Volume 76, Number 3, IN PRESS

Review
Amin Haghani, Todd E. Morgan, Henry Jay Forman, Caleb E. Finch
Air Pollution Neurotoxicity in the Adult Brain: Emerging Concepts from Experimental Findings
Abstract: Epidemiological studies are associating elevated exposure to air pollution with increased risk of Alzheimer’s disease and other neurodegenerative disorders. In effect, air pollution accelerates many aging conditions that promote cognitive declines of aging. The underlying mechanisms and scale of effects remain largely unknown due to its chemical and physical complexity. Moreover, individual responses to air pollution are shaped by an intricate interface of pollutant mixture with the biological features of the exposed individual such as age, sex, genetic background, underlying diseases, and nutrition, but also other environmental factors including exposure to cigarette smoke. Resolving this complex manifold requires more detailed environmental and lifestyle data on diverse populations, and a systematic experimental approach. Our review aims to summarize the modest existing literature on experimental studies on air pollution neurotoxicity for adult rodents and identify key gaps and emerging challenges as we go forward. It is timely for experimental biologists to critically understand prior findings and develop innovative approaches to this urgent global problem. We hope to increase recognition of the importance of air pollution on brain aging by our colleagues in the neurosciences and in biomedical gerontology, and to support the immediate translation of the findings into public health guidelines for the regulation of remedial environmental factors that accelerate aging processes.

Review
Si-Yu Wang*, Peng-Yu Gong*, Yan E*, Ying-Dong Zhang, Teng Jiang *These authors contributed equally to this work.
The Role of TREML2 in Alzheimer’s Disease
Abstract: Late-onset Alzheimer’s disease (AD) accounts for most of all AD cases and is currently considered a complex disorder caused by a combination of environmental and genetic factors. As an important family member of triggering receptor expressed on myeloid cells (TREM), TREM-like transcript 2 gene (TREML2) locates on human chromosome 6p21.1, a newly-identified hot zone for AD susceptibility, and encodes a transmembrane immune receptor. Emerging evidence implied a potential role of TREML2 in the susceptibility and pathogenesis of AD. Here, we review the recent literature about the association of TREML2 variants with AD risk and disease endophenotypes. Moreover, we summarize the latest findings regarding cellular localization and biological functions of TREML2 and speculate its possible role in AD pathogenesis. In addition, we discuss future research directions of TREML2 and AD.

Review
Rui-Ming Liu, Zechen Chong, Jiu-Chiuan Chen
Ozone and Particulate Matter Exposure and Alzheimer’s Disease: A Review of Human and Animal Studies
Abstract: Alzheimer’s disease (AD), an aging-related neurodegenerative disease, is a major cause of dementia in the elderly. Although the early-onset (familial) AD is attributed to mutations in the genes coding for amyloid-β protein precursor (AβPP) and presenilin1/presenilin 2 (PS1/PS2), the cause for the late-onset AD (LOAD), which accounts for more than 95% of AD cases, remains unclear. Aging is the greatest risk factor for LOAD, whereas the apolipoprotein E4 allele (APOE ε4) is believed to be a major genetic risk factor in acquiring LOAD, with female APOE ε4 carriers at highest risk. Nonetheless, not all the elderly, even older female APOE ε4 carriers, develop LOAD, suggesting that other factors, including environmental exposure, must play a role. This review summarizes recent studies that show a potential role of environmental exposure, especially ozone and particulate matter exposure, in the development of AD. Interactions between environmental exposure, genetic risk factor (APOE ε4), and sex in AD pathophysiology are also discussed briefly. Identification of environmental risk factor(s) and elucidation of the complex interactions between genetic and environmental risk factors plus aging and female sex in the onset of AD will be a key to our understanding of the etiology and pathogenesis of AD and the development of the strategies for its prevention and treatment.

Hypothesis
Luigi Attademo, Francesco Bernardini
Air Pollution as Risk Factor for Mental Disorders: In Search for a Possible Link with Alzheimer’s Disease and Schizophrenia
Abstract: As a global problem that has increasingly been causing worldwide concern, air pollution poses a significant and serious environmental risk to health. Risks of cardiovascular and respiratory diseases, as well as various types of cancer, have been consistently associated with the exposure to air pollutants. More recently, various studies have also shown that the central nervous system is also attacked by air pollution. Air pollution appears to be strongly associated with a higher risk of cognitive defects, neurodevelopmental (e.g., schizophrenia) and neurodegenerative (e.g., Alzheimer’s disease) disorders. Subjects with schizophrenia, as well as subjects with Alzheimer’s disease, experience a variety of neuropsychological deficits and cognitive impairments. This determines an adverse effect on social and professional functioning, and it contributes to the long-term disease burden. However, no final conclusions have been drawn on the matter of the direct relationship between schizophrenia and Alzheimer’s disease. In recent years, the topic of urbanicity and mental health has become increasingly important. Urban exposure to environmental toxins and pollution is currently described as a reliable risk factor for schizophrenia and other psychoses, and it has been demonstrated more and more how exposure to air pollutants is associated with increased risk of dementia. Pathways by which air pollution can target and damage the brain, leading to an increased risk for developing schizophrenia and Alzheimer’s disease, are multiple and complex. Results from epidemiological studies suggest potential associations, but are still insufficient to confirm causality. Further studies are needed in order to verify this hypothesis. And if confirmed, the clinical implications could be of substantial relevance for both public and mental health.

Hypothesis
Elisa Mantovani*, Chiara Zucchella*, Federico Schena, Maria Grazia Romanelli, Massimo Venturelli, Stefano Tamburin *These authors contributed equally to this work.
Towards a Redefinition of Cognitive Frailty
Abstract: Background: The progressive aging of the population will dramatically increase the burden of dementia related to Alzheimer’s disease (AD) and other neurodegenerative disorders in the future. Because of the absence of drugs that can modify the neuropathological substrate of AD, research is focusing on the application of preemptive and disease-modifying strategies in the pre-symptomatic period of the disease. In this perspective, the identification of people with cognitive frailty (CF), i.e., those individuals with higher risk of developing dementia, on solid pathophysiological bases and with clear operational clinical criteria is of paramount importance. Objective/Methods: This hypothesis paper reviews the current definitions of CF, presents and discusses some of their limitations, and proposes a framework for updating and improving the conceptual and operational definition of the CF construct. Results: The potential for reversibility of CF should be supported by the assessment of amyloid, tau, and neuronal damage biomarkers, especially in younger patients. Physical and cognitive components of frailty should be considered as separate entities, instead of part of a single macro-phenotype. CF should not be limited to the geriatric population, because trajectories of amyloid accumulation are supposed to start earlier than 65 years in AD. Operational criteria are needed to standardize assessment of CF. Conclusion: Based on the limitations of current CF definitions, we propose a revised one according to a multidimensional subtyping. This new definition might help stratifying CF patients for future trials to explore new lifestyle interventions or disease-modifying pharmacological strategies for AD and dementia.

Short Communication
Kimberly D. van der Willik, Sanne B. Schagen, M. Arfan Ikram
Association Between the Tumor Marker Carcinoembryonic Antigen and the Risk of Dementia
Abstract: There is an ongoing debate about how cancer and dementia relate to each other, and whether their relation is biologically determined or caused by surveillance and survival bias. We aimed to circumvent these biases by determining the relation between the tumor marker carcinoembryonic antigen (CEA) and the risk of dementia in 6,692 participants from the population-based Rotterdam Study. We found that higher levels of CEA were associated with a higher risk of dementia (HR per standard deviation increase in CEA=1.11, 95%CI 1.04;1.18). This finding may indicate that cancer and dementia are positively associated, but the mechanisms underlying the relation between CEA and dementia warrant further investigation.

Spotlight
Aldelmo Emmanuel Reyes-Pablo, B. Berenice Campa-Córdoba, Nabil Itzi Luna-Viramontes, Miguel Ángel Ontiveros-Torres, Ignacio Villanueva-Fierro, Marely Bravo-Muñoz, Bárbara Sáenz-Ibarra, Oralia Barbosa, Parménides Guadarrama-Ortíz, Linda Garcés-Ramírez, Fidel de la Cruz, Charles R. Harrington, Sandra Martínez-Robles, Erik González-Ballesteros, George Perry, Mar Pacheco-Herrero, José Luna-Muñoz (Handling Editor: Paula Moreira)
National Dementia BioBank: A Strategy for the Diagnosis and Study of Neurodegenerative Diseases in México
Abstract: We recently developed the National Dementia Biobank in México (BioBanco Nacional de Demencias, BND) as a unit for diagnosis, research, and tissue transfer for researcher purposes. BND is associated with the Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de Mexico (UNAM), Mexico. The donation of fluids, brain, and other organs of deceased donors is crucial for understanding the underlying mechanisms of neurodegenerative diseases and for the development of successful treatment. Our laboratory research focuses on 1) analysis of the molecular processing of the proteins involved in neurodegenerative diseases named tauopathies and 2) the search for biomarkers for the non-invasive early diagnosis of Alzheimer's disease.

Maggie Roy, François Rheault, Etienne Croteau, Christian-Alexandre Castellano, Mélanie Fortier, Valérie St-Pierre, Jean-Christophe Houde, Éric E. Turcotte, Christian Bocti, Tamas Fulop, Stephen C. Cunnane*, Maxime Descoteaux* (Handling Associate Editor: Michael Hornberger) *These authors are co-senior authors on this work.
Fascicle- and Glucose-Specific Deterioration in White Matter Energy Supply in Alzheimer’s Disease
Abstract:
Background: White matter energy supply to oligodendrocytes and the axonal compartment is crucial for normal axonal function. Although gray matter glucose hypometabolism is extensively reported in Alzheimer’s disease (AD), glucose and ketones, the brain’s two main fuels, are rarely quantified in white matter in AD. Objective: Using a dual-tracer PET method combined with a fascicle-specific diffusion MRI approach, robust to white matter hyperintensities and crossing fibers, we aimed to quantify both glucose and ketone metabolism in specific white matter fascicles associated with mild cognitive impairment (MCI; n = 51) and AD (n = 13) compared to cognitively healthy age-matched controls (Controls; n = 14). Methods: Eight white matter fascicles of the limbic lobe and corpus callosum were extracted and analyzed into fascicle profiles of five sections. Glucose (18F-fluorodeoxyglucose) and ketone (11C-acetoacetate) uptake rates, corrected for partial volume effect, were calculated along each fascicle. Results: The only fascicle with significantly lower glucose uptake in AD compared to Controls was the left posterior cingulate segment of the cingulum (-22%; p = 0.016). Non-significantly lower glucose uptake in this fascicle was also observed in MCI. In contrast to glucose, ketone uptake was either unchanged or higher in sections of the fornix and parahippocampal segment of the cingulum in AD. Conclusion: To our knowledge, this is the first report of brain fuel uptake calculated along white matter fascicles in humans. Energetic deterioration in white matter in AD appears to be specific to glucose and occurs first in the posterior cingulum.

Yueming Hu, Cristiana Meuret, Scholastica Go, Hussein N. Yassine*, Dobrin Nedelkov* (Handling Associate Editor: J. Wesson Ashford) *These authors share senior authorship with equal contributions.
Simple and Fast Assay for Apolipoprotein E Phenotyping and Glycotyping: Discovering Isoform-Specific Glycosylation in Plasma and Cerebrospinal Fluid
Abstract: Background: The mechanisms of how APOE ε4 allele (APOE4) increases the risk of Alzheimer’s disease (AD) pathology have not been fully elucidated. In cerebrospinal fluid (CSF), apoE is heavily glycosylated. Objective: To determine the impact of APOE genotype on the relative abundance of apoE protein isoforms and their specific glycosylation patterns in CSF and plasma via a newly developed mass spectrometric immunoassay (MSIA) assay. Methods: Total glycosylation and isoform-specific glycosylation were analyzed in plasma and CSF from a group of non-demented older individuals (n=22), consisting of homozygous ε3 and ε4 or heterozygous ε3/ε4, ε2/ε3, or ε2/ε4 carriers. The glycan structures were further confirmed after treatment with sialidase. Results: In heterozygous individuals, the apoE3/E2, E4/E2, and E4/E3 isoform ratios were all significantly lower in plasma compared to CSF. For all individuals, a single O-linked glycan was observed in plasma, while two glycans (of the same type) per apoE were observed in CSF. The ratio of glycosylated to total apoE was greater in CSF compared to plasma for all apoE isoforms. In plasma and CSF, a trend of decreasing glycosylation was observed from apoE2>apoE3>apoE4. The difference in the percentage of secondary glycosylation in CSF was significantly greater in apoE4 compared to the other isoforms. Conclusion: The new MSIA apoE assay robustly distinguishes among apoE isoforms and glycoforms in plasma and CSF. ApoE4 is the predominant isoform and least glycosylated in CSF. Assessing apoE isoform-specific glycosylation by MSIA may help clarify brain apoE metabolism and AD risk.

Taiki Sugimoto, Rei Ono, Ai Kimura, Naoki Saji, Shumpei Niida, Toshihiro Sakai, Hiromi Rakugi, Kenji Toba, Takashi Sakurai
Impact of Cognitive Frailty on Activities of Daily Living, Cognitive Function, and Conversion to Dementia Among Memory Clinic Patients with Mild Cognitive Impairment
Abstract: Background: Very few studies have investigated the impact of cognitive frailty in clinical settings, especially in memory clinic populations. Objective: To examine the impact of cognitive frailty on activities of daily living (ADL), cognitive function, and conversion to dementia among memory clinic patients with mild cognitive impairment (MCI). Methods: The subjects of this retrospective study were 248 MCI patients (mean age, 76.3 ± 5.4 years; females, 60.9%). All subjects completed a comprehensive geriatric assessment at baseline and at least one assessment during 3-year follow-up. Frailty was defined by generating a frailty index (FI), and MCI patients with frailty (FI ≥ 0.25) were considered to represent cognitive frailty. As primary outcomes, the Barthel Index, Mini-Mental State Examination, and incident dementia were evaluated during follow-up. At baseline, patients were assessed for apolipoprotein E (APOE) phenotype. A linear mixed model, as well as a Cox proportional hazards regression model with adjustment for confounding variables, was performed. Results: Of these patients, 75 (30.2%) were classified as cognitive frail. APOE ε4 carriers accounted for 26.7% of those with cognitive frailty and 44.5% of those without (p = 0.008). Cognitive frail patients showed a faster ADL decline (estimate, -1.04; standard error, 0.38; p = 0.007) than patients without cognitive frailty. Cognitive frailty was not associated with cognitive decline and incident dementia. Conclusion: Our findings demonstrated cognitive frailty increases the risk of dependence but not cognitive outcomes. Cognitive frailty may have heterogeneous conditions, including APOE ε4-related pathologies, which may affect the cognitive trajectories of patients with MCI.

Jason A. Thomas*, Hannah A. Burkhardt*, Safina Chaudhry, Anthony D. Ngo, Saransh Sharma, Larry Zhang, Rhoda Au, Reza Hosseini Ghomi *These authors contributed equally to this work.
Assessing the Utility of Language and Voice Biomarkers to Predict Cognitive Impairment in the Framingham Heart Study Cognitive Aging Cohort Data
Abstract: Background: There is a need for fast, accessible, low-cost, and accurate diagnostic methods for early detection of cognitive decline. Dementia diagnoses are usually made years after symptom onset, missing a window of opportunity for early intervention. Objective: To evaluate the use of recorded voice features as proxies for cognitive function by using neuropsychological test measures and existing dementia diagnoses. Methods: This study analyzed 170 audio recordings, transcripts, and paired neuropsychological test results from 135 participants selected from the Framingham Heart Study (FHS), which includes 97 recordings of cognitively normal participants and 73 recordings of cognitively impaired participants. Acoustic and linguistic features of the voice samples were correlated with cognitive performance measures to verify their association. Results: Language and voice features, when combined with demographic variables, performed with an AUC of 0.942 (95% CI 0.929-0.983) in predicting cognitive status. Features with good predictive power included the acoustic features mean spectral slope in the 500-1500 Hz band, variation in the F2 bandwidth, and variation in the Mel-Frequency Cepstral Coefficient (MFCC) 1; the demographic features employment, education, and age; and the text features of number of words, number of compound words, number of unique nouns, and number of proper names. Conclusion: Several linguistic and acoustic biomarkers show correlations and predictive power with regard to neuropsychological testing results and cognitive impairment diagnoses, including dementia. This initial study paves the way for a follow-up comprehensive study incorporating the entire FHS cohort.

Zuzanna Angehrn, Jelena Sostar, Clementine Nordon, Andrew Turner, Dianne Gove, Helene Karcher, Alexander Keenan, Brent Mittelstadt, Frederic de Reydet-de Vulpillieres (Handling Associate Editor: José Luis Molinuevo)
Ethical and Social Implications of Using Predictive Modeling for Alzheimer’s Disease Prevention: A Systematic Literature Review
Abstract: Background: The therapeutic paradigm in Alzheimer’s disease (AD) is shifting from symptoms management toward prevention goals. Secondary prevention requires the identification of individuals without clinical symptoms, yet “at-risk” of developing AD dementia in the future, and thus, the use of predictive modeling. Objective: The objective of this study was to review the ethical concerns and social implications generated by this new approach. Methods: We conducted a systematic literature review in Medline, Embase, PsycInfo, and Scopus, and complemented it with a gray literature search between March and July 2018. Then we analyzed data qualitatively using a thematic analysis technique. Results: We identified thirty-one ethical issues and social concerns corresponding to eight ethical principles: (i) respect for autonomy, (ii) beneficence, (iii) non-maleficence, (iv) equality, justice, and diversity, (v) identity and stigma, (vi) privacy, (vii) accountability, transparency, and professionalism, and (viii) uncertainty avoidance. Much of the literature sees the discovery of disease-modifying treatment as a necessary and sufficient condition to justify AD risk assessment, overlooking future challenges in providing equitable access to it, establishing long-term treatment outcomes and social consequences of this approach, e.g., medicalization. The ethical/social issues associated specifically with predictive models, such as the adequate predictive power and reliability, infrastructural requirements, data privacy, potential for personalized medicine in AD, and limiting access to future AD treatment based on risk stratification, were covered scarcely. Conclusion: The ethical discussion needs to advance to reflect recent scientific developments and guide clinical practice now and in the future, so that necessary safeguards are implemented for large-scale AD secondary prevention.

Steinunn Thordardottir, Ove Almkvist, Charlotte Johansson, Henrik Zetterberg, Kaj Blennow, Caroline Graff
Cerebrospinal Fluid YKL-40 and Neurogranin in Familial Alzheimer’s Disease: A Pilot Study
Abstract: Background: YKL-40 and neurogranin are promising additional cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) which reflect different underlying disease mechanisms. Objective: To compare the levels of CSF YKL-40 and neurogranin between asymptomatic carriers of familial AD (FAD) mutations (MC) and non-carriers (NC) from the same families. Another objective was to assess changes in YKL-40 and neurogranin, from the presymptomatic to clinical phase of FAD. Methods: YKL-40 and neurogranin, as well as Aβ42, total tau-protein, and phospho-tau, were measured in the CSF of 14 individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G), and PSEN1 (p.H163Y), as well as in 17 NC from the same families. Five of the MC developed mild cognitive impairment (MCI) during follow-up. Results: In this pilot study, there was no difference in either CSF YKL-40 or neurogranin when comparing the presymptomatic MC to the NC. YKL-40 correlated positively with expected years to symptom onset and to age in both the MC and the NC, while neurogranin had no correlation to either variable in either of the groups. A subgroup of the participants underwent more than one CSF sampling in which half of the MC developed MCI during follow-up. The longitudinal data showed an increase in YKL-40 levels in the MC as the expected symptom onset approached. Neurogranin remained stable over time in both the MC and the NC. Conclusion: These findings support a positive correlation between progression from presymptomatic to symptomatic AD and levels of CSF YKL-40, but not neurogranin.

Laura Luukkainen, Samuli Huttula, Henri Väyrynen, Seppo Helisalmi, Laura Kytövuori, Annakaisa Haapasalo, Mikko Hiltunen, Anne M. Remes, Johanna Krüger
Mutation Analysis of the Genes Associated with Parkinson’s Disease in a Finnish Cohort of Early-Onset Dementia
Abstract: Background: Alzheimer’s disease, frontotemporal lobar degeneration, dementia with Lewy bodies, and Parkinson’s disease (PD) overlap in clinical characteristics, neuropathology, and genetics. Objective: The aim of this study was to evaluate the role of pathogenic mutations and rare variants in genes associated with PD among early-onset dementia (EOD) patients. Methods: Rare non-synonymous variants (MAF<0.01) in ten genes (SNCA, PARK2, PARK7, LRRK2, PINK1, ATP13A2, UCHL1, HTRA2, GBA, and SNCAIP) and low-frequency (MAF<0.05) GBA variants were screened using a targeted next-generation sequencing panel in a strictly defined cohort of 37 early-onset (age at onset (AAO) <65 years) dementia patients presenting with atypical features (e.g., myoclonia or spasticity), rapidly progressive course of the disease or with a family history of dementia. The identified variations were further screened in a larger cohort of EOD (n=279, mean AAO 57, range 36-65) patients. Results: No pathogenic mutations were found, but we identified seven possible risk variants for neurodegeneration (LRRK2 p.Arg793Met, PARK2 p.Ala82Glu, SNCAIP p.Arg240Gln, SNCAIP p.Phe369Leu, GBA p.Asn409Ser, GBA p.Glu365Lys, GBA p.Thr408Met). Discussion: Altogether, the frequency of these variants was two times higher in the first selected cohort compared to the whole cohort. This suggests that specific rare variants in the genes associated with PD might play a role also especially in familial EOD.

Heather Guthrie, Lawrence S. Honig, Helen Lin, Kaycee M. Sink, Kathleen Blondeau, Angelica Quartino, Michael Dolton, Montserrat Carrasco-Triguero, Qinshu Lian, Tobias Bittner, David Clayton, Jillian Smith, Susanne Ostrowitzki
Safety, Tolerability, and Pharmacokinetics of Crenezumab in Patients with Mild-To-Moderate Alzheimer’s Disease Treated with Escalating Doses for up to 133 Weeks
Abstract: Background: Crenezumab is a fully humanized, monoclonal anti-amyloid-β immunoglobulin G4 antibody. Objective: This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of crenezumab at doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated. Methods: In this multicenter, double-blind study, participants (aged 50–90 years) with mild-to-moderate Alzheimer’s disease (AD) and amyloid-positive PET scan were randomized to receive crenezumab 30 or 45 mg/kg (Cohort 1, n=21), 60 mg/kg (Cohort 2, n=21), or 120 mg/kg (Cohort 3, n=19) or corresponding placebo (n=14) intravenously q4w for 13 weeks. Seventy-one participants were subsequently enrolled in an optional open-label extension (OLE) and received crenezumab at the originally assigned dose level, except for Cohort 3 (crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported. Results: Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-microhemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations of crenezumab were dose proportional and maintained for each dose level. Conclusion: Crenezumab doses of ≤120 mg/kg intravenously q4w were well tolerated. The observed safety profile for ≤133 weeks of treatment in a mild-to-moderate AD population was similar to that seen in previous trials.

Xinkun Wan, Bin Ma, Xiaoxuan Wang, Chenjia Guo, Jing Sun, Jing Cui, Liang Li
S-Adenosylmethionine Alleviates Amyloid-β-Induced Neural Injury by Enhancing Trans-Sulfuration Pathway Activity in Astrocytes
Abstract: Background: Glutathione (GSH) is an important endogenous antioxidant protecting cells from oxidative injury. Cysteine (Cys), the substrate limiting the production of GSH, is mainly generated from the trans-sulfuration pathway. S-adenosylmethionine (SAM) is a critical molecule produced in the methionine cycle and can be utilized by the trans-sulfuration pathway. Reductions in GSH and SAM as well as dysfunction in the trans-sulfuration pathway have been documented in the brains of Alzheimer’s disease (AD) patients. Our previous in vivo study revealed that SAM administration attenuated oxidative stress induced by amyloid-β (Aβ) through the enhancement of GSH. Objective: To investigate the effect of Aβ-induced oxidative stress on the trans-sulfuration pathway in astrocytes and neurons, respectively, and the protective effect of SAM on neurons. Methods: APP/PS1 transgenic mice and the primary cultured astrocytes, neurons, and HT22 cells were used in the current study. Results: SAM could rescue the low trans-sulfuration pathway activity induced by Aβ only in astrocytes, accompanying with increasing levels of Cys and GSH. The decrease of cellular viability of neurons caused by Aβ was greatly reversed when co-cultured with astrocytes with SAM intervention. Meanwhile, SAM improved cognitive performance in APP/ PS1 mice. Conclusion: In terms of astrocyte protection from oxidative stress, SAM might be a potent antioxidant in the therapy of AD patients.

Masataka Narukawa, Suzuka Takahashi, Takashi Saito, Takaomi C. Saido, Takumi Misaka
Analysis of Taste Sensitivities in App Knock‑In Mouse Model of Alzheimer’s Disease
Abstract: Background: Some studies have reported a decline in taste sensitivities in patients with Alzheimer’s disease. However, the detail remains unknown. Objective: We investigated the effect of cognitive impairment on taste sensitivity using an App knock‑in mouse model of Alzheimer’s disease. Methods: Behavioral assays, a brief access test, and a 48-h two-bottle preference test, to assess taste sensitivities were started from 12 months of age in mice that were confirmed to have impaired cognition. Results: In the assays, there was no significant difference in taste sensitivities between wild type and App knock-in mice. Additionally, no apparent difference was observed in the expression of taste markers in their taste bud cells. Conclusion: We concluded that cognitive impairment might not greatly affect taste sensitivity.

Manuel Fuentes, Arne Klostermann, Luca Kleineidam, Chris Bauer, Johannes Schuchhardt, Wolfgang Maier, Frank Jessen, Lutz Frölich, Jens Wiltfang, Johannes Kornhuber, Stefan Klöppel, Vera Schieting, Stefan J. Teipel, Michael Wagner, Oliver Peters
Identification of a Cascade of Changes in Activities of Daily Living Preceding Short-Term Clinical Deterioration in Mild Alzheimer’s Disease via Lead-Lag Analysis
Abstract: Background: Cognitive functions and activities of daily living (ADL) become increasingly impaired with progressing Alzheimer’s disease. However, the temporal dynamics of this decline are inconsistent. Objective: To gain insight into the classical temporal cascade of specific cognitive and ADL changes, which may aid in improving detection of an impending clinical deterioration in patients, and to select ADL items and tests most sensitive to change in a specific disease stage. Methods: Patients with mild Alzheimer’s dementia (AD; MMSE = 23.9 ± 2.88) were followed at 12 and 24 months. Lead-lag analysis of changes in cognitive and functional outcome measures (CDR-SOB, 12 neuropsychological subtest scores from the CERAD+ test battery, 25 Bayer-ADL items) was applied to rank the temporal sequence of changes on an ordinal scale. Results: Of 164 patients with mild AD, moderate disease progression was identified in 84 patients over 24 months (ΔMMSE 5.8 ± 8.64; ΔCDR-SOB 4.32 ± 4.03). Ten Bayer-ADL item measures were altered early in moderate progressors and included in a new ADL composite score. Accordingly, the new ADL score surpassed all neuropsychological measures in repeated lead-lag analysis. The Bayer-ADL total score, TMT-A, and MMSE were lagging variables in all lead-lag analyses. Conclusion: Short-term clinical deterioration in mild AD is initially preceded by changes (i.e., decline) in a well-defined set of ADL and not in classical cognitive measures.

James P. Naude, Sascha Gill, Sophie Hu, Alexander McGirr, Nils D. Forkert, Oury Monchi, Peter K. Stys, Eric E. Smith, Zahinoor Ismail, for the Alzheimer’s Disease Neuroimaging Initiative
Plasma Neurofilament Light: A Marker of Neurodegeneration in Mild Behavioral Impairment
Abstract: Background: Assessing neuropsychiatric symptoms (NPS) in older adults is important for determining dementia risk. Mild behavioral impairment (MBI) is an at-risk state for cognitive decline and dementia, characterized by emergent NPS in later life. MBI has significantly higher dementia incidence than late life psychiatric conditions. However, its utility as a proxy for neurodegeneration has not been demonstrated. Plasma neurofilament light (NfL) is a validated biomarker of axonal damage, and has been shown to associate with hallmarks of neurodegeneration. Objective: The purpose of this investigation was to identify associations between NfL rate of change and the presence of MBI symptomatology. Methods: We evaluated the association of MBI with changes in NfL in a cohort (n=584; MBI+ n=190, MBI- n=394) of non-demented participants from the Alzheimer’s Disease Neuroimaging Initiative. MBI was determined by transforming neuropsychiatric questionnaire items using a published algorithm. Change in NfL was calculated over 2 years. Results: Time*MBI status was the only significant interaction to predict change in NfL concentrations (F(1,574)=4.59, p=0.032), even after controlling for age, mild cognitive impairment, and demographics. Analyses reclassifying 64 participants with new onset MBI over 2 years similarly demonstrated greater increases in NfL (F(1,574)=5.82, p=0.016). Conclusion: These findings suggest MBI is a clinical proxy of early phase neurodegeneration with putative utility in identifying those at dementia risk. MBI can be used as a case ascertainment approach to capture those at high risk for cognitive decline and dementia, and is an important construct for clinicians dealing with cognitive and neuropsychiatric symptomatology in older adults.

Kentaro Hayashi, Tina K. Gonzales, Amita Kapoor, Toni E. Ziegler, Sivan Vadakkadath Meethal, Craig S. Atwood
Development of Classification Models for the Prediction of Alzheimer’s Disease Utilizing Circulating Sex Hormone Ratios
Abstract: Background: While sex hormones are essential for normal cognitive health, those individuals with greater endocrine dyscrasia around menopause and with andropause are more likely to develop cognitive loss and Alzheimer’s disease (AD). Objective: To assess whether circulating sex hormones may provide an etiologically significant, surrogate biomarker, for cognitive decline. Methods: Plasma (n=152) and serum (n=107) samples from age- and gender-matched AD and control subjects from the Wisconsin Alzheimer’s Disease Research Center (ADRC) were analyzed for 11 steroids and follicle-stimulating hormone. Logistic regression (LR), correlation analyses, and recursive partitioning (RP) were used to examine the interactions of hormones and hormone ratios and their association with AD. Models generated were then tested on an additional 43 ADRC samples. Results: The wide variation and substantial overlap in the concentrations of all circulating sex steroids across control and AD groups precluded their use for predicting AD. Classification tree analyses (RP) revealed interactions among single hormones and hormone ratios that associated with AD status, the most predictive including only the hormone ratios identified by LR. The strongest associations were observed between cortisol, cortisone, and androstenedione with AD, with contributions from progesterone and 17β-estradiol. Utilizing this model, we correctly predicted 81% of AD test cases and 64% of control test cases. Conclusion: We have developed a diagnostic model for AD, the Wisconsin Hormone Algorithm Test for Cognition (WHAT-Cog), that utilizes classification tree analyses of hormone ratios. Further refinement of this technology could provide a quick and cheap diagnostic method for screening those with AD.

Anthony J. Griswold*, Sathesh K. Sivasankaran*, Derek Van Booven, Olivia K. Gardner, Farid Rajabli, Patrice L. Whitehead, Kara L. Hamilton-Nelson, Larry D. Adams, Aja M. Scott, Natalia K. Hofmann, Jeffery M. Vance, Michael L. Cuccaro, William S. Bush, Eden R. Martin, Goldie S. Byrd, Jonathan L. Haines, Margaret A. Pericak-Vance, Gary W. Beecham *These authors contributed equally to this work.
Immune and Inflammatory Pathways Implicated by Whole Blood Transcriptomic Analysis in a Diverse Ancestry Alzheimer’s Disease Cohort
Abstract: Background: Significant work has identified genetic variants conferring risk and protection for Alzheimer’s disease (AD), but functional effects of these variants is lacking, particularly in under-represented ancestral populations. Expression studies performed in easily accessible tissue, such as whole blood, can recapitulate some transcriptional changes occurring in brain and help to identify mechanisms underlying neurodegenerative processes. Objective: We aimed to identify transcriptional differences between AD cases and controls in a cohort of diverse ancestry. Methods: We analyzed the protein coding transcriptome using RNA sequencing from peripheral blood collected from 234 African American (AA) (115 AD, 119 controls) and 240 non-Hispanic Whites (NHW) (121 AD, 119 controls). To identify case-control differentially expressed genes and pathways, we performed stratified, joint, and interaction analyses using linear regression models within and across ancestral groups followed by pathway and gene set enrichment analyses. Results: Overall, we identified 418 (291 upregulated, 127 downregulated) and 488 genes (352 upregulated, 136 downregulated) differentially expressed in the AA and NHW datasets, respectively, with only 16 genes commonly differentially expressed in both ancestral groups. Joint analyses provided greater power to detect case-control differences and identified 1,102 differentially expressed genes between cases and controls (812 upregulated, 290 downregulated). Interaction analysis identified only 27 genes with different effects in AA compared to NHW. Pathway and gene-set enrichment analyses revealed differences in immune response-related pathways that were enriched across the analyses despite different underlying gene sets. Conclusion: These results support the hypothesis of converging underlying pathophysiological processes in AD across ancestral groups.

Marijn Muurling, Hanneke F.M. Rhodius-Meester, Juha Pärkkä, Mark van Gils, Kristian S. Frederiksen, Marie Bruun, Steen G. Hasselbalch, Hilkka Soininen, Sanna-Kaisa Herukka, Merja Hallikainen, Charlotte E. Teunissen, Pieter Jelle Visser, Philip Scheltens, Wiesje M. van der Flier, Jussi Mattila, Jyrki Lötjönen, Casper de Boer
Gait Disturbances Are Associated with Increased Cognitive Impairment and Cerebrospinal Fluid Tau Levels in a Memory Clinic Cohort
Abstract: Background: Gait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer’s disease and other dementias. It is not clear, however, which gait features are most informative and how these measures relate to Alzheimer’s disease pathology. Objective: In this study, we tested if calculated features of gait 1) differ between cognitively normal subjects (CN), mild cognitive impairment (MCI) patients, and dementia patients, 2) are correlated with cerebrospinal fluid (CSF) biomarkers related to Alzheimer’s disease, and 3) predict cognitive decline. Methods: Gait was measured using tri-axial accelerometers attached to the fifth lumbar vertebra (L5) in 58 CN, 58 MCI, and 26 dementia participants, while performing a walk and dual task. Ten gait features were calculated from the vertical L5 accelerations, following principal component analysis clustered in four domains, namely pace, rhythm, time variability, and length variability. Cognitive decline over time was measured using MMSE, and CSF biomarkers were available in a sub-group. Results: Linear mixed models showed that dementia patients had lower pace scores than MCI patients and CN subjects (p<0.05). In addition, we found associations between the rhythm domain and CSF-tau, especially in the dual task. Gait was not associated with CSF Aβ42 levels and cognitive decline over time as measured with the MMSE. Conclusion: These findings suggest that gait—particularly measures related to pace and rhythm—are altered in dementia and have a direct link with measures of neurodegeneration.

Yingxia Liang*, Frank Raven*, Joseph F. Ward, Sherri Zhen, Siyi Zhang, Haoqi Sun, Sean J. Miller, Se Hoon Choi, Rudolph E. Tanzi, Can Zhang (Handling Associate Editor: Jin-Tai Yu) *These authors contributed equally to this work.
Upregulation of Alzheimer’s Disease Amyloid-β Protein Precursor in Astrocytes both in vitro and in vivo
Abstract: Background: The amyloid cascade hypothesis of Alzheimer’s disease (AD) posits that amyloid-β (Aβ) protein accumulation underlies the pathogenesis of the disease by leading to the formation of amyloid plaques, a pathologic hallmark of AD. Aβ is a proteolytic product of amyloid-β protein precursor (AβPP; APP), which is expressed in both neurons and astrocytes. Although considerable evidence shows that astrocytes may play critical roles in the pathogenesis of AD, the longitudinal changes of amyloid plaques in relationship to AβPP expression in astrocytes and cellular consequences are largely unknown. Objective: Here, we aimed to investigate astrocyte-related pathological changes of Aβ and AβPP using immunohistochemistry and biochemical studies in both animal and cell models. Methods/Results: We utilized 5XFAD transgenic mice and found age-dependent upregulation of AβPP in astrocytes demonstrated with astrocytic reactive properties, which followed appearance of amyloid plaques in the brain. We also observed that AβPP proteins presented well-defined punctate immunoreactivity in young animals, whereas AβPP staining showed disrupted structures surrounding amyloid plaques in older mice. Moreover, we utilized astrocyte cell models and showed that pretreatment of Aβ42 resulted in downstream astrocyte autonomous changes, including upregulation in AβPP and BACE1 levels, as well as prolonged amyloidogenesis that could be reduced by pharmacological inhibition of BACE1. Conclusion: Collectively, our results show that age-dependent AβPP upregulation in astrocytes is a key feature in AD, which will not only provide novel insights for understanding AD progression, but also may offer new therapeutic strategies for treating AD.

Harpreet Kaur, Svetlana Golovko, Mikhail Y. Golovko, Surjeet Singh, Diane C. Darland, Colin K. Combs
Effects of Probiotic Supplementation on Short Chain Fatty Acids in the App NL-G-F Mouse Model of Alzheimer’s Disease
Abstract: Background: The intestinal microbiota and its metabolites, particularly short-chain fatty acids (SCFAs), have been implicated in immune function, host metabolism, and even behavior. Objective: This study was performed to investigate whether probiotic administration influences levels of intestinal microbiota and their metabolites in a fashion that may attenuate brain changes in a mouse model of Alzheimer’s disease (AD). Methods: C57BL/6 wild-type (WT) mice were compared to AppNL-G-Fmice. The animals were treated with either vehicle or probiotic (VSL#3) for 8 weeks. Fecal microbiome analysis along with Aβ, GFAP, Iba-1, c-Fos, and Ki-67 immunohistochemistry was done. SCFAs were analyzed in serum and brains using UPLC-MS/MS. Results: Probiotic (VSL#3) supplementation for 2 months resulted in altered microbiota in both WT and AppNL-G-F mice. An increase in serum SCFAs acetate, butyrate, and lactate were found in both genotypes following VSL#3 treatment. Propionate and isobutyrate were only increased in AppNL-G-F mice. Surprisingly, VSL#3 only increased lactate and acetate in brains of AppNL-G-F mice. No significant differences were observed between vehicle and VSL#3 fed AppNL-G-F hippocampal immunoreactivities of Aβ, GFAP, Iba-1, and Ki-67. However, hippocampal c-Fos staining increased in VSL#3 fed AppNL-G-F mice. Conclusion: These data demonstrate intestinal dysbiosis in the AppNL-G-F mouse model of AD. Probiotic VSL#3 feeding altered both serum and brain levels of lactate and acetate in AppNL-G-F mice correlating with increased expression of the neuronal activity marker, c-Fos.

Wenna Duan, Parshant Sehrawat, Arvind Balachandrasekaran, Ashish B. Bhumkar, Paresh B. Boraste, James T. Becker, Lewis H. Kuller, Oscar L. Lopez, H. Michael Gach, Weiying Dai
Cerebral Blood Flow Is Associated with Diagnostic Class and Cognitive Decline in Alzheimer’s Disease
Abstract: Background: Reliable cerebral blood flow (CBF) biomarkers using a noninvasive imaging technique are sought to facilitate early diagnosis and intervention in early Alzheimer’s disease (AD). Objective: We aim to identify brain regions in which CBF values are affected and related to cognitive decline in early AD using a large cohort. Methods: Perfusion MRIs using continuous arterial spin labeling were acquired at 1.5 T in 58 normal controls (NC), 50 mild cognitive impairments (MCI), and 40 AD subjects from the Cardiovascular Health Study cognition study. Regional absolute CBF and normalized CBF (nCBF) values, without and with correction of partial volume effects, were compared across three groups. Association between regional CBF values and Modified Mini-Mental State Examination (3MSE) were investigated by multiple linear regression analyses adjusted for cardiovascular risk factors. Results: After correcting for partial volume effects and cardiovascular risk factors, ADs exhibited decreased nCBF with the strongest reduction in the bilateral posterior cingulate & precuneus region (p < 0.001) compared to NCs, and the strongest reduction in the bilateral superior medial frontal region (p < 0.001) compared to MCIs. MCIs exhibited the strongest nCBF decrease in the left hippocampus and nCBF increase in the right inferior frontal and insular region. The 3MSE scores within the symptomatic subjects were significantly associated with nCBF in the bilateral posterior and middle cingulate & parietal (p < 0.001), bilateral superior medial frontal (p < 0.001), bilateral temporoparietal (p < 0.02), and right hippocampus (p = 0.02) regions. Conclusion: Noninvasive perfusion MRI can detect functional changes across diagnostic class and serve as staging biomarker of cognitive status.

Maria Chatzistavraki, Panagiota Papazafiri, Spiros Efthimiopoulos
Amyloid-β Protein Precursor Regulates Depolarization-Induced Calcium-Mediated Synaptic Signaling in Brain Slices
Abstract: Background: Coordinated calcium influx upon neuronal depolarization activates pathways that phosphorylate CaMKII, ERKs, and the transcription factor CREB and, therefore, expression of pro-survival and neuroprotective genes. Recent evidence indicates that amyloid-β protein precursor (AβPP) is trafficked to synapses and promotes their formation. At the synapse, AβPP interacts with synaptic proteins involved in vesicle exocytosis and affects calcium channel function. Objective: Herein, we examined the role of AβPP in depolarization-induced calcium-mediated signaling using acute cerebral slices from wild-type C57bl/6 mice and AβPP-/- C57bl/6 mice. Methods: Depolarization of acute cerebral slices from wild-type C57bl/6 and AβPP-/- C57bl/6 mice was used to induce synaptic signaling. Protein levels were examined by western blot and calcium dynamics were assessed using primary neuronal cultures. Results: In the absence of AβPP, decreased pCaMKII and pERKs levels were observed. This decrease was sensitive to the inhibition of N- and P/Q-type Voltage Gated Calcium Channels (N- and P/Q-VGCCs) by ω-conotoxin GVIA and ω-conotoxin MVIIC, respectively, but not to inhibition of L-type VGCCs by nifedipine. However, the absence of AβPP did not result in a statistically significant decrease of pCREB, which is a known substrate of pERKs. Finally, using calcium imaging, we found that downregulation of AβPP in cortical neurons results in a decreased response to depolarization and altered kinetics of calcium response. Conclusion: AβPP regulates synaptic activity-mediated neuronal signaling by affecting N- and P/Q-VGCCs.

Umma Habiba, Sam Merlin, Jeremiah K.H. Lim, Vickie H.Y. Wong, Christine T.O. Nguyen, John W. Morley, Bang V. Bui, Mourad Tayebi
Age-Specific Retinal and Cerebral Immunodetection of Amyloid-β Plaques and Oligomers in a Rodent Model of Alzheimer’s Disease
Abstract: Background: Amyloid-β soluble oligomers (Aβo) are believed to be the cause of the pathophysiology underlying Alzheimer’s disease (AD) and are normally detected some two decades before clinical onset of the disease. Retinal pathology associated with AD pathogenesis has previously been reported, including ganglion cell loss, accumulation of Aβ deposits in the retina, and reduction of nerve fiber layer thickness as well as abnormalities of the microvasculature. Objective: This study’s aim is to better understand the relationship between brain and retinal Aβo deposition and in particular to quantify levels of the toxic Aβo as a function of age in the retina of a rodent model of AD. Methods: Retinas and brain tissue from 5xFAD mice were stained with Congo red, Thioflavin-T (Th-T), and Aβ plaque-specific and Aβo-specific antibodies. Results: We show that retinas displayed an age-dependent increase of Th-T-specific amyloid fibrils. Staining with anti-Aβ antibody confirmed the presence of the Aβ plaques in all 5xFAD retinas tested. In contrast, staining with anti-Aβo antibody showed an age-dependent decrease of retinal Aβo. Of note, Aβo was observed mainly in the retinal nuclear layers. Finally, we confirmed the localization of Aβo to neurons, typically accumulating in late endosomes, indicating possible impairment of the endocytic pathway. Conclusion: Our results demonstrate the presence of intraneuronal Aβo in the retina and its accumulation inversely correlated with retinal Aβ plaque deposition, indicating an age-related conversion in this animal model. These results support the development of an early AD diagnostic test targeting Aβo in the eye.

Marie Charmaine C. Sy*, Adrian I. Espiritu*, Matthew Samuel C. Sy, Roland Dominic G. Jamora**, Veeda Michelle M. Anlacan** *These authors contributed equally to this work. **Joint senior authors
Dementia Research Productivity and Associations with Socioeconomic Factors and Burden of Disease in Southeast Asia
Abstract: Background: Scientific output in the Southeast Asia (SEA) on the topic of dementia is postulated to be low in quality and quantity. It is also speculated that certain socioeconomic variables and measures of disease burden for dementia may play a significant role in driving the research output of a particular country. Objective: This study aimed to determine the research impact of published journal articles on dementia in SEA and its association with country-level socioeconomic factors and measures of disease burden for dementia. Methods: A systematic search was conducted using electronic healthcare databases. We included articles published on dementia until August 2019 with at least 1 author affiliated with any SEA institution. We obtained bibliometric indices, relevant socioeconomic factors, and measures of disease burden for dementia from published sources. Results: One thousand six articles fulfilled the inclusion criteria. The majority of publications were related to Alzheimer’s disease (n=775, 77.0%). Singapore contributed the highest number of publications (n=457, 45.4%). Gross domestic product (GDP) per capita, % GDP for research and development, and total neurologists significantly correlated with several bibliometric indices. On the other hand, the measures of disease burden for dementia in SEA countries were not significantly associated with research productivity. Conclusion: Research productivity in SEA on dementia has substantially increased in recent years. Augmenting GDP per capita and expanding the apportionment of resources to R&D may have a significant role in the advancement of dementia research in SEA.

Leonie J.M. Vergouw*, Hanneke Geut*, Guido Breedveld, Demy J.S. Kuipers, Marialuisa Quadri, Netherlands Brain Bank, Annemieke J.M. Rozemuller, John C. van Swieten, Frank Jan de Jong, Wilma D.J. van de Berg**, Vincenzo Bonifati** *These authors contributed equally to this work. **Joint senior authorship
Clinical and Pathological Phenotypes of LRP10 Variant Carriers with Dementia
Abstract: Background: Rare variants in the low-density lipoprotein receptor related protein 10 gene (LRP10) have recently been implicated in the etiology of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Objective: We searched for LRP10 variants in a new series of brain donors with dementia and Lewy pathology (LP) at autopsy, or dementia and parkinsonism without LP but with various other neurodegenerative pathologies. Methods: Sanger sequencing of LRP10 was performed in 233 donors collected by the Netherlands Brain Bank. Results: Rare, possibly pathogenic heterozygous LRP10 variants were present in three patients: p.Gly453Ser in a patient with mixed Alzheimer’s disease (AD)/Lewy body disease (LBD), p.Arg151Cys in a DLB patient, and p.Gly326Asp in an AD patient without LP. All three patients had a positive family history for dementia or PD. Conclusion: Rare LRP10 variants are present in some patients with dementia and different brain pathologies including DLB, mixed AD/LBD, and AD. These findings suggest a role for LRP10 across a broad neurodegenerative spectrum.

Giulia Maria Sancesario, Giulia Di Lazzaro, Mohammad Alwardat, Benedetta Biticchi, Valerio Basile, Chiara Salimei, Vito Luigi Colona, Paola Sinibaldi Salimei, Sergio Bernardini, Nicola Biagio Mercuri, Antonio Pisani, Tommaso Schirinzi (Handling Associate Editor: Marco Canevelli)
Amyloid-β42/Neurogranin Ratio as a Potential Index for Cognitive Impairment in Parkinson’s Disease
Abstract: Background: Synaptopathy is critical in pathophysiology of Parkinson’s disease (PD). Cerebrospinal fluid (CSF) levels of neurogranin (NG) and amyloid-β42 (Aβ42) are considered markers of synaptic dysfunction in neurodegenerative diseases. Objective: To evaluate the CSF synaptopathy-related biomarkers, especially the novel Aβ42/NG ratio, in PD, establishing possible associations with cognitive level and other clinical parameters. Methods: Levels of NG, Aβ42, amyloid-β40, total and phosphorylated tau, and Aβ42/NG ratio were measured in 30 PD patients and 30 controls and correlated with cognitive and motor parameters. The accuracy in distinguishing the cognitive status was determined. Results: NG and Aβ42 were significantly reduced in PD, with higher NG levels in patients with worse cognition. The Aβ42/NG ratio showed a direct correlation with Mini-Mental State Examination, independently from age and sex, and differentiated cognitively impaired patients with 92% sensitivity and 71.4% specificity, accuracy higher than NG alone. No correlations resulted with motor disturbances or therapy. Conclusions: The novel Aβ42/NG ratio couples either presynaptic or postsynaptic markers of synaptic dysfunction, representing a potential global index of synaptopathy, useful to track cognitive functions in PD.