%0 Journal Article %J J Alzheimers Dis %D 2024 %T Interaction Between Arteriosclerosis and Amyloid-β on Cognitive Function. %A Frentz, Ingeborg %A van Arendonk, Joyce %A Leeuwis, Anna E %A Vernooij, Meike W %A van der Flier, Wiesje M %A Bos, Daniel %A De Deyn, Peter Paul %A Wolters, Frank J %A Ikram, M Arfan %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Arteriosclerosis %K Biomarkers %K Cognition %K Cognitive Dysfunction %K Female %K Humans %K Male %K tau Proteins %X

BACKGROUND: Dementia is a multifactorial disease, with Alzheimer's disease (AD) and vascular pathology often co-occurring in many individuals with dementia. Yet, the interplay between AD and vascular pathology in cognitive decline is largely undetermined.

OBJECTIVE: The aim of the present study was to examine the joint effect of arteriosclerosis and AD pathology on cognition in the general population without dementia.

METHODS: We determined the interaction between blood-based AD biomarkers and CT-defined arteriosclerosis on cognition in 2,229 dementia-free participants of the population-based Rotterdam Study (mean age: 68.9 years, 52% women) cross-sectionally.

RESULTS: Amyloid-β (Aβ)42 and arterial calcification were associated with cognitive performance. After further adjustment for confounders in a model that combined all biomarkers, only arterial calcification remained independently associated with cognition. There was a significant interaction between arterial calcification and Aβ42 and between arterial calcification and the ratio of Aβ42/40. Yet, estimates attenuated, and interactions were no longer statistically significant after adjustment for cardio metabolic risk factors.

CONCLUSIONS: Arteriosclerosis and AD display additive interaction-effects on cognition in the general population, that are due in part to cardio metabolic risk factors. These findings suggest that joint assessment of arteriosclerosis and AD pathology is important for understanding of disease etiology in individuals with cognitive impairment.

%B J Alzheimers Dis %V 97 %P 953-961 %8 2024 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/38217596?dopt=Abstract %R 10.3233/JAD-230604 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis. %A Frenzel, Stefan %A Bis, Josh C %A Gudmundsson, Elias F %A O'Donnell, Adrienne %A Simino, Jeannette %A Yaqub, Amber %A Bartz, Traci M %A Brusselle, Guy G O %A Bülow, Robin %A DeCarli, Charles S %A Ewert, Ralf %A Gharib, Sina A %A Ghosh, Saptaparni %A Gireud-Goss, Monica %A Gottesman, Rebecca F %A Ikram, M Arfan %A Knopman, David S %A Launer, Lenore J %A London, Stephanie J %A Longstreth, W T %A Lopez, Oscar L %A Melo van Lent, Debora %A O'Connor, George %A Satizabal, Claudia L %A Shrestha, Srishti %A Sigurdsson, Sigurdur %A Stubbe, Beate %A Talluri, Rajesh %A Vasan, Ramachandran S %A Vernooij, Meike W %A Völzke, Henry %A Wiggins, Kerri L %A Yu, Bing %A Beiser, Alexa S %A Gudnason, Vilmundur %A Mosley, Thomas %A Psaty, Bruce M %A Wolters, Frank J %A Grabe, Hans J %A Seshadri, Sudha %X

BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.

OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables.

METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.

RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.

CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

%B J Alzheimers Dis %V 90 %P 1073-1083 %8 2022 Nov 22 %G eng %N 3 %R 10.3233/JAD-220667 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Loneliness, Not Social Support, Is Associated with Cognitive Decline and Dementia Across Two Longitudinal Population-Based Cohorts. %A Freak-Poli, Rosanne %A Wagemaker, Nina %A Wang, Rui %A Lysen, Thom S %A Ikram, M Arfan %A Vernooij, Meike W %A Dintica, Christina S %A Vernooij-Dassen, Myrra %A Melis, Rene J M %A Laukka, Erica J %A Fratiglioni, Laura %A Xu, Weili %A Tiemeier, Henning %X

BACKGROUND: Poor social health is likely associated with cognitive decline and risk of dementia; however, studies show inconsistent results. Additionally, few studies separate social health components or control for mental health.

OBJECTIVE: To investigate whether loneliness and social support are independently associated with cognitive decline and risk of dementia, and whether depressive symptoms confound the association.

METHODS: We included 4,514 participants from the population-based Rotterdam Study (RS; aged 71±7SD years) followed up to 14 years (median 10.8, interquartile range 7.4-11.6), and 2,112 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K; aged 72±10SD years) followed up to 10 years (mean 5.9±1.6SD). At baseline, participants were free of major depression and scored on the Mini-Mental State Examination (MMSE) ≥26 for RS and ≥25 for SNAC-K. We investigated loneliness, perceived social support, and structural social support (specifically marital status and number of children). In both cohorts, dementia was diagnosed and cognitive function was repeatedly assessed with MMSE and a global cognitive factor (g-factor).

RESULTS: Loneliness was prospectively associated with a decline in the MMSE in both cohorts. Consistently, persons who were lonely had an increased risk of developing dementia (RS: HR 1.34, 95%CI 1.08-1.67; SNAC-K: HR 2.16, 95%CI 1.12-4.17). Adjustment for depressive symptoms and exclusion of the first 5 years of follow-up did not alter results. Neither perceived or structural social support was associated with cognitive decline or dementia risk.

CONCLUSION: Loneliness, not social support, predicted cognitive decline and incident dementia independently of depressive symptoms.

%B J Alzheimers Dis %V 85 %P 295-308 %8 2022 Jan 04 %G eng %N 1 %R 10.3233/JAD-210330 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Lung Function Impairment and the Risk of Incident Dementia: The Rotterdam Study. %A Xiao, Tian %A Wijnant, Sara R A %A Licher, Silvan %A Terzikhan, Natalie %A Lahousse, Lies %A Ikram, M Kamran %A Brusselle, Guy G %A Ikram, M Arfan %X

BACKGROUND: The etiology of dementia may partly be underpinned by impaired lung function via systemic inflammation and hypoxia.

OBJECTIVE: To prospectively examine the association between chronic obstructive pulmonary disease (COPD) and subclinical impairments in lung function and the risk of dementia.

METHODS: In the Rotterdam Study, we assessed the risk of incident dementia in participants with Preserved Ratio Impaired Spirometry (PRISm; FEV1/FVC≥0.7, FEV1 < 80% predicted) and in participants with COPD (FEV1/FVC < 0.7) compared to those with normal spirometry (controls; FEV1/FVC≥0.7, FEV1≥80% predicted). Hazard ratios (HRs) with 95% confidence intervals (CI) for dementia were adjusted for age, sex, education attainment, smoking status, systolic blood pressure, body mass index, triglycerides, comorbidities and Apolipoprotein E (APOE) genotype.

RESULTS: Of 4,765 participants, 110 (2.3%) developed dementia after 3.3 years. Compared to controls, participants with PRISm, but not COPD, had an increased risk for all-type dementia (adjusted HRPRISm 2.70; 95% CI, 1.53-4.75; adjusted HRCOPD 1.03; 95% CI, 0.61-1.74). These findings were primarily driven by men and smokers. Similarly, participants with FVC% predicted values in the lowest quartile compared to those in the highest quartile were at increased risk of all-type dementia (adjusted HR 2.28; 95% CI, 1.31-3.98), as well as Alzheimer's disease (AD; adjusted HR 2.13; 95% CI, 1.13-4.02).

CONCLUSION: Participants with PRISm or a low FVC% predicted lung function were at increased risk of dementia, compared to those with normal spirometry or a higher FVC% predicted, respectively. Further research is needed to elucidate whether this association is causal and how PRISm might contribute to dementia pathogenesis.

%B J Alzheimers Dis %V 82 %P 621-630 %8 2021 Jul 20 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34057085?dopt=Abstract %R 10.3233/JAD-210162 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Telomere Length and the Risk of Alzheimer's Disease: The Rotterdam Study. %A Fani, Lana %A Hilal, Saima %A Sedaghat, Sanaz %A Broer, Linda %A Licher, Silvan %A Arp, Pascal P %A van Meurs, Joyce B J %A Ikram, M Kamran %A Ikram, M Arfan %X

There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer's disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of Alzheimer's disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer's disease. We found a U-shaped association between telomere length and risk of Alzheimer's disease: compared to the middle tertile the adjusted hazard ratio was 1.59 (95% confidence interval (CI), 1.13-2.23) for the lowest tertile and 1.47 (1.03-2.10) for the highest tertile. Results were similarly U-shaped but slightly attenuated for all-cause dementia. In conclusion, shorter and longer telomere length are both associated with an increased risk of Alzheimer's disease in the general population.

%B J Alzheimers Dis %V 73 %P 707-714 %8 2020 Jan 21 %G eng %N 2 %R 10.3233/JAD-190759 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Secular Trends in Dementia Prevalence and Incidence Worldwide: A Systematic Review. %A Stephan, Blossom C M %A Birdi, Ratika %A Tang, Eugene Yee Hing %A Cosco, Theodore D %A Donini, Lorenzo M %A Licher, Silvan %A Ikram, M Arfan %A Siervo, Mario %A Robinson, Louise %X

BACKGROUND: Time trends for dementia prevalence and incidence rates have been reported over the past seven decades in different countries and some have reported a decline.

OBJECTIVE: To undertake a systematic review to critically appraise and provide an evidence-based summary of the magnitude and direction of the global changes in dementia prevalence and incidence across time.

METHODS: Medline, EMBASE, and PsychINFO were searched for studies focused on secular trends in dementia prevalence and/or incidence until 18 December 2017. In total, 10,992 articles were identified and 43 retained.

RESULTS: Overall, prevalence rates are largely increasing (evidence primarily from record-based surveys and cohort studies in Japan, Canada, and France) or have remained stable (evidence primarily from cohort studies in Sweden, Spain and China). A significant decline in prevalence has however been reported in more recent studies (i.e., from 2010 onwards) from Europe (e.g., UK and Sweden) and the USA. Incidence rates have generally remained stable or decreased in China, Canada, France, Germany, Denmark, Sweden, the Netherlands, UK, and USA. An increase has only been reported in five countries: Italy, Japan, Wales, Germany, and the Netherlands. Only one study reported findings (stability in incidence) from a low and middle-income country using data from Nigeria.

CONCLUSIONS: The evidence on secular trends in the prevalence and incidence of dementia is mixed including contradictory findings using different (and in some cases the same) datasets in some countries (e.g., the USA, UK, and Sweden). This making it difficult to draw concrete conclusions. However, declining trends recently observed in some high-income Western countries in the most recent two decades including the UK, USA, and Sweden are encouraging. Updated dementia prevalence and incidence estimates will inform public health and financial planning as well as development of prevention strategies.

%B J Alzheimers Dis %V 66 %P 653-680 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30347617?dopt=Abstract %R 10.3233/JAD-180375 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Subjective Sleep Quality is not Associated with Incident Dementia: The Rotterdam Study. %A Lysen, Thom S %A Wolters, Frank J %A Luik, Annemarie I %A Ikram, M Kamran %A Tiemeier, Henning %A Ikram, M Arfan %X

BACKGROUND: Poor sleep is related to higher dementia risk, but this association is more equivocal for subjective sleep quality specifically. This study investigates the link between subjective sleep quality and dementia risk in the general population.

OBJECTIVE: To study the role of subjective sleep quality in the risk of dementia in the general population.

METHODS: In the prospective population-based Rotterdam Study, 4,835 persons (mean age 72 years, 58% women) underwent a home interview (2002- 2006) that included the validated Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality. Participants were followed until 2015 for incident dementia, through in-person screening and continuous monitoring of medical records. We used Cox regression models to associate sleep quality with dementia risk, adjusting for age, sex, education, smoking, employment, coffee consumption, alcohol consumption, activities of daily living, cardiovascular risk factors, anxiety, depressive symptoms, cognition, and snoring.

RESULTS: During 41,385 person-years (8.5 years mean), 420 participants developed dementia, of whom 320 Alzheimer's disease (AD). Poorer subjective sleep quality was not associated with the risk of all-cause dementia (hazard ratio [HR] per SD increase in PSQI score: 0.91, 95% CI 0.82- 1.02) or AD (HR 0.92, 95% CI 0.81- 1.05). Similarly, individual components of the PSQI were also not associated with dementia. Several sensitivity analyses, i.e., excluding last years of the follow-up time duration or restricting to those with best MMSE scores at baseline, did not reveal subgroups with increased risks.

CONCLUSION: In this study, we found no association of poor subjective sleep quality with higher risk of dementia.

%B J Alzheimers Dis %V 64 %P 239-247 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865066?dopt=Abstract %R 10.3233/JAD-180055 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Three Decades of Dementia Research: Insights from One Small Community of Indomitable Rotterdammers. %A Wolters, Frank J %A Adams, Hieab H H %A Bos, Daniel %A Licher, Silvan %A Ikram, M Arfan %X

The most commonly encountered opening sentence in scientific publications about dementia undoubtedly relates to the overwhelming burden of disease. Finding an effective preventive or therapeutic intervention against dementia has been considered the most important unmet need in contemporary medicine. While efforts on tackling this devastating disease have increased exponentially, it is difficult to imagine that in the 1980s and early-1990s, the disease did not feature prominently on any public health report. Yet, it was already then that epidemiologists recognized the growing societal burden of dementia and rationalized that dementia is not necessarily part of aging. Indeed, the conviction that dementia is pathologically distinct from aging led to various efforts in search of unravelling its risk factors and understanding its pre-clinical phase. Among the early pioneers, the population-based Rotterdam Study was initiated in 1990 clearly aiming on chronic diseases including dementia, and among this Alzheimer's disease, as one of its focus points. Ever since, the Rotterdam Study has been an important cornerstone in increasing our knowledge about dementia from an epidemiological perspective. Here, we summarize the main findings originating from this study, and put these into perspective with previous and current work in the field. With an expanding scope of the Rotterdam Study over the years, we discuss findings on occurrence, modifiable risk factors, imaging, and its genetic underpinnings. Importantly, we conclude with recommendations- or, perhaps better stated, a wish list- for future research which may help us reach our finish line: finding an effective preventive or therapeutic intervention against dementia.

%B J Alzheimers Dis %V 64 %P S145-S159 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843240?dopt=Abstract %R 10.3233/JAD-179938 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Aortic Valve Calcification and the Risk of dementia: A Population-Based Study. %A Wolters, Frank J %A Bos, Daniel %A Vernooij, Meike W %A Franco, Oscar H %A Hofman, Albert %A Koudstaal, Peter J %A van der Lugt, Aad %A Ikram, M Arfan %X

The association of aortic valve calcification (AVC) with dementia remains unknown. In 2,428 non-demented participants from the population-based Rotterdam Study, we investigated the association of CT-assessed AVC with risk of dementia and cognitive decline. AVC was present in 33.1% of the population. During a median follow-up of 9.3 years, 160 participants developed dementia. We found no association between presence of AVC and risk of all-cause dementia [hazard ratio (HR): 0.89 (95% confidence interval (CI):0.63;1.26)]. Presence of AVC was not associated with cognitive decline on any of the cognitive tests, nor with a measure of global cognition.

%B J Alzheimers Dis %V 55 %P 893-897 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767996?dopt=Abstract %R 10.3233/JAD-160871 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Plasma Amyloid-β Levels, Cerebral Small Vessel Disease, and Cognition: The Rotterdam Study. %A Hilal, Saima %A Akoudad, Saloua %A van Duijn, Cornelia M %A Niessen, Wiro J %A Verbeek, Marcel M %A Vanderstichele, Hugo %A Stoops, Erik %A Ikram, M Arfan %A Vernooij, Meike W %X

BACKGROUND: Plasma amyloid-β (Aβ) levels are increasingly studied as a potential, accessible marker of cognitive impairment and dementia. The most common plasma Aβ isoforms, i.e., Aβ1-40 and Aβ1-42 have been linked with risk of Alzheimer's disease. However, it remains under-explored whether plasma Aβ levels including novel Aβ1-38 relate to vascular brain disease and cognition in a preclinical-phase of dementiaObjective:To examine the association of plasma Aβ levels (i.e., Aβ1-38, Aβ1-40, and Aβ1-42) with markers of cerebral small vessel disease (SVD) and cognition in a large population-based setting.

METHODS: We analyzed plasma Aβ1 levels in 1201 subjects from two independent cohorts of the Rotterdam Study. Markers of SVD [lacunes, white matter hyperintensity (WMH) volume] were assessed on brain MRI (1.5T). Cognition was assessed by a detailed neuropsychological battery. In each cohort, the association of Aβ levels with SVD and cognition was performed using regression models. Estimates were then pooled across cohorts using inverse variance meta-analysis with fixed effects.

RESULTS: Higher levels of plasma Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-40/ Aβ1-42 ratio were associated with increasing lacunar and microbleeds counts. Moreover, higher levels of Aβ1-40 and Aβ1-40/ Aβ1-42 were significantly associated with larger WMH volumes. With regard to cognition, a higher level of Aβ1-38 Aβ1-40 and Aβ1-40/ Aβ1-42 was related to worse performance on cognitive test specifically in memory domain.

CONCLUSION: Higher plasma levels of Aβ levels are associated with subclinical markers of vascular disease and poorer memory. Plasma Aβ levels thus mark the presence of vascular brain pathology.

%B J Alzheimers Dis %V 60 %P 977-987 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984600?dopt=Abstract %R 10.3233/JAD-170458 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Smoking, APOE Genotype, and Cognitive Decline: The Rotterdam Study. %A Wingbermühle, Robin %A Wen, Ke-Xin %A Wolters, Frank J %A Ikram, M Arfan %A Bos, Daniel %X

The association of smoking with preclinical cognitive decline remains unclear and may be modified by the APOEɛ4 genotype. In 5,705 participants (mean age: 63.9±9.1 years; 57.4% women) from the population-based Rotterdam Study, we investigated the relationship between smoking and cognitive decline over a 5.5-year period and examined potential effect modification by APOEɛ4 genotype. We found that current smoking was related to decline in global cognition [difference compared to never smoking: -0.06 (95% C.I.-0.10;-0.01)], as well as decline on specific cognitive tests including the Letter Digit Substitution Task, the 15-Word Learning Test, and the Purdue Pegboard. We found no evidence for effect modification by APOEɛ4 genotype on this relation.

%B J Alzheimers Dis %V 57 %P 1191-1195 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304310?dopt=Abstract %R 10.3233/JAD-170063 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Vitamin D and the Risk of Dementia: The Rotterdam Study. %A Licher, Silvan %A de Bruijn, Renée F A G %A Wolters, Frank J %A Zillikens, M Carola %A Ikram, M Arfan %A Ikram, M Kamran %X

BACKGROUND: Vitamin D has gained interest as a potentially modifiable risk factor for dementia because of its putative neuroprotective effects. However, longitudinal studies examining the association between vitamin D and dementia have provided inconsistent results.

OBJECTIVE: To determine the relationship of serum vitamin D with prevalent and incident dementia in the general population.

METHODS: Within the prospective Rotterdam Study, we measured serum 25-hydroxyvitamin D concentrations between 1997 and 2001 using electrochemiluminescence-immunoassay in 6220 participants 55 years or older. We assessed dementia at baseline and continuously during follow-up until 1 January 2015. We used appropriate regression models to determine the relationship of vitamin D with prevalent and incident dementia, including Alzheimer's disease (AD). We adjusted models for age, sex, and season of blood collection. Additionally, we adjusted for ethnicity, education, cardiovascular risk factors, serum calcium, kidney function, depression, outdoor-activity and APOEɛ4 carriership.

RESULTS: At baseline, 127 of 6,220 participants had dementia, of whom 97 had AD. Lower vitamin D concentrations were associated with a non-significantly higher prevalence of dementia (adjusted OR, per SD decrease 1.20, 95% CI 0.95;1.52), but not with AD (adjusted OR: 0.97, 95% CI 0.74;1.29). Among 6,087 non-demented participants with 68,884 person-years of follow-up, 795 participants developed dementia, of whom 641 had AD. Lower vitamin D concentrations were associated with higher risk of dementia (adjusted HR, per SD decrease 1.11, 95% CI 1.02;1.20) and AD (adjusted HR: 1.13, 95% CI 1.03;1.24).

CONCLUSION: Lower serum vitamin D concentrations are associated with a higher incidence of dementia.

%B J Alzheimers Dis %V 60 %P 989-997 %8 2017 %G eng %N 3 %R 10.3233/JAD-170407 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Coffee Consumption with MRI Markers and Cognitive Function: A Population-Based Study. %A Araújo, Larissa Fortunato %A Mirza, Saira Saeed %A Bos, Daniel %A Niessen, Wiro J %A Barreto, Sandhi Maria %A van der Lugt, Aad %A Vernooij, Meike W %A Hofman, Albert %A Tiemeier, Henning %A Ikram, M Arfan %X

BACKGROUND: Coffee is one of the most widely consumed beverages worldwide and has been of considerable interest in research on cognition and dementia.

OBJECTIVE: To investigate the effect of coffee on preclinical brain MRI markers of dementia and cognitive performance.

METHODS: In 2,914 participants from the population-based Rotterdam Study (mean age: 59.3±7.2 years, 55% females), we assessed coffee consumption, performed brain MRI, and assessed cognition at baseline. To study cognitive change, cognitive assessment was repeated after 5 years of follow-up. Coffee consumption was analyzed continuously (per cup increase) and in categories (0-1, >1-3, >3 cups/day). Using logistic and linear regression, associations of coffee consumption with lacunar infarcts and brain tissue volumes on MRI, and cognitive performance (cross-sectional and longitudinal) were investigated, adjusting for relevant confounders.

RESULTS: We found that higher coffee consumption was associated with a lower prevalence of lacunar infarcts [odds ratio per cup increase: 0.88 (95% CI:0.79;0.98)], and smaller hippocampal volume [difference: -0.01 (95% CI:-0.02;0.00)]. Also, we found that the highest category of coffee consumption was associated with better performance on the Letter Digit Substitution Task [difference: 1.13(95% CI:0.39;1.88)], Word Fluency test [0.74(95% CI:0.04,1.45)], Stroop interference task [1.82(95% CI:0.23;3.41)], and worse performance on the 15-Word Learning test delayed recall [-0.38(95% CI:-0.74;-0.02)]. These associations were not found when cognition was analyzed longitudinally.

CONCLUSION: We found complex associations between coffee consumption, brain structure, and cognition. Higher coffee consumption was cross-sectionally associated with a lower occurrence of lacunar infarcts and better executive function, but also with smaller hippocampal volume and worse memory function.

%B J Alzheimers Dis %V 53 %P 451-61 %8 2016 May 03 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163820?dopt=Abstract %R 10.3233/JAD-160116 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebral Microbleeds and Cerebrovascular Reactivity in the General Population: The EDAN Study. %A Akoudad, Saloua %A Gurol, M Edip %A Fotiadis, Panagiotis %A Koudstaal, Peter J %A Hofman, Albert %A Ikram, M Arfan %A Greenberg, Steven M %A Vernooij, Meike W %X

BACKGROUND: In patients with symptomatic cerebral amyloid angiopathy (CAA), cerebrovascular reactivity to visual stimuli is reduced. Lobar microbleeds are a diagnostic hallmark of CAA, but are also highly prevalent in asymptomatic individuals. Recent data suggest that the latter group might have CAA.

OBJECTIVE: We investigated whether cerebrovascular reactivity is impaired in asymptomatic individuals with lobar microbleeds.

METHODS: From the population-based Rotterdam Study, we invited 35 participants with lobar microbleeds and 15 age-matched controls (all≥55 years) for functional MRI (fMRI) as part of the Early Detection of Angiopathy Network (EDAN) Study. Cerebrovascular reactivity parameters (i.e., amplitude and time to peak responses) were assessed in response to visual stimulation using fMRI. Student's t-test and linear regression were used to compare fMRI parameters in participants with and without microbleeds.

RESULTS: Amplitude and time to peak responses did not differ between participants with and without microbleeds (respectively, p = 0.179 and p = 0.555). Participants with microbleeds had slightly higher amplitude responses compared to participants without microbleeds. After excluding individuals with mixed microbleeds (i.e., lobar and non-lobar microbleeds), we found no significant difference in cerebrovascular reactivity for persons with a single microbleed or multiple microbleeds compared to persons without microbleeds.

CONCLUSIONS: In the general population, lobar microbleeds may not relate to impaired cerebrovascular reactivity. In asymptomatic individuals, lobar microbleeds may either reflect less advanced CAA pathology insufficient to cause functional vascular impairment, or reflect vascular pathology other than CAA.

%B J Alzheimers Dis %V 53 %P 497-503 %8 2016 May 04 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163807?dopt=Abstract %R 10.3233/JAD-151130 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. %A Chouraki, Vincent %A Reitz, Christiane %A Maury, Fleur %A Bis, Joshua C %A Bellenguez, Celine %A Yu, Lei %A Jakobsdottir, Johanna %A Mukherjee, Shubhabrata %A Adams, Hieab H %A Choi, Seung Hoan %A Larson, Eric B %A Fitzpatrick, Annette %A Uitterlinden, Andre G %A De Jager, Philip L %A Hofman, Albert %A Gudnason, Vilmundur %A Vardarajan, Badri %A Ibrahim-Verbaas, Carla %A van der Lee, Sven J %A Lopez, Oscar %A Dartigues, Jean-François %A Berr, Claudine %A Amouyel, Philippe %A Bennett, David A %A van Duijn, Cornelia %A DeStefano, Anita L %A Launer, Lenore J %A Ikram, M Arfan %A Crane, Paul K %A Lambert, Jean-Charles %A Mayeux, Richard %A Seshadri, Sudha %X

Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI =   [1.13-1.21] per standard deviation increase in GRS; p-value =  2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI =   [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI =   [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex =  0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

%B J Alzheimers Dis %V 53 %P 921-32 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340842?dopt=Abstract %R 10.3233/JAD-150749