Aduhelm for the Treatment of Alzheimer’s Disease: a Comprehensive Review

Alzheimer’s disease (AD) is a serious progressive cortical degenerative disease that insidiously takes over the memories, cognitive function and characterised by massive amyloid plaques formation. It begins as subtle difficulty learning and recalling new information, stealthily progresses to episodes of disorientation and confusion. As the disease progresses patients are slowly stripped of their independence and inevitably rely on caregivers.

AD is the most common form of dementia contributing to 60-80% of cases. In addition, women appear to be diagnosed with AD more than men. Aging is thought to be a strong risk factor for developing progressive AD in association with mutations in amyloid precursor protein (APP), presenilin (PSEN) 1, PSEN 2, and apolipoprotein E (APOE) ε4 and ε3 genes. Extracellular accumulations of Aβ40 and Aβ42 peptides and phosphorylation of tau proteins lead to the formation of extracellular senile plaques and intra-neuronal neurofibrillary tangles, respectively. This ultimately leads to toxic effects on neurons causing atrophy, loss of neurotransmitters (such as acetylcholine) and eventual loss of cognitive abilities. In addition, impaired reasoning, judgement and problem solving, impaired facial recognition, spatial recognition, object Agnosia and even delusions and hallucinations can also be seen in later diseases. Utilizing imaging techniques, AD can be detected. Widening of sulcal gaps, narrowing of gyri, and expansion of the lateral ventricles as a result of atrophy are some of the gross anatomic alterations associated with AD. However, microscopic diagnosis is only possible after death.

Pharmacologic therapies such as cholinesterase inhibitors and memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist in combination with cognitive behavioural therapy (CBT) and non-pharmacologic therapies such as aromatherapy, pet therapy, music therapy, and individual recreational activities, have historically been the most widely used for patients with AD.

Currently, Aducanumab (marketed as Aduhelm), the only FDA-approved drug that removes the amyloid plaques which disrupts the major pathogenic process vital to the progression of AD thus slowing the development of the disease. It selectively binds with amyloid aggregates in both the oligomeric and fibrillar states rather than amyloid monomers. It interrupts amyloid aggregation kinetics which is a multistep process that includes primary nucleation from monomeric protein and secondary nucleation on existing fibrils. It binds fibrils and targets them for microglial-mediated removal and interrupts the bridge between neuroprotective amyloid monomers and neurotoxic amyloid oligomers.

Aduhelm's effectiveness was tested before going through with a clinical trial. The study has shown that mice with acute treatment with Aducanumab analog experienced a greater reduction in Aβ plaques. However, it did not show any significant effect on reducing that formation of new Aβ plaques relative to control. In addition, mice with chronic treatment with Aducanumab analog were found to prevent calcium overload and increase NMDA receptor’s permeability to calcium.

The phase I clinical trial for Aducanumab was a single-dose escalation, randomized, double-blind, placebo-controlled study. According to research, an overdose (≤30 mg/kg) can result in Alzheimer’s related imaging abnormality-edema/effusion (ARIA-E) along with headache, diarrhea and upper respiratory tract infection. The medicine is effective in regulating the mental status of patients with Aβ plaque formation, according to phase Ib (entitled “prime”) reports, and it takes very little of it to raise the chance of developing ARIA-E. Phase III trial is entitled “emerge” and “engage”. The primary objective of these trials was to determine the effects of Aducanumab o cognition in AD patients using clinical dementia rating scale sum of boxes (CDR-SB), mini-mental state examination (MMSE), Alzheimer’s disease cooperative study activities of daily living (ADCS-ADL) and Alzheimer’s disease assessment scale-cognition sub-scale 13 (ADAS-cog13). To examine the effects of Aducanumab on Aβ and tau proteins, biomarkers in cerebro-spinal fluid were examined, and positron emission tomography (PET) images were collected. The high dose was found to diminish the overall number or size of Aβ plaques in patients (6 mg/kg for APOE ε4 carriers and 10 mg/kg for non-carriers). High-dose Aducanumab appears to slow the rate of functional and cognitive deterioration in patients with mild AD, according to the "Emerge" study.

The research and medical communities do hold some diametrically opposed viewpoints, though. Aducanumab has been demonstrated to significantly reduce amyloid in all examined cortical brain regions, despite the persistent scepticism in clinical efficacy. In conclusion, Aducanumab has provided hope for those who are trying to give patients a potentially safe and viable treatment option in the management of AD.

Reference:

Haddad, Hannah W et al. “Aduhelm, a novel anti-amyloid monoclonal antibody, for the treatment of Alzheimer's Disease: A comprehensive review.” Health psychology research vol. 10,3 37023. 28 Jul. 2022, doi:10.52965/001c.37023