Volume 75, Number 3, 2020

Pages 685-696

Jung-Min Pyun, Min Ju Kang, Nayoung Ryoo, Jeewon Suh, Young Chul Youn, Young Ho Park, SangYun Kim
Amyloid Metabolism and Amyloid-Targeting Blood-Based Biomarkers of Alzheimer’s Disease
Abstract: Amyloid-β (Aβ) is a key protein in Alzheimer’s disease (AD) in that its accumulation induces complex pathological changes. Although there has been extensive research on the metabolism of Aβ in AD, new compelling results have recently emerged. Historically, the production and clearance of Aβ have been thought to originate in the central nervous system (CNS). However, recent evidence suggests that the production and clearance of Aβ can also occur in the peripheral system, and that the peripherally driven Aβ migrates to the CNS and induces amyloidopathy with subsequent AD pathologic changes in the brain. This concept implies that AD is not restricted to the CNS but is a systemic disease instead. As such, the development of blood-based biomarkers targeting Aβ is of great interest. Central and peripheral Aβ are both active contributors to the pathology of AD and interact bidirectionally. Measuring peripheral Aβ is not just observing the reflection of the residual Aβ removed from the CNS but also tracking the ongoing process of AD pathology. Additionally, blood-based biomarkers could be a more accessible tool in clinical and research settings. Through arduous research, several blood-based biomarker assays have demonstrated notable results. In this review, we describe the metabolism of Aβ and the amyloid-targeting blood-based biomarkers of AD.

Pages 697-704
Marte Kvello-Alme, Geir Bråthen, Linda R. White, Sigrid Botne Sando (Handling Associate Editor: David Knopman)
Incidence of Young Onset Dementia in Central Norway: A Population-Based Study
Abstract: Background: The epidemiology of young onset dementia is little researched compared to late onset dementia. Information on incidence rates is vital for medical professionals, and for government planning purposes. Objective: To determine the incidence of young onset dementia in a defined catchment area of central Norway. Methods: The target area was Trøndelag county in central Norway with a total population of 449,796 inhabitants per January 1, 2016. We applied multiple case ascertainment strategies with sources from both primary and secondary healthcare facilities. Included patients received a diagnosis of dementia according to DSM-IV in the ages 30 to 64 years during the years 2015-2017. Subtypes of dementia were diagnosed according to standardized criteria. Incidence rates for dementia and Alzheimer’s disease with dementia were calculated according to age and sex. Results: A total of 89 incident cases were included. Incidence rates for dementia were 14.8 and 25.0 per 100,000 person-years for the age range 30-64 and 45-64, respectively. Corresponding incidence rates for Alzheimer’s disease were 6.7 and 11.8. Alzheimer’s disease represented half of all dementias. A majority of patients above the age of 50 had neurodegenerative disease, whereas non-degenerative disorders were more prevalent in younger patients. Conclusion: Young onset dementia is a significant contributor to the overall occurrence of dementia in central Norway, and Alzheimer’s disease is by far the most common diagnosis.

Pages 705-715
Mei-Ling Wang, Chong Wang, Miao Tuo, Yang Yu, Lin Wang, Jin-Tai Yu, Lan Tan, Song Chi (Handling Associate Editor: Rhoda Au)
Cognitive Effects of Treating Obstructive Sleep Apnea: A Meta-Analysis of Randomized Controlled Trials
Abstract: Background: Obstructive sleep apnea (OSA) is associated with cognitive impairment and increased risks of dementia. However, the effect of continuous positive airway pressure (CPAP) on cognitive function in patients with OSA is still controversial. Objective: To evaluate the cognitive effects of CPAP treatment on OSA. Methods: We systematically searched PubMed, EMBASE, and Cochrane Library for randomized controlled trials (RCT) in the corresponding fields. Results: Totally 14 studies and 1,926 participants were included in our meta-analysis. Standardized mean difference (SMD) or weighted mean difference (WMD) were calculated for subjective sleepiness and cognitive domains including attention and speed of information processing, executive function, and memory. Individual cognitive scale and subgroup analyses according to OSA severity, length of trial, and RCT design type were further conducted. Significant treatment effect on attention and speed of information processing was only observed in severe OSA patients (SMD, 0.17; 95% CI, 0.02 to 0.31; p=0.025; I2=0%). Conclusions: Therefore, our meta-analysis indicates that CPAP treatment can partially improve cognitive impairment in the population of severe OSA.

Pages 717-728
Damaris Aschwanden, Stephen Aichele, Paolo Ghisletta, Antonio Terracciano, Matthias Kliegel, Angelina R. Sutin, Justin Brown, Mathias Allemand (Handling Associate Editor: Kay Deckers)
Predicting Cognitive Impairment and Dementia: A Machine Learning Approach
Abstract: Background: Efforts to identify important risk factors for cognitive impairment and dementia have to date mostly relied on meta-analytic strategies. A comprehensive empirical evaluation of these risk factors within a single study is currently lacking. Objective: We used a combined methodology of machine learning and semi-parametric survival analysis to estimate the relative importance of 52 predictors in forecasting cognitive impairment and dementia in a large, population-representative sample of older adults. Methods: Participants from the Health and Retirement Study (N = 9,979; aged 50-98 years) were followed for up to 10 years (M = 6.85 for cognitive impairment; M = 7.67 for dementia). Using a split-sample methodology, we first estimated the relative importance of predictors using machine learning (random forest survival analysis), and we then used semi-parametric survival analysis (Cox proportional hazards) to estimate effect sizes for the most important variables. Results: African Americans and individuals who scored high on emotional distress were at relatively highest risk for developing cognitive impairment and dementia. Sociodemographic (lower education, Hispanic ethnicity) and health variables (worse subjective health, increasing BMI) were comparatively strong predictors for cognitive impairment. Cardiovascular factors (e.g., smoking, physical inactivity) and polygenic scores (with and without APOE ε4) appeared less important than expected. Post-hoc sensitivity analyses underscored the robustness of these results. Conclusions: Higher-order factors (e.g., emotional distress, subjective health), which reflect complex interactions between various aspects of an individual, were more important than narrowly defined factors (e.g., clinical and behavioral indicators) when evaluated concurrently to predict cognitive impairment and dementia.

Pages 729-737
Yan Sun, Lin Tan, Wei Xu, Zuo-Teng Wang, Hao Hu, Jie-Qiong Li, Qiang Dong, Lan Tan, Jin-Tai Yu, on behalf of Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Yong Liu)
Plasma Neurofilament Light and Longitudinal Progression of White Matter Hyperintensity in Elderly Persons Without Dementia
Abstract: White matter hyperintensities (WMH) is mainly caused by cerebrovascular injury and may also increase the possibilities of progression to Alzheimer’s disease. The present study aims to determine whether plasma neurofilament light (NFL) protein levels could predict the progression of WMH volume in elderly persons without dementia. The present study enrolled 1029 non-dementia participants from the Alzheimer’s Disease Neuroimaging Initiative in which all had measurements of plasma NFL and WMH at baseline and 589 had longitudinal measurements during follow-up. Spearman correlation analyses and regression models were used to assess cross-sectional and longitudinal associations between plasma NFL and WMH. Plasma NFL concentration had a moderately strong correlation with WMH at baseline (r=0.17, p<0.001). Longitudinal analyses showed that higher baseline plasma NFL concentration was associated with accelerated progression of WMH (β=0.015, p=0.007). Furthermore, higher change rates of plasma NFL could predict faster progression of WMH in the future (β=0.581, p=0.002). The results of the study suggest that plasma NFL level might be used as a noninvasive biomarker to track variation trend in WMH in elderly persons without dementia.

Pages 739-750
Melissa Petersen, James Hall, Thomas Parsons, Leigh Johnson, Sid O’Bryant
Combining Select Blood-Based Biomarkers with Neuropsychological Assessment to Detect Mild Cognitive Impairment among Mexican Americans
Abstract: Background: Recent work has supported use of blood-based biomarkers in detection of amnestic mild cognitive impairment (MCI). Inclusion of neuropsychological measures has shown promise in enhancing utility of biomarkers to detect disease. Objective: The present study sought to develop cognitive-biomarker profiles for detection of MCI. Methods: Data were analyzed on 463 participants (normal control n=378; MCI n=85) from HABLE. Random forest analyses determined proteomic profile of MCI. Separate linear regression analyses determined variance accounted for by select biomarkers per neuropsychological measure. When neuropsychological measure with the least shared variance was identified, it was then combined with select biomarkers to create a biomarker-cognitive profile. Results: The biomarker-cognitive profile was 90% accurate in detecting MCI. Among amnestic MCI cases, the detection accuracy of the biomarker-cognitive profile was 92% and increased to 94% with demographic variables. Conclusion: The biomarker-cognitive profile for MCI was highly accurate in its detection with use of only five biomarkers.

Pages 751-765
Aku Kaipainen, Olli Jääskeläinen, Yawu Liu, Fanni Haapalinna, Niko Nykänen, Ritva Vanninen, Anne M Koivisto, Valtteri Julkunen, Anne M Remes, Sanna-Kaisa Herukka
Cerebrospinal Fluid and MRI Biomarkers in Neurodegenerative Diseases: A Retrospective Memory Clinic-Based Study
Abstract: Background: Cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) biomarkers of neurodegenerative diseases are relatively sensitive and specific in highly curated research cohorts, but proper validation for clinical use is mostly missing. Objective: We studied these biomarkers in a novel memory clinic cohort with a variety of different neurodegenerative diseases. Methods: This study consisted of 191 patients with subjective or objective cognitive impairment who underwent neurological, CSF biomarker (Aβ42, p-tau, and tau) and T1-weighted MRI examinations at Kuopio University Hospital. We assessed CSF and imaging biomarkers, including structural MRI focused on volumetric and cortical thickness analyses, across groups stratified based on different clinical diagnoses, including Alzheimer’s disease (AD), frontotemporal dementia, dementia with Lewy bodies, Parkinson’s disease, vascular dementia, and mild cognitive impairment (MCI), and subjects with no evidence of neurodegenerative disease underlying the cognitive symptoms. Imaging biomarkers were also studied by profiling subjects according to the novel amyloid, tau, and, neurodegeneration (AT(N)) classification. Results: Numerous imaging variables differed by clinical diagnosis, including hippocampal, amygdalar and inferior lateral ventricular volumes and entorhinal, lingual, inferior parietal and isthmus cingulate cortical thicknesses, at a false discovery rate (FDR)-corrected threshold for significance (analysis of covariance; p<0.005). In volumetric comparisons by AT(N) profile, hippocampal volume significantly differed (p<0.001) between patients with normal AD biomarkers and patients with amyloid pathology. Conclusion: Our analysis suggests that CSF and MRI biomarkers function well also in clinical practice across multiple clinical diagnostic groups in addition to AD, MCI, and cognitively normal groups.

Pages 767-777
Seung Hoon Lee, Min Soo Byun, Jun Ho Lee, Dahyun Yi, Bo Kyung Sohn, Jun-Young Lee, Yu Kyeong Kim, Seong A. Shin, Chul-Ho Sohn, Dong Young Leej, for the KBASE Research Group
Sex-Specific Association of Lifetime Body Mass Index with Alzheimer’s Disease Neuroimaging Biomarkers
Abstract: Background: Although recent studies indicate that the relationship between body mass index (BMI) and Alzheimer’s disease (AD) may differ by both sex and age of BMI measurement, little information is available on sex- or age-specific associations between BMI and AD neuropathologies. Objective: To examined whether sex-specific BMIs measured at different life-stages (in early adulthood, midlife, and late life) were associated with cerebral amyloid-β (Aβ) deposition and AD-signature region cortical thickness (AD-CT) in cognitively normal (CN) older adults. Methods: A total of 212 CN subjects aged 60-90 years (females 108, males 104), who participated in the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort study, were included. All participants underwent comprehensive clinical and neuropsychological assessments, [11C] Pittsburgh Compound B positron emission tomography, and brain magnetic resonance imaging. BMIs at different life stages were calculated. Multiple regression analyses were performed separately for either sex. Results: In males, lower early adulthood or midlife BMI was associated with greater cerebral Aβ deposition, but late life BMI was not. Lower midlife BMI was associated with reduced AD-CT, but the BMI in early adulthood and late life was not. In females, no significant association was observed between any lifetime BMI and Aβ deposition or AD-CT. Conclusion: Our results support a male-specific association between BMI prior to late life, and in vivo AD pathologies. Avoiding underweight status early in life may be important to prevent AD dementia in males, but not females.

Pages 779-787
Yi Xing, Zude Zhu, Yifeng Du, Junjian Zhang, Qiumin Qu, Li Sun, Yang Li, Yanjun Guo, Guoping Peng, Yong Liu, Yueyi Yu, Yuchen Qiao, Beijia Xie, Xinrui Shi, Jie Lu, Jianping Jia, Yi Tang (Handling Associate Editor: Jin-Tai Yu)
The Efficacy of COGnitive tRaining in patiEnts with Amnestic mild coGnitive impairmENT (COG-REAGENT): Protocol for a Multi-Center Randomized Controlled Trial
Abstract: Background: Amnestic mild cognitive impairment (aMCI) is often the prodromal stage of Alzheimer’s disease (AD). Although previous studies have suggested that computerized cognitive training is an effective non-pharmacological intervention for aMCI, large-sample, randomized controlled studies are warranted to provide a high level of evidence. Objective: To identify the efficacy of computerized cognitive training for aMCI. Methods: This study will include 260 patients diagnosed with aMCI from 8 centers in China. A computerized multi-domain adaptive training program will be used in this study, and the targeted cognitive domains include memory, attention, language, and executive function. The patients will be randomized into either a cognitive-training group or an active-control group. The intervention is a 12-week internet-based cognitive training performed for 40 minutes per day, 4 days a week. Neuropsychological assessments and structural and functional MRI will be obtained at baseline, at the end of the intervention, and 6 months after randomization. The primary outcome will be the global cognitive function score assessed by Montreal Cognitive Assessment. The secondary outcomes include changes in other neuropsychological assessments and neuroplasticity changes measured by structural and functional MRI. Results: The trial is currently ongoing, and it is anticipated that recruitment will be completed in December 2020. Conclusion: This multi-center, large-sample, randomized controlled trial will investigate the short and long-term effects of computerized cognitive training in patients with aMCI. Furthermore, the combination of functional and structural MRI results will also reveal the underlying mechanisms of the effect of intervention.

Pages 789-805
Kim E. Innes, Usha Sambamoorthi
The Association of Osteoarthritis and Related Pain Burden to Incident Alzheimer’s Disease and Related Dementias: A Retrospective Cohort Study of U.S. Medicare Beneficiaries
Abstract: Background: Emerging evidence suggests osteoarthritis (OA) and related symptom burden may increase risk for Alzheimer’s disease and related dementias (ADRD). However, longitudinal studies are sparse, and none have examined the potential mediating effects of mood or sleep disorders. Objective: To determine the association of OA and related pain to incident ADRD in U.S. elders. Methods: In this retrospective cohort study, we used baseline and two-year follow-up data from linked Medicare claims and Medicare Current Beneficiary Survey files (11 pooled cohorts, 2001-2013). The study sample comprised 16,934 community-dwelling adults ≥65 years, ADRD-free at baseline and enrolled in fee-for-service Medicare. Logistic regression was used to assess the association of OA and related pain (back, neck, joint, neuropathic) to incident ADRD, explore the mediating influence of mood and insomnia-related sleep disorders, and (sensitivity analyses) account for potential survival bias. Results: Overall, 25.5% of beneficiaries had OA at baseline (21.0% with OA and pain); 1149 elders (5.7%) were subsequently diagnosed with ADRD. Compared to beneficiaries without OA, those with OA were significantly more likely to receive a diagnosis of incident ADRD after adjustment for sociodemographics, lifestyle characteristics, comorbidities, and medications (adjusted odds ratio (AOR)=1.23 (95% confidence interval (CI) 1.06, 1.42). Elders with OA and pain at baseline were significantly more likely to be diagnosed with incident ADRD than were those without OA or pain (AOR=1.31, CI 1.08, 1.58). Sensitivity analyses yielded similar findings. Inclusion of depression/anxiety, but not sleep disorders, substantially attenuated these associations. Conclusion: Findings of this study suggest that: OA is associated with elevated ADRD risk, this association is particularly pronounced in those with OA and pain, and mood disorders may partially mediate this relationship.

Pages 807-815
Chenchen Wang, Xi Huang, Sai Tian, Rong Huang, Dan Guo, Hongyan Lin, Jiaqi Wang, Shaohua Wang
High Plasma Resistin Levels Portend the Insulin Resistance-Associated Susceptibility to Early Cognitive Decline in Patients with Type 2 Diabetes Mellitus
Abstract: Background: Metabolic disorders, including insulin resistance, obesity, and hyperlipidemia occur frequently prior to hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and cause mild cognitive impairment (MCI). Objective: We investigated the involvement of resistin in these metabolic abnormalities contributes to MCI in patients with T2DM. Methods: A total of 138 hospitalized patients with T2DM were enrolled and categorized into MCI and non-MCI groups according to the Montreal Cognitive Assessment (MoCA) score. Metabolic indicators and cognitive state were assessed, and plasma resistin levels were determined by ELISA. Results: The resistin levels and homeostasis model assessment of insulin resistance (HOMA-IR) scores of MCI and gender-stratified subgroups were significantly higher than those of controls without MCI (all p < 0.01). Correlation analysis showed that the resistin level was negatively associated with majority of cognitive domains, e.g., MoCA (r = -0.693, p < 0.001) and Mini-Mental State Examination (r = -0.571, p < 0.001), and was related to HOMA-IR (r = 0.667, p < 0.001) but not to obesity and lipid indices. Multivariable regression analysis indicated that resistin (β = -0.675, p < 0.001) and educational level (β = 0.177, p = 0.003) were independent risk factors of MoCA in patients with T2DM. Conclusions: High plasma resistin levels portend the insulin resistance-related susceptibility to early cognitive decline in Chinese patients with T2DM. The involvement of this adipokine in other metabolic disorders leading to diabetic MCI and its clinical value for early disease screening must be further studied.

Pages 817-826
Munira Sultana, Dianne Bryant, J. B. Orange, Taylor Beedie, Manuel Montero-Odasso
Effect of Wii Fit© Exercise on Balance of Older Adults with Neurocognitive Disorders: A Meta-Analysis
Abstract: Background: Exercise is beneficial to maintain balance. Wii Fit©, a video game-based exercise, offers an enjoyable way to exercise and is feasible for older adults with neurocognitive disorders (NCD). Objective: To evaluate the effects of Wii Fit© exercise training on the balance of older adults with NCD. Methods: Systematic review and meta-analysis of randomized control trials using Cochrane collaboration tools. The participants were older adults (60 years and over) with NCD. Balance was measured with Berg Balance Scale (BBS) and Timed Up and Go (TUG). Two reviewers independently searched, selected, extracted data, assessed risk of biases, and determined the quality of evidence. Outcomes were evaluated using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). A meta-analysis was performed. Results: The literature search identified 522 source documents of which titles and abstracts were reviewed for 428 after removing 94 duplicates. The reviewers selected five studies out of 50 after a full text review. The overall effect of Wii Fit© exercise training on BBS was moderate, significant, and clinically meaningful (standardized mean difference [SMD]=0.5 standard deviation [SD] [95% confidence interval [CI] 0.08, 0.84]). No effect was observed with TUG scores (SMD=0.00 SD [95% CI -0.44, 0.44]). The GRADE quality of evidence was very low. Conclusion: Wii Fit© exercise training has a positive effect on balance in older adults with NCD. However, further research with sufficient power is needed to evaluate its effectiveness.

Pages 827-843
Gurjeet Kaur, Anne Poljak, Nady Braidy, John D. Crawford Jessica Lo, Perminder S. Sachdev
Fluid Biomarkers and APOE Status of Early Onset Alzheimer’s Disease Variants: A Systematic Review and Meta-Analysis

Abstract: Background: Numerous studies have reported on cerebrospinal fluid (CSF) and blood biomarkers of Alzheimer’s disease (AD); however, to date, none has compared biomarker patterns across the early-onset subtypes, i.e., early onset sporadic AD (EOsAD) and autosomal dominant AD (ADAD), qualitatively and quantitatively. Objective: To compare the fluid biomarker patterns in early-onset subtypes of AD; EOsAD and ADAD. Methods: Six scientific databases were searched for peer-reviewed research publications. The total number of individuals used in all the meta-analysis were 2,427, comprised of 1,337 patients and 1,090 controls. Results: In the subset of EOsAD cases without APP, PSEN1/PSEN2 mutations, CSF Aβ42 and tau levels were higher when compared to the EOsAD group as a whole. Prevalence of the APOE ε4 allele was more elevated in EOsAD relative to controls, and not significantly elevated in ADAD cases. Conclusion: Established CSF biomarkers confirmed quantitative differences between variants of EOAD. EOsAD is enriched with APOE ε4, but the level is not higher than generally reported in late-onset AD. The results prompt further exploration of the etiopathogenesis of EOsAD, which accounts for ~4-10% of all AD cases, but the reasons for the early onset remain poorly understood.

Pages 845-854
D. P. Devanand, Xinhua Liu, Richard E. Chunga, Hannah Cohen, Howard Andrews, Peter W. Schofield, Yaakov Stern, Edward D. Huey, Jongwoo Choi, Gregory H. Pelton (Handling Associate Editor: David Loewenstein)
Odor Identification Impairment and Change with Cholinesterase Inhibitor Treatment in Mild Cognitive Impairment
Abstract: Background: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer’s disease (AD) pathology, and short-term change in odor identification impairment with cholinesterase inhibitor (CheI) treatment may predict longer term cognitive outcomes. Objective: In patients with mild cognitive impairment (MCI) treated prospectively with donepezil, a CheI, for 52 weeks, to determine if 1) acute decline in odor identification ability with anticholinergic challenge can predict cognitive improvement, and 2) change in odor identification over 8 weeks can predict cognitive improvement. Methods: MCI was diagnosed clinically without AD biomarkers. At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and this dose was maintained for 52 weeks. Main outcomes were ADAS-Cog total score and Selective Reminding Test (SRT) total immediate recall score measured at baseline, 26 and 52 weeks. Results: In 100 study participants, mean age 70.14 (SD 9.35) years, atropine-induced decrease in UPSIT score at baseline was not associated with change in ADAS-Cog or SRT scores over 52 weeks. Change in UPSIT score from 0 to 8 weeks did not show a significant association with change in the ADAS-Cog or SRT measures over 52 weeks. Conclusion: These negative findings in a relatively large sample of patients with MCI did not replicate results in much smaller samples. Change in odor identification with anticholinergic challenge, and over 8 weeks, may not be useful predictors of cognitive improvement with CheI in patients with MCI.

Pages 855-870
Vasilis Z. Marmarelis, Dae C. Shin, Rong Zhang
Dysregulation of CO2-Driven Heart-Rate Chemoreflex Is Related Closely to Impaired CO2 Dynamic Vasomotor Reactivity in Mild Cognitive Impairment Patients
Abstract: Background: Significant reduction of dynamic vasomotor reactivity (DVR) was recently reported in patients with amnestic mild cognitive impairment (MCI) relative to age-matched controls. These results were obtained via a novel approach that utilizes data-based predictive dynamic models to quantify DVR. Objective: Using the same methodological approach, we seek to quantify the dynamic effects of the CO2-driven chemoreflex and baroreflex upon heart-rate in order to examine their possible correlation with the observed DVR impairment in each MCI patient. Methods: The employed approach utilizes time-series data to obtain subject-specific predictive input-output models of the dynamic effects of changes in arterial blood pressure and end-tidal CO2 (putative “inputs”) upon cerebral blood flow velocity in large cerebral arteries, cortical tissue oxygenation, and heart-rate (putative “outputs”). Results: There was significant dysregulation of CO2-driven heart-rate chemoreflex (p=0.0031), but not of baroreflex (p=0.5061), in MCI patients relative to age-matched controls. The model-based index of CO2-driven heart-rate chemoreflex gain (CRG) correlated significantly with the DVR index in large cerebral arteries (p=0.0146), but not with the DVR index in small/micro-cortical vessels (p=0.1066). This suggests that DVR impairment in small/micro-cortical vessels is not mainly due to CO2-driven heart-rate chemoreflex dysregulation, but to other factors (possibly dysfunction of neurovascular coupling). Conclusion: Improved delineation between MCI patients and controls is achieved by combining the DVR index for small/micro-cortical vessels with the CRG index (p=2×10-5). There is significant correlation (p<0.01) between neuropsychological test scores and model-based DVR indices. Combining neuropsychological scores with DVR indices reduces the composite diagnostic index p-value (p ~ 10-10).

Pages 871-878
Silvia Rodrigo-Herrero, Gonzalo Sánchez-Benavides, Leire Ainz-Gómez, Andrea Luque-Tirado, Eugenia Graciani-Cantisán, María Bernal Sánchez-Arjona, Didier Maillet, María Dolores Jiménez-Hernández, Emilio Franco-Macías
Norms for Testing Visual Binding Using the Memory Associative Test (TMA-93) in Older Educationally-Diverse Adults
Abstract: Background: TMA-93 examines binding by images, a potential advantage for less-educated individuals. Objective: To obtain norms from older Spanish adults for TMA-93. Methods: A cross-sectional normative study was undertaken in a general neurology outpatient clinic of a university hospital in the Southern Spanish region of Andalusia. Partners of patients who attended the clinic were systematically recruited when eligible: aged 50 and over, no memory complaints, and a total score equal or above percentile 10 on Phototest. Age, gender, and educational attainment were considered as sociodemographic variables. TMA-93 was administered and the total score was registered. Results: The final sample contained 1,131 participants (mean age = 65.7, SD = 9.2), including 305 individuals (27%) who did not completed primary studies. The total score on TMA-93 showed a non-normal, left asymmetric, and leptokurtic distribution (median=29, interquartile range=27-30, range=16-30) mitigated by lower education and older age. Stratified analysis by age and education showed wide variations of the scores for the 5-percentile. Conclusion: TMA-93 runs with a ceiling effect in non-cognitively impaired older Spanish adults. The score for the 5-percentile depends on age and education. The test is feasible for low-educated individuals.

Pages 879-890
Ragna Espenes, Bjørn-Eivind Kirsebom, Cecilia Eriksson, Knut Waterloo, Erik Hessen, Stein Harald Johnsen, Per Selnes, Tormod Fladby
Amyloid Plaques and Symptoms of Depression Links to Medical Help-Seeking due to Subjective Cognitive Decline
Abstract: Background: Subjective cognitive decline (SCD) is associated with an increased risk of Alzheimer’s disease (AD). However, patients reporting SCD to their general practitioner are not always referred to a memory clinic. Objective: To investigate whether prior history of medical help-seeking is associated with AD biomarker abnormality, worse cognitive performance, and/or depressive symptoms in SCD. Methods: We compared levels of cerebrospinal fluid (CSF) Aβ1-42, cognitive performance, and depressive symptoms (15-item Geriatric Depression Scale, GDS-15) between healthy controls (n=88), SCD with a history of medical help seeking (SCD-HS, n= 67), and SCD non help-seekers (SCD-NHS, n=44). Cases with evidence of amyloid plaques (CSF Aβ1-42≤708 ng/l) and symptoms of depression (GDS-15≥6) were determined in both SCD groups. Results: The SCD-HS group had lower CSF Aβ1-42 (p<0.01), lower word list learning and memory recall (p<0.0001), and an increased level of depressive symptoms (p<0.0001) compared to controls and SCD-NHS cases. The SCD-HS group had more cases with symptoms of depression (n=12, 18%) and amyloid plaques (n=18, 27%) compared to SCD-NHS (n=1, 2% and n=7, 16%, respectively). None of the SCD-HS cases and only one SCD-NHS case had concurrent symptoms of depression and amyloid plaques. The SCD-HS cases showed equal word list learning and memory performance regardless of amyloid status or symptoms of depression. Conclusion: Medical help-seeking in SCD is associated with an increased risk of AD pathology or symptoms of depression. However, subtle memory deficits are seen in SCD help-seekers, also without amyloid plaques or symptoms of depression.

Pages 891-902
Anders Wimo, Ron Handels, Bengt Winblad, Christopher M. Black, Gunilla Johansson, Stina Salomonsson, Maria Eriksdotter*, Rezaul K. Khandker* (Handling Associate Editor: Bernard Michalowsky) *Shared last authorship
Quantifying and Describing the Natural History and Costs of Alzheimer’s Disease and Effects of Hypothetical Interventions
Abstract: Background: A long-term horizon is necessary when the socioeconomic consequences and the potential effects of interventions in Alzheimer’s disease (AD) are estimated. Objectives: To illustrate the potential societal costs of AD across the disease continuum and to illustrate the potential cost-effectiveness of a hypothetical intervention with disease modifying treatment (DMT). Methods: Based on the Swedish dementia registry, a Markov model was used to simulate a virtual cohort of 100,000 people with mild cognitive impairment (MCI) due to AD (AD-MCI) in Sweden for 40 years starting at the age of 60. A simulated hypothetical intervention assumed a 25% reduction in progression rate during AD-MCI and mild AD-dementia. A comprehensive set of sensitivity analyses was included. Results: The cumulative risk to develop dementia was 96%. The mean simulated survival was 19.0 years. The net present value for a person year with dementia was 252,843 SEK (about 29,500 US$). The cost effectiveness model illustrated how the hypothetical scenario of a 25% reduction in progression to AD-dementia would require 41 AD-MCI patients to be treated to prevent one case of AD-dementia (2,447 avoided AD-dementia cases of 100,000 with AD-MCI). Most scenarios illustrated hypothetical cost effectiveness (based on a willingness to pay level of 600,000 SEK (70,000 US$) per gained QALY), but not cost savings. Discussion: Lifetime societal costs of AD are substantial. A future DMT may be potentially cost-effective given assumed treatment effects and costs, but cost savings are unlikely.

Pages 903-910
Tonita Wroolie, Siena Roat-Shumway, Katie Watson, Eric Reiman, Natalie Rasgon
Effects of LDL Cholesterol and Statin Use on Verbal Learning and Memory in Older Adults at Genetic Risk for Alzheimer’s Disease
Abstract: Background: The apolipoprotein epsilon 4 (APOE4) allele is a well-established genetic risk factor for Alzheimer’s disease (AD). However, there are mixed findings as to how the APOE4 allele modifies the effects of both higher low-density lipoprotein cholesterol (LDL) and statin use on cognitive functioning. Objective: This study sought to examine the effects of LDL levels and statin use on verbal learning and memory, as modified by the presence of the APOE4 allele, in a sample of cognitively unimpaired, older adults at risk for AD. Methods: Neuropsychological, LDL, statin use, and APOE4 data were extracted from an ongoing longitudinal study at the Banner Alzheimer’s Institute in Arizona. Participants were cognitively unimpaired based on Mini-Mental State Examination scores within a normal range, aged 47-75, with a family history of probable AD in at least one first-degree relative. Results: In the whole sample, higher LDL was associated with worse immediate verbal memory in APOE4 non-carriers, but did not have an effect on immediate verbal memory in APOE4 carriers. In APOE4 non-carriers, statin use was associated with better verbal learning, but did not have an effect on verbal learning in APOE4 carriers. Among women, higher LDL in APOE4 carriers was associated with worse verbal learning than in APOE4 non-carriers, and statin use in APOE4 non-carriers was associated with better verbal learning and immediate and delayed verbal memory but worse performances on these tasks in APOE4 carriers. Conclusion: LDL and statin use may have differential effects on verbal learning and/or memory depending on genetic risk for AD. Women appear to be particularly vulnerable to statin use depending on their APOE4 status.

Pages 911-921
Levent Sahin, Mariana G. Figueiro
Flickering Red-Light Stimulus for Promoting Coherent 40 Hz Neural Oscillation: A Feasibility Study
Abstract: Background: Coherent 40 Hz (gamma) neural oscillation indicates healthy brain activity and is known to be disrupted in Alzheimer’s disease (AD) patients. 40 Hz entrainment by flickering light is known to significantly attenuate AD pathology in mice. Objective: To demonstrate the feasibility of using a lighting intervention to promote coherent 40 Hz neural oscillation, improved working memory performance, and reduced subjective sleepiness among a population of healthy young adults. If successful, the intervention could be extended to address cognitive impairment associated with mild cognitive impairment and AD. Methods: Nine healthy participants (median age 22 years, 5 females) were exposed to one of two lighting conditions per session in a within-subjects counterbalanced manner. The study’s two sessions were separated by 1 week. Custom-built light masks provided either a 40 Hz flickering red light (FRL) intervention or a dark control condition (i.e., total darkness, light mask not energized) at participants’ eyes. Data were collected 4 times per session: pre-exposure, after 25-min exposure, after 50-min exposure, and post-exposure. Each data collection period included a Karolinska Sleepiness Scale report, an electroencephalogram, and working memory (n-back) auditory performance testing. Results: The FRL intervention induced a significant increase in 40 Hz power and a modest increase in low gamma power. The intervention had no significant impact on working memory performance and subjective sleepiness compared to the control. However, increases in 40 Hz power were significantly correlated with reduced subjective sleepiness. Conclusion: The results clearly demonstrate the feasibility of using a flickering light to increase 40 Hz power.

Pages 923-936
Darshini Ayton, Madeleine Gardam, Stephanie Ward, Henry Brodaty, Elizabeth Pritchard, Arul Earnest, Karolina Krysinska, Jane Banaszak-Holl, John McNeil, Susannah Ahern (Handling Associate Editor: Kay Deckers)
How Can Quality of Dementia Care Be Measured? The Development of Clinical Quality Indicators for an Australian Pilot Dementia Registry
Abstract: Background: A clinical quality registry (CQR) for dementia provides benefits to those living with dementia and their carers by improving the quality and experience of care through benchmarking and monitoring patient outcomes. CQRs use data collected to form clinical quality indicators (CQIs) through which variations in clinical processes and outcomes between different services and jurisdictions can be highlighted. Objective: This modified Delphi study aimed to develop CQIs for a pilot Australian CQR for dementia and mild cognitive impairment. These CQIs are based on evidence, patient and caregiver experience, and clinician perspectives across the trajectory of care from diagnosis to end-of-life. Methods: An initial list of indicators from existing dementia registries, academic literature, and clinical practice guidelines was synthesized. A working group of clinicians and registry experts further refined these indicators. A panel of experts comprised of a consumer, a carer, clinicians, consumer organization representatives, and academics. The experts participated in three phases of the modified Delphi study: 1) online survey for scoring importance and validity, 2) a one-day face-to-face discussion, and 3) final survey round to assess importance, validity, and feasibility. Results: The panel assessed 33 CQIs and confirmed a final set of 18 indicators. The CQIs mapped to the domains of quality of diagnosis, quality of management, access to services and supports, and potentially preventable complications. These CQIs will be tested initially in memory clinics and inform the data collection processes for the Australia Dementia Network Registry (ADNet). Conclusion: A dementia CQR is fundamental to ongoing monitoring and development of good quality and consistent care across Australia.

Pages 937-947
Christina Manniche*, Anja Hviid Simonsen*, Steen Gregers Hasselbalch, Ulf Andreasson, Henrik Zetterberg, Kaj Blennow, Peter Høgh, Marianne Juhler, Anne-Mette Hejl (Handling Associate Editor: Gilles Allali) *These authors contributed equally to this work.
Cerebrospinal Fluid Biomarkers to Differentiate Idiopathic Normal Pressure Hydrocephalus from Subcortical Ischemic Vascular Disease
Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) remains a challenge to differentiate from subcortical ischemic vascular disease (SIVD). Despite major research efforts, the cerebrospinal fluid (CSF) biomarker profiles of the two diseases are still not known in detail. Objective: To determine if novel CSF biomarkers, neurofilament light (NFL) reflecting axonal damage, the synaptic protein neurogranin (NG), and the astroglial marker chitinase-3-like protein 1 (YKL-40), and the core Alzheimer’s disease (AD) biomarkers, amyloid-β 42 (Aβ42), total tau (t-tau), phosphorylated tau (p-tau), can differentiate iNPH from SIVD. Patients with AD and healthy controls (HC) were included for comparison purposes. Methods: Patients with iNPH (n = 28), SIVD (n = 30), AD (n = 57), and HC (n = 33) were retrospectively included from the Danish Dementia Biobank. All patients with iNPH had effect of shunt surgery with a follow-up period of 4 to 69 months. CSF biomarkers were measured using immunoassays. Results: Lower levels of NFL, NG, Aβ42, and t-tau were found in patients with iNPH versus SIVD, while YKL-40 and p-tau were similar in the two diseases. NFL and Aβ42 were the most reliable biomarkers to differentiate iNPH from SIVD with an area under the curve (AUC) on 0.82 and 0.80, respectively. Combining NFL with Aβ42, t-tau, and p-tau resulted in an AUC of 0.90, which was equivalent to the diagnostic accuracy of all six biomarkers combined. Conclusion: An addition of NFL to the CSF panel of Aβ42, t-tau, and p-tau may improve the differentiation of iNPH from SIVD.

Pages 949-958
Ho Jae Lim*, Jung Eun Park*, Byeong C. Kim, Seong-Min Choi, Min-Kyung Song, Soo Hyun Cho, Hyeon Jeong Seo, Jahae Kim, Ho-Chun Song, Kyu Yeong Choi, Jang Jae Lee, Hoo-Won Kim, Jung-Min Ha, Woo Keun Song, Sung-Gyoo Park, Jung Sup Lee, Kun Ho Lee (Handling Associate Editor: Sang Won Seo) *These authors contributed equally to this work.
Comparison of Two Analytical Platforms in Cerebrospinal Fluid Biomarkers for the Classification of Alzheimer’s Disease Spectrum with Amyloid PET Imaging
Abstract: Background: Cerebrospinal fluid (CSF) amyloid-β1-42 (Aβ1-42), total tau protein (t-Tau), and phosphorylated Tau (p-Tau) are ATN biomarkers for Alzheimer’s disease (AD) and reflect pathogenic changes in the brain. CSF biomarkers of AD are considered for inclusion in the diagnostic criteria for research and clinical purposes to reduce the uncertainty of clinical diagnosis and to distinguish among AD stages. Objective: This study aims to compare two commercially available analytical platforms with respect to accuracy and the potential for early diagnosis of AD. Methods: A total of 211 CSF samples from healthy control (HC) and AD subjects were analyzed using two analytical platforms, INNOTEST ELISA and INNOBIA AlzBio3 xMAP kits. The accuracy of diagnosis and AUC values distinguishing study groups were compared between the two analytical platforms. Results: The absolute values for Aβ1-42, t-Tau, and p-Tau181 levels differed between the two platforms. The Aβ1-42 levels decreased, while t-Tau and p-Tau levels increased according to the AD stages. The AUC of Aβ1-42 and t-Tau, which distinguish the early stages of AD (preclinical and prodromal AD), were similar between the two platforms, whereas there were significant differences in p-Tau AUC values. CSF p-Tau using the INNOBIA was highly accurate for distinguishing both preclinical AD (AUC = 0.826, cut-off score ≥ 38.89) and prodromal AD (AUC = 0.862, cut-off score ≥ 41.88) from HC. Conclusion: The accuracy of CSF p-Tau levels in the preclinical and prodromal AD is higher for the INNOBIA than the INNOTEST, and the early stage AD can be accurately distinguished from HC.

Pages 959-969
Christopher M. Callahan, Liana G. Apostolova, Sujuan Gao, Shannon L. Risacher, Jamie Case, Andrew J. Saykin, Kathleen A. Lane, Cecily G. Swinford, Mervin C. Yoder (Handling Associate Editor: Jack de la Torre)
Novel Markers of Angiogenesis in the Setting of Cognitive Impairment and Dementia
Abstract:Background: Aberrant angiogenesis may play a role in the development of Alzheimer’s disease and related dementia. Objective: To explore the relationship between angiogenesis activity and evidence of neurodegeneration among older adults. Methods: Cross-sectional study of 49 older adults clinically characterized as cognitively normal, mild cognitive impairment, or early Alzheimer’s disease. In addition to neuroimaging, we completed assays on peripheral blood, including: vascular endothelial growth factor, tumor necrosis factor, fibroblast growth factor, and amyloid-β peptide 40. We used advanced polychromatic flow cytometry to phenotype circulating mononuclear cells to assess angiogenesis activity. Results: Although we documented differences in cognitive performance, structural changes on neuroimaging, and burden of amyloid and tau on positron emission tomography, angiogenesis activity did not vary by group. Interestingly, VEGF levels were shown to be increased among subjects with mild cognitive impairment. In ANCOVA models controlling for age, sex, intracranial volume, and monocyte subpopulations, angiogenesis activity was correlated with increased white matter hyperintensities. Conclusion: We demonstrate a significant association between angiogenesis activity and cerebrovascular disease. To better understand the potential of angiogenesis as an intervention target, longitudinal studies are needed.

Pages 971-992
Qunxi Dong*, Jie Zhang*, Qingyang Li, Junwen Wang, Natasha Leporé, Paul M. Thompson, Richard J. Caselli, Jieping Ye, Yalin Wang, for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Integrating Convolutional Neural Networks and Multi-Task Dictionary Learning for Cognitive Decline Prediction with Longitudinal Images
Abstract: Background: Disease progression prediction based on neuroimaging biomarkers is vital in Alzheimer’s disease (AD) research. Convolutional neural networks (CNN) have been proved to be powerful for various computer vision research by refining reliable and high-level feature maps from image patches. Objective: A key challenge in applying CNN to neuroimaging research is the limited labeled samples with high dimensional features. Another challenge is how to improve the prediction accuracy by joint analysis of multiple data sources (i.e., multiple time points or multiple biomarkers). To address these two challenges, we propose a novel multi-task learning framework based on CNN. Methods: First, we pre-trained CNN on the ImageNet dataset and transferred the knowledge from the pre-trained model to neuroimaging representation. We used this deep model as feature extractor to generate high-level feature maps of different tasks. Then a novel unsupervised learning method, termed Multi-task Stochastic Coordinate Coding (MSCC), was proposed for learning sparse features of multi-task feature maps by using shared and individual dictionaries. Finally, Lasso regression was performed on these multi-task sparse features to predict AD progression measured by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog). Results: We applied this novel CNN-MSCC system on the Alzheimer’s Disease Neuroimaging Initiative dataset to predict future MMSE/ADAS-Cog scales. We found our method achieved superior performances compared with seven other methods. Conclusion: Our work may add new insights into data augmentation and multi-task deep model research and facilitate the adoption of deep models in neuroimaging research.

Pages 993-1002
Milan Fiala, Yik Chai Charles Lau, Anthony Aghajani, Sneha Bhargava, Eli Aminpour, Karolina Elżbieta Kaczor-Urbanowicz, Hayk Mirzoyan, India Nichols, Meng-Wei Ko, Marco Morselli, Joslyn Santana, Johnny Dang, James Sayre, Ketema Paul, Matteo Pellegrini
Omega-3 Fatty Acids Increase Amyloid-β Immunity, Energy, and Circadian Rhythm for Cognitive Protection of Alzheimer’s Disease Patients Beyond Cholinesterase Inhibitors
Abstract: Background: The cholinesterase inhibitor therapeutics (CI) approved for use in Alzheimer’s disease (AD) are palliative for a limited time. Objective: To examine the outcome of AD patients with add-on therapy of the omega-3 fatty acid drink Smartfish. Methods: We performed a prospective study using Mini-Mental State Examination, amyloid-β (Aβ) phagocytosis blood assay, and RNA-seq of peripheral blood mononuclear cells in 28 neurodegenerative patients who had failed their therapies, including 8 subjective cognitive impairment (SCI), 8 mild cognitive impairment (MCI), 2 AD dementia, 1 frontotemporal dementia (FTD), 2 vascular cognitive impairment, and 3 dementia with Lewy bodies (DLB) patients. Results: MCI, FTD, and DLB patients patients volunteered for the addition of a ω-3 fatty acid drink Smartfish protected by anti-oxidants to failing CI therapy. On this therapy, all MCI patients improved in the first year energy transcripts, Aβ phagocytosis, cognition, and activities of daily living; in the long term, they remained in MCI status two to 4.5 years. All FTD and DLB patients rapidly progressed to dementia. On in vivo or in vitro ω-3 treatments, peripheral blood mononuclear cells of MCI patients upregulated energy enzymes for glycolysis and citric acid cycle, as well as the anti-inflammatory circadian genes CLOCK and ARNTL2. Conclusion: Add-on ω-3 therapy to CI may delay dementia in certain patients who had failed single CI therapy.

Pages 1003-1016
Leonardo Iaccarino*, Arianna Sala*, Silvia Paola Caminiti*, Luca Presotto, Daniela Perani, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Annalena Venneri) *These authors contributed equally to this work.
In vivo MRI Structural and PET Metabolic Connectivity Study of Dopamine Pathways in Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is characterized by an involvement of brain dopamine (DA) circuitry, the presence of which has been associated with emergence of both neuropsychiatric symptoms and cognitive deficits. Objective: In order to investigate whether and how the DA pathways are involved in the pathophysiology of AD, we assessed by in vivo neuroimaging the structural and metabolic alterations of subcortical and cortical DA pathways and targets. Methods: We included 54 healthy control participants, 53 amyloid-positive subjects with mild cognitive impairment due to AD (MCI-AD), and 60 amyloid-positive patients with probable dementia due to AD (ADD), all with structural 3T MRI and 18F-FDG-PET scans. We assessed MRI-based gray matter reductions in the MCI-AD and ADD groups within an anatomical a priori-defined Nigrostriatal and Mesocorticolimbic DA pathways, followed by 18F-FDG-PET metabolic connectivity analyses to evaluate network-level metabolic connectivity changes. Results: We found significant tissue loss in the Mesocorticolimbic over the Nigrostriatal pathway. Atrophy was evident in the ventral striatum, orbitofrontal cortex, and medial temporal lobe structures, and already plateaued in the MCI-AD stage. Degree of atrophy in Mesocorticolimbic regions positively correlated with the severity of depression, anxiety, and apathy in MCI-AD and ADD subgroups. Additionally, we observed significant alterations of metabolic connectivity between the ventral striatum and fronto-cingulate regions in ADD, but not in MCI-AD. There were no metabolic connectivity changes within the Nigrostriatal pathway. Conclusion: Our cross-sectional data support a clinically-meaningful, yet stage-dependent, involvement of the Mesocorticolimbic system in AD. Longitudinal and clinical correlation studies are needed to further establish the relevance of DA system involvement in AD.

Pages 1017-1027
Hana Marie Broulikova, Marketa Arltova, Marie Kuklova, Tomas Formanek, Pavla Cermakova
Hospitalizations and Mortality of Individuals with Dementia: Evidence from Czech National Registers
Abstract: Background: Facing an increasing prevalence of dementia, the Czech Republic is developing a new nationwide strategy for the management and prevention of dementia. Lack of evidence about characteristics of individuals with dementia in the country is a major obstacle. Objective: The study aimed to 1) characterize individuals with dementia, 2) compare their mortality with the general population, and 3) analyze differences in survival between different dementia disorders. Methods: The study capitalizes on two nationwide registers in the Czech Republic, from which information about individuals who were hospitalized with dementia or died from it between 1994 and 2014 was retrieved. Standardized intensity of hospitalizations was calculated for each year, mortality was studied using standardized mortality ratio, life-tables, Kaplan-Mayer curves, and Cox proportional hazard models. Results: Standardized intensity of hospitalizations for dementia increased more than 3 times from 1994 to 2014. Standardized mortality ratio was 3.03 (95% confidence interval 2.97–3.08). One-year survival rate was 45% and five-year survival rate 16%. Vascular dementia was the most common type of dementia disorders and was associated with higher hazard of death than Alzheimer’s disease, even after adjusting for sociodemographic and clinical covariates (hazard ratio 1.04; 95% confidence interval 1.02-1.05). Conclusion: The study provides estimates on demographic characteristics and mortality of the Czech hospitalized dementia population, which have not been so far available and which are unique also in the context of the entire region of Central and Eastern Europe.

Pages 1029-1047
Mirjana Babić Leko, Matea Nikolac Perković, Nataša Klepac, Dubravka Švob Štrac, Fran Borovečki, Nela Pivac, Patrick R. Hof, Goran Šimić
IL-1β, IL-6, IL-10, and TNFα Single Nucleotide Polymorphisms in Human Influence the Susceptibility to Alzheimer’s Disease Pathology
Abstract: Neuroinflammation plays an important role in Alzheimer’s disease (AD). During this process, activated microglia release pro-inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor α (TNFα) that participate in neuron damage, but also anti-inflammatory cytokines (such as IL-10), which maintain homeostasis of immune response. Previous studies showed the association of IL-1α -889C/T (rs1800587), IL-1β -1473G/C (rs1143623), IL-6 -174C/G (rs1800795), IL-10 -1082G/A (rs1800896), and TNFα -308A/G (rs1800629) polymorphisms with AD. In this study, we assessed whether people carrying certain genotypes in these polymorphisms are more prone to develop AD-related pathology, reflected by pathological levels of cerebrospinal fluid (CSF) AD biomarkers including amyloid β1–42, total tau (t-tau), tau phosphorylated at Thr 181 (p-tau181), Ser 199 (p‐tau199), and Thr 231 (p‐tau231), and visinin‐like protein 1 (VILIP‐1). The study included 115 AD patients, 53 patients with mild cognitive impairment, and 11 healthy controls. A significant increase in p-tau CSF levels was found in patients with the AA IL-10 -1082G/A and GG TNFα -308A/G genotypes, and in carriers of a G allele in IL-1β -1473C/G and IL-6 -174C/G polymorphisms. t-tau levels were increased in carriers of a G allele in IL-1β -1473C/G polymorphism. An increase in VILIP-1 levels was observed in patients with CG and GG IL-1β -1473C/G, GC IL-6 -174C/G, and GG TNFα -308A/G genotype. These results suggest that persons carrying certain genotypes in IL10 (-1082G/A), IL1β (1473C/G), IL6 (-174C/G), and TNFα (-308A/G) could be more vulnerable to development of neuroinflammation, and consequently of AD.

Pages 1049-1059
Stephanie Torres, Angel Alexander, Sid O’Bryant, Luis D. Medina
Cognition and the Predictive Utility of Three Risk Scores in an Ethnically Diverse Sample
Abstract: Background: Various factors, such as age, cardiovascular concerns, and lifestyle patterns, are associated with risk for cognitive decline and Alzheimer’s disease (AD). Risk scores model predictive risk of developing a disease (e.g., dementia, stroke). Many of these scores have been primarily developed in largely non-Hispanic/Latino (non-H/L) White samples and little is known about their applicability in ethno-racially diverse populations. Objective: The primary aim was to examine the relationship between three established risk scores and cognitive performance. These relationships were compared across ethnic groups. Methods: We conducted a cross-sectional study with a multi-ethnic, rural-dwelling group of participants (Mage=61.6±12.6 years, range: 40–96 years; 373F:168M; 39.7% H/L). The Cardiovascular Risk Factors, Aging and Dementia (CAIDE), Framingham Risk Score (FRS), and Washington Heights-Inwood Columbia Aging Project (WHICAP) score were calculated for each participant. Results: All three scores were significantly associated with cognition in both H/L and non-H/L groups. In H/Ls, cognition was predicted by FRS: β=-0.08, p=0.022; CAIDE: β=-0.08, p<0.001; and WHICAP: β=-0.04, p<0.001. In non-H/Ls, cognition was predicted by FRS: β=-0.11, p<0.001; CAIDE: β=-0.14, p<0.001; and WHICAP: β=-0.08, p<0.001. The strength of this relationship differed between groups for FRS [t(246)=-4.61, p<0.001] and CAIDE [t(420)=-3.20, p=0.001], but not for WHICAP [t(384)=-1.03, p=0.30], which already includes ethnicity in its calculation. Conclusion: These findings support the utility of these three risk scores in predicting cognition while underscoring the need to account for ethnicity. Moreover, our results highlight the importance of cardiovascular and other demographic factors in predicting cognitive outcomes.

Pages 1061-1069
Rosalía García-García-Patino, Julián Benito-León, Alex J. Mitchell, Damián Pastorino-Mellado, Ricardo García García, Valentina Ladera-Fernández, Jose Luis Vicente-Villardón, María Victoria Perea-Bartolomé, Jesús Cacho
Memory and Executive Dysfunction Predict Complex Activities of Daily Living Impairment in Amnestic Multi-Domain Mild Cognitive Impairment
Abstract: Background: Specific cognitive alterations could be one of the predictors that lead to the complex activities of daily living (CADL) impairment in mild cognitive impairment (MCI) and, hence, help to explain the continuum between MCI and dementia. Objective: We aimed to reevaluate the existing uncertainty regarding the impact of memory and executive functions on CADL in patients with MCI. Methods: Caregivers of 161 patients with amnestic multi-domain MCI and of 150 patients with incipient Alzheimer’s disease as well as 100 age-, sex-, and education-matched controls, completed the Interview for Deterioration in Daily Living Activities in Dementia, a suitable instrument for the description and discrimination of CADL. In addition, all patients and controls were assessed with a neuropsychological battery to measure explicit memory and executive functions performance. Results: Multiple regression analyses showed that in the group of patients with amnestic multi-domain MCI, 67.4% of the variability of the CADL impairment was explained by worse performance on executive functions tests (p < 0.0001) and 41.8% by different explicit memory components impairment (p < 0.0001). Further, in patients with incipient AD, 44.0% of the variability of CADL impairment was explained by worse performance on executive functions tests (p < 0.0001) and 39.9% by different explicit memory components worsening (p < 0.0001). Conclusions: Memory and executive functions alterations impact similarly on the CADL in both amnestic multi-domain MCI and incipient Alzheimer's disease. Given the continuum that exists between both conditions, we conclude that CADL impairment may be an important early step in the evolution towards Alzheimer’s disease from amnestic multi-domain MCI.