Preventive and new therapeutic strategies

Can modifying risk factors prevent dementia?

Twelve modifiable risk factors have been identified for Alzheimer’s disease and it has been estimated that addressing them might prevent or delay the development of Alzheimer’s disease by 40%,¹ said Professor Alina Solomon, Kuopio, Finland.

Addressing modifiable risk factors might prevent or delay the development of dementia by 40%¹

These risk factors are lack of education in early life; hearing loss, brain injury, hypertension, over 21 units of alcohol/week, and obesity in midlife; and smoking, depression, social isolation, physical inactivity, air pollution and diabetes in later life.¹

However, despite the attractiveness and promise of multimodal risk factor interventions as a preventive strategy — and it makes sense to promote them — it is important to manage expectations, said Professor Robert Perneczky, Munich, Germany.

Multimodal interventions are promising but current evidence does not show they prevent dementia²

Based on the small amount of research currently available, a 2021 Cochrane review found two randomized controlled trials that provided high-certainty evidence on dementia incidence. These two studies showed no evidence that multidomain interventions prevent dementia, but there was a signal of improved cognitive function, which was strongest for those receiving cognitive training.²

Therapeutic strategies for Alzheimer’s disease

Mechanisms of action for agents being investigated for dementia are disease-modifying, cognitive enhancement, and improvement of neuropsychiatric manifestations³

Nearly 150 agents are in Phase 1, 2, and 3 trials for treatment of different aspects of dementia,³ said Professor Perneczky. Most of these agents (68%) in Phase 3 studies are disease-modifying compounds, but other mechanisms of action include agents to improve cognition and to treat neuropsychiatric symptoms.³

He commented that of the 21 disease-modifying compounds in Phase 3 studies, 29% are targeting amyloid. Targets for other agents are synaptic plasticity and neuroprotection, neuroinflammation, tau, metabolism, vasculature, neurotransmitters, and proteostasis.³

Professor Perneczky highlighted the following factors to consider for therapeutic strategies:

The main targets for disease-modifying compounds are amyloid, tau and neuroinflammation³

• The roles of amyloid, tau, and synaptic function in dementia are not clear⁴
• Data from a genome-wide association study indicate that amyloid, tau, and neuroinflammation are probably the main relevant targets⁵
• The different forms of amyloid (monomers, oligomers, fibrils) to target need to be considered⁶
• Amyloid-related imaging abnormalities (ARIA) cause symptoms in approximately 25% of patients treated with a monoclonal antibody targeting amyloid and are more common in apolipoprotein ε4 carriers and with higher doses⁷