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0000000000005290
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Helena.Horder@neuro.gu.
Neurology 2018;0:e1-e8. doi:10.1212/WNL.0000000000005290 se
Objective Editorial
To investigate whether greater cardiovascular fitness in midlife is associated with decreased Fitness and dementia risk:
dementia risk in women followed up for 44 years. Further evidence of the
heart-brain connection
Methods Page 675
A population-based sample of 1,462 women 38 to 60 years of age was examined in 1968. Of
these, a systematic subsample comprising 191 women completed a stepwise-increased maximal
ergometer cycling test to evaluate cardiovascular fitness. Subsequent examinations of dementia
incidence were done in 1974, 1980, 1992, 2000, 2005, and 2009. Dementia was diagnosed
according to DSM-III-R criteria on the basis of information from neuropsychiatric examina-
tions, informant interviews, hospital records, and registry data up to 2012. Cox regressions were
performed with adjustment for socioeconomic, lifestyle, and medical confounders.
Results
Compared with medium fitness, the adjusted hazard ratio for all-cause dementia during the
44-year follow-up was 0.12 (95% confidence interval [CI] 0.03–0.54) among those with high
fitness and 1.41 (95% CI 0.72–2.79) among those with low fitness. High fitness delayed age at
dementia onset by 9.5 years and time to dementia onset by 5 years compared to medium fitness.
Conclusions
Among Swedish women, a high cardiovascular fitness in midlife was associated with a decreased
risk of subsequent dementia. Promotion of a high cardiovascular fitness may be included in
strategies to mitigate or prevent dementia. Findings are not causal, and future research needs to
focus on whether improved fitness could have positive effects on dementia risk and when during
the life course a high cardiovascular fitness is most important.
From the Neuropsychiatric Epidemiology Unit (H.H., L.J., X.G., S.K., S.Ö., I.S.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health–AGECAP,
and Department of Clinical Neuroscience (G.G.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
The Article Processing Charge was funded by the Swedish Research Council.
This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. e1
Glossary
CI = confidence interval; FINGER = Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability;
PPSW = Prospective Population Study of Women; RCT = randomized controlled trial.
Systematic reviews and meta-analyses of observational studies 1,462 women were examined (participation rate 90%). The
constantly link physical activity to preserved cognitive func- details and procedures for the examination of the original
tioning and decreased risk for dementia.1–3 These studies are sample have been described elsewhere.13 A systematic sub-
limited by reliance on self-reported physical activity and not sample (born on the sixth day of uneven months, e.g., January,
objectively assessed fitness. Thus, it remains unclear whether March, etc) were admitted to an exercise test, and 191 took
the association between physical activity and dementia is part (response rate 81%): 29 who were 38 years, 41 who were
mediated by social and cognitive stimulation rather than by 46 years, 37 who were 50 years, 47 who were 54 years, and 37
level of physical fitness. Furthermore, most studies are con- who were 60 years of age.14 Follow-ups for dementia di-
ducted in people >60 years of age at baseline, and few have agnoses were performed in 1974 to 1975 (n = 174, 8 had died,
a follow-up of >20 years (mean follow-up 3–7 years), making 9 refused), 1980 to 1981 (n = 147, 20 had died, 24 refused),
causal inferences difficult.4–6 1992 to 1993 (n = 99, 57 had died, 35 refused), 2000 to 2001
(n = 68, 92 had died, 31 refused), 2005 to 2006 (n = 46, 118
Aerobic exercise programs aiming at improving cardiovascular had died, 27 refused), and 2009 to 2010 (n = 13, 151 had died,
fitness seem to have moderate effects on cognitive function 27 refused). Cases of dementia were also identified via the
among healthy older person.5,7 However, current data from Swedish Hospital Discharge Register until December 2012.
randomized controlled trials (RCTs) are insufficient to show
that these improvements are due to improved cardiovascular Participants in the exercise test did not differ from the total
fitness.5 sample in age or in cumulative dementia incidence (23.0% vs
22.1%, p = 0.780).
Presently, no RCTs and very few long-term prospective
studies have been able to relate fitness to dementia incidence. Standard protocol approvals, registrations,
The US Cooper Center Longitudinal Study recently reported and patient consents
that a high midlife fitness, assessed by a maximal treadmill test, The Ethics Committee of the University of Gothenburg ap-
was associated with lower risk of developing dementia over proved the study. All women gave informed consent to par-
a mean follow-up period of 24 years.8 Furthermore, 1 large ticipate in accordance with the provisions of the Declaration
register study among men in Sweden reported that low car- of Helsinki.
diovascular fitness, assessed with a bicycle ergometer test at 18
years of age, was associated with an increased risk of early- Work capacity
onset (<60 years) dementia.9 This is interesting because the Cardiovascular fitness was tested at baseline in 1968 by
etiology of early-onset dementia is supposed to have strong a stepwise-increased ergometer cycling test until exhaustion
genetic components. Finally, 1 population study from Finland that was supervised by a physician. Details on the full pro-
found that poor self-rated fitness in mid to late life was as- cedure and exclusion criteria have been described pre-
sociated with increased dementia risk over 25 years of follow- viously.14 Briefly, after initial submaximal tests of 6 minutes on
up.10 Thus, there is a need for studies that examine objective 200 kilopond m/min (32 W) and 400 kilopond m/min (64
fitness before old age with follow-up of dementia until very W), the test was interrupted for 5 minutes before the women
old age. were brought to maximal workload. The level of maximal
workload was chosen on basis of the results from the pre-
Midlife has been suggested as a “sensitive period” for the effect ceding submaximal test with the aim of achieving an ap-
of cardiovascular risk factors on dementia.11,12 We therefore proximate working time of 6 minutes before voluntary fatigue.
tracked dementia incidence for a period of 44 years among If the person had not reached her limit of exhaustion, the
women enrolled in the Prospective Population Study of workload was increased by an additional 50 to 100 kilopond
Women (PPSW) who performed a test of maximal cardio- m/min toward the end of the test. During the period of
vascular fitness in midlife. maximal work, heart rate and ECG were registered every
minute, blood pressure was registered after 1 and 2 minutes,
and respiratory frequency and perceived exertion according to
the Borg-scale15 were noted after 3 minutes and then every
Methods minute. The maximal exercise test aimed at arriving at maxi-
The study is part of the PPSW, which was initiated in 1968.13 mal subjective exhaustion as indicated by the Borg scale15;
Women born in 1908, 1914, 1918, 1922, and 1930 were altogether, 93% perceived their maximal load as strenuous
systematically sampled from the Swedish Population Register (scale point ≥15) and half of the participants as very, very
on the basis of specific birth dates. Among those sampled, strenuous (scale point 19–20).14 The term peak workload is
Age, mean (SD), y 50.2 (7.0) 52.3 (6.7) 49.6 (6.9) 48.6 (7.0) 0.225
Compulsory education only, n (%) 132 (69) 44 (75) 60 (65) 28 (70) 0.530
Wine consumption: never drinker, n (%) 106 (56) 40 (68) 50 (54) 16 (40) 0.008
Hypertension (>140/90 mm Hg) or treatment, n (%) 93 (49) 40 (68) 41 (45) 12 (30) <0.001
Systolic blood pressure, mean (SD), mm Hg 138.5 (24.2) 148.6 (24.8) 137.1 (24.3) 126.8 (16.4) <0.001
Diastolic blood pressure, mean (SD), mm Hg 84.6 (11.4) 87.2 (12.9) 84.6 (11.1) 80.6 (8.4) 0.028
Body mass index, mean (SD), kg/m2 24.6 (4.0) 24.7 (4.8) 24.3 (3.4) 24.5 (4.4) 0.902
Weight, mean (SD), kg 65.4 (11.4) 64.9 (11.7) 65.0 (8.5) 67.0 (16.0) 0.590
Height, mean (SD), cm 163.5 (5.6) 162.1 (4.9) 163.8 (5.6) 164.9 (6.4) 0.163
Cholesterol, mean (SD), mmol/L 7.1 (1.8) 7.1 (1.2) 7.2 (2.3) 6.8 (1.0) 0.303
Triglycerides, mean (SD), mmol/L 1.2 (0.8) 1.2 (0.4) 1.3 (1.1) 1.2 (0.6) 0.558
Diabetes mellitus until 2001, n (%) 15 (8) 4 (7) 8 (9) 3 (8) 0.853
Myocardial infarction until 2001, n (%) 25 (13) 9 (15) 8 (9) 8 (20) 0.655
Persons still alive in 2012, n (%) 28 (14.7) 6 (10.1) 15 (16.3) 7 (17.5) 0.279
Age at death, mean (SD), y 80.4 (11.2) 80.1 (10.6) 80.3 (11.0) 81.3 (12.8) 0.882
Fitness is assessed by a stepwise-increased ergometer cycling test until exhaustion. Low fitness = crude peak workload <72 W or test interrupted at <64 W;
medium fitness = crude peak workload 80 to 112 W; and high fitness = crude peak workload ≥122 W. The p value for trend is by χ2 test for dichotomous data
and analysis of variance for continuous data.
population are presented in table 1. Women with high fitness Table 2 shows the relation between peak workload and cu-
more often had their own income and higher wine con- mulative dementia incidence. It is noteworthy that the de-
sumption and less often had hypertension compared to those mentia incidence among those who interrupted the test at
with medium or low fitness. Mean age at death was 80.4 years, submaximal workload was 45%.
and 15% were still alive at the end of the study. We found no
statistical difference between the groups in age at death or When categorized into 3 fitness groups based on the peak
survival. workload, the cumulative incidence of all-cause dementia was
32% for low, 25% for medium, and 5% for high fitness. Similar
In total, 44 women (23.0%) developed dementia during 5,544 results were seen for peak workload/body weight (table 3).
person-years of follow-up from 1968 to 2012. The mean
follow-up period was 29 years. Diagnoses included 20 cases of The mean time to dementia onset was 5 years longer for those
pure Alzheimer dementia, 8 of vascular dementia, 12 of mixed with high compared to those with medium peak workload.
dementia, and 4 of other dementias. Altogether, 28 cases of The mean age at dementia onset was 11 years higher among
dementia were diagnosed on the basis of information from the those with high peak workload compared to those with me-
examinations, and another 16 (36%) were diagnosed from dium peak workload (table 3).
registers and case records. The mean time to dementia onset
from midlife examination was 29.0 years, and the mean age at Compared to medium peak workload, the adjusted hazard
dementia onset was 80.5 years. ratio for all-cause dementia was 0.12 (95% confidence interval
Table 3 Dementia incidence according to midlife cardiovascular fitness among women followed up for up to 44 years
from 1968 to 2012 (n = 191)
All-cause dementia Alzheimer disease Mean (SD) time to dementia onset Mean (SD) age at
incidence, n (%) incidence, n (%) from midlife examination, y dementia onset, y
a a b
High fitness (n = 40) 2 (5) 0 (0) 33 (2) 90 (3)
b a b
High fitness (n = 44) 6 (14) 1 (2) 33 (11) 79 (11)
Fitness assessed by a stepwise-increased ergometer cycling test until exhaustion. Crude peak workload: low fitness = peak work load ≤80 W; medium fitness =
peak work load 88 to 112 W; and high fitness = peak work load ≥120 W. Peak work load/body weight: low fitness = stanine score 1 to 3; medium fitness =
stanine score 4 to 6; and high fitness stanine score 7 to 9.
a
For trend between fitness groups, p < 0.01 (χ2 for proportions and analysis of variance for dichotomous).
b
For trend between fitness groups, p < 0.05 (χ2 for proportions and analysis of variance for dichotomous).