Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Alzheimer's disease affects mostly women over 65, who make up nearly two-thirds of cases. Subjective cognitive complaints (SCC) can precede Alzheimer's disease by years. While physical activity supports healthy aging, the long-term impact of midlife physical activity (PA) on late-life SCCs in women is limited. RESEARCH DESIGN AND METHODS/METHODS:Using data from 4,397 participants (mean age=46.2 years at baseline; 78.7 years at SCC assessment) in the New York University Women's Health Study (NYUWHS), a prospective cohort of 14,274 women enrolled in 1985-1991, we examined the association between midlife PA and SCC reported nearly 30 years later. PA was assessed at baseline using self-reported weekly hours of mild, moderate, and vigorous activity, converted to metabolic equivalent hours per week (MET-hours/week). Odds ratios and 95% CIs were estimated using unconditional logistic regression, adjusting for demographics and midlife and late-life health conditions. Multiple imputation and inverse probability weighting addressed missing data and potential selection bias. RESULTS:Women in the highest tertile of total midlife PA had 20% lower odds of reporting ≥2 SCCs compared with those in the lowest tertile (OR = 0.80; 95% CI = 0.68-0.95). The inverse association was stronger among never smokers (OR = 0.68; p for interaction=0.029). The inverse association was consistent for moderate and vigorous, but not mild PA. Findings were consistent across sensitivity analyses using alternative SCC definitions, exclusion criteria, and inverse probably weights. DISCUSSION AND IMPLICATIONS/CONCLUSIONS:Higher level of midlife PA was associated with fewer late-life SCCs, suggesting that midlife PA may be an important behavioral correlate of later-life cognitive health in women.

BACKGROUND:The role of modifiable environmental factors in Alzheimer's disease (AD) risk remains poorly understood. Built environment features such as neighbourhood walkability (NW) may influence long-term cognitive health among women. METHODS:The New York University Women's Health Study recruited 14 273 cognitively healthy women aged 35-65 years between 1985 and 1991, with follow-up for over 30 years. We geocoded residential addresses for each participant to derive a validated four-item baseline NW measure and a two-item average annual NW index over the follow-up period. We conducted a nested case-control study of 1865 AD cases identified via linkage to Medicare claims during follow-up matched to 3730 controls on age, race/ethnicity and Medicare coverage using risk-set sampling. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals for AD in relation to tertiles of NW measures, adjusting for potential confounders. Subgroup analyses examined potential effect modification. RESULTS:Compared with women living in areas with the lowest baseline NW, those in the middle and highest tertiles had lower odds of having a diagnosis of AD during follow-up, with an OR of 0.95 (0.82-1.11) and 0.83 (0.71-0.98), respectively (P-trend = .03). Results were similar when using average annual NW. The association did not differ appreciably by age, smoking status, education or body mass index. CONCLUSIONS:Higher midlife NW was associated with reduced odds of AD later in life. These findings highlight the potential for built environment interventions to promote cognitive health and support healthy ageing in women.

PURPOSE/OBJECTIVE:Few studies have examined the association between dietary nutrients and subjective cognitive complaints (SCCs), which are potential predictors of Alzheimer's disease-related dementia (ADRD). We aimed to examine the association of midlife intake of macronutrients, as well as of a few other nutrients, with SCC development. METHODS:We included 5119 participants who responded to the 2018 or 2020 follow-up questionnaire of the New York University Women's Health Study. Dietary data were collected using a validated self-administered Block food frequency questionnaire, and nutrient intake were calculated using food lists and food composition tables. SCCs were assessed using a standardized questionnaire. RESULTS:Dietary intakes of fiber, carbohydrates, and potassium were inversely associated with having ≥ 2 SCC (p-trend = 0.0047, 0.026, and 0.0015, respectively), whereas higher intakes of total fat and saturated fat, as well as a higher ratio of fat to carbohydrates, were positively associated with ≥ 2 SCCs (p-trend = < 0.0001, 0.0015, and 0.0025, respectively). The positive associations of total fat intake and the log-ratio of fat to carbohydrates with ≥ 2 SCCs remained significant after controlling for other nutrients (p-trend = 0.008 and 0.036, respectively). The association between total fat intake and SCCs was stronger among participants with lower caloric intake (< median = 1430 kcal) compared with those consuming higher intake (≥ 1430 kcal) (p-value for interaction = 0.0049). The associations did not differ appreciably by other factors. CONCLUSION/CONCLUSIONS:We observed a positive association between midlife dietary fat intakes and SCCs in later life in a cohort of women.

BACKGROUND:Midkine is a heparin-binding growth factor that is overexpressed in most human malignancies, including breast cancer. While elevated midkine levels have been associated with tumor progression and aging, its role as a predictive biomarker for breast cancer risk in healthy individuals remains unclear. We previously showed that higher midkine expression in estrogen receptor-positive (ER +) breast cancer in younger (< 55) women is associated with shorter disease-free survival. We investigated whether serum midkine levels in premenopausal women are associated with subsequent risk of ER + breast cancer. METHODS:We conducted a prospective, nested case-control study within the New York University Women's Health Study (NYUWHS). Serum midkine levels were measured in baseline blood samples from 249 premenopausal women who developed ER + breast cancer more than 10 years after blood collection and 249 matched controls. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) across quartiles and continuous midkine levels, adjusting for key breast cancer risk factors. RESULTS:Higher circulating midkine levels were associated with a marginally statistically significant lower risk of ER + breast cancer. Compared to the lowest quartile, women in the highest quartile had an OR of 0.55 (95% CI: 0.30-0.99; P for trend = 0.10). A doubling in midkine was associated with a 34% reduction in risk (OR = 0.66; 95% CI: 0.42-1.02). The inverse association was generally consistent across subgroups. CONCLUSION/CONCLUSIONS:These findings suggest that higher baseline serum midkine levels in premenopausal women are associated with a reduced long-term risk of ER + breast cancer. This challenges prior assumptions about midkine's uniformly pro-tumorigenic role and suggests it may be a context-dependent biomarker in breast cancer development.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental chemicals that have been linked to pancreatic cancer in animal studies, but evidence in humans remains limited. We evaluated associations between pre-diagnostic circulating concentrations of 11 PFAS and pancreatic cancer risk in a nested case-control study within the New York University Women's Health Study, a prospective cohort of 14,273 women. Serum samples collected prior to diagnosis from 116 pancreatic cancer cases and 346 matched controls were analyzed for PFAS levels. Associations between individual PFAS and pancreatic cancer risk were assessed using multivariable conditional logistic regression, and mixture effects were examined using repeated holdout weighted quantile sum (WQSRH) regression and Bayesian kernel machine regression (BKMR). Ten PFAS met the inclusion criteria for analysis. In single-chemical models, N-methyl perfluorooctane sulfonamidoacetic acid (NMFOSAA) and perfluorooctanoate (PFOA) were inversely associated with pancreatic cancer risk, but associations did not remain significant after false discovery rate correction. WQSRH models with negative constraints suggested a borderline inverse association with the PFAS mixture, primarily driven by NMFOSAA, PFOA, and perfluoroundecanoate (PFUNDA), while no significant associations were observed in positively constrained WQSRH or BKMR models. Overall, these findings do not support a positive association between circulating PFAS and pancreatic cancer risk in women. Although some compounds showed suggestive inverse associations, the overall findings indicate no clear link between PFAS exposure and pancreatic cancer risk.

OBJECTIVE:Research into risk factors for subjective cognitive complaints (SCCs) may offer insight into the etiology and prevention of Alzheimer's disease. Ultra-processed foods (UPFs) contain food additives that improve palatability and processed raw materials. Evidence is limited on the role of mid-life UPF intake in the development of late-life SCCs. METHODS:We included 5119 participants who responded to the 2018 or 2020 follow-up of the New York University Women's Health Study, a prospective cohort of 14,274 women recruited in New York City, United States, in 1985-91. Data on diet were collected at baseline using a validated modified Block food frequency questionnaire. Energy-adjusted total intake of UPFs and subgroups of UPFs, defined following the nova guidelines, were estimated using the residual method. RESULTS:The odds ratios (ORs) and 95 % confidence intervals (CIs) for reporting ≥2 SCCs were 1.15 (0.94-1.39), 1.06 (0.87-1.30), 1.20 (0.99-1.46), and 1.24 (1.02-1.51) for women in the 2nd, 3rd, 4th, and 5th quintiles of energy-adjusted UPF intake, respectively, compared to those in the bottom quintile (p-trend = 0.02). The associations were similar in sensitivity analyses using Multiple Imputation and Inverse Probability Weighting to account for potential selection bias. CONCLUSIONS:Higher UPF intakes in midlife were associated with higher odds of late-life SCCs in women.

BACKGROUND:The relationship between body mass index (BMI) changes across the lifespan and cognitive health in later life remains unclear. This study evaluated the association between BMI changes from midlife to late-life and subsequent subjective cognitive complaints (SCCs) in women. METHODS:We analysed data from 5160 women in the New York University Women's Health Study, a prospective cohort with over 30 years of follow-up. BMI was calculated using self-reported height and weight at baseline and follow-up. SCCs were assessed using a validated questionnaire in 2018-2020. Odds ratios (ORs) for reporting ≥2 SCCs were estimated using unconditional logistic regression. RESULTS:BMI at specific life stages was not significantly associated with SCC risk. BMI changes from midlife to late-life were associated with SCC risk. Compared to women with stable BMI (≤5% change), moderate BMI loss (5.1-10% decrease) was associated with higher odds of ≥2 SCCs (OR: 1.23, 95% CI: 1.02-1.48), large BMI gain (>10% increase) was associated with lower odds of ≥2 SCCs (OR: 0.81, 95% CI: 0.67-0.97). These findings were consistent across sensitivity analyses, including varying age cut-offs and excluding BMI changes occurring 5-10 years before late-life. CONCLUSIONS:Our findings emphasize the importance of considering lifelong weight changes in assessing cognitive health risks. In particular, significant weight loss from midlife to late-life may serve as a potential indicator of cognitive decline in older adults. Further research is needed to elucidate the underlying mechanisms of this association and to explore effective interventions for mitigating cognitive health risks.

BACKGROUND:Among premenopausal women, higher body mass index (BMI) is associated with lower breast cancer risk, although the underlying mechanisms are unclear. Investigating adiposity distribution may help clarify impacts on breast cancer risk. This study was initiated to investigate associations of central and peripheral adiposity with premenopausal breast cancer risk overall and by other risk factors and breast cancer characteristics. METHODS:We used individual-level data from 14 prospective cohort studies to estimate hazard ratios (HRs) for premenopausal breast cancer using Cox proportional hazards regression. Analyses included 440,179 women followed for a median of 7.5 years (interquartile range: 4.0-11.3) between 1976 and 2017, with 6,779 incident premenopausal breast cancers. RESULTS:All central adiposity measures were inversely associated with breast cancer risk overall when not controlling for BMI (e.g. for waist circumference, HR per 10 cm increase: 0.92, 95% confidence interval (CI): 0.90-0.94) whereas in models adjusting for BMI, these measures were no longer associated with risk (e.g. for waist circumference: HR 0.99, 95% CI: 0.95-1.03). This finding was consistent across age categories, with some evidence that BMI-adjusted associations differed by breast cancer subtype. Inverse associations for in situ breast cancer were observed with waist-to-height and waist-to-hip ratios and a positive association was observed for oestrogen-receptor-positive breast cancer with hip circumference (HR per 10 cm increase: 1.08, 95% CI: 1.10-1.14). For luminal B, HER2-positive breast cancer, we observed an inverse association with hip circumference (HR per 10 cm: 0.84, 95% CI: 0.71-0.98), but positive associations with waist circumference (HR per 10 cm: 1.18, 95% CI: 1.03-1.36), waist-to-hip ratio (HR per 0.1 units: 1.29, 95% CI: 1.15-1.45) and waist-to height ratio (HR per 0.1 units: 1.46, 95% CI: 1.17-1.84). CONCLUSIONS:Our analyses did not support an association between central adiposity and overall premenopausal breast cancer risk after adjustment for BMI. However, our findings suggest associations might differ by breast cancer hormone receptor and intrinsic subtypes.

BACKGROUND:The American Cancer Society recommends physicians inform average risk women about endometrial cancer (EC) risk on reaching menopause, but new diagnoses are rising fastest in women <50 years. Educating these women about EC risks requires knowledge of risk factors. However, EC in young women is rare and challenging to study in single study populations. METHODS:We included 13,846 incident EC patients (1,639 < 50 years) and 30,569 matched control individuals from the Epidemiology of Endometrial Cancer Consortium. We used generalized linear models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 6 risk factors and EC risk. We created a risk score to evaluate the combined associations and population attributable fractions of these factors. RESULTS:In younger and older women, we observed positive associations with BMI and diabetes, and inverse associations with age at menarche, oral contraceptive use, and parity. Current smoking was associated with reduced risk only in women ≥50 years (PHet<0.01). BMI was the strongest risk factor [OR≥35 vs <25 kg/m2=5.57 (95% CI:4.33-7.16) for <50 years; OR≥35 vs <25 kg/m2=4.68 (95% CI : 4.30-5.09) for ≥50 years; PHet=0.14]. Possessing ≥4 risk factors was associated with ∼9-fold increased risk in women <50 years and ∼4-fold increased risk in women ≥50 years (PHet<0.01). Together, 59.1% of ECs in women <50 and 55.6% in women ≥50 were attributable to these factors. CONCLUSIONS:Our data confirm younger and older women share common EC risk factors. Early educational efforts centered on these factors may help mitigate the rising EC burden in young women.

PURPOSE/OBJECTIVE:To examine the association between cumulative exposure to neighborhood walkability (NW) and diabetes risk. METHODS:A total of 11,037 women free of diabetes at enrollment were included. We constructed a 4-item NW index at baseline, and a 2-item average annual NW across years of follow-up that captured both changes in neighborhood features and residential moves. We used multivariable Cox PH regression models with robust variance to estimate the hazard ratios (HRs) of diabetes by NW scores. RESULTS:Compared with women living in areas with lowest NW (Q1), those living in areas with highest NW (Q4) had 33 % (26 %-39 %) reduced risk of incident diabetes, using baseline NW, and 25 % (95 % CI 11 %-36 %), using average annual NW. Analysis using time-varying exposure showed that diabetes risks decreased by 13 % (10 %-16 %) per -standard deviation increase in NW. The associations remained similar when using inverse probability of attrition weights and/or competing risk models to account for the effect of censoring due to death or non-response. The associations of average annual NW with incident diabetes were stronger in postmenopausal women as compared to premenopausal women. CONCLUSION/CONCLUSIONS:Long-term residence in more walkable neighborhoods may be protective against diabetes in women, especially postmenopausal women.