Volume 93, Number 2, 2023

Pages 395-401
Short Communication

Sami Heikkinen, Nadine Huber, Kasper Katisko, Tarja Kokkola, Päivi Hartikainen, Johanna Krüger, Ville Leinonen, Ville E. Korhonen, Sanna-Kaisa Herukka, Anne M. Remes, Barbara Borroni, Antonella Alberici, Ilenia Libri, Eino Solje, Annakaisa Haapasalo
Serum Cathepsin S Levels Do Not Show Alterations in Different Clinical, Neuropathological, or Genetic Subtypes of Frontotemporal Dementia Patients nor in Comparison to Healthy Control Individuals
Abstract: Frontotemporal dementia (FTD) can manifest as diverse clinical phenotypes and is frequently caused by mutations in different genes, complicating differential diagnosis. This underlines the urgent need for valid biomarkers. Altered lysosomal and immune functions proposedly contribute to FTD pathogenesis. Cathepsins, including cathepsin S, are enzymes preferentially expressed in brain in microglia, which influence lysosomal and immune function. Here, we examined whether alterations in serum cathepsin S levels associate with specific clinical, genetic, or neuropathological FTD subgroups, but no such alterations were observed. However, further research on other lysosomal proteins may reveal new biologically relevant biomarkers in FTD.

Pages 403-409
Short Communication

Jee-Min Rhyu, Joonhong Park, Byoung-Soo Shin, Young-Eun Kim, Eun-Joo Kim, Ko Woon Kim, Yong Gon Cho
A Novel c.800G>C Variant of the ITM2B Gene in Familial Korean Dementia
Abstract: Mutations in ITM2B have been reported to be associated with several familial dementias, such as Familial British dementia and familial Danish dementia. These are autosomal dominant disorders characterized by progressive dementia with an onset at around the fifth decade of life. We describe a family with cognitive impairment caused by a novel ITM2B p.*267Serext*11 mutation. The probands presented with cognitive impairment and cerebral infarction. MRI revealed diffuse white matter hyperintensity and microbleeds. Amyloid deposition was not observed on amyloid positron emission tomography. Our case suggests that the BRI2 mutation impacts cognition regardless of amyloid-β accumulation.

Pages 411-419
Einar Sulheim, Marius Widerøe, Marcus Bäck, K. Peter R. Nilsson, Per Hammarström, Lars N.G. Nilsson, Catharina de Lange Davies, Andreas K. O. Åslund (Handling Associate Editor: Nils Richter)
Contrast Enhanced Magnetic Resonance Imaging of Amyloid-β Plaques in a Murine Alzheimer’s Disease Model
Abstract: Background: Early detection of amyloid-β (Aβ) aggregates is a critical step to improve the treatment of Alzheimer’s disease (AD) because neuronal damage by the Aβ aggregates occurs before clinical symptoms are apparent. We have previously shown that luminescent conjugated oligothiophenes (LCOs), which are highly specific towards protein aggregates of Aβ, can be used to fluorescently label amyloid plaque in living rodents. Objective: We hypothesize that the LCO can be used to target gadolinium to the amyloid plaque and hence make the plaque detectable by T1-weighted magnetic resonance imaging (MRI). Methods: A novel LCO-gadolinium construct was synthesized to selectively bind to Aβ plaques and give contrast in conventional T1-weighted MR images after intravenous injection in Tg-APPSwe mice. Results: We found that mice with high plaque-burden could be identified using the LCO-Gd constructs by conventional MRI. Conclusion: Our study shows that MR imaging of amyloid plaques is challenging but feasible, and hence contrast-mediated MR imaging could be a valuable tool for early AD detection.

Pages 421-433
Nanna Eithz, Jan Sørensen, Liza Sopina (Handling Associate Editor: Bernhard Michalowsky)
Healthcare Costs in the Year Before and After Alzheimer’s Disease Diagnosis: A Danish Register-Based Matched Cohort Study
Abstract: Background: Alzheimer’s disease (AD) carries a significant economic burden, with costs peaking around the time of diagnosis. However, the cost of diagnosis, including the time leading up to it, has not been studied thoroughly. Furthermore, regionalized healthcare structure could result in differences in the pre-diagnostic costs for people with suspected AD. Objective: This study set out to estimate the excess healthcare costs before and after AD diagnosis compared to a matched non-AD population and to investigate regional variation in AD healthcare costs in Denmark. Methods: We used a register-based cohort of 25,523 matched pairs of new cases of AD and non-AD controls. The healthcare costs included costs on medication, and inpatient-, outpatient-, and primary care visits. Generalized estimating equations were employed to estimate the excess healthcare cost attributable to diagnosing AD, and the variation in costs across regions. Results: Mean excess costs attributable to AD were €3,284 and €6,173 in the year before and after diagnosis, respectively. Regional differences in healthcare costs were identified in both the AD and control groups and were more pronounced in patients with AD (PwAD). Conclusion: PwAD incur higher healthcare costs across all cost categories in the year before and after diagnosis. Regional differences in healthcare utilization by PwAD may reveal potential variation in access to healthcare. These findings suggest that a more standardized and targeted diagnostic process may help reduce costs and variation in access to healthcare.

Pages 435-448
Lin Qian, Wenjuan Bian, Diqi Wang, Zhuoqun Ming, Yu Zhang, Linbo Zhang, Lu Fu
Adeno-Associated Virus-Mediated Immunotherapy Based on Bispecific Tandem scFv for Alzheimer’s Disease
Abstract: Background: Patients with Alzheimer's disease (AD) have considerably increased globally as a result of population aging, placing a significant burden on the global economy and the medical system. The outcome of clinical trials for AD immunotherapy that solely targeted amyloid-β (Aβ) or phosphorylated tau protein (p-Tau) was unsatisfactory. Therefore, blocking both Aβ and p-Tau’s pathological processes simultaneously while also preventing their interaction may be the key to developing an effective AD therapy. Objective: To develop a novel immunotherapy based on bispecific tandem scFv (TaFv) against AD. Methods: Bispecific single-chain antibody that targets both Aβ and p-Tau were obtained using E. coli expression system. Biological ability of TaFvs were determined by ELISA, SDS-PAGE, and immunohistochemical assay. Recombinant adeno-associated virus 9 (rAAV9) were packaged to create TaFv. The in vivo activity of rAAV9 were detected in mouse, using biophotonic imaging and frozen section methods. Results: The outcomes demonstrated that both Aβ and p-Tau had a high affinity for the bispecific TaFv. Additionally, it can bind to the amyloid plaques and neuronal tangles in the brain slices of an AD mouse model. Moreover, the rAAV9 could infect neuronal cells, transverse the blood-brain barrier, and express TaFv in the mouse brain. Conclusion: This novel immunotherapy offers a fresh concept for the immunotherapy of AD and successfully delivers the double target antibody into the brain, acting on both pathogenic substances Aβ and p-Tau.

Pages 449-457
Kevin Duff, Laura Wan, Lindsay Embree, John M. Hoffman (Handling Associate Editor: Munira Sultana)
Change in the Quick Dementia Rating System Across Time in Older Adults with and without Cognitive Impairment
Abstract: Background: The Quick Dementia Rating System (QDRS) is a brief, informant-reported dementia staging tool that approximates scores on the Clinical Dementia Rating Scale in patients with Alzheimer’s disease (AD). Objective: The current study sought to examine change in the QDRS across time, which is necessary for clinical and research efforts. Methods: One-hundred ten older adults (intact, mild cognitive impairment [MCI], mild AD, classified with Alzheimer’s Disease Neuroimaging Initiative criteria) were rated on the QDRS by an informant and had an amyloid positron emission tomography scan at baseline. The informant re-rated each participant on the QDRS after one year. Dependent t-tests compared the entire sample and various subgroups (e.g., cognitive status, amyloid status) on baseline and follow-up QDRS scores. Results: In the entire sample, the Total score on the QDRS significantly increased (i.e., worsened) on follow-up (p<0.001). When subgroups were analyzed, the MCI and mild AD subjects showed increasing (i.e., worsening) QDRS Total scores (both p<0.001), but the intact subjects remained stable over time (p=0.28). Additionally, those classified as being amyloid positive at baseline showed significantly increased QDRS Total scores at follow-up (p<0.001) compared to those who were amyloid negative at baseline, whose QDRS Total scores remained stable over time (p=0.63). Conclusion: The QDRS can potentially demonstrate worsening functioning status across one year, especially in those who have MCI or mild AD and those who are amyloid positive. Therefore, the current results preliminarily suggest that the QDRS may provide an efficient tool for tracking progression in clinical trials in AD.

Pages 459-469
Yanjun Ma, Chenglong Li, Rong Hua, Chao Yang, Wuxiang Xie, Luxia Zhang
Association Between Serum Cystatin C and Cognitive Decline Independently from Creatinine: Evidence from Two Nationally Representative Aging Cohorts
Abstract: Background: Studies on the association between cystatin C based estimated glomerular filtration rate (eGFRcys) and cognitive outcomes yielded inconsistent results. Objective: The present study aimed to examine the potential association of eGFRcys with subsequent cognitive decline rate. Methods: A total of 11,503 community-based participants were involved in our analyses, including 5,837 (aged 72.9±6.3; 58.6% women) in the Health and Retirement Study (HRS) from the US and 5,666 (aged 58.1±9.2; 49.0% women) in the China Health and Retirement Longitudinal Study (CHARLS). The association of eGFRcys with subsequent cognitive decline rate was evaluated by linear mixed models. Results: During 85,266 person-years of follow-up, both baseline elevated serum cystatin C (-0.048 standard deviation [SD]/year per mg/L; 95% confidence interval [CI], -0.060 to -0.036; p < 0.001) and decreased eGFRcys (0.026 SD/year per 30 mL/min/1.73m2; 95% CI, 0.020 to 0.032; p < 0.001) were associated with faster cognitive decline rate after full adjustment. Compared with those had eGFRcys ≥ 90 mL/min/1.73m2, participants with eGFRcys between 60 to 90 mL/min/1.73m2 (-0.012 SD/year; 95%CI, -0.020 to -0.004; p = 0.004) and those with eGFRcys < 60 mL/min/1.73m2 (-0.048 SD/year; 95%CI, -0.058 to -0.039; p < 0.001) experienced statistically significantly faster cognitive decline after adjustment. The associations were independent from serum creatinine/eGFRcre (eGFR that was calculated from serum creatinine). Conclusion: Decreased eGFRcys are significantly associated with faster cognitive decline after full adjustment, independently from serum creatinine/eGFRcre. Serum cystatin C might be a risk factor or a prodromal biomarker of cognitive decline.

Pages 471-481
Yuna H. Bae-Shaaw, Victoria Shier, Neeraj Sood, Seth A. Seabury, Geoffrey Joyce (Handling Associate Editor: Bernhard Michalowsky)
Potentially Inappropriate Medication Use in Community-Dwelling Older Adults Living with Dementia
Abstract: Background: The Beers Criteria identifies potentially inappropriate medications (PIMs) that should be avoided in older adults living with dementia. Objective: The aim of this study was to provide estimates of the prevalence and persistence of PIM use among community-dwelling older adults living with dementia in 2011-2017. Methods: Medicare claims data were used to create an analytic dataset spanning from 2011 to 2017. The analysis included community-dwelling Medicare fee-for-service beneficiaries aged 65 and older who were enrolled in Medicare Part D plans, had diagnosis for dementia, and were alive for at least one calendar year. Dementia status was determined using Medicare Chronic Conditions Date Warehouse (CCW) Chronic Condition categories and Charlson Comorbidity Index. PIM use was defined as 2 or more prescription fills with at least 90 days of total days-supply in a calendar year. Descriptive statistics were used to report the prevalence and persistence of PIM use. Results: Of 1.6 million person-year observations included in the sample, 32.7% used one or more PIMs during a calendar year in 2011-2017. Breakdown by drug classes showed that 14.9% of the sample used anticholinergics, 14.0% used benzodiazepines, and 11.0% used antipsychotics. Conditional on any use, mean annual days-supply for all PIMs was 270.6 days (SD=102.7). The mean annual days-supply for antipsychotic use was 302.7 days (SD=131.2). Conclusion: Significant proportion of community-dwelling older adults with dementia used one or more PIMs, often for extended periods of time. The antipsychotic use in the community-dwelling older adults with dementia remains as a significant problem.

Pages 483-493
Yong-Bo Zheng*, Jie Sun*, Le Shi*, Si-Zhen Su, Xuan Chen, Qian-Wen Wang, Yue-Tong Huang, Yi-Jie Wang, Xi-Mei Zhu, Jian-Yu Que, Na Zeng, Xiao Lin, Kai Yuan, Wei Yan, Jia-Hui Deng, Jie Shi, Yan-Ping Bao, Lin Lu *These authors contributed equally to this work.
Association of Caffeine Consumption and Brain Amyloid Positivity in Cognitively Normal Older Adults
Abstract: Background: Several epidemiological studies have reported the protective role of caffeine on health outcomes; however, it remained debatable on caffeine consumption and brain amyloid positivity. Objective: We aimed to determine the relationship between caffeine consumption and brain amyloid pathology in cognitively normal older adults. Methods: The dataset used for analysis in this cross-sectional study was selected from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Study. Multivariable logistic regression analyses were performed to explore the association between caffeine consumption and amyloid positivity using odds ratios (ORs) and 95% confidence intervals (CIs). Results: In total, 4,394 participants were included in the final analysis. No significant association between caffeine consumption and amyloid positivity was observed in the whole participants (OR, 0.95; 95% CI, 0.78–1.14; p=0.558). Subgroup analysis showed that caffeine intake was significantly associated with decreased amyloid positivity in males (OR, 0.72; 95% CI, 0.54–0.97; p=0.032) but not in females (OR, 1.14; 95% CI, 0.90–1.46; p=0.280), and the association between caffeine and amyloid positivity was not affected by age or APOE genotypes. In addition, different levels of caffeine were not associated with amyloid positivity. Conclusion: The findings suggest that caffeine consumption was not significantly associated with amyloid positivity in the whole sample. However, caffeine consumption may be inversely associated with amyloid positivity among males but not females. More studies are needed to explore the mechanisms underlying caffeine consumption and brain amyloid positivity.

Pages 495-507
Nandakumar Nagaraja, Wei-en Wang, Ranjan Duara, Steven T. Dekosky, David Vaillancourt (Handling Associate Editor: Josephine Barnes)
Mediation of Reduced Hippocampal Volume by Cerebral Amyloid Angiopathy in Pathologically Confirmed Patients with Alzheimer’s Disease
Abstract: Background: Hippocampal atrophy in cerebral amyloid angiopathy (CAA) has been reported to be similar to that in Alzheimer’s disease (AD). Objective: To evaluate if CAA pathology partly mediates reduced hippocampal volume in patients with AD. Methods: Patients with a clinical diagnosis of AD and neuropathological confirmation of AD+/-CAA in the National Alzheimer’s Coordinating Center database were included in the study. The volumes of temporal lobe structures were calculated on T1-weighted imaging (T1-MRI) using automated freesurfer software, from images acquired on average 5 years prior to death. Multivariate regression analysis was performed to compare brain volumes in four CAA groups. The hippocampal volume on T1-MRI was correlated with Clinical Dementia Rating sum of boxes (cdrsb) score, apolipoprotein E (APOE) genotype, and hippocampal atrophy at autopsy. Results: The study included 231 patients with no (n=45), mild (n=70), moderate (n=67), and severe (n=49) CAA. Among the four CAA groups, patients with severe CAA had a smaller mean left hippocampal volume (p=0.023) but this was not significant when adjusted for APOE ε4 (p=0.07). The left hippocampal volume on MRI correlated significantly with the hippocampal atrophy grading on neuropathology (p=0.0003). Among patients with severe CAA, the left hippocampal volume on T1-MRI: (a) decreased with an increase in the number of APOE ε4 alleles (p=0.04); but (b) had no evidence of correlation with cdrsb score (p=0.57). Conclusion: Severe CAA was associated with smaller left hippocampal volume on T1-MRI up to five years prior to death among patients with neuropathologically confirmed AD. This relationship was dependent on APOE ε4 genotype.

Pages 509-519
Chenhui Mao, Hui You, Bo Hou, Shanshan Chu, Wei Jin, Xinying Huang, Li Shang, Feng Feng, Bin Peng, Jing Gao
Differentiation of Alzheimer’s Disease from Frontotemporal Dementia and Mild Cognitive Impairment Based on Arterial Spin Labeling Magnetic Resonance Imaging: A Pilot Cross-Sectional Study from PUMCH Dementia Cohort
Abstract: Background: Arterial spin labeling (ASL) is helpful in early diagnosis and differential diagnosis of Alzheimer’s disease (AD), with advantages including no exposure to radioactivity, no injection of a contrast agent, more accessible, and relatively less expensive. Objective: To establish the perfusion pattern of different dementia in Chinese population and evaluate the effectiveness of ASL in differentiating AD from cognitive unimpaired (CU), mild cognitive impairment (MCI), and frontotemporal dementia (FTD). Methods: Four groups of participants were enrolled, including AD, FTD, MCI, and CU based on clinical diagnosis from PUMCH dementia cohort. ASL image was collected using 3D spiral fast spin echo–based pseudo-continuous ASL pulse sequence with background suppression and a high resolution T1-weighted scan covering the whole brain. Data processing was performed using Dr. Brain Platform to get cerebral blood flow (ml/100g/min) in every region of interest cortices. Results: Participants included 66 AD, 26 FTD, 21 MCI, and 21 CU. Statistically, widespread hypoperfusion neocortices, most significantly in temporal-parietal-occipital cortices, but not hippocampus and subcortical nucleus were found in AD. Hypoperfusion in parietal lobe was most significantly associated with cognitive decline in AD. Hypoperfusion in parietal lobe was found in MCI and extended to adjacent temporal, occipital and posterior cingulate cortices in AD. Significant reduced perfusion in frontal and temporal cortices, including subcortical nucleus and anterior cingulate cortex were found in FTD. Hypoperfusion regions were relatively symmetrical in AD and left predominant especially in FTD. Conclusion: Specific patterns of ASL hypoperfusion were helpful in differentiating AD from CU, MCI, and FTD.

Pages 521-532
Ayu Imai, Teruyuki Matsuoka, Jin Narumoto
Emotional Dysregulation in Mild Behavioral Impairment Is Associated with Reduced Cortical Thickness in the Right Supramarginal Gyrus
Abstract: Background: Mild behavioral impairment (MBI) has attracted attention as a possible precursor symptom of dementia, but its neural basis has not been fully investigated. Objective: We aimed to investigate the relationship between MBI and surface area, cortical thickness, and volume in the temporal and parietal lobes, which are strongly associated with dementia and emotional disorders. Methods: This retrospective study evaluated 123 participants: 90 with mild cognitive impairment (MCI), 13 with subjective cognitive decline (SCD), and 20 cognitively healthy (CH). Using analysis of covariance (ANCOVA) with sex, age, and MMSE score as covariates, cortical thickness, surface area, and volume in 10 regions were compared between groups with and without MBI. Groups with MBI emotional dysregulation were also compared with groups without MBI. Results: ANCOVA revealed significantly smaller cortical thickness in the MBI group’s right parahippocampal (p = 0.01) and supramarginal gyri (p = 0.002). After multiple comparison correction, only the right supramarginal gyrus was significantly smaller (p = 0.02). When considering only MBI emotional dysregulation, the right parahippocampal and supramarginal gyrus’ cortical thicknesses were significantly smaller in this MBI group (p = 0.03, 0.01). However, multiple comparison correction identified no significant differences (p = 0.14, 0.11). Conclusion: Overall MBI and the emotional dysregulation domains were associated with reduced cortical thickness in the right parahippocampal and supramarginal gyri. Since neurodegeneration in the medial temporal and parietal lobe precedes early Alzheimer's disease (AD), MBI, particularly emotion dysregulation, may predict early AD below the diagnostic threshold.

Pages 533-543
Isabel J. Sible, Daniel A. Nation for the Alzheimer’s Disease Neuroimaging Initiative
Visit-to-Visit Blood Pressure Variability and Cognitive Decline in Apolipoprotein ε4 Carriers versus Apolipoprotein ε3 Homozygotes
Abstract: Background: Blood pressure variability (BPV) is associated with cognitive decline and Alzheimer’s disease (AD), but relationships with AD risk gene apolipoprotein (APOE) ε4 remain understudied. Objective: Examined the longitudinal relationship between BPV and cognitive change in APOE ε4 carriers and APOE ε3 homozygotes. Methods: 1,194 Alzheimer’s Disease Neuroimaging Initiative participants (554 APOE ε4 carriers) underwent 3-4 blood pressure measurements between study baseline and 12-month follow-up. Visit-to-visit BPV was calculated as variability independent of mean over these 12 months. Participants subsequently underwent ≥1 neuropsychological exam at 12-month follow-up or later (up to 156 months later). Composite scores for the domains of memory, language, executive function, and visuospatial abilities were determined. Linear mixed models examined the 3-way interaction of BPV x APOE ε4 carrier status x time predicting change in composite scores. Results: Higher systolic BPV predicted greater decline in memory (+1 SD increase of BPV: β = -0.001, p < 0.001) and language (β = -0.002, p < 0.0001) among APOE ε4 carriers, but not APOE ε3 homozygotes (memory: +1 SD increase of BPV: β = 0.0001, p = 0.57; language: β = 0.0001, p = 0.72). Systolic BPV was not significantly associated with change in executive function or visuospatial abilities in APOE ε4 carriers (ps = 0.08 - 0.16) or APOE ε3 homozygotes (ps = 0.48 - 0.12). Conclusion: Cognitive decline associated with high BPV may be specifically accelerated among APOE ε4 carriers.

Pages 545-560
Junyao Zhang, Tong Zhang, Yinuo Wang, Liangfang Yao, Junyan Yao
Gα13-Mediated Signaling Cascade Is Related to the Tau Pathology Caused by Anesthesia and Surgery in 5XFAD Transgenic Mice
Abstract: Background: Our previous studies indicated that anesthesia and surgery could aggravate cognitive impairment of 5XFAD transgenic (Tg) mice, and this aggravation was associated with tau hyperphosphorylation. We previously identified that GNA13 (the gene encoding Gα13) was a hub gene with tau hyperphosphorylation. Objective: This study aims to further investigate the mechanism that whether the Gα13-mediated signaling pathway acts as an instigator to regulate cofilin activation and autophagy impairment in this process. Methods: 5XFAD Tg mice and their littermate (LM) mice were randomly allocated into four groups: LM Control group, LM Anesthesia/Surgery group, AD Control group, and AD Anesthesia/Surgery group. For mice in the Anesthesia/Surgery groups, abdominal surgery was performed under 1.4% isoflurane anesthesia followed by sustaining anesthetic inhalation for up to 2 h. Results: Compared with the AD Control group, protein levels of Gα13, ROCK2, LPAR5, and p-tau/tau46 ratio were increased, while p-cofilin/cofilin protein expression ratio was decreased in the AD Anesthesia/Surgery group. However, the differences in these protein levels were not significant among LM groups. Conclusion: This study demonstrated that anesthesia and surgery might exacerbate p-tau accumulation in 5XFAD Tg mice but not in LM mice. And this might be closely related to cofilin activation via Gα13-mediated signaling cascade.

Pages 561-575
Roshni Biswas, Claudia Kawas, Thomas J. Montine, Syed A Bukhari, Luohua Jiang, Maria M. Corrada (Handling Associate Editor: Erin Abner)
Superior Global Cognition in Oldest-Old Is Associated with Resistance to Neurodegenerative Pathologies: Results from The 90+ Study
Abstract: Background: Some oldest-old individuals can maintain superior cognition despite advanced age. Little is known about the neuropathological changes in the brains of oldest-old superior cognitive performers. Objective: Our objective was to examine the associations between Alzheimer’s disease (AD) and non-AD neuropathologic features in relation to superior cognitive performance in oldest-old individuals. Methods: We analyzed brain autopsy data from 102 participants with normal cognition from The 90+ Study. Superior global cognitive performers (SGCP) were defined as having Mini-Mental State Examination (MMSE) score 28 in the last visit 12 to 2 months before death. To examine the associations between individual and multiple comorbid neuropathologic features with SGCP status we used multiple logistic regression models adjusting for age, sex, and education. Results: Alzheimer’s disease neuropathological change (ADNC) and low levels of vascular pathologic change were not associated with superior cognition. In contrast, participants with limbic (OR=8.37; 95% CI: 1.48-47.44) and neocortical (OR= 10.80;95% CI:1.03-113.82) Lewy body disease (LBD), or with hippocampal sclerosis (HS) (OR= 5.28; 95%CI: 1.10-25.47) were more likely to be non-SGCP. High total burden of multiple comorbid neuropathologic features was associated with a lower likelihood of being SGCP. Conclusion: Oldest-old superior cognitive performers were resilient to ADNC and low levels of vascular pathologic change and were resistant to non-AD neurodegenerative changes and multiple comorbid neuropathologic features. Understanding the factors underlying the ability of superior cognitive performers to resist these changes might provide useful insights on maintenance of superior cognition despite advanced age.

Pages 577-584
Clayton C. McIntyre, Julian M. Gaitán, Kyle J. Edmunds, Sarah R. Lose, Barbara B. Bendlin, Mark Sager, Sanjay Asthana, Sterling C. Johnson, Ozioma C. Okonkwo (Handling Associate Editor: Suzanne Craft)
Insulin Homeostasis Mediates the Relationship Between Cardiorespiratory Fitness and Cognitive Speed in Aging Adults
Abstract: Background: Cardiorespiratory fitness (CRF) supports cognition, though it is unclear what mechanisms underly this relationship. Insulin resistance adversely affects cognition but can be reduced with habitual exercise. Objective: We investigated whether insulin resistance statistically mediates the relationship between CRF and cognition. Methods: In our observational study, we included n=1,131 cognitively unimpaired, nondiabetic older adults from a cohort characterized by elevated Alzheimer’s disease (AD) risk. We estimated CRF (eCRF) using a validated equation that takes age, sex, body mass index, resting heart rate, and habitual physical activity as inputs. The Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) quantified insulin resistance. Standardized cognitive factor scores for cognitive speed/flexibility, working memory, verbal learning/memory, and immediate memory were calculated from a battery of neuropsychological tests. Linear regression models and bootstrapped estimates of indirect effects were used to determine whether HOMA-IR mediated significant relationships between eCRF and cognition. Results: eCRF was positively associated with cognitive speed/flexibility (p=0.034). When controlling for HOMA-IR, eCRF was no longer associated with cognitive speed/flexibility (p=0.383). HOMA-IR had a significant indirect effect on the eCRF-cognition relationship (B=0.025, CI = [0.003,0.051]). eCRF was not associated with working memory (p=0.236), immediate memory (p=0.345), or verbal learning/memory (p=0.650). Conclusion: Among older adults at risk for AD, peripheral insulin resistance mediates the relationship between CRF and cognitive speed.

Pages 585-594
Zixiao Zhao, Jie Wang, Ying Wang, Xia Liu, Kun He, Qihao Guo, Fang Xie, Qi Huang, Zijing Li (Handling Associate Editor: Ziqi Wang)
18F-AV45 PET and MRI Reveal the Influencing Factors of Alzheimer’s Disease Biomarkers in Subjective Cognitive Decline Population
Abstract: Background: Subjective cognitive decline (SCD) is a self-perceived decline in cognitive ability, which exhibits no objective impairment but increased risk of conversion to mild cognitive impairment and Alzheimer’s disease (AD). Objective: To investigate how influencing factors (risk gene, age, sex, and education) affect amyloid-β (Aβ) deposition and gray matter (GM) atrophy in SCD population. Methods: 281 SCD subjects were included in this study, who underwent clinical evaluation, cognitive ability assessment, apolipoprotein E (APOE) genotyping, 18F-Florbetapir positron emission computed tomography, and magnetic resonance imaging screening. Two-sample t tests and analysis of variance were performed based on voxel-wise outcome. Results: In 281 SCD subjects with an average age of 63.86, 194 subjects (69.04%) were females, and 56 subjects carried APOE ε4 genes. Statistical results revealed APOE ε4 gene, age, and sex influenced Aβ deposition in different brain regions; moreover, only the interaction exhibited between age and APOE ε4 genes. The GM atrophy of hippocampal, amygdala, precentral, and occipital lobes occurred in the group age over 60. The GM volume of the hippocampal, frontal, and occipital lobe in females was less than males. Education had an effect only on cognitive function. Conclusion: In SCD, APOE ε4 gene, age, and sex significantly influenced Aβ deposition and APOE ε4 gene can interact with age in impacting Aβ deposition. Both age and sex can affect GM atrophy. The results suggested that female SCD with APOE ε4 genes and aged more than 60 years old might exhibit advanced AD biomarkers.

Pages 595-603
Li-Ya Zhang, Duo-Zi Wang, Jian Wang, Lei Guo, Bing-Hu Li, Jian-Hong Wang (Handling Associate Editor: Yu-Hui Liu)
Associations of Serum Antimicrobial Peptide LL-37 with Longitudinal Cognitive Decline and Neurodegeneration Among Older Adults with Memory Complaints
Abstract: Background: A potential role of the antimicrobial peptide LL-37, which is upregulated after infection, in the pathogenesis of Alzheimer’s disease (AD) was identified. However, the clinical relevance of LL-37 in AD is not clear yet. Objective: This study aims to investigate the association of circulating LL-37 with longitudinal cognitive decline and neurodegeneration among older adults with memory complaints. Methods: This cohort study recruited 357 older adults with memory complaints. Participants were followed-up for two years and the cognitive functions were assessed using the Mini-Mental State Examination (MMSE). Serum LL-37, pTau181, and tTau levels were determined at baseline. Associations of baseline LL-37 with longitudinal cognitive decline and change of neurodegenerative biomarkers were analyzed. Results: No difference was found in the slope of longitudinal cognitive decline during follow-up between the low and high LL-37 group, adjusting for age, sex, education, body mass index, APOE ε4 carrier status, comorbidities, and baseline MMSE scores (difference in slope: 0.226, 95% CI: -0.169 to 0.621). Higher LL-37 levels were associated with longitudinal cognitive decline, as indicated by a decrease of MMSE scores of 3 points or above during follow-up (RR=2.11, 95%CI: 1.32 to 3.38). The high LL-37 group had larger slopes of the increase in neurofilament light (difference in slope: 3.759, 95% CI: 2.367 to 5.152) and pTau181 (difference in slope: 0.325, 95% CI: 0.151 to 0.499) than the low LL-37 group. Conclusion: These findings support an association of the antimicrobial peptide LL-37 with AD from a clinical perspective.

Pages 605-619
Jing Tian*, Chase Stucky*, Tienju Wang, Nancy A. Muma, Michael Johnson, Heng Du *These authors contributed equally to this work.
Mitochondrial Dysfunction Links to Impaired Hippocampal Serotonin Release in a Mouse Model of Alzheimer’s Disease
Abstract: Background: Deprivation of extracellular serotonin has been linked to cognitive decline and neuropsychiatric disturbances in Alzheimer’s disease (AD). However, despite degeneration of serotonin-producing neurons, whether serotonin release is affected in AD-sensitive brain regions is unknown. Objective: This study investigated the impact of mitochondrial dysfunction in decreased hippocampal serotonin release in AD amyloidosis mouse model 5xFAD mice. Methods: Electrochemical assays were applied to examine hippocampal serotonin release. We also employed multidisciplinary techniques to determine the role of oligomeric amyloid-β (Aβ) in hippocampal mitochondrial deficits and serotonin release deficiency. Results: 5xFAD mice exhibited serotonin release decrease and relatively moderate downregulation of serotonergic fiber density as well as serotonin content in the hippocampal region. Further experiments showed an inhibitory effect of oligomeric amyloid-β (Aβ) on hippocampal serotonin release without affecting the density of serotonergic fibers. Pharmaceutical uncoupling of mitochondrial oxidative phosphorylation (OXPHOS) disrupted hippocampal serotonin release in an ex vivo setting. This echoes the mitochondrial defects in serotonergic fibers in 5xFAD mice and oligomeric Aβ-challenged primary serotonergic neuron cultures and implicates a link between mitochondrial dysfunction and serotonin transmission defects in AD-relevant pathological settings. Conclusion: The most parsimonious interpretation of our findings is that mitochondrial dysfunction is a phenotypic change of serotonergic neurons, which potentially plays a role in the development of serotonergic failure in AD-related conditions.

Pages 621-631
Miquel Aguilar Barberà, Paquita Soler Girabau, Ana Isabel Tabuenca Martín, Laura Prieto del Val
Fortasyn Connect Improves Neuropsychiatric Symptoms in Patients with Mild Cognitive Impairment and Dementia: Results from a Retrospective Real-World Study
Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) manifest in the early stages of the disease and impair patients’ and caregivers’ quality of life. Objective: To assess the effectiveness of the nutritional supplement Fortasyn Connect on BPSD for 12 months in people with mild cognitive impairment (MCI) and dementia in clinical practice. Methods: Retrospective, national, single-center study of 236 patients (158 MCI and 78 dementia; 55.1% of AD etiology). BPSD were assessed with the Neuropsychiatric Inventory (NPI) at month 3, 6, and 12. Cognition (Mini-Mental State Examination, MMSE), depression (Geriatric Depression Scale, GDS), and everyday functioning (Blessed Dementia Scale, BLS-D; Rapid Disability Rating Scale 2, RDRS2) were also evaluated. Results: Total NPI score, caregiver impact, and symptoms of depression, anxiety, apathy, and irritability improved after 3, 6, and 12 months from Fortasyn Connect initiation (p < 0.001). NPI decreases were more pronounced when baseline NPI score was higher than >20 points (p < 0.001). The benefit was independent of gender, age, diagnosis, etiology, or concomitant treatment (p < 0.0001), although larger decreases in NPI total score were observed in MCI patients (p < 0.0001). After 12 months, GDS scores decreased (p=0.042), and MMSE, BLS-D, and RDRS 2 scores remained stable. Conclusion: Fortasyn Connect improved BPSD over at least a year in patients with MCI and dementia. Depression, anxiety, apathy, and irritability were the symptoms that improved the most. The benefit was independent of patients’ characteristics and treatment but was greater if prescribed early and when baseline NPI scores were higher.

Pages 633-651
Jessica Stark, Kelly J. Hiersche, Ju-Chi Yu, Alexander N. Hasselbach, Hervé Abdi, Scott M. Hayes for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Mark Bondi)
Partial Least Squares Regression Analysis of Alzheimer’s Disease Biomarkers, Modifiable Health Variables, and Cognitive Change in Older Adults with Mild Cognitive Impairment
Abstract: Background: Prior work has shown that certain modifiable health, Alzheimer’s disease (AD) biomarker, and demographic variables are associated with cognitive performance. However, less is known about the relative importance of these different domains of variables in predicting longitudinal change in cognition. Objective: Identify novel relationships between modifiable physical and health variables, AD biomarkers, and slope of cognitive change over two years in a cohort of older adults with mild cognitive impairment (MCI). Methods: Metrics of cardiometabolic risk, stress, inflammation, neurotrophic/growth factors, and AD pathology were assessed in 123 older adults with MCI at baseline from the Alzheimer’s Disease Neuroimaging Initiative (mean age = 73.9; SD = 7.6; mean education = 16.0; SD = 3.0). Partial least squares regression (PLSR)—a multivariate method which creates components that best predict an outcome—was used to identify whether these physiological variables were important in predicting slope of change in episodic memory or executive function over two years. Results: At two-year follow-up, the two PLSR models predicted, respectively, 20.0% and 19.6% of the variance in change in episodic memory and executive function. Baseline levels of AD biomarkers were important in predicting change in both episodic memory and executive function. Baseline education and neurotrophic/growth factors were important in predicting change in episodic memory, whereas cardiometabolic variables such as blood pressure and cholesterol were important in predicting change in executive function. Conclusion: These data-driven analyses highlight the impact of AD biomarkers on cognitive change and further clarify potential domain specific relationships with predictors of cognitive change.

Pages 653-664
Emily S. Brook, Zachary J. D’Alonzo, Virginie Lam, Dick Chan, Satvinder Singh Dhaliwal, Gerald F. Watts, John C. L Mamo, Ryusuke Takechi
Plasma Amyloid-β Homeostasis Is Associated with Body Mass Index and Weight Loss in People with Overweight and Obesity
Abstract: Background: Obesity is linked to a higher incidence of Alzheimer’s disease (AD). Studies show that plasma amyloid-β (Aβ) dyshomeostasis, particularly low 42/40 ratio indicates a heightened risk for developing AD. However, the relationship between body mass index (BMI) and circulating plasma Aβ has not been extensively studied. Objective: We hypothesized that people with a high BMI have altered plasma Aβ homeostasis compared with people with a lower BMI. We also tested whether reducing BMI by calorie-restriction could normalize plasma concentrations of Aβ. Methods: Plasma concentrations of Aβ40, Aβ42, and Aβ42/40 ratio were measured in 106 participants with BMIs classified as lean, overweight, or obese. From this cohort, twelve participants with overweight or obese BMIs entered a 12-week calorie-restriction weight loss program. We then tested whether decreasing BMI affected plasma Aβ concentrations. Results: Plasma Aβ42/40 ratio was 17.54% lower in participants with an obese BMI compared to lean participants (p<0.0001), and 11.76% lower compared to participants with an overweight BMI (p<0.0001). The weight loss regimen decreased BMI by an average of 4.02% (p=0.0005) and was associated with a 6.5% decrease in plasma Aβ40 (p=0.0425). However, weight loss showed negligible correlations with plasma Aβ40, Aβ42, and Aβ42/40 ratio. Conclusion: Obesity is associated with aberrant plasma Aβ homeostasis which may be associated with an increased risk for AD. Weight loss appears to lower Aβ40, but large-scale longitudinal studies in addition to molecular studies are required to elucidate the underlying mechanisms of how obesity and weight loss influence plasma Aβ homeostasis.

Pages 665-682
Yurika Otoki*, Di Yu*, Qing Shen, Demetrios J. Sahlas, Joel Ramirez, Fuqiang Gao, Mario Masellis, Richard H. Swartz, Pak Cheung Chan, Jacqueline A. Pettersen, Shunji Kato, Kiyotaka Nakagawa, Sandra E. Black, Walter Swardfager**, Ameer Y. Taha** *,**These authors contributed equally to this work.
Quantitative Lipidomic Analysis of Serum Phospholipids Reveals Dissociable Markers of Alzheimer’s Disease and Subcortical Cerebrovascular Disease
Abstract: Background: Circulating phospholipid species have been shown to predict Alzheimer’s disease (AD) prognosis but the link between phospholipid disturbances and subcortical small vessel cerebrovascular disease (CeVD) common in AD patients is not known. Objective: This study used quantitative lipidomics to measure serum diacyl, alkenyl (ether), alkyl, and lyso phospholipid species in individuals with extensive CeVD (n=29), AD with minimal CeVD (n=16), and AD with extensive CeVD (n=14), and compared them to age-matched controls (n=27). Memory was assessed using the California Verbal Learning Test. 3.0T MRI was used to assess hippocampal volume, atrophy, and white matter hyperintensity (WMH) volumes as manifestations of CeVD. Results: AD was associated with significantly higher concentrations of choline plasmalogen 18:0_18:1 and alkyl-phosphocholine 18:1. CeVD was associated with significantly lower lysophospholipids containing 16:0. Phospholipids containing arachidonic acid (AA) were associated with poorer memory in controls, whereas docosahexaenoic acid (DHA)-containing phospholipids were associated with better memory in individuals with AD+CeVD. In controls, DHA-containing phospholipids were associated with more atrophy and phospholipids containing linoleic acid and AA were associated with less atrophy. Lysophospholipids containing 16:0, 18:0, and 18:1 were correlated with less atrophy in controls, and of these, alkyl-phosphocholine 18:1 was correlated with smaller WMH volumes. Conversely, 16:0_18:1 choline plasmalogen was correlated with greater WMH volumes in controls. Conclusion: This study demonstrates discernable differences in circulating phospholipids in individuals with AD and CeVD, as well as new associations between phospholipid species with memory and brain structure that were specific to contexts of commonly comorbid vascular and neurodegenerative pathologies.

Pages 683-704
Elizabeth Williams, Menekșe Mutlu-Smith, Ashli Alex, Xi Wei Chin, Tara Spires-Jones, Szu-Han Wang
Mid-Adulthood Cognitive Training Improves Performance in a Spatial Task but Does Not Ameliorate Hippocampal Pathology in a Mouse Model of Alzheimer’s Disease
Abstract: Background: Prior experience in early life has been shown to improve performance in aging and mice with Alzheimer’s disease (AD) pathology. However, whether cognitive training at a later life stage would benefit subsequent cognition and reduce pathology in AD mice needs to be better understood. Objective: This study aimed to verify if behavioral training in mid-adulthood would improve subsequent cognition and reduce AD pathology and astrogliosis. Methods: Mixed-sex APP/PS1 and wildtype littermate mice received a battery of behavioral training, composed of spontaneous alternation in the Y-maze, novel object recognition and location tasks, and spatial training in the water maze, or handling only at 7 months of age. The impact of AD genotype and prior training on subsequent learning and memory of aforementioned tasks were assessed at 9 months. Results: APP/PS1 mice made more errors than wildtype littermates in the radial-arm water maze (RAWM) task. Prior training prevented this impairment in APP/PS1 mice. Prior training also contributed to better efficiency in finding the escape platform in both APP/PS1 mice and wildtype littermates. Short-term and long-term memory of this RAWM task, of a reversal task, and of a transfer task were comparable among APP/PS1 and wildtype mice, with or without prior training. Amyloid pathology and astrogliosis in the hippocampus were also comparable between the APP/PS1 groups. Conclusion: These data suggest that cognitive training in mid-adulthood improves subsequent accuracy in AD mice and efficiency in all mice in the spatial task. Cognitive training in mid-adulthood provides no clear benefit on memory or on amyloid pathology in midlife.

Pages 705-726
Manisha Singh, Divya Jindal, Rupesh Kumar, Pranav Pancham, Shazia Haider, Vivek Gupta, Shalini Mani, Rachana R, Raj Kumar Tiwari, Silpi Chanda
Molecular Docking and Network Pharmacology Interaction Analysis of Gingko Biloba (EGB761) Extract with Dual Target Inhibitory Mechanism in Alzheimer’s Disease
Abstract: Background: Alzheimer's disease (AD) is the most common type of neurodegenerative dementia affecting people in their later years of life. The AD prevalence rate has significantly increased due to a lack of early detection technology and low therapeutic efficacy. Despite recent scientific advances, some aspects of AD pathological targets still require special attention. Certain traditionally consumed phytocompounds have been used for thousands of years to treat such pathologies. The standard extract of Gingko biloba (EGB761) is a combination of 13 macro phyto-compounds and various other micro phytocompounds that have shown greater therapeutic potential against the pathology of AD. Objective: Strong physiological evidence of cognitive health preservation has been observed in elderly people who keep an active lifestyle. According to some theories, consuming certain medicinal extracts helps build cognitive reserve. We outline the research employing EGB761 as a dual target for AD. Methods: This study investigates various inhibitory targets against AD using computational approaches such as molecular docking, network pharmacology, ADMET (full form), and bioactivity prediction of the selected compounds. Results: After interaction studies were done for all the phytoconstituents of EGB761, it was concluded that all four of the phytocompounds (kaempferol, isorhamnetin, quercetin, and ginkgotoxin) showed the maximum inhibitory activity against acetylcholinesterase (AChE) and GSK3β. Conclusion: The highly active phytocompounds of EGB761, especially quercetin, kaempferol, and isorhamnetin, have better activity against AChE and GSK3β than its reported synthetic drug, according to molecular docking and network pharmacology research. These compounds may act on multiple targets in the protein network of AD. The AChE theory was primarily responsible for EGB761's therapeutic efficacy in treating AD.

Pages 727-741
Victoria J. Williams, Rebecca Koscik, Kamil Sicinski, Sterling C. Johnson, Pamela Herd, Sanjay Asthana
Associations Between Midlife Menopausal Hormone Therapy Use, Incident Diabetes, and Late Life Memory in the Wisconsin Longitudinal Study
Abstract: Background: Prior research suggests a link between menopausal hormone therapy (MHT) use, memory function, and diabetes risk. The menopausal transition is a modifiable period to enhance long-term health and cognitive outcomes, although studies have been limited by short follow-up periods precluding a solid understanding of the lasting effects of MHT use on cognition. Objective: We examined the effects of midlife MHT use on subsequent diabetes incidence and late life memory performance in a large, same-aged, population-based cohort. We hypothesized that the beneficial effects of MHT use on late life cognition would be partially mediated by reduced diabetes risk. Methods: 1,792 women from the Wisconsin Longitudinal Study (WLS) were included in analysis. We employed hierarchical linear regression, Cox regression, and causal mediation models to test the associations between MHT history, diabetes incidence, and late life cognitive performance. Results: 1,088/1,792 women (60.7%) reported a history of midlife MHT use and 220/1,792 (12.3%) reported a history of diabetes. MHT use history was associated with better late life immediate recall (but not delayed recall), as well as a reduced risk of diabetes with protracted time to onset. Causal mediation models suggest that the beneficial effect of midlife MHT use on late life immediate recall were at least partially mediated by diabetes risk. Conclusion: Our data support a beneficial effect of MHT use on late life immediate recall (learning) that was partially mediated by protection against diabetes risk, supporting MHT use in midlife as protective against late life cognitive decline and adverse health outcomes.

Pages 743-754
Yorito Hattori, Satoshi Saito, Yuriko Nakaoku, Soshiro Ogata, Masashi Hattori, Mio Nakatsuji, Kunihiro Nishimura, Masafumi Ihara
Taxifolin for Cognitive Preservation in Patients with Mild Cognitive Impairment or Mild Dementia
Abstract: Background: The development of numerous disease-modifying drugs for age-related dementia has been attempted based on the amyloid-β (Aβ) hypothesis without much success. Taxifolin (TAX), a natural bioactive flavonoid, shows pleiotropic neuroprotective effects with inhibition of Aβ aggregation, production, and glycation, antiinflammatory effects, and amelioration of the waste clearance system. We hypothesized that TAX intake is associated with the suppression of cognitive deterioration. Objective: To investigate associations between TAX intake and cognitive changes. Methods: We retrospectively identified patients who orally took TAX 300 mg/day and regularly underwent Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog) and Montreal Cognitive Assessment (MoCA) and compared the temporal changes in ADAS-Cog and MoCA between the non-treatment (pre-TAX) period (180±100 days) and following treatment (on-TAX) period (180±100 days) from June 2020 to November 2021. Since some additional patients underwent the Mini-Mental State Examination (MMSE) instead of the MoCA at the beginning of the pre-TAX period, the same comparison was performed using the MoCA total score converted from MMSE as a sensitivity analysis. Results: Sixteen patients were identified. TAX intake was associated with significantly higher interval changes in the MoCA subscale scores of visuospatial/executive function (p=0.016), verbal fluency (p=0.02), and the total score (p=0.034), but not with ADAS-Cog (total score, p=0.27). In the sensitivity analysis, 29 patients were included. TAX intake was associated with a significantly higher interval change in the total MoCA score (p=0.004) but not with ADAS-Cog (p=0.41). Conclusion: Our findings provide a basis for TAX as a novel strategy for maintaining brain health during aging. A prospective cohort study is required to confirm these findings.

Pages 755-763
See Ann Soo, Dilip Kumar, Yi Jin Leow, Chen Ling Koh, Seyed Ehsan Saffari, Nagaendran Kandiah
Usefulness of the Visual Cognitive Assessment Test in Detecting Mild Cognitive Impairment in the Community
Abstract: Background: A delay in the detection of mild cognitive impairment (MCI) in the community delays the opportunity for early intervention. Accurate tools to detect MCI in the community are lacking. The Visual Cognitive Assessment Test (VCAT) is a visual based cognitive test useful for multilingual populations without the need for translation. Objective: Here, we evaluate the usefulness of VCAT in detecting MCI in a community population in Singapore. Methods: We recruited 301 participants from the community who completed a detailed neuropsychological assessment and 170 of them completed a 3T magnetic resonance imaging (MRI) brain scan. We performed a receiver operating characteristics analysis to test the diagnostic performance of VCAT compared to Montreal Cognitive Assessment (MoCA) in distinguishing MCI from cognitively normal (CN) by measuring area under the curve (AUC). To test for the association of VCAT with structural MRI, we performed a Pearson’s correlation analysis for VCAT and MRI variables. Results: We recruited 39 CN and 262 MCI participants from Dementia Research Centre (Singapore). Mean age of the cohort was 63.64, SD=9.38, mean education years was 13.59, SD=3.70 and majority were women (55.8%). VCAT was effective in detecting MCI from CN with an AUC of 0.794 (95% CI 0.723-0.865) which was slightly higher than MoCA 0.699 (95% CI 0.621-0.777). Among subjects with MCI, VCAT was associated with medial temporal lobe atrophy (ρ= -0.265, p = 0.001). Conclusion: The VCAT is useful in detecting MCI in the community in Singapore and may be an effective measure of neurodegeneration.

Pages 765-777
Charles D. Chen, Maria Rosana Ponisio, Jordan A. Lang, Shaney Flores, Suzanne E. Schindler, Anne M. Fagan, John C. Morris, Tammie L.S. Benzinger
Comparing Tau PET Visual Interpretation with Tau PET Quantification, Cerebrospinal Fluid Biomarkers, and Longitudinal Clinical Assessment
Abstract: Background: 18F-flortaucipir PET received FDA approval to visualize aggregated neurofibrillary tangles (NFTs) in brains of adult patients with cognitive impairment being evaluated for Alzheimer’s disease (AD). However, manufacturer’s guidelines for visual interpretation of 18F-flortaucipir PET differ from how 18F-flortaucipir PET has been measured in research settings using standardized uptake value ratios (SUVRs). How visual interpretation relates to 18F-flortaucipir PET SUVR, cerebrospinal fluid (CSF) biomarkers, or longitudinal clinical assessment is not well understood. Objective: We compare various diagnostic methods in participants enrolled in longitudinal observational studies of aging and memory (n=189, 23 were cognitively impaired). Methods: Participants had tau PET, Aβ PET, MRI, and clinical and cognitive evaluation within 18 months (n=189); the majority (n=144) also underwent lumbar puncture. Two radiologists followed manufacturer’s guidelines for 18F-flortaucipir PET visual interpretation. Results: Visual interpretation had high agreement with SUVR (98.4%)and moderate agreement with CSF p-tau181 (86.1%). Two participants demonstrated 18F-flortaucipir uptake from meningiomas. Visual interpretation could not predict follow-up clinical assessment in 9.52% of cases. Conclusion: Visual interpretation was highly consistent with SUVR (discordant participants had hemorrhagic infarcts or occipital-predominant AD NFT deposition) and moderately consistent with CSF p-tau181 (discordant participants had AD pathophysiology not detectable on tau PET). However, close association between AD NFT deposition and clinical onset in group-level studies does not necessarily hold at the individual level, with discrepancies arising from atypical AD, vascular dementia, or frontotemporal dementia. A better understanding of relationships across imaging, CSF biomarkers, and clinical assessment is needed to provide appropriate diagnoses for these individuals.

Pages 779-789
Martha Hickey, Trine K. Hueg, Lærke Priskorn, Cecilie S. Uldbjerg, Astrid L. Beck, Kaarin J. Anstey, Youn-Hee Lim*, Elvira V. Bräuner* *These authors contributed equally to this work.
Depression in Mid- and Later-Life and Risk of Dementia in Women: A Prospective Study within the Danish Nurses Cohort
Abstract: Background: Depression and dementia confer substantial global health burdens, particularly in women. Understanding the association between depression and dementia may inform new targets for prevention and/or early intervention. Objective: To investigate the association between depression in mid- and later-life and dementia (all-cause, Alzheimer’s disease (AD) or vascular dementia (VaD)) in women. Methods: A prospective study design. Nurses were followed from age 60 years or entry into the cohort, whichever came last, until date of dementia, death, emigration, or end of follow-up, whichever came first. Cox regression models with age as the underlying timeline were used to estimate the associations between time-varying depression and incident dementia. Results: The study included 25,651 female Danish nurses (≥45 years) participating in the Danish Nurse Cohort. During an average of 23 years of follow-up, 1,232 (4.8%) nurses developed dementia and 8,086 (31.5%) were identified with at least two episodes of treated depression. In adjusted analyses, nurses with depression were at a statistically significant 5.23-fold higher risk of all-cause dementia (aHR 5.23: 95%CI, 4.64-5.91) compared to those with no history of depression. The differential effects of depression were greater for VaD (aHR 7.96: 95%CI, 5.26-12.0) than AD (aHR 4.64: 95%CI, 3.97-5.42). Later life depression (>60 years) (aHR 5.85: 95% CI, 5.17-6.64) and recurrent depression (aHR 3.51: 95% CI, 2.67-4.61) elevated dementia risk. Severe depression tripled the risk of all cause dementia (aHR 3.14: 95%CI, 2.62-3.76). Conclusion: Both later life and severe depression substantially increase dementia risk in women, particularly VaD.

Pages 791-801
Yaqiong Xiao, Liangjun Liao, Kaiyu Huang, Shun Yao, Lei Gao; for the Alzheimer’s Disease Neuroimaging Initiative
Coupling Between Hippocampal Parenchymal Fraction and Cortical Grey Matter Atrophy at Different Stages of Cognitive Decline
Abstract: Background: Hippocampal atrophy is a significant brain marker of pathology in Alzheimer’s disease (AD). The hippocampal parenchymal fraction (HPF) was recently developed to better assess the hippocampal volumetric integrity, and it has been shown to be a sensitive measure of hippocampal atrophy in AD. Objective: To investigate the clinical relevance of hippocampal volumetric integrity as measured by the HPF and the coupling between the HPF and brain atrophy during AD progression. Methods: We included data from 143 cognitively normal (CN), 101 mild cognitive impairment (MCI), and 125 AD participants. We examined group differences in the HPF, associations between HPF and cognitive ability, and coupling between the HPF and cortical grey matter volume in the CN, MCI, and AD groups. Results: We observed progressive decreases in HPF from CN to MCI and from MCI to AD, and increases in the asymmetry of HPF, with the lowest asymmetry index (AI) in the CN group and the highest AI in the AD group. There was a significant association between HPF and cognitive ability across participants. The coupling between HPF and cortical regions was observed in bilateral hippocampus, parahippocampal gyrus, temporal, frontal, and occipital regions, thalamus, and amygdala in CN, MCI, and AD groups, with a greater involvement of temporal, occipital, frontal, and subcortical regions in MCI and AD patients, especially in AD patients. Conclusion: This study provides novel evidence for the neuroanatomical basis of cognitive decline and brain atrophy during AD progression, which may have important clinical implications for the prognosis of AD.

Pages 803-813
Rudolph J. Castellani, Elisheva Shanes, Matthew McCord, Nicholas J. Reish, Margaret E. Flanagan, M-Marsel Mesulam, Pouya Jamshidi
Neuropathology of Anti-Amyloid-β Immunotherapy: A Case Report
Abstract: Host responses to anti-amyloid-β (Aβ) antibody therapy are evident in neuroimaging changes and clinical symptoms in a subset of clinical trial subjects receiving such therapy. The pathological basis for the imaging changes and clinical symptoms is not known, nor is the precise mechanism of Aβ clearing. We report the autopsy findings in a 65-year-old woman who received three open label infusions of the experimental anti-Aβ drug lecanemab over about one month. Four days after the last infusion, she was treated with tissue plasminogen activator for acute stroke symptoms and died several days later with multifocal hemorrhage. Neuropathological examination demonstrated histiocytic vasculitis involving blood vessels with cerebral amyloid angiopathy. Fragmentation and phagocytosis of vascular Aβ were present throughout the cerebral cortex. Phagocytosis of parenchymal Aβ plaques was noted. Changes suggestive of Aβ and phosphorylated tau “clearing” were also noted. The findings overall suggest that anti-Aβ treatment stimulated a host response to Aβ, i.e., target engagement. The findings also provide evidence that amyloid-related imaging abnormalities might be indicative of an Aβ phagocytic syndrome within cerebral vasculature and parenchymal brain tissue in some cases.

Pages 815-819

Evan Fletcher
Multifactorial Modeling of Cognitive Trajectories Using an Advanced Regression Technique: Improving Our Understanding of Biomarkers and Modifiable Variables that Support Cognition
Abstract: Current research trends emphasize complex models of cognitive outcomes, with multiple, interacting predictors, including factors amenable to interventions toward sustaining healthy cognitive aging. Such models often require advanced analysis techniques. The article by Stark et al., ‘Partial least squares regression analysis of Alzheimer's disease biomarkers, modifiable health variables, and cognitive change in older adults with mild cognitive impairment’, uses partial least squares regression to examine the associations to memory and executive change of 29 biomarker and demographic variables. This commentary discusses the significance of their results and methods within the context current research foci.