodromal disease. Trials for the most part have failed to reach cognitive endpoints or were terminated secondary to adverse events. A number of complicating issues in previous trials have included patient population, small age spread, reduction in heterogeneity, requirement for more extensive biomarkers, drug toxicity, late intervention, bioavailability and potential need for combination drugs.

Several drugs for symptomatic improvement of cognitive function are available, but typically the effectiveness of these medications is quite limited.

Despite multiple Alzheimer trial failures in the past 15 years, there was a notable report in October 2019 with reference to the monoclonal antibody Aducanamab. The Engage/Emerge Phase III trials for Aducanamab had actually been closed in March 2019 secondary to a "futility analysis." This analysis had been based on limited data which predicted that both studies would not meet their endpoints. Over subsequent months, additional data was reviewed and suggested that Aducanamab was effective in slowing cognitive decline. In October 2019, Biogen announced these results and reported plans to file with the FDA and to resume the trial as a redosing study.

The Coronavirus pandemic has, at least in the short term, affected the ability to maintain many of these trials which require IV treatments. Patient safety in this elderly population with risk of exposure to COVID-19 has in a very practical fashion affected comfort levels of patients, families, research staff and physicians. Study sponsors have taken these problems into account while attempting to maintain patient population to continue recruitment. These efforts appear to be successful in continuing most trials.

Present and future therapeutic strategies include:

1) Reduce Amyloid Beta production.

2) Increase Amyloid Beta clearance from the CNS.

3) Prevention Tau aggregation.

4) Enhance an anti-inflammatory mechanism.

5) Accelerate microglial breakdown.

At present there are several active Phase III trials. There remain high expectations for these Amyloid and Tau targeted studies. Future trials and better understanding of this disease process should lead to increasingly effective forms of treatment. Alois Alzheimer's long wait may be coming to an end.

Lee Stein, MD, is a long-time Memphis neurologist who has been with The Neurology Clinic for the past 20 years and practiced for 15 years at Semmes-Murphey prior to that. He is lead investigator for the clinic's research division having conducted numerous clinical trials primarily on Multiple Sclerosis and Alzheimer's disease.


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