Modifiable pathways in Alzheimer’s disease: Mendelian randomisation analysis

Objective To determine which potentially modifiable risk factors, including socioeconomic, lifestyle/dietary, cardiometabolic, and inflammatory factors, are associated with Alzheimer’s disease.

Design Mendelian randomisation study using genetic variants associated with the modifiable risk factors as instrumental variables.

Setting International Genomics of Alzheimer’s Project.

Participants 17 008 cases of Alzheimer’s disease and 37 154 controls.

Main outcome measures Odds ratio of Alzheimer’s per genetically predicted increase in each modifiable risk factor estimated with Mendelian randomisation analysis.

Results This study included analyses of 24 potentially modifiable risk factors. A Bonferroni corrected threshold of P=0.002 was considered to be significant, and P<0.05 was considered suggestive of evidence for a potential association. Genetically predicted educational attainment was significantly associated with Alzheimer’s. The odds ratios were 0.89 (95% confidence interval 0.84 to 0.93; P=2.4×10−6) per year of education completed and 0.74 (0.63 to 0.86; P=8.0×10−5) per unit increase in log odds of having completed college/university. The correlated trait intelligence had a suggestive association with Alzheimer’s (per genetically predicted 1 SD higher intelligence: 0.73, 0.57 to 0.93; P=0.01). There was suggestive evidence for potential associations between genetically predicted higher quantity of smoking (per 10 cigarettes a day: 0.69, 0.49 to 0.99; P=0.04) and 25-hydroxyvitamin D concentrations (per 20% higher levels: 0.92, 0.85 to 0.98; P=0.01) and lower odds of Alzheimer’s and between higher coffee consumption (per one cup a day: 1.26, 1.05 to 1.51; P=0.01) and higher odds of Alzheimer’s. Genetically predicted alcohol consumption, serum folate, serum vitamin B12, homocysteine, cardiometabolic factors, and C reactive protein were not associated with Alzheimer’s disease.

Conclusion These results provide support that higher educational attainment is associated with a reduced risk of Alzheimer’s disease.

Reference: BMJ 2017;359:j5375


Contemporary Hormonal Contraception and the Risk of Breast Cancer


Little is known about whether contemporary hormonal contraception is associated with an increased risk of breast cancer.


We assessed associations between the use of hormonal contraception and the risk of invasive breast cancer in a nationwide prospective cohort study involving all women in Denmark between 15 and 49 years of age who had not had cancer or venous thromboembolism and who had not received treatment for infertility. Nationwide registries provided individually updated information about the use of hormonal contraception, breast-cancer diagnoses, and potential confounders.


Among 1.8 million women who were followed on average for 10.9 years (a total of 19.6 million person-years), 11,517 cases of breast cancer occurred. As compared with women who had never used hormonal contraception, the relative risk of breast cancer among all current and recent users of hormonal contraception was 1.20 (95% confidence interval [CI], 1.14 to 1.26). This risk increased from 1.09 (95% CI, 0.96 to 1.23) with less than 1 year of use to 1.38 (95% CI, 1.26 to 1.51) with more than 10 years of use (P=0.002). After discontinuation of hormonal contraception, the risk of breast cancer was still higher among the women who had used hormonal contraceptives for 5 years or more than among women who had not used hormonal contraceptives. Risk estimates associated with current or recent use of various oral combination (estrogen–progestin) contraceptives varied between 1.0 and 1.6. Women who currently or recently used the progestin-only intrauterine system also had a higher risk of breast cancer than women who had never used hormonal contraceptives (relative risk, 1.21; 95% CI, 1.11 to 1.33). The overall absolute increase in breast cancers diagnosed among current and recent users of any hormonal contraceptive was 13 (95% CI, 10 to 16) per 100,000 person-years, or approximately 1 extra breast cancer for every 7690 women using hormonal contraception for 1 year.


The risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use; however, absolute increases in risk were small. (Funded by the Novo Nordisk Foundation.)

Reference: N Engl J Med 2017; 377:2228-2239December 7, 2017



Simulation of Growth Trajectories of Childhood Obesity into Adulthood


Although the current obesity epidemic has been well documented in children and adults, less is known about long-term risks of adult obesity for a given child at his or her present age and weight. We developed a simulation model to estimate the risk of adult obesity at the age of 35 years for the current population of children in the United States.


We pooled height and weight data from five nationally representative longitudinal studies totaling 176,720 observations from 41,567 children and adults. We simulated growth trajectories across the life course and adjusted for secular trends. We created 1000 virtual populations of 1 million children through the age of 19 years that were representative of the 2016 population of the United States and projected their trajectories in height and weight up to the age of 35 years. Severe obesity was defined as a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 35 or higher in adults and 120% or more of the 95th percentile in children.


Given the current level of childhood obesity, the models predicted that a majority of today’s children (57.3%; 95% uncertainly interval [UI], 55.2 to 60.0) will be obese at the age of 35 years, and roughly half of the projected prevalence will occur during childhood. Our simulations indicated that the relative risk of adult obesity increased with age and BMI, from 1.17 (95% UI, 1.09 to 1.29) for overweight 2-year-olds to 3.10 (95% UI, 2.43 to 3.65) for 19-year-olds with severe obesity. For children with severe obesity, the chance they will no longer be obese at the age of 35 years fell from 21.0% (95% UI, 7.3 to 47.3) at the age of 2 years to 6.1% (95% UI, 2.1 to 9.9) at the age of 19 years.


On the basis of our simulation models, childhood obesity and overweight will continue to be a major health problem in the United States. Early development of obesity predicted obesity in adulthood, especially for children who were severely obese. (Funded by the JPB Foundation and others.)

A Controlled Trial of Erenumab for Episodic Migraine


We tested erenumab, a fully human monoclonal antibody that inhibits the calcitonin gene–related peptide receptor, for the prevention of episodic migraine.


We randomly assigned patients to receive a subcutaneous injection of either erenumab, at a dose of 70 mg or 140 mg, or placebo monthly for 6 months. The primary end point was the change from baseline to months 4 through 6 in the mean number of migraine days per month. Secondary end points were a 50% or greater reduction in mean migraine days per month, change in the number of days of use of acute migraine–specific medication, and change in scores on the physical-impairment and everyday-activities domains of the Migraine Physical Function Impact Diary (scale transformed to 0 to 100, with higher scores representing greater migraine burden on functioning).


A total of 955 patients underwent randomization: 317 were assigned to the 70-mg erenumab group, 319 to the 140-mg erenumab group, and 319 to the placebo group. The mean number of migraine days per month at baseline was 8.3 in the overall population; by months 4 through 6, the number of days was reduced by 3.2 in the 70-mg erenumab group and by 3.7 in the 140-mg erenumab group, as compared with 1.8 days in the placebo group (P<0.001 for each dose vs. placebo). A 50% or greater reduction in the mean number of migraine days per month was achieved for 43.3% of patients in the 70-mg erenumab group and 50.0% of patients in the 140-mg erenumab group, as compared with 26.6% in the placebo group (P<0.001 for each dose vs. placebo), and the number of days of use of acute migraine–specific medication was reduced by 1.1 days in the 70-mg erenumab group and by 1.6 days in the 140-mg erenumab group, as compared with 0.2 days in the placebo group (P<0.001 for each dose vs. placebo). Physical-impairment scores improved by 4.2 and 4.8 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 2.4 points in the placebo group (P<0.001 for each dose vs. placebo), and everyday-activities scores improved by 5.5 and 5.9 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 3.3 points in the placebo group (P<0.001 for each dose vs. placebo). The rates of adverse events were similar between erenumab and placebo.


Erenumab administered subcutaneously at a monthly dose of 70 mg or 140 mg significantly reduced migraine frequency, the effects of migraines on daily activities, and the use of acute migraine–specific medication over a period of 6 months. The long-term safety and durability of the effect of erenumab require further study. (Funded by Amgen and Novartis; STRIVE number, NCT02456740.)

Fremanezumab for the Preventive Treatment of Chronic Migraine


Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene–related peptide (CGRP), is being investigated as a preventive treatment for migraine. We compared two fremanezumab dose regimens with placebo for the prevention of chronic migraine.


In this phase 3 trial, we randomly assigned patients with chronic migraine (defined as headache of any duration or severity on ≥15 days per month and migraine on ≥8 days per month) in a 1:1:1 ratio to receive fremanezumab quarterly (a single dose of 675 mg at baseline and placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), or matching placebo. Both fremanezumab and placebo were administered by means of subcutaneous injection. The primary end point was the mean change from baseline in the average number of headache days (defined as days in which headache pain lasted ≥4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine–specific medication [triptans or ergots] was used to treat a headache of any severity or duration) per month during the 12 weeks after the first dose.


Of 1130 patients enrolled, 376 were randomly assigned to fremanezumab quarterly, 379 to fremanezumab monthly, and 375 to placebo. The mean number of baseline headache days (as defined above) per month was 13.2, 12.8, and 13.3, respectively. The least-squares mean (±SE) reduction in the average number of headache days per month was 4.3±0.3 with fremanezumab quarterly, 4.6±0.3 with fremanezumab monthly, and 2.5±0.3 with placebo (P<0.001 for both comparisons with placebo). The percentage of patients with a reduction of at least 50% in the average number of headache days per month was 38% in the fremanezumab-quarterly group, 41% in the fremanezumab-monthly group, and 18% in the placebo group (P<0.001 for both comparisons with placebo). Abnormalities of hepatic function occurred in 5 patients in each fremanezumab group (1%) and 3 patients in the placebo group (<1%).


Fremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo in this 12-week trial. Injection-site reactions to the drug were common. The long-term durability and safety of fremanezumab require further study. (Funded by Teva Pharmaceuticals; number, NCT02621931.)

Guidance for CCGs on items not to be routinely prescribed

NHS England has published Items which should not routinely be prescribed in primary care: guidance for CCGs. This guidance is addressed to CCGs to support them to fulfil their duties around appropriate use of prescribing resources supporting CCGs in their decision-making, to address unwarranted variation, and to provide clear national advice to make local prescribing practices more effective.

Additional link: NHS Clinical Commissioners press release

Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes

Question  Can oral insulin delay or prevent clinically diagnosed type 1 diabetes?

Findings  In this randomized clinical trial that included 389 participants in the primary analysis who were first- and second-degree relatives of patients with type 1 diabetes, oral insulin compared with placebo did not significantly reduce the risk of diabetes onset over a median of 2.7 years (insulin group, 28.5% and placebo group, 33%; hazard ratio, 0.87).

Meaning  Oral insulin as used in this study was not effective in prevention of type 1 diabetes.

Reference: JAMA. 2017;318(19):1891-1902.