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Background and Aims: Physical inactivity and poor sleep are common in older adults and may interact to contribute to age- and disease-related cognitive decline. However, prior work regarding the associations among physical activity, and cognition in older adults is primarily limited to subjective questionnaires that are susceptible to inaccuracies and recall bias. Therefore, this study examined whether objectively measured physical activity and sleep characteristics, each estimated using actigraphy, are independently or interactively associated with cognitive performance., Methods: The study included 157 older adults free of dementia (136 cognitively unimpaired; 21 MCI; M age = 71.7) from the BIOCARD cohort., Results: Using multiple linear regression, cognition was regressed on estimated total volume of physical activity (TVPA), sleep efficiency (SE), wake after sleep onset (WASO), and total sleep time (TST) (adjusted for age, sex, education, diagnosis, vascular risk factors, and Apolipoprotein E (APOE)-e4 genetic status). Models were also run for domain-specific cognitive composite scores. TVPA and SE each were positively associated with a global cognitive composite score. TVPA was positively associated with executive function and language composites, and SE was positively related to executive function, visuospatial, and language composites. Importantly, a TVPA by SE interaction (p = 0.015) suggested that adults with the poorest SE experienced the greatest benefit from physical activity in relation to global cognition. The other sleep metrics were unrelated to cognitive performance., Conclusion: These results suggest that TVPA and SE may synergistically benefit cognition in older adults., Competing Interests: Conflicts of Interest: Dr. Vadim Zipunnikov consults with Takeda Pharmaceuticals. The details of the contracts are disclosed through the Johns Hopkins University eDisclose system and have no direct or apparent relationship with the current paper. Adam Spira received payment for serving as a consultant for Merck, received honoraria from Springer Nature Switzerland AG for guest editing special issues of Current Sleep Medicine Reports, and is a paid consultant to Sequoia Neurovitality and BellSant, Inc. Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Greater physical activity and better sleep are associated with reduced risk of cognitive decline and dementia among older adults, but little is known about their combined associations with measures of brain function and neuropathology. This study investigated potential independent and interactive cross-sectional relationships between actigraphy-estimated total volume of physical activity (TVPA) and sleep patterns [i.e., total sleep time (TST), sleep efficiency (SE)] with resting-state functional magnetic resonance imaging (rs-fMRI) measures of large scale network connectivity and positron emission tomography (PET) measures of amyloid-β. Participants were 135 non-demented older adults from the BIOCARD study (116 cognitively normal and 19 with mild cognitive impairment; mean age = 70.0 years). Using multiple linear regression analyses, we assessed the association between TVPA, TST, and SE with connectivity within the default-mode, salience, and fronto-parietal control networks, and with network modularity, a measure of network segregation. Higher TVPA and SE were independently associated with greater network modularity, although the positive relationship of SE with modularity was only present in amyloid-negative individuals. Additionally, higher TVPA was associated with greater connectivity within the default-mode network, while greater SE was related to greater connectivity within the salience network. In contrast, longer TST was associated with lower network modularity, particularly among amyloid-positive individuals, suggesting a relationship between longer sleep duration and greater network disorganization. Physical activity and sleep measures were not associated with amyloid positivity. These data suggest that greater physical activity levels and more efficient sleep may promote more segregated and potentially resilient functional networks and increase functional connectivity within specific large-scale networks and that the relationship between sleep and functional networks connectivity may depend on amyloid status., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The accumulation of neurofibrillary tau tangles, a neuropathological hallmark of Alzheimer's disease (AD), occurs in medial temporal lobe (MTL) regions early in the disease process, with some of the earliest deposits localized to subregions of the entorhinal cortex. Although functional specialization of entorhinal cortex subregions has been reported, few studies have considered functional associations with localized tau accumulation., Methods: In this study, stepwise linear regressions were used to examine the contributions of regional tau burden in specific MTL subregions, as measured by 18 F-MK6240 PET, to individual variability in cognition. Dependent measures of interest included the Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini Mental State Examination (MMSE), and composite scores of delayed episodic memory and language. Other model variables included age, sex, education, APOE4 status, and global amyloid burden, indexed by 11 C-PiB., Results: Tau burden in right Brodmann area 35 (BA35), left and right Brodmann area 36 (BA36), and age each uniquely contributed to the proportion of explained variance in CDR-SB scores, while right BA36 and age were also significant predictors of MMSE scores, and right BA36 was significantly associated with delayed episodic memory performance. Tau burden in both left and right BA36, along with education, uniquely contributed to the proportion of explained variance in language composite scores. Importantly, the addition of more inclusive ROIs, encompassing less granular segmentation of the entorhinal cortex, did not significantly contribute to explained variance in cognition across any of the models., Discussion: These findings suggest that the ability to quantify tau burden in more refined MTL subregions may better account for individual differences in cognition, which may improve the identification of non-demented older adults who are on a trajectory of decline due to AD., 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 © 2023 Rani, Alm, Corona-Long, Speck, Soldan, Pettigrew, Zhu, Albert and Bakker.)

Objective: This study examined whether cerebrospinal fluid (CSF) baseline levels of the synaptic protein NPTX2 predict time to onset of symptoms of mild cognitive impairment (MCI), both alone and when accounting for traditional CSF Alzheimer's disease (AD) biomarker levels. Longitudinal NPTX2 levels were also examined., Methods: CSF was collected longitudinally from 269 cognitively normal BIOCARD Study participants (mean baseline age = 57.7 years; mean follow-up = 16.3 years; n = 77 progressed to MCI/dementia). NPTX2 levels were measured from 3 correlated peptides using quantitative parallel reaction monitoring mass spectrometry. Levels of Aβ 42 /Aβ 40 , p-tau 181 , and t-tau were measured from the same CSF specimens using Lumipulse automated electrochemiluminescence assays., Results: In Cox regression models, lower baseline NPTX2 levels were associated with an earlier time to MCI symptom onset (hazard ratio [HR] = 0.76, SE = 0.09, p = 0.023). This association was significant for progression within 7 years (p = 0.036) and after 7 years from baseline (p = 0.001). Baseline NPTX2 levels improved prediction of time to MCI symptom onset after accounting for baseline AD biomarker levels (p < 0.01), and NPTX2 did not interact with the CSF AD biomarkers or APOE-ε4 genetic status. In linear mixed effects models, higher baseline p-tau 181 and t-tau levels were associated with higher baseline levels of NPTX2 (both p < 0.001) and greater rates of NPTX2 declines over time., Interpretation: NPTX2 may be a valuable prognostic biomarker during preclinical AD that provides additive and independent prediction of MCI onset among individuals who are cognitively normal. We hypothesize that NPTX2-mediated circuit homeostasis confers resilience during the early phase of AD. ANN NEUROL 2023;94:620-631., (© 2023 American Neurological Association.)

Velocity-selective inversion (VSI) based velocity-selective arterial spin labeling (VSASL) has been developed to measure cerebral blood flow (CBF) with low susceptibility to the prolonged arterial transit time and high sensitivity to brain perfusion signal. The purpose of this magnetic resonance imaging study is to evaluate the test-retest reliability of a VSI-prepared 3D VSASL protocol with whole-brain coverage to detect baseline CBF variations among cognitively normal participants in different brain regions. Coefficients of variation (CoV) of both absolute and relative CBF across scans or sessions, subjects, and gray matter regions were calculated, and corresponding intraclass correlation coefficients (ICC) were computed. The higher between-subject CoV of absolute CBF (13.4 ± 2.0%) over within-subject CoV (within-session: 3.8 ± 1.1%; between-session: 4.9 ± 0.9%) yielded moderate to excellent ICC (within-session: 0.88±0.08; between-session: 0.77±0.14) to detect normal variations of individual CBF. The higher between-region CoV of relative CBF (11.4 ± 3.0%) over within-region CoV (within-session: 2.3 ± 0.9%; between-session: 3.3 ± 1.0%) yielded excellent ICC (within-session: 0.92±0.06; between-session: 0.85±0.12) to detect normal variations of regional CBF. Age, blood pressure, end-tidal CO 2 , and hematocrit partially explained the variability of CBF across subjects. Together these results show excellent test-retest reliability of VSASL to detect both between-subject and between-region variations supporting its clinical utility., (Copyright © 2023. Published by Elsevier Inc.)

Background: Both Alzheimer's disease (AD) genetic risk factors and indices of cognitive reserve (CR) influence risk of cognitive decline, but it remains unclear whether they interact. This study examined whether a CR index score modifies the relationship between AD genetic risk factors and long-term cognitive trajectories in a large sample of individuals with normal cognition., Methods: Analyses used data from the Preclinical AD Consortium, including harmonized data from 5 longitudinal cohort studies. Participants were cognitively normal at baseline (M baseline age = 64 years, 59% female) and underwent 10 years of follow-up, on average. AD genetic risk was measured by (i) apolipoprotein-E (APOE) genetic status (APOE-ε2 and APOE-ε4 vs. APOE-ε3; N = 1819) and (ii) AD polygenic risk scores (AD-PRS; N = 1175). A CR index was calculated by combining years of education and literacy scores. Longitudinal cognitive performance was measured by harmonized factor scores for global cognition, episodic memory, and executive function., Results: In mixed-effects models, higher CR index scores were associated with better baseline cognitive performance for all cognitive outcomes. APOE-ε4 genotype and AD-PRS that included the APOE region (AD-PRS APOE ) were associated with declines in all cognitive domains, whereas AD-PRS that excluded the APOE region (AD-PRS w/oAPOE ) was associated with declines in executive function and global cognition, but not memory. There were significant 3-way CR index score × APOE-ε4 × time interactions for the global (p = 0.04, effect size = 0.16) and memory scores (p = 0.01, effect size = 0.22), indicating the negative effect of APOE-ε4 genotype on global and episodic memory score change was attenuated among individuals with higher CR index scores. In contrast, levels of CR did not attenuate APOE-ε4-related declines in executive function or declines associated with higher AD-PRS. APOE-ε2 genotype was unrelated to cognition., Conclusions: These results suggest that APOE-ε4 and non-APOE-ε4 AD polygenic risk are independently associated with global cognitive and executive function declines among individuals with normal cognition at baseline, but only APOE-ε4 is associated with declines in episodic memory. Importantly, higher levels of CR may mitigate APOE-ε4-related declines in some cognitive domains. Future research is needed to address study limitations, including generalizability due to cohort demographic characteristics., (© 2023. The Author(s).)

Introduction: Oxygen extraction fraction (OEF) reflects the balance between oxygen delivery and consumption. We longitudinally measured OEF in older adults to examine the relationship with markers of Alzheimer's disease (AD) and vascular pathology., Methods: One hundred thirty-seven participants were studied at two time-points at an interval of 2.16 years. OEF was measured using T 2 -relaxation-under-spin-tagging (TRUST) magnetic resonance imaging (MRI). The association between OEF and vascular risks, white matter hyperintensities (WMH), cerebrospinal fluid (CSF) measures of amyloid beta (Aβ), total tau (t-tau), and phosphorylated tau 181 (p-tau181) was examined., Results: OEF increased from baseline to follow-up. The increase in OEF was more prominent in individuals with high vascular risks compared to those with low vascular risks, and was associated with progression of vascular risks and the growth in WMH volume. OEF change was not related to CSF markers of AD pathology or their progression., Discussion: Longitudinal OEF change in older adults is primarily related to vascular pathology., (© 2022 the Alzheimer's Association.)

Introduction: We examined longitudinal cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker changes among cognitively normal individuals with 10.7 years follow-up, on average., Methods: Analyses included 278 participants ( M age = 57.5 years); 94 have progressed from normal cognition to mild cognitive impairment (MCI). Amyloid beta (Aβ) 42 /Aβ 40 , phosphorylated tau 181 (p-tau 181 ), and total tau (t-tau) were measured using automated electrochemiluminescence assays., Results: Apolipoprotein E ( APOE ) ε4 carriers had lower baseline Aβ 42 /Aβ 40 , but longitudinal Aβ 42 /Aβ 40 decreases did not differ by APOE ε4 after accounting for Aβ 42 /Aβ 40 positivity. Lower baseline Aβ 42 /Aβ 40 was associated with greater increases in tau (more strongly in males), and APOE ε4 genotype was associated with greater tau increases after reaching Aβ 42 /Aβ 40 positivity. Participants who progressed to MCI had more abnormal biomarker levels and greater tau increases prior to MCI symptom onset. Biomarkers were more abnormal among older adults, but unrelated to sex or education., Discussion: Our results confirm accelerated biomarker changes during preclinical AD and highlight the important role of amyloid levels in tau accelerations., Competing Interests: CP, AS, JW, and MCW have no disclosures. Dr. Greenberg is Editor‐in‐Chief of the other open access journal of the Alzheimer's Association: Alzheimer's & Dementia—Translational Research and Clinical Interventions. Dr. Albert is an advisor to Eli Lilly. Dr. Moghekar receives research support to JHU (but no direct or indirect salary support) from Fujirebio Diagnostics to analyze CSF preanalytics., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background and Objectives: This study aimed to examine whether baseline CSF measures of Alzheimer disease (AD)-related pathology are associated with the time to onset of mild cognitive impairment (MCI) and whether these associations differ by age, sex, Apolipoprotein E ( ApoE4 ) status, and proximal (≤7 years) vs distal (>7 years) time to symptom onset., Methods: Measures of amyloid (Aβ1-42 and Aβ1-40), phospho-tau (ptau181), and total tau (t-tau) were determined from CSF samples obtained at baseline from participants in an ongoing longitudinal project, known as the Biomarkers for Older Controls at Risk for Alzheimer Disease study (BIOCARD) study. The fully automated, Lumipulse G immunoassay was used to analyze the specimens. Cox regression models were used to examine the relationship of baseline biomarker levels with time to symptom onset of MCI and interactions with age, sex, and ApoE allelic status in subjects who progressed from normal cognition to MCI., Results: Analyses included 273 participants from the BIOCARD cohort, who were cognitively normal and predominantly middle-aged at baseline, and have been followed for an average of 16 years (max = 23.6). During follow-up, 94 progressed to MCI (median time to symptom onset = 6.9 years). In Cox regression models, elevated ptau181 and t-tau levels were associated with time to MCI symptom onset if it occurred within 7 years of baseline (HR 1.386 and 1.329; p = 0.009 and 0.017, respectively), while a lower Aβ42/Aβ40 ratio was associated with symptom onset if it occurred >7 years from baseline (HR 0.596, p = 0.003). There were also significant 3-way CSF × age × sex interactions for ptau181 and Aβ42/Aβ40, with follow-up analyses indicating that associations between these biomarkers and progression to MCI were stronger among men than among women, but this difference between sexes diminished with increasing age., Discussion: The lengthy follow-up of BIOCARD participants permitted an examination of time-varying associations between CSF AD biomarkers with MCI symptom onset and the influence of sex, baseline age, and ApoE4 genotype on these associations. These factors may inform clinical trial enrollment strategies, or trial duration and outcomes, which may use these measures as surrogate markers of treatment response., (© 2022 American Academy of Neurology.)

Higher physical activity levels are associated with reduced cognitive decline among older adults; however, current understanding of underlying brain mechanisms is limited. This cross-sectional study investigated the relationship between actigraphy-estimated total volume of physical activity (TVPA) and magnetic resonance imaging (MRI) measures of white matter hyperintensities (WMH), and functional and structural brain connectivity, measured by resting-state functional MRI and diffusion tensor imaging. Study participants (N = 156, mean age = 71 years) included 136 with normal cognition and 20 with Mild Cognitive Impairment. Higher TVPA was associated with greater functional connectivity within the default-mode network and greater network modularity (a measure of network specialization), as well as with greater anisotropy and lower radial diffusion in white matter, suggesting better structural connectivity. These associations with functional and structural connectivity were independent of one another and independent of the level of vascular risk, APOE-ε4 status, cognitive reserve, and WMH volume, which were not associated with TVPA. Findings suggest that physical activity is beneficial for brain connectivity among older individuals with varying levels of risk for cognitive decline., (Copyright © 2022. Published by Elsevier Inc.)

Neurobiological substrates of cognitive decline in cognitively normal older individuals have been investigated by resting-state functional magnetic resonance imaging, but little is known about the relationship between longitudinal changes in the whole brain. In this study, we examined two-year changes in functional connectivity among 80 gray matter areas and investigated the relationship to two-year changes in cognitive performance. A cross-validated permutation variable importance measure was applied to select features related to a change in cognitive performance. Age-corrected changes in eleven pairs of functional connections were selected as important features, all related to brain areas that belong to the default mode network. A linear regression model with cross-validation demonstrated a mean correlation coefficient of 0.55 between measured and predicted changes in the cognitive composite score. These results suggest that intra- and inter-network connections in the default mode network are associated with cognitive changes over two years among cognitively normal individuals., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This cross-sectional study examined whether performance on the computerized Paired Associate Learning (PAL) task from the Cambridge Neuropsychological Test Automated Battery is associated with amyloid positivity as measured by Positron Emission Tomography, regional volume composites as measured by Magnetic Resonance Imaging, and cognitive impairment. Participants from the BIOCARD Study (N = 73, including 62 cognitively normal and 11 with mild cognitive impairment; M age = 70 years) completed the PAL task, a comprehensive clinical and neuropsychological assessment, and neuroimaging as part of their annual study visit. In linear regressions covarying age, sex, years of education and diagnosis, higher PAL error scores were associated with amyloid positivity but not with medial temporal or cortical volume composites. By comparison, standard neuropsychological measures of episodic memory and global cognition were unrelated to amyloid positivity, but better performance on the verbal episodic memory measures was associated with larger cortical volume composites. Participants with mild cognitive impairment demonstrated worse cognitive performance on all of the cognitive measures, including the PAL task. These findings suggest that this computerized visual paired associate learning task may be more sensitive to amyloid positivity than standard neuropsychological tests, and may therefore be a promising tool for detecting amyloid positivity in non-demented participants., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Motoric cognitive risk (MCR), a clinical syndrome characterized by slow gait speed and subjective cognitive complaints, has been associated with dementia risk. The neuropathological features underlying MCR remain poorly understood., Methods: The Atherosclerosis Risk in Communities (ARIC) community-based cohort study classified participants using standardized criteria as MCR+/- and mild cognitive impairment (MCI)+/- at study baseline (2011-2013). We examined the 5-year dementia risk and baseline brain structural/molecular abnormalities associated with MCR+ and MCI+ status., Results: Of 5023 nondemented participants included, 204 were MCR+ and 1030 were MCI+. Both MCR+ and MCI+ participants demonstrated increased dementia risk. The pattern of structural brain abnormalities associated with MCR+ differed from that of MCI+. Whereas MCI+ was associated with comparatively smaller volumes in brain regions vulnerable to Alzheimer's disease pathology, MCR+ status was associated with smaller volumes in frontoparietal regions and greater white matter abnormalities., Discussion: MCR may represent a predementia syndrome characterized by prominent white matter abnormalities and frontoparietal atrophy., (© 2021 the Alzheimer's Association.)

The brain signature concept aims to characterize brain regions most strongly associated with an outcome of interest. Brain signatures derive their power from data-driven searches that select features based solely on performance metrics of prediction or classification. This approach has important potential to delineate biologically relevant brain substrates for prediction or classification of future trajectories. Recent work has used exploratory voxel-wise or atlas-based searches, with some using machine learning techniques to define salient features. These have shown undoubted usefulness, but two issues remain. The preponderance of recent work has been aimed at categorical rather than continuous outcomes, and it is rare for non-atlas reliant voxel-based signatures to be reported that would be useful for modelling and hypothesis testing. We describe a cross-validated signature region model for structural brain components associated with baseline and longitudinal episodic memory across cognitively heterogeneous populations including normal, mild impairment and dementia. We used three non-overlapping cohorts of older participants: from the UC Davis Aging and Diversity cohort (n = 255; mean age 75.3 ± 7.1 years; 128 cognitively normal, 97 mild cognitive impairment, 30 demented and seven unclassified); from Alzheimer's Disease Neuroimaging Initiative (ADNI) 1 (n = 379; mean age 75.1 ± 7.2; 82 cognitively normal, 176 mild cognitive impairment, 121 Alzheimer's dementia); and from ADNI2/GO (n = 680; mean age 72.5 ± 7.1; 220 cognitively normal, 381 mild cognitive impairment and 79 Alzheimer's dementia). We used voxel-wise regression analysis, correcting for multiple comparisons, to generate an array of regional masks corresponding to different association strength levels of cortical grey matter with baseline memory and brain atrophy with memory change. Cognitive measures were episodic memory using Spanish and English Neuropsychological Assessment Scales instruments for UC Davis and ADNI-Mem for ADNI 1 and ADNI2/GO. Performance metric was the adjusted R2 coefficient of determination of each model explaining outcomes in two cohorts other than where it was computed. We compared within-cohort performances of signature models against each other and against other recent signature models of episodic memory. Findings were: (i) two independently generated signature region of interest models performed similarly in a third separate cohort; (ii) a signature region of interest generated in one imaging cohort replicated its performance level when explaining cognitive outcomes in each of other, separate cohorts; and (iii) this approach better explained baseline and longitudinal memory than other recent theory-driven and data-driven models. This suggests our approach can generate signatures that may be easily and robustly applied for modelling and hypothesis testing in mixed cognition cohorts., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To determine whether vascular risk and Alzheimer disease (AD) biomarkers have independent or synergistic effects on cognitive decline and whether vascular risk is associated with the accumulation of AD pathology as measured by change in biomarkers over time., Methods: At baseline, participants (n = 168) were cognitively normal and primarily middle-aged (mean 56.4 years, SD 10.9 years) and had both vascular risk factor status and proximal CSF biomarkers available. Baseline vascular risk was quantified with a composite vascular risk score reflecting the presence or absence of hypertension, hypercholesterolemia, diabetes, current smoking, and obesity. CSF biomarkers of β-amyloid (Aβ) 1-42 , total tau (t-tau), and phosphorylated tau (p-tau) were used to create dichotomous high and low AD biomarker groups (based on Aβ 1-42 and tau). Linear mixed-effects models were used to examine change in a cognitive composite score (mean follow-up 13.9 years) and change in CSF biomarkers (mean follow-up 4.2 years)., Results: There was no evidence of a synergistic relationship between the vascular risk score and CSF AD biomarkers and cognitive decline. Instead, the vascular risk score (estimate -0.022, 95% confidence interval [CI] -0.043 to -0.002, p = 0.03) and AD biomarkers (estimate -0.060, 95% CI -0.096 to -0.024, p = 0.001) were independently and additively associated with cognitive decline. In addition, the vascular risk score was unrelated to levels of or rate of change in CSF Aβ 1-42 , t-tau, or p-tau., Conclusions: The results of this observational cohort study suggest that vascular risk and biomarkers of AD pathology, when measured in midlife, act along independent pathways and underscore the importance of accounting for multiple risk factors for identifying cognitively normal individuals at the greatest risk of cognitive decline., (© 2020 American Academy of Neurology.)

Introduction: We sought to examine whether depressive symptoms and level of Alzheimer's disease (AD) pathology are independently or interactively associated with the risk of progression to mild cognitive impairment (MCI)., Methods: The study included a total of 216 participants from the Biomarkers for Older Controls at Risk for Alzheimer's Disease study, a cohort of individuals who were cognitively normal at baseline (mean age = 57) and followed for more than 20 years (mean = 12.7 years), who had baseline Hamilton Depression Scale (HAM-D) scores and cerebrospinal fluid (CSF) amyloid beta (Aβ) 1-42 , t-tau, and p-tau measures available., Results: Cox regression demonstrated that baseline HAM-D and CSF AD biomarkers were both associated with time to onset of MCI. There was an interaction between HAM-D scores and markers of AD pathology, in which depression was associated with time of onset in participants with low levels of AD pathology (hazard ratio = 0.64; 95% confidence interval = 0.43-0.95; P = .026)., Discussion: The effect of depressive symptoms on progression to clinical symptoms of MCI may be most evident among individuals with low levels of AD pathology., Competing Interests: Dr. Marilyn Albert is an advisor to Eli Lilly. The following authors report no competing interests: Dr. Carol Chan, Dr. Anja Soldan, Dr. Corinne Pettigrew, Ms. Jiangxia Wang, Dr. Paul Rosenberg., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Several concepts, which in the aggregate get might be used to account for "resilience" against age- and disease-related changes, have been the subject of much research. These include brain reserve, cognitive reserve, and brain maintenance. However, different investigators have use these terms in different ways, and there has never been an attempt to arrive at consensus on the definition of these concepts. Furthermore, there has been confusion regarding the measurement of these constructs and the appropriate ways to apply them to research. Therefore the reserve, resilience, and protective factors professional interest area, established under the auspices of the Alzheimer's Association, established a whitepaper workgroup to develop consensus definitions for cognitive reserve, brain reserve, and brain maintenance. The workgroup also evaluated measures that have been used to implement these concepts in research settings and developed guidelines for research that explores or utilizes these concepts. The workgroup hopes that this whitepaper will form a reference point for researchers in this area and facilitate research by supplying a common language., (© 2019 the Alzheimer's Association.)

Objective: Examine whether cognitive reserve moderates the association of 1) vascular risk factors and 2) white matter hyperintensity burden with risk of clinical progression and longitudinal cognitive decline., Methods: BIOCARD Study participants were cognitively normal and primarily middle-aged (M = 57 years) at baseline and have been followed with annual cognitive and clinical assessments (M = 13 years). Baseline cognitive reserve was indexed with a composite score combining education with reading and vocabulary scores. Baseline vascular risk (N = 229) was assessed with a composite risk score reflecting five vascular risk factors. Baseline white matter hyperintensity load (N = 271) was measured with FLAIR magnetic resonance imaging. Cox regression models assessed risk of progression from normal cognition to onset of clinical symptoms of Mild Cognitive Impairment. Longitudinal mixed effects models measured the relationship of these variables to cognitive decline, using a global composite score, and executive function and episodic memory sub-scores., Results: Both vascular risk and white matter hyperintensities were associated with cognitive decline, particularly in executive function. Higher vascular risk, but not white matter hyperintensity burden, was associated with an increased risk of progression to Mild Cognitive Impairment. Higher cognitive reserve was associated with a reduced risk of symptom onset and higher levels of baseline cognition but did not modify the associations between the vascular risk score and white matter hyperintensities with clinical progression or cognitive decline., Interpretation: Although cognitive reserve has protective effects on clinical and cognitive outcomes, it does not mitigate the negative impact of vascular risk and small vessel cerebrovascular disease on these same outcomes., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Systemic inflammation has emerged as a risk factor for cognitive decline and Alzheimer's disease, but inflammation's effect on distributed brain networks is unclear. We examined the relationship between peripheral inflammatory markers and subsequent functional connectivity within five large-scale cognitive networks and evaluated the modifying role of cortical amyloid and APOE ε4 status., Methods: Blood levels of soluble tumor necrosis factor-alpha receptor-1 and interleukin 6 were assessed in 176 participants (at baseline mean age: 65 (SD 9) years; 63% women; 85% cognitively normal, 15% mild cognitive impairment (MCI)) and were combined to derive an Inflammatory Index. Approximately six years later, participants underwent resting-state functional magnetic resonance imaging to quantify functional connectivity; a subset of 137 participants also underwent 11 C Pittsburgh compound-B (PiB) PET imaging to assess cortical amyloid burden., Results: Using linear regression models adjusted for demographic characteristics and cardiovascular risk factors, a higher Inflammatory Index was associated with lower connectivity within the Default Mode (β = -0.013; 95% CI: -0.023, -0.003) and the Dorsal Attention Networks (β = -0.017; 95% CI: -0.028, -0.006). The strength of these associations did not vary by amyloid status (positive/negative). However, there was a significant interaction between Inflammatory Index and APOE ε4 status, whereby ε4-positive participants with a higher Inflammatory Index demonstrated lower connectivity. Inflammatory Index was unrelated to connectivity within other large-scale cognitive networks (Control, Limbic, and Salience/Ventral Attention networks)., Conclusion: Peripheral pro-inflammatory signaling in older adults without dementia, especially among APOE ε4-positive individuals, is associated with altered connectivity within two large-scale cognitive networks., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Recent studies suggest that white matter hyperintensities (WMH) on MRI, which primarily reflect small vessel cerebrovascular disease, may play a role in the evolution of Alzheimer disease (AD). In a longitudinal study, we investigated whether WMH promote the progression of AD pathology, or alter the association between AD pathology and risk of progression from normal cognition to mild cognitive impairment (MCI)., Methods: Two sets of analyses were conducted. The relationship between whole brain WMH load, based on fluid-attenuated inversion recovery MRI, obtained in initially cognitively normal participants (n = 274) and time to onset of symptoms of MCI (n = 60) was examined using Cox regression models. In a subset of the participants with both MRI and CSF data (n = 204), the interaction of WMH load and CSF AD biomarkers was also evaluated., Results: Baseline WMH load interacted with CSF total tau (t-tau) with respect to symptom onset, but not with CSF β-amyloid 1-42 or phosphorylated tau (p-tau) 181. WMH volume was associated with time to symptom onset of MCI among individuals with low t-tau (hazard ratio [HR] 1.35, confidence interval [CI] 1.06-1.73, p = 0.013), but not those with high t-tau (HR 0.86, CI 0.56-1.32, p = 0.47). The rate of change in the CSF biomarkers over time was not associated with the rate of change in WMH volumes., Conclusion: These results suggest that WMH primarily affect the risk of progression when CSF measures of neurodegeneration or neuronal injury (as reflected by t-tau) are low. However, CSF biomarkers of amyloid and p-tau and WMH appear to have largely independent and nonsynergistic effects on the risk of progression to MCI., (© 2019 American Academy of Neurology.)

Significant evidence demonstrates that aging is associated with variability in cognitive performance, even among individuals who are cognitively normal. In this study, we examined measures from magnetic resonance imaging and cerebrospinal fluid (CSF) to investigate which measures, alone or in combination, were associated with individual differences in episodic memory performance. Using hierarchical linear regressions, we compared the ability of diffusion tensor imaging (DTI) metrics, CSF measures of amyloid and tau, and gray matter volumes to explain variability in memory performance in a cohort of cognitively normal older adults. Measures of DTI microstructure were significantly associated with variance in memory performance, even after accounting for the contribution of the CSF and magnetic resonance imaging gray matter volume measures. Significant associations were found between DTI measures of the hippocampal cingulum and fornix with individual differences in memory. No such relationships were found between memory performance and CSF markers or gray matter volumes. These findings suggest that DTI metrics may be useful in identifying changes associated with aging or age-related diseases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Large longitudinal biomarkers database focusing on middle age is needed for Alzheimer's disease (AD) prevention., Methods: Data for cerebrospinal fluid analytes, molecular imaging of cerebral fibrillar β-amyloid with positron emission tomography, magnetic resonance imaging-based brain structures, and clinical/cognitive outcomes were harmonized across eight AD biomarker studies. Statistical power was estimated., Results: The harmonized database included 7779 participants with clinical/cognitive data: 3542 were 18∼65 years at the baseline, 5865 had longitudinal cognitive data for a median of 4.7 years, 2473 participated in the cerebrospinal fluid studies (906 had longitudinal data), 2496 participated in the magnetic resonance imaging studies (1283 had longitudinal data), and 1498 participated in the positron emission tomography amyloid studies (849 had longitudinal data). The database provides adequate power for detecting early biomarker changes, and demonstrates the feasibility of AD prevention trials on middle-aged individuals., Discussion: The harmonized database is an optimum resource to design AD prevention trials decades before symptomatic onset., (Copyright © 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the long-term cognitive trajectories of individuals with normal cognition at baseline and distinct amyloid/tau/neurodegeneration (ATN) profiles., Methods: Pooling data across 4 cohort studies, 814 cognitively normal participants (mean baseline age = 59.6 years) were classified into 8 ATN groups using baseline CSF levels of β-amyloid 1-42 as a measure of amyloid (A), phosphorylated tau 181 as a measure of tau (T), and total tau as a measure of neurodegeneration (N). Cognitive performance was measured using a previously validated global factor score and with the Mini-Mental State Examination. We compared the cognitive trajectories across groups using growth curve models (mean follow-up time = 7 years)., Results: Using different model formulations and cut points for determining biomarker abnormality, only the group with abnormal levels of amyloid, tau, and neurodegeneration (A+T+N+) showed consistently greater cognitive decline than the group with normal levels of all biomarkers (A-T-N-). Replicating prior findings using the 2011 National Institute on Aging-Alzheimer's Association/suspected non-Alzheimer disease pathophysiology schema, only individuals with abnormal levels of both amyloid and phosphorylated tau 181 or total tau (stage 2) showed greater cognitive decline than those with normal biomarker levels (stage 0)., Conclusion: The results are consistent with the hypothesis that both elevated brain amyloid and neurofibrillary tangles are necessary to observe accelerated neurodegeneration, which in turn leads to cognitive decline., (© 2019 American Academy of Neurology.)

The extent and spatial location of white matter hyperintensities (WMH) on brain MRI may be relevant to the development of cognitive decline in older persons. Here, we introduce a new method, known as the Multi-atlas based Detection and Localization (MADL), to evaluate WMH on fluid-attenuated inversion recovery (FLAIR) data. This method simultaneously parcellates the whole brain into 143 structures and labels hyperintense areas within each WM structure. First, a multi-atlas library was established with FLAIR data of normal elderly brains; and then a multi-atlas fusion algorithm was developed by which voxels with locally abnormal intensities were detected as WMH. At the same time, brain segmentation maps were generated from the multi-atlas fusion process to determine the anatomical location of WMH. Areas identified using the MADL method agreed well with manual delineation, with an interclass correlation of 0.97 and similarity index (SI) between 0.55 and 0.72, depending on the total WMH load. Performance was compared to other state-of-the-art WMH detection methods, such as BIANCA and LST. MADL-based analyses of WMH in an older population revealed a significant association between age and WMH load in deep WM but not subcortical WM. The findings also suggested increased WMH load in selective brain regions in subjects with mild cognitive impairment compared to controls, including the inferior deep WM and occipital subcortical WM. The proposed MADL approach may facilitate location-dependent characterization of WMH in older individuals with memory impairment., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Our objectives were to characterize the inter-relation of known dementia-related neuropathologies in one comprehensive model and quantify the extent to which accumulation of neuropathologies accounts for the association between age and dementia., Methods: We used data from 1,362 autopsied participants of three community-based clinicopathological cohorts: the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. We estimated a series of structural equation models summarizing a priori hypothesized neuropathological pathways between age and dementia risk individually and collectively., Results: At time of death (mean age, 89 years), 44% of our sample had a clinical dementia diagnosis. When considered individually, our vascular, amyloid/tau, neocortical Lewy body, and TAR DNA-binding protein 43 (TDP-43)/hippocampal sclerosis pathology pathways each accounted for a substantial proportion of the association between age and dementia. When considered collectively, the four pathways fully accounted for all variance in dementia risk previously attributable to age. Pathways involving amyloid/tau, neocortical Lewy bodies, and TDP-43/hippocampal sclerosis were interdependent, attributable to the importance of amyloid beta plaques in all three. The importance of the pathways varied, with the vascular pathway accounting for 32% of the association between age and dementia, wheraes the remaining three inter-related degenerative pathways together accounted for 68% (amyloid/tau, 24%; the Lewy body, 1%; and TDP-43/hippocampal sclerosis, 43%)., Interpretation: Age-related increases in dementia risk can be attributed to accumulation of multiple pathologies, each of which contributes to dementia risk. Multipronged approaches may be necessary if we are to develop effective therapies. Ann Neurol 2018;84:10-22., (© 2018 American Neurological Association.)

The concept of cognitive reserve (CR) was proposed to account for the discrepancy between levels of brain pathologic features or damage and clinical and cognitive function. This article provides a detailed review of prospective longitudinal studies that have investigated the interaction between CR and Alzheimer's disease (AD) biomarkers on clinical and cognitive outcomes among individuals with preclinical AD. Current evidence shows that higher levels of CR are associated with a delay in the onset of symptoms of mild cognitive impairment and that there may be multiple pathways by which CR exerts its protective effects., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We examined if baseline levels of cognitive reserve (CR) and of Alzheimer's disease (AD) biomarkers modify the rate of change in cognition among individuals with normal cognition at baseline (n = 303, mean baseline age = 57 years, mean follow-up = 12 years); 66 participants subsequently developed mild cognitive impairment (MCI) or dementia due to AD. CR was indexed by years of education, reading, and vocabulary measures. AD biomarkers were measured with a composite score composed of measures of amyloid, phosphorylated tau, and neurodegeneration. Higher CR scores were associated with better cognitive performance but did not modify the rate of change in cognition among those who remained cognitively normal, nor among those who progressed to MCI before symptom onset, independent of baseline biomarker levels. However, higher CR scores were associated with faster cognitive decline after symptom onset of MCI. These results suggest that the mechanism by which CR mediates the relationship between pathology and cognitive function is by delaying the onset of symptoms rather than reducing the rate of cognitive decline., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study examined whether longitudinal MRI trajectories in medial temporal lobe (MTL) brain regions differed among groups of cognitively normal individuals defined by their cerebrospinal fluid (CSF) levels when they were first enrolled ( N  = 207; mean clinical follow-up = 13.3 years (max = 20 years), mean MRI follow-up = 2.4 years (max = 8 years)). We first compared atrophy rates among groups defined by CSF amyloid and phosphorylated-tau (p-tau) vs. CSF amyloid and total tau (t-tau). We also examined whether, in the presence of amyloid or tau/p-tau, the atrophy rates differed based on whether the subjects ultimately progressed to a diagnosis of mild cognitive impairment (MCI), as well as whether apolipoprotein ε4 (Apoε4) status had an impact on the longitudinal MRI trajectories. The primary finding was that when the groups were defined using CSF amyloid and p-tau, individuals with low levels of CSF amyloid and high levels of CSF p-tau (referred to as Stage 2) showed a significantly greater rate of atrophy in a composite measure of MTL volumes compared to groups defined by evidence of abnormal CSF levels in only one of the brain proteins (but not both), or no evidence of CSF abnormality. In contrast, there were no differences in rate of MTL atrophy when the groups were defined by levels of CSF amyloid and t-tau (instead of p-tau). Additionally, the rate of MTL atrophy did not differ between subjects who progressed to MCI at follow-up vs. those who remained cognitively normal when CSF levels of amyloid, t-tau, or p-tau were covaried. Lastly, the presence of an APOE ε4 genotype did not modulate the degree of MTL atrophy once baseline levels of CSF amyloid, p-tau or t-tau were accounted for. These results suggest that abnormal levels of CSF amyloid and CSF p-tau (but not t-tau) maximize the likelihood of observing significant MTL atrophy over time among individuals with normal cognition at baseline, and emphasize the importance of differentiating biomarkers that primarily reflect neurofibrillary tangle pathology (CSF p-tau) compared with biomarkers of neuronal injury (CSF t-tau).

Introduction: We established a method for diagnostic harmonization across multiple studies of preclinical Alzheimer's disease and validated the method by examining its relationship with clinical status and cognition., Methods: Cognitive and clinical data were used from five studies ( N  = 1746). Consensus diagnoses established in each study used criteria to identify progressors from normal cognition to mild cognitive impairment. Correspondence was evaluated between these consensus diagnoses and three algorithmic classifications based on (1) objective cognitive impairment in 2+ tests only; (2) a Clinical Dementia Rating (CDR) of ≥0.5 only; and (3) both. Associations between baseline cognitive performance and cognitive change were each tested in relation to progression to algorithm-based classifications., Results: In each study, an algorithmic classification based on both cognitive testing cutoff scores and a CDR ≥0.5 provided optimal balance of sensitivity and specificity (areas under the curve: 0.85-0.95). Over an average 6.6 years of follow-up (up to 28 years), N  = 186 initially cognitively normal participants aged on average 64 years at baseline progressed (incidence rate: 15.3 people/1000 person-years). Baseline cognitive scores and cognitive change were associated with future diagnostic status using this algorithmic classification., Discussion: Both cognitive tests and CDR ratings can be combined across multiple studies to obtain a reliable algorithmic classification with high specificity and sensitivity. This approach may be applicable to large cohort studies and to clinical trials focused on preclinical Alzheimer's disease because it provides an alternative to implementation of a time-consuming adjudication panel.

This study examined whether cognitive reserve (CR) alters the relationship between magnetic resonance imaging (MRI) measures of cortical thickness and risk of progression from normal cognition to the onset of clinical symptoms associated with mild cognitive impairment (MCI). The analyses included 232 participants from the BIOCARD study. Participants were cognitively normal and largely middle aged (M age = 56.5) at their baseline MRI scan. After an average of 11.8 years of longitudinal follow-up, 48 have developed clinical symptoms of MCI or dementia (M time from baseline to clinical symptom onset = 7.0 years). Mean thickness was measured over eight 'AD vulnerable' cortical regions, and cognitive reserve was indexed by a composite score consisting of years of education, reading, and vocabulary measures. Using Cox regression models, CR and cortical thickness were each independently associated with risk of clinical symptom onset within 7 years of baseline, suggesting that the neuronal injury occurring proximal to symptom onset has a direct association with clinical outcomes, regardless of CR. In contrast, there was a significant interaction between CR and mean cortical thickness for risk of progression more than 7 years from baseline, suggesting that individuals with high CR are better able to compensate for cortical thinning that is beginning to occur at the very earliest phase of AD.

Mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia are preceded by a phase of disease, referred to as 'preclinical AD', during which cognitively normal individuals have evidence of AD pathology in the absence of clinical impairment. This study examined whether a magnetic resonance imaging (MRI) measure of cortical thickness in brain regions, collectively known as 'AD vulnerable' regions, predicted the time to onset of clinical symptoms associated with MCI and whether cortical thickness was similarly predictive of clinical symptom onset within 7 years post baseline versus progression at a later point in time. These analyses included 240 participants from the BIOCARD study, a cohort of longitudinally followed individuals who were cognitively normal at the time of their MRI (mean age = 56 years). Participants have been followed for up to 18 years (M follow-up = 11.8 years) and 50 participants with MRIs at baseline have developed MCI or dementia over time (mean time to clinical symptom onset = 7 years). Cortical thickness in AD vulnerable regions was based on the mean thickness of eight cortical regions. Using Cox regression models, we found that lower mean cortical thickness was associated with an increased risk of progression from normal cognition to clinical symptom onset within 7 years of baseline (p = 0.03), but not with progression > 7 years from baseline (p = 0.30). Lower cortical thickness was also associated with higher levels of phosphorylated tau, measured in cerebrospinal fluid at baseline. These results suggest that cortical thinning in AD vulnerable regions is detectable in cognitively normal individuals several years prior to the onset of clinical symptoms that are a harbinger of a diagnosis of MCI, and that the changes are more likely to be evident in the years proximal to clinical symptom onset, consistent with hypothetical AD biomarker models.

The pathophysiological processes underlying Alzheimer's disease (AD) are hypothesized to begin years to decades before clinical symptom onset, while individuals are still cognitively normal. Although many studies have examined the effect of biomarkers of amyloid pathology on measures of cognitive performance, less is known about the effect of tau pathology on cognitive performance. The present study examined the association between cerebrospinal fluid (CSF) biomarkers of AD pathology (amyloid, total tau (t-tau), and phosphorylated tau (p-tau)) and cognition in a large sample of cognitively normal middle-aged and older adults. Associations were examined with multivariate regressions, in which either amyloid and t-tau or amyloid and p-tau were included as simultaneous predictors of cognitive performance. Cognitive performance was measured with three composite scores assessing working memory, verbal episodic memory, and visuospatial episodic memory. In their respective models, CSF measures of both t-tau and p-tau were associated with the visuospatial episodic memory composite score (p<.001 and p=.02, respectively), but not with the other measures of cognition. In contrast, CSF amyloid was not significantly associated with cognitive performance, raising the possibility that measures of tau pathology have a more direct relationship with cognition in cognitively normal individuals. These results also suggest that tau pathology may have effects on visuospatial episodic memory during preclinical AD that precede alterations in other cognitive domains., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Although many epidemiological studies suggest the beneficial effects of higher cognitive reserve (CR) in reducing age-related cognitive decline and dementia risk, the neural basis of CR is poorly understood. To our knowledge, the present study represents the first electrophysiological investigation of the relationship between CR and neural reserve (i.e., neural efficiency and capacity). Specifically, we examined whether CR modulates event-related potentials associated with performance on a verbal recognition memory task with 3 set sizes (1, 4, or 7 letters) in healthy younger and older adults. Neural data showed that as task difficulty increased, the amplitude of the parietal P3b component during the probe phase decreased and its latency increased. Notably, the degree of these neural changes was negatively correlated with CR in both age groups, such that individuals with higher CR showed smaller changes in P3b amplitude and less slowing in P3b latency (i.e., smaller changes in the speed of neural processing) with increasing task difficulty, suggesting greater neural efficiency. These CR-related differences in neural efficiency may underlie reserve against neuropathology and age-related burden., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Graph theory is increasingly being used to study brain connectivity across the spectrum of Alzheimer's disease (AD), but prior findings have been inconsistent, likely reflecting methodological differences. We systematically investigated how methods of graph creation (i.e., type of correlation matrix and edge weighting) affect structural network properties and group differences. We estimated the structural connectivity of brain networks based on correlation maps of cortical thickness obtained from MRI. Four groups were compared: 126 cognitively normal older adults, 103 individuals with Mild Cognitive Impairment (MCI) who retained MCI status for at least 3 years (stable MCI), 108 individuals with MCI who progressed to AD-dementia within 3 years (progressive MCI), and 105 individuals with AD-dementia. Small-world measures of connectivity (characteristic path length and clustering coefficient) differed across groups, consistent with prior studies. Groups were best discriminated by the Randić index, which measures the degree to which highly connected nodes connect to other highly connected nodes. The Randić index differentiated the stable and progressive MCI groups, suggesting that it might be useful for tracking and predicting the progression of AD. Notably, however, the magnitude and direction of group differences in all three measures were dependent on the method of graph creation, indicating that it is crucial to take into account how graphs are constructed when interpreting differences across diagnostic groups and studies. The algebraic connectivity measures showed few group differences, independent of the method of graph construction, suggesting that global connectivity as it relates to node degree is not altered in early AD.