Interleukin-1α, interleukin-1β and tumor necrosis factor-α genetic variants and risk of dementia in the very old: evidence from the “Monzino 80-plus” prospective study

Abstract

The association among single nucleotide polymorphisms in inflammatory genes as interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β) or tumor necrosis factor alpha (TNF-α) and dementia has been explored mostly in Alzheimer's disease, while few data addressing their association with dementia in very old people are available. We performed a prospective, door-to-door population-based study of 80 years or older residents in eight municipalities of Varese province, Italy (the Monzino 80-plus study). No difference was found by a cross-sectional approach comparing IL-1α rs1800587, IL-1β rs3087258 and TNF-α rs1799724 genotypic and allelic frequencies between those affected and not affected by dementia. After a 5-year follow-up, the elderly carriers of T-allele of TNF-α rs1799724 were at an increased risk of dementia (p = 0.03). This association was no more significant adjusting for the apolipoprotein E epsilon-4 allele (APOE-ε4, p = 0.26), which was an independent predictor of dementia onset (p = 0.0002). In short, in this Italian population of oldest olds, dementia was associated to the APOE-ε4 allele only.

Chronic inflammation as predictor of 1‐year hospitalization and mortality in elderly population

“…Whether the association of IL-1ra levels with an increased risk of adverse outcomes in elderly subjects represents a direct casual pathway remains unclear. Allelic variations in the regulatory regions of inflammatory cytokine genes have been shown to affect the expression of some cytokines [21]; however, previous investigation suggested that the age-related increase in plasma levels of IL-1ra is not likely to be genetically regulated [22]. The contextual dependence of cytokines cannot be ignored.…”

“…Recent publications are in line with our IL-1ra data: in a population-based sample (aged 25-91 years), Stowe et al [19] proposed that successful ageing is intimately associated with lower levels of IL-1ra. Allelic variations in the regulatory regions of inflammatory cytokine genes have been shown to affect the expression of some cytokines [21]; however, previous investigation suggested that the age-related increase in plasma levels of IL-1ra is not likely to be genetically regulated [22]. Whether the association of IL-1ra levels with an increased risk of adverse outcomes in elderly subjects represents a direct casual pathway remains unclear.…”

Alzheimer’s Disease, Oligomers, and Inflammation

“…Thus, to change the trajectory of the disease early intervention on both flanks is necessary. The contribution of inflammation should be monitored by measuring biological markers in the blood or—though less convenient—in the CSF, in combination with the profiles of genes encoding inflammatory factors [ 142, 143 ] and analysis of the microbioma. Furthermore, as reviewed by Knezevic & Mizrahi [ 144 ], PET analysis offers the possibility of monitoring microglial activation in the brain of AD and MCI subjects, with a series of ligands.…”

Clinical implications of neuropharmacogenetics

“…Controlled randomised clinical trials found no association between APOE genotypes and the clinical response to donepezil [7], galantamine [8; 9], or rivastigmine [10]. Most subsequent open-label label studies or cohorts of patients have confirmed these results [11][12][13][14][15][16][17][18][19][20][21], although some of them reported a better response to cholinesterase inhibitors for APOE-4 allele carriers [22; 23], but also the reverse result [24; 25]. This discrepancy is probably due to different effects of the drugs depending on treatment duration and/or of the stage of the disease [10; 22].…”