Alzheimer's Disease 15 Dec, 2022 Read Time: 3 mins

Preventive and new therapeutic strategies

Current progress in preventive and new therapeutic strategies for Alzheimer’s disease were presented by experts at EAN 2022. Topics discussed were modifiable risk factors, multidomain interventions, and the 143 agents in Phase 1, 2, and 3 clinical trials.

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 proteosis.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

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References

  1. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413–46.
  2. Hafdi M, Hoevenaar-Blom MP, Richard E. Multi-domain interventions for the prevention of dementia and cognitive decline. Cochrane Database Syst Rev. 2021;11(11):CD013572.
  3. Cummings J, Lee G, Nahed P, et al. Alzheimer's disease drug development pipeline: 2022. Alzheimers Dement (N Y). 2022;8(1):e12295.
  4. Pereira JB, Janelidze S, Ossenkoppele R, et al. Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer's disease. Brain. 2021;144(1):310–24.
  5. Bellenguez C, Küçükali F, Jansen IE, et al. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022;54(4):412–36.
  6. van Dyck CH. Anti-amyloid-β monoclonal antibodies for Alzheimer's disease: Pitfalls and promise. Biol Psychiatry. 2018;83(4):311–19.
  7. Salloway S, Chalkias S, Barkhof F, et al. Amyloid-related imaging abnormalities in 2 Phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol. 2022;79(1):13–21.