Volume 91, Number 3, IN PRESS

Obituary
George Perry
Beyond the Clouds: B.R. Brinkley (1936-2020)

Short Communication
Jianping Jia, Yue Zhang, Yuqing Shi, Xuping Yin, Shiyuan Wang, Yan Li, Tan Zhao, Wenying Liu, Aihong Zhou, Longfei Jia
A 19-Year-Old Adolescent with Probable Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) primarily affects older adults. In this report, we present the case of a 19-year-old male with gradual memory decline for 2 years and World Health Organization-University of California Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT) results also showing memory impairment. Positron emission tomography-magnetic resonance imaging with 18F fluorodeoxyglucose revealed atrophy of the bilateral hippocampus and hypometabolism in the bilateral temporal lobe. Examination of the patient’s cerebrospinal fluid showed an increased concentration of p-tau181 and a decreased amyloid-β 42/40 ratio. However, through whole-genome sequencing, no known gene mutations were identified. Considering the above, the patient was diagnosed with probable AD.

Editorial
George Perry
Alzheimer's Disease: Not Just for the Aged?

Short Communication
Hóngyi Zhào*, Wei Wei*, Hongyang Xie, Yonghua Huang *These authors contributed equally to this work.
Motoric Cognitive Risk Syndrome Among Chinese Older Adults with White Matter Lesions: A Cross-Sectional Observational Study
Abstract: Brain aging is characterized by the declines in motor and cognitive features. The present study is to detect motor cognitive risk syndrome (MCRS) in older adults with white matter lesions (WML). 134 WML aged patients were recruited and diagnosed with the criteria for MCRS. Numerous cognitive function tests and walking tests were performed. The frequency of MCRS is 28.35%. Verbal fluency test, Mini-Mental State Examination, and dual-task walking speed were independent risk factor of MCRS. These findings indicated that MCRS was common in WML seniors. MCRS was associated with the pathologies of WML in older adults.

Emily Reeve, Lynn Chenoweth, Mouna Sawan, Tuan Anh Nguyen, Lisa Kalisch Ellett, Julia Gilmartin-Thomas, Edwin Tan, Janet K. Sluggett, Lyntara S. Quirke, Kham Tran, Nagham Ailabouni, Katherine Cowan, Ron Sinclair, Lenore de la Perrelle, Judy Deimel, Josephine To, Stephanie Daly, Craig Whitehead, Sarah N. Hilmer
Consumer and Healthcare Professional Led Priority Setting for Quality Use of Medicines in People with Dementia: Gathering Unanswered Research Questions
Abstract: Background: Historically, research questions have been posed by the pharmaceutical industry or researchers, with little involvement of consumers and healthcare professionals. Objective: To determine what questions about medicine use are important to people living with dementia and their care team and whether they have been previously answered by research. Methods: The James Lind Alliance Priority Setting Partnership process was followed. A national Australian qualitative survey on medicine use in people living with dementia was conducted with consumers (people living with dementia and their carers including family, and friends) and healthcare professionals. Survey findings were supplemented with key informant interviews and relevant published documents (identified by the research team). Conventional content analysis was used to generate summary questions. Finally, evidence checking was conducted to determine if the summary questions were ‘unanswered’. Results: A total of 545 questions were submitted by 228 survey participants (151 consumers and 77 healthcare professionals). Eight interviews were conducted with key informants and four relevant published documents were identified and reviewed. Overall, analysis resulted in 68 research questions, grouped into 13 themes. Themes with the greatest number of questions were related to co-morbidities, adverse drug reactions, treatment of dementia, and polypharmacy. Evidence checking resulted in 67 unanswered questions. Conclusion: A wide variety of unanswered research questions were identified. Addressing unanswered research questions identified by consumers and healthcare professionals through this process will ensure that areas of priority are targeted in future research to achieve optimal health outcomes through quality use of medicines.

Crystal M. Glover, Konstantinos Arfanakis, Neelum T. Aggarwal, David A. Bennett, David X. Marquez, Lisa L. Barnes (Handling Associate Editor: Brian Gordon)
A Qualitative Examination of Knowledge, Experiences, and Considerations of PET Brain Scan Participation among Older Black and Latino Adults
Abstract: Background: Biological biomarkers yielded from positron emission tomography (PET) brain scans serve as a pathway to understanding Alzheimer’s disease pathology. PET brain scan data remain limited for populations traditionally under-included in aging research. Objective: The purpose of this qualitative study was to examine participant-identified barriers to PET brain scan consent and characterize participant-informed elements of educational materials needed to facilitate PET brain scan participation among older Black and Latino adults. Methods: Participants (N=31) were older adults (mean age=71 years) who self-identified as either non-Latino Black (n=15) or Latino (n=16). Each participant took part in a one-time, in-depth individual interview. Researchers analyzed data guided by a Grounded Theory Approach with both Open Coding and Constant Comparative Coding. Results: Four overarching themes emerged across all participants: 1) knowledge limitations; 2) requirements for consent; 3) motivators for participation; and 4) social networks. Within the four themes, there were differences based on participant ethnoracial group. For example, for Theme Three, older Black adults indicated that they would expect compensation for PET brain scan participation. Conversely, older Latinos stated that they would appreciate, but not anticipate, a financial incentive. All participants stressed the importance of written educational materials with subsequent verbal discussions with study staff. Conclusion: Findings inform the development and implementation of scientifically-relevant and culturally-cognizant engagement approaches, educational materials, and recruitment strategies to increase PET brain scan participation by diverse older adults.

Huiyue Li, Hongliang Liu, Michael W. Lutz, Sheng Luo, for the Alzheimer’s Disease Neuroimaging Initiative
Novel Genetic Variants in TP37, PIK3R1, CALM1, and PLCG2 of the Neurotrophin Signaling Pathway Are Associated with the Progression from Mild Cognitive Impairment to Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is a common neurodegenerative disease and mild cognitive impairment (MCI) is considered as the prodromal stage of AD. Previous studies showed that changes in the neurotrophin signaling pathway could lead to cognitive decline in AD. However, the association of single nucleotide polymorphisms (SNPs) in genes that are involved in this pathway with AD progression from MCI remains unclear. Objective: We investigated the associations between SNPs involved in the neurotrophin signaling pathway with AD progression. Methods: We performed single-locus analysis to identify neurotrophin-signaling-related SNPs associated with the AD progression using 767 patients from the Alzheimer's Disease Neuroimaging Initiative study and 1,373 patients from the National Alzheimer's Coordinating Center study. We constructed polygenic risk scores (PRSs) using the identified independent non-APOE SNPs and evaluated its prediction performance on AD progression. Results: We identified 25 SNPs significantly associated with AD progression with Bayesian false-discovery probability ≤ 0.8. Based on the linkage disequilibrium-clumping and expression quantitative trait loci analysis, we found 6 potentially functional SNPs that were associated with AD progression independently. The PRS analysis quantified the combined effects of these SNPs on longitudinal cognitive assessments and biomarkers from cerebrospinal fluid and neuroimaging. The addition of PRSs to the prediction model for 3-year survival in absence of AD-progression significantly increased the predictive accuracy. Conclusion: Genetic variants in the specific genes of the neurotrophin signaling pathway are predictors of AD progression. eQTL analysis supports that these SNPs regulate expression of key genes involved in the neurotrophin signaling pathway.

Yuek Ling Chai, Nathan Hao Ping Liang, Joyce R. Chong, Narayanaswamy Venketasubramanian, Boon Yeow Tan, Saima Hilal, Christopher P. Chen, Mitchell K. P. Lai
Serum Cathepsin D Is a Potential Biomarker for Alzheimer’s Disease Dementia and Cognitive Decline
Abstract: Background: The lysosomal protease cathepsin D (catD) has been reported to be upregulated in postmortem Alzheimer’s disease (AD) cortex, where it colocalized with neurofibrillary tangles and correlated with levels of phosphorylated tau, suggesting pathophysiological links between catD and neurodegeneration. In contrast, studies of serum catD in AD have yielded conflicting results, and potential associations between baseline serum catD and functional outcomes of patients are at present unknown. Objective: We aimed to examine the status of serum catD in a Singapore-based longitudinal study of dementia and investigate catD associations with functional and cognitive decline. Methods: 35 subjects with no cognitive impairment, 40 patients with cognitive impairment no dementia and 34 with AD dementia underwent annual neuropsychological assessments (mean follow-up = 4.3 years), as well as collection of baseline serum for catD measurements by ELISA. Results: Higher serum catD at baseline was associated with AD clinical diagnosis (odds ratios [OR]: 10.0; 95% confidence interval [CI]: 1.02-97.95) as well as with cortical atrophy. Furthermore, higher catD was associated with global cognitive and functional decline (OR: 9.94; 95% CI: 1.02-97.34). Conclusion: The associations of serum catD with AD dementia as well as atrophy provide further support for the proposed links between catD and neurodegeneration, as well as for the assessment of serum catD as a prognostic biomarker predicting global cognitive and functional decline in larger studies.

Somayeh Meysami, Cyrus A. Raji, Ryan M. Glatt, Emily S. Popa, Aarthi S. Ganapathi, Tess Bookheimer, Colby B. Slyapich, Kyron P. Pierce, Casey J. Richards, Melanie G. Lampa, Jaya M. Gill, Molly K. Rapozo, John F. Hodes, Ynez M. Tongson, Claudia L. Wong, Mihae Kim, Verna R. Porter, Scott A. Kaiser, Stella E. Panos, Richelin V. Dye, Karen J. Miller, Susan Y. Bookheimer, Neil A. Martin, Santosh Kesari, Daniel F. Kelly, Jennifer E. Bramen, Prabha Siddarth, David A. Merrill
Handgrip Strength Is Related to Hippocampal and Lobar Brain Volumes in a Cohort of Cognitively Impaired Older Adults with Confirmed Amyloid Burden
Abstract: Background: Strength and mobility are essential for activities of daily living. With aging, weaker handgrip strength, mobility, and asymmetry predict poorer cognition. We therefore sought to quantify the relationship between handgrip metrics and volumes quantified on brain magnetic resonance imaging (MRI). Objective: To model the relationships between handgrip strength, mobility, and MRI volumetry. Methods: We selected 38 participants with Alzheimer’s disease dementia: biomarker evidence of amyloidosis and impaired cognition. Handgrip strength on dominant and non-dominant hands was measured with a hand dynamometer. Handgrip asymmetry was calculated. Two-minute walk test (2MWT) mobility evaluation was combined with handgrip strength to identify non-frail versus frail persons. Brain MRI volumes were quantified with Neuroreader. Multiple regression adjusting for age, sex, education, handedness, body mass index, and head size modeled handgrip strength, asymmetry and 2MWT with brain volumes. We modeled non-frail versus frail status relationships with brain structures by analysis of covariance. Results: Higher non-dominant handgrip strength was associated with larger volumes in the hippocampus (p=0.02). Dominant handgrip strength was related to higher frontal lobe volumes (p=0.02). Higher 2MWT scores were associated with larger hippocampal (p=0.04), frontal (p=0.01), temporal (p=0.03), parietal (p=0.009), and occipital lobe (p=0.005) volumes. Frailty was associated with reduced frontal, temporal, and parietal lobe volumes. Conclusion: Greater handgrip strength and mobility were related to larger hippocampal and lobar brain volumes. Interventions focused on improving handgrip strength and mobility may seek to include quantified brain volumes on MR imaging as endpoints.

Qianyun Chen, Jill Abrigo, Min Deng, Lin Shi, Yi-Xiang Wang, Winnie Chiu Wing Chu, and for the Alzheimer’s Disease Neuroimaging Initiative
Diffusion Changes in Hippocampal Cingulum in Early Biologically Defined Alzheimer’s Disease
Abstract: Background: Diagnosis of Alzheimer’s disease (AD) was recently shifted from clinical to biological construct to reflect underlying neuropathological status, where amyloid deposition designated patients to the AD continuum, and additional tau positivity represented AD. Objective: To investigate white matter (WM) alteration in the brain of patients in the AD continuum. Methods: A total of 236 subjects across the clinical and biological spectra of AD were included and stratified by normal/abnormal (−/+) amyloid (A) and tau (T) status based on positron emission tomography results, yielding five groups: A−T− cognitively normal (CN), A+T− CN, A+T+ CN, A+T+ mild cognitive impairment, and A+T+ AD. WM alteration was measured by diffusion tensor imaging (DTI). Group differences, correlation of DTI measures with amyloid and tau, and diagnostic performance of such measures were evaluated. Results: Compared with A−T− CN, widespread WM alteration was observed in the AD continuum, including hippocampal cingulum (CGH), cingulum of the cingulate gyrus, and uncinate fasciculus. Diffusion changes measured by regional mean fractional anisotropy (FA) in the bilateral CGH were first detected in the A+T+ CN group and associated with tau burden in the AD continuum (p < 0.001). For discrimination between A+T+ CN and A−T− CN groups, CGH FA achieved accuracy, sensitivity, and specificity of 74%, 58%, and 78% for right CGH and 57%, 83%, and 47% respectively for left CGH. Conclusion: WM alteration is widespread in the AD continuum. Diffusion alteration in CGH occurred early and was correlated with tau pathology, thus may be a promising biomarker in preclinical AD.

Ke Cao, Allison A. Bay, Ihab Hajjar, Whitney Wharton, Felicia Goldstein, Deqiang Qiu, Todd Prusin, J. Lucas McKay, Molly M. Perkins, Madeleine E. Hackney
Rationale and Design of the PARTNER Trial: Partnered Rhythmic Rehabilitation for Enhanced Motor-Cognition in Prodromal Alzheimer’s Disease
Abstract: Background: Functional decline in Alzheimer’s disease (AD) is impacted by impaired ability to integrate and modulate complex cognitive and motor abilities, commonly known as motor-cognitive integration. Impaired motor-cognitive integration occurs in the early stages of AD, prodromal AD (pAD), and may precede other symptoms. Combined motor and cognitive training have been recommended for people with pAD and need to be better researched. Our data suggest that partnered rhythmic rehabilitation (PRR) improves motor-cognitive integration in older adults with cognitive impairment. PRR is an ideal intervention to simultaneously target cardiovascular, social, and motor-cognitive domains important to AD. Objective/Methods: We propose to conduct a 1-year Phase II, single-blind randomized controlled trial using PRR in 66 patients with pAD. Participants will be assigned to three months of biweekly sessions, followed by nine months of weekly sessions of PRR or group walking (WALK) with 1:1 allocation. Group walking in the control group will allow us to compare physical exercise alone versus the added benefit of the cognitively engaging elements of PRR. Results/Conclusion: Using an intent-to-treat approach, this innovative pilot study will 1) Determine acceptability, safety, tolerability, and satisfaction with PRR; 2) Compare efficacy of PRR versus WALK for improving motor-cognitive integration and identify the most sensitive endpoint for a Phase III trial from a set of motor-cognitive, volumetric MRI, and cognitive measures. The study will additionally explore potential neural, vascular, and inflammatory mechanisms by which PRR affects pAD to derive effect size of these intermediary measures and aid us in estimating sample size for a future trial.

Wen-Zhuo Dai, Lu Liu, Meng-Zhuo Zhu, Jing Lu, Jian-Ming Ni, Rong Li, Tao Ma, Xi-Chen Zhu
Morphological and Structural Network Analysis of Sporadic Alzheimer’s Disease Brains Based on the APOE4 Gene
Abstract: Background: Alzheimer's disease (AD) is an increasingly common type of dementia. Apolipoprotein E (APOE) gene is a strong risk factor for AD. Objective: Here, we explored alterations in grey matter structure (GMV) and networks in AD, as well as the effects of the APOE ε4 allele on neuroimaging regions based on structural magnetic resonance imaging (sMRI). Methods: All subjects underwent an sMRI scan. GMV and cortical thickness were calculated using voxel-based morphological analysis, and structural networks were constructed based on graph theory analysis to compare differences between AD and normal controls. Results: The volumes of grey matter in the bilateral inferior temporal gyrus, right middle temporal gyrus, right inferior parietal lobule, right limbic lobe, right frontal lobe, left anterior cingulate gyrus, and bilateral olfactory cortex of patients with AD were significantly decreased. The cortical thickness in patients with AD was significantly reduced in the left lateral occipital lobe, inferior parietal lobe, orbitofrontal region, precuneus, superior parietal gyrus, right precentral gyrus, middle temporal gyrus, pars opercularis gyrus, insular gyrus, superior marginal gyrus, bilateral fusiform gyrus, and superior frontal gyrus. In terms of local properties, there were significant differences between the AD and control groups in these areas, including the right bank, right temporalis pole, bilateral middle temporal gyrus, right transverse temporal gyrus, left postcentral gyrus, and left parahippocampal gyrus. Conclusion: There were significant differences in the morphological and structural covariate networks between AD patients and healthy controls under APOE ε4 allele effects.

Richard J. Caselli, Yinghua Chen, Kewei Chen, Robert J. Bauer III, Dona E.C. Locke, Bryan K. Woodruff (Handling Associate Editor: Kerryn Pike)
Cognition Before and After COVID-19 Disease in Older Adults: An Exploratory Study
Abstract: Background: Older age is a major risk factor for severe COVID-19 disease which has been associated with a variety of neurologic complications, both acutely and chronically. Objective: We sought to determine whether milder COVID-19 disease in older vulnerable individuals is also associated with cognitive and behavioral sequelae. Methods: Neuropsychological, behavioral, and clinical outcomes before and after contracting COVID-19 disease, were compared in members of two ongoing longitudinal studies, the Arizona APOE Cohort and the national Alzheimer’s Disease Research Center (ADRC). Results: 152 APOE and 852 ADRC cohort members, mean age overall roughly 70 years, responded to a survey that indicated 21 APOE and 57 ADRC members had contracted COVID-19 before their ensuing (post-COVID) study visit. The mean interval between test sessions that preceded and followed COVID was 2.2 years and 1.2 years respectively for the APOE and ADRC cohorts. The magnitude of change between the pre and post COVID test sessions did not differ on any neuropsychological measure in either cohort. There was, however, a greater increase in informant (but not self) reported cognitive change in the APOE cohort (p=0.018), but this became nonsignificant after correcting for multiple comparisons. Conclusion: Overall members of both cohorts recovered well despite their greater age-related vulnerability to more severe disease.

Filip Morys, Olivier Potvin, Yashar Zeighami, Jacob Vogel, Rémi Lamontagne-Caron, Simon Duchesne, Alain Dagher for the Alzheimer's Disease Neuroimaging Initiative (Handling Associate Editor: Yume Imahori)
Obesity-Associated Neurodegeneration Pattern Mimics Alzheimer's Disease in an Observational Cohort Study
Abstract: Background: Excess weight in adulthood leads to health complications such as diabetes, hypertension, or dyslipidemia. Recently, excess weight has also been related to brain atrophy and cognitive decline. Reports show that obesity is linked with Alzheimer's disease (AD)-related changes, such as cerebrovascular damage or amyloid-β accumulation. However, to date no research has conducted a direct comparison between brain atrophy patterns in AD and obesity. Objective: Here, we compared patterns of brain atrophy and amyloid-β/tau protein accumulation in obesity and AD using a sample of over 1,300 individuals from four groups: AD patients, healthy controls, obese otherwise healthy individuals, and lean individuals. Methods: We age- and sex-matched all groups to the AD-patients group and created cortical thickness maps of AD and obesity. This was done by comparing AD patients with healthy controls, and obese individuals with lean individuals. We then compared the AD and obesity maps using correlation analyses and permutation-based tests that account for spatial autocorrelation. Similarly, we compared obesity brain maps with amyloid-β and tau protein maps from other studies. Results: Obesity maps were highly correlated with AD maps but were not correlated with amyloid-β/tau protein maps. This effect was not accounted for by the presence of obesity in the AD group. Conclusion: Our research confirms that obesity-related grey matter atrophy resembles that of AD. Excess weight management could lead to improved health outcomes, slow down cognitive decline in aging, and lower the risk for AD.

Emily Eruysal, Lisa Ravdin, Cenai Zhang, Hooman Kamel, Costantino Iadecola, Makoto Ishii
Sexually Dimorphic Association of Circulating Plasminogen Activator Inhibitor-1 Levels and Body Mass Index with Cerebrospinal Fluid Biomarkers of Alzheimer’s Pathology in Preclinical Alzheimer’s Disease
Abstract: Background: Plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis that is associated with adiposity, has been implicated in Alzheimer’s disease (AD) pathogenesis. However, whether circulating PAI-1 levels are altered during preclinical AD remains unclear. Objective: To measure plasma PAI-1 levels in cognitively normal cerebrospinal fluid (CSF) AD biomarker positive and biomarker negative participants and to examine the association of plasma PAI-1 levels with CSF AD biomarkers and Mini-Mental State Examination (MMSE) scores. Methods: In this cross-sectional study, plasma PAI-1 levels were measured in 155 cognitively normal (Clinical Dementia Rating, CDR 0) non-obese older adults. 29 men and 26 women were classified as preclinical AD by previously established CSF tau/Aβ42 criteria. All analyses were sex stratified due to reported sex differences in PAI-1 expression. Results: Plasma PAI-1 levels were associated with body mass index (BMI) but not age in men and women. In men, plasma PAI-1 levels and BMI were lower in preclinical AD compared to control. Plasma PAI-1 levels were positively associated with CSF amyloid-β42 (Aβ42) and CSF Aβ42/Aβ40 and negatively associated with CSF tau/Aβ42, while BMI was positively associated with CSF Aβ42 and negatively associated with CSF p-tau181 and CSF tau/Aβ42. In women, plasma PAI-1 levels and BMI were similar between preclinical AD and control and were not associated with CSF AD biomarkers. For men and women, plasma PAI-1 levels and BMI were not associated with MMSE scores. Conclusion: These findings suggest that there are significant sex differences in the systemic metabolic changes seen in the preclinical stage of AD.

Hong-Jian Gong*, Xingyao Tang*, Yin-He Chai, Yu-Shun Qiao, Hui Xu, Ikramulhaq Patel, Jin-Yan Zhang, Rafael Simó, Jian-Bo Zhou *These authors contributed equally to this work.
Relationship Between Weight-Change Patterns and Cognitive Function: A Retrospective Study
Abstract: Background: Obesity has been linked to cognitive impairment. However, how changes in body mass index (BMI) over the life course influence cognitive function remains unclear. Objective: The influence of distinct weight-change patterns from young adulthood to midlife and late adulthood on cognitive function in older adults was explored. Methods: A total of 5,809 individuals aged ≥ 60 years were included and categorized into four groups on the basis of BMI change patterns. Cognitive function was assessed using four cognition tests in the baseline survey. The relationship between the weight-change patterns and cognition was evaluated using regression models. Results: In comparison with participants who remained at non-obese, those moving from the non-obese to obese weight-change pattern from young (25 years of age) to middle adulthood showed lower Digit Symbol Substitution Test (DSST) scores (β = -1.28; 95% confidence interval [CI]: -2.24 to -0.32). A non-obese to obese change pattern from age 25 years of age to 10 years before baseline was associated with a higher risk of DSST impairment (odds ratio = 1.40; 95% CI: 1.09 to 1.79). In comparison with participants whose heaviest weight was recorded after 60 years of age, those with the heaviest weight between 18 and 40 years of age had lower DSST scores (β= -1.46; 95% CI: -2.77 to -1.52). Conclusion: Our results suggest that the transition from the non-obese to obese category in early adulthood and appearance of the heaviest weight between 18 and 40 years of age are associated with lower cognitive function in later life.

Xiaoli Deng*, Zhao Geng*, Juan Yu*, Xiaoyan Dai, Xunjie Kuang, Xia Chen, Ruifeng Li, Ting Liu, Chongyi Li (Handling Associate Editor: Wang-Sheng Jin) *These authors contributed equally to this work.
The Association Between Cataract and Cognitive Functions in Older Adults: A Longitudinal Cohort Study
Abstract: Background: The association between cataracts and cognitive functions has been reported in several studies. However, the dynamic trajectories of cognitive changes in patients with cataracts remain unelucidated. Objective: The aim of the study was to evaluate the dynamic trajectories of cognitive changes in patients with cataracts. Methods: This observational cohort study recruited 1,146 patients with age-related cataracts (ARC) from the Department of Ophthalmology, Daping Hospital, from September 2020 to November 2021. The cognitive functions of the patients were assessed using a Chinese version of the Telephone Interview of Cognitive Status-40 (TICS-40) test at baseline and 6 months of follow-up. The trajectories and the associated risk factors for the longitudinal cognitive decline during the 6-month follow-up were investigated. Results: Patients with severe ARC [median (IQR): 0 month, 24 (22, 25); 6 months, 23 (21,25)] had lower TICS-40 scores than those with non-severe ARC [0 month, 31 (24, 33), p<0.001; 6 months, 31 (23,33), p<0.001] and controls [0 month, 32 (28, 35), p<0.001; 6 months, 32 (28, 35), p<0.001] at both baseline and 6 months of follow-up. Age (OR: 1.311, 95% CI: 1.229 to 1.398) and cataract grade (OR: 5.569, 95% CI: 2.337 to 13.273) were found to be the risk factors of cognitive decline as indicated by a decrease in the TICS-40 scores. Conclusion: ARC is associated with an increased risk of longitudinal cognitive decline; however, the reversibility of such declines needs to be investigated further.

Alexander Ivan B. Posis, Natalie M. Yarish, Linda K. McEvoy, Purva Jain, Candyce H. Kroenke, Nazmus Saquib, Farha Ikramuddin, Peter F. Schnatz, John Bellettiere, Stephen R. Rapp, Mark A. Espeland, Aladdin H. Shadyab
Association of Social Support with Mild Cognitive Impairment and Dementia Among Older Women: The Women’s Health Initiative Memory Study
Abstract: Background: Social support may be a modifiable risk factor for cognitive impairment. However, few long-term, large prospective studies have examined associations of various forms of social support with incident mild cognitive impairment (MCI) and dementia. Objective: To examine associations of perceived social support with incident MCI and dementia among community-dwelling older women. Methods: This prospective cohort study included 6,670 women from the Women’s Health Initiative Memory Study who were cognitively unimpaired at enrollment. We used Cox proportional hazards models to assess associations between perceived social support with incident MCI, dementia, or either MCI/dementia during an average 10.7 (SD=6.1)-year follow-up. Modelling was repeated for emotional/information support, affection support, tangible support, and positive social interaction subscales of social support. Results: Among 6,670 women (average age=70 years [SD=3.8]; 97.0% non-Hispanic/Latina; 89.8% White), greater perceived social support was associated with lower risk of MCI/dementia after adjustment for age, ethnicity, race, hormone therapy, education, income, diabetes, hypertension, and body mass index (Tertile [T]3 versus T1: HR=0.85, 95%CI 0.74-0.99; ptrend=0.08). Associations were significant for emotional/information support (T3 versus T1: HR=0.84, 95%CI 0.72-0.97; ptrend=0.04) and positive social interaction (T3 versus T1: HR=0.85, 95%CI 0.72-0.99; ptrend=0.06) subscales. Associations were attenuated and not significant after adjustment for depressive symptom severity. Conclusion: Perceived social support, emotional/information support, and positive social interaction were associated with incident MCI/dementia among older women. Results were not significant after adjustment for depressive symptom severity. Improving social support may reduce risk of MCI and dementia in older women.

Jia-Yao Liu*, Ling-Zhi Ma*, Jun Wang, Xin-Jing Cui, Ze-Hu Sheng, Yan Fu, Meng Li, Ya-Nan Ou, Jin-Tai Yu, Lan Tan, Yan Lian (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Age-Related Association Between APOE ε4 and Cognitive Progression in de novo Parkinson’s Disease
Abstract: Background: APOE ε4 genotype was correlated with exacerbation of pathology and higher risk of dementia in Parkinson’s disease (PD). Meanwhile, the differential influence of APOE ε4 on cognition in young and old individuals interpreted as antagonistic pleiotropy. Objective: To examine whether the effect of APOE ε4 on cognitive progression in de novo PD is age dependent. Methods: In this study, 613 de novo PD patients were recruited from Parkinson’s Progression Markers Initiative (PPMI). To examine the age-dependent relationship between APOE ε4 and cognitive changes, we added 3-way interaction of APOE ε4*baseline age*time to the linear mixed-effect (LME) models and evaluated the specific roles of APOE ε4 in the middle age group and elderly group separately. Cox regression was utilized to examine the progression of cognition in age-stratified PD participants. Results: Age significantly modified relationship between APOE ε4 and cognitive changes in most cognitive domains (pinteraction <0.05). In the elderly group, APOE ε4 carriers showed steeper decline in global cognition (p=0.001) as well as in most cognitive domains, and they had a greater risk of cognitive progression (adjusted HR 1.625, 95% CI 1.143-2.310, p=0.007), compared with non-carriers. However, in the middle age group, no significant relationships between APOE ε4 and cognitive decline can be detected. Conclusion: Our results indicated that the APOE ε4 allele has an age-dependent effect on cognitive decline in PD patients. The underlying mechanisms need to be investigated in the future.

Yue Leng, Katie L. Stone, Kristine Yaffe
Race Differences in the Association Between Sleep Medication Use and Risk of Dementia
Abstract: Background: The effect of sleep medications on cognition in older adults is controversial, possibly dependent upon sleep quality, and may differ by race. Objective: To determine the longitudinal association between sleep medication use and incident dementia over 15 years, and to explore whether the association is independent of nighttime sleep disturbances and if it differs by race. Methods: We examined 3,068 community-dwelling older adults (aged 74.1±2.9 years, 41.7% Black, 51.5% female) without dementia. Sleep medication use was recorded three times by asking “Do you take sleeping pills or other medications to help you sleep?” with the response options: “Never (0)”, “Rarely (≤1/month)”, “Sometimes (2-4/month)”, “Often (5-15/month)”, or “Almost Always (16-30/month)”. Incident dementia was defined using hospitalization records, dementia medication prescription or clinically significant decline in global cognition. Results: 138 (7.71%) of Whites and 34 (2.66%) of Blacks reported taking sleep medications “often or almost always”. Whites were almost twice as likely to take all prescription hypnotics. 617 participants developed dementia over the follow-up. After adjustment for all covariates, participants who reported taking sleep medications ≥5/month versus ≤1/month were significantly more likely to develop dementia, and the association was only observed among Whites (HR=1.79,1.21-2.66) but not Blacks (HR=0.84,0.38-1.83); p for interaction=0.048. Further adjustment for nighttime sleep did not appreciably alter the results. The association was similar for the cumulative frequency of sleep medication use and remained after introducing a time lag of 3 years. Conclusion: Frequent sleep medication use was associated with an increased risk of dementia in White older adults. Further research is needed to determine underlying mechanisms.

Daniel C. Parker, William E. Kraus, Heather E. Whitson, Virginia B. Kraus, Patrick J. Smith, Harvey Jay Cohen, Carl F. Pieper, Richard A. Faldowski, Katherine S. Hall, Janet L. Huebner, Olga R. Ilkayeva, James R. Bain, L. Kristin Newby, Kim M. Huffman (Handling Associate Editor: Michelle Mielke)
Tryptophan Metabolism and Neurodegeneration: Longitudinal Associations of Kynurenine Pathway Metabolites with Cognitive Performance and Plasma Alzheimer’s Disease and Related Dementias Biomarkers in the Duke Physical Performance Across the LifeSpan Study
Abstract: Background: The kynurenine pathway (KP) comprises a family of tryptophan-derived metabolites that some studies have reported are associated with poorer cognitive performance and an increased risk of Alzheimer’s disease and related dementias (ADRD). Objective: The objective of this study was to determine the associations of plasma KP metabolites (kynurenine [KYN], kynurenic acid [KA], and tryptophan [TRP]) with a panel of plasma ADRD biomarkers (Aβ42/ β40 ratio, pTau-181, glial fibrillary acidic protein [GFAP], and neurofilament light [NfL]) and cognitive performance in a subset of older adults drawn from the Duke Physical Performance Across the LifeSpan (PALS) study. Methods: The Montreal Cognitive Assessment (MoCA) was used to assess cognitive performance. We used multivariate multiple regression to evaluate associations of the KYN/TRP and KA/KYN ratios with MoCA score and plasma ADRD biomarkers at baseline and over two years (n=301; Age=74.8±8.7). Results: Over two years, an increasing KYN/TRP ratio was associated with increasing plasma concentrations of plasma p-Tau181 (β=6.151; 95%CI [0.29, 12.01]; p=0.040), GFAP (β=11.12; 95%CI [1.73, 20.51]; p=0.020), and NfL (β=11.13; 95%CI [2.745, 19.52]; p=0.009), but not MoCA score or the Aβ42/Aβ40 ratio. There were no significant associations of KA/KYN with MoCA score or plasma ADRD biomarkers. Conclusion: Our findings provide evidence that greater concentrations of KP metabolites are associated longitudinally over two years with greater biomarker evidence of neurofibrillary tau pathology (pTau-181), neuroinflammation (GFAP), and neurodegeneration (NfL), suggesting that dysregulated KP metabolism may play a role in ADRD pathogenesis.

Nádia S. Canário, Lília P. Jorge, Isabel J. Santana, Miguel S. Castelo-Branco
Hemispheric Patterns of Recruitment of Object Processing Regions in Early Alzheimer’s Disease: A Study Along the Entire Ventral Stream
Abstract: Background: Investigation of neural response patterns along the entire network of functionally defined object recognition ventral stream regions in Alzheimer’s disease (AD) is surprisingly lacking. Objective: We aimed to investigate putative functional reorganization along a wide-ranging network of known regions in the ventral visual stream in mild AD. Methods: Overall we investigated 6 regions of interest (5 of which were not investigated before), in 19 AD patients and 19 controls, in both hemispheres along the ventral visual stream: Fusiform Face Area, Fusiform Body Area, Extrastriate Body Area, Lateral Occipital Cortex, Parahippocampal Place Area, and Visual Word Form Area, while assessing object recognition performance. Results: We found group differences in dprime measures for all object categories, corroborating generalized deficits in object recognition. Concerning neural responses, we found region dependent group differences respecting a priori expected Hemispheric asymmetries. Patients showed significantly decreased BOLD responses in the right hemisphere-biased Fusiform Body Area, and lower left hemisphere responses in the Visual Word Form Area (with a priori known left hemispheric bias), consistent with deficits in body shape and word/pseudoword processing deficits. This hemispheric dominance related effects were preserved when controlling for performance differences. Whole brain analysis during the recognition task showed enhanced activity in AD group of left dorsolateral prefrontal cortex, left cingulate gyrus, and in the posterior cingulate cortex—a hotspot of amyloid-β accumulation. Conclusion: These findings demonstrate region dependent respecting hemispheric dominance patterns activation changes in independently localized selective regions in mild AD, accompanied by putative compensatory activity of frontal and cingular networks.

Simona Schäfer, Elisa Mallick, Louisa Schwed, Alexandra König, Jian Zhao, Nicklas Linz, Timothy Hadarsson Bodin, Johan Skoog, Nina Possemis, Daphne ter Huurne, Anna Zettergren, Silke Kern, Simona Sacuiu, Inez Ramakers, Ingmar Skoog, Johannes Tröger (Handling Associate Editor: Sid O'Bryant)
Screening for Mild Cognitive Impairment Using a Machine Learning Classifier and the Remote Speech Biomarker for Cognition: Evidence from Two Clinically Relevant Cohorts
Abstract: Background: Modern prodromal Alzheimer’s disease (AD) clinical trials might extend outreach to a general population, causing high screen-out rates and thereby increasing study time and costs. Thus, screening tools that cost-effectively detect mild cognitive impairment (MCI) at scale are needed. Objective: Develop a screening algorithm that can differentiate between healthy and MCI participants in different clinically relevant populations. Methods: Two screening algorithms based on the remote ki:e speech biomarker for cognition (ki:e SB-C) were designed on a Dutch memory clinic cohort (N = 121) and a Swedish birth cohort (N = 404). MCI classification was each evaluated on the training cohort as well as across on the unrelated validation cohort. Results: The algorithms achieved a performance of AUC ~0.73 and AUC ~0.77 in the respective training cohorts and AUC ~0.81 in the unseen validation cohort. Conclusion: The results indicate that a ki:e SB-C based algorithm robustly detects MCI across different cohorts and languages, which has the potential to make current trials more efficient and improve future primary health care.

Kenji Sakai, Moeko Noguchi-Shinohara, Hidetomo Tanaka, Tokuhei Ikeda, Tsuyoshi Hamaguchi, Akiyoshi Kakita, Masahito Yamada, Kenjiro Ono (Handling Associate Editor: Masafumi Ihara)
Cerebrospinal Fluid Biomarkers and Amyloid-β Elimination from the Brain in Cerebral Amyloid Angiopathy-Related Inflammation
Abstract: Background: Cerebrospinal fluid (CSF) biomarkers in patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) have demonstrated inconsistent results. Objective: We investigated the relationship between CSF amyloid-β protein (Aβ) and vascular pathological findings to elucidate the mechanisms of Aβ elimination from the brain in CAA-ri. Methods: We examined Aβ40 and Aβ42 levels in CSF samples in 15 patients with CAA-ri and 15 patients with Alzheimer’s disease and cerebral amyloid angiopathy (AD-CAA) using ELISA as a cross-sectional study. Furthermore, we pathologically examined Aβ40 and Aβ42 depositions on the leptomeningeal blood vessels (arteries, arterioles, and veins) using brain biopsy samples from six patients with acute CAA-ri and brain tissues of two autopsied patients with CAA-ri. Results: The median Aβ40 and Aβ42 levels in the CSF showed no significant difference between pre-treatment CAA-ri (Aβ40, 6837 pg/ml; Aβ42, 324 pg/ml) and AD-CAA (Aβ40, 7669 pg/ml, p = 0.345; Aβ42, 355 pg/ml, p = 0.760). Aβ40 and Aβ42 levels in patients with post-treatment CAA-ri (Aβ40, 1770 pg/ml, p = 0.056; Aβ42, 167 pg/ml, p = 0.006) were lower than those in patients with pre-treatment CAA-ri. Regarding Aβ40 and Aβ42 positive arteries, acute CAA-ri cases showed a higher frequency of partially Aβ-deposited blood vessels than postmortem CAA-ri cases (Aβ40, 20.8% versus 3.9%, p = 0.0714; Aβ42, 27.4% versus 2.0%, p = 0.0714, respectively). Conclusion: Lower levels of CSF Aβ40 and Aβ42 could be biomarkers for the cessation of inflammation in CAA-ri reflecting the recovery of the intramural periarterial drainage pathway and vascular function.

Brian Downer, Chih-Ying Li, Soham Al Snih
Hospitalizations and Emergency Room Admissions by Mexican American Older Adults with and without Dementia and Caregiver Mental Health
Abstract: Background: Evidence from predominately non-Hispanic White populations indicates that emergency room (ER) admissions and hospitalizations by older adults with and without dementia are associated with caregiver stress and depressive symptoms. These results may not generalize to Hispanic populations because of cultural differences in caregiving roles, responsibilities, and perspectives about care burden. Objective: Investigate the association between ER admissions and hospitalizations by Mexican American older adults with and without dementia and symptoms of depression and stress among family caregivers. Methods: Data came from the 2010/11 wave of the Hispanic Established Populations for the Epidemiologic Study of the Elderly and Medicare claims files. The final sample included 326 older adults and their caregivers. Negative binomial regression was used to model the association between hospitalizations and ER admissions by older adults in the previous two years and caregivers' depressive symptoms and stress in 2010/11. Results: The number of older adult ER admissions and hospitalizations was not associated with caregiver depressive symptoms. Two or more ER admissions (incident rate ratio [IRR]=1.26, 95% CI=1.05-1.51) and two or more hospitalizations (IRR=1.32, 95% CI=1.07-1.61) were associated with significantly higher caregiver stress. Additionally, ER admissions and hospitalizations for a circulatory disease or injury and poisoning were associated with significantly higher caregiver stress. These associations were not modified by the care recipient’s dementia status. Conclusion: Hospitalizations and ER admissions by older Mexican Americans were associated with greater caregiver stress but not depressive symptoms. These associations were similar for caregivers to older adults with and without dementia.

Yuzhao Chen*, Yilin Zhang*, Qiuxuan Chen, Yuxiang Liu, Xuemin Wei, Meijian Wu, Keke Zhang, Yinghua Liu, Wei Wei *These authors contributed equally to this work.
Inhibition of mGluR5/PI3K-AKT Pathway Alleviates Alzheimer’s Disease-Like Pathology Through the Activation of Autophagy in 5XFAD Mice
Abstract: Background: The metabotropic glutamate receptor 5 (mGluR5) is widely expressed in postsynaptic neurons and plays a vital role in the synaptic plasticity of the central nervous system. mGluR5 is a coreceptor for amyloid-β (Aβ) oligomer, and downregulation or pharmacological blockade of mGluR5 presents the therapeutic potential of Alzheimer’s disease (AD). However, the abnormality of mGluR5 in the pathogenesis of AD and its mechanism of pathology is not clear. Objective: In this study, we would like to investigate the expression of mGluR5 in the process of AD and explore the effects and the underlying mechanisms of antagonizing mGluR5 on cognitive function, synaptic structure, and inflammation in 5xFAD mice. Methods: mGluR5 expression and interactions with PrPc in 5XFAD mice were detected using western blot and co-immunoprecipitation. The selective mGluR5 antagonist MPEP was infused into 4-month-old 5XFAD mice for 60 consecutive days. Then, cognitive function, AD-like pathology and synaptic structure were measured. Further observations were made in mGluR5 knockdown 5XFAD mice. Results: mGluR5 expression was increased with Aβ levels at 6 months in 5XFAD mice. mGluR5 antagonist rescued cognitive disorders, promoted synaptic recovery, and alleviated both the Aβ plaque load and abnormal hyperphosphorylation in 6-month-old 5XFAD mice. Meanwhile, the results were validated in mGluR5 knockdown mice. Blockade of mGluR5 efficiently alleviates AD-like pathologies by inhibiting the PI3K/AKT/mTOR pathway and activates autophagy in 5XFAD mice. Furthermore, antagonism of mGluR5 attenuated neuroinflammation by inactivating the IKK/NF-κB pathway. Conclusion: These findings suggest that mGluR5 may be an effective drug target for AD treatment, and inhibition of the mGluR5/PI3K-AKT pathway alleviates AD-like pathology by activating autophagy and anti-neuroinflammation in 5XFAD mice.

Victoria Fleming, Brian C. Helsel, Lauren T. Ptomey, H. Diana Rosas, Benjamin Handen, Charles Laymon, Bradley T. Christian, Elizabeth Head, Mark Mapstone, Florence Lai, Sharon Krinsky-McHale, Shahid Zaman, Beau M. Ances, Joseph H. Lee, Sigan L. Hartley and the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC-DS) Consortium
Weight Loss and Alzheimer’s Disease in Down Syndrome
Abstract: Background: Virtually all adults with Down syndrome (DS) develop Alzheimer’s disease (AD) pathology, but research gaps remain in understanding early signs of AD in DS. Objective: The goal of the present study was to determine if unintentional weight loss is part of AD in DS. The specific aims were to: 1) examine relation between chronological age, weight, AD pathology, and AD-related cognitive decline were assessed in a large cohort of adults with DS, and 2) determine if baseline PET amyloid-β (Aβ) and tau PET status (- versus +) and/or decline in memory and mental status were associated with weight loss prior to AD progression. Methods: Analyses included 261 adults with DS. PET data were acquired using [11C] PiB for Aβ and [18F] AV-1451 for tau. Body mass index (BMI) was calculated from weight and height. Direct measures assessed dementia and memory. Clinical AD status was determined using a case consensus process. Percent weight decline across 16-20 months was assessed in a subset of participants (n = 77). Results: Polynomial regressions indicated an 0.23 kg/m2 decrease in BMI per year beginning at age 36.5 years, which occurs alongside the period during which Aβ and tau increase and memory and mental status decline. At a within-person level, elevated Aβ, decline in memory and mental status were associated with higher percent weight loss across 16-20 months. Conclusion: Unintentional weight loss occurs alongside Aβ deposition and prior to onset of AD dementia, and thus may be a useful sign of AD in DS.