Midlife Lung Disease Linked to Later Dementia

Damian McNamara

November 30, 2018

Lung disease or impaired lung function in midlife is tied to an increased risk for subsequent dementia or mild cognitive impairment (MCI), results of a large, longitudinal study show.

Overall, individuals with restrictive lung disease had a 58% higher risk for dementia or MCI compared to their counterparts without the condition. Those with obstructive lung disease had a 33% higher risk.

"These findings reiterate the importance of treating each patient as a whole, taking into account all of their various medical conditions," principal investigator Pamela L. Lutsey, MD, PhD, an associate professor in the Division of Epidemiology and Community Health in the School of Public Health at the University of Minnesota in Minneapolis, told Medscape Medical News.

"Clearly, treating lung disease is inherently important," she added. "Our findings suggest that in addition to improving lung function, treating lung disease may have an added benefit of also possibly reducing dementia risk."

The study was published online November 15 in the American Journal of Respiratory and Critical Care Medicine.

Twenty-Year Follow-up

The current study is not the first to point to an association between pulmonary health and later cognitive impairment. For example, previous research has shown a link between compromised lung function and greater risk for dementia or worsening cognitive ability.

In addition, previous research has shown an association between a history of chronic obstructive pulmonary disease (COPD) and decreasing cognitive performance over time.

"Though these prior studies provide valuable information about the possible role of lung health in dementia risk, they often lacked comprehensive event adjudication or had relatively short follow-up," the researchers note.

To strengthen the evidence-base, the investigators assessed 14,184 individuals who constituted a subpopulation of the prospective, multicenter Atherosclerosis Risk in Communities (ARIC) study and who were assessed from 1987 to 1989.

The average age of the cohort was 54 years at study entry; 55% were women, and 26% were African American. The researchers analyzed baseline spirometry results and later neurocognitive performance using ARIC Neurocognitive Study results from 2011 to 2013.

A total 6471 of 6538 ARIC participants at the 2011-2013 visit underwent a detailed neurocognitive assessment; some underwent neurologic examination and MRI.

The researchers contacted 1461 participants who had been unable or unwilling to attend the in-person examination. These people completed the Modified Telephone Interview for Cognitive Status. To identify incident dementia, the researchers studied hospital diagnostic codes from 1987 to 2013 for the full cohort.

Pulmonary function, determined on the basis of spirometry, included measures of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio as a percentage of age-, race- and sex-specific predicted values and lower limit of normal values.

At baseline, mean FEV1 was 2.82 ± 0.77 L; FVC was 3.80 ± 0.99 L; and the FEV1/FVC ratio was 74.4 ± 8.1%.

At baseline, 17.6% participants had a COPD pattern, 5.9% had restrictive impairment, 33.5% had respiratory symptoms with normal spirometric results, and 43.1% were normal. Men, participants with lower educational attainment, and current smokers were less likely to have normal lung function.

The researchers identified 1407 incident dementia events among participants during a median follow-up of 23 years.

Table 1. Associations With Restrictive Lung Impairment in Midlife*

  Odds Ratio 95% Confidence Interval
Dementia or MCI 1.58 1.14 - 2.19
Dementia 1.16 0.56 - 2.40
MCI 1.71 1.23 - 2.38
Dementia or MCI due to Alzheimer disease 1.79 1.24 - 2.58
Dementia or MCI due to cerebrovascular disease 1.60 0.78 - 3.31
*Comparisons are to participants with normal lung function after adjustment for physical activity, body mass index, cardiovascular risk factors, prevalent cardiovascular disease, and APOE genotype.


Participants who were classified by spirometry into the lowest quartile of percent predicted FEV1 and FVC were more likely to have later MCI and dementia than those in the highest quartile.

Compared to the highest quartile of FEV1%, for example, those in the lowest quartile were at greater risk for dementia or MCI (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.05 - 1.54).

The risks were also higher for dementia or MCI due to Alzheimer's disease (OR, 1.23; 95% CI, 0.98 - 1.54) and for dementia or MCI due to cerebrovascular disease (OR, 1.43; 95% CI, 0.91 - 2.24).

These findings come from a model that was adjusted for physical activity, body mass index, cardiovascular risk factors, prevalent cardiovascular disease, and APOE genotype.

The investigators found stronger associations for participants in the lowest quartile of FVC% compared to participants in the highest quartile for dementia or MCI (OR, 1.24; 95% CI, 1.04 - 1.51), for dementia or MCI due to Alzheimer disease (OR, 1.30; 95% CI, 1.04 - 1.62), and for dementia or MCI due to cerebrovascular disease (OR, 1.51; 95% CI, 0.95 - 2.39). These analyses were adjusted for the same potential confounders.

Interestingly, the FEV1/FVC % predicted was not associated with risk for any of the dementia-related outcomes, regardless of degree of adjustment.

The connections persisted when researchers compared nonsmokers to the overall study population, suggesting that other mechanisms may be driving the risk.

This finding "suggests that impaired lung function is linked to dementia and MCI risk independent of smoking and smoking-related confounders," the researchers note.

Adjusted for race, there was some "suggestive but nonsignificant" results. For example, compared to those with normal lung function, the COPD pattern was most associated with elevated odds for dementia or MCI among black participants (OR, 2.13; 95% CI, 1.34 - 3.40). No such association was found among white participants.

However, compared to those with normal lung function, the restrictive impairment pattern was strongly associated with increased odds for later dementia among whites (OR, 1.79; 95% CI, 1.27 - 2.54). There was no such association among black participants.

The researchers called these dichotomous results "an unexpected finding."

Although both COPD and restrictive lung disease were associated with higher risk, the link was stronger for those with restrictive impairment.

Table 2. Associations With COPD Pattern in Midlife*

  Odds Ratio 95% Confidence Interval
Dementia or MCI 1.33 1.07 - 1.64
Dementia 1.16 0.74 - 1.82
MCI 1.40 1.12 - 1.76
Dementia or MCI due to Alzheimer disease 1.24 0.97 - 1.60
Dementia or MCI due to cerebrovascular disease 1.33 0.79 - 2.23
*Comparisons are to participants with normal lung function after adjustment for physical activity, body mass index, cardiovascular risk factors, prevalent cardiovascular disease, and APOE genotype.


"I had actually expected to see the strongest associations with obstructive lung disease," Lutsey said. "However, the stronger association with restrictive impairment is not entirely surprising."

Diseases such as idiopathic pulmonary fibrosis and sarcoidosis that result in restrictive impairment are characterized by reduced lung volumes and low oxygen levels. Extensive work in experimental rodent models of sleep apnea have suggested that intermittent low oxygen levels may damage neurons, she added.

Chronic Hypoxemia the Culprit?

The mechanism behind the associations in the study could be largely mediated through chronic hypoxemia, the researchers note. Systemic inflammation, oxidative stress, physiologic stress, as well as cerebral arterial stiffness and small-vessel damage related to hypoxemia are possible contributive factors.

"Our study is novel in that relatively little research has evaluated the impact of a constant state of hypoxemia — which may be common in the context of restrictive impairment — on neurologic structure and function," Lutsey said.

As strengths of the study, the researchers cited the 23-year follow-up period between assessments of lung health in middle age and later neurocognitive function; the large community-based sample; use of objective measurements of lung function; comprehensive neurocognitive assessment; and representation of race, sex, men, women, blacks, and whites.

The study's limitations include the single assessment of lung function, a lack of biomarkers to verify Alzheimer-type dementia, and residual confounding and poor precision for some comparisons despite the relatively large sample size.

The current study only points to an association, the researchers note.

"Proving causality in this context is challenging, since dementia takes many years to develop, and it would be unethical to randomize people to exposures that would reduce their lung function," Lutsey said.

"However, it may be interesting to evaluate whether genetic markers of lung function are associated with dementia risk. This would provide some evidence of causality, since genes are assigned at birth and thus not influenced by behaviors."

If future research confirms a causative relationship between lung disease and dementia, "both individuals and policy makers would have added incentive to make changes that protect lung health, as doing so may also prevent dementia," she added.

"Intriguing Study"

Commenting on the findings for Medscape Medical News, Sucharita R. Kher, MD, director of the Outpatient Pulmonary Clinic, pulmonary attending physician, and instructor at Tufts University School of Medicine in Boston, Massachusetts, said the study makes an important contribution to the knowledge base.

Lung disease and dementia are "highly prevalent in the general population, so they are two big diseases," she said.

Some of the notable features of the study are the large number of participants and the fact that both restrictive and obstructive lung diseases were evaluated, she added.

"Interestingly, in this paper, the association between impaired lung function or lung diseases and the risk of incident dementia persisted even when they looked at nonsmokers. So something other than smoking may be a commonality here.

"It's a very intriguing study, but I'd like to add a word of caution, because they have identified an association and not necessarily a causal relationship," she

For this reason, Kher suggested that the findings are hypothesis generating and called for additional research to study causality.

The National Heart, Lung and Blood Institute and the National Institute of Neurologic Disorders and Stroke supported the ARIC study. Dr Lutsey and Dr Kher have disclosed no relevant financial relationships.

Am J Respir Crit Care Med. Published online November 15, 2018. Abstract

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