Paths to Alzheimer's disease prevention: from modifiable risk factors to biomarker enrichment strategies.

Alzheimer's disease (AD) represents an increasing worldwide healthcare epidemic. Secondary preventive disease-modifying treatments under clinical development are considered most effective when initiated as early as possible in the pathophysiological course and progression of the disease. Major targets are to enhance clearance and to reduce cerebral accumulation of amyloid, decrease hyperphosphorylation of tau and the generation of neurofibrillary tangles, reduce inflammation, and finally progressive neurodegeneration. Comprehensive sets of biological markers are needed to characterize the pathophysiological mechanisms, indicate effects of treatment and to facilitate early characterisation and detection of AD during the prodromal or even at asymptomatic stages. No primary or secondary preventive treatments for AD have been approved. Epidemiological research, however, has provided evidence of specifically modifiable risk and protective factors. Among them are vascular, lifestyle and psychological risk factors that may act both independently and by potentiating each other. These factors may be substantially impacted by single or multi-domain strategies to prevent or postpone the onset of AD-related pathophysiology. Researchers have recently started the European Dementia Prevention Initiative (EDPI), an international consortium to improve strategies for preventing dementia. EDPI, in particular, includes the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) which aims at optimizing the early identification of subjects at increased risk of late-life cognitive deterioration, and at the evaluation of multi-domain intervention strategies. The ongoing discussion on new diagnostic criteria provided by the International Working Group (IWG), as well as by the recommendations summoned by the National Institute on Aging and Alzheimer's Association (NIA-AA) initiative, has inspired the creation of novel study designs and the definition of earlier target populations for trials in pre- and asymptomatic at-risk and prodromal stages of AD. As a result, a number of promising international prevention trials are currently ongoing. In this review, we critically discuss the main paths to AD prevention through control of modifiable risk factors and lifestyle changes. We will also review the role of biomarkers to identify subgroups of patients who would most likely benefit from secondary prevention strategies, and to evaluate the benefit of treatment in such patients.