Experimental laboratory models as tools for understanding modifiable dementia risk

Abstract

Experimental laboratory research has an important role to play in dementia prevention. Mechanisms underlying modifiable risk factors for dementia are promising targets for dementia prevention but are difficult to investigate in human populations due to technological constraints and confounds. Therefore, controlled laboratory experiments in models such as transgenic rodents, invertebrates and in vitro cultured cells are increasingly used to investigate dementia risk factors and test strategies which target them to prevent dementia. This review provides an overview of experimental research into 15 established and putative modifiable dementia risk factors: less early-life education, hearing loss, depression, social isolation, life stress, hypertension, obesity, diabetes, physical inactivity, heavy alcohol use, smoking, air pollution, anesthetic exposure, traumatic brain injury, and disordered sleep. It explores how experimental models have been, and can be, used to address questions about modifiable dementia risk and prevention that cannot readily be addressed in human studies. HIGHLIGHTS: Modifiable dementia risk factors are promising targets for dementia prevention. Interrogation of mechanisms underlying dementia risk is difficult in human populations. Studies using diverse experimental models are revealing modifiable dementia risk mechanisms. We review experimental research into 15 modifiable dementia risk factors. Laboratory science can contribute uniquely to dementia prevention.

Keywords: dementia; experimental model; laboratory research; modifiable risk factor; prevention.

FIGURE 1

Modifiable dementia risk factors and examples of experimental laboratory models which are used to study them. For more detail on specific models see Table S1. ^# Potential modifiable risk factors not recognized in Lancet commission review. Equivalence of human and rodent life stages is approximate only, adapted from Ref. , Figure created with BioRender.com. iPSCs, induced pluripotent stem cells; mo, months; yrs, years.

FIGURE 2

Interrelatedness of modifiable dementia risk factors across the lifespan. PAF estimates (in circles), communality estimates (in rectangles) and life stages of dementia risk (colored) were derived from Ref. whose data came predominantly from high‐income countries and, whose data came from low‐ and middle‐income countries. ^# These risk factors were not included in Ref. or Ref. and timing and extent of risk effects are currently unclear; ^&These risk factors were included in Ref. but not Ref. Blue = early life, green = mid‐life, red = later‐life. Dotted lines indicate overlap between dementia risk factors in laboratory animal models of dementia. Figure created with BioRender.com. PAF, population attributable fraction.