Jane A. Driver

Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study

Objectives To relate cancer since entry into the Framingham Heart Study with the risk of incident Alzheimer’s disease and to estimate the risk of incident cancer among participants with and without Alzheimer’s disease. Design Community based prospective cohort study; nested age and sex matched case-control study. Setting Framingham Heart Study, USA. Participants 1278 participants with and without a history of cancer who were aged 65 or more and free of dementia at baseline (1986-90). Main outcome measures Hazard ratios and 95% confidence intervals for the risks of Alzheimer’s disease and cancer. Results Over a mean follow-up of 10 years, 221 cases of probable Alzheimer’s disease were diagnosed. Cancer survivors had a lower risk of probable Alzheimer’s disease (hazard ratio 0.67, 95% confidence interval 0.47 to 0.97), adjusted for age, sex, and smoking. The risk was lower among survivors of smoking related cancers (0.26, 0.08 to 0.82) than among survivors of non-smoking related cancers (0.82, 0.57 to 1.19). In contrast with their decreased risk of Alzheimer’s disease, survivors of smoking related cancer had a substantially increased risk of stroke (2.18, 1.29 to 3.68). In the nested case-control analysis, participants with probable Alzheimer’s disease had a lower risk of subsequent cancer (0.39, 0.26 to 0.58) than reference participants, as did participants with any Alzheimer’s disease (0.38) and any dementia (0.44). Conclusions Cancer survivors had a lower risk of Alzheimer’s disease than those without cancer, and patients with Alzheimer’s disease had a lower risk of incident cancer. The risk of Alzheimer’s disease was lowest in survivors of smoking related cancers, and was not primarily explained by survival bias. This pattern for cancer is similar to that seen in Parkinson’s disease and suggests an inverse association between cancer and neurodegeneration.

Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer’s disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term ‘cistauosis’, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer’s disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy (CTE) and Alzheimers disease (AD), whose defining pathologic features include tauopathy made of phosphorylated tau (p-tau). However, tauopathy has not been detected in early stages after TBI and how TBI leads to tauopathy is unknown. Here we find robust cis p-tau pathology after sport- and military-related TBI in humans and mice. Acutely after TBI in mice and stress in vitro, neurons prominently produce cis p-tau, which disrupts axonal microtubule network and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, termed “cistauosis”, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis p-tau is a major early driver after TBI and leads to tauopathy in CTE and AD, and cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.

Parkinson disease and risk of mortality: a prospective comorbidity-matched cohort study.

Objective: To evaluate the association between Parkinson disease (PD) and mortality after adjustment for comorbidities. Methods: We conducted a matched cohort analysis among 22,071 participants in the Physicians’ Health Study. Five hundred sixty incident PD cases were identified by self-report. We used a modified Charlson Comorbidity Index to calculate a comorbidity score. Each PD case was matched by age to a comparator who was alive and had an identical comorbidity score at the time of PD diagnosis of the case. Both cohorts were followed for all-cause mortality. We used proportional hazards models to calculate hazard ratios (HRs) for mortality. Results: A total of 330 participants died over a median follow-up of 5.8 years, 200 (35.7%) in the PD group and 130 (23.2%) in the reference group. After adjustment for smoking and age at PD onset, the HR for mortality was 2.32 (95% CI 1.85–2.92). The mortality risk remained significant with increasing age at onset, even in those aged ≥80 years (HR = 2.10; 95% CI 1.44–3.00). The increased risk was apparent for short PD duration (<2 years) and remained stable with increasing duration. We found no different risk of mortality associated with PD according to smoking status. Conclusions: In this large prospective cohort of men and after matching on comorbidities, we found that Parkinson disease patients had an increased risk of all-cause mortality. Mortality was increased regardless of disease duration, did not diminish with increasing age at onset, and was not influenced by smoking status. GLOSSARY: BMI = body mass index; COPD = chronic obstructive pulmonary disease; HR = hazard ratio; ICD-9 = International Classification of Diseases, 9th Revision; PD = Parkinson disease; PHS = Physicians’ Health Study; RR = relative risk; WHO = World Health Organization.

A Prospective Cohort Study of Cancer Incidence Following the Diagnosis of Parkinson's Disease

Background: Prior studies suggest a decreased risk of cancer among patients with Parkinsons disease (PD). Methods: Matched cohort analysis among the 22,071 participants in the Physicians Health Study. A total of 487 incident cases of PD without preceding cancer were identified by self-report. Each PD case was matched by age to a reference participant who was alive and cancer free at the time of PD diagnosis. Both cohorts were followed for incident cancer. We used proportional hazards models to calculate adjusted relative risks (RR) for cancer. Results: A total of 121 cancers were confirmed during a median follow-up of 5.2 years (PD) and 5.9 years (reference). Those with PD developed less cancer (11.0% versus 14.0%), with an adjusted RR of 0.85 [95% confidence interval (95% CI), 0.59-1.22]. Reduced risk was present for smoking-related cancers such as lung (RR, 0.32), colorectal (RR, 0.54), and bladder (RR, 0.68), as well as for most non–smoking-related cancers such as prostate cancer (RR, 0.74). In contrast, PD patients were at significantly increased risk (RR, 6.15; 95% CI, 1.77-21.37) for melanoma. PD patients who smoked were at reduced risk for smoking-related cancer (RR, 0.33; 95% CI, 0.12-0.92), whereas nonsmokers with PD were at increased risk (RR, 1.80; 95% CI, 0.60-5.39). This interaction was statistically significant (Pinteraction = 0.02). Conclusions: Our results suggest a decreased incidence of most cancers in patients with PD. PD patients had a significantly increased risk of malignant melanoma, a finding consistent with prior studies. We confirmed an interaction between smoking and the relationship of PD to smoking-related cancer that may fit the pattern of a gene-environment interaction. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1260–5)

Incidence and remaining lifetime risk of Parkinson disease in advanced age

Objective: To estimate the incidence and lifetime risk (LTR) of Parkinson disease (PD) in a large cohort of men. Background: Age is the strongest risk factor for PD, but whether its incidence continues to increase after age 80 years remains unclear. Methods: Prospective cohort of 21,970 US male physicians aged 40–84 years at baseline who did not report PD before study entry. Participants self-reported PD on yearly follow-up questionnaires, and all deaths were confirmed. We calculated incidence rates and cumulative incidence using a modified Kaplan–Meier analysis. LTR was estimated by adjusting cumulative incidence for competing risks of death. Results: Five hundred sixty-three cases of PD were identified over 23 years of follow-up. The crude incidence rate of PD was 121 cases/100,000 person-years. Age-specific incidence rates increased sharply beginning at age 60 years, peaked in those aged 85–89 years, and declined beginning at age 90 years. Cumulative incidence substantially overestimated the long-term risk of PD, particularly in those aged 80 years and older. Cumulative incidence was 9.9% (95% confidence interval [CI] 8.48%–11.30%) from ages 45 to 100 years, whereas LTR for the same period was 6.7% (95% CI 6.01%–7.43%). The incidence and LTR of PD decreased with increasing exposure to smoking. Conclusions: Our study provides evidence that the incidence of Parkinson disease (PD) in men increases through age 89 years. Whether the subsequent decline represents a true decrease in risk remains to be established. A history of smoking substantially decreased the incidence and lifetime risk of PD. Incidence studies that do not adjust for competing risks of death may overestimate the true risk of PD in the elderly.

Incidence of cardiovascular disease and cancer in advanced age: prospective cohort study.

Objective To investigate the influence of increasing age on the incidence and remaining lifetime risk of cardiovascular disease and cancer in a cohort of older men. Design Prospective cohort study. Setting United States. Participants 22 048 male doctors aged 40-84 who were free of major disease in 1982. Main outcome measures Incidence and remaining lifetime risk of major cardiovascular disease (myocardial infarction, stroke, and death from cardiovascular disease) and cancer. Results 3252 major cardiovascular events and 5400 incident cancers were confirmed over 23 years of follow-up. The incidence of major cardiovascular disease continued to increase to age 100. Beginning at age 80, however, major cardiovascular disease was more likely to be diagnosed at death. The incidence of cancer peaked in those aged 80-89 and then declined. Cancers detected by screening accounted for most of the decline, whereas most cancers for which there was no screening continued to increase to age 100. Unadjusted cumulative incidence overestimated the risk of cardiovascular disease by 16% and cancer by 8.5%. The remaining lifetime risk of cancer at age 40 was 45.1% (95% confidence interval 43.8% to 46.3%) and at age 90 was 9.6% (7.2% to 11.9%). The remaining lifetime risk of major cardiovascular disease at age 40 was 34.8% (33.1% to 36.5%) and at age 90 was 16.7% (12.9% to 20.6%). Conclusions In this prospective cohort of men, the incidence of new cardiovascular disease continued to increase after age 80 but was most often diagnosed at death. The decrease in incidence of cancer late in life seemed largely due to a decline in cancers usually detected by screening. These findings suggest that people aged 80 and older have a substantial amount of undiagnosed disease. The remaining lifetime risk of both diseases approached a plateau in the 10th decade. This may be due to decreased detection of disease and reporting of symptoms and increased resistance to disease in those who survive to old age. Accurate estimates of disease risk in an aging population require adjustment for competing risks of mortality.

Prospective Cohort Study of Type 2 Diabetes and the Risk of Parkinson's Disease

OBJECTIVE—To evaluate the association between type 2 diabetes and newly reported Parkinsons disease. RESEARCH DESIGN AND METHODS—Our study included 21,841 participants in the Physicians’ Health Study, a cohort of U.S. male physicians. Diabetes and Parkinsons disease were self-reported via questionnaire. We used time-varying Cox regression to calculate adjusted relative risk (RR) for Parkinsons disease. RESULTS—Over 23 years, 556 individuals with Parkinsons disease were identified. Subjects with diabetes had an increased Parkinsons disease risk (multivariable-adjusted RR 1.34 [95% CI 1.01–1.77]). The association remained significant after exclusion of those with known vascular disease. The diagnosis of diabetes was clustered around the diagnosis of Parkinsons disease and was more apparent among men with short diabetes duration and those without complications from diabetes. CONCLUSIONS—Results of this large prospective study in men do not suggest that diabetes is a preceding risk factor for Parkinsons disease. Whether the positive association may be explained by ascertainment bias or a common underlying biological mechanism remains to be established.

Pin1: a new genetic link between Alzheimer's disease, cancer and aging.

Epidemiologic data suggest that people who develop neurodegenerative diseases of aging have a decreased risk of cancer. This is intriguing, since there is growing evidence that neurodegeneration and carcinogenesis share a number of biological pathways, such as abnormal entry into the cell cycle. The unique enzyme Pin1 plays a key role in the pathogenesis of Alzheimers disease and many human cancers. Pin1 acts on proteins after they have been phosphorylated at specific sites, causing them to twist between two completely distinct conformations. This conformational change profoundly affects protein activity and is a major method of cellular signaling and regulation. In the neuron, Pin1 promotes cellular health by restoring phosphorylated tau and amyloid precursor protein to a functional state. The loss of active Pin1 leads to the accumulation of abnormal tau and the overproduction of β-amyloid, the cardinal features of Alzheimers disease. Pin1 also regulates the cell cycle and is a necessary enzyme for cell division. Over-expression of Pin1 can promote oncogenesis through a number of signaling pathways. We hypothesize that Pin1 might help explain an inverse relationship between Alzheimers disease and cancer. Pin1 deficiency in mice leads to an early-aging phenotype, suggesting that Pin1 activity is necessary for healthy aging and the prevention of age-related diseases. We review the role of Pin1 in cancer and neurodegeneration, discuss the relationship between Pin1 and aging, and explore its potential as a diagnostic and therapeutic target.

Alzheimer’s as a metabolic disease

Empirical evidence indicates that impaired mitochondrial energy metabolism is the defining characteristic of almost all cases of Alzheimer’s disease (AD). Evidence is reviewed supporting the general hypothesis that the up-regulation of OxPhos activity, a metabolic response to mitochondrial dysregulation, drives the cascade of events leading to AD. This mode of metabolic alteration, called the Inverse Warburg effect, is postulated as an essential compensatory mechanism of energy production to maintain the viability of impaired neuronal cells. This article appeals to the inverse comorbidity of cancer and AD to show that the amyloid hypothesis, a genetic and neuron-centric model of the origin of sporadic forms of AD, is not consistent with epidemiological data concerning the age-incidence rates of AD. A view of Alzheimer’s as a metabolic disease—a condition consistent with mitochondrial dysregulation and the Inverse Warburg effect, will entail a radically new approach to diagnostic and therapeutic strategies.

Use of non-steroidal anti-inflammatory drugs and risk of Parkinson’s disease: nested case-control study

Objective To evaluate the relation between Parkinson’s disease and prior use of non-steroidal anti-inflammatory drugs (NSAIDs) in a large cohort of men. Design Case-control analysis nested in the Physicians’ Health Study. Participants 22 007 male physicians aged 40–84 years without indications for or contraindications to regular NSAID use and free of Parkinson’s disease at baseline. Cases and controls were matched by age alone or by age and scores for confounders (comorbidity and indicators of NSAID use). Up to five controls were matched to each of 616 cases by age and 565 cases by age and confounder scores. Setting United States. Main outcome measures Odds of having been exposed to prior non-aspirin NSAID or aspirin use by participants with Parkinson’s disease and by their controls in each case-control set. Results Participants who had ever used non-aspirin NSAIDs had an increased risk of Parkinson’s disease (odds ratio 1.28 (95% CI 1.05 to 1.56) in the age matched group but not in the group also matched on confounder scores (odds ratio 1.17 (0.94 to 1.46)). There was an increased risk of Parkinson’s disease in men who had 1–2 years of regular non-aspirin NSAID use (odds ratio 1.35 (1.07 to 1.70)), a finding that remained significant after matching for confounder scores as well (odds ratio 1.35 (1.05 to 1.75)). In contrast, the significant association of use of non-aspirin NSAIDs for ≥5 years (odds ratio 1.48 (1.05 to 2.09)) in the age matched group was entirely attenuated in the group also matched on confounder scores (1.03 (0.70 to 1.53)). There was also a suggestion that men who regularly used aspirin had an increased risk of Parkinson’s disease. Positive associations between non-aspirin NSAID or aspirin and risk of Parkinson’s disease tended to disappear when analyses were limited to drug use ≥5 years before the disease diagnosis. Conclusions This case-control study did not find evidence that NSAID use reduces Parkinson’s disease risk. The positive associations observed between NSAID use and Parkinson’s disease might have been due to confounding by indication as the use was clustered in the few years before disease diagnosis.