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To access publisher's full text version of this article click on the hyperlink below ; OBJECTIVE: To study the association of fish and fish-liver oil consumption across the lifespan with CHD later in life among Icelandic women, with special emphasis on the effects of consumption in adolescence. DESIGN: Prevalence association study. Logistic regression was used to estimate odds ratios and 95 % confidence intervals of CHD according to fish or fish-liver oil exposure. Models were adjusted for age, education, concurrent diet and other known risk factors. SETTING: The study was nested within the AGES-Reykjavik Study, conducted in Reykjavik, Iceland. SUBJECTS: Participants were 3326 women aged 66-96 years, with available information on CHD status at entry to the study and information on fish and fish-liver oil consumption during midlife and adolescence. Dietary habits were assessed retrospectively using a validated FFQ. RESULTS: CHD was identified in 234 (7·9 %) women. Compared with women with no intake of fish-liver oil in adolescence or midlife, women who consumed fish-liver oil at least three times weekly in adolescence or in midlife had a decreased risk of CHD (OR=0·62; 95 % CI 0·45, 0·85 and OR=0·68; 95 % CI 0·50, 0·94, respectively). No associations were observed between fish intake (>2 portions/week v. ≤2 portions/week) in adolescence or midlife and CHD in this population with high fish intake. CONCLUSIONS: Fish-liver oil consumption, from early life, may reduce the risk of CHD in older women. Lifelong nutrition may be of importance in the prevention of CHD in older women. ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Aging (NIA) Icelandic Heart Association Icelandic Parliament United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Aging (NIA) Icelandic Parlament

Objective To test the hypothesis that age-related macular degeneration (AMD) and retinal microvascular signs are differentially associated with lobar and deep cerebral microbleeds (CMBs). Methods CMBs in lobar regions indicate cerebral amyloid angiopathy (CAA). β-Amyloid deposits are implicated in both CAA and AMD. Deep CMBs are associated with hypertension, a major risk factor for retinal microvascular damage. This population-based cohort study included 2,502 participants in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study who undertook binocular digital retinal photographs at baseline (2002–2006) to assess retinal microvascular signs and AMD and brain MRI scan at both baseline and follow-up (2007–2011) to assess CMBs. We assessed retinal microvascular lesion burden by counting the 3 retinal microvascular signs (focal arteriolar narrowing, arteriovenous nicking, and retinopathy) concurrently present in the participant. We used multiple logistic models to examine the association of baseline retinal pathology to incident CMBs detected at follow-up. Results During an average 5.2 years of follow-up, 461 people (18.3%) developed new CMBs, including 293 in exclusively lobar regions and 168 in deep regions. Pure geographic atrophy was significantly associated with strictly lobar CMBs (multivariable-adjusted odds ratio 2.59, 95% confidence interval [CI] 1.01–6.65) but not with deep CMBs. Concurrently having ≥2 retinal microvascular signs was associated with a 3-fold (95% CI 1.73–5.20) increased likelihood for deep CMBs but not exclusively lobar CMBs. Conclusions Retinal microvascular signs and pure geographic atrophy may be associated with deep and exclusively lobar CMBs, respectively, in older people. These results have implications for further research to define the role of small vessel disease in cognitive impairment. ; The AGES-Reykjavik Study was funded by the NIH (contract N01-AG-12100); the Intramural Research Program of the National Institute on Aging and the National Eye Institute (ZIAEY000401), NIH; and the Icelandic Heart Association and the Icelandic Parliament. None of the funding organizations or sponsors were involved in study design; in the collection, analysis, or interpretation of data; in writing of the report; or in the decision to submit the manuscript for publication. ; Peer Reviewed

To access publisher's full text version of this article click on the hyperlink at the bottom of the page ; There is little evidence on the long-term association between physical activity (PA) and depressive symptoms in old age. We examined the association of midlife PA and depressive symptoms in late life. ; A large community-based population residing in Reykjavik, Iceland, participated in a longitudinal study with an average of 25 years of follow up. Midlife PA was categorized as active and inactive groups (n = 4,140, Active = 1,292, Inactive = 2,848, mean age 52±7 years). The main outcome had six or higher depressive symptoms assessed by the 15-item Geriatric Depression scale. Participants who had a history of depression (n = 226), and were diagnosed with dementia (n = 393), and had incomplete cognitive data (n = 595) and incomplete analytical data (n = 422) were excluded. Level of weekly PA was ascertained by a questionnaire at midlife. Depressive symptoms were assessed on average 25 (±4) years later. ; After controlling for demographic and health-related risk factors, those who were active at midlife were less likely to have high level of depressive symptomatology (6 or higher Geriatric Depression scale scores, odds ratio = 0.58, 95% confidence interval: 0.41-0.83, p < .005) compared with those who were inactive in midlife. After full adjustment of three domains of late-life cognitive function the results remained significant (odds ratio = 0.61, 95% confidence interval: 0.43-0.86, p = .005). ; Our study shows that midlife PA is associated with lower depressive symptoms 25 years later. Participating in regular PA in midlife may improve mental health in late life. ; National Institutes of Health/N01-AG-12100 National Institute on Aging Intramural Research Program Icelandic Heart Association Landspitali University Hospital Icelandic Parliament

Publisher's version (útgefin grein) ; Recent studies indicate that lifestyle factors in early life affect breast cancer risk. We therefore explored the association of high consumption of meat, milk, and whole grain products in adolescence and midlife, on breast cancer risk. We used data from the population based AGES-Reykjavik cohort (2002–2006), where 3,326 women with a mean age of 77 years (SD 6.0) participated. For food items and principal component derived dietary patterns we used Cox proportional models to calculate multivariate hazard ratios (HR) with 95% confidence intervals (95% CI). During a mean follow-up of 8.8 years, 97 women were diagnosed with breast cancer. For both adolescence and midlife, daily consumption of rye bread was positively associated with breast cancer (HR 1.7, 95% CI 1.1–2.6 and HR 1.8, 95% CI 1.1–2.9, respectively). In contrast, persistent high consumption of oatmeal was negatively associated with breast cancer (0.4, 95% CI 0.2–0.9). No association was found for other food items or dietary patterns that included rye bread. High rye bread consumption in adolescence and midlife may increase risk of late-life breast cancer whilst persistent consumption of oatmeal may reduce the risk. ; The AGES-Reykjavik Study was funded by NIH contract N01-AG-12100, the Intramural Research Program of the National Institute on Aging, by the Icelandic Heart Association and the Icelandic Parliament. This work was supported by the The Icelandic Centre for Research, RANNIS grant number: 152495051, (http://en.rannis.is/) (A. Haraldsdottir) and the Public Health Fund of the Icelandic Directorate of Health (A. Haraldsdottir). The funding agencies (National Institute on Aging, Icelandic Heart Association and Icelandic Parlament,) for the AGES-Reykjavik Study, RANNIS, or Directorate of Health had no role in the design, analysis or writing of this article. ; Peer Reviewed

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/Open To access publisher's full text version of this article click on the hyperlink at the bottom of the page ; Background: Little is known about fish intake throughout the life course and the risk of breast cancer.Methods: We used data on the first residence of 9,340 women born 1908 to 1935 in the Reykjavik Study as well as food frequency data for different periods of life from a subgroup of the cohort entering the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study (n = 2,882).Results: During a mean follow-up of 27.3 years, 744 women were diagnosed with breast cancer in the Reykjavik Study. An inverse association of breast cancer was observed among women who lived through the puberty period in coastal villages, compared with women residing in the capital area [HR, 0.78; 95% confidence interval (CI), 0.61-0.99]. In the subgroup analysis of this Icelandic population, generally characterized by high fish intake, we found an indication of lower risk of breast cancer among women with high fish consumption (more than 4 portions per week) in adolescence (HR, 0.71; 95% CI, 0.44-1.13) and midlife (HR, 0.46; 95% CI, 0.22-0.97), compared with low consumers (2 portions per week or less). No association was found for fish liver oil consumption in any time period, which could be due to lack of a reference group with low omega-3 fatty acids intake in the study group.Conclusions: Our findings suggest that very high fish consumption in early to midlife may be associated with a reduced risk of breast cancer.Impact: Very high fish consumption in early adulthood to midlife may be associated with decreased risk of breast cancer. Cancer Epidemiol Biomarkers Prev; 26(3); 346-54. ©2016 AACR. ; NIH Intramural Research Program of the National Institute on Aging Icelandic Heart Association Icelandic Parliament Icelandic Centre for Research, RANNIS Public Health Fund of the Icelandic Directorate of Health

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. ; The aim of this study was to investigate the associations between loss of a life partner and the development of dementia and decline in cognitive function in later life. We used an Icelandic cohort of 4,370 participants in the Age, Gene/Environment Susceptibility-Reykjavik Study who were living as married in 1978 (born in 1907-1935) and were either still married (unexposed cohort) or widowed (exposed cohort) at follow-up (in 2002-2006). We ascertained history of marital status and spouse's death by record linkage to the Registry of the Total Population, Statistics Iceland. The outcome measures were as follows: 1) dementia and mild cognitive impairment; and 2) memory, speed of processing, and executive function. During the observation period, 3,007 individuals remained married and 1,363 lost a spouse through death. We did not find any significant associations between loss of a spouse and our outcome variables, except that widowed women had poorer executive function (mean = -0.08) during the first 2 years after their husbands' deaths compared with still-married women (mean = 0.09). Our findings do not support the notion that the risk of dementia is increased following the loss of a spouse, yet women demonstrate a seemingly temporary decline in executive function following the death of a partner. ; University of Iceland Research Fund for Graduate Students Icelandic Research Fund for Graduate Students (Rannis) Memorial Fund of Helga Jonsdottir and Sigurlidi Kristjansson Research Fund of Oldrunarrad Islands Icelandic Gerontological Society Research Fund Fund of Gudmundur Andresson Swedish Society for Medical Research National Institute on Aging N01-AG-1-2100 National Institute on Aging Icelandic Parliament Icelandic Heart Association

Publisher's version (útgefin grein) ; Background: Lipids are implicated in the pathogenesis of age-related macular degeneration (AMD). The relationship between systemic lipids and AMD has not been well characterized. The objective was to investigate the relationship between serum lipids and AMD in older adults using a lipidomic approach. Methods: In a case-control study, 240 adults, aged ≥66 years, a third each having geographic atrophy, neovascular AMD, or no signs of AMD, were selected from a population-based sample of participants in the Age Gene/Environment Susceptibility-Reykjavik Study. The exposure was serum lipids and risk factors for AMD. The outcome was late AMD, assessed through fundus images taken through dilated pupils using a 45-degree digital camera and grading for neovascular AMD and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System. Results: Of 177 serum lipid species measured, there were no significant differences in serum lipids between controls and those with geographic atrophy or neovascular AMD, respectively. Adults with neovascular AMD had higher total serum lysophosphatidylcholine (LPC) (P = 0.004) and serum LPC 18:0 (P = 0.0002) compared to those with geographic atrophy. Conclusion: Late AMD was not characterized by alterations in systemic lipids compared with normal controls. These findings suggest that there may be differences in the LPC pathway between adults with neovascular AMD and geographic atrophy. ; This work was supported by National Institutes of Health grants R01 AG027012 and R01 EY017362, the Intramural Research Programs of the National Institute on Aging and the National Eye Institute (ZIAEY00401 and National Institutes of Health contract numbers N01-AG-1-2100 and HHSN271201200022C), the Iceland Heart Association, the Icelandic Parliament, and the University of Iceland Research Fund. The National Eye Institute was involved in the design and conduct of the study in regard to collection of fundus photographs. The funders had no role in data collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. ; Peer Reviewed

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download ; Lipids are implicated in the pathogenesis of age-related macular degeneration (AMD). The relationship between systemic lipids and AMD has not been well characterized. The objective was to investigate the relationship between serum lipids and AMD in older adults using a lipidomic approach. In a case-control study, 240 adults, aged ≥66 years, a third each having geographic atrophy, neovascular AMD, or no signs of AMD, were selected from a population-based sample of participants in the Age Gene/Environment Susceptibility-Reykjavik Study. The exposure was serum lipids and risk factors for AMD. The outcome was late AMD, assessed through fundus images taken through dilated pupils using a 45-degree digital camera and grading for neovascular AMD and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System. Of 177 serum lipid species measured, there were no significant differences in serum lipids between controls and those with geographic atrophy or neovascular AMD, respectively. Adults with neovascular AMD had higher total serum lysophosphatidylcholine (LPC) (P = 0.004) and serum LPC 18:0 (P = 0.0002) compared to those with geographic atrophy. Late AMD was not characterized by alterations in systemic lipids compared with normal controls. These findings suggest that there may be differences in the LPC pathway between adults with neovascular AMD and geographic atrophy. ; National Institutes of Health National Institute on Aging National Eye Institute Iceland Heart Association Icelandic Parliament University of Iceland Research Fund

Publisher's version (útgefin grein) ; The etiology of monoclonal gammopathy of undetermined significance (MGUS), the precursor state of multiple myeloma (MM), is mostly unknown and no studies have been conducted on the effect of diet on MGUS or progression from MGUS to MM. We aimed to explore the association between common foods and MGUS and progression to MM. Data from the population-based AGES Study (N = 5,764) were utilized. Food frequency questionnaire was used to assess dietary intake during adolescence, midlife, and late life. Serum protein electrophoresis and serum free light-chain assay was performed to identify MGUS (n = 300) and LC-MGUS cases (n = 275). We cross linked our data with the Icelandic Cancer Registry to find cases of MM in the study group. We found that intake of fruit at least three times per week during adolescence was associated with lower risk of MGUS when compared to lower fruit consumption (OR = 0.62, 95% CI 0.41–0.95). We additionally found that intake of fruit at least three times per week during the late life period was associated with decreased risk of progressing from MGUS to MM (HR = 0.34, 95% CI 0.13–0.89) when compared to lower intake. Adolescent intake of fruit may reduce risk of MGUS, whereas fruit intake after MGUS onset may reduce risk of progressing to MM. Our findings suggest that diet might alter the risk of developing MGUS and progression to MM. ; The AGES-Reykjavik Study was funded by NIH contract N01-AG-012100, the Intramural Research Program of the National Institute on Aging, by the Icelandic Heart Association, and the Icelandic Parliament. This work was supported by the Icelandic Centre for Research, RANNIS (S.Y. Kristinsson), the Landspitali University Hospital Research Fund (S.Y. Kristinsson), the Karolinska Instituted Foundations (S.Y. Kristinsson), the Marie Curie CIG (S.Y. Kristinsson), and the Memorial Sloan Kettering Core Grant (P30 CA008748) from the National Cancer Institute (O.Landgren). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ; Peer Reviewed

Publisher's version (útgefin grein) ; Importance: Dual decline in both memory and gait speed may characterize a group of older individuals at high risk for future dementia. Objective: To assess the risk of dementia in older persons who experience parallel declines in memory and gait speed compared with those who experience no decline or decline in either memory or gait speed only. Design, Setting, and Participants: A multicohort meta-analysis was performed of 6 prospective cohort studies conducted between 1997 and 2018 in the United States and Europe. Participants were 60 years or older, had an initial gait speed of more than 0.6 m/s (ie, free of overt dismobility), with repeated measures of memory and gait speed before dementia diagnosis during a mean follow-up of 6.6 to 14.5 years. Within each study, participants were divided into 4 groups: memory decline only, gait speed decline only, dual decline, or no decline (hereafter referred to as usual agers). Gait decline was defined as a loss of 0.05 m/s or more per year; memory decline was defined as being in the cohort-specific lowest tertile of annualized change. Main Outcomes and Measures: Risk of incident dementia according to group membership was examined by Cox proportional hazards regression with usual agers as the reference, adjusted for baseline age, sex, race/ethnicity, educational level, study site, and baseline gait speed and memory. Results: Across the 6 studies of 8699 participants, mean age ranged between 70 and 74 years and mean gait speed ranged between 1.05 and 1.26 m/s. Incident dementia ranged from 5 to 21 per 1000 person-years. Compared with usual agers, participants with only memory decline had 2.2 to 4.6 times higher risk for developing dementia (pooled hazard ratio, 3.45 [95% CI, 2.45-4.86]). Those with only gait decline had 2.1 to 3.6 times higher risk (pooled hazard ratio, 2.24 [95% CI, 1.62-3.09]). Those with dual decline had 5.2 to 11.7 times the risk (pooled hazard ratio, 6.28 [95% CI, 4.56-8.64]). Conclusions and Relevance: In this study, dual decline of memory and gait speed was associated with increased risk of developing dementia among older individuals, which might be a potentially valuable group for preventive or therapeutic interventions. Why dual decline is associated with an elevated risk of dementia and whether these individuals progress to dementia through specific mechanisms should be investigated by future studies. ; This research work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (Drs Tian, Resnick, Launer, Simonsick, Studenski, and Ferrucci). The BLSA was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The AGES-Reykjavik Study was funded by contract N01-AG-12100 from the National Institutes of Health; by the Intramural Research Program of the National Institute on Aging; and by the Icelandic Heart Association and the Icelandic Parliament. The Health ABC study was supported by National Institute on Aging contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; National Institute on Aging grant R01-AG028050; and National Institute of Nursing Research grant R01-NR012459, and was funded in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The MCSA was supported by funding from the National Institutes of Health, National Institute on Aging (U01 AG006786), the Gerald and Henrietta Rauenhorst Foundation, and the Mayo Foundation for Medical Education and Research; and was made possible by the Rochester Epidemiology Project (R01 AG034676). The SNAC-K was supported by the funders of the Swedish National Study on Aging and Care; the Ministry of Health and Social Affairs, Sweden; the participating County Councils and Municipalities; and the Swedish Research Council. The InCHIANTI study was supported by National Institute on Aging contracts 263MD9164 (Dr Ferrucci) and 263 MD 821336, N01-AG-1-1, N01-AG-10211, and N01-AG-5-0002 (Dr Bandinelli), and partially supported by grant n PE 2011 02350413 of the Italian Ministry of Health (Dr Cherubini). ; Peer Reviewed

Article in press ; Dynamic sitting, such as fidgeting and desk work, might be associated with health, but remains difficult toidentify out of accelerometry data. We examined, in a laboratory study, whether dynamic sitting can beidentified out of triaxial activity counts. Among 18 participants (56% men, 27.3 ± 6.5 years), up to 236 countsper minute were recorded in the anteroposterior and mediolateral axes during dynamic sitting using a hip-worn accelerometer. Subsequently, we examined in 621 participants (38% men, 80.0 ± 4.7 years) from theAGES-Reykjavik Study whether dynamic sitting was associated with cardio-metabolic health. Compared toparticipants who recorded the fewest dynamic sitting minutes (Q1), those with more dynamic sittingminutes had a lower BMI (Q2=−1.39 (95%CI =−2.33;–0.46); Q3=−1.87 (−2.82;–0.92); Q4=−3.38 (−4.32;–2.45)), a smaller waist circumference (Q2=−2.95 (−5.44;–0.46); Q3=−3.47 (−6.01;–0.93); Q4=−8.21 (−10.72;–5.71)), and a lower odds for the metabolic syndrome (Q2= 0.74 [0.45;1.20] Q3= 0.58 [0.36;0.95]; Q4=0.36[0.22;0.59]). Our findings suggest that dynamic sitting might be identified using accelerometry and that thisbehaviour was associated with health. This might be important given the large amounts of time peoplespend sitting. Future studies with a focus on validation, causation and physiological pathways are needed tofurther examine the possible relevance of dynamic sitting. ; This work was supported by the National Institute on Aging;National Institutes of Health [N01-AG-12100];FP7 People: Marie-Curie Actions (FP7- PEOPLE-2011-CIG) [PCIG09-GA-2011-293621];Icelandic Heart Association; Icelandic Parliament. ; Peer reviewed

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download ; Dynamic sitting, such as fidgeting and desk work, might be associated with health, but remains difficult to identify out of accelerometry data. We examined, in a laboratory study, whether dynamic sitting can be identified out of triaxial activity counts. Among 18 participants (56% men, 27.3 ± 6.5 years), up to 236 counts per minute were recorded in the anteroposterior and mediolateral axes during dynamic sitting using a hip-worn accelerometer. Subsequently, we examined in 621 participants (38% men, 80.0 ± 4.7 years) from the AGES-Reykjavik Study whether dynamic sitting was associated with cardio-metabolic health. Compared to participants who recorded the fewest dynamic sitting minutes (Q1), those with more dynamic sitting minutes had a lower BMI (Q2 = -1.39 (95%CI = -2.33;-0.46); Q3 = -1.87 (-2.82;-0.92); Q4 = -3.38 (-4.32;-2.45)), a smaller waist circumference (Q2 = -2.95 (-5.44;-0.46); Q3 = -3.47 (-6.01;-0.93); Q4 = -8.21 (-10.72;-5.71)), and a lower odds for the metabolic syndrome (Q2 = 0.74 [0.45;1.20] Q3 = 0.58 [0.36;0.95]; Q4 = 0.36 [0.22;0.59]). Our findings suggest that dynamic sitting might be identified using accelerometry and that this behaviour was associated with health. This might be important given the large amounts of time people spend sitting. Future studies with a focus on validation, causation and physiological pathways are needed to further examine the possible relevance of dynamic sitting. ; National Institute on Aging National Institutes of Health FP7 People: Marie-Curie Actions (FP7-PEOPLE-2011-CIG) Icelandic Heart Association Icelandic Parliament

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. ; Melatonin has anticarcinogenic properties in experimental models. We undertook a case-cohort study of 928 Icelandic men without prostate cancer (PCa) nested within the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort to investigate the prospective association between first morning-void urinary 6-sulfatoxymelatonin (aMT6s) levels and the subsequent risk for PCa, under the hypothesis that men with lower aMT6s levels have an increased risk for advanced PCa. We used weighted Cox proportional hazards models to assess the association between first morning-void aMT6s levels and PCa risk, adjusting for potential confounders. A total of 111 men were diagnosed with incident PCa, including 24 with advanced disease. Men who reported sleep problems at baseline had lower morning aMT6s levels compared with those who reported no sleep problems. Men with morning aMT6s levels below the median had a fourfold statistically significant increased risk for advanced disease compared with men with levels above the median (hazard ratio: 4.04; 95% confidence interval, 1.26-12.98). These results require replication in larger prospective studies with longer follow-up. ; In this report, we evaluated the prospective association between urinary aMT6s levels and risk of PCa in an Icelandic population. We found that lower levels of aMT6s were associated with an increased risk for advanced PCa. ; RANNIS (the Icelandic Research Fund) National Institutes of Health (NIH) National Center for Research Resources UL1-RR-025758 KL2-RR-025757 Icelandic Cancer Society NIH National Cancer Institute R25-CA-098566 T32-CA-09001-35 Prostate Cancer Foundation NIH National Institutes on Aging (NIA) N01-AG-12100 Icelandic Heart Association Icelandic Parliament NIH NIA P01-AG-009975

Structural brain magnetic resonance imaging (MRI) traits share part of their genetic variance with cognitive traits. Here, we use genetic association results from large meta-analytic studies of genome-wide association (GWA) for brain infarcts (BI), white matter hyperintensities, intracranial, hippocampal, and total brain volumes to estimate polygenic scores for these traits in three Scottish samples: Generation Scotland: Scottish Family Health Study (GS:SFHS), and the Lothian Birth Cohorts of 1936 (LBC1936) and 1921 (LBC1921). These five brain MRI trait polygenic scores were then used to: (1) predict corresponding MRI traits in the LBC1936 (numbers ranged 573 to 630 across traits), and (2) predict cognitive traits in all three cohorts (in 8,115–8,250 persons). In the LBC1936, all MRI phenotypic traits were correlated with at least one cognitive measure, and polygenic prediction of MRI traits was observed for intracranial volume. Meta-analysis of the correlations between MRI polygenic scores and cognitive traits revealed a significant negative correlation (maximal r = 0.08) between the HV polygenic score and measures of global cognitive ability collected in childhood and in old age in the Lothian Birth Cohorts. The lack of association to a related general cognitive measure when including the GS:SFHS points to either type 1 error or the importance of using prediction samples that closely match the demographics of the GWA samples from which prediction is based. Ideally, these analyses should be repeated in larger samples with data on both MRI and cognition, and using MRI GWA results from even larger meta-analysis studies.

Introduction: Many consequences of cerebrovascular disease are identifiable by magnetic resonance imaging (MRI), but variation in methods limits multicenter studies and pooling of data. The European Union Joint Program on Neurodegenerative Diseases (EU JPND) funded the HARmoNizing Brain Imaging MEthodS for VaScular Contributions to Neurodegeneration (HARNESS) initiative, with a focus on cerebral small vessel disease. Methods: Surveys, teleconferences, and an in-person workshop were used to identify gaps in knowledge and to develop tools for harmonizing imaging and analysis. Results: A framework for neuroimaging biomarker development was developed based on validating repeatability and reproducibility, biological principles, and feasibility of implementation. The status of current MRI biomarkers was reviewed. A website was created at www.harness-neuroimaging.org with acquisition protocols, a software database, rating scales and case report forms, and a deidentified MRI repository. Conclusions: The HARNESS initiative provides resources to reduce variability in measurement in MRI studies of cerebral small vessel disease.