Dementia Action Week (15th – 21st September)

The recently published Dementia in Australia report highlights the growing burden of dementia in Australia. In 2023, dementia was the leading cause of death, responsible for around 9.5% of all deaths.

While there are many forms of dementia, Alzheimer’s disease is the most common, accounting for 60-80% of all cases. Management primarily involves supportive care and non-pharmacological interventions, although medications are available that may help manage symptoms and slow disease progression.

Four medications are available on the Pharmaceutical Benefits Scheme (PBS) for Alzheimer’s disease: the anticholinesterases (donepezil, galantamine, and rivastigmine) and the N-methyl-D-aspartate (NMDA) antagonist, memantine. These medications may provide modest benefits, although this often comes at the expense of significant adverse effects. More recently, targeted therapies have been developed which are hoped to modify the disease process.

Donanemab

The pathological hallmark of Alzheimer’s disease is the accumulation of amyloid beta protein plaques, which occurs early in the disease. Other characteristic brain changes include the development of neurofibrillary tangles composed of tau protein. While the role of these protein aggregates in Alzheimer’s disease is not entirely understood, they are accompanied by neuronal loss and brain atrophy.

Donanemab, approved in Australia in May 2025, is indicated for mild cognitive impairment due to Alzheimer’s disease and mild Alzheimer’s dementia. Donanemab binds to a form of amyloid beta that is only present in brain amyloid plaques, triggering the immune system to remove these toxic deposits via microglial-mediated phagocytosis.

Donanemab has been shown to significantly reduce the amount of amyloid in the brain. In the TRAILBLAZER-ALZ 2 trial, patients with early symptomatic Alzheimer disease were randomly assigned to receive donanemab or placebo. At 76 weeks, brain amyloid plaque levels reduced by 87.0 Centiloids (95% CI, −88.90 to −85.17) in the donanemab group compared to a reduction of 0.67 Centiloids (95% CI, −2.45 to 1.11) in the placebo group. Amyloid clearance (defined as a level of <24.1 Centiloids) was achieved in 76.4% (95% CI, 72.87%-79.57%) of the donanemab group and 0.3% (95% CI, 0.08%-1.05%) of the placebo group.

The gradual reduction in plaque load is thought to slow the progression of Alzheimer’s disease. The primary outcome of the TRAILBLAZER-ALZ 2 trial was the change in the integrated Alzheimer Disease Rating Scale (iADRS). This score combines assessments of cognition and daily function, providing a better measure of clinical efficacy.. The majority of participants (68%) in this study was classified as having low/medium tau pathology, while the remainder (32%) had high tau pathology. Donanemab was associated with a 35.1% slowing of disease progression in the low/medium tau population compared to placebo. In the combined population, disease progression was slowed by 22.3%. A slowing of clinical progression that is greater than 20% is considered clinically meaningful.

Donanemab is administered as an intravenous infusion every four weeks. It is recommended to continue treatment until amyloid plaques are cleared, up to a maximum of 18 months. If monitoring of amyloid plaques is not possible, 18 months is the recommended treatment duration.

Safety concerns

Anti-amyloid antibodies, such as donanemab, can cause amyloid-related imaging abnormalities (ARIA). These events can be classified as ARIA with oedema (ARIA-E) or ARIA with hemosiderin deposition (ARIA-H).

While ARIA events are usually asymptomatic, serious events can occur. Major intracerebral haemorrhages, including some fatal events, have been reported in patients treated with this class of medications. Focal neurologic deficits similar to those observed in an ischaemic stroke have also been associated with ARIA-E.

In the TRAILBLAZER-ALZ 2 trial, ARIA-E and ARIA-H occurred in 24.0% and 19.7% of the donanemab group, respectively (compared to 1.9% and 7.4% of the placebo group). Around a quarter of the ARIA-E events in the donanemab group were symptomatic. Serious symptoms of ARIA-E were reported in 1.5% of patients receiving donanemab.

While donanemab is approved for use in Australia, it is not subsidised on the PBS. The Pharmaceutical Benefits Advisory Committee (PBAC) recently rejected an application for PBS listing citing the small and uncertain benefits along with the high burden of the treatment on patients and the health system.

Prevention

Ageing is considered the main risk factor for dementia. While this is a non-modifiable risk factor, it is thought that 45% of a person’s dementia risk is potentially modifiable by addressing the following risk factors:

• Less education
• Hearing loss
• Hypertension
• Smoking
• Obesity
• Depression
• Physical inactivity
• Diabetes
• Excessive alcohol consumption
• Traumatic brain injury
• Air pollution
• Social isolation
• Untreated vision loss
• High LDL cholesterol.

In the 2024 update of the Lancet Commission on dementia, specific actions are provided to address these risk factors. These actions include individual interventions as well as population-based policy change. It has been demonstrated that engaging in protective factors (e.g. social engagement, cognitively stimulating work) and avoiding risk factors (e.g. excessive alcohol consumption) can prevent or significantly delay a large proportion of dementia cases.

Summary

While there is no cure for dementia, there are strategies (pharmacological and non-pharmacological) that can help manage symptoms and may improve quality of life for people living with dementia.

Medications provide modest benefits for dementia but may be associated with serious adverse effects. Therefore, minimising modifiable risk factors should be considered an important strategy to prevent dementia.

Further information: Dementia Australia offers professional development and training courses for healthcare workers supporting people living with dementia.