Volume 78, Number 1, IN PRESS

Obituary
Julie A. Schneider, Neelum T. Aggarwal
A Tribute to Martha Clare Morris, ScD: A Zest for Life and a Passion for Science

Commentary
Kaarin J. Anstey, Ruth Peters, Lidan Zheng, Deborah E. Barnes, Carol Brayne, Henry Brodaty, John Chalmers, Linda Clare, Roger A. Dixon, Hiroko Dodge, Nicola T. Lautenschlager, Laura Middleton, Chengxuan Qiu, Glenn Rees, Suzana Shahar, Kristine Yaffe
Future Directions for Dementia Risk Reduction and Prevention Research: An International Research Network on Dementia Prevention Consensus
Abstract:In the past decade a large body of evidence has accumulated on risk factors for dementia, primarily from Europe and North America. Drawing on recent integrative reviews and a consensus workshop, the International Research Network on Dementia Prevention developed a consensus statement on priorities for future research. Significant gaps in geographical location, representativeness, diversity, duration, mechanisms, and research on combinations of risk factors were identified. Future research to inform dementia risk reduction should fill gaps in the evidence base, take a life-course, multi-domain approach, and inform population health approaches that improve the brain-health of whole communities.

Review
Anna M. Pietroboni, Annalisa Colombi, Tiziana Carandini, Elio Scarpini, Daniela Galimberti, Marco Bozzali
The Role of Amyloid-β in White Matter Damage: Possible Common Pathogenetic Mechanisms in Neurodegenerative and Demyelinating Diseases
Abstract: Just as multiple sclerosis (MS) has long been primarily considered a white matter (WM) disease, Alzheimer’s disease (AD) has for decades been regarded only as a grey matter disorder. However, convergent evidences have suggested that WM abnormalities are also important components of AD, at the same extent as axonal and neuronal loss is critically involved in MS pathophysiology since early clinical stages. These observations have motivated a more thorough investigation about the possible mechanisms that could link neuroinflammation and neurodegeneration, focusing on amyloid-β (Aβ). Neuroimaging studies have found that patients with AD have widespread WM abnormalities already at the earliest disease stages and prior to the presence of Aβ plaques. Moreover, a correlation between cerebrospinal fluid (CSF) Aβ levels and WM lesion load was found. On the other hand, recent studies suggest a predictive role for CSF Aβ levels in MS, possibly due in the first instance to the reduced capacity for remyelination, consequently to a higher risk of WM damage progression, and ultimately to neuronal loss. We undertook a review of the recent findings concerning the involvement of CSF Aβ levels in the MS disease course and of the latest evidence of AD related WM abnormalities, with the aim to discuss the potential causes that may connect WM damage and amyloid pathology.

Anna E. Blanken, Daniel A. Nation
Does Gender Influence the Relationship Between High Blood Pressure and Dementia? Highlighting Areas for Further Investigation
Abstract: Background: Gender differences have been noted in studies linking blood pressure to all-cause dementia, and the two most common forms of dementia: Alzheimer’s disease (AD) and vascular dementia (VaD). However, how gender modifies the relationship between blood pressure and dementia remains unclear. Objective: To review evidence for a gender modifying effect on the link between blood pressure and all-cause dementia. Methods: A systematic review was conducted according to PRISMA guidelines. Sixteen out of 256 reviewed articles met inclusion criteria. Results: For women, higher midlife systolic blood pressure (SBP) and hypertension were both associated with greater risk of all-cause dementia, AD, and VaD, in six out of seven studies. Two of these studies reported higher midlife SBP/hypertension were associated with greater risk for all-cause dementia in women, but not men. One study reported higher midlife SBP associated with greater AD risk in women, but not men. However, another study reported that midlife hypertension associated with AD risk in men, but not women. No clear gender differences were reported in the relationship between late-life high blood pressure/hypertension with all-cause dementia or AD. Conclusion: Studies rarely, and inconsistently, analyzed or reported gender effects. Therefore, interpretation of available evidence regarding the role of gender in blood pressure associated dementia was difficult. Several studies indicated higher midlife SBP was associated with greater risk of all-cause dementia for women, compared to men. Future studies should evaluate women-specific aging processes that occur in midlife when considering the association between blood pressure and dementia risk.

Christopher J. Harris, Nora E. Gray, Maya Caruso, Marguex Hunter, Martina Ralle, Joseph F. Quinn
Copper Modulation and Memory Impairment due to Hippocampal Tau Pathology
Abstract: Background: Environmental copper has been implicated in the pathogenesis of Alzheimer’s disease based on evidence that: 1) brain copper levels increase with age, 2) copper promotes misfolding and toxicity of amyloid-β in vitro, 3) copper-modulating interventions reduce amyloid pathology in animal models. However, the effect of copper upon non-amyloid Alzheimer’s pathology is relatively under-explored. Objective: To determine if modulation of brain copper level affects brain tau pathology and/or associated cognitive impairment. Methods: We tested the hypothesis that brain copper modulates tau pathology by manipulating brain levels of copper in the PS19 transgenic mouse model of tau pathology. We treated PS19 and wild-type mice with oral zinc acetate, an established therapy for long term control of excess brain copper, and examined treatment effects upon brain copper, brain tau, NFT-like pathology, and spatial memory. We treated a second cohort of mice with exogenous dietary copper in order to evaluate whether excess environmental copper promotes brain tau pathology. Results: Copper-lowering with oral zinc attenuated spatial memory impairment in female but not male PS19 mice, without a significant effect upon tau pathology. Copper loading increased brain copper, but did not have an effect on brain tau pathology or spatial memory function. Conclusion: These findings suggest that a strategy to lower brain copper may be viable for symptomatic benefit in the setting of tau neuropathology, but unlikely to have robust effects on the underlying pathology. These findings are consistent with dietary or other exogenous copper being unlikely to promote tau pathology.

Yebo Gu, Zhou Wu, Fan Zeng, Muzhou Jiang, Jessica L. Teeling, Junjun Ni, Ichiro Takahashi
Systemic Exposure to Lipopolysaccharide from Porphyromonas gingivalis Induces Bone Loss-Correlated Alzheimer’s Disease-Like Pathologies in Middle-Aged Mice
Abstract: Background: Alzheimer’s disease (AD) and bone loss are clinically exacerbated. However, the mechanism of exacerbation remains understood. Objective: We tested our hypothesis that periodontitis is involved in the exacerbation, contributing to AD pathologies. Methods: The bone, memory, and inflammation in bone and brain were examined in 12-month-old mice after systemic exposure to lipopolysaccharide from Porphyromonas gingivalis (PgLPS) for 3 consecutive weeks. Results: Compared with control mice, bone loss in tibia (26% decrease) and memory decline (47% decrease) were induced in mice with a positive correlation after exposure to PgLPS (r=0.7378, p=0.0011). The IL-6 and IL-17 expression in tibia was negatively correlated with the bone volume/total tissue volume (r=-0.6619, p=0.0052; r=-0.7129, p=0.0019), while that in the cortex was negatively correlated with the memory test latency (r=-0.7198, p=0.0017; p=0.0351, r=-0.5291). Furthermore, the IL-17 expression in microglia was positively correlated with Aβ42 accumulation in neurons (r=0.8635, p<0.0001). In cultured MG6 microglia, the PgLPS-increased IL-6 expression was inhibited by a PI3K-specific inhibitor (68% decrease), and that of IL-17 was inhibited by IL-6 antibody (41% decrease). In cultured N2a neurons, conditioned medium from PgLPS-stimulated microglia (MCM) but not PgLPS increased the productions of AβPP, CatB, and Aβ42, which were significantly inhibited by pre-treatment with IL-17 antibody (67%, 51%, and 41% decrease). Conclusion: These findings demonstrated that chronic systemic exposure to PgLPS simultaneously induces inflammation-dependent bone loss and AD-like pathologies by elevating IL-6 and IL-17 from middle age, suggesting that periodontal bacteria induce exacerbation of bone loss and memory decline, resulting in AD progression.

Ruth Stephen, Alina Solomon, Tiia Ngandu, Esko Levälahti, Juha O. Rinne, Nina Kemppainen, Riitta Parkkola, Riitta Antikainen, Timo Strandberg, Miia Kivipelto, Hilkka Soininen, Yawu Liu for the FINGER study group
White Matter Changes on Diffusion Tensor Imaging in the FINGER Randomized Controlled Trial
Abstract: Background: Early pathological changes in white matter microstructure can be studied using the diffusion tensor imaging (DTI). It is not only important to study these subtle pathological changes leading to cognitive decline, but also to ascertain and how an intervention would impact the white matter microstructure and cognition in persons at-risk of dementia. Objectives: To study the impact of a multidomain lifestyle intervention on white matter and cognitive changes during the 2-year Finnish Geriatric Intervention Study to prevent Cognitive Impairment and Disability (FINGER), a randomized controlled trial in at-risk older individuals (age 60-77 years) from the general population. Methods: This exploratory study consisted of a subsample of 60 FINGER participants. Participants were randomized to either a multidomain intervention (diet, exercise, cognitive training, and vascular risk management, n=34) or control group (general health advice, n=26). All underwent baseline and 2-year brain DTI. Changes in fractional anisotropy (FA), diffusivity along domain (F1) and non-domain (F2) diffusion orientations, mean diffusivity (MD), axial diffusivity (AxD), radial diffusivity (RD), and their correlations with cognitive changes during the 2-year multidomain intervention were analyzed. Results: FA decreased, and cognition improved more in the intervention group compared to the control group (p<0.05), with no significant intergroup differences for changes in F1, F2, MD, AxD, or RD. The cognitive changes were significantly positively related to FA change, and negatively related to RD change in the control group, but not in the intervention group. Conclusion: The 2-year multidomain FINGER intervention may modulate white matter microstructural alterations.

Reagon Karki, Sumit Madan, Yojana Gadiya, Daniel Domingo-Fernández, Alpha Tom Kodamullil, Martin Hofmann-Apitius
Data-Driven Modeling of Knowledge Assemblies in Understanding Comorbidity Between Type 2 Diabetes Mellitus and Alzheimer’s Disease
Abstract: Background: Recent studies have suggested comorbid association between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) through identification of shared molecular mechanisms. However, the inference is pre-dominantly literature-based and lacks interpretation of pre-disposed genomic variants and transcriptomic measurables. Objective: In this study, we aim to identify shared genetic variants and dysregulated genes in AD and T2DM and explore their functional roles in the comorbidity between the diseases. Methods: The genetic variants for AD and T2DM were retrieved from GWAS catalog, GWAS central, dbSNP, and DisGeNet and subjected to linkage disequilibrium analysis. Next, shared variants were prioritized using RegulomeDB and Polyphen-2. Afterwards, a knowledge assembly embedding prioritized variants and their corresponding genes was created by mining relevant literature using Biological Expression Language. Finally, coherently perturbed genes from gene expression meta-analysis were mapped to the knowledge assembly to pinpoint biological entities and processes and depict a mechanistic link between AD and T2DM. Results: Our analysis identified four genes (i.e., ABCG1, COMT, MMP9, and SOD2) that could have dual roles in both AD and T2DM. Using cartoon representation, we have illustrated a set of causal events surrounding these genes which are associated to biological processes such as oxidative stress, insulin resistance, apoptosis and cognition. Conclusion: Our approach of using data as the driving force for unraveling disease etiologies eliminates literature bias and enables identification of novel entities that serve as the bridge between comorbid conditions.

Jade de Oliveira, Daiane F. Engel, Gabriela C. de Paula, Danúbia B. dos Santos, Jadna B. Lopes, Marcelo Farina, Eduardo L.G. Moreira, Andreza F. de Bem
High Cholesterol Diet Exacerbates Blood-Brain Barrier Disruption in LDLr-/- Mice: Impact on Cognitive Function
Abstract: Background: Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in low-density lipoprotein receptor knockout mice (LDLr-/-), a mouse model of familial hypercholesterolemia. Objective: Herein we investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6 wild-type and LDLr-/- mice. Methods: Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr-/- mice were submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice’s prefrontal cortices and hippocampi. Results: A tenfold elevation in plasma cholesterol levels of LDLr-/- mice was observed after a hypercholesterolemic diet, while in wild-type mice, the hypercholesterolemic diet exposure increased plasma cholesterol levels only moderately and did not induce cognitive impairment. LDLr-/- mice presented memory impairment regardless of the diet. We observed BBB disruption as an increased permeability to sodium fluorescein in the prefrontal cortices and hippocampi and a decrease on hippocampal claudin-5 and occludin mRNA levels in both wild-type and LDLr-/- mice treated with a hypercholesterolemic diet. The LDLr-/- mice fed with a regular diet already presented BBB dysfunction. The BBB-increased leakage in the hippocampi of LDLr-/- mice was related to high microvessel content and intense astrogliosis, which did not occur in the control mice. Conclusion: Therefore, LDLr-/- mice seem to be more susceptible to cognitive impairments and BBB damage induced by exposure to a high cholesterol diet. Finally, BBB disruption appears to be a relevant event in hypercholesterolemia-induced brain alterations.

Oriol Turró-Garriga, Vanesa Viñas-Díez, Josep Lluís Conde-Sala, Laia Calvó-Perxas, Marta Cullell-Juncà, Glòria Mas-Vall-Llosera, Margarida Flaqué, Antoni Turon-Estrada, Dolors Juvinyà-Canal, Eneida Mioshi, Josep Garre-Olmo
Caregivers’ Sense of Coherence: Implications on Direct and Indirect Costs of Dementia Care
Abstract: Background: Dementia care is associated with physical, emotional, and monetary impact on the informal carers providing unpaid care. Differences in the personal characteristics of caregivers may help explain the variations in the costs of dementia care. Objective: The aim of this study was to analyze the effect of caregivers’ sense of coherence (SOC) on direct and indirect costs in dementia care. Methods: A cross-sectional study was conducted in community dwelling caregivers of patients with Alzheimer’s disease. Data of healthcare services were obtained from clinical registries, and information was collected from caregivers regarding their use of social care resources and time spent caregiving. The transformation of all costs into Euros was made assigning a fixed cost of 10.29 €/h and 16.24 €/h for assisting in instrumental and basic activities of daily living, respectively. Caregivers’ SOC was assessed using the Orientation to Life Questionnaire (OLQ-13). Adjusted regression models were developed, with different types of costs as dependent variables. Results: A sample of 147 caregivers was recruited. The mean OLQ-13 score was 73.3 points (SD = 11.6). The regression models showed a small association between caregivers’ SOC and direct costs, mainly linked to the use of social care resources (r2 = 0.429; β = -15.6 €/month), and a greater association between SOC and indirect costs (r2 = 0.562; β = -222.3 €/month). Conclusion: Increasing caregivers’ SOC could reduce dementia care costs by decreasing the use of social care resources and caregiving time.

Wei Wang, Cuibai Wei, Meina Quan, Tingting Li, Jianping Jia
Sulforaphane Reverses the Amyloid-β Oligomers Induced Depressive-Like Behavior
Abstract: Background: Depression is one of the most common behavioral and psychological symptoms in people with Alzheimer’s disease (AD). To date, however, the molecular mechanisms underlying the clinical association between depression and AD remained elusive. Objective: Here, we study the relationship between memory impairment and depressive-like behavior in AD animal model, and investigate the potential mechanisms. Methods: Male SD rats were administered amyloid-β oligomers (AβOs) by intracerebroventricular injection, and then the depressive-like behavior, neuroinflammation, oxidative stress, and the serotonergic system were measured in the brain. Sulforaphane (SF), a compound with dual capacities of anti-inflammation and anti-oxidative stress, was injected intraperitoneally to evaluate the therapeutic effect. Results: The results showed that AβOs induced both memory impairment and depressive-like behavior in rats, through the mechanisms of inducing neuroinflammation and oxidative stress, and impairing the serotonergic axis. SF could reduce both inflammatory factors and oxidative stress parameters to protect the serotonergic system and alleviate memory impairment and depressive-like behavior in rats. Conclusion: These results provided insights into the biological mechanisms underlying the clinical link between depressive disorder and AD, and offered new drug options for the treatment of depressive symptoms in dementia.

Matthew John Mold, Adam O’Farrell, Benjamin Morris, Christopher Exley
Aluminum and Neurofibrillary Tangle Co-Localization in Familial Alzheimer’s Disease and Related Neurological Disorders
Abstract: Background: Protein misfolding disorders are frequently implicated in neurodegenerative conditions. Familial Alzheimer’s disease (fAD) is an early-onset and aggressive form of Alzheimer’s disease (AD), driven through autosomal dominant mutations in genes encoding the amyloid precursor protein and presenilins 1 and 2. The incidence of epilepsy is higher in AD patients with shared neuropathological hallmarks in both disease states, including the formation of neurofibrillary tangles. Similarly, in Parkinson’s disease, dementia onset is known to follow neurofibrillary tangle deposition. Objective: Human exposure to aluminum has been linked to the etiology of neurodegenerative conditions and recent studies have demonstrated a high level of co-localization between amyloid-β and aluminum in fAD. In contrast, in a donor exposed to high levels of aluminum later developing late-onset epilepsy, aluminum and neurofibrillary tangles were found to deposit independently. Herein, we sought to identify aluminum and neurofibrillary tangles in fAD, Parkinson’s disease, and epilepsy donors. Methods: Aluminum-specific fluorescence microscopy was used to identify aluminum in neurofibrillary tangles in human brain tissue. Results: We observed aluminum and neurofibrillary-like tangles in identical cells in all respective disease states. Co-deposition varied across brain regions, with aluminum and neurofibrillary tangles depositing in different cellular locations of the same cell. Conclusion: Neurofibrillary tangle deposition closely follows cognitive-decline, and in epilepsy, tau phosphorylation associates with increased mossy fiber sprouting and seizure onset. Therefore, the presence of aluminum in these cells may exacerbate the accumulation and misfolding of amyloidogenic proteins including hyperphosphorylated tau in fAD, epilepsy, and Parkinson’s disease.

Yi-Hsuan Liu, Xiang Gao, Muzi Na, Penny M. Kris-Etherton, Diane C. Mitchell, Gordon L. Jensen
Dietary Pattern, Diet Quality, and Dementia: A Systematic Review and Meta-Analysis of Prospective Cohort Studies
Abstract: Background: Diet is an important lifestyle factor that may prevent or slow the onset and progression of neurodegeneration. Some, but not all, recent studies have suggested that adherence to a healthy dietary pattern may be associated with reduced risk of dementia. Objective: In this meta-analysis, we systematically examined the associations between overall dietary patterns, assessed a priori and a posteriori, and risk of dementia. Methods: We systematically searched PubMed, Web of Science, and the Cumulative Index for Nursing and Allied Health databases from January 1, 1981 to September 11, 2019. Prospective studies published in English were included. Random-effects model was used to calculate the pooled risk ratios and 95% confidence intervals (CIs). Results: Sixteen research articles were identified in the systematic review and 12 research articles including 66,930 participants were further included for the meta-analysis. Adherence to high diet quality or a healthy dietary pattern was significantly associated with lower risk of overall dementia (pooled risk ratio=0.82; 95% CI: 0.70, 0.95; n=12) and Alzheimer’s disease (pooled risk ratio=0.61; 95% CI: 0.47, 0.79; n=6) relative to those with low diet quality or an unhealthy dietary pattern. Subgroup analyses stratified by age, sex, follow-up duration, diet quality assessment approach, study location, and study quality generated similar results. Conclusion: Adherence to a healthy dietary pattern was associated with lower risk of overall dementia. Further randomized controlled trials are needed to provide additional evidence about the role of a healthy diet on the development and progression of dementia.

Abolfazl Alipour, Azadeh Mozhdehfarahbakhsh, Saba Nouri, Peyman Petramfar, Mahshid Tahamtan, Ali-Mohammad Kamali, Rao KS, Mohammad Nami
Studies on the Bottom-Up and Top-Down Neural Information Flow Alterations in Neurodegeneration
Abstract: Background: A proper explanation for perceptual symptoms in neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease (PD) is still lacking. Objective: This study aimed at investigating the imbalance between ‘bottom-up’ and ‘top-down’ information flow (IF) and processing in PD in relation with visual hallucination symptoms. Methods: Here, we looked at bottom-up and top-down IF markers using resting state electroencephalographic (EEG) data from PD patients analyzed through three different IF measures (direct Directed Transfer Function (dDTF), full frequency Directed Transfer Function (ff-DTF), and renormalized Partial Directed Coherence (rPDC). Results: We observed an increased gamma band IF and a reduced beta band IF in PD patients compared to healthy controls. Additionally, we noticed a reduced theta band IF in PD patients using dDTF as a measure of IF. By source localizing the EEG activity of the PD patients and healthy controls, we looked at the alterations of IF in the prefrontal cortex of PD patients as well. Conclusion: In line with previous studies, our results suggest that the delicate balance between bottom-up and top-down IF is disrupted in Parkinson’s disease potentially contributing to the cognitive symptoms of PD patients.

Tam Watermeyer, Alejandra Marroig, Craig W. Ritchie , Karen Ritchie, Kaj Blennow, Graciela Muniz-Terrera on behalf of the EPAD Consortium
Cognitive Dispersion Is Not Associated with Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Results from the European Prevention of Alzheimer’s Dementia (EPAD) v500.0 Cohort
Abstract: Background: Cognitive dispersion, variation in performance across cognitive domains, is posited as a non-invasive and cost-effective marker of early neurodegeneration. Little work has explored associations between cognitive dispersion and Alzheimer’s disease (AD) biomarkers in healthy older adults. Even less is known about the influence or interaction of biomarkers reflecting brain pathophysiology or other risk factors on cognitive dispersion scores. Objective: The main aim of this study was to examine whether higher cognitive dispersion was associated with cerebrospinal fluid (CSF) levels of amyloid-β (Aβ42), total tau (t-tau), phosphorylated tau (p-tau), and amyloid positivity in a cohort of older adults at various severities of AD. A secondary aim was to explore which AD risk factors were associated with cognitive dispersion scores. Methods: Linear and logistic regression analyses explored the associations between dispersion and CSF levels of Aβ42, t-tau, and p-tau and amyloid positivity (Aβ42<1000 pg/ml). Relationships between sociodemographics, APOE ε4 status, family history of dementia, and levels of depression and dispersion were also assessed. Results: Dispersion did not emerge as associated with any of the analytes nor amyloid positivity. Older (β=-0.007, SE=0.002, p=0.001) and less educated (β=-0.009, SE=0.003, p =0.009) individuals showed greater dispersion. Conclusion: Dispersion was not associated with AD pathology, but was associated with age and years of education, highlighting individual differences in cognitive aging. The use of this metric as a screening tool for existing AD pathology is not supported by our analyses. Follow-up work will determine if dispersion scores can predict changes in biomarker levels and/or positivity status longitudinally.

Yejin Yun*, Sang-Yeon Lee*, Won Hoon Choi, Jong-Chan Park, Dong Han Lee, Yun Kyung Kim, Jung Hoon Lee, Jun-Young Lee, Min Jae Lee, Young Ho Kim *These authors contributed equally to this work.
Proteasome Activity in the Plasma as a Novel Biomarker in Mild Cognitive Impairment with Chronic Tinnitus
Abstract: Background: Although the existence of proteasomes in human blood, termed circulating proteasomes (c-proteasomes), has been reported previously, their origin and pathophysiological functions remain largely unknown. Objective: Given that c-proteasome activity was significantly reduced in Alzheimer’s disease model mice and relatively high frequency of mild cognitive impairment (MCI) is accompanied by chronic tinnitus in aged patients, we examined whether c-proteasome activity in human plasma was associated with cognitive function in patients with chronic tinnitus. Methods: c-Proteasome activity in the plasma of tinnitus patients (N = 56) was measured with fluorogenic reporter substrate, suc-LLVY-AMC. To assess MCI, the Montreal Cognitive Assessment was conducted with a cut-off score of 22/23. All patients underwent audiological and psychoacoustic analyses. Levels of c-proteasomes, Aβ42, and Aβ40 were measured using ELISA, and their association with c-proteasome activity was evaluated. Results: The activity of circulating proteasomes was significantly lower in patients with chronic tinnitus and MCI (p = 0.042), whereas activities of other plasma enzymes showed little correlation. In addition, c-proteasome activity was negatively associated with the level of plasma Aβ and was directly dependent on its own concentration in the plasma of patients with chronic tinnitus. Conclusion: Our current work provides a new perspective for understanding the potential relationship between circulating proteasomes in the plasma and cognitive dysfunction, suggesting a novel, non-invasive biomarker in the context of MCI diagnosis.

Rebecca Henkel, Matthias Brendel, Marco Paolini, Eva Brendel, Leonie Beyer, Andreas Gutzeit, Oliver Pogarell, Axel Rominger, Janusch Blautzik
FDG PET Data Is Associated with Cognitive Performance in Patients from a Memory Clinic
Abstract: Background: Various reasons may lead to cognitive symptoms in elderly, including the development of cognitive decline and dementia. Often, mixed pathologies such as neurodegeneration and cerebrovascular disease co-exist in these patients. Diagnostic work-up commonly includes imaging modalities such as FDG PET, MRI, and CT, each delivering specific information. Objective: To study the informative value of neuroimaging-based data supposed to reflect neurodegeneration (FDG PET), cerebral small vessel disease (MRI), and cerebral large vessel atherosclerosis (CT) with regard to cognitive performance in patients presenting to our memory clinic. Methods: Non-parametric partial correlations and an ordinal logistic regression model were run to determine relationships between scores for cortical hypometabolism, white matter hyperintensities, calcified plaque burden, and results from Mini-Mental State Examination (MMSE). The final study group consisted of 162 patients (female: 94; MMSE: 6–30). Results: Only FDG PET data was linked to and predicted cognitive performance (r(157) =-0.388, p<0.001). Overall, parameters linked to cerebral small and large vessel disease showed no significant association with cognition. Further findings demonstrated a relationship between white matter hyperintensities and FDG PET data (r(157)=0.230, p=0.004). Conclusion: Only FDG PET imaging mirrors cognitive performance, presumably due to the examination’s ability to reflect neurodegeneration and vascular dysfunction, thus capturing a broader spectrum of pathologies. This makes the examination a useful imaging-based diagnostic tool in the work-up of patients presenting to a memory clinic. Parameters of vascular dysfunction alone as depicted by conventional MRI and CT are less adequate in such a situation, most likely because they reflect one pathology complex only.

Liang-Yu Huang, He-Ying Hu, Zuo-Teng Wang, Ya-Hui Ma, Qiang Dong, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu)
Association of Occupational Factors and Dementia or Cognitive Impairment: A Systematic Review and Meta-Analysis
Abstract: Background: Several existing studies have reported that occupational factors might play an important part in cognitive function with aging. Objective: We aim to explore the associations between modifiable occupational factors and risk of dementia or mild cognitive impairment (MCI). Methods: Adopting random-effect models, this study conducted primary analyses for all occupational factors and subgroup analyses for the effect of occupation type based on prospective cohort and case-control studies searched from PubMed and EMBASE databases up to March 2020. Results: Among the 38,111 identified literatures, 9 studies on occupation type, 4 studies on work complexity, and 30 studies on occupational exposure were included. In terms of occupation type, mental work conferred a 44% reduced risk (95% CI=0.34-0.94, I²=85.00%, p<0.01) for MCI. In terms of work complexity, higher work complexity conferred a 5% reduced risk (95% CI=0.91-1.00, I²=57.00%, p<0.01) for dementia. In terms of occupational exposure, high strain and passive job in the longest-held job conferred a 1.21- and 1.15-fold excess risk (95% CI=1.05-1.39 I²=62.00%, p<0.05; 95% CI=1.05-1.26 I²= 31.00%, p=0.23; respectively) of cognitive decline. Besides, magnetic field exposure conferred a 1.26-fold excess risk (95% CI=1.01-1.57, I²=69.00%, p<0.01) for dementia. Conclusion: Novel prevention strategies based on occupational factors may hold promise against dementia and MCI.

Paula Squarzoni, Daniele de Paula Faria, Mônica Sanches Yassuda, Fábio Henrique de Gobbi Porto, Artur Martins Coutinho, Naomi Antunes da Costa, Ricardo Nitrini, Orestes Vicente Forlenza, Fábio Luiz de Souza Duran, Sonia Maria Dozzi Brucki, Carlos Alberto Buchpiguel, Geraldo F. Busatto (Handling Associate Editor: Jack de la Torre)
Relationship Between PET-Assessed Amyloid Burden and Visual and Verbal Episodic Memory Performance in Elderly Subjects
Abstract: Background: Studies of elderly subjects using biomarkers that are proxies for Alzheimer’s disease (AD) pathology have the potential to document meaningful relationships between cognitive performance and biomarker changes along the AD continuum. Objective: To document cognitive performance differences across distinct AD stages using a categorization based on the presence of PET-assessed amyloid-β (Aβ) burden and neurodegeneration. Methods: Patients with mild dementia compatible with AD (n=38) or amnestic mild cognitive impairment (aMCI; n=43) and a cognitively unimpaired group (n=27) underwent PET with Pittsburgh compound-B (PiB) assessing Aβ aggregation (A+) and [18F]FDG-PET assessing neurodegeneration ((N)+). Cognitive performance was assessed with verbal and visual episodic memory tests and the Mini-Mental State Examination. Results: The A+(N)+ subgroup (n=32) showed decreased (p<0.001) cognitive test scores compared to both A+(N)- (n=18) and A-(N)- (n=49) subjects, who presented highly similar mean cognitive scores. Despite its modest size (n=9), the A-(N)+ subgroup showed lower (p<0.043) verbal memory scores relative to A-(N)- subjects, and trend lower (p=0.096) scores relative to A+(N)- subjects. Continuous Aβ measures (standard uptake value ratios of PiB uptake) were correlated most significantly with visual memory scores both in the overall sample and when analyses were restricted to dementia or (N)+ subjects, but not in non-dementia or (N)- groups. Conclusion: These results demonstrate that significant Aβ-cognition relationships are highly salient at disease stages involving neurodegeneration. The fact that findings relating Aβ burden to memory performance were detected only at (N)+ stages, together with the similarity of test scores between A+(N)- and A-(N)- subjects, reinforce the view that Aβ-cognition relationships during early AD stages may remain undetectable unless substantially large samples are evaluated.

Ursula S. Sandau*, Jack T. Wiedrick*, Sierra J. Smith, Trevor J. McFarland, Theresa A. Lusardi, Babett Lind, Christina A. Harrington, Jodi A. Lapidus, Douglas R. Galasko, Joseph F. Quinn, Julie A. Saugstad (Handling Associate Editor: Robert Rissman) *These authors contributed equally to this work.
Performance of Validated MicroRNA Biomarkers for Alzheimer's Disease in Mild Cognitive Impairment
Abstract: Background: Cerebrospinal fluid (CSF) microRNA (miRNA) biomarkers of Alzheimer's disease (AD) have been identified, but have not been evaluated in prodromal AD, including mild cognitive impairment (MCI). Objective: To assess whether a set of validated AD miRNA biomarkers in CSF are also sensitive to early-stage pathology as exemplified by MCI diagnosis. Methods: We measured the expression of 17 miRNA biomarkers for AD in CSF samples from AD, MCI, and cognitively normal controls (NC). We then examined classification performance of the miRNAs individually and in combination. For each miRNA, we assessed median expression in each diagnostic group and classified markers as trending linearly, nonlinearly, or lacking any trend across the three groups. For trending miRNAs, we assessed multimarker classification performance alone and in combination with apolipoprotein E ɛ4 allele (APOE ɛ4) genotype and amyloid-β42 to total tau ratio (Aβ42:T-Tau). We identified predicted targets of trending miRNAs using pathway analysis. Results: Five miRNAs showed a linear trend of decreasing median expression across the ordered diagnoses (control to MCI to AD). The trending miRNAs jointly predicted AD with area under the curve (AUC) of 0.770, and MCI with AUC of 0.705. Aβ42:T-Tau alone predicted MCI with AUC of 0.758 and the AUC improved to 0.813 (p = 0.051) after adding the trending miRNAs. Multivariate correlation of the five trending miRNAs with Aβ42:T-Tau was weak. Conclusion: Selected miRNAs combined with Aβ42:T-Tau improved classification performance (relative to protein biomarkers alone) for MCI, despite a weak correlation with Aβ42:T-Tau. Together these data suggest that that these miRNAs carry novel information relevant to AD, even at the MCI stage. Preliminary target prediction analysis suggests novel roles for these biomarkers.

Breton M. Asken, Fanny M. Elahi, Renaud La Joie, Amelia Strom, Adam M. Staffaroni, Cutter A. Lindbergh, Alexandra C. Apple, Michelle You, Sophia Weiner-Light, Nivetha Brathaban, Nicole Fernandes, Anna Karydas, Paul Wang, Julio C. Rojas, Adam L. Boxer, Bruce L. Miller, Gil D. Rabinovici, Joel H. Kramer, Kaitlin B. Casaletto (Handling Associate Editor: Michelle Mielke)
Plasma Glial Fibrillary Acidic Protein Levels Differ Along the Spectra of Amyloid Burden and Clinical Disease Stage
Abstract: Background: Measuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-β (Aβ) may shed light on astrocytic changes in aging and Alzheimer’s disease (AD). Objective: To examine associations between plasma GFAP and cortical Aβ deposition in older adults across the typical aging-to-AD dementia spectrum. Methods: We studied two independent samples from UCSF (Cohort 1, N=50; Cohort 2, N=37) covering the spectra of clinical severity (CDR Sum of Boxes; CDR-SB) and Aβ-PET burden. Aβ-PET was completed with either florbetapir or Pittsburgh Compound B and standardized uptake value ratios were converted to the Centiloid (CL) scale for analyses. All participants with CDR-SB>0 were Aβ-PET positive, while clinically normal participants (CDR-SB=0) were a mix of Aβ-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aβ-PET, and clinical severity. Results: In both cohorts, plasma GFAP increased linearly with Aβ-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aβ-PET burden, the association between Aβ and GFAP became curvilinear (inverted U-shape; quadratic model R2 change=0.165, p=0.009), and Aβ-PET interacted with CDR-SB (R2 change=0.164, p=0.007): older adults with intermediate functional impairment (CDR-SB=0.5-4.0) showed a weak (negative) association between Aβ-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB>4.0) showed a strong, negative association of higher Aβ-PET CLs with lower plasma GFAP. Conclusion: The relationship between astrocytic integrity and cortical Aβ may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages.

Yan Li*, Sha Li*, Shunjiang Xu, Hong Yu, Longmei Tang, Xiaoyun Liu, Xuemei Wang, Yuanyuan Zhang, Kaixia Zhang, Shixiong Mi, Meiqin Chen, Huixian Cui (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Association of Androgens and Gonadotropins with Amnestic Mild Cognitive Impairment and Probable Alzheimer’s Disease in Chinese Elderly Men
Abstract: Background: Age-related hormone changes play important roles in cognitive decline in older men, and apolipoprotein E ɛ4 (APOE ɛ4) is a risk factor for Alzheimer’s disease (AD). Objective: This study aimed to investigate the interactive role of androgen decline and APOE ɛ4 genotype in the pathogenesis of amnestic mild cognitive impairment (aMCI) and AD. Methods: In total, 576 elderly men over 65 years old from communities in Shijiazhuang were enrolled in this study, including 243 with normal cognition (NC), 271 with aMCI, and 62 with probable AD. Cognitive function was evaluated with a battery of neuropsychological tests. The serum levels of androgen and gonadotropin were detected by ELISA and chemiluminescence immunoassay. Results: The levels of free testosterone (FT) and dihydrotestosterone (DHT) were lower in the aMCI group (p < 0.05), and even lower in the AD group (p < 0.001), but the levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were higher in AD group (p < 0.01), comparing with that in NC or aMCI group. The interaction of lower FT or DHT levels with APOE ɛ4 had a risk role in global cognitive impairment (p < 0.05). The area under the curve (AUC) of the ROC curve for predicting aMCI by serum FT levels was 0.745. Conclusion: These results indicated that the interaction of androgen decline and APOE ɛ4 genotype play a role in aMCI and AD. Serum FT levels have a predictive value for aMCI and might be a potential biomarker for prodromal AD.

Claudio Del Percio, Wilhelmus Drinkenburg, Susanna Lopez, Maria Teresa Pascarelli, Roberta Lizio, Giuseppe Noce, Raffaele Ferri, Jesper Frank Bastlund, Bettina Laursen, Ditte Zerlang Christensen, Jan T. Pedersen, Gianluigi Forloni, Angelisa Frasca, Francesco M. Noè, Paolo Francesco Fabene, Giuseppe Bertini, Valeria Colavito, Marina Bentivoglio Jonathan Kelley, Sophie Dix, Francesco Infarinato, Andrea Soricelli, Fabrizio Stocchi, Jill C. Richardson, Claudio Babiloni on behalf of PharmaCog Consortium
Ongoing Electroencephalographic Rhythms Related to Exploratory Movements in Transgenic TASTPM Mice
Abstract: Background: The European PharmaCog study (http://www.pharmacog.org) has reported a reduction in delta (1-6 Hz) electroencephalographic (EEG) power (density) during cage exploration (active condition) compared with quiet wakefulness (passive condition) in PDAPP mice (hAPP Indiana V717F mutation) modeling Alzheimer’s disease (AD) amyloidosis and cognitive deficits. Objective: Here, we tested the reproducibility of that evidence in TASTPM mice (double mutation in APP KM670/671NL and PSEN1 M146V), which develop brain amyloidosis and cognitive deficits over aging. The reliability of that evidence was examined in four research centers of the PharmaCog study. Methods: Ongoing EEG rhythms were recorded from a frontoparietal bipolar channel in 29 TASTPM and 58 matched “wild type” C57 mice (range of age: 12-24 months). Normalized EEG power was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during the passive and active conditions. Results: Compared with the “wild type” group, the TASTPM group showed a significantly lower reduction in IDF power during the active over the passive condition (p < 0.05). This effect was observed in 3 out of 4 EEG recording units. Conclusion: TASTPM mice were characterized by “poor reactivity” of delta EEG rhythms during the cage exploration in line with previous evidence in PDAPP mice. The reliability of that result across the centers was moderate, thus unveiling pros and cons of multicenter preclinical EEG trials in TASTPM mice useful for planning future studies.

Jenna Katherine Blujus, Laura Elizabeth Korthauer, Elizabeth Awe, Marijam Frahmand, Ira Driscoll
Single Nucleotide Polymorphisms in Alzheimer’s Disease Risk Genes Are Associated with Intrinsic Connectivity in Middle Age
Abstract: Background: It is critical to identify individuals at risk for Alzheimer’s disease (AD) earlier in the disease time course, such as middle age and preferably well prior to the onset of clinical symptoms, when intervention efforts may be more successful. Genome-wide association and candidate gene studies have identified single nucleotide polymorphisms (SNPs) in APOE, CLU, CR1, PICALM, and SORL1 that confer increased risk of AD. Objective: In the current study, we investigated the associations between SNPs in these genes and resting-state functional connectivity within the default mode network (DMN), frontoparietal control network (FPN), and executive control network (ECN) in healthy, non-demented middle-aged adults (age 40 – 60; N = 123; 74 females). Methods: Resting state networks of interest were identified through independent components analysis using a template-matching procedure and individual spatial maps and time courses were extracted using dual regression. Results: Within the posterior DMN, functional connectivity was associated with CR1 rs1408077 and CLU rs9331888 polymorphisms (ps < 0.05). FPN connectivity was associated with CR1 rs1408077, CLU rs1136000, SORL1 rs641120, and SORL1 rs689021 (ps < 0.05). Functional connectivity within the ECN was associated with the CLU rs11136000 (p < 0.05). There were no APOE- or PICALM-related differences in any of the networks investigated (ps > 0.05). Conclusion: This is the first demonstration of the relationship between intrinsic network connectivity and AD risk alleles in CLU, CR1, and SORL1 in healthy, middle-aged adults. These SNPs should be considered in future investigations aimed at identifying potential preclinical biomarkers for AD.

Ying Xia*, Nawaf Yassi*, Parnesh Raniga, Pierrick Bourgeat, Patricia Desmond, James Doecke, David Ames, Simon M. Laws, Christopher Fowler, Stephanie R. Rainey-Smith, Ralph Martins, Paul Maruff, Victor L. Villemagne, Colin L. Masters, Christopher C. Rowe, Jurgen Fripp, Olivier Salvado for the AIBL Research Group *These authors contributed equally to this work.
Comorbidity of Cerebrovascular and Alzheimer’s Disease in Aging
Abstract: Background: Cerebrovascular disease often coexists with Alzheimer’s disease (AD). While both diseases share common risk factors, their interrelationship remains unclear. Increasing the understanding of how cerebrovascular changes interact with AD is essential to develop therapeutic strategies and refine biomarkers for early diagnosis. Objective: We investigate the prevalence and risk factors for the comorbidity of amyloid-β (Aβ) and cerebrovascular disease in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing, and further examine their cross-sectional association. Methods: A total of 598 participants (422 cognitively normal, 89 with mild cognitive impairment, 87 with AD) underwent positron emission tomography and structural magnetic resonance imaging for assessment of Aβ deposition and cerebrovascular disease. Individuals were categorized based on the comorbidity status of Aβ and cerebrovascular disease (V) as Aβ-V-, Aβ-V+, Aβ+V-, or Aβ+V+. Results: Advancing age was associated with greater likelihood of cerebrovascular disease, high Aβ load and their comorbidity. Apolipoprotein E ε4 carriage was only associated with Aβ positivity. Greater total and regional WMH burden were observed in participants with AD. However, no association were observed between Aβ and WMH measures after stratification by clinical classification, suggesting that the observed association between AD and cerebrovascular disease was driven by the common risk factor of age. Conclusion: Our observations demonstrate common comorbid condition of Aβ and cerebrovascular disease in later life. While our study did not demonstrate a convincing cross-sectional association between Aβ and WMH burden, future longitudinal studies are required to further confirm this.

Kimberley E. Stuart, Christine Padgett (Handling Associate Editor: Robert Rissman)
A Systematic Review of the Association Between Psychological Stress and Dementia Risk in Humans
Abstract: Background: It has been estimated that one third of dementia cases may be preventable through modifiable lifestyle interventions. Epidemiological evidence suggests a link between stressful life events and aging-related cognitive decline and dementia; however, inherent methodological limitations in examining subjective and biological measures of stress separately leads to interpretive constraints. Objective: The aim of the current study was to conduct a systematic review of the research literature investigating the effect of perceived and biological measures of stress on dementia risk. Methods: A systematic review was conducted of cohort, case-control, longitudinal prospective or retrospective studies examining the association between stress and risk of developing dementia. Studies were identified from a systematic search across major electronic databases from inception to February 2020. Results: Overall, 22 studies were identified including a total of 496,556 participants, approximately 50% were females, with sample sizes ranging from 62–270,977. There was considerable heterogeneity in the definition and measurement of stress. Most of the identified studies reported a significant positive association between stress and dementia risk. Conclusion: Evidenced from the current review is that personality traits linked to increased perceived stress, elevated reported perceived stress, are associated with greater statistical risk for dementia. However, this review highlights that caution must be exhibited in interpreting these findings, as methodological issues with confounding adjustment may mediate these results. Future research should focus on the investigation of stress on dementia risk with a full range of confounding adjustment, and on biological measures of stress.

Natália Chermont dos Santos Moreira, Jéssica Ellen Barbosa de Freitas Lima, Talita Perez Cantuaria Chierrito, Ivone Carvalho, Elza Tiemi Sakamoto-Hojo (Handling Associate Editor: Ronan O'Caoimh)
Novel Hybrid Acetylcholinesterase Inhibitors Induce Differentiation and Neuritogenesis in Neuronal Cells in vitro Through Activation of the AKT Pathway
Abstract: Background: Alzheimer's disease (AD) is characterized by a progressive loss of episodic memory associated with amyloid-β peptide aggregation and the abnormal phosphorylation of the tau protein, leading to the loss of cholinergic function. Acetylcholinesterase (AChE) inhibitors are the main class of drugs used in AD therapy. Objective: The aim of the current study was to evaluate the potential of two tacrine-donepezil hybrid molecules (TA8Amino and TAHB3), which are AChE inhibitors, to induce neurodifferentiation and neuritogenesis in SH-SY5Y cells. Methods: The experiments were carried out to characterize neurodifferentiation, cellular changes related to responses to oxidative stress and pathways of cell survival in response to drug treatments. Results: The results indicated that the compounds did not present cytotoxic effects in SH-SY5Y or HepG2 cells. TA8Amino and TAHB3 induced neurodifferentiation and neuritogenesis in SH-SY5Y cells. These cells showed increased levels of intracellular and mitochondrial reactive oxygen species; the induction of oxidative stress was also demonstrated by an increase in SOD1 expression in TA8Amino and TAHB3-treated cells. Cells treated with the compounds showed an increase in PTEN(Ser380/Thr382/383) and AKT(Ser473) expression, suggesting the involvement of the AKT pathway. Conclusion: Our results demonstrated that TA8Amino and TAHB3 present advantages as potential drugs for AD therapy and that they are capable of inducing neurodifferentiation and neuritogenesis.

Lisa V. Graves, Emily C. Edmonds, Kelsey R. Thomas, Alexandra J. Weigand, Shanna Cooper, Mark W. Bondi (Handling Associate Editor: David Loewenstein)
Evidence for the Utility of Actuarial Neuropsychological Criteria Across the Continuum of Normal Aging, Mild Cognitive Impairment, and Dementia
Abstract: Background: Research suggests that actuarial neuropsychological criteria improve the accuracy of mild cognitive impairment (MCI) diagnoses relative to conventional diagnostic methods. Objective: We sought to examine the utility of actuarial criteria relative to consensus diagnostic methods used in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS), and more broadly across the continuum of normal aging, MCI, and dementia. Methods: We compared rates of cognitively normal (CN), MCI, and dementia diagnoses at baseline using actuarial versus consensus diagnostic methods in 1524 individuals from the NACC UDS. Results: Approximately one-third (33.59%) of individuals diagnosed as CN and more than one-fifth (22.03%) diagnosed with dementia based on consensus methods, met actuarial criteria for MCI. Many participants diagnosed with MCI via consensus methods also appeared to represent possible diagnostic errors. Notably, the CNa/CNc group (i.e., participants diagnosed as CN based on both actuarial [a] and consensus [c] criteria) had a lower proportion of apolipoprotein E ε4 carriers than the MCIa/MCIc group, which in turn had a lower proportion of ε4 carriers than the dementia (Dem)a/Demc group. Proportions of ε4 carriers were comparable between the CNa/CNc and CNa/MCIc, MCIa/MCIc and MCIa/CNc, MCIa/MCIc and MCIa/Demc, and Dema/Demc and Dema/MCIc groups. These results were largely consistent with diagnostic agreement/discrepancy group comparisons on neuropsychological performance. Conclusion: The present results extend previous findings and suggest that actuarial neuropsychological criteria may enhance diagnostic accuracy relative to consensus methods, and across the wider continuum of normal aging, MCI, and dementia. Findings have implications for both clinical practice and research.

Cinzia Coppola, Dario Saracino, Mariano Oliva, Gianfranco Puoti, Giacomo Lus, Isabelle Le Ber, Jérémie Pariente, Alessandro Tessitore, Luisa Benussi, Roberta Ghidoni, Matteo Carrara, Martina Ricci, Veronica Redaelli, Pietro Tiraboschi, Paola Caroppo, Giorgio Giaccone, Simona Bonavita, Giacomina Rossi
The Rise of the GRN C157KfsX97 Mutation in Southern Italy: Going Back to the Fall of the Western Roman Empire
Abstract: Background: Frontotemporal lobar degeneration (FTLD) designates a group of neurodegenerative diseases with remarkable clinical, pathological, and genetic heterogeneity. Mutations in progranulin gene (GRN) are among the most common causes of familial FTLD. The GRN C157KfsX97 mutation is the most frequent mutation occurring in Southern Italy and has been already described in a previous work. Objective: In this study, we reported on additional cases carrying the same mutation and performed a genetic study on the whole cohort, aiming at demonstrating the existence of a founder effect and estimating the age of this mutation. Methods/Results: Based on the haplotype sharing analysis, a founder effect was highly probable, while the age of the mutation, estimated by means of DMLE+ software, resulted in a range between 52 and 82 generations, with the highest frequency at about 62 generations, 1,550 years ago. Conclusion: This is the first study that reports the age estimation of the most recent common ancestor for the GRN C157KfsX97 mutation recurring in Southern Italy. Mutation dating in a geographically restricted population may be useful in order to plan genetic counseling and screening programs in the field of public health.

Rui-Qi Zhang, Shi-Dong Chen, Xue-Ning Shen, Yu-Xiang Yang, Jia-Ying Lu, Mei Cui, Chuan-Tao Zuo, Qiang Dong, Lan Tan, Jin-Tai Yu, Alzheimer’s Disease Neuroimaging Initiative
Elevated Tau PET Signal Depends on Abnormal Amyloid Levels and Correlates with Cognitive Impairment in Elderly Persons without Dementia
Abstract: Background: The recent developed PET ligands for amyloid-β (Aβ) and tau allow these two neuropathological hallmarks of Alzheimer’s disease (AD) to be mapped and quantified in vivo and to be examined in relation to cognition. Objective: To assess the associations among Aβ, tau, and cognition in non-demented subjects. Methods: Three hundred eighty-nine elderly participants without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent tau and amyloid PET scans. Cross-sectional comparisons and longitudinal analyses were used to evaluate the relationship between Aβ and tau accumulation. The correlations between biomarkers of both pathologies and performance in memory and executive function were measured. Results: Increased amyloid-PET retention was associated with greater tau-PET retention in widespread cortices. We observed a significant tau increase in the temporal composite regions of interest over 24 months in Aβ+ but not Aβ- subjects. Finally, tau-PET retention but not amyloid-PET retention significantly explained the variance in memory and executive function. Higher level of tau was associated with greater longitudinal memory decline. Conclusion: These findings suggested PET-detectable Aβ plaque pathology may be a necessary antecedent for tau-PET signal elevation. Greater tau-PET retention may demonstrate poorer cognition and predict prospective memory decline in non-demented AD subjects.

Stelios Zygouris, Paraskevi Iliadou, Eftychia Lazarou, Dimitrios Giakoumis, Konstantinos Votis, Anastasios Alexiadis, Andreas Triantafyllidis, Sofia Segkouli, Dimitrios Tzovaras, Thrasyvoulos Tsiatsos, Sotirios Papagianopoulos, Magda Tsolaki
Detection of Mild Cognitive Impairment in an At-Risk Group of Older Adults: Can a Novel Self-Administered Serious Game-Based Screening Test Improve Diagnostic Accuracy?
Abstract: Background: Literature supports the use of serious games and virtual environments to assess cognitive functions and detect cognitive decline. This promising assessment method, however, has not yet been translated into self-administered screening instruments for pre-clinical dementia. Objective: The aim of this study is to assess the performance of a novel self-administered serious game-based test, namely the Virtual Supermarket Test (VST), in detecting mild cognitive impairment (MCI) in a sample of older adults with subjective memory complaints (SMC), in comparison with two well-established screening instruments, the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). Methods: Two groups, one of healthy older adults with SMC (N=48) and one of MCI patients (N=47) were recruited from day centers for cognitive disorders and administered the VST, the MoCA, the MMSE, and an extended pencil and paper neuropsychological test battery. Results: The VST displayed a correct classification rate (CCR) of 81.91% when differentiating between MCI patients and older adults with SMC, while the MoCA displayed of CCR of 72.04% and the MMSE displayed a CCR of 64.89%. Conclusion: The three instruments assessed in this study displayed significantly different performances in differentiating between healthy older adults with SMC and MCI patients. The VST displayed a good CCR, while the MoCA displayed an average CCR and the MMSE displayed a poor CCR. The VST appears to be a robust tool for detecting MCI in a population of older adults with SMC.

Hugo Geerts, Athan Spiros
Simulating the Effects of Common Comedications and Genotypes on Alzheimer’s Cognitive Trajectory Using a Quantitative Systems Pharmacology Approach
Abstract: Background: Many Alzheimer’s disease patients in clinical practice are on polypharmacy for treatment of comorbidities. Objective: While pharmacokinetic interactions between drugs have been relatively well established with corresponding treatment guidelines, many medications and common genotype variants also affect central brain circuits involved in cognitive trajectory, leading to complex pharmacodynamic interactions and a large variability in clinical trials. Methods: We applied a mechanism-based and ADAS-Cog calibrated Quantitative Systems Pharmacology biophysical model of neuronal circuits relevant for cognition in Alzheimer’s disease, to standard-of-care cholinergic therapy with COMTVal158Met, 5-HTTLPR rs25531, and APOE genotypes and with benzodiazepines, antidepressants, and antipsychotics, all together 9,585 combinations. Results: The model predicts a variability of up to 14 points on ADAS-Cog at baseline (COMTVV 5-HTTLPRss APOE 4/4 combination is worst) and a four-fold range for the rate of progression. The progression rate is inversely proportional to baseline ADAS-Cog. Antidepressants, benzodiazepines, first-generation more than second generation, and most antipsychotics with the exception of aripiprazole worsen the outcome when added to standard-of-care in mild cases. Low dose second-generation benzodiazepines revert the negative effects of risperidone and olanzapine, but only in mild stages. Non APOE4 carriers with a COMTMM and 5HTTLPRLL are predicted to have the best cognitive performance at baseline but deteriorate somewhat faster over time. However, this effect is significantly modulated by comedications. Conclusion: Once these simulations are validated, the platform can in principle provide optimal treatment guidance in clinical practice at an individual patient level, identify negative pharmacodynamic interactions with novel targets and address protocol amendments in clinical trials.

Xiaodong Yuan, Lu Wang, Neha Tendon, Huili Sun, Jing Tian, Heng Du, Juan M. Pascual, Lan Guo (Handling Associate Editor: P. Hemachandra Reddy)
Triheptanoin Mitigates Brain ATP Depletion and Mitochondrial Dysfunction in a Mouse Model of Alzheimer’s Disease
Abstract: Background: Brain energy failure is an early pathological event associated with synaptic dysfunction in Alzheimer’s disease (AD). Thus, mitigation or enhancement of brain energy metabolism may offer a therapeutic avenue. However, there is uncertainty as to what metabolic process(es) may be more appropriate to support or augment since metabolism is a multiform process such that each of the various metabolic precursors available is utilized via a specific metabolic pathway. In the brain, these pathways sustain not only a robust rate of energy production but also of carbon replenishment. Objective: Triheptanoin, an edible odd-chain fatty acid triglyceride, is uncommon in that it replenishes metabolites in the tricarboxylic acid cycle (TCA) cycle via anaplerosis in addition to fueling the cycle via oxidation, thus potentially leading to both carbon replenishment and enhanced mitochondrial ATP production. Methods: To test the hypothesis that triheptanoin is protective in AD, we supplied mice with severe brain amyloidosis (5×FAD mice) with dietary triheptanoin for four and a half months, followed by biological and biochemical experiments to examine mice metabolic as well as synaptic function. Results: Triheptanoin treatment had minimal impact on systemic metabolism and brain amyloidosis as well as tauopathy while attenuating brain ATP deficiency and mitochondrial dysfunction including respiration and redox balance in 5×FAD mice. Synaptic density, a disease hallmark, was also preserved in hippocampus and neocortex despite profound amyloid deposition. None of these effects took place in treated control mice. Conclusion: These findings support the energy failure hypothesis of AD and justify investigating the mechanisms in greater depth with ultimate therapeutic intent.

Dongxue Li, Yuancheng Liu, Xianchun Zeng, Zhenliang Xiong, Yuanrong Yao, Daiyi Liang, Hao Qu, Hui Xiang, Zhenggui Yang, Lisha Nie, Pu-Yeh Wu, Rongpin Wang
Quantitative Study of the Changes in Cerebral Blood Flow and Iron Deposition During Progression of Alzheimer’s Disease
Abstract: Background: Advanced Alzheimer’s disease (AD) has no effective treatment, and identifying early diagnosis markers can provide a time window for treatment. Objective: To quantify the changes in cerebral blood flow (CBF) and iron deposition during progression of AD. Methods: 94 subjects underwent brain imaging on a 3.0-T MRI scanner with techniques of three-dimensional arterial spin labeling (3D-ASL) and quantitative susceptibility mapping (QSM). The subjects included 22 patients with probable AD, 22 patients with mild cognitive impairment (MCI), 25 patients with subjective cognitive decline (SCD), and 25 normal controls (NC). The CBF and QSM values were obtained using a standardized brain region method based on the Brainnetome Atlas. The differences in CBF and QSM values were analyzed between and within groups using variance analysis and correlation analysis. Results: CBF and QSM identified several abnormal brain regions of interest (ROIs) at different stages of AD (p<0.05). Regionally, the CBF values in several ROIs of the AD and MCI subjects were lower than for NC subjects (p<0.001). Higher QSM values were observed in the globus pallidus. The CBF and QSM values in multiple ROI were negatively correlated, while the putamen was the common ROI of the three study groups (p<0.05). The CBF and QSM values in hippocampus were cross-correlated with scale scores during the progression of AD (p<0.05). Conclusion: Iron deposition in the basal ganglia and reduction in blood perfusion in multiple regions existed during the progression of AD. The QSM values in putamen can be used as an imaging biomarker for early diagnosis of AD.

Irina Alafuzoff, Sylwia Libard
Mixed Brain Pathology Is the Most Common Cause of Cognitive Impairment in the Elderly
Abstract: Background: Systemic diseases, diabetes mellitus (DM), and cardiovascular disease (CaVD) have been suggested being risk factors for cognitive impairment (CI) and/or influence Alzheimer’s disease neuropathologic change (ADNC). Objective: The purpose was to assess the type and the extent of neuropathological alterations in the brain and to assess whether brain pathology was associated with CaVD or DM related alterations in peripheral organs, i.e., vessels, heart, and kidney. Methods: 119 subjects, 15% with DM and 24% with CI, age range 80 to 89 years, were chosen and neuropathological alterations were assessed applying immunohistochemistry. Results: Hyperphosphorylated τ (HPτ) was seen in 99%, amyloid-β (Aβ) in 71%, transactive DNA binding protein 43 (TDP43) in 62%, and α-synuclein (αS) in 21% of the subjects. Primary age related tauopathy was diagnosed in 29% (more common in females), limbic predominant age-related TDP encephalopathy in 4% (14% of subjects with CI), and dementia with Lewy bodies in 3% (14% of subjects with CI) of the subjects. High/intermediate level of ADNC was seen in 47% and the extent of HPτ increased with age. The extent of ADNC was not associated with the extent of pathology observed in peripheral organs, i.e., DM or CaVD. Contrary, brain alterations such as pTDP43 and cerebrovascular lesions (CeVL) were influenced by DM, and CeVL correlated significantly with the extent of vessel pathology. Conclusion: In most (66%) subjects with CI, the cause of impairment was “mixed pathology”, i.e., ADNC combined with TDP43, αS, or vascular brain lesions. Furthermore, our results suggest that systemic diseases, DM and CaVD, are risk factors for CI but not related to ADNC.

Aziz M. Mezlini, Colin Magdamo, Emily Merrill, Lori B. Chibnik, Deborah L. Blacker, Bradley T. Hyman, Sudeshna Das
Characterizing Clinical and Neuropathological Traits of APOE Haplotypes in African Americans and Europeans
Abstract: Background: The APOE ε4 allele is the largest genetic risk factor for late-onset Alzheimer’s disease (AD). Recent literature suggested that the contribution of APOE ε4 to AD risk could be population-specific, with ε4 conferring a lower risk to Blacks or African Americans. Objective: To investigate the effect of APOE haplotypes on AD risk in individuals with European ancestry (EU) and Blacks or African Americans (AA). Methods: We selected data from 1) the National Alzheimer’s Coordinating Center: a total of 3,486 AD cases and 4,511 controls (N=7,997, 60% female) with genotypes from the Alzheimer’s Disease Genetics Consortium (ADGC), and 2) the Rush University Religious Orders Study and Memory and Aging Project (ROSMAP) cohort with 578 AD and 670 controls (N=1,248, 60% female). Using ε3 homozygotes as the reference, we compared the association of various APOE haplotypes with the clinical and neuropathological correlates of dementia in AA and EU. Results: In both cohorts, we find no difference in the odds or age of onset of AD among the ε4-linked haplotypes defined by rs769449 within either AA or EU. Additionally, while APOE ε4 was associated with a faster rate of decline, no differences were found in rate of decline, clinical or neuropathological features among the ε4-linked haplotypes. Further analysis with other variants near the APOE locus failed to identify any effect modification. Conclusion: Our study finds similar effects of the ε4-linked haplotypes defined by rs769449 on AD as compared to ε3 in both AA and EU. Future studies are required to understand the heterogeneity of APOE conferred risk of AD among various genotypes and populations.