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On World Alzheimer’s Day, This Is Beirut recalls the history of this debilitating condition, from Alois Alzheimer’s first observations in 1906 to the new biological treatment.
November 3, 1906: Alois Alzheimer (1864-1915), a German clinical psychiatrist and neuroanatomist, signals a “particularly acute pathology in the cerebral cortex” at the 37th psychiatric conference held in Tübingen, in south-west Germany. He describes the symptoms of a 50-year-old lady, Auguste Deter, whom he had been monitoring since she was admitted into the Frankfurt municipal asylum for the epileptic and mentally insane. Deter had, prior to that, shown signs of paranoia, progressive sleep and memory disorder, aggressiveness and confusion. Alzheimer treated Deter until her death five years later, on April 8, 1906.
The conference was attended by such distinguished scientists as Oswald Bumke (1877-1950), Otto Binswanger (1852-1929) and Hans Curschmann (1875-1950), who expressed no interest in Alzheimer’s theory. Only a brief summary was later included in the official record of the meeting. And while the Tübingen press largely covered psychoanalytical conferences, only two lines were dedicated to Alzheimer’s symposium. The conference in question would mark the beginning of a far-reaching scientific quest, riddled with obstacles and challenges, whose objective was to uncover the mysteries of this debilitating illness that bears the name of the man who discovered it.
An unusual clinical scheme
Before delving into the universe of the classic and innovative treatments of Alzheimer’s disease, let us look into its history. When Auguste Deter passed away, her brain and medical file were transported from Frankfurt to Munich, where Dr. Alzheimer lived. The German psychiatrist then urged the medical examiners to perform a quick cerebral autopsy in order to study the etiology of his patient’s condition. Alongside the Italian neurologist Gaetano Perusini (1879-1915), Alzheimer detected an atrophy of the cerebral cortex and an alteration of the area that governs memory, language, judgment and thought. He also discovered amyloid plaques between neurons, as well as neurofibrillary tangles inside these. This clinical scheme, far from unusual for an 80-year-old patient, is highly atypical considering that Auguste Deter was only 57 at the time of her death.
An unresolved riddle
These observations later contributed to the discovery of neuropathological characteristics typical of this type of dementia. Ultimately, Emil Kraepelin (1856-1926) would use the expression “Alzheimer’s disease” for the first time, in the second volume of the eighth edition of his Psychiatric Treaty (1910). Ever since, the prevalence of this disease grew exponentially worldwide. According to epidemiological figures, the number of Alzheimer’s patients is expected to exceed 150 million by 2050. Such alarming numbers highlight the importance of developing research on this illness whose etiology is as complex as its origins are obscure. That being said, phenomena such as the abnormal accumulation of the amyloid beta protein, the hyperphosphorylation of the protein tau and chronic neuro-inflammation are believed to be aggravating factors.
Limited therapeutic arsenal
To this day, no therapy has been developed to stop the progression of Alzheimer’s disease, let alone recover damaged or lost neurons. However, seven molecules have obtained the approval of the U.S. Food and Drug Administration (FDA) for medical use. The molecules in question are tacrine (approved in 1993 then banned in 2013 for its hepatic toxicity), donepezil (approved in 1996), rivastigmine (approved in 1997), galanthamine (approved in 2001), memantine (approved in 2003), aducanumab (approved in 2021) and lecanemab (approved in 2023). The first four are inhibitors of acetylcholinesterase, an enzyme that degrades an important neurotransmitter, acetylcholine. Thus, this therapeutic class promotes the persistence of neuronal activity and the development of memory. As for memantine, it allows for the reduction of neuronal apoptosis and neurotoxicity caused by excitant amino acids.
A controversial treatment
It is important to note that the aforementioned medicines only serve to reduce symptoms: they delay the occurrence of Alzheimer’s disease but do not cure it. More recently, the FDA approved aducanumab, a monoclonal antibody, for the treatment of patients with mild symptoms. This antibody has been designed to target and eliminate amyloid plaques. The safety and efficiency of aducanumab have been assessed through two randomized phase 3 clinical trials (ENGAGE and EMERGE) with patients suffering from early Alzheimer’s. The results are mixed: ENGAGE did not achieve its main objective, while EMERGE did.
These inconsistent results have cast doubt on the effectiveness of targeting the amyloid beta protein, thereby challenging the primary theory about the disease’s origin. FDA’s approval of aducanumab in 2021 caused heated debate, as some criticized its high cost, side effects and lack of efficiency. A number of experts believe that the proof to its efficacy remains insufficient, while others are convinced that it can bring hope for the treatment of the otherwise incurable Alzheimer’s disease.
Lecanemab, another antibody that targets the amyloid beta protein – and amyloid plaques – was approved in January 2023. The results of phase 3 blinded multicentric clinical trials showed that lecanemab has slowed the rate of cognitive decline by 27% throughout an 18-month study conducted on early Alzheimer’s patients. According to this same study, published in the New England Journal of Medicine (NEJM), the occurrence of undesired events was 21.3% for patients who received lecanemab treatment, compared to 9.3% for those who received a placebo. Longer-term experiments need to be made to establish the efficiency and safety of this treatment beyond a reasonable doubt.
All in all, Alzheimer’s disease remains a major public health challenge despite all medical advancements. That is why the scientific community spares no effort towards finding better treatment strategies.