Volume 82, Number 2, IN PRESS

Editorial
Jorge R. Barrio, Peter Whitehouse, Abass Alavi, Poul F. Høilund-Carlsen
New IDEAS Amyloid Imaging 2021 Study: Running in Place with Ineffective Anti-Amyloid Treatments for Alzheimer’s Disease Patients

Review
Hong Yang, Yinpei Luo, Qingrong Hu, Xuelong Tian, Huizhong Wen
Benefits in Alzheimer’s Disease of Sensory and Multisensory Stimulation
Abstract: Alzheimer's disease (AD) is a serious neurodegenerative disease, which seriously affects the behavior, cognition, and memory of patients. Studies have shown that sensory stimulation can effectively improve the cognition and memory of AD patients, and its role in brain plasticity and neural regulation is initially revealed. This paper aims to review the effect of various sensory stimulation and multisensory stimulation for AD, and to explain the possible mechanism, so as to provide some new ideas for further research in this field. We searched the Web of Science and PubMed databases (from 2000 to October 27, 2020) for literature on the treatment of AD with sensory and multisensory stimulation, including music therapy, aromatherapy, rhythmic (e.g., visual or acoustic) stimulation, light therapy, multisensory stimulation, and virtual reality assisted therapy, then conducted a systematic analysis. Results show these sensory and multisensory stimulations can effectively ameliorate the pathology of AD, arouse memory, and improve cognition and behaviors. What's more, it can cause brain nerve oscillation, enhance brain plasticity, and regulate regional cerebral blood flow. Sensory and multisensory stimulation are very promising therapeutic methods, and they play an important role in the improvement and treatment of AD, but their potential mechanism and stimulation parameters need to be explored and improved.

Short Communication
Petra Riegerová, Jindřich Brejcha, Dagmar Bezděková, Tomáš Chum, Eva Mašínová, Nikola Čermáková, Saak V. Ovsepian, Marek Cebecauer, Martin Štefl
Expression and Localization of AβPP in SH-SY5Y Cells Depends on Differentiation State
Abstract: Neuroblastoma cell line SH-SY5Y, due to its capacity to differentiate into neurons, easy handling, and low cost, is a common experimental model to study molecular events leading to Alzheimer’s disease (AD). However, it is prevalently used in its undifferentiated state, which does not resemble neurons affected by the disease. Here, we show that the expression and localization of amyloid-β protein precursor (AβPP), one of the key molecules involved in AD pathogenesis, is dramatically altered in SH-SY5Y cells fully differentiated by combined treatment with retinoic acid and BDNF. We show that insufficient differentiation of SH-SY5Y cells results in AβPP mislocalization.

Oleg Yerstein, Leila Parand, Li-Jung Liang, Adrienne Isaac, Mario F. Mendez
Benson’s Disease or Posterior Cortical Atrophy, Revisited
Abstract: Background: D. Frank Benson and colleagues first described the clinical and neuropathological features of posterior cortical atrophy (PCA) from patients in the UCLA Neurobehavior Program. Objective: We reviewed the Program’s subsequent clinical experience with PCA, and its potential for clarifying this relatively rare syndrome in comparison to the accumulated literature on PCA. Methods: Using the original criteria derived from this clinic, 65 patients with neuroimaging-supported PCA were diagnosed between 1995 and 2020. Results: On presentation, most have visual localization complaints and related visuospatial symptoms, but nearly half had memory complaints followed by symptoms of depression. Neurobehavioral testing showed predominant difficulty with visuospatial constructions, Gerstmann’s syndrome, and Balint’s syndrome, but also impaired memory and naming. On retrospective application of the current Consensus Criteria for PCA, 59 (91%) met PCA criteria with a modification allowing for “significantly greater visuospatial over memory and naming deficits.” There were 37 deaths (56.9%) with the median overall survival of 10.3 years (95% CI: 9.6-13.6 years), consistent with a slow neurodegenerative disorder in most patients. Conclusion: Together, these findings recommend modifying the PCA criteria for “relatively spared” memory, language, and behavior to include secondary memory and naming difficulty and depression, with increased emphasis on the presence of Gerstmann’s and Balint’s syndromes.

Xian Li, Yan Tian, Yu-Xiang Yang, Ya-Hui Ma, Xue-Ning Shen, Shi-Dong Chen, Prof Qiang Dong, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu)
Life Course Adiposity and Alzheimer’s Disease: A Mendelian Randomization Study
Abstract: Background: Several studies showed that life course adiposity was associated with Alzheimer’s disease (AD). However, the underlying causality remains unclear. Objective: We aimed to examine the causal relationship between life course adiposity and AD using Mendelian randomization (MR) analysis. Methods: Instrumental variants were obtained from large genome-wide association studies (GWAS) for life course adiposity, including birth weight (BW), childhood body mass index (BMI), adult BMI, waist circumference (WC), waist-to-hip ratio (WHR), and body fat percentage (BFP). A meta-analysis of GWAS for AD including 71,880 cases and 383,378 controls was used in this study. MR analyses were performed using inverse variance weighted (IVW), weighted median, and MR-Egger regression methods. We calculated odds ratios (ORs) per genetically predicted standard deviation (1-SD) unit increase in each trait for AD. Results: Genetically predicted 1-SD increase in adult BMI was significantly associated with higher risk of AD (IVW: OR = 1.03, 95% confidence interval [CI] = 1.01-1.05, p = 2.7×10-3) after Bonferroni correction. The weighted median method indicated a significant association between BW and AD (OR = 0.94, 95%CI = 0.90-0.98, p = 1.8×10-3). We also found suggestive associations of AD with WC (IVW: OR = 1.03, 95%CI = 1.00-1.07, p = 0.048) and WHR (weighted median: OR = 1.04, 95%CI = 1.00-1.07, p = 0.029). No association was detected of AD with childhood BMI and BFP. Conclusion: Our study demonstrated that lower BW and higher adult BMI had causal effects on increased AD risk.

Can Sheng, Li Lin, Hua Lin, Xiaoni Wang, Ying Han, Shu-Lin Liu
Altered Gut Microbiota in Adults with Subjective Cognitive Decline: The SILCODE Study
Abstract: Background: Subjective cognitive decline (SCD) is the earliest symptomatic manifestation of preclinical Alzheimer’s disease (AD). Gut microbiota may serve as a susceptibility factor for AD. Altered gut microbiota has been reported in patients with mild cognitive impairment (MCI) and AD dementia. However, whether gut microbial compositions changed in SCD remains largely unknown. Objective: To characterize the gut microbiota in SCD. Methods: In this study, a total of 105 participants including 38 normal controls (NC), 53 individuals with SCD, and 14 patients with cognitive impairment (CI) were recruited. Gut microbiota of all participants isolated from fecal samples were investigated using 16S ribosomal RNA (rRNA) Illumina Miseq sequencing technique. The gut microbial compositions were compared among the three groups, and the association between altered gut microbiota and cognitive performance was analyzed. To validate the alteration of gut microbiota in SCD, we conducted amyloid positron emission tomography (PET) in selected participants and further compared the gut microbiota among subgroups. Results: The abundance of phylum Firmicutes, class Clostridia, order Clostridiales, family Ruminococcaceae, and genus Faecalibacterium showed a trend toward a progressive decline from NC to SCD and CI. Specifically, the abundance of the anti-inflammatory genus Faecalibacterium was significantly decreased in SCD compared with NC. In addition, altered bacterial taxa among the three groups were associated with cognitive performance. The findings were validated in SCD participants with positive amyloid evidence. Conclusion: The composition of gut microbiota is altered in individuals with SCD. This preliminary study will provide novel insights into the pathophysiological mechanism of AD.

Hui Han, Feng Wang, Juanjuan Chen, Xingxing Li, Gaoqing Fu, Jiawei Zhou, Dongsheng Zhou, Wei Wu, Haimin Chen
Changes in Biothiol Levels Are Closely Associated with Alzheimer’s Disease
Abstract: Background: Serum homocysteine (Hcy) level is considered to be an important biomarker for Alzheimer’s disease (AD); however, the status of Hcy in brain tissue, and the association between brain and serum levels of Hcy in AD patients remain unclear. Objective: We aimed to examine whether the changes of three thiols are consistent in serum of AD patients and the brain of APP/PS1 mice, and to verify the effectiveness of Hcy as a biomarker for early AD detection. Methods: The levels of Hcy, cysteine (Cys), and glutathione (GSH) in Aβ1-42-treated PC12 cells, the brain and hippocampus of APP/PS1 mouse, and the serum of AD patients were evaluated using ethyl (E)-3-(9-chloro-11-oxo-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f] pyrido [3,2,1 -ij] quinolin-10-yl)-2-cyanoacrylate (Probe 1) and ELISA assay or LC-MS. Results: Measurement by Probe 1 revealed a significant increase in Hcy level, and a decrease in Cys and GSH levels in Aβ1-42-treated PC12 cells and the serum of AD patients. The hippocampus and whole brain of APP/PS1 mice also showed a significant increase in Hcy level alongside the accumulation of age-related AD symptoms. The upregulation of Hcy and the downregulation of Cys and GSH were reversed in the Aβ1-42-treated PC12 cells and the brain of APP/PS1 mice when supplemented with VB6. Conclusion: Changes in Hcy, Cys, and GSH levels in the brain of APP/PS1 mice and Aβ1-42-treated PC12 cells were observed in situ with a new fluorescent probe, which were consistent with the abnormal changes in Hcy, Cys, and GSH levels in the serum of AD patients. VB6 supplementation was successful in ameliorating abnormal increases in Hcy levels.

Josh King-Robson, Heather Wilson, Marios Politis for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Brian Gordon)
Associations Between Amyloid and Tau Pathology, and Connectome Alterations, in Alzheimer’s Disease and Mild Cognitive Impairment
Abstract: Background: The roles of amyloid-β and tau in the degenerative process of Alzheimer’s disease (AD) remain uncertain. [18F]AV-45 and [18F]AV-1451 PET quantify amyloid-β and tau pathology, respectively, while diffusion tractography enables detection of their microstructural consequences. Objective: Examine the impact of amyloid-β and tau pathology on the structural connectome and cognition, in mild cognitive impairment (MCI) and AD. Methods: Combined [18F]AV-45 and [18F]AV-1451 PET, diffusion tractography, and cognitive assessment in 28 controls, 32 MCI, and 26 AD patients. Results: Hippocampal connectivity was reduced to the thalami, right lateral orbitofrontal, and right amygdala in MCI; alongside the insula, posterior cingulate, right entorhinal, and numerous cortical regions in AD (all p<0.05). Hippocampal strength inversely correlated with [18F]AV-1451 SUVr in MCI (r=-0.55, p=0.049) and AD (r=-0.57, p=0.046), while reductions in hippocampal connectivity to ipsilateral brain regions correlated with increased [18F]AV-45 SUVr in those same regions in MCI (r=-0.33, p=0.003) and AD (r=-0.31, p=0.006). Cognitive scores correlated with connectivity of the right temporal pole in MCI (r=-0.60, p=0.035) and left hippocampus in AD (r=0.69, p=0.024). Clinical Dementia Rating Scale scores correlated with [18F]AV-1451 SUVr in multiple areas reflecting Braak stages I-IV, including the right (r=0.65, p=0.004) entorhinal cortex in MCI; and Braak stages III-VI, including the right (r=0.062, p=0.009) parahippocampal gyrus in AD. Conclusion: Reductions in hippocampal connectivity predominate in the AD connectome, correlating with hippocampal tau in MCI and AD, and with amyloid-β in the target regions of those connections. Cognitive scores correlate with microstructural changes and reflect the accumulation of tau pathology.

Bibek Gyanwali, Celestine Xue Ting Cai, Christopher Chen, Henri Vrooman, Chuen Seng Tan, Saima Hilal
The Effects of Mean of Visit-to-Visit Blood Pressure on Incident Brain Vascular Lesions and Functional-Cognitive Decline
Abstract: Background: Cerebrovascular disease (CeVD) is an underlying cause of cognitive impairment and dementia. Hypertension is a known risk factor of CeVD, but the effects of mean of visit-to-visit blood pressure (BP) on incident CeVD and functional-cognitive decline remains unclear. Objective: To determine the association between mean of visit-to-visit BP with the incidence and progression of CeVD [white matter hyperintensities (WMH), infarcts (cortical infarcts and lacunes), cerebral microbleeds (CMBs), intracranial stenosis, and hippocampal volume] as well as functional-cognitive decline over 2 years of follow-up. Methods: 373 patients from a memory-clinic underwent BP measurements at baseline, year 1, and year 2. The mean of visit-to-visit systolic BP, diastolic BP, pulse pressure, and mean arterial pressure were calculated. Baseline and year 2 MRI scans were graded for WMH, infarcts, CMBs, intracranial stenosis, and hippocampal volume. Functional-cognitive decline was assessed using locally validated protocol. Logistic and linear regression models with odds ratios, mean difference, and 95% confidence interval were constructed to analyze associations of visit-to-visit BP on CeVD incidence and progression as well as functional-cognitive decline. Results: Higher mean of visit-to-visit diastolic BP was associated with WMH progression. Higher tertiles of diastolic BP was associated with WMH progression and incident CMBs. There was no association between mean of visit-to-visit BP measures with incident cerebral infarcts, intracranial stenosis, change in hippocampal volume, and functional-cognitive decline. Conclusion: These findings suggest the possibility of hypertension-related vascular brain damage. Careful monitoring and management of BP in elderly patients is essential to reduce the incidence and progression of CeVD.

Barbara Blicher Thomsen*, Cecilie Madsen*, Katrine Tækker Krohn, Camilla Thygesen, Trine Schütt, Athanasios Metaxas, Sultan Darvesh, Jørgen Steen Agerholm, Martin Wirenfeldt, Mette Berendt#, Bente Finsen# *These authors contributed equally to this work. #Shared last authorship.
Mild Microglial Responses in the Cortex and Perivascular Macrophage Infiltration in Subcortical White Matter in Dogs with Age-Related Dementia Modelling Prodromal Alzheimer’s Disease
Abstract: Background: Microglia contribute to Alzheimer’s disease (AD) pathogenesis by clearing amyloid-β (Aβ) and driving neuroinflammation. Domestic dogs with age-related dementia (canine cognitive dysfunction (CCD)) develop cerebral amyloidosis like humans developing AD, and studying such dogs can provide novel information about microglial response in prodromal AD. Objective: The aim was to investigate the microglial response in the cortical grey and the subcortical white matter in dogs with CCD versus age-matched cognitively normal dogs. Methods: Brains from aged dogs with CCD and age-matched controls without dementia were studied. Cases were defined by dementia rating score. Brain sections were stained for Aβ, thioflavin S, hyperphosphorylated tau, and the microglial-macrophage ionized calcium binding adaptor molecule 1 (Iba1). Results were correlated to dementia rating score and tissue levels of Aβ. Results: Microglial numbers were higher in the Aβ plaque-loaded deep cortical layers in CCD versus control dogs, while the coverage by microglial processes were comparable. Aβ plaques were of the diffuse type and without microglial aggregation. However, a correlation was found between the % Iba1 area and insoluble Aβ42 and N-terminal pyroglutamate modified Aβ(N3pE)-42. The % Iba1 area was higher in white matter, showing phosphorylation of S396 tau, versus grey matter. Perivascular macrophage infiltrates were abundant in the white matter particularly in CDD dogs. Conclusion: The results from this study of the microglial-macrophage response in dogs with CCD are suggestive of relatively mild microglial responses in the Aβ plaque-loaded deep cortical layers and perivascular macrophage infiltrates in the subcortical white matter, in prodromal AD.

Eduardo Marques Zilli, Adrienne O’Donnell, Joel Salinas, Hugo J. Aparicio, Mitzi Michelle Gonzales, Mini Jacob, Alexa Beiser, Sudha Seshadri (Handling Associate Editor: Hugo Lövheim)
Herpes Labialis, Chlamydophila pneumoniae, Helicobacter pylori, and Cytomegalovirus Infections and Risk of Dementia: The Framingham Heart Study
Abstract: Background: An association between chronic infectious diseases and development of dementia has been suspected for decades, based on the finding of pathogens in postmortem brain tissue and on serological evidence. However, questions remain regarding confounders, reverse causality, and how accurate, reproducible and generalizable those findings are. Objective: Investigate whether exposure to Herpes simplex (manifested as herpes labialis), Chlamydophila pneumoniae (C. pneumoniae), Helicobacter pylori (H. pylori), and cytomegalovirus (CMV) modifies the risk of dementia in a populational cohort. Methods: Questionnaires regarding incidence of herpes infections were administered to Original Framingham Study participants (n=2,632). Serologies for C. pneumoniae, H. pylori, and CMV were obtained in Original (n=2,351) and Offspring cohort (n=3,687) participants. Participants are under continuous dementia surveillance. Brain MRI and neuropsychological batteries were administered to Offspring participants from 1999-2005. The association between each infection and incident dementia was tested with Cox models. Linear models were used to investigate associations between MRI or neuropsychological parameters and serologies. Results: There was no association between infection serologies and dementia incidence, total brain volume, and white matter hyperintensities. Herpes labialis was associated with reduced 10-year dementia risk (HR 0.66, CI 0.46-0.97), but not for the duration of follow-up. H. pylori antibodies were associated with worse global cognition (β -0.14, CI -0.22, -0.05). Conclusion: We found no association between measures of chronic infection and incident dementia, except for a reduction in 10-year dementia risk for patients with herpes labialis. This unexpected result requires confirmation and further characterization, concerning antiviral treatment effects and capture of episodes.

Rafia S. Rasu, Nistha Shrestha, Aliza R. Karpes Matusevich, Rana Zalmai, Stephanie Large, Leigh Johnson, Sid E. O’Bryant (Handling Associate Editor: Erin Abner)
Polypharmacy and Cognition Function Among Rural Adults
Abstract: Background: Polypharmacy (using ≥5 medications) is associated with poor health outcomes. Mixed results from past studies surrounding chronic medication use, control of chronic conditions, and their effects on cognitive performance warrant further attention. Objective: Investigate a link between polypharmacy and cognition function in rural-dwelling adults in Texas, USA. Methods: Project FRONTIER (Facing Rural Obstacles to Healthcare Now Through Intervention, Education & Research) is a cross-sectional epidemiological study using community-based participatory research in three counties of Texas. Residents age >40 were eligible for inclusion. The primary outcome is cognitive impairment, and exposures of interest are polypharmacy; comorbidities; and diabetes, hypertension, and depression medication. Logistic regression was used to assess association. Results: Six hundred eighty-nine individuals participated; the mean age was 61, and the majority were female (68.7%).The median number of medications taken by participants was 3.3 (IQR: 0-5); the rate of polypharmacy was 29.6%. Anti-hypertensive agents were the most common medications (15%) used. Polypharmacy users were 2.84 times more likely to have cognitive impairment [OR: 2.84, 95% CI (1.32-6.09)] than those using < 5 medications. Participants on hypertensive medications had 1.85 times higher odds [OR: 1.85, 95% CI (1.14-3.01)] of having cognitive impairment than those who did not have cognitive impairment. Conclusion: Polypharmacy increases the odds of cognitive impairment. The odds of presenting with cognitive impairment increased as the number of medications increased. Additionally, we identified a large, concerning number of participants with pharmacotherapy and poor chronic disease management. A larger study should examine medication adherence among rural elders to manage chronic disease and any healthcare barriers to adherence.

Tian Xiao*, Sara R.A. Wijnant*, Silvan Licher, Natalie Terzikhan, Lies Lahousse, M. Kamran Ikram, Guy G. Brusselle, M. Arfan Ikram *These authors contributed equally to this work.
Lung Function Impairment and the Risk of Incident Dementia: The Rotterdam Study
Abstract: Background: The etiology of dementia may partly be underpinned by impaired lung function via systemic inflammation and hypoxia. Objective: To prospectively examine the association between chronic obstructive pulmonary disease (COPD) and subclinical impairments in lung function and the risk of dementia. Methods: In the Rotterdam Study, we assessed the risk of incident dementia in participants with Preserved Ratio Impaired Spirometry (PRISm; FEV1/FVC≥0.7, FEV1<80%) and in participants with COPD (FEV1/FVC<0.7) compared to those with normal spirometry (controls; FEV1/FVC≥0.7, FEV1≥80%). Hazard ratios (HRs) with 95% confidence intervals (CI) for dementia were adjusted for age, sex, education attainment, smoking status, systolic blood pressure, body mass index, triglycerides, comorbidities and Apolipoprotein E (APOE) genotype. Results: Of 4,765 participants, 110 (2.3%) developed dementia after 3.3 years. Compared to controls, participants with PRISm, but not COPD, had an increased risk for all-type dementia (adjusted HRPRISm 2.70; 95% CI, 1.53–4.75; adjusted HRCOPD 1.03; 95% CI, 0.61–1.74). These findings were primarily driven by men and smokers. Similarly, participants with FVC% predicted values in the lowest quartile compared to those in the highest quartile were at increased risk of all-type dementia (adjusted HR 2.28; 95% CI, 1.31–3.98), as well as Alzheimer’s disease (AD; adjusted HR 2.13; 95% CI, 1.13–4.02). Conclusion: Participants with PRISm or a low FVC% predicted lung function were at increased risk of dementia, compared to those with normal spirometry or a higher FVC% predicted, respectively. Further research is needed to elucidate whether this association is causal and how PRISm might contribute to dementia pathogenesis.

Wei Wei*, Yinghua Liu*, Chunling Dai, Narjes Baazaoui, Yunn-Chyn Tung, Fei Liu, Khalid Iqbal *These authors contributed equally to the paper.
Neurotrophic Treatment Initiated During Early Postnatal Development Prevents the Alzheimer-Like Behavior and Synaptic Dysfunction
Abstract: Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Cognitive dysfunction and loss of neuronal plasticity are known to begin decades before the clinical diagnosis of the disease. The important influence of congenital genetic mutations on the early development of AD provides a novel opportunity to initiate treatment during early development to prevent the Alzheimer-like behavior and synaptic dysfunction. Objective: To explore strategies for early intervention to prevent Alzheimer's disease. Methods: In the present study, we investigated the effect of treatment during early development with a ciliary neurotrophic factor (CNTF) derived peptidergic compound, P021 (Ac-DGGLAG-NH2) on cognitive function and synaptic plasticity in 3xTg-AD transgenic mouse model of AD. 3xTg-AD and genetic background-matched wild type female mice were treated from birth to postnatal day 120 with P021 in diet or as a control with vehicle diet, and cognitive function and molecular markers of neuroplasticity were evaluated. Results: P021 treatment during early development prevented cognitive impairment and increased expressions of pCREB and BDNF that activated downstream various signaling cascades such as PLC/PKC, MEK/ERK and PI3K/Akt, and ameliorated synaptic protein deficit in 4-month-old 3xTg-AD mice. Conclusion: These findings indicate that treatment with the neurotrophic peptide mimetic such as P021 during early development can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial AD and related tauopathies.

Shama D. Karanth, Frederick A. Schmitt, Peter T. Nelson, Yuriko Katsumata, Richard J. Kryscio, David W. Fardo, Jordan P. Harp, Erin L. Abner (Handling Associate Editor: Gabriella Macron)
Four Common Late-Life Cognitive Trajectories Patterns Associate with Replicable Underlying Neuropathologies
Abstract: Background: Late-life cognitive function is heterogeneous, ranging from no decline to severe dementia. Prior studies of cognitive trajectories have tended to focus on a single measure of global cognition or individual tests scores, rather than considering longitudinal performance on multiple tests simultaneously. Objective: The current study aimed to examine cognitive trajectories from two independent datasets to assess whether similar patterns might describe longitudinal cognition in the decade preceding death, as well as what participant characteristics were associated with trajectory membership. Methods: Data were drawn from autopsied longitudinally followed participants of two cohorts (total N=1,346), community-based cohort at the University of Kentucky Alzheimer’s Disease Research Center (n=365) and National Alzheimer’s Coordinating Center (n=981). We used group-based multi-trajectory models (GBMTM) to identify cognitive trajectories over the decade before death using Mini-Mental State Exam, Logical Memory-Immediate, and Animal Naming performance. Multinomial logistic and Random Forest analyses assessed characteristics associated with trajectory groups. Results: GBMTM identified four similar cognitive trajectories in each dataset. In multinomial models, death age, Braak neurofibrillary tangles (NFT) stage, TDP-43, and α-synuclein were associated with declining trajectories. Random Forest results suggested the most important trajectory predictors were Braak NFT stage, cerebral atrophy, death age, and brain weight. Multiple pathologies were most common in trajectories with moderate or accelerated decline. Conclusion: Cognitive trajectories associated strongly with neuropathology, particularly Braak NFT stage. High frequency of multiple pathologies in trajectories with cognitive decline suggests dementia treatment and prevention efforts must consider multiple diseases simultaneously.

Mirjana Babić Leko, Jasna Jurasović, Matea Nikolac Perković, Ena Španić, Ankica Sekovanić, Tatjana Orct, Vesna Lukinović Škudar, Koraljka Bačić Baronica, Spomenka Kiđemet-Piskač, Željka Vogrinc, Nela Pivac, Fran Borovečki, Patrick R. Hof, Goran Šimić
The Association of Essential Metals with APOE Genotype in Alzheimer’s Disease
Abstract: Background: The major confirmed genetic risk factor for late-onset, sporadic Alzheimer’s disease (AD) is variant ε4 of apolipoprotein E gene (APOE). It is proposed that ApoE, a protein involved in transport of cholesterol to neurons can cause neurodegeneration in AD through interaction with metals. Previous studies mostly associated copper, iron, zinc, and calcium with ApoE4-mediated toxicity. Objective: To test the association of essential metals with APOE genotype. Methods: We compared plasma and cerebrospinal fluid (CSF) levels of copper, zinc, iron, sodium, magnesium, calcium, cobalt, molybdenum, manganese, boron, and chromium, and CSF ferritin levels among AD, mild cognitive impairment (MCI) patients, and healthy controls (HC) with different APOE genotype. Results: Sodium, copper, and magnesium levels were increased in carriers of ɛ4 allele. Additionally, the increase in sodium, calcium and cobalt plasma levels was observed in carriers of ɛ4/ɛx genotype. The decrease in boron plasma levels was observed in carriers of ɛ4 allele and ɛ4/ɛ4 genotype. Additionally, CSF zinc levels as well as plasma sodium levels were increased in AD patients compared to HC. Conclusion: These results indicate that the molecular underpinnings of association of essential metals and metalloids with APOE should be further tested and clarified in vivo and in vitro.

Pavapriya Ponvel, Suzana Shahar, Devinder Kaur Ajit Singh, Arimi Fitri Mat Ludin, Roslee Rajikan, Nor Fadilah Hj Rajab, Chin Ai-Vyrn, Normah Che Din, Norhayati Ibrahim, Ponnusamy Subramaniam, Hasnah Haron, Aniza Ismail, Razinah Sharif, Kalavathy Ramasamy, Abu Bakar Abdul Majeed, Nazlena Mohamad Ali, Mazlyfarina Mohamad, Shahrul Azman Mohd Noah, Azianah Mohd Ibrahim, Aisyah Mohd Safien, Norhayati Mustafa Khalid, Nurul Hidayah Md Fadzil, Francesca Mangialasche, Miia Kivipelto
Multidomain Intervention for Reversal of Cognitive Frailty: Towards a Personalized Approach (AGELESS Trial): Study Design
Abstract: Background: Cognitive frailty (CF) is identified as one of the main precursors of dementia. Multidomain intervention has been found to delay or prevent the onset of CF. Objective: The aim of our present study is to determine the effectiveness of a comprehensive, multidomain intervention on CF; to evaluate its cost effectiveness and the factors influencing adherence toward this intensive intervention. Methods: A total of 1,000 community dwelling older adults, aged 60 years and above will be screened for CF. This randomized controlled trial involves recruitment of 327 older adults with CF from urban, semi-urban, and rural areas in Malaysia. Multidomain intervention comprised of physical, nutritional, cognitive, and psychosocial aspects will be provided to participants in the experimental group (n=164). The control group (n=164) will continue their usual care with their physician. Primary outcomes include CF status, physical function, psychosocial and nutritional status as well as cognitive performance. Vascular health and gut microbiome will be assessed using blood and stool samples. A 24-month intensive intervention will be prescribed to the participants and its sustainability will be assessed for the following 12 months. The effective intervention strategies will be integrated as a personalized telerehabilitation package for the reversal of CF for future use. Results: The multidomain intervention developed from this trial is expected to be cost effective compared to usual care as well as able to reverse CF. Conclusion: This project will be part of the World-Wide FINGERS (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) Network, of which common identifiable data will be shared and harmonized among the consortia.

Xiaoyan Sun*, Chuanhui Dong*, Bonnie Levin, Michelle Caunca, Adina Zeki Al Hazzouri, Janet T. DeRosa, Yaakov Stern, Ying Kuen Cheung, Mitchell S.V. Elkind, Tatjana Rundek, Clinton B. Wright, Ralph L. Sacco (Handling Associate Editor: Wei Qiao Qiu) *These authors contributed equally to this study.
Systolic Blood Pressure and Cognition in the Elderly: The Northern Manhattan Study
Abstract: Background: Increasing evidence suggests that hypertension is a risk factor for cognitive impairment and dementia. The relationship between blood pressure and cognition in a racially and ethnically diverse population remains unclear. Objective: To study association of blood pressure with cognition cross-sectionally and longitudinally in the elderly. Methods: Participants are stroke-free individuals from the racially and ethnically diverse Northern Manhattan Study (NOMAS) (n=1215). General linear models are constructed to examine blood pressure in relation to cognition cross-sectionally and longitudinally at a five-year follow-up. Results: We found a cross-sectional association of systolic blood pressure (SBP) with word fluency/semantic memory, executive function, and processing speed/visual motor integration (VMI) function. This association was independent of demographics, vascular risk factors, white matter hyperintensity volume (WMHV), and carotid intima-media thickness (cIMT). The cross-sectional association of SBP with processing speed/VMI and executive function was attenuated after adjusting anti-hypertension medications in the models. Baseline SBP was associated with the change of processing speed/VMI function after adjusting vascular risk factors, WMHV, and cIMT at a 5-year follow-up. This longitudinal association was not found after adjusting anti-hypertension medications in the models. Further analyses revealed that individuals with category SBP from < 120 mmHg to ≥140 mmHg had a linear decline in processing speed/VMI function at a 5-year follow-up. Conclusion: We show that SBP is negatively associated with cognition cross-sectionally and longitudinally in the elderly. Anti-hypertension treatment eliminates the negative association of SBP with processing speed/VMI function longitudinally. Our findings support the treatment of stage 1 systolic hypertension in the elderly.

Taeko Makino, Hiroyuki Umegaki, Masahiko Ando, Xian Wu Cheng, Koji Ishida, Hiroshi Akima, Yoshiharu Oshida, Yasuko Yoshida, Kazuki Uemura, Hiroyuki Shimada, Masafumi Kuzuya
Effects of Aerobic, Resistance, or Combined Exercise Training Among Older Adults with Subjective Memory Complaints: A Randomized Controlled Trial
Abstract: Background: Physical exercise is suggested to be effective for preventing cognitive decline in older adults, but the relative efficacy of different types of exercise have yet to be clarified. Objective: This single-blinded randomized controlled trial was designed to investigate the differential effects of aerobic exercise training (AT), resistance exercise training (RT), and combined exercise training (CT) on cognition in older adults with subjective memory complaints (SMC). Methods: Community-dwelling older adults with SMC (n=415; mean age=72.3 years old) were randomly assigned to one of the four groups: AT, RT, CT, or control group. The study consisted of two phases: a 26-week intervention and a 26-week follow-up. The participants were evaluated at baseline, 26 weeks (postintervention), and 52 weeks (follow-up). The primary outcome of this study was memory function, which was assessed using the Logical Memory II subtest of the Wechsler Memory Scale-Revised (WMS-R) score. The secondary outcomes included global cognitive function, verbal fluency, working memory, processing speed, and executive functions. Results: Intention-to-treat analysis by a mixed-effect model repeated measure showed that the AT group had significantly improved performance on the WMS-R Logical Memory II test (2.74 [1.82–3.66] points) than the control group (1.36 [0.44–2.28] points) at the postintervention assessment (p=0.037). The effect was more pronounced in those without amnesia than those with amnesia. No significant improvement was observed in the RT and CT groups. Conclusion: This study suggests that AT intervention can improve delayed memory in community-dwelling older adults, particularly in individuals without objective memory decline.

Mitsuru Shinohara, Kaoru Suzuki, Guojun Bu, Naoyuki Sato
Interaction Between APOE Genotype and Diabetes in Longevity
Abstract: Background: While both apolipoprotein E (APOE) genotype and diabetes affect longevity as well as Alzheimer’s disease, their relationship remains to be elucidated. Objective: The current study investigated the potential interaction between diabetes and APOE for lifespan and their relationship with cognitive status. Methods: We reviewed the National Alzheimer’s Coordinating Center (NACC) dataset, which documents longitudinally clinical records of 24,967 individuals with APOE genotype and diabetic status. Results: Diabetes was associated with shorter lifespan in APOE3 carriers (n=12,415, HR = 1.29, 95% CI = 1.17-1.42, p < 0.001) and APOE2 carriers (n=2,390, HR = 1.37, 95% CI = 1.10-1.69, p = 0.016), while such associations were weaker and not significant in APOE4 carriers (n=9,490, HR = 1.11, 95% CI = 0.99-1.24, p = 0.162). As there is a significant interactive effect of cognitive status and diabetes on lifespan (p<0.001), we stratified subjects by cognitive status and observed persistent APOE-dependent harmful effects of diabetes in nondemented individuals but not demented individuals. Notably, questionnaire-based activity status, with which we previously observed an association between APOE genotype and longevity, was also significantly affected by diabetes only in non-APOE4 carriers. Conclusion: The effects of diabetes on longevity vary among APOE genotype. These effects are observed in nondemented individuals and are potentially associated with activity status during their lifespan.

Margarete Delazer, Laura Zamarian, Atbin Djamshidian
Handwriting in Alzheimer’s Disease
Abstract: Background: Agraphia is a typical feature in the clinical course of Alzheimer’s disease (AD). Objective: Assess the differences between AD and normal aging as regards kinematographic features of handwriting and elucidate writing deficits in AD. Methods: The study included 23 patients with AD (78.09 years/SD=7.12; MMSE 21.39/SD=3.61) and 34 healthy controls (75.56 years/SD=5.85; MMSE 29.06/SD=0.78). Both groups performed alphabetical and non-alphabetical writing tasks. The kinematographic assessment included the average number of inversions per stroke (NIV; number of peaks in the velocity profile in a single up or down stroke), percentage of automated segments, frequency (average number of strokes per second), writing pressure, and writing velocity on paper. Results: A total of 14 patients showed overt writing difficulties reflected by omissions or substitutions of letters. AD patients showed less automated movements (as measured by NIV), lower writing velocity, and lower frequency of up-and-down strokes in non-alphabetical as well as in alphabetical writing. In the patient group, Spearman correlation analysis between overt writing performance and NIV was significant. That means patients who had less errors in writing a sentence showed a higher automaticity in handwriting. The correctness of alphabetical writing and some kinematographic measures in writing non-alphabetical material reached excellent diagnostic values in ROC analyses. There was no difference in the application of pressure on the pen between patients and controls. Conclusion: Writing disorders are multi-componential in AD and not strictly limited to one processing level. The slow and poorly automated execution of motor programs is not bound to alphabetical material.

Brandy L. Callahan, Michael McLaren-Gradinaru, Ford Burles, Giuseppe Iaria
How Does Dementia Begin to Manifest in Bipolar Disorder? A Description of Prodromal Clinical and Cognitive Changes
Abstract: Background: Older adults with bipolar disorder (BD) have increased dementia risk, but signs of dementia are difficult to detect in the context of pre-existing deficits inherent to BD. Objective: To identify the emergence of indicators of early dementia in BD. Methods: One hundred and fifty-nine non-demented adults with BD from the National Alzheimer Coordinating Center (NACC) data repository underwent annual neuropsychological assessment up to 14 years (54.0 months average follow-up). Cognitive performance was examined longitudinally with linear mixed-effects models, and yearly differences between incident dementia and controls cases were examined in the six years prior to diagnosis. Results: Forty participants (25.2%) developed dementia over the follow-up period (‘incident cases’). Alzheimer’s disease was the most common presumed etiology, though this was likely a result of sampling biases within NACC. Incident cases showed declining trajectories in memory, language, and speeded attention two years prior to dementia onset. Conclusion: In a sample of BD patients enriched for Alzheimer’s type dementia, prodromal dementia in BD can be detected up to two years before onset using the same cognitive tests used in psychiatrically-healthy older adults (i.e., measures of verbal recall and fluency). Cognition in the natural course of BD is generally stable, and impairment or marked decline on measures of verbal episodic memory or semantic retrieval may indicate an early neurodegenerative process.

Ines Ben Ayed*, Naomie Castor-Guyonvarch*, Souad Amimour, Salma Naija, Chirine Aouichaoui, Sana Ben Omor, Zouhair Tabka, Farid El Massioui *These authors contributed equally to this work.
Acute Exercise and Cognitive Function in Alzheimer’s Disease
Abstract: Background: Many studies have shown the impact of acute aerobic exercises (AAE) on cognition in healthy adults or at a pre-dementia stage. Few studies, however, have explored the positive effects of AAE in moderate Alzheimer’s disease (ADM) patients. Objective: Evaluating the effect of AAE on cognitive functions in ADM patients. Methods: Overall, 79 (age: 69.62 ± 0.99) ADM patients were recruited. Participants were divided into three groups according to the task: aerobic exercises done alone or combined with cognitive games presented on a screen, and a control group who performed a reading task. The aerobic exercise protocol consisted of a 20-min cycling exercise of moderate intensity, corresponding to 60% of the individual target maximal heart rate recorded in a 6-minute walking test. The participants’ cognition was monitored before and after the intervention using the Tower of Hanoi, Digit Span, and Stroop tasks. Results: After the exercise, the participants’ attention in both the physical and combined groups improved for the Stroop, the forward and backward Digit Span tasks, as well as the time taken to solve the Tower of Hanoi, although no significant differences were found in the number of moves taken in the latter. By contrast, the control group did not show any significant improvement for most of the cognitive tasks after the reading session. Conclusion: Current evidence suggests that AAE may help to improve cognitive functions in ADM patients. This improvement is enhanced when the exercise is combined with cognitive games. Safe and progressive types of exercises should be promoted among ADM patients.

Anita Korpioja, Johanna Krüger, Susanna Koivuluoma, Katri Pylkäs, Virpi Moilanen, Seppo Helisalmi, Mikko Hiltunen, Anne M. Remes (Handling Associate Editor: Ling-Qiang Zhu)
Novel Rare SORL1 Variants in Early-Onset Dementia
Abstract: Background: Rare variants of SORL1 have been associated with an increased risk of early-onset or late-onset Alzheimer’s disease (AD). However, a lot remains to be clarified about their significance in the pathogenesis of the disease. Objective: To evaluate the role of SORL1 variants among Finnish patients with early-onset AD (EOAD). Methods: The rare SORL1variants were screened in a cohort of 115 Finnish EOAD patients (mean age at onset 58.3 years, range 46-65 years) by using the whole-exome sequencing. Results: We found one novel nonsense variant (p.Gln290*) and eight missense variants in SORL1. This is the first study reporting the SORL1 variants p.Lys80Arg, p.Ala789Val and p.Arg866Gln in EOAD patients. Furthermore, two of these three missense variants were overrepresented in EOAD patients compared to gnomAD non-neuro Finnish samples. Conclusion: This study strengthens the earlier findings, that the rare variants in SORL1 are associated with EOAD.

Margaret C. Sewell*, Judith Neugroschl*, Mari Umpierre, Shehan Chin, Carolyn W. Zhu, Nelly Velasco, Sabrina Gonzalez, Alexandra Acabá-Berrocal, Luca Bianchetti, Gabriela Silva, Alma Collazo, Mary Sano (Handling Associate Editor: Megan Zuelsdorff) *These authors contributed equally to this work.
Research Attitudes and Interest Among Elderly Latinxs: The Impact of a Collaborative Video and Community Peers
Abstract: Background: Latinx elders are underrepresented in dementia research. In a previous study we assessed research attitudes in urban minority elders and found a significant minority expressed neutral to negative attitudes relating to trust, safety, and personal responsibility to help research. Objective: To assess the impact of a composite intervention on attitudes toward research and research participation among elderly Latinx. The intervention was a collaboratively produced research participation video shown during presentations with our elderly community advisory board (CAB) as co-presenters. Methods: The video was created by the ADRC and CAB. All senior center attendees were eligible to participate. Afterwards, the Research Attitudes Questionnaire (RAQ) and a brief questionnaire on the impact of the video were administered. Using Wilcoxon Rank Sum Tests, Chi Square, and OLS regressions, RAQ responses were compared to those from a historical cohort from similar centers. Results: 74 in the “Historical Cohort 1” and 104 in “Intervention Cohort 2” were included. RAQ total score was higher in Cohort 2 than Cohort 1 (28.5 versus 26.1, p<0.05) after controlling for age, education, and country of origin. In response to the question “Has the video influenced your willingness and interest to participate in research”, 88.7% of the participants in Cohort 2 reported being “more” or “much more” interested in research. Conclusion: Tailoring community research recruitment programs to include relatable peers using novel recruitment techniques may have positive implications for improving enrollment of diverse elderly individuals in research.

Johan Svensson, Maria Blomqvist, Petronella Kettunen, Carl Eckerström, Marcus Henricsson, Michael Jonsson, Maria Bjerke, Jan-Eric Månsson, Anders Wallin
Cerebrospinal Fluid Sulfatide Levels Lack Diagnostic Utility in the Subcortical Small Vessel Type of Dementia
Abstract: Background: Sulfatides (STs) in cerebrospinal fluid (CSF), as well as magnetic resonance imaging (MRI)-detected white matter hyperintensities (WMHs), may reflect demyelination. Here, we investigated the diagnostic utility of CSF ST levels in the subcortical small vessel type of dementia (SSVD), which is characterized by the presence of brain WMHs. Objective: To study the diagnostic utility of CSF ST levels in SSVD. Methods: This was a mono-center, cross-sectional study of SSVD (n=16), Alzheimer’s disease (n=40), mixed dementia (n=27), and healthy controls (n=33). Totally, 20 ST species were measured in CSF by liquid chromatography-mass spectrometry (LC-MS/MS). Results: CSF total ST levels, as well as CSF levels of hydroxylated and nonhydroxylated ST species, did not differ across the study groups. In contrast, CSF neurofilament light chain (NFL) levels separated the patient groups from the controls. CSF total ST level correlated with CSF/serum albumin ratio in the total study population (r=0.64, p<0.001) and in all individual study groups. Furthermore, CSF total ST level correlated positively with MRI-estimated WMH volume in the total study population (r=0.30, p<0.05), but it did not correlate with CSF NFL level. Conclusion: Although there was some relation between CSF total ST level and WMH volume, CSF ST levels were unaltered in all dementia groups compared to the controls. This suggests that CSF total ST level is a poor biomarker of demyelination in SSVD. Further studies are needed to investigate the mechanisms underlying the marked correlation between CSF total ST level and CSF/serum albumin ratio.

Frank A. Greco, Ann C. McKee, Neil W. Kowall, Eugene B. Hanlon
Near-Infrared Optical Spectroscopy In Vivo Distinguishes Subjects with Alzheimer’s Disease from Age-Matched Controls
Abstract: Background: Medical imaging methods such as PET and MRI aid clinical assessment of Alzheimer’s disease (AD). Less expensive, less technically demanding, and more widely deployable technologies are needed to expand objective screening for diagnosis, treatment, and research. We previously reported brain tissue near-infrared optical spectroscopy (NIR) in vitro indicating the potential to meet this need. Objective: To determine whether completely non-invasive, clinical, NIR in vivo can distinguish AD patients from age-matched controls and to show the potential of NIR as a clinical screen and monitor of therapeutic efficacy. Methods: NIR spectra were acquired in vivo. Three groups were studied: autopsy-confirmed AD, control and mild cognitive impairment (MCI). A feature selection approach using the first derivative of the intensity normalized spectra was used to discover spectral regions that best distinguished “AD-alone” (i.e., without other significant neuropathology) from controls. The approach was then applied to other autopsy-confirmed AD cases and to clinically diagnosed MCI cases. Results: Two regions about 860 and 895 nm completely separate AD patients from controls and differentiate MCI subjects according to the degree of impairment. The 895 nm feature is more important in separating MCI subjects from controls (ratio-of-weights: 1.3); the 860 nm feature is more important for distinguishing MCI from AD (ratio-of-weights: 8.2). Conclusion: These results form a proof of the concept that near-infrared spectroscopy can detect and classify diseased and normal human brain in vivo. A clinical trial is needed to determine whether the two features can track disease progression and monitor potential therapeutic interventions.

Xuan Zhao*, Cancan Li*, Guoyong Ding, Yuanyuan Heng, An Li, Wei Wang, Haifeng Hou, Jun Wen, Yanbo Zhang *These authors contributed equally to this work.
The Burden of Alzheimer’s Disease Mortality in the United States, 1999-2018
Abstract: Background: The increasing prevalence of Alzheimer’s disease (AD), along with the associated burden on healthcare systems, presents a substantial public health challenge. Objective: This study aimed to investigate trends in AD mortality and the relevant burden across the United States (U.S.) from 1999 to 2018 and to predict mortality trends between 2019 and 2023. Methods: Data on AD-related deaths between 1999 and 2018 were collected from the WONDER database administered by the U.S. Centers for Disease Control and Prevention (CDC). The Joinpoint Regression Program was used to analyze mortality trends due to AD. Years of life lost (YLL) were calculated to explore the burden of AD deaths. An autoregressive integrated moving average (ARIMA) model was employed to forecast mortality trends from 2019 to 2023. Results: Over a recent 20-year period, the number of AD deaths in the U.S. increased from 44,536 (31,145 females and 13,391 males) to 122,019 (84,062 females and 37,957 males). The overall age-adjusted mortality rate increased from 16.5/100,000 in 1999 to 30.5/100,000 in 2018. AD mortality is projected to reach 42.40/100000 within the year 2023. Overall, AD resulted in 322,773.00 YLL (2.33 per 1000 population) in 1999 and 658,501.87 YLL (3.68 per 1000 population) in 2018. Conclusion: Our findings demonstrate an increase in AD mortality in the U.S. from 1999 to 2018 as well as a rapid increase from 2019 to 2023. The high burden of AD deaths emphasizes the need for targeted prevention, early diagnosis, and hierarchical management.

Regina Silva Paradela, Naomi Vidal Ferreira, Mariana Penteado Nucci, Brenno Cabella, Luiza Menoni Martino, Laura Aló Torres, Danielle Irigoyen da Costa, Fernanda Marciano Consolim-Colombo, Claudia Kimie Suemoto, Maria Claudia Irigoyen
Relation of a Socioeconomic Index with Cognitive Function and Neuroimaging in Hypertensive Individuals
Abstract: Background: Socioeconomic factors are important contributors to brain health. However, data from developing countries (where social inequalities are the most prominent) are still scarce, particularly about hypertensive individuals. Objective: To evaluate the relationship between socioeconomic index, cognitive function, and cortical brain volume, as well as determine whether white matter hyperintensities are mediators of the association of the socioeconomic index with cognitive function in hypertensive individuals. Methods: We assessed 92 hypertensive participants (mean age = 58±8.6 years, 65.2% female). Cognitive evaluation and neuroimaging were performed and clinical and sociodemographic data were collected using questionnaires. A socioeconomic index was created using education, income, occupation (manual or non-manual work), and race. The associations of the socioeconomic index with cognitive performance and brain volume were investigated using linear regression models adjusted for age, sex, time of hypertension since diagnosis, and comorbidities. A causal mediation analysis was also conducted. Results: Better socioeconomic status was associated with better visuospatial ability, executive function, and global cognition. We found associations between a better socioeconomic index and a higher parietal lobe volume. White matter hyperintensities were also not mediators in the relationship between the socioeconomic index and cognitive performance. Conclusion: Socioeconomic disadvantages are associated with worse cognitive performance and brain volume in individuals with hypertension.

Debora Melo van Lent, Adrienne O’Donnell, Alexa S. Beiser, Ramachandran S. Vasan, Charles S. DeCarli, Nikolaos Scarmeas, Michael Wagner, Paul F. Jacques, Sudha Seshadri, Jayandra J. Himali*, Matthew P. Pase* (Handling Associate Editor: Puja Agarwal) *These authors contributed equally as co-senior authors.
MIND Diet Adherence and Cognitive Performance in the Framingham Heart Study
Abstract: Background: Adherence to the Mediterranean-DASH for Neurodegenerative Delay (MIND) diet has previously been associated with cognitive decline and dementia. To our knowledge, no prior study has investigated the association between the MIND diet and measures of brain volume, silent brain infarcts (SBIs), or brain atrophy. Objective: We evaluated whether adherence to the MIND diet associated with superior cognitive function, larger brain volumes, fewer SBIs, and less cognitive decline in the community-based Framingham Heart Study. Methods: 2,092 participants (mean±SD, age 61±9) completed Food Frequency Questionnaires, averaged across a maximum of 3-time points (examination cycles 5, 6, and 7), cognitive testing at examination cycle 7 (present study baseline: 1998-2001) and after a mean±SD of 6.6±1.1 years from baseline (n=1,584). A subset of participants also completed brain magnetic resonance imaging (MRI) at examination cycle 7 (n=1,904). In addition, participants with dementia, stroke, and other relevant neurological diseases such as significant head trauma, subdural hematoma, or multiple sclerosis were excluded from the analyses. Results: Higher MIND diet scores were associated with better global cognitive function (β±SE, +0.03SD±0.01; p=0.004), verbal memory, visual memory, processing speed, verbal comprehension/reasoning, and with larger total brain volume (TBV) following adjustments for clinical, lifestyle and demographic covariates, but not with other brain MRI measures (i.e., hippocampal volume, lateral ventricular volume, white matter hyperintensity volume, and SBIs) or cognitive decline. Conclusion: Higher MIND diet scores associated with better cognitive performance and larger TBV at baseline, but not with cognitive decline. Clinical trials are needed to ascertain whether adopting the MIND diet affects trajectories of cognitive decline.

Dorothee Schoemaker, Lina Velilla, Yesica Zuluaga, Ana Baena, Carolina Ospina, Yamile Bocanegra, Sergio Alvarez, Martin Ochoa-Escudero, Edmarie Guzmán-Vélez, Jairo Martinez, Francisco Lopera, Joseph F. Arboleda-Velasquez, Yakeel T. Quiroz (Handling Associate Editor: Rónán O'Caoimh)
Global Cardiovascular Risk Profile and Cerebrovascular Abnormalities in Presymptomatic Individuals with CADASIL or Autosomal Dominant Alzheimer’s Disease
Abstract: Background: Cardiovascular risk factors increase the risk of developing dementia, including Alzheimer’s disease and vascular dementia. Objective: Studying individuals with autosomal dominant mutations leading to the early onset of dementia, this study examines the effect of the global cardiovascular risk profile on early cognitive and neuroimaging features of Alzheimer's disease and vascular dementia. Methods: We studied 85 non-demented and stroke-free individuals, including 20 subjects with Presenilin1 (PSEN1) E280A mutation leading to the early onset of autosomal dominant Alzheimer's disease (ADAD), 20 subjects with NOTCH3 mutations leading to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to the early onset of vascular dementia, and 45 non-affected family members (non-carriers). All subjects underwent clinical and neuropsychological evaluations and an MRI. The global cardiovascular risk profile was estimated using the office-based Framingham Cardiovascular Risk Profile (FCRP) score. Results: In individuals with CADASIL, a higher FCRP score was associated with a reduced hippocampal volume (B=-0.06, p<0.05) and an increased severity of cerebral microbleeds (B=0.13, p<0.001), lacunes (B=0.30, p<0.001), and perivascular space enlargement in the basal ganglia (B=0.50, p<0.05). There was no significant association between the FCRP score and neuroimaging measures in ADAD or non-carrier subjects. While the FCRP score was related to performance in executive function in non-carrier subjects (B=0.06, p<0.05), it was not significantly associated with cognitive performance in individuals with CADASIL or ADAD. Conclusion: Our results suggest that individuals with CADASIL and other forms of vascular cognitive impairment might particularly benefit from early interventions aimed at controlling cardiovascular risks.

Jiahui Niu, Khalid Iqbal, Fei Liu, Wen Hu
Rats Display Sexual Dimorphism in Phosphorylation of Brain Tau with Age
Abstract: Background: Women have a two-fold higher risk than men to Alzheimer’s disease (AD) at midlife. Larger brain tau burden was consistently shown in older women than age-matched men. The biological basis for this gender disparity remains elusive. Objective: We sought to know whether tau expression and phosphorylation physiologically differ between males and females. Methods: We used western blots and immunohistochemistry to compare the levels of total tau and phosphorylated tau in the hippocampus and entorhinal cortex (EC) between sexes in Wistar rats at 40 days, and 8 and 20 months of age. Results: We detected no statistically significant difference in total tau, 3R-tau, and 4R-tau between sexes. However, female rats exhibited lower levels of tau unphosphorylated at the Tau-1 site at 40 days of age. At 8 months of age, females showed higher levels of tau phosphorylated at Ser190, Ser387, and Ser395 (Ser199, Ser396, and Ser404 of human tau, respectively) than males in EC. At 20 months of age, both brain regions of female rats consistently showed higher levels than males of tau phosphorylated at Ser253, Ser387, PHF-1 (Ser387/395), and Ser413 sites, which correspond to Ser262, Ser396, Ser396/404, and Ser422 of human tau, respectively. Conclusion: Rats of both sexes have comparable levels of total tau, 3R-tau, and 4R-tau, whereas females exhibit higher levels of tau phosphorylated at multiple sites that are implicated in AD tau pathology, indicating a sexual dimorphism of tau phosphorylation that may potentially underlie the disparity in brain tau burden and risk for AD between sexes.

Fabrizio Vecchio, Francesca Miraglia, Francesca Alù, Alessandro Orticoni, Elda Judica, Maria Cotelli, Paolo Maria Rossini
Contribution of Graph Theory Applied to EEG Data Analysis for Alzheimer’s Disease versus Vascular Dementia Diagnosis
Abstract: Background: Most common progressive brain diseases in the elderly are Alzheimer’s disease (AD) and vascular dementia (VaD). They present with relatively similar clinical symptoms of cognitive decline, but the underlying pathophysiological mechanisms are different. Objective: The aim is to explore the brain connectivity differences between AD and VaD patients compared to mild cognitive impairment (MCI) and normal elderly (Nold) subjects applying graph theory, in particular the Small World (SW) analysis. Methods: 274 resting state EEGs were analyzed in 100 AD, 80 MCI, 40 VaD, and 54 Nold subjects. Graph theory analyses were applied to undirected and weighted networks obtained by lagged linear coherence evaluated by eLORETA tool. Results: VaD and AD patients presented more ordered low frequency structure (lower value of SW) than Nold and MCI subjects, and more random organization (higher value of SW) in low and high frequency alpha rhythms. Differences between patients have been found in high frequency alpha rhythms in VaD (higher value of SW) with respect to AD, and in theta band with a trend which is more similar to MCI and Nold than to AD. MCI subjects presented a network organization which is intermediate, in low frequency bands, between Nold and patients. Conclusion: Graph theory applied to EEG data has proved very useful in identifying differences in brain network patterns in subjects with dementia, proving to be a valid tool for differential diagnosis. Future studies will aim to validate this method to diagnose especially in the early stages of the disease and at single subject level.