Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy (CTE) and Alzheimer's 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.

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 . Main outcome measuresHazard 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. IntroductionLimited data suggest that cancer survivors have a decreased risk of Alzheimer's disease and that people with Alzheimer's disease have lower rates of cancer. [1][2][3][4][5][6] Evidence of an inverse relation between Parkinson's disease and most cancers is now convincing. [7][8][9][10][11][12][13] A link between cancer and neurodegeneration is plausible as they share several genes and biological pathways, including inappropriate activation and deregulation of the cell cycle. [14][15][16][17][18][19][20][21][22] Signaling along these pathways results in opposite end points: in the case of cancer, uncontrolled cell proliferation, and in the case of neurodegeneration, apoptotic cell death. Proteins such as p53, a major regulator of apoptosis, and Pin1, which has a dual role in cell cycle control and protein folding, play a key part in the pathophysiology of both Alzheimer's disease and cancer. 15 A better understanding of the biological links between these two families of diseases is already opening new therapeutic horizons.In one population based cohort study, people with prevalent cancer had a 43% lower risk of ever developing Alzheimer's disease, and thos...

ContextThe lifetime risk of heart failure at age 40 years is approximately 1 in 5 in the general population; however, little is known about the association between modifiable lifestyle factors and the remaining lifetime risk of heart failure.Objective To examine the association between modifiable lifestyle factors and the lifetime risk of heart failure in a large cohort of men.Design, Setting, and Participants Prospective cohort study using data from 20 900 men (mean age at baseline, 53.6 years) from the Physicians' Health Study I who were apparently healthy at baseline. Six modifiable lifestyle factors were assessed: body weight, smoking, exercise, alcohol intake, consumption of breakfast cereals, and consumption of fruits and vegetables.Main Outcome Measure Lifetime risk of heart failure.Results During a mean follow-up of 22.4 years, 1200 men developed heart failure. Overall, the lifetime risk of heart failure was 13.8% (95% confidence interval [CI], 12.9%-14.7%) at age 40 years. Lifetime risk remained constant in men who survived free of heart failure through age 70 years and reached 10.6% (95% CI, 9.4%-11.7%) at age 80 years. Lifetime risk of heart failure was higher in men with hypertension than in those without hypertension. Healthy lifestyle habits (normal body weight, not smoking, regular exercise, moderate alcohol intake, consumption of breakfast cereals, and consumption of fruits and vegetables) were individually and jointly associated with a lower lifetime risk of heart failure, with the highest risk in men adhering to none of the 6 lifestyle factors (21.2%; 95% CI, 16.8%-25.6%) and the lowest risk in men adhering to 4 or more desirable factors (10.1%; 95% CI, 7.9%-12.3%). ConclusionIn this cohort of apparently healthy men, adherence to healthy lifestyle factors is associated with a lower lifetime risk of heart failure.

Studies on cancer risk among patients with PD collectively show significantly reduced cancer risk ratios. Further research to explain the biological mechanisms, particularly for the association with non-smoking-related cancers, appears warranted.

Background Frailty is a key determinant of clinical outcomes. We sought to describe frailty among U.S. Veterans and its association with mortality. Methods Nationwide retrospective cohort study of regular Veterans Affairs (VA) users, aged at least 65 years in 2002–2012, followed through 2014, using national VA administrative and Medicare and Medicaid data. A frailty index (FI) for VA (VA-FI) was calculated using the cumulative deficit method. Thirty-one age-related deficits in health from diagnostic and procedure codes were included and were updated biennially. Survival analysis assessed associations between VA-FI and mortality. Results A VA-FI was calculated for 2,837,152 Veterans over 10 years. In 2002, 35.5% were non-frail (FI = 0–0.10), 32.6% were pre-frail (FI = 0.11–0.20), 18.9% were mildly frail (FI = 0.21–0.30), 8.7% were moderately frail (FI = 0.31–0.40), and 4.3% were severely frail (FI > 0.40). From 2002 to 2012, the prevalence of moderate frailty increased to 12.7%and severe frailty to 14.1%. Frailty was strongly associated with survival and was independent of age, sex, race, and smoking; the VA-FI better predicted mortality than age alone. Although prevalence of frailty rose over time, compared to non-frail Veterans, 2 years’ hazard ratios (95% confidence intervals) for mortality declined from a peak in 2004 of 2.01 (1.97–2.04), 3.49 (3.44–3.55), 5.88 (5.79–5.97), and 10.39 (10.23–10.56) for pre-frail, mildly, moderately, and severely frail, respectively, to 1.51 (1.49–1.53), 2.36 (2.33–2.39), 3.68 (3.63–3.73), 6.62 (6.53–6.71) in 2012. At every frailty level, risk of mortality was lower for women versus men and higher for blacks versus whites. Conclusions Frailty affects at least 3 of every 10 U.S. Veterans aged 65 years and older, and is strongly associated with mortality. The VA-FI could be used to more accurately estimate life expectancy and individualize care for Veterans.

After accounting for confounding by indication, metformin was associated with a lower risk of subsequent dementia than sulfonylurea use in veterans <75 years of age. Further work is needed to identify which patients may benefit from metformin for the prevention of dementia.

Growing evidence suggests an unusual epidemiologic association between cancer and certain neurological conditions, particularly age-related neurodegenerative diseases. Cancer survivors have a 20-50% lower risk of developing Parkinson's and Alzheimer's disease, and patients with these neurodegenerative conditions have a substantially lower incidence of cancer. We review the epidemiologic evidence for this inverse co-morbidity and show that it is not simply an artifact of survival bias or under-diagnosis. We then review the potential biological explanations for this association, which is intimately linked to the very different nature of dividing cells and neurons. The known genetic and metabolic connections between cancer and neurodegeneration generally fall within two categories. The first includes shared genes and pathways such as Pin1 and the ubiquitin proteasome system that are dysregulated in different directions to cause one disease or the other. The second includes common pathophysiological mechanisms such as mitochondrial dysfunction, oxidative stress and DNA damage that drive both conditions, but with different cellular fates. We discuss examples of these biological links and their implications for developing new approaches to prevention and treatment of both diseases.

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 in-crease 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.