In this large prospective cohort study among male physicians, the average annual incidence of PD was 121 cases/100,000 person-years. The age-specific incidence increased steeply through age 89 years and then declined in the 10th decade of life. Unadjusted cumulative incidence substantially overestimated the true risk of PD in those aged 80 years and older. The lifetime risk curve for PD reached a plateau by age 90 years. The cumulative incidence and lifetime risks of PD decreased substantially with increasing smoking exposure.
Our study has several strengths, including its large number of participants and outcome events, prospective design, and well-defined population with a long follow-up. We were able to adjust cumulative incidence for competing risks using mortality information from the same population and could perform stratified analyses by smoking status.
A number of limitations should be considered in the interpretation of our results. First, our diagnosis of PD was based on self-reports. However, prior work has shown the self-reported diagnosis of PD to be highly valid in a population of health professionals.14
Direct validation of more than 10% of self-reported PD diagnoses using available medical records revealed an accuracy of 90%, which is similar to that found in validation studies of self-reported hypercholesterolemia and hypertension in the PHS.15
However, despite this good validation, misclassification of PD remains possible. A number of factors limit the generalizability of our results to other populations. Our cohort was composed of white men of the same educational level and profession who were motivated to modify their risks for disease. They also may have higher rates of disease diagnosis than nonphysicians because of easier access to medical care. However, our incidence estimates for PD were similar to that of a population-based study with direct ascertainment.16
We were unable to estimate the incidence and risk of PD in women.
Prior estimates of PD incidence have varied widely depending on nationality, sex, population age distribution, and case ascertainment methods. General populations have an average estimate of 13 cases/100,000 (range 1.5–26),17
whereas populations aged 65 years and older have an average of 180 cases/100,000 (range 89–332).16,18–22
We recalculated the incidence rates of studies that evaluated most or all population members using accepted diagnostic criteria and reported age-specific incidence in older white men (). The rate obtained in our cohort (224 cases/100,000 person-years) was similar to that of the Rotterdam Study (261 cases/100,000 person-years),16
a primarily white population-based cohort in which the diagnosis of PD was obtained by direct screening followed by a detailed clinical workup. Thirty-nine percent of PD cases were newly diagnosed by study physicians, demonstrating the substantial number of patients with PD who are missed when case finding is based on medical records alone. Despite the fact that our participants are physicians with easy access to medical care, our rate was lower than that of two door-to-door studies of elders in Italy and Spain, in which PD was directly ascertained.18,19
Finally, our rate was higher than that in three US-based studies in which no population screening was performed and cases were found through health care providers or medical records systems.6,21,22
Table 4 Comparison of the Physicians' Health Study with studies using widely accepted diagnostic criteria that report crude annual incidence of Parkinson disease in men
In our cohort, PD incidence increases through age 89 years and then declines in the 10th decade of life. In the majority of studies reporting age-specific incidence in white men, incidence increases through the oldest age group,16,18,19,21–23
as it does in our study when those aged 85 years and older are combined. However, a number of well-conducted studies show a decline in PD incidence in men after age 75 or 79 years.6,23–25
Similar results have been found for AD in a cohort characterized by exceptional longevity in which the incidence of AD in men began to decline in their early 90s.26
It is unclear whether the observed decline represents a true decrease in the risk of PD or is simply due to underdiagnosis. Older patients may become lost to follow-up, particularly in studies with less-intensive cohort surveillance.23
Because parkinsonian signs as well as comorbidities increase markedly with age,27
the decline of PD in the oldest old may also reflect the difficulty of distinguishing idiopathic PD from other causes of parkinsonism.20
In the Rochester Epidemiology Project, the incidence of PD declined in men after age 79 years when strict diagnostic criteria were used, but continued to increase through age 99 years when broad criteria were used.28
When we included PD patients with concurrent dementia, the incidence rate increased slightly but still declined after age 89 years (data not shown). Our study provides evidence that PD incidence increases at least to age 90 years, thus shifting to the right the age where we can be confident that incidence is still increasing.
Cumulative incidence is often used to provide a measure of long-term disease risk. However, it overestimates the incidence when the disease has a prevalence of 10% or greater, or the competing risk of mortality is high.29
The lifetime risk method adjusts the incidence rate of a disease by the all-cause mortality rate in the population. It thus provides the actual risk of developing the disease before dying of some other cause, assuming one has survived free of that disease to a specified age. Lifetime risk estimates are helpful as an absolute measure of long-term individual risk and are easily understood by the lay public. They are increasingly being used by researchers and policy makers to predict population risks30
and develop clinical practice guidelines.31,32
Our study illustrates the importance of adjusting for the competing risk of death when estimating the incidence of a disease in an older population. The cumulative incidence of PD from ages 45 to 100 years was 9.9% (1 in 10), but mortality-adjusted lifetime risk for the same period was 6.7% (1 in 15). Our estimate of lifetime cumulative incidence at age 40 years was remarkably similar to that of the Rochester Epidemiology Project (10.9%), but our estimates of lifetime risk were higher. This likely reflects the increased longevity of our cohort, which has a life expectancy of 49.3 additional years at age 40 years, 12 years longer than that of 40-year-old men in the general US population.33
Populations with a longer life expectancy have a longer period at risk; thus, lifetime risk estimates cannot be compared across different populations unless they have similar mortality rates.
Although smoking is known to decrease PD risk,34
it increases the risk of many other major diseases and of death. The cumulative incidence of PD decreased as the level of smoking exposure increased, suggesting a dose–response relationship between smoking and protection from PD. The lifetime risk of PD followed the same pattern (), and lifetime risk in heavy smokers (2.3%) was substantially less than in never-smokers (7.8%). The difference in lifetime risk curves between ever- and never-smokers was accounted for by increased mortality from cardiovascular disease, cancer, and pulmonary disease among smokers (data not shown). Because we had relatively few current smokers in the cohort, smoking-associated mortality rates were lower than might be found in a general population. In a cohort with a higher smoking exposure, both cumulative incidence and lifetime risks of PD among smokers might be even lower. It is worth emphasizing that while smoking may decrease the incidence of PD by some protective factors, it decreases the lifetime risk of PD by substantially increasing the risk of death from smoking-related diseases.
We were unable to address the incidence and lifetime risk of PD in women. Women are known to have a twofold decreased risk of PD compared with men,20
which seems to persist even to very old ages.18
On the other hand, older women have increased longevity compared with men and are less likely to be smokers. Thus, although incidence in men is higher at all ages, the difference in lifetime risk between men and women likely decreases with age.6
Further studies of lifetime risk in elderly women are needed.
Our results illustrate the sensitivity of PD incidence and risk estimates to a number of factors, including the age and longevity of the population, methods of case finding, the strictness of PD criteria, and the prevalence of smoking. In this population of health-conscious male physicians with exceptional longevity, PD incidence increased sharply to age 90 years, and lifetime risk was as high as 1 in 15 at age 40 years. As life expectancy increases worldwide, similar lifetime risks can be expected in general populations.