Volume 79, Number 3, 2021

Pages 931-948

Ian Albert Clark, Bryce Vissel
Broader Insights into Understanding Tumor Necrosis Factor and Neurodegenerative Disease Pathogenesis Infer New Therapeutic Approaches
Abstract: Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post- traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer’s disease and Parkinson’s disease sufferers. In contrast, Alzheimer’s disease and Parkinson’s disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this.

Pages 949-959

Rachel Tham, Tamara Schikowski
The Role of Traffic-Related Air Pollution on Neurodegenerative Diseases in Older People: An Epidemiological Perspective
Abstract: Traffic-related air pollution is ubiquitous and almost impossible to avoid. It is important to understand the role that traffic-related air pollution may play in neurodegenerative diseases, such as dementia, Alzheimer’s disease, and Parkinson’s disease, particularly among older populations and at-risk groups. There is a growing interest in this area among the environmental epidemiology literature and the body of evidence identifying this role is emerging and strengthening. This review focuses on the principal components of traffic-related air pollutants (particulate matter and nitrogen oxides) and the epidemiological evidence of their contribution to common neurodegenerative diseases. All studies reported are currently observational in nature and there are mixed findings depending on the study design, assessment of traffic-related air pollutant levels, assessment of the neurodegenerative disease outcome, time period of assessment, and the role of confounding environmental factors and at-risk genetic characteristics. All current studies have been conducted in income-rich countries where traffic-related air pollution levels are relatively low. Additional longer-term studies are needed to confirm the levels of risk, consider other contributing environmental factors and to be conducted in settings where air pollution exposures are higher and at-risk populations reside and work. Better understanding of these relationships will help inform the development of preventive measures and reduce chronic cognitive and physical health burdens (cost, quality of life) at personal and societal levels.

Pages 961-968

Wolfgang J. Streit, Habibeh Khoshbouei, Ingo Bechmann
The Role of Microglia in Sporadic Alzheimer’s Disease
Abstract: Microglia constitute the brain’s immune system and their involvement in Alzheimer’s disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer’s disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea.

Pages 969-978

Taya L. Farugia, Carla Cuni-Lopez, Anthony R. White
Potential Impacts of Extreme Heat and Bushfires on Dementia
Abstract: Australia often experiences natural disasters and extreme weather conditions such as: flooding, sandstorms, heatwaves, and bushfires (also known as wildfires or forest fires). The proportion of the Australian population aged 65 years and over is increasing, alongside the severity and frequency of extreme weather conditions and natural disasters. Extreme heat can affect the entire population but particularly at the extremes of life, and patients with morbidities. Frequently identified as a vulnerable demographic in natural disasters, there is limited research on older adults and their capacity to deal with extreme heat and bushfires. There is a considerable amount of literature that suggests a significant association between mental disorders such as dementia, and increased vulnerability to extreme heat. The prevalence rate for dementia is estimated at 30% by age 85 years, but there has been limited research on the effects extreme heat and bushfires have on individuals living with dementia. This review explores the differential diagnosis of dementia, the Australian climate, and the potential impact Australia’s extreme heat and bushfires have on individuals from vulnerable communities including low socioeconomic status Indigenous and Non-Indigenous populations living with dementia, in both metropolitan and rural communities. Furthermore, we investigate possible prevention strategies and provide suggestions for future research on the topic of Australian bushfires and heatwaves and their impact on people living with dementia. This paper includes recommendations to ensure rural communities have access to appropriate support services, medical treatment, awareness, and information surrounding dementia.

Pages 979-1002

Conrad N. Trumbore
Shear-Induced Amyloid Aggregation in the Brain: V. Are Alzheimer’s and Other Amyloid Diseases Initiated in the Lower Brain and Brainstem by Cerebrospinal Fluid Flow Stresses?
Abstract: Amyloid-β (Aβ) and tau oligomers have been identified as neurotoxic agents responsible for causing Alzheimer’s disease (AD). Clinical trials using Aβ and tau as targets have failed, giving rise to calls for new research approaches to combat AD. This paper provides such an approach. Most basic AD research has involved quiescent Aβ and tau solutions. However, studies involving laminar and extensional flow of proteins have demonstrated that mechanical agitation of proteins induces or accelerates protein aggregation. Recent MRI brain studies have revealed high energy, chaotic motion of cerebrospinal fluid (CSF) in lower brain and brainstem regions. These and studies showing CSF flow within the brain have shown that there are two energetic hot spots. These are within the third and fourth brain ventricles and in the neighborhood of the circle of Willis blood vessel region. These two regions are also the same locations as those of the earliest Aβ and tau AD pathology. In this paper, it is proposed that cardiac systolic pulse waves that emanate from the major brain arteries in the lower brain and brainstem regions and whose pulse waves drive CSF flows within the brain are responsible for initiating AD and possibly other amyloid diseases. It is further proposed that the triggering of these diseases comes about because of the strengthening of systolic pulses due to major artery hardening that generates intense CSF extensional flow stress. Such stress provides the activation energy needed to induce conformational changes of both Aβ and tau within the lower brain and brainstem region, producing unique neurotoxic oligomer molecule conformations that induce AD.

Pages 1003-1008
Short Communication

Akinori Futamura, Sotaro Hieda, Yukiko Mori, Azusa Sugimoto, Hideyo Kasai, Takeshi Kuroda, Satoshi Yano, Kensaku Kasuga, Hidetomo Murakami, Takeshi Ikeuchi, Kenjiro Ono (Handling Associate Editor: Giulio Pasinetti)
Cingulate Island Sign in Single Photon Emission Computed Tomography: Clinical Biomarker Correlations in Lewy Body Disease and Alzheimer’s Disease
Abstract: We compared ‘CIScore’ determined by quantitative single photon emission computed tomography studies of the cingulate island sign to cerebrospinal fluid (CSF) biomarkers in Lewy body disease (LBD) and Alzheimer's disease (AD) to assess its usefulness and pathological background. Among the 16 each age-matched LBD and AD patients, the CIScore differed significantly but was not correlated with CSF biomarkers. In LBD, hippocampal atrophy significantly correlated with Clinical Dementia Rating and CSF p-tau and t-tau levels. Our results showed CIS was not related to CSF biomarkers in LBD and high CSF tau levels were related to clinical disease severity and hippocampal atrophy.

Pages 1009-1014
Short Communication
Ganesh M. Babulal, Ann Johnson, Anne M. Fagan, John C. Morris, Catherine M. Roe
Identifying Preclinical Alzheimer’s Disease Using Everyday Driving Behavior: Proof of Concept
Abstract: We examined whether driving behavior can predict preclinical Alzheimer’s disease (AD). Data from 131 cognitively normal older adults with cerebrospinal fluid (CSF) and/or positron emission tomography (PET) biomarkers were examined with naturalistic driving behavior. Receiver operating characteristic curves were used to predict the highest 10%, 25%, and 50% of values for CSF tau/Aβ42, ptau181/Aβ42, or amyloid PET. Six in vivo driving variables alone yielded area under the curves (AUC) from 0.64-0.82. Addition of age, Apolipoprotein ε4, and neuropsychological measures to the models improved the AUC (0.81 to 0.90). Driving can be used as novel neurobehavioral marker to identify presence of preclinical AD.

Pages 1015-1021
Short Communication

Natalia Soldevila-Domenech, Laura Forcano, Anna Boronat, Thais Lorenzo, Iris Piera, Albert Puig-Pijoan, Julian Mateus, José María González de Echevarri Gómez, Iva Knezevic, Anna Soteras, Karine Fauria, Nieves Pizarro, Jose Luis Molinuevo, Rafael de la Torre, PENSA Study Group
Effects of COVID-19 Home Confinement on Mental Health in Individuals with Increased Risk of Alzheimer’s Disease
Abstract: We explored the impact of the Spanish COVID-19 strict home confinement on mental health and cognition in non-infected subjects (N=16, 60-80 years) diagnosed with subjective cognitive decline and APOE ε3/ε4 carriers. Mental health was monitored for 2 months on a daily, weekly, or monthly basis, and compared to pre-confinement values. Emotional distress, anxiety, and depression scores increased to pathological threshold values during and after confinement. Those with lower mood during confinement experienced a decline in their mood after confinement. Cognition did not change. These preliminary results suggest that mental health consequences of corona measures in preclinical stages of Alzheimer’s disease should be further evaluated.

Pages 1023-1032
Yingren Mai*, Qun Yu*, Feiqi Zhu*, Yishan Luo, Wang Liao, Lei Zhao, Chunyan Xu, Wenli Fang, Yuting Ruan, Zhiyu Cao, Ming Lei, Lisa Au, Vincent C.T. Mok, Lin Shi, Jun Liu (Handling Associate Editor: Jianping Jia) *These authors contributed equally to this work.
AD Resemblance Atrophy Index as a Diagnostic Biomarker for Alzheimer's Disease: A Retrospective Clinical and Biological Validation
Abstract: Background: Magnetic resonance imaging (MRI) provides objective information about brain structural atrophy in patients with Alzheimer’s disease (AD). This multi-structural atrophic information, when integrated as a single differential index, has the potential to further elevate the accuracy of AD identification from normal control (NC) compared to the conventional structure volumetric index. Objective: We herein investigated the performance of such an MRI-derived AD index, AD-Resemblance Atrophy Index (AD-RAI), as a neuroimaging biomarker in clinical scenario. Method: Fifty AD patients (19 with the Amyloid, Tau, Neurodegeneration (ATN) results assessed in cerebrospinal fluid) and 50 age- and gender-matched NC (19 with ATN results assessed using positron emission tomography) were recruited in this study. MRI-based imaging biomarkers, i.e., AD-RAI, were quantified using AccuBrain®. The accuracy, sensitivity, specificity, and area under the ROC curve (AUC) of these MRI-based imaging biomarkers were evaluated with the diagnosis result according to clinical criteria for all subjects and ATN biological markers for the subgroup. Results: In the whole groups of AD and NC subjects, the accuracy of AD-RAI was 91%, sensitivity and specificity were 88% and 96%, respectively, and the AUC was 92%. In the subgroup of 19 AD and 19 NC with ATN results, AD-RAI results matched completely with ATN classification. AD-RAI outperforms the volume of any single brain structure measured. Conclusion: The finding supports the hypothesis that MRI-derived composite AD-RAI is a more accurate imaging biomarker than individual brain structure volumetry in the identification of AD from NC in the clinical scenario.

Pages 1033-1040
Ethan Schonfeld, Elan Schonfeld, Casey Aman, Navroop Gill, Dami Kim, Sydney Rabin, Bushraa Shamshuddin, Lloyd Sealey, Ricardo Gabriel Senno (Handling Associate Editor: Alba Malara)
Lateralized Deficits in Motor, Sensory, and Olfactory Domains in Dementia
Abstract: Background: There exist functional deficits in motor, sensory, and olfactory abilities in dementias. Measures of these deficits have been discussed as potential clinical markers. Objective: We measured the deficit of motor, sensory, and olfactory functions on both the left and right body side, to study potential body lateralizations. Methods: This IRB-approved study (N=84) performed left/right clinical tests of gross motor (dynamometer test), sensory (Von Frey test), and olfactory (peppermint oil test) ability. The Mini-Mental Status Exam was administered to determine level of dementia; medical and laboratory data were collected. Results: Sensory and olfactory deficits lateralized to the left side of the body, while motor deficits lateralized to the right side. We found clinical correlates of motor lateralization: female, depression, MMSE<15, and diabetes. While clinical correlates of sensory lateralization: use of psychotherapeutic agent, age≥85, MMSE<15, and male. Lastly, clinical correlates of olfactory lateralization: age<85, number of medications>10, and male. Conclusion: These lateralized deficits in body function can act as early clinical markers for improved diagnosis and treatment. Future research should identify correlates and corresponding therapies to strengthen at-risk areas.

Pages 1041-1054
Burcu F. Darst, Zhiguang Huo, Erin M. Jonaitis, Rebecca L. Koscik, Lindsay R. Clark, Qiongshi Lu, William S. Kremen, Carol E. Franz, Brinda Rana, Michael J. Lyons, Kirk J. Hogan, Jinying Zhao, Sterling C. Johnson, Corinne D. Engelman (Handling Associate Editor: Roger Dixon)
Metabolites Associated with Early Cognitive Changes Implicated in Alzheimer’s Disease
Abstract:Background: Understanding metabolic mechanisms associated with cognitive changes preceding an Alzheimer’s disease (AD) diagnosis could advance our understanding of AD progression and inform preventive methods. Objective: We investigated the metabolomics of early changes in executive function and delayed recall, the earliest aspects of cognitive function to change in the course of AD development, in order to better understand mechanisms that could contribute to early stages and progression of this disease. Methods: This investigation used longitudinal plasma samples from the Wisconsin Registry for Alzheimer’s Prevention (WRAP), a cohort of participants who were dementia free at enrollment and enriched with a parental history of AD. Metabolomic profiles were quantified for 2,324 fasting plasma samples among 1,200 participants, each with up to three study visits, which occurred every two years. Metabolites were individually tested for association with executive function and delayed recall trajectories across age. Results: Of 1,097 metabolites tested, levels of seven were associated with executive function trajectories, including an amino acid cysteine S-sulfate and three fatty acids, including erucate (22:1n9), while none were associated with delayed recall trajectories. Replication was attempted for four of these metabolites that were present in the Vietnam Era Twin Study of Aging (VETSA). Although none reached statistical significance, three of these associations showed consistent effect directions. Conclusion: Our results suggest potential metabolomic mechanisms that could contribute to the earliest signs of cognitive decline. In particular, fatty acids may be associated with cognition in a manner that is more complex than previously suspected.

Pages 1055-1062
Hiroshi Kumon, Yuta Yoshino, Yu Funahashi, Hiroaki Mori, Mariko Ueno, Yuki Ozaki, Kiyohiro Yamazaki, Shinichiro Ochi, Takaaki Mori, Jun-ichi Iga, Masahiro Nagai, Masahiro Nomoto, Shu-ichi Ueno
PICALM mRNA Expression in the Blood of Patients with Neurodegenerative Diseases and Geriatric Depression
Abstract: Background: Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a validated genetic risk factor for late-onset Alzheimer’s disease (AD) and is associated with other neurodegenerative diseases. However, PICALM expression in the blood of neurodegenerative diseases remains elusive. Objective: This study aimed to assess the usefulness of PICALM expression levels in the blood of patients with AD, Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and geriatric major depressive disorder (MDD) as a diagnostic biomarker. Methods: In total, 45, 20, 21, and 19 patients with AD, PD, DLB, and geriatric MDD, respectively, and 54 healthy controls (HCs) were enrolled in the study. Expression data from Gene Expression Omnibus database (GSE97760), (GSE133347) and (GSE98793), (GSE48350), and (GSE144459) were used to validate the ability of biomarkers in the blood of patients with AD, PD, geriatric MDD, and a postmortem human AD brain and animal model of AD (3xTg-AD mouse), respectively. Results: PICALM mRNA expression in human blood was significantly increased in patients with AD compared with that in HCs. PICALM mRNA expression and age were negatively correlated only in patients with AD. PICALM mRNA expression in human blood was significantly lower in patients with PD than in HCs. No changes in PICALM mRNA expression were found in patients with DLB and geriatric MDD. Conclusion: PICALM mRNA expression in blood was higher in patients with AD, but lower in patients with PD, which suggests that PICALM mRNA expression in human blood may be a useful biomarker for differentiating neurodegenerative diseases and geriatric MDD.

Pages 1063-1074
Tom C. Russ, Mark P.C. Cherrie, Chris Dibben, Sam Tomlinson, Stefan Reis, Ulrike Dragosits, Massimo Vieno, Rachel Beck, Ed Carnell, Niamh K. Shortt, Graciela Muniz-Terrera, Paul Redmond, Adele M. Taylor, Tom Clemens, Martie van Tongeren, Raymond M. Agius, John M. Starr, Ian J. Deary, Jamie R. Pearce
Life Course Air Pollution Exposure and Cognitive Decline: Modelled Historical Air Pollution Data and the Lothian Birth Cohort 1936
Abstract: Background: Air pollution has been consistently linked with dementia and cognitive decline. However, it is unclear whether risk is accumulated through long-term exposure or whether there are sensitive/critical periods. A key barrier to clarifying this relationship is the dearth of historical air pollution data. Objective: To demonstrate the feasibility of modelling historical air pollution data and using them in epidemiological models. Methods: Using the EMEP4UK atmospheric chemistry transport model, we modelled historical fine particulate matter (PM2.5) concentrations for the years 1935, 1950, 1970, 1980, and 1990 and combined these with contemporary modelled data from 2001 to estimate life course exposure in 572 participants in the Lothian Birth Cohort 1936 with lifetime residential history recorded. Linear regression and latent growth models were constructed using cognitive ability (IQ) measured by the Moray House Test at the ages of 11, 70, 76, and 79 years to explore the effects of historical air pollution exposure. Covariates included sex, IQ at age 11 years, social class, and smoking. Results: Higher air pollution modelled for 1935 (when participants would have been in utero) was associated with worse change in IQ from age 11-70 years (β=-0.006, SE=0.002, p=0.03) but not cognitive trajectories from age 70-79 years (p>0.05). There was no support for other critical/sensitive periods of exposure or an accumulation of risk (all p>0.05). Conclusion: The life course paradigm is essential in understanding cognitive decline and this is the first study to examine life course air pollution exposure in relation to cognitive health.

Pages 1075-1090
Margaret Ryan, Valerie T.Y. Tan, Nasya Thompson, Diane Guévremont, Bruce G. Mockett, Warren P. Tate, Wickliffe C. Abraham*, Stephanie M. Hughes*, Joanna Williams* *These authors contributed equally to this work.
Lentivirus-Mediated Expression of Human Secreted Amyloid Precursor Protein-Alpha Promotes Long-Term Induction of Neuroprotective Genes and Pathways in a Mouse Model of Alzheimer’s Disease
Abstract: Background: Secreted amyloid precursor protein-alpha (sAPPα) can enhance memory and is neurotrophic and neuroprotective across a range of disease-associated insults, including amyloid-β toxicity. In a significant step toward validating sAPPα as a therapeutic for Alzheimer’s disease (AD), we demonstrated that long-term overexpression of human sAPPα (for 8 months) in a mouse model of amyloidosis (APP/PS1) could prevent the behavioral and electrophysiological deficits that develop in these mice. Objective: To explore the underlying molecular mechanisms responsible for the significant physiological and behavioral improvements observed in sAPPα-treated APP/PS1 mice. Methods: We assessed the long-term effects on the hippocampal transcriptome following continuous lentiviral delivery of sAPPα or empty-vector to male APP/PS1 mice and wild-type controls using Affymetrix Mouse Transcriptome Assays. Data analysis was carried out within the Affymetrix Transcriptome Analysis Console and an integrated analysis of the resulting transcriptomic data was performed with Ingenuity Pathway analysis (IPA). Results: Mouse transcriptome assays revealed expected AD-associated gene expression changes in empty-vector APP/PS1 mice, providing validation of the assays used for the analysis. By contrast, there were specific sAPPα-associated gene expression profiles which included increases in key neuroprotective genes such as Decorin, betaine-GABA transporter, and protocadherin beta-5, subsequently validated by qRT-PCR. An integrated biological pathways analysis highlighted regulation of GABA receptor signaling, cell survival, and inflammatory responses. Furthermore, upstream gene regulatory analysis implicated sAPPα activation of Interleukin-4, which can counteract inflammatory changes in AD. Conclusion: This study identified key molecular processes that likely underpin the long-term neuroprotective and therapeutic effects of increasing sAPPα levels in vivo.

Pages 1091-1104
Shoko Nozaki, Norie Sawada, Yutaka J. Matsuoka, Ryo Shikimoto, Masaru Mimura, Shoichiro Tsugane (Handling Associate Editor: Akihiko Nunomura)
Association Between Dietary Fish and PUFA Intake in Midlife and Dementia in Later Life: The JPHC Saku Mental Health Study
Abstract: Background: The relationship between midlife dietary habits and risk of dementia remains unclear. Objective: To investigate the association between dietary fish and n-3 polyunsaturated fatty acid (PUFA) consumption in midlife and risk of dementia in later life. Methods: This population-based cohort study assessed food frequency (average intake in 1995 and 2000) and cognition (2014-2015) in 1,127 participants (aged 45-64 in 1995). We used logistic regression analyses to calculate odds ratios (ORs) for dementia and mild cognitive impairment (MCI) diagnoses for consumption quartiles of fish, PUFA-rich fish, total n-3 PUFAs, total n-6 PUFAs, types of PUFAs, and n-3/n-6 PUFA ratio. Estimated ORs were adjusted for age; sex; education; smoking status; alcohol consumption frequency; physical activity; histories of cancer, myocardial infarction, and diabetes mellitus; and depression. Results: Significantly reduced risks of dementia over non-dementia (MCI plus cognitively normal) were observed in the second (OR = 0.43 (95%CI = 0.20-0.93)), third (OR = 0.22 (95% CI = 0.09-0.54)), and highest quartiles (OR = 0.39 (95% CI = 0.18-0.86)) for fish; the third (OR = 0.39(95% CI = 0.16-0.92)) and highest quartiles (OR = 0.44(95% CI = 0.19-0.98)) for eicosapentaenoic acid (EPA); the second (OR = 0.39(95% CI = 0.18-0.84)), third (OR = 0.30(95% CI = 0.13-0.70)), and highest quartiles (OR = 0.28(95% CI = 0.12-0.66)) for docosahexaenoic acid (DHA); and the third (OR = 0.36 (95% CI = 0.16-0.85)) and highest quartiles (OR = 0.42 (95% CI = 0.19-0.95)) for docosapentaenoic acid (DPA). Conclusion: High intake of fish in midlife might aid in preventing dementia.

Pages 1105-1119
Karissa Barthelson, Stephen Martin Pederson, Morgan Newman, Michael Lardelli
Brain Transcriptome Analysis of a Protein-Truncating Mutation in Sortilin-Related Receptor 1 Associated with Early-Onset Familial Alzheimer's Disease Indicates Early Effects on Mitochondrial and Ribosome Function
Abstract: Background: The early cellular stresses leading to Alzheimer’s disease (AD) remain poorly understood because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic, late-onset AD (LOAD). SORL1 protein has been shown to act in the trafficking of the amyloid β A4 precursor protein (AβPP) that is proteolysed to form one of the pathological hallmarks of AD, amyloid-β (Aβ) peptide. However, other functions of SORL1 in AD are less well understood. Objective: To investigate the effects of heterozygosity for an EOfAD-like mutation in SORL1 on the brain transcriptome of young-adult mutation carriers using zebrafish as a model organism. Methods: We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1 and performed RNA-sequencing on mRNA isolated from the young adult brains of siblings in a family of fish either wild type (non-mutant) or heterozygous for the EOfAD-like mutation. Results: We identified subtle differences in gene expression indicating changes in mitochondrial and ribosomal function in the mutant fish. These changes appear to be independent of changes in mitochondrial content or the expression of AβPP-related proteins in zebrafish. Conclusion: These findings provided evidence supporting that EOfAD mutations in SORL1 affect mitochondrial and ribosomal function and provide the basis for future investigation elucidating the nature of these effects.

Pages 1121-1132
Zhenrong Fu, Mingyan Zhao, Xuetong Wang, Yirong He, Yuan Tian, Yujing Yang, Ying Han, Shuyu Li
Altered Neuroanatomical Asymmetries of Subcortical Structures in Subjective Cognitive Decline, Amnestic Mild Cognitive Impairment, and Alzheimer’s Disease
Abstract: Background: Individuals with subjective cognitive decline (SCD), defined by self-reported memory complaints but normal performance in objective neuropsychological tests, may be at higher risk of worsening or more frequent memory loss until conversion to Alzheimer’s disease (AD) or related dementia. Asymmetry in two hemispheres is a cardinal character of human brain’s structure and function, and altered brain asymmetry has also been connected with AD. Objective: This study aimed to determine whether the asymmetry of subcortical structures in individuals with SCD and amnestic mild cognitive impairment (aMCI) and AD patients are altered compared with normal controls (NC). Methods: We investigated neuroanatomical alterations in 35 SCD, 43 aMCI, and 41 AD subjects compared with 42 NC, focusing on asymmetrical changes in subcortical structures based on structural magnetic resonance images (sMRI). General linear model was conducted to test group differences, and partial correlation was used to model the interaction between asymmetry measurements and cognitive tests. Results: Individuals with SCD (lateral ventricle and cerebellum-WM), aMCI patients (lateral ventricle, pallidum, hippocampus, amygdala, accumbens, and ventral DC), and AD patients (lateral-ventricle, cerebellum-cortical pallidum, thalamus, hippocampus, amygdala, accumbens, and ventral DC) exhibited significant altered neuroanatomical asymmetries of volume, surface area, and shape compared with NC. Significant associations between shape asymmetry and neuropsychological examinations were found in the hippocampus and accumbens. Conclusion: Altered neuroanatomical asymmetries of subcortical structures were significantly detected in SCD individuals and aMCI patients as well AD patients, and these specific asymmetry alterations are potential to be used as neuroimaging markers and for monitoring disease progression.

Pages 1133-1142
Christopher Gonzalez, Nicole S. Tommasi, Danielle Briggs, Michael J. Properzi, Rebecca E. Amariglio, Gad A. Marshall, for the Alzheimer’s Disease Neuroimaging Initiative
Financial Capacity and Regional Cerebral Tau in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer’s Disease Dementia
Abstract: Background: Financial capacity is often one of the first instrumental activities of daily living to be affected in cognitively normal (CN) older adults who later progress to amnestic mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. Objective: The objective of this study was to investigate the association between financial capacity and regional cerebral tau. Methods: Cross-sectional financial capacity was assessed using the Financial Capacity Instrument – Short Form (FCI-SF) in 410 CN, 199 MCI, and 61 AD dementia participants who underwent flortaucipir tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Linear regression models with backward elimination were used with FCI-SF total score as the dependent variable and regional tau and tau-amyloid interaction as predictors of interest in separate analyses. Education, age sex, Rey Auditory Verbal Learning Test Total Learning, and Trail Making Test B were used as covariates. Results: Significant associations were found between FCI-SF and tau regions (entorhinal: p<0.001; inferior temporal: p<0.001; dorsolateral prefrontal: p=0.01; posterior cingulate: p=0.03; precuneus: p<0.001; and supramarginal gyrus: p=0.005) across all participants. For the tau-amyloid interaction, significant associations were found in four regions (amyloid and dorsolateral prefrontal tau interaction: p=0.005; amyloid and posterior cingulate tau interaction: p=0.005; amyloid and precuneus tau interaction: p<0.001; and amyloid and supramarginal tau interaction: p=0.002). Conclusion: Greater regional tau burden was modestly associated with financial capacity impairment in early-stage AD. Extending this work with longitudinal analyses will further illustrate the utility of such assessments in detecting clinically meaningful decline, which may aid clinical trials of early-stage AD.

Pages 1143-1156
María J. Benítez, Raquel Cuadros, Juan S. Jiménez
Phosphorylation and Dephosphorylation of Tau Protein by the Catalytic Subunit of PKA, as Probed by Electrophoretic Mobility Retard
Abstract: Background: Tau is a microtubule associated protein that regulates the stability of microtubules and the microtubule-dependent axonal transport. Its hyperphosphorylated form is one of the hallmarks of Alzheimer’s disease and other tauopathies and the major component of the paired helical filaments that form the abnormal proteinaceous tangles found in these neurodegenerative diseases. It is generally accepted that the phosphorylation extent of tau is the result of an equilibrium in the activity of protein kinases and phosphatases. Disruption of the balance between both types of enzyme activities has been assumed to be at the origin of tau hyperphosphorylation and the subsequent toxicity and progress of the disease. Objective: We explore the possibility that, beside the phosphatase action on phosphorylated tau, the catalytic subunit of PKA catalyzes both tau phosphorylation and also tau dephosphorylation, depending on the ATP/ADP ratio. Methods: We use the shift in the relative electrophoretic mobility suffered by different phosphorylated forms of tau, as a sensor of the catalytic action of the enzyme. Results: The results are in agreement with the long-known thermodynamic reversibility of the phosphorylation reaction (ATP + Protein = ADP + Phospho-Protein) catalyzed by PKA and many other protein kinases. Conclusion: The results contribute to put the compartmentalized energy state of the neuron and the mitochondrial-functions disruption upstream of tau-related pathologies.

Pages 1157-1170
Angélique A. Gruters, Inez H.G.B. Ramakers, Annemarie P.M. Stiekema, Frans R.J. Verhey, Roy P.C. Kessels, Marjolein E. de Vugt
An Exploratory Study of the Development and Pilot Testing of an Interactive Visual Tool of Neuropsychological Test Results in Memory Clinics
Abstract: Background: Neuropsychological feedback is an important part of the neuropsychological assessment process. However, patients have difficulties remembering this information. Objective: The aim of this study was to develop a web-based visual tool to improve the understanding of neuropsychological results, information retention, and psychologist-patient communication. Methods: The visual tool was developed and optimized using an iterative three-phase stepwise approach to determine its usability, technology acceptance, and feasibility in a memory clinic population. Feedback from different user perspectives (patients, family members, and psychologists) was obtained in each phase using a multimethod approach (e.g., a multidisciplinary brainstorm session, think-aloud sessions, focus groups). The prototype was subsequently tested in a pilot study. Results: The first phases offered insights that led to optimization of the prototype. On a scale ranging from 0 to 100, psychologists evaluated the usability as high [88.1±7.6,70-87]. During the pilot study, both patients and significant others gave positive feedback, but information retention in patients remained low. All participants thought the benefits of the visual tool included seeing cognitive strengths and weaknesses with a translation to daily life all at one glance and receiving feedback on paper to take home. Important barriers were mentioned by psychologists, such as a limited set of tests included and no integration with hospital systems. Conclusion: Overall, patients, family members, and psychologists reported that a visual display of the cognitive profile with insights into daily life had added value to clinical practice. Feedback from the pilot study was adopted in the tool for future implementation purposes.

Pages 1171-1184
Lihong Zhu#, Qiongru Yuan#, Zhaohao Zeng, Ruiyi Zhou, Rixin Luo, Jiawei Zhang, Chi Kwan Tsang, Wei Bi *These authors contributed equally to this work.
Rifampicin Suppresses Amyloid-β Accumulation Through Enhancing Autophagy in the Hippocampus of a Lipopolysaccharide-Induced Mouse Model of Cognitive Decline
Abstract: Background: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition. The metabolism of Aβ is critically affected by autophagy. Although rifampicin is known to mediate neuroinflammation, the underlying mechanism by which rifampicin regulates the cognitive sequelae remains unknown. Objective: Based on our previous findings that rifampicin possesses neuroprotective effects on improving cognitive function after neuroinflammation, we aimed to examine in this study whether rifampicin can inhibit Aβ accumulation by enhancing autophagy in a mouse model of lipopolysaccharide (LPS)-induced cognitive impairment. Methods: Adult C57BL/6 mice were intraperitoneally injected with rifampicin, chloroquine, and/or LPS every day for 7 days. Pathological and biochemical assays and behavioral tests were performed to determine the therapeutic effect and mechanism of rifampicin on the hippocampus of LPS-induced mice. Results: We found that rifampicin ameliorated cognitive impairments in the LPS-induced mice. In addition, rifampicin attenuated the inhibition of autophagosome formation, suppressed the accumulation of Aβ1–42, and protected the hippocampal neurons against LPS-induced damage. Our results further demonstrated that rifampicin improved the neurological function by promoting autophagy through the inhibition of Akt/mTOR/p70S6K signaling pathway in the hippocampus of LPS-induced mice. Conclusion: Rifampicin ameliorates cognitive impairment by suppression of Aβ1–42 accumulation through inhibition of Akt/mTOR/p70S6K signaling and enhancement of autophagy in the hippocampus of LPS-induced mice.

Pages 1185-1194
Charalambos Themistocleous, Bronte Ficek, Kimberly Webster, Dirk-Bart den Ouden, Argye E. Hillis, Kyrana Tsapkini
Automatic Subtyping of Individuals with Primary Progressive Aphasia
Abstract: Background: The classification of patients with primary progressive aphasia (PPA) into variants is time-consuming, costly, and requires combined expertise by clinical neurologists, neuropsychologists, speech pathologists, and radiologists. Objective: The aim of the present study is to determine whether acoustic and linguistic variables provide accurate classification of PPA patients into one of three variants: nonfluent PPA, semantic PPA, and logopenic PPA. Methods: In this paper, we present a machine learning model based on deep neural networks (DNN) for the subtyping of patients with PPA into three main variants, using combined acoustic and linguistic information elicited automatically via acoustic and linguistic analysis. The performance of the DNN was compared to the classification accuracy of Random Forests, Support Vector Machines, and Decision Trees, as well as to expert clinicians’ classifications. Results: The DNN model outperformed the other machine learning models as well as expert clinicians’ classifications with 80% classification accuracy. Importantly, 90% of patients with nfvPPA and 95% of patients with lvPPA was identified correctly, providing reliable subtyping of these patients into their corresponding PPA variants. Conclusion: We show that the combined speech and language markers from connected speech productions can inform variant subtyping in patients with PPA. The end-to-end automated machine learning approach we present can enable clinicians and researchers to provide an easy, quick, and inexpensive classification of patients with PPA.

Pages 1195-1201
Hulya Ulugut Erkoyun, Sven J. van der Lee, Bas Nijmeijer, Rosalina van Spaendonk, Anne Nelissen, Marta Scarioni, Anke Dijkstra, Bedia Samancı, Hakan Gürvit, Zerrin Yıldırım, Fatih Tepgeç, Basar Bilgic, Frederik Barkhof, Annemieke Rozemuller, Wiesje M. van der Flier, Philip Scheltens, Petra Cohn-Hokke, Yolande Pijnenburg
The Right Temporal Variant of Frontotemporal Dementia Is Not Genetically Sporadic: A Case Series
Abstract: Background: Right temporal variant frontotemporal dementia (rtvFTD) has been generally considered as a right sided variant of semantic variant primary progressive aphasia (svPPA), which is a genetically sporadic disorder. Recently, we have shown that rtvFTD has a unique clinical syndrome compared to svPPA and behavioral variant frontotemporal dementia. Objective: We challenge the assumption that rtvFTD is a sporadic, non-familial variant of FTD by identifying potential autosomal dominant inheritance and related genes in rtvFTD. Methods: We collected all subjects with a diagnosis of FTD or primary progressive aphasia who had undergone genetic screening (n=284) and subsequently who had a genetic variant (n=48) with a diagnosis of rtvFTD (n=6) in 2 specialized memory clinics. Results: Genetic variants in FTD related genes were found in 33% of genetically screened rtvFTD cases; including MAPT (n=4), GRN (n=1), and TARDBP (n=1) genes, whereas only one svPPA case had a genetic variant in our combined cohorts. Additionally, 4 out of 6 rtvFTD subjects had a strong family history for dementia. Conclusion: Our results demonstrate that rtvFTD, unlike svPPA, is not a pure sporadic, but a heterogeneous potential genetic variant of FTD, and screening for genetic causes for FTD should be performed in patients with rtvFTD.

Pages 1203-1211
Janice L. Atkins*, Luke C. Pilling*, Christine J. Heales, Sharon Savage, Chia-Ling Kuo, George A. Kuchel, David C. Steffens, David Melzer *These authors contributed equally to this work.
Hemochromatosis Mutations, Brain Iron Imaging, and Dementia in the UK Biobank Cohort
Abstract: Background: Brain iron deposition occurs in dementia. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males. Objective: To estimated p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort. Methods: UK Biobank participants with follow-up hospitalization records (mean 10.5 years). MRI in 206 p.C282Y homozygotes versus 23,349 without variants, including T2* measures (lower values indicating more iron). Results: European ancestry participants included 2,890 p.C282Y homozygotes. Male p.C282Y homozygotes had lower T2* measures in areas including the putamen, thalamus, and hippocampus, compared to no HFE mutations. Incident dementia was more common in p.C282Y homozygous men (Hazard Ratio HR=1.83; 95% CI 1.23 to 2.72, p=0.003), as was delirium. There were no associations in homozygote women or in heterozygotes. Conclusion: Studies are needed of whether early iron reduction prevents or slows related brain pathologies in male HFE p.C282Y homozygotes.

Pages 1213-1226
Linda Gjøra, Bjørn Heine Strand, Sverre Bergh, Tom Borza, Anne Brækhus, Knut Engedal, Aud Johannessen, Marte Kvello-Alme, Steinar Krokstad, Gill Livingston, Fiona E. Matthews, Christian Myrstad, Håvard Skjellegrind, Pernille Thingstad, Eivind Aakhus, Stina Aam, Geir Selbæk (Handling Associate Editor: Anne Fink)
Current and Future Prevalence Estimates of Mild Cognitive Impairment, Dementia, and Its Subtypes in a Population-Based Sample of People 70 Years and Older in Norway: The HUNT Study
Abstract: Background: Having accurate, up-to-date information on the epidemiology of mild cognitive impairment (MCI) and dementia is imperative. Objective: To determine the prevalence of MCI and dementia in Norway using data from a large population-based study. Methods: All people 70+ years of age, n=19,403, in the fourth wave of the Trøndelag Health Study (HUNT4) were invited to participate in the study HUNT4 70+. Trained health personnel assessed participants using cognitive tests at a field station, at homes, or at their nursing home. Interviewers also completed a structured carer questionnaire in regard to participants suspected of having dementia. Clinical experts made diagnoses according to DSM-5 criteria. We calculated prevalence weighing the data to ensure population representativeness. Results: A total of 9,930 (51.1%) of the possible 19,403 people participated, and 9,663 of these had sufficient information for analysis. Standardized prevalence of dementia and MCI was 14.6% (95% confidence interval (CI) 13.9–15.4) and 35.3% (95% CI 34.3–36.4), respectively. Dementia was more prevalent in women and MCI more prevalent in men. The most prevalent dementia subtype was Alzheimer’s disease (57%). By adding data collected from a study of persons ≤ 70 years in the same region, we estimate that there are 101,118 persons with dementia in Norway in 2020, and this is projected to increase to 236,789 and 380,134 in 2050 and 2100, respectively. Conclusion: We found a higher prevalence of dementia and MCI than most previous studies. The present prevalence and future projections are vital for preparing for future challenges to the healthcare system and the entire society.

Pages 1227-1233
Raymond R. Romano III, Michael A. Carter, Mary S. Dietrich, Ronald L. Cowan, Stephen P. Bruehl, Todd B. Monroe
Could Altered Evoked Pain Responsiveness Be a Phenotypic Biomarker for Alzheimer’s Disease Risk? A Cross-Sectional Analysis of Cognitively Healthy Individuals
Abstract: Background: This study evaluated whether the apolipoprotein ε4 (APOE4) allele, a genetic marker associated with increased risk of developing late-onset Alzheimer’s disease (AD), was associated with differences in evoked pain responsiveness in cognitively healthy subjects. Objective: The aim was to determine whether individuals at increased risk of late-onset AD based on APOE allele genotype differ phenotypically in their response to experimentally-induced painful stimuli compared to those who do not have at least one copy of the ε4 allele. Methods: Forty-nine cognitively healthy subjects aged 30-89 years old with the APOE4 allele (n=12) and without (n=37) were assessed for group differences in pain thresholds and affective (unpleasantness) responses to experimentally-induced thermal pain stimuli. Results: Statistically significant main effects of APOE4 status were observed for both the temperature at which three different pain intensity percepts were reached (p=0.040) and the level of unpleasantness associated with each (p=0.014). APOE4 positive participants displayed lower overall pain sensitivity than those who were APOE4 negative and also greater overall levels of pain unpleasantness regardless of intensity level. Conclusion: Cognitively healthy APOE4 carriers at increased risk of late-onset AD demonstrated reduced thermal pain sensitivity but greater unpleasantness to thermal pain stimuli relative to individuals at lower risk of late-onset AD. These results suggest that altered evoked pain perception could potentially be used as a phenotypic biomarker of late-onset AD risk prior to disease onset. Additional studies of this issue may be warranted.

Pages 1235-1255
Mona Sohrabi, Heidi L. Pecoraro, Colin K. Combs
Gut Inflammation Induced by Dextran Sulfate Sodium Exacerbates Amyloid-β Plaque Deposition in the AppNL-G-F Mouse Model of Alzheimer’s Disease
Abstract: Background: Although it is known that the brain communicates with the gastrointestinal (GI) tract via the well-established gut-brain axis, the influence exerted by chronic intestinal inflammation on brain changes in Alzheimer’s disease (AD) is not fully understood. We hypothesized that increased gut inflammation would alter brain pathology of a mouse model of AD. Objective: Determine whether colitis exacerbates AD-related brain changes. Methods: To test this idea, 2% dextran sulfate sodium (DSS) was dissolved in the drinking water and fed ad libitum to male C57BL/6 wild type and AppNL-G-F mice at 6-10 months of age for two cycles of three days each. DSS is a negatively charged sulfated polysaccharide which results in bloody diarrhea and weight loss, changes similar to human inflammatory bowel disease (IBD). Results: Both wild type and AppNL-G-F mice developed an IBD-like condition. Brain histologic and biochemical assessments demonstrated increased insoluble Aβ1-40/42 levels along with the decreased microglial CD68 immunoreactivity in DSS treated AppNL-G-F mice compared to vehicle treated AppNL-G-F mice. Conclusion: These data demonstrate that intestinal dysfunction is capable of altering plaque deposition and glial immunoreactivity in the brain. This study increases our knowledge of the impact of peripheral inflammation on Aβ deposition via an IBD-like model system.

Pages 1257-1268
Marta Fernández-Matarrubia, Leticia Goni, Teresa Rognoni, Cristina Razquin, César Ignacio Fernández-Lázaro, Maira Bes-Rastrollo, Miguel Ángel Martínez-González, Estefanía Toledo
An Active Lifestyle Is Associated with Better Cognitive Function Over Time in APOE ε4 Non-Carriers
Abstract: Background: Available evidence on the association of physical activity (PA) or sedentary behavior with cognitive decline is inconclusive. Objective: To assess the association between an active lifestyle score and leisure-time physical activity (LTPA) and changes in cognitive function in the Seguimiento Universidad de Navarra (SUN) prospective cohort. Methods: Cognitive function was evaluated in a subsample of 806 participants of the SUN cohort study using the validated Telephone Interview for Cognitive Status-modified (STICS-m) questionnaire at baseline and after 6 years. LTPA was evaluated with a previously validated 17-item self-administered questionnaire and with information on sedentary lifestyles. We also calculated a multidimensional 8-item PA score. Multivariable linear regression analysis evaluated the association between PA and changes in cognitive function and its interaction by APOE genotype. Results: Mean age of participants was 66 (SD 5.3) years and 69.7% were male. When stratifying by APOE variants, no significant associations between the active lifestyle score or LTPA and changes in cognitive performance over time were found among APOE ε4 carriers. However, we observed that a higher adherence to an active lifestyle (high versus low PA score β=0.76 95%CI 0.15,1.36; p trend=0.011) and a high LTPA (Q4 versus Q1 β=0.63; 95%CI -0.01,1.26; p trend=0.030) were associated with more favorable changes in cognitive function over time among APOE ε4 non-carriers with statistically significant interactions in both cases (p for interaction=0.042 for PA score, and p=0.039 for LTPA). Conclusion: The results of the present study suggest that an active lifestyle is associated with a better status of cognitive function over time only among APOE ε4 non-carriers.

Pages 1269-1283
Manu J. Sharma, Brandy L. Callahan (Handling Associate Editor: Peter Whitehouse)
Cerebrovascular and Neurodegenerative Pathologies in Long-Term Stable Mild Cognitive Impairment
Abstract: Background: Mild cognitive impairment (MCI) is considered by some to be a prodromal phase of a progressive disease (i.e., neurodegeneration) resulting in dementia; however, a substantial portion of individuals (ranging from 5-30%) remain cognitively stable over the long term (sMCI). The etiology of sMCI is unclear but may be linked to cerebrovascular disease (CVD), as evidence from longitudinal studies suggest a significant proportion of individuals with vasculopathy remain stable over time. Objective: To quantify the presence of neurodegenerative and vascular pathologies in individuals with long-term (>5-year) sMCI, in a preliminary test of the hypothesis that CVD may be a contributor to non-degenerative cognitive impairment. We expect frequent vasculopathy at autopsy in sMCI relative to neurodegenerative disease, and relative to individuals who convert to dementia. Methods: In this retrospective study, using data from the National Alzheimer’s Coordinating Center, individuals with sMCI (n = 28) were compared to those with MCI who declined over a 5 to 9-year period (dMCI; n = 139) on measures of neurodegenerative pathology (i.e., Aβ plaques, neurofibrillary tangles, TDP-43, and cerebral amyloid angiopathy) and CVD (infarcts, lacunes, microinfarcts, hemorrhages, and microbleeds). Results: Alzheimer’s disease pathology (Aβ plaques, neurofibrillary tangles, and cerebral amyloid angiopathy) was significantly higher in the dMCI group than the sMCI group. Microinfarcts were the only vasculopathy associated with group membership; these were more frequent in sMCI. Conclusion: The most frequent neuropathology in this sample of long-term sMCI was microinfarcts, tentatively suggesting that silent small vessel disease may characterize non-worsening cognitive impairment.

Pages 1285-1296
Mehnaz Ahmed, Nathan Herrmann, Jinghan Jenny Chen, Mahwesh Saleem, Paul I. Oh, Ana C. Andreazza, Alexander Kiss, Krista L. Lanctôt
Glutathione Peroxidase Activity Is Altered in Vascular Cognitive Impairment-No Dementia and Is a Potential Marker for Verbal Memory Performance
Abstract: Background: Coronary artery disease (CAD) increases risk for vascular cognitive impairment-no dementia (VCIND), a precursor to dementia, potentially through persistent oxidative stress. Objective: This study assessed peripheral glutathione peroxidase activity (GPX), which is protective against oxidative stress, in VCIND versus cognitively normal CAD controls (CN). GPX activity was also evaluated as a biomarker of cognition, particularly verbal memory. Methods: 120 CAD patients with VCIND (1SD below norms on executive function or verbal memory (VM)) or without (CN) participated in exercise rehabilitation for 24 weeks. Neurocognitive and cardiopulmonary fitness (VO2 peak) assessments and plasma were collected at baseline and 24-weeks. Results: GPX was higher in VCIND compared to CN (F1,119=3.996, p=0.048). Higher GPX was associated with poorer baseline VM (β=-0.182, p=0.048), and longitudinally with VM decline controlling for sex, body mass index, VO2 peak, and education (b[SE]=-0.02[0.01], p=0.004). Only CN participants showed improved VM performance with increased fitness (b[SE]=1.30[0.15], p<0.005). Conclusion: GPX was elevated in VCIND consistent with a compensatory response to persistent oxidative stress. Increased GPX predicted poorer cognitive outcomes (verbal memory) in VCIND patients despite improved fitness.

Pages 1297-1305
Ira Driscoll, Yue Ma, Catherine L. Gallagher, Sterling C. Johnson, Sanjay Asthana, Bruce P. Hermann, Mark A. Sager, Kaj Blennow, Henrik Zetterberg, Cynthia M. Carlsson, Corinne D. Engelman, Dena B. Dubal, Ozioma C. Okonkwo (Handling Associate Editor: Michelle Mielke)
Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes
Abstract: Background: Identification of new genetic variants that modify Alzheimer’s disease (AD) risk will elucidate novel targets for curbing the disease progression or delaying symptom onset. Objective: To examine whether the functionally advantageous KLOTHO gene KL-VS variant attenuates age-related alteration in cerebrospinal fluid (CSF) biomarkers or cognitive function in middle-aged and older adults enriched for AD risk. Methods: Sample included non-demented adults (N=225, mean age = 63±8, 68% women) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center who were genotyped for KL-VS, underwent CSF sampling and had neuropsychological testing data available proximal to CSF draw. Covariate-adjusted multivariate regression examined relationships between age group (Younger versus Older; mean split at 63 years), AD biomarkers, and neuropsychological performance tapping memory and executive function, and whether these relationships differed between KL-VS non-carriers (KL-VSNC) and heterozygote (KL-VSHET). Results: In the pooled analyses, older age was associated with higher levels of total tau (tTau), phosphorylated tau (pTau), and their respective ratios to amyloid-β (Aβ)42 (ps ≤ 0.002), and with poorer performance on neuropsychological tests (ps ≤ 0.001). In the stratified analyses, KL-VSNC exhibited this age-related pattern of associations with CSF biomarkers (all ps ≤ 0.001), and memory and executive function (ps ≤ 0.003), which were attenuated in KL-VSHET (ps ≥ 0.14). Conclusion: Worse memory and executive function, and higher tau burden with age were attenuated in carriers of a functionally advantageous KLOTHO variant. KL-VS heterozygosity seems to be protective against age-related cognitive and biomolecular alterations that confer risk for AD.

Pages 1307-1316
Yibing Yan*, Xingqi Wu*, Xiaojing Wang, Zhi Geng, Lu Wang, Guixian Xiao, Yue Wu, Shanshan Zhou, Ling Wei, Yanghua Tian, Kai Wang *These authors contributed equally to this work.
The Retinal Vessel Density Can Reflect Cognitive Function in Patients with Alzheimer’s Disease: Evidence from Optical Coherence Tomography Angiography
Abstract: Background: There is increasing evidence that Alzheimer's disease (AD) patients may present decreased cerebral blood perfusion before pathological brain changes. Using the retina as a window to the brain, we can study disorders of the central nervous system through the eyes. Objective: This study aimed to investigate differences in retinal structure and vessel density (VD) between patients with mild AD and healthy controls (HCs). Furthermore, we explored the relationship between retinal VD and cognitive function. Methods: We enrolled 37 patients with AD and 29 age-matched HCs who underwent standard ophthalmic optical coherence tomography angiography (OCTA) for evaluation of the retinal layer thickness and VD parameters. Cognitive function was evaluated using a battery of neuropsychological assessments. Finally, the correlations among retinal layer thickness, VD parameters, and cognitive function were evaluated. Results: The retinal fiber layer thickness and retinal VD of patients with AD were significantly reduced compared with HCs. The retinal VD was significantly correlated with overall cognition, memory, executive, and visual-spatial perception functions. However, there was no significant between-group difference in the macular thickness. Conclusion: Our findings indicate a positive correlation between retinal VD and some, but not all, cognitive function domains. Most importantly, we demonstrated the role of OCTA in detecting early capillary changes, which could be a noninvasive biomarker for early AD.

Pages 1317-1325
Jiaojiao Jing*, Feng Zhang*, Li Zhao*, Jinghui Xie, Jianwen Chen, Rujia Zhong, Yanjun Zhang*, Chunbo Dong *These authors contributed equally to this work.
Correlation Between Brain 18F-AV45 and 18F-FDG PET Distribution Characteristics and Cognitive Function in Patients with Mild and Moderate Alzheimer’s Disease
Abstract: Background: Florbetapir (AV45) and fluorodeoxyglucose (FDG) PET imaging are valuable techniques to detect the amyloid-β (Aβ) load and brain glucose metabolism in patients with Alzheimer's disease (AD). Objective: The purpose of this study is to access the characteristics of Aβ load and FDG metabolism in brain for further investigating their relationships with cognitive impairment in AD patients. Methods: Twenty-seven patients with AD (average 70.6 years old, N=13 male, N=14 female) were enrolled in this study. These AD patients underwent the standard clinical assessment and received detailed imaging examinations of the nervous system by using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), 18F-AV45, and 18F-FDG PET scans. Results: Of 27 AD patients, 22 patients (81.5%) showed significantly increases in Aβ load and 26 patients (96.3%) had significantly reductions in FDG metabolism. The moderate AD patients had more brain areas of reduced FDG metabolism and more severe reductions in some regions compared to mild AD patients, with no differences in Aβ load observed. Moreover, the range and degree of reduced FDG metabolism in several regions were positively correlated with the total score of MMSE or MOCA, whereas the range of Aβ load did not. No correlation was found between the range of Aβ load and the range of reduced FDG metabolism in this study. Conclusion: The reduction in FDG metabolisms captured by 18F-FDG imaging can be used as a potential biomarker for AD diagnosis in the future. 18F-AV45 imaging did not present valuable evidence for evaluating AD patient in this study.

Pages 1327-1344
Mostafa J. Khan, Heather Desaire, Oscar L. Lopez, M. Ilyas Kamboh, Renã A.S. Robinson
Why Inclusion Matters for Alzheimer’s Disease Biomarker Discovery in Plasma
Abstract: Background: African American/Black adults have a disproportionate incidence of Alzheimer’s disease (AD) and are underrepresented in biomarker discovery efforts. Objective: This study aimed to identify potential diagnostic biomarkers for AD using a combination of proteomics and machine learning approaches in a cohort that included African American/Black adults. Methods: We conducted a discovery-based plasma proteomics study on plasma samples (N=113) obtained from clinically diagnosed AD and cognitively normal adults that were self-reported African American/Black or non-Hispanic White. Sets of differentially-expressed proteins were then classified using a support vector machine (SVM) to identify biomarker candidates. Results: In total, 740 proteins were identified of which, 25 differentially-expressed proteins in AD came from comparisons within a single racial and ethnic background group. Six proteins were differentially-expressed in AD regardless of racial and ethnic background. Supervised classification by SVM yielded an area under the curve (AUC) of 0.91 and accuracy of 86% for differentiating AD in samples from non-Hispanic White adults when trained with differentially-expressed proteins unique to that group. However, the same model yielded an AUC of 0.49 and accuracy of 47% for differentiating AD in samples from African American/Black adults. Other covariates such as age, APOE4 status, sex, and years of education were found to improve the model mostly in the samples from non-Hispanic White adults for classifying AD. Conclusion: These results demonstrate the importance of study designs in AD biomarker discovery, which must include diverse racial and ethnic groups such as African American/Black adults to develop effective biomarkers.

Pages 1345-1367
Ashley D. Innis, Magdalena I. Tolea, James E. Galvin
The Effect of Baseline Patient and Caregiver Mindfulness on Dementia Outcomes
Abstract: Background: Mindfulness is the practice of awareness and living in the present moment without judgment. Mindfulness-based interventions may improve dementia-related outcomes. Before initiating interventions, it would be beneficial to measure baseline mindfulness to understand targets for therapy and its influence on dementia outcomes. Objective: This cross-sectional study examined patient and caregiver mindfulness with patient and caregiver rating scales and patient cognitive performance and determined whether dyadic pairing of mindfulness influences patient outcomes. Methods: Individuals (N=291) underwent comprehensive evaluations, with baseline mindfulness assessed using the 15-item Applied Mindfulness Process Scale (AMPS). Correlation, regression, and mediation models tested relationships between patient and caregiver mindfulness and outcomes. Results: Patients had a mean AMPS score of 38.0±11.9 and caregivers had a mean AMPS score of 38.9±11.5. Patient mindfulness correlated with activities of daily living, behavior and mood, health-related quality of life, subjective cognitive complaints, and performance on episodic memory and attention tasks. Caregiver mindfulness correlated with preparedness, care confidence, depression, and better patient cognitive performance. Patients in dyads with higher mindfulness had better cognitive performance, less subjective complaints, and higher health-related quality of life (all p-values<0.001). Mindfulness effects on cognition were mediated by physical activity, social engagement, frailty, and vascular risk factors. Conclusion: Higher baseline mindfulness was associated with better patient and caregiver outcomes, particularly when both patients and caregivers had high baseline mindfulness. Understanding the baseline influence of mindfulness on the completion of rating scales and neuropsychological test performance can help develop targeted interventions to improve well-being in patients and their caregivers.

Pages 1369-1380
Saima Hilal, Henri J.M.M Mutsaerts, Doeschka A. Ferro, Jan Petr, Hugo J. Kuijf, Geert Jan Biessels, Christopher Chen (Handling Associate Editor: Masafumi Ihara)
The Effects of Intracranial Stenosis on Cerebral Perfusion and Cognitive Performance
Abstract: Background: Intracranial stenosis (ICS) may contribute to cognitive dysfunction by decreased cerebral blood flow (CBF) which can be measured quantitatively by arterial spin labelling (ASL). Interpretation of CBF measurements with ASL, however, becomes difficult in patients with vascular disease due to prolonged arterial transit time (ATT). Recently, spatial coefficient of variation (sCoV) of ASL signal has been proposed that approximates ATT and utilized as a proxy marker for assessment of hemodynamic status of cerebral circulation. Objective: We investigate the association of ICS with CBF and sCoV parameters and its eventual effects on cognition in a memory clinic population. Methods: We included 381 patients (mean age = 72.3 ± 7.9 years, women = 53.7%) who underwent 3T MRI and detailed neuropsychological assessment. ICS was defined as ≥50% stenosis in any intracranial vessel on 3D Time-of-Flight MR Angiography. Gray matter sCoV and CBF were obtained from 2D EPI pseudo-continuous ASL images. Results: ICS was present in 58 (15.2%) patients. Patients with ICS had higher gray matter sCoV and lower CBF. The association with sCoV remained statistically significant after correction for cardiovascular risk factors. Moreover, ICS was associated with worse performance on visuoconstruction, which attenuated with higher sCoV. Mediation analysis showed that there was an indirect effect of ICS on visuoconstruction via sCoV. Conclusion: These findings suggest that compromised CBF as detected by higher sCoV is related to cognitive impairment among individuals diagnosed with ICS. We also showed that sCoV partially mediates the link between ICS and cognition. Therefore, sCoV may provide valuable hemodynamic information in patients with vascular disease.