Volume 68, Number 4, 2019

Pages 1311-1316
Ethics Review

Andrew D. Watt, Nicole L. Jenkins, Gawain McColl, Steven Collins, Patricia M. Desmond
Ethical Issues in the Treatment of Late-Stage Alzheimer’s Disease
Abstract: There is hope that the continuing efforts of researchers will yield a disease-modifying drug for Alzheimer’s disease. Such a drug is likely to be capable of halting, or significantly slowing, the underlying pathological processes driving cognitive decline; however, it is unlikely to be capable of restoring brain function already lost through the pathological process. A therapy capable of halting Alzheimer’s disease, while not providing restoration of function, may prompt serious ethical questions. For example, is there a stage in the disease process when it becomes too late for therapeutic intervention to commence? And who bears the responsibility of making such a decision? Conversations regarding the ethics of treating neurodegenerative conditions with non-restorative drugs have been largely absent within both clinical and research communities. Such discussions are urgently required to ensure that patients’ rights and well-being are protected when such therapeutic options become available.

Pages 1317-1319
Ethics Response

Allyson C. Rosen, Leslie Toy, Ashley Langston (Handling Associate Editor: J. Wesson Ashford)
Are Disease Modifying Treatments Enough? Improving Quality of Life in Late-Stage Patients
Abstract: The potential for successful disease modifying treatments for Alzheimer’s disease (AD) opens up the possibility that there will be a large cohort of patients living with late-stage dementia and poor quality of life. There must thus be a parallel effort to leverage restorative therapies that improve quality of life in these patients. With the potential for stopping the onset of new patients with AD must come a commitment to those patients living with this chronic disability for many more years than first thought. Legal and ethical implications surrounding who makes decisions and equity in receiving care will become increasingly important if AD is no longer a terminal illness.

Pages 1321-1323
Ethics Response

Andrew D. Watt, Nicole L. Jenkins, Gawain McColl, Steven Collins, Patricia M. Desmond
“To Treat or not To Treat”: Informing the Decision for Disease-Modifying Therapy in Late-Stage Alzheimer’s Disease
Abstract: Rosen et al. thoughtfully extend the ethical discussion surrounding disease-modifying therapies in late-stage Alzheimer’s disease (AD) to correctly emphasize that the perceived quality of life (QoL) of the individual living with the disease is a critical component to decisions regarding their clinical care. The primary purpose of our original article regarding the use of disease-modifying therapeutics in late-stage AD was to ensure that those affected by AD and their primary care team are empowered to make informed care decisions in the best interest of the individual living with AD. Consequently, it appears axiomatic that major therapeutic decisions need to incorporate consideration of the current and future QoL of individuals living with dementia; however, in the absence of effective restorative therapies, it is important to acknowledge the context within which extant QoL measures were developed and question whether such measures are adequate to inform treatment decisions that may hold the potential to significantly or perhaps indefinitely prolong severe disability.

Pages 1325-1337

Alexandra Wuttke-Linnemann, Ricarda Baake, Andreas Fellgiebel
Dyadic Wind of Change: New Approaches to Improve Biopsychological Stress Regulation in Patients with Dementia and Their Spousal Caregivers
Abstract: Patients with dementia (PWD) and their caregivers experience long-term stress, leading to accelerated disease progression and to stress-related morbidity. Previous research focused on intrapersonal biopsychological stress responses. Quite recently, dyadic interrelations between caregivers and PWD and their effects on stress and caregiver burden have received more attention, giving rise to dyadic intervention studies. However, while it is of importance to consider both the patient and the caregiver from a dyadic point of view, evaluation of these dyadic interventions considering underlying mechanisms is still lacking. We therefore extend the current literature on dyadic processes between PWD and caregivers by transferring the knowledge about underlying stress-modulating dyadic processes in healthy couples to the dementia patient-caregiver constellation. By targeting dyadic stress co-regulation between PWD and caregivers, we expect significant therapeutic effectiveness. The aims of this article are two-fold: 1) We aim to provide a rationale for incremental benefits of considering dyadic processes among caregivers and PWD by means of elucidating underlying mechanisms and 2) we aim to emphasize the need to evaluate these underlying mechanisms by means of objective physiological stress markers in both PWD and caregivers. Knowledge on these underlying mechanisms will ultimately help developing dyadic interventions tailored to the needs of both PWD and their caregivers.

Pages 1339-1370

Abhishek Wadhawan, John W. Stiller, Eileen Potocki, Olaoluwa Okusaga, Aline Dagdag, Christopher A. Lowry, Michael E. Benros, Teodor T. Postolache
Traumatic Brain Injury and Suicidal Behavior: A Review
Abstract: Given the increasing rate of death by suicide in the United States, it is imperative to examine specific risk factors and to identify possible etiologies of suicidal behavior in at-risk clinical subpopulations. There is accumulating evidence to support an elevated risk of death by suicide in individuals with a history of traumatic brain injury (TBI). In this review article, after defining terms used in suicidology, we discuss the associations of TBI with death by suicide, suicide attempt, and suicidal ideation. A model for repetitive TBIs, chronic traumatic encephalopathy, is also discussed as a neuroinflammatory process, with discussion about its possible link with suicide. The review concludes with an overview of interventions to prevent suicidal behavior.

Pages 1371-1390

Maurizio Manigrasso, Carmela Protano, Matteo Vitali, Pasquale Avino
Where Do Ultrafine Particles and Nano-Sized Particles Come From?
Abstract: This paper presents an overview of the literature studies on the sources of ultrafine particles (UFPs), nanomaterials (NMs), and nanoparticles (NPs) occurring in indoor (occupational and residential) and outdoor environments. Information on the relevant emission factors, particle concentrations, size, and compositions is provided, and health relevance of UFPs and NPs is discussed. Particular attention is focused on the fraction of particles that upon inhalation deposit on the olfactory bulb, because these particles can possibly translocate to brain and their possible role in neurodegenerative diseases is an important issue emerging in the recent literature.

Pages 1391-1400
Huifang Guo*, Zhaohua Zhao*, Ruisan Zhang, Peng Chen, Xiaohua Zhang, Fan Cheng, Xingchun Gou *These authors contributed equally to this work.
Monocytes in the Peripheral Clearance of Amyloid-β and Alzheimer’s Disease
Abstract: Aging societies have high incidence rates of Alzheimer’s disease (AD). AD is diagnosed at later disease stages and has a poor prognosis, and effective drugs and treatments for AD are lacking. The molecular mechanism of AD is not clear, and current research focuses primarily on amyloid-β (Aβ) deposition and tau protein hyperphosphorylation. Aβ deposition is the most frequently hypothesized initiating factor of AD, and Aβ clearance during the pathogenesis of AD may be an optional strategy to suppress AD development. Monocytes play important roles in the peripheral clearance of Aβ. Therefore, the present review summarizes our current knowledge of the potential roles of infiltrating macrophages, circulating monocytes, and Kupffer cells in the peripheral clearance of Aβ in AD.

Pages 1401-1414

Angelo Bianchetti, Nicola Ferrara, Alessandro Padovani, Elio Scarpini, Marco Trabucchi, Stefania Maggi
Timely Detection of Mild Cognitive Impairment in Italy: An Expert Opinion
Abstract: Mild cognitive impairment (MCI) generally evolves in a gradually progressive decline in memory and non-memory cognitive domains that may eventually decay to dementia. This process might be preventable by improving early detection of the MCI syndrome followed by proper and timely interventions. The aim of this work was providing helpful indications for a standardized early diagnosis of MCI, mainly focusing on the Italian elderly population. We reviewed here MCI epidemiology and classification, as well as the most recent advancements in early detection of the patient with MCI in the Italian scenario. Specialist centers in connection with general practitioners (GPs) have been established across the country and designated as Centers for Cognitive Disorders and Dementia (CDCD). CDCDs are dedicated to the diagnosis and management of patients for all forms of dementia across all the complex staging spectrum. New tools were made available by the advancements of imaging techniques and of the research on biomarkers, leading to novel approaches based on the combination of imaging and biomarker detection, to improve accuracy and effectiveness in the early diagnosis of MCI. Moreover, patient genotyping, alone or in combination with other techniques, was also revealed as a promising method in evaluating and preventing MCI progression. We recommend the introduction of all these novel tools in the diagnostic practice of the specialist centers and that further efforts and resources are spent into the research of the most effective techniques and biomarkers to be introduced as first-level tests into the practice of early diagnosis of MCI.

Pages 1415-1427
Angela Kuhla, Elaine Brichmann, Claire Rühlmann, Robin Thiele, Lou Meuth, Brigitte Vollmar
Metformin Therapy Aggravates Neurodegenerative Processes in ApoE-/- Mice
Abstract: Epidemiological studies suggest that individuals with diabetes mellitus are at greater risk of developing Alzheimer’s disease. A well-known insulin-sensitizing drug and the most widely prescribed oral medication for diabetes is metformin. There is evidence that metformin acts in a neuroprotective manner via the AMPK/mTOR pathway by inhibiting the tau phosphorylation. In addition, it is known that metformin upregulates Fgf21, which in turn activates the AMPK/mTOR pathway and mediates neuroprotection. Thus, metformin-induced Fgf21 release may be involved in AMPK/mTOR activation. However, some studies reported that metformin causes cognition impairment. Due to the controversial data on the neuroprotective properties of metformin, we treated Apolipoprotein E deficient (ApoE-/-) mice, a mouse model of tauopathy, with metformin for 18 weeks. Metformin-treated mice revealed increased expression of lipogenic genes, i.e., lxrα and srebp1c. In line with this, metformin caused an increase in plasma triglyceride leading to enhanced gliosis as indicated by an increase of GFAP-positive cells. Although the systemic Fgf21 concentration was increased, metformin did not activate the FgfR1c/AMPK/mTOR pathway suggesting a Fgf21-resistant state. Further, metformin-treated mice showed increased tau phosphorylation and reduced numbers of NeuN- and PSD95-positive cells. Thus, metformin-associated lipogenesis as well as inflammation aggravated neurodegenerative processes in ApoE-/- mice. Consequently, this study supports previous observations showing that metformin causes impairment of cognition.

Pages 1429-1438
Lauren M. Wright, Thor D. Stein, Gyungah Jun, Jaeyoon Chung, Kate McConnell, Marissa Fiorello, Nicole Siegel, Steven Ness, Weiming Xia, Kelley L. Turner, Manju L. Subramanian
Association of Cognitive Function with Amyloid-β and Tau Proteins in the Vitreous Humor
Abstract: Background: The eye may serve as source for diagnostic testing for early detection of Alzheimer’s disease (AD). Examination of amyloid-β (Aβ) and tau protein content in human vitreous and its correlation to neuro-cognition may improve ocular-based AD detection methods. Objective: To evaluate levels of Aβ and tau protein in human vitreous humor and investigate the clinical predictive role of these proteins as early diagnostic markers of AD. Methods: A prospective, single-center, multi-surgeon cohort study. Vitreous humor samples from 80 eyes were measured quantitatively for Aβ40-42, pTau, and tTau. Linear regression was used to test associations between AD biomarker levels, Mini-Mental State Exam (MMSE), and serum apolipoprotein E (APOE) allele status, with adjustment for age, sex, and education level of patients. Results: Lower MMSE scores were significantly associated with lower levels of vitreous Aβ40 (p=0.015), Aβ42 (p=0.0066), and tTau (p=0.0085), and these biomarkers were not associated with any pre-existing eye conditions. Presence of the ε4 allele and the ε2 allele approached significance with reduced Aβ40 level (p=0.053) and increased p-Tau level (p=0.056), respectively. Conclusion: Patients with poor cognitive function have significantly lower vitreous humor levels of AD-related biomarkers Aβ40, Aβ42, and tTau. These biomarkers do not correlate with underlying eye conditions, suggesting their specificity in association with cognitive change. This is the first study to our knowledge to correlate cognition with AD-related proteins in the vitreous humor. Results suggest ocular proteins may have a role for early dementia detection in individuals at risk for AD.

Pages 1439-1451
Kayela Robertson, Eric B. Larson, Paul K. Crane, Brenna Cholerton, Suzanne Craft, Wayne C. McCormick, Susan M. McCurry, James D. Bowen, Laura D. Baker, Emily H. Trittschuh (Handling Associate Editor: Andrew Saykin)
Using Varying Diagnostic Criteria to Examine Mild Cognitive Impairment Prevalence and Predict Dementia Incidence in a Community-Based Sample
Abstract: Lack of a unitary operational definition of mild cognitive impairment (MCI) has resulted in mixed prevalence rates and unclear predictive validity regarding conversion to dementia and likelihood of reversion. We examined 1,721 nondemented participants aged 65 and older from the Adult Changes in Thought (ACT) community-based cohort. Participants were followed longitudinally through biennial visits (average years assessed=5.38). Categorization of MCI was based on: 1) deviation of neuropsychological test scores from a benchmark based on either standard or individualized expectations of a participant’s mean premorbid cognitive ability, and 2) cutoff for impairment (1.0 versus 1.5 standard deviations [sd] below benchmark). MCI prevalence ranged from 56-92%; using individualized benchmarks and less stringent cutoffs produced higher rates. During follow-up, 17% of the cohort developed dementia. Examination of sensitivity, specificity, and predictive validity revealed that the criterion of 1.5 sd from the standardized benchmark was optimal, but still had limited predictive validity. Participants meeting this criterion at their first visit were three times more likely to develop dementia and this increased to seven times if participants had this diagnosis at the second timepoint as well. Those who did not have an MCI diagnosis at their first visit, but did at their second, had a significant increase of risk (but to a lesser extent than those diagnosed at both visits), while those who had an MCI diagnosis at their first visit, but not their second, did not have a significantly increased risk. These results highlight how assessing MCI stability greatly improves prediction of risk.

Pages 1453-1468
Hilkka Liedes, Jyrki Lötjönen, Juha M Kortelainen, Gerald Novak, Mark van Gils, Mark Forrest Gordon, for the Alzheimer’s Disease Neuroimaging Initiative, and the Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing
Multivariate Prediction of Hippocampal Atrophy in Alzheimer’s Disease
Abstract: Background: Hippocampal atrophy (HA) is one of the biomarkers for Alzheimer’s disease (AD). Objective: To identify the best biomarkers and develop models for prediction of HA over 24 months using baseline data. Methods: The study included healthy elderly controls, subjects with mild cognitive impairment, and subjects with AD, obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI 1) and the Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing (AIBL) databases. Predictor variables included cognitive and neuropsychological tests, amyloid-β, tau, and p-tau from cerebrospinal fluid samples, apolipoprotein E, and features extracted from magnetic resonance images (MRI). Least-mean-squares regression with elastic net regularization and least absolute deviation regression models were tested using cross-validation in ADNI 1. The generalizability of the models including only MRI features was evaluated by training the models with ADNI 1 and testing them with AIBL. The models including the full set of variables were not evaluated with AIBL because not all needed variables were available in it. Results: The models including the full set of variables performed better than the models including only MRI features (root-mean-square error (RMSE) 1.76-1.82 versus 1.93-2.08). The MRI-only models performed well when applied to the independent validation cohort (RMSE 1.66-1.71). In the prediction of dichotomized HA (fast versus slow), the models achieved a reasonable prediction accuracy (0.79-0.87). Conclusions: These models can potentially help identifying subjects predicted to have a faster HA rate. This can help in selection of suitable patients into clinical trials testing disease-modifying drugs for AD.

Pages 1469-1478
Kathrin Heser, Luca Kleineidam, Birgitt Wiese, Anke Oey, Susanne Roehr, Alexander Pabst, Hanna Kaduszkiewicz, Hendrik van den Bussche, Christian Brettschneider, Hans-Helmut König, Siegfried Weyerer, Jochen Werle, Angela Fuchs, Michael Pentzek, Edelgard Mösch, Horst Bickel, Wolfgang Maier, Martin Scherer, Steffi G. Riedel-Heller, Michael Wagner (Handling Associate Editor: Erin Sundermann)
Subjective Cognitive Decline May Be a Stronger Predictor of Incident Dementia in Women than in Men
Abstract: Background/Objective: Subjective cognitive decline (SCD) has often been associated with an increased risk for subsequent dementia. However, sex-specific associations are understudied until now. Methods: Cross-sectional and longitudinal associations over a follow-up period of up to 13 years were investigated in a sample of participants without objective cognitive impairment at baseline (n = 2,422, mean age = 79.63 years). Logistic regression and Cox proportional hazards models were conducted. Results: Women less frequently reported SCD without worries (p < 0.001), but tended to report more often SCD with worries (p = 0.082) at baseline compared to men. In models adjusted for age, education, cognitive status, and depressive symptoms, SCD at baseline increased the risk for subsequent dementia (p < 0.001), and this effect was less pronounced in males (interaction sex x SCD: p = 0.022). Stratified analyses showed that SCD increased the risk for subsequent dementia in women (HR = 1.77, p < 0.001), but not in men (HR = 1.07, p = 0.682). Similar results were found in analyses with SCD without and with worries, except that SCD with worries also predicted subsequent Alzheimer’s disease (AD) in men (p = 0.037). Conclusion: At baseline, men reported more SCD without worries and women tended to report more SCD with worries. SCD in women was more strongly associated with subsequent dementia. SCD without and with worries was related to incident dementia and AD in women, whereas in men only SCD with worries increased the risk for AD, but not for all-cause dementia.

Pages 1479-1488
Chris Moran, Kenneth Xie, Su Poh, Sarah Chew, Richard Beare, Wei Wang , Michele Callisaya, Velandai Srikanth (Handling Associate Editor: Ronan O'Caoimh)
Observational Study of Brain Atrophy and Cognitive Decline Comparing a Sample of Community-Dwelling People Taking Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Over Time
Abstract: Background: Hypertension is an established risk factor for dementia. However, it is unclear whether there are differential effects of angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARB) on brain health. In human observational studies, the evidence for superiority of either agent remains unclear. Objective: To compare brain atrophy and cognitive decline between people treated with ACEi or ARB. Methods: Participants aged 55-90 years without dementia had brain magnetic resonance imaging and neuropsychological assessments performed at 3 time points. The sample was enriched with people with type 2 diabetes (T2D). Multivariable mixed models were used to examine longitudinal associations of antihypertensive medication class with change in cognition and total brain volume. Results: Of 565 people with longitudinal data, there were 163 on ACEi (mean age 69.9 years, T2D:64% with) and 125 on ARB (mean age 69.6 years, T2D:62%) at baseline. The baseline characteristics of those taking either an ACEi or ARB were similar with regards to age, sex, blood pressure control, and vascular risk factors. The mean duration of follow up was 3.2 years. The baseline association of ACEi and ARB use with total brain volume was similar in both groups. However, those taking an ARB had a slower rate of brain atrophy than those taking an ACEi (p=0.031). Neither ACEi nor ARB use was associated with baseline cognitive function or cognitive decline. Conclusions: These results support the theory that ARB may be preferable to ACEi to reduce brain atrophy. The mechanisms underlying this differential association warrant further investigation.

Pages 1489-1497
Nasim Sheikh-Bahaei, Roido Manavaki, S. Ahmad Sajjadi, Andrew N. Priest, John T. O’Brien, Jonathan H. Gillard
Correlation of Lobar Cerebral Microbleeds with Amyloid, Perfusion, and Metabolism in Alzheimer’s Disease
Abstract: Background: Despite the well-documented relationship between lobar cerebral microbleeds (lCMB) and Alzheimer’s disease (AD), there is limited knowledge about the role of lCMB in AD pathology. Objective: To understand the nature of this relationship, we investigated the association between lCMB, amyloid load, perfusion, and metabolism. Methods: Participants with AD, mild cognitive impairment (MCI), and healthy controls were recruited and scanned with 11C-Pittsburg-Compound B (PiB), Fluorodeoxyglucose (FDG) PET, and susceptibility-weighted MRI. Early PiB-PET frames were used to estimate perfusion. The association between lCMB and PET uptake in each anatomical lobe was measured using multiple regression models. Results: The presence of lCMB predicted increased total (p<0.001) and regional (p=0.0002) PiB uptake, as well as decreased cerebral perfusion (p=0.03). Cases with lCMB had hypometabolism in their temporal lobe (p=0.04). Conclusion: There are significant relationships between lCMBs and various markers of AD pathology. lCMB has a spatial association with Aβ load and a complex effect on perfusion and metabolism.

Pages 1499-1510
Rónán O’Caoimh, Yang Gao, Anton Svendrovski, Maddalena Illario, Guido Iaccarino, Burcu Balam Yavuz, Patrick Gavin Kehoe, D. William Molloy (Handling Associate Editor: Whitney Wharton)
Effect of Visit-to-Visit Blood Pressure Variability on Cognitive and Functional Decline in Mild to Moderate Alzheimer’s Disease
Abstract Background: Visit-to-visit blood pressure (BP) variability (VVV) is increasingly recognized as a marker of cardiovascular risk. Although implicated in cognitive decline, few studies are currently available assessing its effects on established dementia. Objective: To investigate if VVV is associated with one-year rate of decline in measures of cognition and function in patients with mild to moderate Alzheimer’s disease (AD) in the Doxycycline And Rifampicin for Alzheimer’s Disease study. Methods: Patients were included if ≥3 BP readings were available (n=392). VVV was defined using different approaches including the coefficient of variation (CV) in BP readings between visits. Outcomes included rates of decline in the Standardized Alzheimer’s Disease Assessment Scale–Cognitive Subscale (SADAS-cog), Standardized MMSE, Clinical Dementia Rating Scale, the Quick Mild Cognitive Impairment screen and the Lawton-Brody activities of daily living (ADL) scale. Results: Half of the patients (196/392) had a ≥4-point decline in the SADAS-cog over one-year. Using this cut-off, there were no statistically significant associations between any measures of VVV, for systolic or diastolic BP, with and without adjustment for potential confounders including treatment allocation, history of hypertension and use of anti-hypertensive and cognitive enhancing medications. Multiple regression models examining the association between systolic BP CV by quartile and decline over one-year likewise showed no clinically significant effects, apart from a U-shaped pattern of ADL decline of borderline clinical significance. Conclusions: This observational study does not support recent research showing that VVV predicts cognitive decline in AD. Further studies are needed to clarify its effects on ADL in AD.

Pages 1511-1519
Kailey Langer, Deirdre O’Shea, Liselotte De Wit, Brittany DeFeis, Andrea Mejia, Priscilla Amofa, Melanie Chandler, Dona Locke, Julie Fields, Vaishali Phatak, Pamela Dean, Glenn Smith (Handling Associate Editor: J. Luis Conde-Sala)
Self-Efficacy Mediates the Association between Physical Function and Perceived Quality of Life in Individuals with Mild Cognitive Impairment
Abstract: Background: Research has shown that individuals with mild cognitive impairment (MCI) value quality of life (QoL) above and beyond cognitive function or other potential outcomes in MCI. There is evidence supporting the negative impact of poor physical function on QoL ratings. Objective: The study explored whether a modified measure of self-efficacy for managing MCI and education mediated and/or moderated the relationship between physical function and QoL in persons with MCI. Methods: Baseline data from 200 participants with MCI were obtained from a larger study assessing the effectiveness of a behavioral intervention. Physical function was assessed by the Short Physical Performance Battery. QoL was assessed with the Quality of Life in Alzheimer’s Disease scale. Memory-related self-efficacy was assessed using a modified 9-item version of the Chronic Disease Self-Efficacy Scales. Mediation and moderation analyses tested the hypotheses that self-efficacy and education alter the association between physical function and QoL in individuals with MCI. All analyses were adjusted for age, cognitive severity, and sex. Results: Self-efficacy for managing MCI was a significant mediator of the association between physical function and perceived QoL. Individuals with better physical function reported higher self-efficacy which was associated with higher QoL ratings. Conclusions: Greater self-efficacy for managing MCI mediated the negative association between physical function and quality of life in this exploratory study. Interventions aimed at enhancing memory self-efficacy in MCI may improve perceived QoL, even in the presence of poor physical function. Future research is needed to investigate this further.

Pages 1521-1534
Adrià Rofes, Vânia de Aguiar, Bronte Ficek, Haley Wendt, Kimberly Webster, Kyrana Tsapkini (Handling Associate Editor: Albert Lladó)
The Role of Word Properties in Performance on Fluency Tasks in People with Primary Progressive Aphasia
Abstract: People with primary progressive aphasia (PPA) present language difficulties that require lengthy assessments and follow-ups. Despite individual differences, people with PPA are often classified into three variants that present some distinctive language difficulties. We analyzed the data of 6 fluency tasks (i.e., “F”, “A”, “S”, “Fruits”, “Animals”, “Vegetables”). We used random forests to pinpoint relevant word properties and error types in the classification of the three PPA variants: conditional inference trees to indicate how relevant variables may interact with one another and ANOVAs to cross-validate the results. Results indicate that total word count helps distinguish healthy individuals (N=10) from people with PPA (N=29). Furthermore, mean familiarity differentiates people with svPPA (N=8) from people with lvPPA (N=10) and nfvPPA (N=11). No other word property or error type was relevant in the classification. These results relate to previous literature, as familiarity effects have been reported in people with svPPA in naming and spontaneous speech. Also, they strengthen the relevance of using familiarity to identify a specific group of people with PPA. This paper enhances our understanding of what determines word retrieval in people with PPA, complementing and extending data from naming studies.

Pages 1535-1547
Olivia Belbin, Kevin Morgan, Chris Medway, Donald Warden, Mario Cortina-Borja, Cornelia M. van Duijn, Hieab H.H. Adams, Ana Frank-Garcia, Keeley Brookes, Pascual Sánchez-Juan, Victoria Alvarez, Reinhard Heun, Heike Kölsch, Eliecer Coto, Patrick G. Kehoe, Eloy Rodriguez-Rodriguez, Maria J Bullido, M. Arfan Ikram, A. David Smith, Donald J. Lehmann (Handling Associate Editor: Javier Vitorica)
The Epistasis Project: A Multi-Cohort Study of the Effects of BDNF, DBH, and SORT1 Epistasis on Alzheimer’s Disease Risk
Abstract: Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer’s disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin). We performed a multi-cohort case-control association study of the BDNF, DBH, and SORT1 loci comprising 5,682 controls and 2,454 AD patients from Northern Europe (87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; OR=1.1-1.2, p=0.005-0.3), an effect size that was consistent in the Northern European (OR=1.1-1.2, p=0.002-0.8) but not the smaller Spanish (OR=0.8-1.6, p=0.4-1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SF=1.3-1.5 p=0.002-0.02) translated to a greater risk of AD associated with BDNF in women (OR=1.2-1.3, p=0.007-0.00008) than men (OR=0.9-1.0, p=0.3-0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (OR=1.1, p=0.04) the synergistic interaction (SF=2.2, p=0.007) between BDNF (rs6265) and DBH (rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SF=2.4, p=0.04) than men (SF=2.0, p=0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women.

Pages 1549-1559
Barbara E. Spencer, Robin G. Jennings, James B. Brewer; for the Alzheimer’s Disease Neuroimaging Initiative
Combined Biomarker Prognosis of Mild Cognitive Impairment: An 11-Year Follow-Up Study in the Alzheimer’s Disease Neuroimaging Initiative
Abstract: Background: Biomarkers may soon be used to predict decline in older individuals. Extended follow-up studies are needed to determine the stability of such biomarker-based predictions. Objective: To examine the long-term performance of baseline cognitive, neuroimaging, and cerebrospinal fluid (CSF) biomarker-assisted prognosis in patients with mild cognitive impairment. Methods: Established, biomarker-defined, cohorts of subjects with mild cognitive impairment were examined for progression to dementia. Subjects with a baseline volumetric MRI, lumbar puncture, and Rey Auditory Verbal Learning Test were included. Dementia-free survival time in each biomarker-defined risk group was determined with Kaplan-Meier survival curves. The influence of each risk factor or combination of factors on dementia-free survival was examined with Cox proportional hazard analyses. Results: 185 subjects were followed longitudinally for a mean (SD) 4.3 (2.8) years. 59% of participants converted within the follow-up period and the median dementia-free survival time was 2.8 years. Each individual risk factor predicted conversion to dementia (HR 1.9–3.7). The joint presence of any two risk factors increased risk for conversion (HR 7.1–11.0), with the presence of medial temporal atrophy and memory impairment showing the greatest risk for decline. Concordant atrophy, memory impairment, and abnormal CSF amyloid and tau was associated with the highest risk for conversion (HR 15.1). The presence of medial temporal atrophy was associated with the shortest dementia-free survival time, both alone and in combination with memory impairment, abnormal CSF amyloid and tau, or both. Conclusion: These results suggest that baseline biomarker-assisted predictions of decline to dementia are stable over the long term, and that combinations of complementary biomarkers can improve the accuracy of these predictions.

Pages 1561-1574
Sibylle Robens, Petra Heymann, Regine Gienger, Andreas Hett, Stephan Müller, Christoph Laske, Roland Loy, Thomas Ostermann, Ulrich Elbing
The Digital Tree Drawing Test for Screening of Early Dementia: An Explorative Study Comparing Healthy Controls, Patients with Mild Cognitive Impairment, and Patients with Early Dementia of the Alzheimer Type
Abstract: The digital tree drawing test (dTDT) is a newly developed screening tool for the early detection of Alzheimer’s disease. It is performed with a digitizing pen, recording each pen stroke with temporal and spatial precision. It was hypothesized that movement characteristics recorded during the painting process contribute to the identification of patients with mild cognitive impairment (MCI) and early dementia of the Alzheimer type (eDAT). The study population consisted of 187 participants (67 healthy controls, 64 MCI, and 56 eDAT patients) with a mean age of 68.6±10.6 years. Between-group comparisons of the dTDT-variables were conducted with analysis of variance. The diagnostic power of dTDT variables was analyzed with stepwise logistic regressions and areas under curve (AUC) of receiver operating control curves. Cognitively impaired persons used less colors and line widths and changed them less often than healthy subjects (p-values≤0.05). Compared to control, eDAT patients had larger not-painting periods, were slower, and their pictures had less contrast, image size, and complexity (p-values≤0.01). Logistic regression models of stepwise selected dTDT variables resulted in an AUC of 0.84 (95% confidence interval (CI) [0.79, 0.90], sensitivity=0.78, specificity=0.77) for discriminating healthy subjects from all cognitive impaired, an AUC of 0.77. (95% CI [0.69; 0.85], sensitivity=0.56, specificity=0.83) for discriminating healthy controls from MCI patients and an AUC of 0.90 (95% CI [0.84, 0.96], sensitivity=0.86, specificity=0.82) for discriminating controls from eDAT patients. The results suggest that digital recording of pen-stroke data during the drawing process can contribute to the screening of cognitive impaired patients.

Pages 1575-1585
Christopher Black, Richard B. Lipton, Ellen Thiel, Matthew Brouillette, Rezaul Khandker
Relationship between Treatment Initiation and Healthcare Costs in Alzheimer’s Disease
Abstract: The relationship between Alzheimer’s disease (AD) treatment patterns and healthcare costs is unknown. Administrative claims data from the MarketScan Commercial and Medicare databases covering 2010 through 2016 were used to identify the comorbidities, treatment patterns, and healthcare costs in the three years prior to and one year post medical diagnosis of AD in 21,448 patients with no treatment and 57,970 patients with treatment. Pre-index mean annual costs ranged from $14,228 to $26,876, and post-index mean annual costs ranged from $21,052 to $45,685 depending on age and treatment timing. After adjusting for baseline characteristics, patients 50-100 years old who initiated treatment with an FDA approved drug prior to or concurrent with diagnosis had healthcare costs 9%-19% lower in the year following diagnosis than those who did not receive treatment. Early or concurrent treatment is associated with lower overall healthcare costs in the year following AD diagnosis.

Pages 1587-1601
Grazia D’Onofrio, Daniele Sancarlo, Massimiliano Raciti, Megan Burke, Aimee Teare, Tanja Kovacic, Keith Cortis, Kathy Murphy, Eva Barrett, Sally Whelan, Aisling Dolan, Alessandro Russo, Francesco Ricciardi, Geoff Pegman, Valentina Presutti, Thomas Messervey, Filippo Cavallo, Francesco Giuliani, Andy Bleaden, Dympna Casey, Antonio Greco
MARIO Project: Validation and Evidence of Service Robots for Older People with Dementia
Abstract: Background: In the EU funded MARIO project, specific technological tools are adopted for the people living with dementia (PLWD). In the final stage of the project, a validation of the MARIO companion robot was performed from August to October 2017. Objective: The aims of the present study are: 1) to illustrate the key results and evidence obtained in the final evaluation phase of the project across the three different pilot sites; 2) to assess the engagement dimensions of the PLWD who interacted with the MARIO robot; and 3) to assess the acceptability and efficacy of the MARIO companion robot on clinical, cognitive, neuropsychiatric, affective and social aspects, resilience, quality of life in PLWD, and burden level of the caregivers. Methods: 38 people (M=14; F=24) with Alzheimer’s disease were screened for eligibility and all were included. The following tests were administered Pre and Post interactions with MARIO: Observational Measurement of Engagement (OME), Mini-Mental State Examination (MMSE), Clock Drawing Test (CDT), Frontal Assessment Battery (FAB), Neuropsychiatric Inventory (NPI), Cornell Scale for Depression in Dementia (CSDD), Multidimensional Scale of Perceived Social Support (MSPSS), 14-item Resilience Scale (RS-14), Quality of Life in Alzheimer's Disease (QOL-AD), Caregiver Burden Inventory (CBI), Tinetti Balance Assessment (TBA), and Comprehensive Geriatric Assessment (CGA) was carried out. Results: In Post-MARIO interactions, significant improvements were observed in RS-14 (p=0.020). Considering the age of the people, PLWD with 68-76 years perceived that they had major social support (MSPSS Total: p=0.016) and friends to support them (MSPSS Fri: p=0.014). Indeed, the younger people (55-67 years) were less depressed (CSDD: p=0.033), and more resilient (RS-14: p=0.003). The people aged 77-85 years perceived they had major family support (MSPSS Fam: p=0.018). The participants were gender and education matched without any statistically significant difference. Conclusion: MARIO may be a useful tool in mitigating depression and loneliness, while enhancing social connectedness, resilience, and overall quality of life for people with dementia.

Pages 1603-1610
Roberta Baschi*, Vincenzo Restivo*, Alessandra Nicoletti, Calogero Edoardo Cicero, Antonina Luca, Deborah Recca, Mario Zappia, Roberto Monastero (Handling Associate Editor: Patrizia Mecocci) *These authors contributed equally to this work.
Mild Behavioral Impairment in Parkinson’s Disease: Data from the PArkinson’s disease COgnitive impairment Study
Abstract: Neuropsychiatric symptoms (NPS) have been frequently described in Parkinson’s disease (PD), even in the earliest stages of the disease. Recently the construct of mild behavioral impairment (MBI) has been proposed as an at-risk state for incident cognitive decline and dementia. The aim of the present study is to evaluate the prevalence and associated factors of MBI in PD. Cross-sectional data from 429 consecutive PD patients enrolled in the PArkinson’s disease COgnitive impairment Study (PACOS) were included in the study. All subjects underwent neuropsychological assessment, according to the MDS Level II criteria. NPS were evaluated with the Neuropsychiatric Inventory. Multivariate logistic regression models were used to evaluate clinical and behavioral characteristics, which are associated with PD-MBI. The latter was ascertained in 361 (84.1%) subjects of whom 155 (36.1%) were newly diagnosed patients (disease duration ≤1 year) and 206 (48.0%) had a disease duration >1 year. Furthermore, 68 (15.9%) out of 429 subjects were PDw (without MBI). Across the MBI domains, Impulse Dyscontrol was significantly more prevalent among PD-MBI with disease duration >1 year than newly diagnosed patients. The frequency of Social Inappropriateness and Abnormal Perception significantly increased throughout the entire PD-MBI sample with increasing Hoehn and Yahr (H&Y) stages. PD-MBI in newly diagnosed PD was significantly associated with H&Y stage (OR 2.35, 95% CI 1.05-5.24) and marginally with antidepressant drug use (OR 2.94, 95% CI 0.91-9.47), while in patients with a disease duration >1 year was associated with UPDRS-ME (OR 3.37, 95% CI 1.41-8.00). The overall MBI frequency in the PACOS sample was 84% and 36% among newly diagnosed patients. The presence of MBI mainly related to motor impairment and disability.

Pages 1611-1624
Rachel Mis, Kathryn Devlin, Deborah Drabick, Tania Giovannetti (Handling Associate Editor: David Loewenstein)
Heterogeneity of Informant-Reported Functional Performance in Mild Cognitive Impairment: A Latent Profile Analysis of the Functional Activities Questionnaire
Abstract: Heterogeneity of subtle functional difficulties in mild cognitive impairment (MCI) remains poorly understood. We characterized patterns of informant reports of functional abilities among participants with MCI and the relation between functional ability pattern and cognitive abilities and subsequent decline. Data from 4,273 MCI participants from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) were included in latent profile analyses (LPA) of informant responses on the Functional Activities Questionnaire (FAQ). Profiles from the best fitting model were compared on demographic, clinical, and cognitive variables. The best fitting model supported three profiles varying by level and type of difficulty: intact function (n=3,299), intermediate (n=769), and high ratings of difficulty (n=205). For the Intermediate profile, items related to finances, remembering dates, and travel were rated as most difficult. The High Ratings profile also had elevated ratings on the meal preparation item. Participants with either the Intermediate or High Ratings profile demonstrated a three-fold increase in conversion to dementia as compared to participants with the Intact profile. Demographically, the Intact profile was younger and consisted of a higher proportion of minorities. On cognitive tests, the Intact profile showed the best performance, and the Intermediate profile performed comparably to or better than the High Ratings profile. There is meaningful heterogeneity in informant ratings of function in MCI, though individuals with MCI whose informants report even intermediate-level functional difficulties are more likely to progress to dementia, suggesting that even subtle functional difficulties place individuals at higher risk for future decline.

Pages 1625-1633
Catherine M. Roe, Sarah H. Stout, Ganesh Rajasekar, Beau M. Ances, Jessica M. Jones, Denise Head Tammie L.S. Benzinger, Monique M. Williams, Jennifer Duncan Davis, Brian R. Ott, David K. Warren, Ganesh M. Babulal
A 2.5-Year Longitudinal Assessment of Naturalistic Driving in Preclinical Alzheimer’s Disease
Abstract: Background: Emerging evidence shows that cognitively normal older adults with preclinical Alzheimer’s disease (AD) make more errors and are more likely to receive a marginal/fail rating on a standardized road test compared to older adults without preclinical AD, but the extent to which preclinical AD impacts everyday driving behavior is unknown. Objective: To examine self-reported and naturalistic longitudinal driving behavior among persons with and without preclinical AD. Method: We prospectively followed cognitively normal drivers (aged 65+ years) with (n=10) and without preclinical AD (n=10) for 2.5 years. Preclinical AD was assessed using amyloid positron emission tomography (PET) with Pittsburgh Compound B. The Driving Habits Questionnaire assessed self-reported driving outcomes. Naturalistic driving was captured using a commercial GPS data logger plugged into the on-board diagnostics II port of each participant’s vehicle. Data were sampled every 30 seconds and all instances of speeding, hard braking, and sudden acceleration were recorded. Results: Preclinical AD participants went to fewer places/unique destinations, traveled fewer days, and took fewer trips than participants without preclinical AD. The preclinical AD group reported a smaller driving space, greater dependence on other drivers, and more difficulty driving due to vision difficulties. Persons with preclinical AD had fewer trips with any aggression and showed a greater decline across the 2.5-year follow-up period in the number of days driving per month and the number of trips between 1-5 miles. Conclusion: Changes in driving occur even during the preclinical stage of AD.

Pages 1635-1656
Hamel Patel, Richard J.B. Dobson*, Stephen J. Newhouse* *These authors are joint last authors.
A Meta-Analysis of Alzheimer’s Disease Brain Transcriptomic Data
Abstract: Background: Microarray technologies have identified imbalances in the expression of specific genes and biological pathways in Alzheimer’s disease (AD) brains. However, there is a lack of reproducibility across individual AD studies, and many related neurodegenerative and mental health disorders exhibit similar perturbations. Objective: Meta-analyze publicly available transcriptomic data from multiple brain-related disorders to identify robust transcriptomic changes specific to AD brains. Methods: Twenty-two AD, eight schizophrenia, five bipolar disorder, four Huntington's disease, two major depressive disorder, and one Parkinson's disease dataset totaling 2,667 samples and mapping to four different brain regions (temporal lobe, frontal lobe, parietal lobe, and cerebellum) were analyzed. Differential expression analysis was performed independently in each dataset, followed by meta-analysis using a combining p-value method known as Adaptively Weighted with One-sided Correction. Results: Meta-analysis identified 323, 435, 1,023, and 828 differentially expressed genes specific to the AD temporal lobe, frontal lobe, parietal lobe, and cerebellum brain regions, respectively. Seven of these genes were consistently perturbed across all AD brain regions with SPCS1 gene expression pattern replicating in RNA-Seq data. A further nineteen genes were perturbed specifically in AD brain regions affected by both plaques and tangles, suggesting possible involvement in AD neuropathology. In addition, biological pathways involved in the “metabolism of proteins” and viral components were significantly enriched across AD brains. Conclusion: This study identified transcriptomic changes specific to AD brains, which could make a significant contribution toward the understanding of AD disease mechanisms and may also provide new therapeutic targets.

Pages 1657-1666
Guillaume Sacco, Grégory Ben-Sadoun, Jérémy Bourgeois, Roxane Fabre, Valeria Manera, Philippe Robert
Comparison between a Paper-Pencil Version and Computerized Version for the Realization of a Neuropsychological Test: The Example of the Trail Making Test
Abstract: Background: Neuropsychological tests are particularly important for the clinical evaluation and Alzheimer’s disease (AD) diagnosis. However, the tests currently employed for neuropsychological assessment have been developed several decades ago, and thus they do not fully exploit the potential provided by modern digital tools. One of the tests most commonly employed to assess attention and executive functions is the Trail Making Test (TMT). Objective: The aim of this study was to evaluate whether the TMT developed and used for the serious exergame X-Torp (TMTX-Torp) can be used to evaluate cognitive functions such as mental flexibility. Methods: Adjusted multivariate mixed model was used to compare performances in the TMTX-Torp to performances in the standard variant (TMTs) in three populations. 21 participants with AD (78.6y ± 8.5 y), 27 with mild cognitive impairment (MCI) (76.8y ± 8.5 y), and 27 healthy (HEC) (71.8y ± 7.4 y) were included. Results: A difference was observed for the TMT A between AD and HEC and for the TMT B between AD and MCI and between AD and HEC. Whatever the variant of the TMT, we found a positive linear correlation between the time to complete the TMTX-Torp and the TMTS for HEC (TMT A: r = 0.75, p < 0.001; TMT B: r = 0.52, p = 0.008) and MCI participants (TMT A: r = 0.53, p = 0.005; TMT B: r = 0.48, p = 0.025) but not for AD participants. Conclusion: Although these versions of the TMT were not identical, the results showed that both versions were able to discriminate between HEC, MCI, and AD populations.

Pages 1667-1675
Xiaowen Shi, Yasuyuki Ohta, Xia Liu, Jingwei Shang, Ryuta Morihara, Yumiko Nakano, Tian Feng, Yong Huang, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Koji Abe
Acute Anti-Inflammatory Markers ITIH4 and AHSG in Mice Brain of a Novel Alzheimer’s Disease Model
Abstract: Alzheimer’s disease (AD) is the most common dementia and a progressive neurodegenerative disorder aggravated by chronic hypoperfusion (HP). Since numerous evidence suggests that inflammation is related with AD pathology, we investigated the expression change of two anti-inflammatory markers, inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) and alpha-2-HS-glycoprotein (AHSG), in a novel AD model (APP23) with HP at 12 month of age. As compared with wild type (WT, n=10), immunohistochemical analysis showed a higher ITIH4 and a lower AHSG expressions in the cerebral cortex, hippocampus, and thalamus of the APP23 + HP group (n=12) than the simple APP23 (n=10) group (*p < 0.05 and **p < 0.01 versus WT; # p < 0.05 and ## p < 0.01 versus APP23). The present study provides an upregulation of anti-inflammatory ITIH4 and a downregulation of pro-inflammatory TNFα-dependent AHSG in a novel AD plus HP mice model.

Pages 1677-1686
Yoshiyuki Soeda, Marino Saito, Sumihiro Maeda, Kohki Ishida, Akira Nakamura, Shuichi Kojima, Akihiko Takashima
Methylene Blue Inhibits Formation of Tau Fibrils but not of Granular Tau Oligomers: A Plausible Key to Understanding Failure of a Clinical Trial for Alzheimer’s Disease
Abstract: Alzheimer’s disease pathology is characterized by extracellular deposits of amyloid-β (Aβ) and intracellular inclusions of hyperphosphorylated tau. Although genetic studies of familial Alzheimer’s disease suggest a causal link between Aβ and disease symptoms, the failure of various Aβ-targeted strategies to slow or halt disease progression has led to consideration of the idea that inhibition of tau aggregation might be a more promising therapeutic approach. Methylene blue (MB), which inhibits tau aggregation and rescue memory deficits in a mouse model of tauopathy, however, lacked efficacy in a recent Phase III clinical trial. In order to gain insight into this failure, the present study was designed to examine the mechanism through which MB inhibits tau aggregation. We found that MB inhibits heparin-induced tau aggregation in vitro, as measured by thioflavin T fluorescence. Further, MB reduced the amount of tau in precipitants recovered after ultracentrifugation of the aggregation mixture. Atomic force microscopy revealed that MB reduces the number of tau fibrils but increases the number of granular tau oligomers. The latter result was confirmed by sucrose gradient centrifugation: MB treatment was associated with higher levels of granular tau oligomers (fraction 3) and lower levels of tau fibrils (fractions 5 and 6). We previously demonstrated that the formation of granular tau oligomers, rather than tau fibrils, is essential for neuronal death. Thus, the fact that MB actions are limited to inhibition of tau fibril formation provides a mechanistic explanation for the poor performance of MB in the recent Phase III clinical trial.

Pages 1687-1697
Shiming Ju, Chen Xu, Gan Wang, Lin Zhang (Handling Associate Editor: Yong Guo)
VEGF-C Induces Alternative Activation of Microglia to Promote Recovery from Traumatic Brain Injury
Abstract: Traumatic brain injury (TBI), a brain disorder that causes death and long-term disability in humans, is increasing in prevalence, though there is a lack of protective or therapeutic strategies for mitigating the damage after TBI and for preserving neurological functionality. Microglia cells play a key role in neuroinflammation following TBI, but their regulation and polarization by a member of the vascular endothelial growth factor (VEGF) family, VEGF-C, is unknown. Here, we show that VEGF-C induced M2 polarization in a murine microglia cell line, BV-2, in vitro, by a mechanism that required signaling from its unique receptor, VEGF receptor 3 (VEGFR3). Moreover, in a TBI model in rats, VEGF-C administration induced M2 polarization of microglia cells, significantly improved motor deficits after experimental TBI, and significantly improved neurological function following TBI, likely through a reduction in cell apoptosis. Together, our data reveal a previously unknown role of VEGF-C/VEGFR3 signaling in the regulation of post-TBI microglia cell polarization, which appears to be crucial for recovery from TBI.

Pages 1699-1710
Susan A. Farr, Elizabeth Roesler, Michael L. Niehoff, Deborah A. Roby, Alexis McKee, John E. Morley (Handling Associate Editor: D. Allan Butterfield)
Metformin Improves Learning and Memory in the SAMP8 Mouse Model of Alzheimer’s Disease
Abstract: Metformin is used for the treatment of insulin resistant diabetes. Diabetics are at an increased risk of developing dementia. Recent epidemiological studies suggest that metformin treatment prevents cognitive decline in diabetics. A pilot clinical study found cognitive improvement with metformin in patients with mild cognitive impairment (MCI). Preclinical studies suggest metformin reduces Alzheimer-like pathology in mouse models of Alzheimer’s disease (AD). In the current study, we used 11-month-old SAMP8 mice. Mice were given daily injections of metformin at 20 mg/kg/sc or 200 mg/kg/sc for eight weeks. After four weeks, mice were tested in T-maze footshock avoidance, object recognition, and Barnes maze. At the end of the study, brain tissue was collected for analysis of PKC (PKCζ, PKCι, PKCα, PKCγ, PKCε), GSK-3β, pGSK-3βser9, pGSK-3βtyr216, pTau404, and APP. Metformin improved both acquisition and retention in SAMP8 mice in T-maze footshock avoidance, retention in novel object recognition, and acquisition in the Barnes maze. Biochemical analysis indicated that metformin increased both atypical and conventional forms of PKC; PKCζ, and PKCα at 20 mg/kg. Metformin significantly increased pGSK-3βser9 at 200 mg/kg, and decreased Aβ at 20 mg/kg and pTau404 and APPc99 at both 20 mg/kg and 200 mg/kg. There were no differences in blood glucose levels between the aged vehicle and metformin treated mice. Metformin improved learning and memory in the SAMP8 mouse model of spontaneous onset AD. Biochemical analysis indicates that metformin improved memory by decreasing APPc99 and pTau. The current study lends support to the therapeutic potential of metformin for AD.