The year was 1906, when a German scientist, by the name of Alois Alzheimer, first described a peculiar, severe disease of the cerebral cortex, which is now commonly known as ‘Alzheimer’s disease’. A 50-year old woman, Auguste Deter, was admitted to a hospital in Frankfurt for paranoia, progressive memory loss, sleeping disturbances, aggression and confusion. She passed away five years later.1 On post-mortem examination of Auguste’s brain, Alois discovered and described plaques and tangles, which remain the two cardinal hallmarks of Alzheimer’s disease.2
The devastating clinical effects and consequences of Alzheimer’s disease are captured in a moving series of self-portraits by the artist William Utermohlen (see below). William suffered from Alzheimer’s disease for more than a decade and depicted the progression of his illness from the time of diagnosis until his admission into a nursing home.3
The global incidence of Alzheimer’s disease is estimated to be above 35 million, with nearly 7 million new cases per annum.4 Alzheimer’s disease is the most common cause of dementia in the elderly. The economic costs of dementia are currently around $260 billion per annum and are projected to quadruple in the next three decades.5 Ageing is a major risk factor for the disease but the aetiology (cause) of Alzheimer’s disease remains unknown. Clinically, it is characterised by an ongoing insidious decline of memory and other cognitive domains, that leads to an inability to perform normal daily activities.
To describe the pathophysiology (disease process) of Alzheimer’s disease, amyloid cascade hypothesis was proposed in 1992 and though contentious, remains the most widely accepted hypothesis.6 The proposition by John Hardy posits a serial model of causality whereby amyloid β protein (Aβ), the main component of plaques, initiates a cascade of events. This leads to formation of tangles, composed of aggregated tau protein, inflammation, vascular damage, and neurodegeneration (death of neurons).
Bearing this in mind, the first active immunotherapy strategy came in the form of AN-1792, which was developed thanks to a collaboration between Pfizer and Janssen.7 The rationale behind AN-1792 was to induce an adaptive immune response that would remove brain amyloid plaque deposition.8 AN-1792 was tipped to change the treatment landscape of the Alzheimer’s field but failed to live up to its potential.
Subsequently, The Phase 2 trial in 372 patients with mild to moderate Alzheimer’s disease was terminated because 6% of patients developed meningoencephalitis (inflammation of the brain and its surrounding protective membranes). A four-and-a-half-year follow-up study was conducted in 159 patients (129 treated with AN-1792, 30 with placebo) from the Phase 2 trial.9 Only 25 patients were found to produce antibody titres against Aβ and thus classified as responders. Furthermore, patients with sustained immune response showed significantly reduced functional decline.
On the contrary, AN-1792 treated patients showed clearance of amyloid plaques, however this did not prevent progressive neurodegeneration.10 The data suggested that if Aβ is the initial trigger for the disease, then the treatment came too late because the disease had already progressed, and perhaps targeting tau would have been more beneficial at that stage.
Immune therapies have been tried in patients with early Alzheimer’s disease, where preformed antibodies against Aβ have been used. For example, Aducanumab11 (Biogen) and gantenerumab12,13(Roche) have shown reductions in the disease injury markers, but no clinical benefits were observed. More than 121 agents are currently being tried to tackle Alzheimer’s disease, of which 16.5% and 11.3% are targeting amyloid and tau respectively.14
The reason for the lack of efficacy with clinical trials is also due to the complex disease processes operant in Alzheimer’s disease. For example, 50% of patients with Alzheimer’s disease exhibit α-synuclein pathology (usually observed in Parkinson’s disease), while 30% show TDP43 pathology (usually observed in motor neuron disease/Amyotrophic lateral sclerosis).15 It appears that we need to devise multiple therapies to find a suitable combination to slow the disease process in Alzheimer’s disease.
Despite the enormous amount of work that has gone into the arcane field of Alzheimer’s, there are currently only four licensed treatments that deal with the symptoms but do not modify the disease pathogenesis. The key to a successful fight against Alzheimer’s disease would require timely diagnosis and timely intervention, ideally years before a patient manifests symptoms. As life expectancy increases, more people will likely develop Alzheimer’s disease, making it of paramount importance to identify what individuals can do to reduce their chances of developing the disease. Improving diet, regular exercise, cognitive training, and monitoring vascular risks have all been shown to improve or maintain cognitive functioning.16
Although the story is more than a century old, it has become increasingly relevant. With multiple interventions in development to help with different facets of dementia, the future of therapeutics in Alzheimer’s disease looks promising. However, it is unlikely that a single treatment would alter the disease process, rather a combination of therapies (that suppress harmful effects of Aβ, tau, inflammation) would be required to slow down neurodegeneration. Furthermore, there are usually other comorbidities (diseases) associated with Alzheimer’s disease, as it rarely occurs on its own.
It is likely that a more personalised medicine approach and combinatorial therapy would be required, tailored to individual patient’s needs. Although the quest for a cure for Alzheimer’s disease has been a long and frustrating journey, we are perhaps closer than ever before to achieving it.
By Dr. Azhaar Ashraf
