Cumulative Smoking Exposure In The Non-Demented Older People And The Risk Of Cognitive Decline (NEDICES)

doi:10.21203/rs.3.rs-1451270/v1

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Cumulative Smoking Exposure In The Non-Demented Older People And The Risk Of Cognitive Decline (NEDICES)

https://doi.org/10.21203/rs.3.rs-1451270/v1

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Background: Whether cumulative smoking exposure is a risk factor for cognitive decline among older adults remains majorly unresolved. We assessed whether cumulative smoking exposure in non-demented older people was associated with a higher risk of cognitive decline.

Methods: Baseline cigarette smoking habits were assessed in 2,624 non-demented elderly (≥65 years) Spanish participants. A 37-item version of the Mini-Mental State Examination (MMSE) was administered at two visits (baseline and follow-up, approximately three years later). Change in 37-MMSE (baseline 37-MMSE score − follow-up 37-MMSE score) was divided into tertiles (lower tertile ≥2 points improvement in score, higher tertile ≥2 point decline in score). We dichotomized this variable into higher (cognitive decline) vs. middle and lower tertiles for the current analyses.

Results: Any cumulative smoking exposure, regardless of intensity, was associated with a higher risk of cognitive decline, with a non-linear dose-response. Multivariable-adjusted hazard ratios for higher risk of cognitive decline were 1.00 (reference) in the never smokers, 1.32 (95% confidence interval 1.0-1.74) in the lower tertile of pack-years (<19), 1.55 (1.15-2.07) in the middle tertile of pack-years (19-47), and 1.83 (1.36-2.47) in the higher tertile of pack-years (>47). Multivariable-adjusted hazard ratios for higher risk of cognitive decline were 1.00 (reference) in the never smokers, 1.37 (1.03-1.83) in former smokers, and 1.57 (1.23-2.02) in current smokers.

Conclusions and relevance: The association between cumulative smoking exposure and cognitive decline in the elderly population was dose-dependent. Results underscore the cognitive health risk of smoking and the potential benefits of quitting it.

Cognitive decline

elderly

epidemiology

population-based study

smoking.

Dementia is currently the seventh leading cause of death and remains one of the major causes of long-term disability and dependency among older people across the globe.[1] Dementia has physical, mental, social, and economic impacts and has a remarkable influence on several aspects of the life of the caregivers, families, and community at large.[2] Despite continuous focused scientific research for decades, no practical therapeutic approach to prevent deterioration has been identified. Unsurprisingly, to prevent the consequences of cognitive decline and dementia, the search for potential predictors is getting much attention nowadays. Vascular diseases have been among the most established risk factors for dementia in the elderly.[3] Smoking in itself is a potent risk factor, even in low doses, for vascular diseases, including stroke,[4–6] which forms a basis of the relationship between smoking and dementia. Observational studies reveal a consistent association between current smoking status and dementia; however, current smoking and cognitive decline are less consistent.[7–10]

Prospective population-based studies are preferential when investigating risk factors for cognitive decline.[11, 12] The few prospective population-based studies addressing the association between smoking in the elderly population and cognitive decline have conveyed discrepant results.[8, 10, 13, 14] Besides, in these previous studies, unmeasured confounders, which are pretty prevalent and well-known to be associated with cognitive decline in older people, e.g., sedentary lifestyle,[15] depressive symptoms,[16] and use of medications that can potentially affect cognitive function (e.g., anxiolytics, stimulants, antipsychotics, anti-depressants, antihistamines, or antiepileptic drugs),[17] may have influenced the results. Therefore, whether cumulative smoking exposure is a risk factor for cognitive decline among older people remains majorly unresolved. The authors, therefore, tested the hypothesis that the higher the lifelong exposure to smoking among non-demented older persons, the higher the risk of cognitive decline. To address this question, we used data from the Neurological Disorders in Central Spain (NEDICES) study, in which participants were prospectively evaluated at two times points separated by three years.[18–20]

Study population

Data for these analyses were derived from the NEDICES study, a longitudinal, population-based survey of the prevalence, incidence, and determinants of primary age-associated conditions of the elderly.[18–20] Detailed accounts of the study population and sampling methods have been published.[18–20]

The survey area consisted of three communities: (1) Las Margaritas (approximately 14,800 inhabitants), a working-class neighborhood in Getafe (Greater Madrid); (2) Lista (approximately 150,000 inhabitants), a professional-class neighborhood in Central Madrid, and (3) Arévalo (approximately 9,000 inhabitants), the agricultural zone of Arévalo County (125 km northwest of Madrid).[18–20] Up-to-date residents list was generated from population registers. In each community, survey eligibility was restricted to residents aged 65 years or older who were present there on December 31, 1993, or during six or more months of 1993.[18–20] Eligible persons who had moved away from the survey area were not traced. In Margaritas and Arévalo, every eligible subject was to be screened.[18–20] However, because of the large number of elderly residents in Lista, proportionate stratified random sampling was used to select subjects for screening.[18–20]

Study evaluation

Briefly, at the time of their baseline assessment (1994–1995), 5,278 elderly subjects were interviewed using a 500-item screening questionnaire that assessed demographic factors and medical conditions.[18–20] Data were collected on demographics, current medications, and medical conditions during the face-to-face interview.[18–20] Subjects were asked to bring all medications taken in the past one week to the clinic, where the interviewer recorded the name and dose.[18–20] We assessed depressive symptoms by self-report, using a single screening question (‘Do you suffer from depression?’). The same approach has been used in previous population-based studies of depression.[21, 22] A comorbidity index was calculated based on the presence of the following conditions, according to a published comorbidity score developed in ambulatory care settings: atrial fibrillation, cancer, chronic obstructive pulmonary disease, depression, dementia, diabetes, epilepsy (treated), heart failure, myocardial infarction, psychiatric disorders, renal disease, and stroke.[23] To assess sleep duration, each participant was asked to indicate their "total hours of actual sleep in 24 hours ".[24, 25] Participants indicated their typical total daily sleep duration as the sum of nighttime sleep and daytime napping.[24, 25] Physical activity was classified as sedentary, light, moderate, and high.[15] Details of the measurement of physical activity in the NEDICES study have been reported elsewhere.[15]

A Spanish adaptation of the Pfeffer Functional Activities Questionnaire was administered to participants.[26] This version includes 11 items; the total score for the 11 items ranges from 0 (completely independent) to 33 (completely dependent).[26] Participants were asked to rate their current health using a 5-point scale using the question "In general terms, how would you describe your health: excellent, good, fair, poor, or very poor?".[27, 28] There were a small number of subjects in several categories. Hence, as in several previous studies, we collapsed response options into three categories.[28, 29] These three categories were very good/good, fair, and poor/very poor.[28, 29]

The same methods were used during the second (i.e., follow-up) evaluation (1997–1998).

As described,[30, 31] a 37-item Mini-Mental State Examination (37-MMSE) was administered at both the baseline assessment (1994–1995) and the follow-up assessment (1997–1998). This was a Spanish adaptation of the standard MMSE. [30, 31] It included all of the standard MMSE items and three additional items: (1) an attention task, i.e., "say 1, 3, 5, 7, 9 backward", (2) a visual order, i.e., a man raising his arms, and (3) a simple construction task, i.e., copying two overlapping circles.[30, 31]

The diagnosis of dementia was assigned using the Diagnostic and Statistical Manual of Mental Disorders (DSM)–IV criteria[32] and required evidence of cognitive impairment and impairment in social or occupational function.

Final selection of participants

Of the 5,278 participants evaluated at baseline, we excluded 467 participants with dementia, including 306 with dementia diagnosed at baseline evaluation (1994–1995) (i.e., prevalent cases),[33] and 161 who developed dementia by the follow-up evaluation (1997–1998) (i.e., incident cases).[34] We further excluded 2,187 participants who were evaluated at baseline because they declined a follow-up assessment or had incomplete follow-up assessments, had died or were unreachable (N = 1,246) or with incomplete 37-MMSE examinations (N = 938) or incomplete smoking status (N = 3).

The final sample of 2,624 was similar to the base sample of 5,278 participants in terms of sex (1,485 [56.6%] vs. 3,040 [57.6%] women, chi-square = 0.72, p = 0.395). However, they were more educated (268 [10.1%] vs. 711 [13.6%] were illiterate, chi-square = 18.58, p < 0.001) and, on average, 1.6 years younger (72.7 ± 5.9 vs. 74.3 ± 7.0 years, t = 11.0, p < 0.001).

Statistical analyses

Statistical analyses were performed in SPSS Version 25.0 (SPSS, Inc., Chicago, IL). None of the continuous variables (age, years of education, drink-years, comorbidity index, body mass index, and Pfeffer Functional Activities Questionnaire total score) was normally distributed (Kolmogorov-Smirnov, p < 0.001), even after log-transformation. Therefore, baseline characteristics scores were compared using Mann–Whitney and Kruskal–Wallis tests. The Chi-square test was applied to determine associations between categorical variables.

For all participants, we calculated baseline pack-years (i.e., packs of cigarettes smoked per day multiplied by years smoked). Pack-years were categorized into tertiles (< 19.0, 19.0–47.0, > 47.0). Participants who had never smoked were coded as having zero pack-years, and they served as the reference group in those analyses, which included all participants. In addition, for other analyses, participants were classified into three groups: never smokers, ex-smokers, and current smokers.

Data on ethanol consumption (average number of drinks consumed per day and duration of consumption in years) were used to compute drink-years.[35, 36] One "drink-year" was defined as the intake of one ethanol drink per day for one year. One drink consisted of one can of beer (360 mL), one glass of wine (120 mL), or 30 mL of liquor.[35, 36]

Change in 37-MMSE (baseline 37-MMSE score − follow-up 37-MMSE score) was divided into tertiles (lower tertile ≥ 2 points improvement in score, higher tertile ≥ 2 point decline in score). We dichotomized this variable into higher (cognitive decline) vs. middle and lower tertiles for the current analyses.

We used Cox proportional-hazards models to estimate hazard ratios (HRs) for the risk of cognitive decline, generating 95% confidence intervals (CIs). The time variable was the years from the first evaluation date (1994 to 1995) to the date of the second evaluation (1997 to 1998). The dependent (outcome) variable was a higher tertile of 37-MMSE change (cognitive decline), with the other two tertiles as the reference group. We considered baseline variables associated with either higher tertile of 37-MMSE change or long-life cumulative smoking exposure. Variables assessed at baseline that we considered included age in years, sex, years of education, sleep duration (≤ 5, 6–8 ≥ 9 hours), drink-years, use of medications that potentially affect cognitive function, comorbidity index, body mass index, depressive symptoms, subjective wellbeing (good/excellent, average and bad/terrible), physical activity (sedentary lifestyle, mild, moderate, and high physical activity), and Pfeffer Functional Activities Questionnaire total score. The exposure variable was pack-years tertiles (< 19.2, 19.2–49.0, > 49.0). The reference group was composed of those who have never smoked (zero pack-years). In other analyses, the exposure variable was the smoking status (ex-smoker and current smoker); the reference group was those who have never smoked.

The 2,624 participants had a mean duration of follow-up of 3.3 years (median = 3.3 years; range = 1.5–4.7 years). There were significant differences in baseline age, years of study, and the Pfeffer Functional Activities Questionnaire total score when participants within the higher tertile of 37-MMSE changed and the remaining tertiles were compared (Table 1).

Table 1

Baseline (1994–1995) demographic and clinical characteristics of participants within the higher tertile of 37-MMSE change vs. those within the remaining tertiles.
	Higher Tertile of 37-MMSE change (N = 850)	Middle and Lower Tertiles of 37-MMSE change (N = 1774)	p-Value
Age in years	73.3 (72.0) ± 6.2	72.4 (71.0) ± 5.7	< 0.001 ^a
Sex (women)	491 (57.8%)	994 (56.0%)	0.402 ^b
Years of education	6.8 (7.0) ± 5.4	7.2 (7.0) ± 5.2	0.018 ^a
Sleep duration (hours per day)* ≤ 5 6–8 ≥ 9	101 (11.9%) 391 (46.2%) 354 (41.8%)	183 (10.4%) 897 (51.0%) 678 (38.6%)	0.06 ^b
Drink-years*	53.1 (13.7) ± 68.9	54.2 (16.5) ± 69.5	0.558 ^a
Use of medications that potentially affect cognitive function	139 (16.4%)	272 (15.3%)	0.501 ^b
Comorbidity index	0.9 (0.0) ± 1.2	0.9 (0.0) ± 1.3	0.994 ^a
Body mass index*	27.8 (27.3) ± 4.9	27.8 (27.2) ± 5.8	0.889 ^a
Depressive symptoms*	210 (24.8%)	424 (24.1%)	0.678 ^b
Subjective wellbeing * Good / very good Normal Bad / very bad	506 (59.8%) 248 (29.3%) 92 (10.9%)	1090 (61.6%) 509 (28.8%) 170 (9.6%)	0.528 ^b
Physical activity* Sedentary lifestyle Mild Moderate High	202 (25.2%) 238 (29.6%) 168 (20.9%) 195 (24.3%)	356 (21.5%) 474 (28.7%) 382 (23.1%) 441 (26.7%)	0.130 ^b
Pfeffer Functional Activities Questionnaire total score*	1.4 (0.0) ± 3.4	1.2 (0.0) ± 2.9	0.024 ^a
^a Mann-Whitney test; ^b Chi-square test.
*Data on some participants were missing.
Mean (median) ± standard deviation and frequency (%) are reported.
MMSE = Mini-Mental State Examination.

Baseline characteristics of the participants according to their long-life cumulative smoking exposure are shown in Table 2. At baseline, those who never smoked were older, less educated, drank less, used more medications that potentially affected cognitive function, scored higher in Pfeffer Functional Activities Questionnaire, and rated their health as bad / very bad. In addition, they were likely to be women with a higher body mass index and more depressed. Those in the highest tertile of pack-years had more comorbidities and a more sedentary lifestyle. In addition, they were likely to be long sleepers.

Table 2

Baseline (1994–1995) demographic and clinical characteristics of participants (N = 2,624) according to their long-life cumulative smoking exposure.
	Never smokers (N = 1,592)	Lower tertile of pack-years (< 19) (N = 344)	Middle tertile of pack-years (19–47) (N = 345)	Higher tertile of pack-years (> 47.0) (N = 343)	p value
Age in years	73.0 (72.0) ± 6.0	72.9 (71.0) ± 6.0	71.3 (70.0) ± 5.3	72.3 (71.0) ± 5.5	< 0.001 ^a
Sex (women)	1348 (84.7%)	85 (24.7%)	34 (9.9%)	18 (5.2%)	< 0.001 ^b
Years of education	6.5 (7.0) ± 4.5	8.1 (8.0) ± 5.8	8.3 (8.0) ± 6.8	7.2 (7.0) ± 5.7	< 0.001 ^a
Sleep duration (hours per day)* ≤ 5 6–8 ≥ 9	204 (12.9%) 781 (49.5%) 592 (37.5%)	25 (7.3%) 179 (52.0%) 140 (40.7%)	25 (7.3%) 183 (53.4%) 135 (39.4%)	30 (8.8%) 145 (42.6%) 165 (48.5%)	< 0.001 ^b
Drink-years*	29.9 (0.0) ± 53.3	76.6 (63.4) ± 67.7	90.3 (102.0) ± 73.3	105.3 (114.0) ± 80.1	< 0.001 ^a
Use of medications that potentially affect cognitive function	290 (18.2%)	45 (13.1%)	41 (11.9%)	35 (10.2%)	< 0.001 ^b
Comorbidity index	0.8 (0.0) ± 1.2	0.9 (0.0) ± 1.2	1.0 (0.0) ± 1.3	1.2 (1.0) ± 1.4	< 0.001 ^a
Body mass index*	28.3 (27.5) ± 6.4	26.9 (26.8) ± 3.8	27.3 (27.2) ± 4.2	27.0 (26.8) ± 3.6	< 0.001 ^a
Depressive symptoms*	449 (28.4%)	72 (21.2%)	55 (16.0%)	58 (17.0%)	< 0.001 ^b
Subjective wellbeing* Good / very good Normal Bad / very bad	905 (57.0%) 495 (31.2%) 189 (11.9%)	232 (68.2%) 85 (25.0%) 23 (6.8%)	241 (70.0%) 79 (23.0%) 24 (7.0%)	218 (63.7%) 98 (28.7%) 26 (7.6%)	< 0.001 ^b
Physical activity* Sedentary lifestyle Mild Moderate High	312 (21.1%) 429 (28.9%) 326 (22.0%) 415 (28.0%)	76 (23.2%) 90 (27.5%) 75 (22.9%) 86 (26.3%)	76 (23.2%) 99 (30.3%) 78 (23.9%) 74 (22.6%)	94 (29.4%) 94 (29.4%) 71 (22.2%) 61 (19.1%)	0.028 ^b
Pfeffer Functional Activities Questionnaire total score*	1.5 (0.0) ± 3.3	0.8 (0.0) ± 2.3	0.9 (0.0) ± 2.4	1.0 (0.0) ± 2.8	< 0.001 ^a
^a Kruskal–Wallis test; ^b Fisher's exact test or Chi-square test.
*Data on some participants were missing. Mean (median) ± standard deviation and frequency (%) are reported.

Any cumulative smoking exposure, regardless of intensity, was associated with a higher risk of cognitive decline, with a non-linear dose-response. Multivariable-adjusted hazard ratios for higher risk of cognitive decline were 1.00 (reference) in the never smokers, 1.32 (95% confidence interval 1.0 to 1.74) in the lower tertile of pack-years (< 19), 1.55 (1.15 to 2.07) in the middle tertile of pack-years (19–47), and 1.83 (1.36 to 2.47) in the higher tertile of pack-years (> 47) (Table 3). Multivariable-adjusted hazard ratios for higher risk of cognitive decline were 1.00 (reference) in the never smokers, 1.37 (1.03 to 1.83) in former smokers, and 1.57 (1.23 to 2.02) in current smokers (Table 3).

Table 3

Risk of cognitive decline with multiple adjustments for all variables.
	Cumulative Smoking Exposure				Smoking Status
	Hazard ratio	95% confidence interval	p-value		Hazard ratio	95% confidence interval	p-value
Age in years	1.03	1.01–1.04	< 0.001	Age in years	1.03	1.01–1.04	< 0.001
Women Men	1.60 1.0	1.26–2.03 -	< 0.001	Women Men	1.57 1.0	1.24–1.98 -	< 0.001
Years of education	1.01	1.0-1.03	0.111	Years of education	1.01	1.0-1.03	0.120
Sleep duration (hours) ≥ 9 ≤ 5 6–8 (reference)	0.87 0.98 1.0	0.70–1.07 0.74–1.32 -	0.175 0.918 -	Sleep duration (hours) ≥ 9 ≤ 5 6–8 (reference)	0.86 1.03 1.0	0.70–1.06 0.75–1.34 -	0.172 0.986 -
Drink-years	1.0	0.99-1.0	0.619	Drink-years	1.0	0.99-1.0	0.791
Use of medications that potentially affect cognitive function Yes No (reference)	1.0 1.0	0.80–1.25 -	0.979	Use of medications that potentially affect cognitive function Yes No (reference)	0.99 1.0	0.80–1.25 -	0.999
Comorbidity index	1.01	0.95–1.08	0.659	Comorbidity index	1.01	0.95–1.08	0.628
Body mass index	0.982	0.97-1.0	0.019	Body mass index	0.98	0.97-1.0	0.017
Depressive symptoms Yes No (reference)	1.26 1.0	1.04–1.53 -	0.019	Depressive symptoms Yes No (reference)	1.26 1.0	1.04–1.53 -	0.019
Subjective wellbeing Bad / very bad Normal Good / excellent (reference)	0.83 0.89 1.00	0.64–1.07 0.75–1.06 -	0.160 0.202 -	Subjective wellbeing Bad / very bad Normal Good / very good (reference)	0.84 0.90 1.00	0.65–1.09 0.76–1.07 -	0.188 0.218 -
Physical activity High Moderate Mild Sedentary lifestyle (reference)	0.66 0.67 0.81 1.0	0.49–0.89 0.51–0.87 0.66–0.99 -	0.007 0.003 0.048 -	Physical activity High Moderate Mild Sedentary lifestyle (reference)	0.65 0.66 0.81 1.0	0.48–0.88 0.51–0.87 0.66–0.99 -	0.005 0.003 0.049 -
Pfeffer Functional Activities Questionnaire total score	0.98	0.95–1.01	0.176	Pfeffer Functional Activities Questionnaire total score	0.981	0.95–1.01	0.182
Cumulative Smoking Exposure Higher tertile of pack-years (> 47) Middle tertile of pack-years (19–47) Lower tertile of pack-years (< 19) Never smokers (reference)	1.83 1.55 1.32 1.0	1.36–2.47 1.15–2.07 1.0-1.74 -	< 0.001 0.003 0.048 -	Smoking status Current smokers Former smokers Never smokers (reference)	1.57 1.37 1.00	1.23–2.02 1.03–1.83 -	< 0.001 0.032 -

In this prospective, population-based study, comprised of non-demented elderly Spanish people, we have identified a dose-dependent relationship between lifetime smoking exposure and a higher risk of cognitive decline. We have found the risk to be exponentially more significant between the lower (light smokers), middle (moderate smokers), and higher (heavy smokers) tertiles for pack-years smoked. These results confirm no safe threshold for smoking about the risk of cognitive decline, and even light smokers were at increased risk for future cognitive decline. This study has also identified an increase in the risk of cognitive decline among current smokers versus former smokers. Results of this study strongly underscore the benefit of complete abstinence from smoking, even among light smokers, on cognitive outcomes.

The literature concerning cognitive functioning and smoking has been inconsistent, particularly in the elderly. In a meta-analysis published in 2008, which included 13 studies that assessed cognitive decline and current smoking, the authors had found that seven of those studies demonstrated a significant association with increased risk. The remaining six of those revealed no significant association.[8] The analysis of this meta-analysis deciphered a significant relationship between increased risk of Alzheimer's disease and current smoking, and summary ratios more than one for vascular dementia, dementia unspecified, and cognitive decline, although they were not significant.[8] In the Atherosclerosis Risk in Communities Study, that included 13,002 men and women aged 52–75 years, using a composite cognitive score created from three tests measured at two time points (1996–1998 and 2011–2013), there were no differences in rates of cognitive decline by smoking status.[10] In contrast, in a population-based cohort study of older adults in Saarland, Germany, cognitive function was assessed with a validated telephone-based instrument at the five-year follow-up in a subsample of N = 1,697 participants with a baseline age > 65 years.[13] Current smoking was associated with lower scores in the cognitive assessment.[13] Concerning lifetime exposure, higher cumulative doses of lifetime smoking assessed in pack-years were associated with lower scores in both current and ever smokers compared to never smokers, with associations being stronger in current than in ever smokers.[13] In line with this, in the population-based Rotterdam Study, which included middle-aged and elderly persons, current smoking was related to a decline in global cognition; no evidence for effect modification by APOE ɛ4 genotype on this relation.[14]

Although the current findings suggest that smoking is associated with a higher cognitive decline in the elderly, this association's mechanisms remain incompletely understood. Cerebral small vessel disease burden (the presence of white matter hyperintensities and lacunar infarcts) increases the risk of cognitive decline [37], and it is well known that chronic smoking is associated with white matter hyperintensities [38] and silent cerebral strokes.[39] White matter degeneration is an early and integral component of Alzheimer’s disease and mild cognitive impairment.[40] Smoking may contribute to white matter degeneration by inhibiting the expression of genes needed for myelin synthesis and maintenance and, therefore, could be a key risk factor for several neurodegenerative diseases, including pre-AD stages.[41] Smoking is also associated with hippocampus atrophy, as demonstrated in a large cohort of healthy elderly participants (N = 1111). Current smokers had more significant annualized hippocampus atrophy rates than either non or former smokers, independent of their lifetime tobacco consumption.[42] These findings suggest that chronic smoking exposure is associated with accelerated brain aging.[43]

Using a prospective, population-based design, we demonstrated that lifetime smoking exposure in non-demented community-dwelling elders was associated with an increased risk of cognitive decline. This study provides further evidence of an association between smoking and cognitive decline. More studies are required to elucidate this association in non-demented community-dwelling elders.

Limitations section

This study had a few limitations too. Firstly, while the base sample comprised 5,278 participants, due to the many exclusions, the final sample comprised 2,624, and the final sample, though population-based, in some respects resembled a convenience sample. However, most of the participants had died or were unreachable (N = 1,246) or with incomplete 37-MMSE examinations (N = 938), a fact that commonly occurs in most prospective population-based studies. Secondly, the 37-MMSE is a relatively abbreviated screening tool for cognitive assessment. Applying formal neuropsychological testing would enable future researchers to study these changes more closely. However, even with this relatively simple, abbreviated tool, we established apparent risk differences among smokers compared to the control group. This study also had several strengths. Firstly, the study was population-based, allowing us to assess a group of non-demented people who were unselected for treatment considerations. Secondly, the assessments were conducted prospectively in a standardized manner. Finally, yet importantly, we were able to adjust for the potential confounding effects of several essential factors.

Ethical Approval and Consent to participate

The ethical standards committees approved all procedures on human experimentation at the University Hospitals "12 de Octubre" (Madrid) and "La Princesa" (Madrid). Written (signed) informed consent was obtained from all enrollees.

Consent for publication

Not applicable

Availability of data and materials

The data that supports the findings of this study are available on request from the corresponding author, J.B.-L. The data is not publicly available due to privacy restrictions for the individual participants.

Competing interests

Dr. Benito-León reports no disclosures.

Dr. Ghosh reports no disclosures.

Dr. Contador reports no disclosures.

Dr. Lapeña reports no disclosures.

Dr. Bermejo-Pareja reports no disclosures.

Funding

The Spanish Health Research Agency and the Spanish Office of Science and Technology supported NEDICES. J. Benito-León is supported by the National Institutes of Health, Bethesda, MD, USA (NINDS #R01 NS39422), European Commission (grant ICT-2011-287739, NeuroTREMOR), the Ministry of Economy and Competitiveness (grant RTC-2015-3967-1, NetMD—platform for the tracking of movement disorder), and the Spanish Health Research Agency (grant FIS PI12/01602 and grant FIS PI16/00451).

Authors' contributions

All authors contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by Drs. Benito-León and Bermejo-Pareja. All authors read and approved the final manuscript. The first draft of the manuscript was written by Drs. Benito-León and Ghosh.

Acknowledgments

Not applicable

Authors' information

From the Department of Neurology,¹ University Hospital “12 de Octubre”, Madrid, Spain;

Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas

(CIBERNED),²Spain; Department of Medicine,³Complutense University, Madrid, Spain;

Department of General Medicine,⁴ Burdwan Medical College, Burdwan, West Bengal,

India; Department of Basic Psychology, Psychobiology and Methodology of Behavioral

Sciences,⁵University of Salamanca, Spain.

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No competing interests reported.

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Cumulative Smoking Exposure In The Non-Demented Older People And The Risk Of Cognitive Decline (NEDICES)

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Study evaluation

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