In this study the performance in memory, abstract-visuospatial and language domains over time declined in individuals free of dementia or cognitive impairment at baseline, and increased age was associated with lower scores in all cognitive domains. Current smoking was associated with faster cognitive decline only in memory among subjects older than 75 years without the APOE-ε4 allele. Past smoking was not associated with poor performance in any cognitive domain at any specific time interval, or decline in any domain over time.
The mechanisms by which smoking affects cognitive performance remain unclear. It has been proposed that smoking may increase the risk of dementia through cerebrovascular disease 35
, or that it augments cholinergic metabolism by upregulation of cholinergic nicotinic receptors in the brain 36
. Cholinergic deficits, characterized by reduced levels of acetylcholine and nicotinic receptors, are found in AD 37
. However, nicotine increases acetylcholine release, elevates the number of nicotinic receptors, and improves attention and information processing 38
. These actions may be opposed by high oxidative stress caused by smoking, which is a putative mechanism in AD 39,40
, through generation of free radicals and affecting inflammatory-immune systems, which activate phagocytes that generate further oxidative damage 41
. There is also evidence that smokers have a lower dietary intake of antioxidants compared with nonsmokers 42
Studies examining the role of smoking in cognitive function reported inconsistent results. Several case-control studies suggested that smoking might be related to a lower risk of AD 6
, but prospective studies reported an increased risk of AD 4,5,7
or no association 8-10
Our results are consistent with studies showing an increased risk of AD in current smokers. The main cognitive domain affected in AD is memory 43,44
and it seems reasonable to postulate that if smoking is related to a higher risk of AD, it must be related to decline in memory.
We found that the association between current smoking and AD was restricted to persons older than 75 years of age. The risk of AD increases with age 43
, and our finding may indicate that smoking increases the risk of memory decline in those who are more likely to develop memory decline. We also found that the association between current smoking and faster cognitive decline was confined to subjects without the APOE-ε4 allele. This is in agreement with two previous studies reporting an increased risk of AD in participants without the APOEε4 allele. The presence of the APOE-ε4 allele increases the risk of AD 45
. Older individuals with the APOE-ε4 may have an increased risk of memory decline 46
in a such a way that other risk factors may not increase the risk further. Another potential explanation for the lack of association of smoking to memory decline in APOEε-4 carriers is that smoking may be harmful through vascular mechanisms, but also partly beneficial in APOEε4 carriers. This hypothesis is supported by previous findings that persons with AD who are APOEε4 carriers have fewer nicotinic receptor binding sites and lower activity of choline acetyltransferase than non-carriers 47
. Smoking could counterbalance the APOEε4 associated impairment by facilitating the release of acetylcholine or increasing the density of nicotine receptors.
There are several potential alternative explanations for our findings. One is chance, particularly in the context of multiple comparisons. However, our findings were not unexpected, are consistent with our previous findings relating current smoking to a higher risk of AD 5
, and consistent with other studies as described in the previous paragraph; these facts make chance due to multiple comparisons an unlikely explanation for our findings 48
. Another potential explanation is bias. For example, that only subjects with preclinical AD reported smoking while subjects that would not develop AD did not. This type of reporting bias seems unlikely and we excluded cases of incipient dementia or cognitive impairment that could have influenced our results. Another potential explanation is confounding. For example, if lower education is related to current smoking, and persons with lower education are more likely to be diagnosed with AD, then it is possible that a relation between smoking and cognitive decline could be due to confounding by socioeconomic factors. We adjusted for years of education and ethnicity as markers of socioeconomic status to account for this possibility. Finally, another explanation is genetic confounding. It may be that smoking propensity is associated with a gene or combination of genes (but not APOE) which in turn is associated with the risk of AD. Therefore, it is possible that smoking is related to other behaviors related to poor health or genetic factors, that in turn may increase the risk of AD, that we could not adjust for, and we cannot eliminate the possibility of lack of control for unknown confounders as a potential explanation for our findings.
This study has several strengths. We had a comprehensive and sensitive neuropsychological battery validated for use in the communities of northern Manhattan 18
. We also excluded from our analyses persons with dementia and cognitive impairment without dementia at baseline that may have biased the analyses, and had several evaluation time points that allowed prospective analyses.
The main limitation of this study is the ascertainment of smoking status. We relied on self-report by participants, and did not have information on quantity or duration of smoking. Assuming random misclassification of smoking, this would have resulted in the underestimation of the association between smoking and cognitive impairment. Given that we excluded subjects with dementia and with cognitive impairment without dementia at baseline from the analyses, it seems unlikely that the report of smoking status was influenced by cognitive status.
It is important to point out that this study was conducted in an elderly multiethnic community in an urban setting with a high prevalence of risk factors for morbidity and mortality, such as diabetes and hypertension. Persons who dropped out of the study before completing at least three follow-up visits were at baseline older, less educated and had a higher prevalence of vascular risk factors than those who remained in the study. Also, smoking is related to higher mortality from various causes, and it is possible that many smokers would have demonstrated cognitive decline had they not died prior to inclusion in this cohort. Thus, there are important biases related to the sample of this study that should be taken into account in the interpretation and generalization of these findings.