Search

BACKGROUND: The Anti-Amyloid in Asymptomatic Alzheimers Disease (A4) Study failed to show a treatment benefit with solanezumab, but the longitudinal consequences of elevated amyloid were observed in study participants with objective decline on the Preclinical Alzheimer Cognitive Composite (PACC) and subjective decline on the combined Cognitive Function Index (participant + study partner CFI), during the trial period. OBJECTIVES: We sought to expand on previous findings by comparing longitudinal patterns of participant and study partner CFI separately and their associations with the PACC stratified by baseline amyloid tertile over the course of the A4 Study. DESIGN: Cognitively unimpaired older adult participants and their study partners were independently administered the CFI at screen prior to amyloid PET disclosure and then at 3 subsequent visits (week 48, week 168, week 240) of the study. PACC collected at visits concurrent with CFI administration were also examined longitudinally. SETTING: The A4 Study was conducted at 67 sites in Australia, Canada, Japan, and the United States. PARTICIPANTS: 1,147 participants with elevated amyloid based on florbetapir PET were enrolled in the A4 Study and included in these analyses. 583 were on placebo and 564 were treated with solanezumab. MEASUREMENTS: The PACC was used to assess objective cognitive performance and the CFI was used to assess change in everyday cognitive functioning by the participant and their study partner independently. Amyloid level was characterized by Centiloid tertiles (77.2 CL). Participants were aware of their elevated amyloid status, but not their CL tertile, or specific level of amyloid. Longitudinal correlations between participant and study partner CFI and PACC were examined at all visits where assessments were available. The impact of baseline amyloid tertile on CFI and PACC associations was also examined. RESULTS: Both participant and study partner CFI increased over the duration of the study indicating worsening cognitive functioning. Results did not differ by treatment group. The association between higher CFI and worse PACC for both for participant and study partner became progressively stronger over the course of the study. PACC had a significantly higher correlation with study partner CFI than with participant CFI by week 168. The stronger correlations between study partner CFI and PACC were driven by those in the highest amyloid tertile. CONCLUSION: Both participant and study partner report captured subtle changes in everyday cognitive functioning for participants with biomarker confirmed and disclosed preclinical AD. Moreover, study partner report was most highly aligned with cognitive decline, particularly among those with the highest amyloid load.

The 2020 COVID-19 pandemic has disrupted Alzheimer's disease (AD) clinical studies worldwide. Digital technologies may help minimize disruptions by enabling remote assessment of subtle cognitive and functional changes over the course of the disease. The EU/US Clinical Trials in Alzheimer's Disease (CTAD) Task Force met virtually in November 2020 to explore the opportunities and challenges associated with the use of digital technologies in AD clinical research. While recognizing the potential of digital tools to accelerate clinical trials, improve the engagement of diverse populations, capture clinically meaningful data, and lower costs, questions remain regarding the stability, validity, generalizability, and reproducibility of digital data. Substantial concerns also exist regarding regulatory acceptance and privacy. Nonetheless, the Task Force supported further exploration of digital technologies through collaboration and data sharing, noting the need for standardization of digital readouts. They also concluded that while it may be premature to employ remote assessments for trials of novel experimental medications, remote studies of non-invasive, multi-domain approaches may be feasible at this time.

Background and Objectives: Hippocampal volume (HV) atrophy is a well-known biomarker of memory impairment. However, compared with β-amyloid (Aβ) and tau imaging, it is less specific for Alzheimer disease (AD) pathology. This lack of specificity could provide indirect information about potential copathologies that cannot be observed in vivo. In this prospective cohort study, we aimed to assess the associations among Aβ, tau, HV, and cognition, measured over a 10-year follow-up period with a special focus on the contributions of HV atrophy to cognition after adjusting for Aβ and tau., Methods: We enrolled 283 older adults without dementia or overt cognitive impairment in the Harvard Aging Brain Study. In this report, we only analyzed data from individuals with available longitudinal imaging and cognition data. Serial MRI (follow-up duration 1.3-7.0 years), neocortical Aβ imaging on Pittsburgh Compound B PET scans (1.9-8.5 years), entorhinal and inferior temporal tau on flortaucipir PET scans (0.8-6.0 years), and the Preclinical Alzheimer Cognitive Composite (3.0-9.8 years) were prospectively collected. We evaluated the longitudinal associations between Aβ, tau, volume, and cognition data and investigated sequential models to test the contribution of each biomarker to cognitive decline., Results: We analyzed data from 128 clinically normal older adults, including 72 (56%) women and 56 (44%) men; median age at inclusion was 73 years (range 63-87). Thirty-four participants (27%) exhibited an initial high-Aβ burden on PET imaging. Faster HV atrophy was correlated with faster cognitive decline ( R 2 = 0.28, p < 0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of Aβ and tau measures, uniquely accounting for 10% of the variance. Altogether, 45% of the variance in cognitive decline was explained by combining the change measures in the different imaging biomarkers., Discussion: In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of Aβ or tau, suggesting that non-AD pathologies (e.g., TDP-43, vascular) may contribute to hippocampal-mediated cognitive decline. Serial HV measures, in addition to AD-specific biomarkers, may help evaluate the contribution of non-AD pathologies that cannot be measured otherwise in vivo.

Subjective cognitive decline (SCD) is defined as self-experienced, persistent concerns of decline in cognitive capacity in the context of normal performance on objective cognitive measures. Although SCD was initially thought to represent the "worried well," these concerns can be linked to subtle brain changes prior to changes in objective cognitive performance and, therefore, in some individuals, SCD may represent the early stages of an underlying neurodegenerative disease process (e.g., Alzheimer's disease). The field of SCD research has expanded rapidly over the years, and this review aims to provide an update on new advances in, and contributions to, the field of SCD in key areas and themes identified by researchers in this field as particularly important and impactful. First, we highlight recent studies examining sociodemographic and genetic risk factors for SCD, including explorations of SCD across racial and ethnic minoritized groups, and examinations of sex and gender considerations. Next, we review new findings on relationships between SCD and in vivo markers of pathophysiology, utilizing neuroimaging and biofluid data, as well as associations between SCD and objective cognitive tests and neuropsychiatric measures. Finally, we summarize recent work on interventions for SCD and areas of future growth in the field of SCD., Competing Interests: None of the authors (C.E.M, R.B., X.C., G.C., C.G., R.J.J., J.M., I.O., T.R., E.W., Y.T.Q., J.R.G., P.V., and R.A.) have any relevant disclosures or conflicts of interest. Author disclosures are available in the Supporting Information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Subjective cognitive decline (SCD) has been associated with elevated amyloid levels and increased risk of future cognitive decline, as well as modifiable variables, including depression, anxiety, and physical inactivity. Participants generally endorse greater and earlier concerns than their close family and friends (study partners [SPs]), which may reflect subtle changes at the earliest stages of disease among participants with underlying neurodegenerative processes. However, many individuals with subjective concerns are not at risk of Alzheimer's disease (AD) pathology, suggesting that additional factors, such as lifestyle habits, may be contributory., Methods: We examined the relation between SCD, amyloid status, lifestyle habits (exercise, sleep), mood/anxiety, and demographic variables among 4481 cognitively unimpaired older adults who are being screened for a multi-site secondary prevention trial (A4 screen data; mean ±SD: age = 71.3 ±4.7, education = 16.6 ±2.8, 59% women, 96% non-Hispanic or Latino, 92% White]., Results: On the Cognitive Function Index (CFI) participants endorsed higher concerns compared to SPs. Participant concerns were associated with older age, positive amyloid status, worse mood/anxiety, lower education, and lower exercise, whereas SP concerns were associated with older participant age, male gender of participant, positive amyloid status of participant, and worse participant-reported mood/anxiety., Discussion: Findings suggest that modifiable/lifestyle factors (e.g., exercise, education) may be associated with participant concerns among cognitively unimpaired individuals and highlight the importance of further examining how modifiable factors impact participant- and SP-reported concerns, which may inform trial recruitment and clinical interventions., Competing Interests: G. Reynolds, R. Buckley, K. Papp, S. Schultz, and R. Amariglio have nothing relevant to disclose. D. Rentz has nothing to disclose related to this project but other disclosures include the Dana Corporation, and Scientific Advisory Boards at Northwestern and UC Davis. R. Sperling has served as a paid consultant for AC Immune, Alector, Acumen, Alnylam, Genentech, Janssen, Neuraly, Oligomerix, Prothena, Renew, and Vaxxinity; receives research support from Eisai and Eli Lilly (these relationships are not related to the content in the manuscript); and also receives research support from the following grants: P01 AG036694,U24 AG057437, R01 AG063689, R01 AG054029, R01 AG053798, GHR Foundation, Fidelity Biosciences, and the Alzheimer's Association. Author disclosures are available in the Supporting Information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Subjective cognitive decline (SCD) may be an early symptom of Alzheimer's disease. We aimed to estimate the prevalence of SCD in Brazil and its association with dementia modifiable risk factors., Methods: We used data of 8138 participants from the Brazilian Longitudinal Study of Aging (ELSI-Brazil), a population-based study that included clinical and demographic variables of individuals across the country. We calculated the prevalence of SCD and its association with dementia modifiable risk factors., Results: We found that the prevalence of SCD in Brazil was 29.21% (28.22%-30.21%), varying according to region, sex, and age. SCD was strongly associated with hearing loss, low education, psychological distress, Brown/Pardo and Black races., Discussion: The prevalence of SCD in Brazil is higher than in high-income countries. Brown/Black races and dementia modifiable risk factors were associated with SCD. Public strategies that target SCD may help mitigate the incidence of dementia., Competing Interests: None., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Efficient identification of cognitive decline and Alzheimer's disease (AD) risk in early stages of the AD disease continuum is a critical unmet need. Subjective cognitive decline is increasingly recognized as an early symptomatic stage of AD. Dyadic cognitive report, including subjective cognitive complaints (SCC) from a participant and an informant/study partner who knows the participant well, represents an accurate, reliable, and efficient source of data for assessing risk. However, the separate and combined contributions of self- and study partner report, and the dynamic relationship between the two, remains unclear. The Subjective Cognitive Decline Professional Interest Area within the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment convened a working group focused on dyadic patterns of subjective report. Group members identified aspects of dyadic-report information important to the AD research field, gaps in knowledge, and recommendations. By reviewing existing data on this topic, we found evidence that dyadic measures are associated with objective measures of cognition and provide unique information in preclinical and prodromal AD about disease stage and progression and AD biomarker status. External factors including dyad (participant-study partner pair) relationship and sociocultural factors contribute to these associations. We recommend greater dyad report use in research settings to identify AD risk. Priority areas for future research include (1) elucidation of the contributions of demographic and sociocultural factors, dyad type, and dyad relationship to dyad report; (2) exploration of agreement and discordance between self- and study partner report across the AD syndromic and disease continuum; (3) identification of domains (e.g., memory, executive function, neuropsychiatric) that predict AD risk outcomes and differentiate cognitive impairment due to AD from other impairment; (4) development of best practices for study partner engagement; (5) exploration of study partner report as AD clinical trial endpoints; (6) continued development, validation, and optimization, of study partner report instruments tailored to the goals of the research and population., Competing Interests: R.L.N. receives research support in the form of grants to the institution from the NIH (K01 AG055692, 1RF1AG059009, 1R33AG062867), California Department of Public Health (19‐10616), and Genentech, Inc. (G‐89294); and declares no potential conflicts of interest. E.K. receives research support by the University of Caen Normandy, the Institut National de la Santé et de la Recherche Médicale (Inserm), and Fondation Philippe Chatrier; and declares no potential conflicts of interest. R.E.A. receives research support in the form of grants to the institution from the NIH (R01AARG‐17‐529011). All other authors have no declarations of interest. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: Subjective Cognitive Decline (SCD) may be an early indicator of risk for Alzheimer's disease (AD). Findings regarding sex differences in SCD are inconsistent. Studying sex differences in SCD within cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia, may inform sex-related SCD variations in preclinical AD. We examined sex differences in SCD within cognitively unimpaired mutation carriers from the world's largest ADAD kindred and sex differences in the relationship between SCD and memory performance., Methods: We included 310 cognitively unimpaired Presenilin-1 (PSEN-1) E280A mutation carriers (51% females) and 1998 noncarrier family members (56% females) in the study. Subjects and their study partners completed SCD questionnaires and the CERAD word list delayed recall test. ANCOVAs were conducted to examine group differences in SCD, sex, and memory performance. In carriers, partial correlations were used to examine associations between SCD and memory performance covarying for education., Results: Females in both groups had greater self-reported and study partner-reported SCD than males (all p < 0.001). In female mutation carriers, greater self-reported ( p = 0.02) and study partner-reported SCD ( p < 0.001) were associated with worse verbal memory. In male mutation carriers, greater self-reported ( p = 0.03), but not study partner-reported SCD ( p = 0.11) was associated with worse verbal memory., Conclusions: Study partner-reported SCD may be a stronger indicator of memory decline in females versus males in individuals at risk for developing dementia. Future studies with independent samples and preclinical trials should consider sex differences when recruiting based on SCD criteria.

Background: The COVID-19 pandemic has disproportionately impacted the most vulnerable and widened the health disparity gap in both physical and mental well-being. Consequentially, it is vital to understand how to best support elderly individuals, particularly Black Americans and people of low socioeconomic status, in navigating stressful situations during the COVID-19 pandemic and beyond. The aim of this study was to investigate perceived levels of stress, posttraumatic growth, coping strategies, socioeconomic status, and mental health between Black and non-Hispanic, White older adults, the majority over the age of 70. Additionally, we investigated which variables, if any, were associated with posttraumatic growth in these populations., Methods: One hundred seventy-six community dwelling older adults (mean age = 76.30 ±8.94), part of two observational studies (The Harvard Aging Brain Study and Instrumental Activities of Daily Living Study) in Massachusetts, US, were included in this cross-sectional study. The survey, conducted from March 23, 2021 to May 13, 2021, measured perceived stress, behavioral coping strategies, posttraumatic growth, and mental health during the COVID-19 pandemic. We investigated associations with post-traumatic growth in a multiple linear regression model and examined their differences by race with t -tests, Wilcoxon rank-sum tests, and Fisher's exact tests. A second multiple linear regression model was used to examine which coping strategies were associated with posttraumatic growth., Findings: Our results indicated no significant difference between the groups in terms of mental health or stress. However, Black participants showed significantly greater posttraumatic growth compared to non-Hispanic, White participants. Additionally, the coping strategies of religion and positive reframing were found to be significantly associated with posttraumatic growth. Furthermore, even with the effects of stress and coping strategies controlled for, race remained significantly associated with posttraumatic growth., Interpretation: The COVID-19 pandemic has differentially impacted Black and non-Hispanic White older adults. These results may help encourage further analysis on geriatric psychiatry as well as understanding how cultural values and adaptations impact posttraumatic growth and mental health in diverse populations., Funding: The Harvard Aging Brain Study (HABS) has been funded by NIH-NIA P01 AG036694 (PI: Reisa Sperling). The IADL study is funded by the National Institute on Aging (R01 AG053184, PI: Gad A. Marshall)., Competing Interests: Dr. Dossett reports personal fees from UpToDate, personal fees from Harvard Health Publishing, and grants from NCCIH, outside the submitted work. Dr. Quiroz reports grants from US National Institute on Aging, grants from Alzheimer's Association, and consulting fees from Biogen, outside the submitted work. Dr. Rentz reports consulting from Digital Cognition Technologies, consulting from Biogen Idec, and is on the Scientific Advisory Board for Neurotrack, outside the submitted work. Dr. Sperling reports grants or contracts from Eli Lilly and Co. and Eisai and Co., and consulting fees from AC Immune, Janssen, Ionis, NervGen, Oligomerix, and Genentech, outside the submitted work. Dr. Marshall has received research salary support from Eisai Inc., Eli Lilly and Company, Janssen Alzheimer Immunotherapy, Novartis, and Genentech, and consulting fees from Grifols Shared Services North America, Inc., and Eisai Inc, outside the submitted work. All other authors have nothing to declare., (© 2022 The Authors.)

Whereas discrepancies between participant- and study partner-reported cognitive concerns on the Alzheimer's disease (AD) continuum have been observed, more needs to be known regarding the longitudinal trajectories of participant- vs. study partner-reported concerns, particularly their relationship to AD biomarkers and mood symptomology. Additionally, it is unclear whether years of in-clinic data collection are needed to observe relationships with AD biomarkers, or whether more frequent, remote assessments over shorter periods of time would suffice. This study primarily sought to examine the relationships between longitudinal trajectories of participant- and study partner-rated cognitive decline and baseline biomarker levels [i.e., amyloid and tau positron emission tomography (PET)], in addition to how mood symptomatology may alter these trajectories of concerns over a 2-year period. Baseline mood was associated with longitudinal participant-rated concerns, such that participants with elevated depression and anxiety scores at baseline had decreasing concerns about cognitive decline over time (fixed estimate = -0.17, 95% CI [-0.29 to -0.05], t = -2.75, df = 457, adj. p = 0.012). A significant interaction between baseline amyloid (fixed estimate = 4.07, 95% CI [1.13-7.01], t = 2.72, df = 353, adj. p = 0.026) and tau (fixed estimate = 3.50, 95% CI [0.95-6.06], t = 2.70, df = 331, adj. p = 0.030) levels was associated with increasing study partner concerns, but not participant concerns, over time. The interaction between amyloid and study partner concerns remained significant when utilizing only the first year of concern-related data collection. Overall, these results suggest that frequent, remote assessment of study partner-reported concerns may offer additional insight into the AD clinical spectrum, as study partners appear to more accurately update their concerns over time with regard to pathology, with these concerns less influenced by participants' mood symptomatology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Munro, Buckley, Vannini, DeMuro, Sperling, Rentz, Johnson, Gatchel and Amariglio.)

Noninvasive biomarkers of early neuronal injury may help identify cognitively normal individuals at risk of developing Alzheimer's disease (AD). A recent diffusion-weighted imaging (DWI) method allows assessing cortical microstructure via cortical mean diffusivity (cMD), suggested to be more sensitive than macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with amyloid-β and tau pathology in older adults, and whether cMD predicts longitudinal cognitive decline, neurodegeneration and clinical progression. The study sample comprised n = 196 cognitively normal older adults (mean[SD] 72.5 [9.4] years; 114 women [58.2%]) from the Harvard Aging Brain Study. At baseline, all participants underwent structural MRI, DWI, 11 C-Pittsburgh compound-B-PET, 18 F-flortaucipir-PET imaging, and cognitive assessments. Longitudinal measures of Preclinical Alzheimer Cognitive Composite-5 were available for n = 186 individuals over 3.72 (1.96)-year follow-up. Prospective clinical follow-up was available for n = 163 individuals over 3.2 (1.7) years. Surface-based image analysis assessed vertex-wise relationships between cMD, global amyloid-β, and entorhinal and inferior-temporal tau. Multivariable regression, mixed effects models and Cox proportional hazards regression assessed longitudinal cognition, brain structural changes and clinical progression. Tau, but not amyloid-β, was positively associated with cMD in AD-vulnerable regions. Correcting for baseline demographics and cognition, increased cMD predicted steeper cognitive decline, which remained significant after correcting for amyloid-β, thickness, and entorhinal tau; there was a synergistic interaction between cMD and both amyloid-β and tau on cognitive slope. Regional cMD predicted hippocampal atrophy rate, independently from amyloid-β, tau, and thickness. Elevated cMD predicted progression to mild cognitive impairment. Cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration and clinical progression, suggesting utility in clinical trials., (© 2021. The Author(s).)

Assessing the impact of the COVID-19 pandemic on perceived stress in older adults is critical to understanding how to best support elderly individuals navigating stressful situations, with the aim to lessen the impact of stressors on their brain health. Here, we collected measures on perceived stress, resilience, and behavioral coping strategies, in the context of the COVID-19 pandemic, in a cross-sectional sample of 141 community dwelling older adults (mean age = 74.4 ± 8.4, 59% females) who were part of two longitudinal observational studies in Massachusetts, U.S. Our results indicate that participants demonstrated moderate levels of stress related to COVID-19 and showed relatively high levels of resilience. Higher resilience was associated with greater use of adaptive coping behaviors and less use of maladaptive coping behaviors. The use of maladaptive coping strategies was associated with more stress. Moreover, hierarchical regression analyses revealed that resilience was the strongest unique predictor of stress, thus, largely accounting for the observed coping-outcome associations. Individual differences in resilience levels moderated the effects of two coping strategies (planning and self-blame) on stress. Specifically, planning was associated with increased levels of stress for people with low resilience. In contrast, high personal resilience attenuated the negative effect of self-blame on their stress levels. Taken together, our findings suggest that resilience is critical for coping with stress during the COVID-19 pandemic. Future approaches for augmenting resilience could prove to be important potential interventions to help support older adults navigating stressful situations as well as lessen adverse effects on neurocognitive and mental health in the future., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: In the COVID-19 pandemic, older adults from vulnerable ethnoracial groups are at high risk of infection, hospitalization, and death. We aimed to explore the pandemic's impact on the well-being and cognition of older adults living in the United States (US), Argentina, Chile, Mexico, and Peru., Methods: 1,608 (646 White, 852 Latino, 77 Black, 33 Asian; 72% female) individuals from the US and four Latin American countries aged ≥ 55 years completed an online survey regarding well-being and cognition during the pandemic between May and September 2020. Outcome variables (pandemic impact, discrimination, loneliness, purpose of life, subjective cognitive concerns) were compared across four US ethnoracial groups and older adults living in Argentina, Chile, Mexico, and Peru., Findings: Mean age for all participants was 66.7 ( SD  = 7.7) years and mean education was 15.4 ( SD  = 2.7) years. Compared to Whites, Latinos living in the US reported greater economic impact ( p  < .001, η p 2  =  0 .031); while Blacks reported experiencing discrimination more often ( p  < .001, η p 2  =  0 .050). Blacks and Latinos reported more positive coping ( p  < .001, η p 2  =  0. 040). Compared to Latinos living in the US, Latinos in Chile, Mexico, and Peru reported greater pandemic impact, Latinos in Mexico and Peru reported more positive coping, Latinos in Argentina, Mexico, and Peru had greater economic impact, and Latinos in Argentina, Chile, and Peru reported less discrimination., Interpretation: The COVID-19 pandemic has differentially impacted the well-being of older ethnically diverse individuals in the US and Latin America. Future studies should examine how mediators like income and coping skills modify the pandemic's impact., Funding: Massachusetts General Hospital Department of Psychiatry., Competing Interests: Dr. Thumala reports personal fees from National Agency for Research and Development, during the conduct of the study. Dr. Miranda-Castillo reports grants and personal fees from National Agency for Research and Development, during the conduct of the study. Dr. Gatchel reports grants from NIH/NIA, grants from Alzheimer's Association, and served as a one-time consultant with Huron Consulting, outside the submitted work. Dr. Sperling reports personal fees from Roche, Takeda Pharmaceuticals, Eisai, Biogen, AC Immune, Neurocentria, Janssen, Neuraly, Alnylam Pharmaceuticals, Renew, JOMDD, Acumen, Prothena, Cytox, Oligomerix, Inc., and Genentech; grants from Eisai, Eli Lilly, Janssen, NIA, and Alzheimer's Association; personal fees and honorarium (consulting) for Dr. Sperling's spouse (Dr. Keith Johnson) from Novartis, AC Immune, Janssen, and Cerveau, outside the submitted work. Dr. Rentz reports consulting from Digital Cognition Technologies, Neurotrack, and Biogen Idec, outside the submitted work. All other authors have nothing to declare., (© 2021 The Authors.)

Virtual Reality (VR) has had significant advances in rehabilitation, due to the gamification of cognitive activities that facilitate treatment. On the other hand, Immersive Virtual Reality (IVR) produces outstanding results due to the interactive features with the user. This work introduces a VR application for memory rehabilitation by walking through a maze and using the Oculus Go head-mounted display (HMD) technology. The mechanics of the game require memorizing geometric shapes while the player progresses in two modes, autonomous or manual, with two levels of difficulty depending on the number of elements to remember. The application is developed in the Unity 3D video game engine considering the optimization of computational resources to improve the performance in the processing and maintaining adequate benefits for the user, while the generated data is stored and sent to a remote server. The maze task was assessed with 29 subjects in a controlled environment. The obtained results show a significant correlation between participants' response accuracy in both the maze task and a face-pair test. Thus, the proposed task is able to perform memory assessments.

Sensor systems for the Internet of Things (IoT) make it possible to continuously monitor people, gathering information without any extra effort from them. Thus, the IoT can be very helpful in the context of early disease detection, which can improve peoples' quality of life by applying the right treatment and measures at an early stage. This paper presents a new use of IoT sensor systems-we present a novel three-door smart cupboard that can measure the memory of a user, aiming at detecting potential memory losses. The smart cupboard has three sensors connected to a Raspberry Pi, whose aim is to detect which doors are opened. Inside of the Raspberry Pi, a Python script detects the openings of the doors, and classifies the events between attempts of finding something without success and the events of actually finding it, in order to measure the user's memory concerning the objects' locations (among the three compartments of the smart cupboard). The smart cupboard was assessed with 23 different users in a controlled environment. This smart cupboard was powered by an external battery. The memory assessments of the smart cupboard were compared with a validated test of memory assessment about face-name associations and a self-reported test about self-perceived memory. We found a significant correlation between the smart cupboard results and both memory measurement methods. Thus, we conclude that the proposed novel smart cupboard successfully measured memory.

Background: There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline., Objective: We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members., Methods: 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol)., Results: The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals' estimated age of clinical onset., Conclusions: The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD.

Objective: To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD)., Methods: We examined self-reported and study partner-based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing., Results: Self-reported SMC were greater in carriers than noncarriers ( p = 0.02). Study partner-based SMC did not differ between groups ( p = 0.21), but in carriers increased with age ( r = 0.66, p < 0.001) and decreased with hippocampal volume ( r = -0.35, p = 0.08)., Conclusions: Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset., (© 2017 American Academy of Neurology.)

Introduction: Sensitive detection of cognitive decline over the course of preclinical Alzheimer's disease is critical as the field moves toward secondary prevention trials., Methods: We examined amyloid β (Aβ)-related change in several variations of the preclinical Alzheimer cognitive composite (PACC) and each individual PACC component in clinically normal (CN) older participants in the Harvard Aging Brain Study. We then examined the PACC variations in the Alzheimer's Disease Cooperative Study Prevention Instrument Study as a replication cohort., Results: Aβ+ CN individuals demonstrated longitudinal decline on all individual PACC components and all PACC variations. Aβ group differences emerged earlier when Free and Cued Selective Reminding Test Free Recall was included in the PACC. PACC decline was associated with Clinical Dementia Rating progression., Discussion: This independent data set and a replication cohort confirm the ability of the PACC to capture both early and late cognitive decline during the preclinical stages of Alzheimer's disease, which may prove advantageous in the prevention trial design., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

While loss of insight of cognitive deficits, anosognosia, is a common symptom in Alzheimer's disease dementia, there is a lack of consensus regarding the presence of altered awareness of memory function in the preclinical and prodromal stages of the disease. Paradoxically, very early in the Alzheimer's disease process, individuals may experience heightened awareness of memory changes before any objective cognitive deficits can be detected, here referred to as hypernosognosia. In contrast, awareness of memory dysfunction shown by individuals with mild cognitive impairment (MCI) is very variable, ranging from marked concern to severe lack of insight. This study aims at improving our mechanistic understanding of how alterations in memory self-awareness are related to pathological changes in clinically normal (CN) adults and MCI patients. 297 CN and MCI patients underwent PiB-PET (Positron Emission Tomography using Pittsburgh Compound B) in vivo amyloid imaging. Amyloid burden was estimated from Alzheimer's disease vulnerable regions, including the frontal, lateral parietal and lateral temporal, and retrosplenial cortex. Memory self-awareness was assessed using discrepancy scores between subjective and objective measures of memory function. A set of univariate analysis of variance were performed to assess the relationship between self-awareness of memory and amyloid pathology. Whereas CN individuals harboring amyloid pathology demonstrated hypernosognosia, MCI patients with increased amyloid pathology demonstrated anosognosia. In contrast, MCI patients with low amounts of amyloid were observed to have normal insight into their memory functions. Altered self-awareness of memory tracks with amyloid pathology. The findings of variability of awareness may have important implications for the reliability of self-report of dysfunction across the spectrum of preclinical and prodromal Alzheimer's disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Subjective cognitive decline (SCD) manifesting before clinical impairment could serve as a target population for early intervention trials in Alzheimer's disease (AD). A working group, the Subjective Cognitive Decline Initiative (SCD-I), published SCD research criteria in the context of preclinical AD. To successfully apply them, a number of issues regarding assessment and implementation of SCD needed to be addressed., Methods: Members of the SCD-I met to identify and agree on topics relevant to SCD criteria operationalization in research settings. Initial ideas and recommendations were discussed with other SCD-I working group members and modified accordingly., Results: Topics included SCD inclusion and exclusion criteria, together with the informant's role in defining SCD presence and the impact of demographic factors., Discussion: Recommendations for the operationalization of SCD in differing research settings, with the aim of harmonization of SCD measurement across studies are proposed, to enhance comparability and generalizability across studies., (Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

At a meeting of the EU/US/Clinical Trials in Alzheimer's Disease (CTAD) Task Force in December 2016, an international group of investigators from industry, academia, and regulatory agencies reviewed lessons learned from ongoing and planned prevention trials, which will help guide future clinical trials of AD treatments, particularly in the pre-clinical space. The Task Force discussed challenges that need to be addressed across all aspects of clinical trials, calling for innovation in recruitment and retention, infrastructure development, and the selection of outcome measures. While cognitive change provides a marker of disease progression across the disease continuum, there remains a need to identify the optimal assessment tools that provide clinically meaningful endpoints. Patient- and informant-reported assessments of cognition and function may be useful but present additional challenges. Imaging and other biomarkers are also essential to maximize the efficiency of and the information learned from clinical trials., Competing Interests: P. Aisen: NeuroPhage, Eli Lilly, Merck, Roche, Amgen, Abbvie, Pfizer, Novartis, Janssen, Lundbeck, Biogen, iPerian, Probiodrug, Anavex, Cohbar, Cytox, aTyr, Avanir; R. Bateman: Abbvie, AstraZeneca, Biogen, Eisai, Eli Lilly and Co., Hoffman La-Roche Inc., Janssen, Pfizer, Sanofi-Aventi; N. Fox: Janssen, Roche, Eli Lilly, Novartis, GSK, Biogen; S. Gauthier: Eli Lilly, TauRx, Roche, Eisai, Lundbeck, Schwabe; L. Schneider: Eli Lilly, Novartis, Roche/Genentech, Takeda; P. Tariot: Roche, Novartis, Amgen, Abbvie, Eli Lilly, AstraZeneca, Lundbeck, AC Immune, Merck, Takeda, Boehringer-Ingelheim; K. Welsh-Bohmer: Takeda, Merck, Biogen, Roche, J and J; B. Vellas: Biogen, Eli Lilly, Roche, Nestlé, Merck; R. Sperling: Avid/Lilly, Janssen, Bracket, Genetech, Sanofi, Roche, Abbvie, Lundbeck, Otsuka, Merck. S. Henrix: Pentara Corporation; R. Doody: Genentech/Roche; C. Ho, J. Breitner, R. Amariglio, M. Grundman, R. Raman, M. Isaac: No conflict of interest. The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work.

This commentary outlines a conceptual model for subjective cognitive decline (SCD) in relation to Alzheimer's disease (AD) biomarkers in the preclinical stages of disease and a framework for effectively utilizing SCD in secondary prevention clinical trials. Mounting evidence supports the notion that SCD is sensitive to encroaching Aβ-amyloid and neurodegeneration. SCD has also been shown to provide additive information of AD-dementia risk beyond what is known about the biomarker status of the individual. Thus, we provide recommendations for the implementing SCD measurement in clinical trials. We argue that SCD can be measured at three catch points within the course of the clinical trial: firstly, at the initial recruitment and screening phase; secondly, to create more robust estimates of rates of AD-dementia progression; and finally, to measure subjective experiences of cognitive change and quality of life over the course of the trial as a proxy of clinically meaningful functional improvement. We provide recommendations of how SCD can be approached at each of these points. SCD is an important component of the preclinical AD-dementia trajectory. Future studies need to elucidate the interactive influence of Aβ-amyloid and tau on SCD from a spatiotemporal perspective. Even as this evidence accrues, it is clear that SCD can provide unique and additive information about rates of progression and subjectively experienced cognitive change within clinical trials.

Importance: A substantial proportion of clinically normal (CN) older individuals are classified as having suspected non-Alzheimer disease pathophysiology (SNAP), defined as biomarker negative for β-amyloid (Aβ-) but positive for neurodegeneration (ND+). The etiology of SNAP in this population remains unclear., Objective: To determine whether CN individuals with SNAP show evidence of early Alzheimer disease (AD) processes (ie, elevated tau levels and/or increased risk for cognitive decline)., Design, Setting, and Participants: This longitudinal observational study performed in an academic medical center included 247 CN participants from the Harvard Aging Brain Study. Participants were classified into preclinical AD stages using measures of Aβ (Pittsburgh Compound B [PIB]-labeled positron emission tomography) and ND (hippocampal volume or cortical glucose metabolism from AD-vulnerable regions). Classifications included stages 0 (Aβ-/ND-), 1 (Aβ+/ND-), and 2 (Aβ+/ND+) and SNAP (Aβ-/ND+). Continuous levels of PiB and ND, tau levels in the medial and inferior temporal lobes, and longitudinal cognition were examined. Data collection began in 2010 and is ongoing. Data were analyzed from 2015 to 2016., Main Outcomes and Measures: Evidence of amyloid-independent tau deposition and/or cognitive decline., Results: Of the 247 participants (142 women [57.5%]; 105 men [42.5%]; mean age, 74 [range, 63-90] years), 64 (25.9%) were classified as having SNAP. Compared with the stage 0 group, the SNAP group was not more likely to have subthreshold PiB values (higher values within the Aβ- range), suggesting that misclassification due to the PiB cutoff was not a prominent contributor to this group (mean [SD] distribution volume ratio, 1.08 [0.05] for the SNAP group; 1.09 [0.05] for the stage 1 group). Tau levels in the medial and inferior temporal lobes were indistinguishable between the SNAP and stage 0 groups (entorhinal cortex, β = -0.005 [SE, 0.036]; parahippocampal gyrus, β = -0.001 [SE, 0.027]; and inferior temporal lobe, β = -0.004 [SE, 0.027]; P ≥ .88) and were lower in the SNAP group compared with the stage 2 group (entorhinal cortex, β = -0.125 [SE, 0.041]; parahippocampal gyrus, β = -0.074 [SE, 0.030]; and inferior temporal lobe, β = -0.083 [SE, 0.031]; P ≤ .02). The stage 2 group demonstrated greater cognitive decline compared with all other groups (stage 0, β = -0.239 [SE, 0.042]; stage 1, β = -0.242 [SE, 0.051]; and SNAP, β = -0.157 [SE, 0.044]; P ≤ .001), whereas the SNAP group showed a diminished practice effect over time compared with the stage 0 group (β = -0.082 [SE, 0.037]; P = .03)., Conclusions and Relevance: In this study, clinically normal adults with SNAP did not exhibit evidence of elevated tau levels, which suggests that this biomarker construct does not represent amyloid-independent tauopathy. At the group level, individuals with SNAP did not show cognitive decline but did show a diminished practice effect. SNAP is likely heterogeneous, with a subset of this group at elevated risk for short-term decline. Future refinement of biomarkers will be necessary to subclassify this group and determine the biological correlates of ND markers among Aβ- CN individuals., Competing Interests: Potential Conflicts of Interest E. Mormino received funding from NIH grant F32AG044054 and P01 AG036694. K. Papp received funding from NIH grant P01 AG036694 and the Charles King Trust Foundation. D. Rentz received research support from the NIH grants P01 AG036694, R01 MH090291, U01 AG024904, R01 AG027435, R01 AG037497 and P50 AG005134, Alzheimer Association grant IIRG-08-90934 and Fidelity Biosciences. She has also served as a paid consultant for Eli Lilly, Janssen Pharmaceuticals and Neurotrack. These relationships are not related to the content in the manuscript. A. Schultz has no conflicts to report. M. LaPoint has no conflicts to report. R. Amariglio received funding from the Alzheimer’s Association NIRG-12-243012 and NIH P01AG036694, RO1-AG027435. B. Hanseeuw received support from the Belgian American Education Foundation (BAEF). G. Marshall received research support from NIH grants K23AG033634, P50AG005134, P01AG036694, R01AG027435, and U01AG024904, he received salary support from Eisai Inc. and Eli Lilly and Company, and he served as a paid consultant for Halloran/GliaCure. These relationships are not related to the content in the manuscript. T. Hedden received funding from NIH grants K01 AG040197, P01 AG036694, and R01 AG034556. K. Johnson has served as paid consultant for Bayer, GE Healthcare, Janssen Alzheimer’s Immunotherapy, Siemens Medical Solutions, Genzyme, Novartis, Biogen, Roche, ISIS Pharma, AZTherapy, GEHC, Lundberg, and Abbvie. He is a site coinvestigator for Lilly/Avid, Pfizer, Janssen Immunotherapy, and Navidea. He has spoken at symposia sponsored by Janssen Alzheimer’s Immunotherapy and Pfizer. These relationships are not related to the content in the manuscript. K. Johnson receives funding from NIH grants R01EB014894, R21 AG038994, R01 AG026484, R01 AG034556, P50 AG00513421, U19 AG10483, P01 AG036694, R13 AG042201174210, R01 AG027435, and R01 AG037497 and the Alzheimer’s Association grant ZEN-10-174210. R. Sperling has served as a paid consultant for Abbvie, Biogen, Bracket, Genentech, Lundbeck, Roche, and Sanofi. She has served as a co-investigator for Avid, Eli Lilly, and Janssen Alzheimer Immunotherapy clinical trials. She has spoken at symposia sponsored by Eli Lilly, Biogen, and Janssen. R. Sperling receives research support from Janssen Pharmaceuticals, and Eli Lilly and Co. These relationships are not related to the content in the manuscript. She also receives research support from the following grants: P01 AG036694, U01 AG032438, U01 AG024904, R01 AG037497, R01 AG034556, K24 AG035007, P50 AG005134, U19 AG010483, R01 AG027435, Fidelity Biosciences, Harvard NeuroDiscovery Center, and the Alzheimer’s Association.

Objective: Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer disease (AD), staging and monitoring of disease progression, and development of disease-modifying therapies., Methods: We acquired tau positron emission tomography (PET) using (18)F T807 (AV1451), and amyloid-β PET using (11)C Pittsburgh compound B (PiB) in older clinically normal individuals, and symptomatic patients with mild cognitive impairment or mild AD dementia., Results: We found abnormally high cortical (18)F T807 binding in patients with mild cognitive impairment and AD dementia compared to clinically normal controls. Consistent with the neuropathology literature, the presence of elevated neocortical (18)F T807 binding particularly in the inferior temporal gyrus was associated with clinical impairment. The association of cognitive impairment was stronger with inferior temporal (18)F T807 than with mean cortical (11)C PIB. Regional (18)F T807 was correlated with mean cortical (11)C PiB among both impaired and control subjects., Interpretation: These findings suggest that (18)F T807 PET could have value as a biomarker that reflects both the progression of AD tauopathy and the emergence of clinical impairment., (© 2015 American Neurological Association.)

Recently published guidelines suggest that the most opportune time to treat individuals with Alzheimer's disease is during the preclinical phase of the disease. This is a phase when individuals are defined as clinically normal but exhibit evidence of amyloidosis, neurodegeneration and subtle cognitive/behavioral decline. While our standard cognitive tests are useful for detecting cognitive decline at the stage of mild cognitive impairment, they were not designed for detecting the subtle cognitive variations associated with this biomarker stage of preclinical Alzheimer's disease. However, neuropsychologists are attempting to meet this challenge by designing newer cognitive measures and questionnaires derived from translational efforts in neuroimaging, cognitive neuroscience and clinical/experimental neuropsychology. This review is a selective summary of several novel, potentially promising, approaches that are being explored for detecting early cognitive evidence of preclinical Alzheimer's disease in presymptomatic individuals.