Drug treatment of Alzheimer's disease: what has changed in 30 years?

Abstract

The Geriatric Therapeutics Review series in this journal can look proudly on what has been achieved over the last 30-plus years — pharmacists, doctors and other health professionals are now more aware of the issues impacting on prescribing and administering medications to older people. In some respects, it is ‘job done’ for the series — the end of a long journey. The mission of developing effective and safe therapies for Alzheimer's disease sadly cannot yet make the same claim, but we can say we are at the end of the beginning, with disease-modifying drugs, such as the monoclonal antibody lecanemab, now approved in some countries and under consideration by the Therapeutic Goods Administration in Australia. These drugs target the underlying disease process — accumulation of amyloid — and have been demonstrated to impact favourably on the progression of symptoms.^{1, 2} This is a significant milestone in a very long mission.

It is grounding to re-read the article reprinted below, written in 1994 by Hopwood and Morris,³ two leading clinicians in the diagnosis and treatment of Alzheimer's disease at that time, based at the Heidelberg Repatriation Hospital. In describing the limited treatment options for Alzheimer's disease in 1994, their vision, and even desperation, are apparent. But also clear is what has plagued this mission for so many decades — lots of possible therapeutic targets that ultimately came to nothing. For a quarter of a century, since the cholinergic therapies and memantine, we had nothing new that was effective in treating the progressive cognitive and functional impairments caused by Alzheimer's. The brain is a hard nut to crack, as those on similar missions with other neurodegenerative diseases (think Parkinson's and motor neuron disease) have found.

Hopwood and Morris³ concentrated on the restoration of chemical neurotransmission to boost the ‘function of surviving neurons’. That was reasonable — it was a ‘low hanging fruit’, with a well-demonstrated reduction in the activity of choline acetyltransferase (the enzyme responsible for the synthesis of acetylcholine) in people with Alzheimer's disease and early promising results with the short-acting cholinesterase inhibitor physostigmine. The first clinical trials of Alzheimer's disease therapeutics, with tacrine (a longer-acting cholinesterase inhibitor), began in Australia following the publication of a 1986 study by Summers et al.⁴ that was cited in the Hopwood and Morris article,³ but concentrating on these chemicals was never likely to have the more fundamental effect needed — disease modification.

In their article, Hopwood and Morris³ stated that ‘effective preventative strategies aimed at preventing neuronal degeneration remain speculative’, but they did flag this as a future direction (‘[e]ventually strategies may be based on altering biochemical pathways involved in amyloid production’). When I reviewed the field for the Geriatric Therapeutics series 18 years later, in 2012, various potentially disease-modifying treatments had been developed and trialled.⁵ The early excitement around drugs that reduced amyloid production, and the early monoclonal antibodies targeting amyloid, was soon tempered by reality — they were not effective. But the field did not retreat. Despite a 99% failure rate, there was still a huge amount of resources thrown at this ultimately fatal disease.

Dementia research sites in Australia, such as the Heidelberg Repatriation Hospital, were involved in this journey from almost the beginning. Some 30 years down the track, after trialling over 150 individual investigational products in over 200 clinical trials around Australia, we are at the end of this first phase in the development of disease-modifying treatments for Alzheimer's disease, but we have a long way to go. It is likely that the key to the next phase of success will be secondary prevention — targeting amyloid and other disease mechanisms before significant neurodegeneration and symptoms occur, using combination or sequential therapies and tailoring therapies to individual genetic and pharmacogenomic profiles. Analogies with cancer therapeutics are attractive, but we must not again fall into the trap of oversimplifying the brain or trying to replicate what has worked for other diseases. And we must never lose sight of the need to attend to non-pharmacological preventative approaches throughout life, including diet, exercise, and physical and social activities.⁶ Hopwood and Morris were also prescient in noting that there will (always) be more to managing Alzheimer's disease than just drugs (‘[d]rug treatment must always be considered as just one part of the management plan’).³

So just as the 30-plus year journey of Geriatric Therapeutics has left us wiser and with a toolbox for the quality use of medications in older people, the even longer mission to treat Alzheimer's disease effectively is also at a milestone, but we are not there yet!

The author has received honoraria for expert advice and speaker fees from pharmaceutical companies including Roche, Merck, Jannsen, Eli Lilly, Eisai, Biogen, Actinogen, Anavex, Inmune Bio, Novo Nordisk, GSK and Pfizer. Austin Health has received pharmaceutical industry funding for Alzheimer's disease research, used to partly pay salary. The author has no shares or direct employment with any pharma or biotech company.

No funding was received for this article.