In the past years, the role of proinflammatory cytokines in healthy aging, mild cognitive impairment and neurodegenerative diseases has attracted much interest. One major proinflammatory cytokine is the tumor necrosis factor (TNF)-α. Animal studies in rodents (TNF knockout mice) suggest that TNF-α deficiency leads to widespread effects in cognitive function throughout the aging process and it appears that low levels of TNF appear essential for normal cognitive function. With respect to TNF-α, the role of several polymorphisms has been examined in Alzheimer's disease (AD) and with regard to cognitive function in healthy aging. These association studies show that the AA genotype of the functional TNF-α -308 A/G single nucleotide polymorphism (SNP) is associated with the risk to develop AD. The -308 G→A SNP (rs1800629) denotes a G (TNF-α1)→A (TNF-α2) single nucleotide exchange. The -308 A allele has been found to confer stronger transcriptional activity than the -308 G allele.

Opposed to pathological aging, there have only been few association studies in healthy aging on the functional TNF-α -308 A/G SNP addressing cognitive function. Such studies are of importance, because genetic differences between elderly individuals might account for the increasing variance in cognitive function during aging and the relevance of differences in genetic factors increasing with age. Existing association studies on the TNF-α -308 A/G SNP in elderly individuals suggest that A-allele carriers revealed compromised memory and motor functions, but elevated speed of processing, compared with the GG genotype group in standard neuropsychological tests. Further results suggest that cortical atrophy in the aging brain is partly mediated via the effects of cytokines. Though these studies provide first evidence for a role of the functional TNF-α -308 A/G SNP in aging, the answers to the questions of the role this SNP plays for attentional processes in healthy elderly individuals and what precise neurophysiological (sub) processes are affected remain elusive.

In aging, attentional selection processes are of particular importance, because these show remarkable declines that might also be causative for the prominent memory deficits observed in elderly individuals. Attentional processes in elderly individuals might also be of special interest in the context of TNF-α, because a couple of studies in young adults suggest that attentional processes are affected by the TNF-α -308 A/G SNP. In this study, the A allele was associated with better attentional processes. This might be possible, because TNF-α facilitates glutamatergic neural transmission, which has frequently been shown to boost attentional selection processes. Moreover, TNF-α has further been suggested to play an important role in neuronal network integrity in the occipital cortex, a region that is of critical importance for visual attentional selection processes. In these regions, cholinergic neural transmission plays an important role in attentional selection processes, too. Studies in animals and humans have shown that α7 nicotinic acetylcholine receptors (nAChRs) are involved in attentional processes and it is known that these receptors are strongly influenced by TNF-α turnover.

Based on the effects of TNF-α turnover of glutamatergic neural transmission, one might assume that the more active -308 A allele renders attentional selection processes more efficient in elderly individuals. However, in the long-term, increased TNF-α signaling leads to apoptotic effects, which is because of its effects on glutamatergic signaling. Moreover, TNF-α impairs cholinergic neural transmission. It is hence more likely that attentional selection processes are compromised in elderly A allele carriers, compared with carriers of the GG genotype, which would also fit with results suggesting that the A allele is a risk factor in pathological aging.

In the current study scientists examined this hypothesis in healthy elderly individuals using a visual search paradigm, which is a challenging task for older subjects. They have analyzed neurophysiological processes using event-related potentials (ERPs) and wavelet decomposition.

In the visual search task, participants usually search for a predefined target stimulus among a number of distractor stimuli that can be more or less similar to the distractor. It has been shown that elderly have more difficulties than young people in selecting and identifying targets, when these are similar to the distractors. This impairment might be because of less efficient inhibitory control leading to enhanced distractibility.

Neurophysiological (ERP) studies in this paradigm found that the P1 and N1, reflecting the allocation of attention, are enhanced when attention is focused on a target item, to improve signal-to-noise ratio. This seems to be mediated via oscillations in the alpha frequency band. In aging, these processes are compromised, reflecting increased effort to discriminate target from distractor at the attended location and disinhibition of sensory flow and subsequent distractibility.

Later components, like the P2, possibly reflect visual feature discrimination. The frontocentral N2 component was also associated with attentional processes like visual novelty, attentional mismatch, cognitive control, and response selection or decision-making in general. These processes are considerably reduced and delayed in elderly individuals.

Following the early attentional selection processes, the P3a appears, which has been suggested to reflect involuntary stimulus-based attention switching. A larger P3a has been related to a larger distractibility or higher effort to resist involuntary shifts of attention toward task-irrelevant stimuli. Age-related decreases were repeatedly found regarding the P3b, which is associated with the allocation of cognitive resources to the relevant task and working memory encoding.

In summary, this study provides evidence that the functional TNF-α -308 A/G is an important modulator of attentional selection processes in healthy elderly individuals. The analysis shows that deficits in elderly A allele carriers emerge early in the stream of processing (i.e., bottom-up attentional selection processes; P1/N1). This induces subsequent distractibility and involuntary allocation of attention toward irrelevant stimuli (P3a). The subsequent response selection mechanisms are also adversely affected in A allele carriers, which besides dysfunctions in attentional selection processes, might contribute to the deficits observed. The TF analyses suggest that allelic variations in the TNF-α -308 A/G polymorphism exert their effects by modulating oscillations in the alpha frequency band at parietal electrode leads in the GG genotype group, whereas the enhanced P3a in A allele carriers seems to be associated with enhanced oscillatory activity in the beta frequency range at frontal leads. On a neurobiological level, these effects of the functional TNF-α -308 A/G polymorphism might be because of the interaction of TNF-α with glutamatergic neural transmission in which TNF-α boosts glutamatergic neural transmission, ultimately contributing to apoptotic cell death in elderly individuals.

Keywords: polymorphism, TNF-α, cognitive function, neurobiology.