Clinical Manifestations.

Background: Higher level of cognitive reserve (CR), measured using proxies such as years of education or literacy, is associated with reduced risk of Mild Cognitive Impairment (MCI) and dementia. Little is known about how CR and other lifestyle factors impact non-cognitive outcomes, including depression and other neuropsychiatric symptoms (e.g.

Clinical Manifestations.

Background: Although it is well established that lower cognitive performance, on average, is associated with a greater risk of developing Alzheimer's disease (AD) dementia, it is unclear whether distinct cognitively-defined subgroups exist among non-demented older adults and whether such profiles map onto distinct AD neuroimaging measure profiles.

Method: The sample consisted of 167 non-demented older adults from the BIOCARD study with comprehensive neuropsychological and clinical evaluations, amyloid PET and brain MRI scans. The MRI measure included: global cortical volume in AD-signature regions and a medial-temporal lobe composite; resting-state functional connectivity within 5 large-scale cognitive networks; global white matter microstructure, index by fractional anisotropy (FA) and radial diffusion (RD) on DTI scans; and global white matter hyperintensity (WMH) volume on FLAIR scans.

Blood-Based Biomarkers and Risk of Onset of Mild Cognitive Impairment Over the Short and Long Term.

Background And Objectives: Blood-based biomarkers of amyloid and tau have been shown to predict Alzheimer disease (AD) dementia. Much less is known about their ability to predict risk of mild cognitive impairment (MCI), an earlier disease stage. This study examined whether levels of blood biomarkers of amyloid (Aβ/Aβ ratio), tau (p-tau), neurodegeneration (NfL), and glial activation and neuroinflammation (glial fibrillary acidic protein [GFAP], YKL40, soluble triggering receptor expressed on myeloid cells 2 [sTREM2]) collected when participants were cognitively normal are associated with the time to onset of MCI.

Independent associations of sleep and physical activity with cognition are mediated by hippocampal microstructure in middle-aged and older adults.

Sleep and physical activity levels are both associated with cognitive performance among older adults; however, the brain mechanisms underlying these beneficial relationships remain poorly understood. This study investigated cross-sectional associations of actigraphic estimates of physical activity and sleep with cognition and diffusion imaging-based measures of medial temporal lobe (MTL) gray matter microstructural integrity in adults free of dementia. Participants were 132 older adults from the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD) cohort study (119 cognitively unimpaired and 13 with mild cognitive impairment; mean age=70.

Acceleration of Brain Atrophy and Progression From Normal Cognition to Mild Cognitive Impairment.

Importance: It remains unclear which risk factors accelerate brain atrophy along with a progression from normal cognition to mild cognitive impairment (MCI).

Objective: To examine risk factors associated with the acceleration of brain atrophy and progression from normal cognition to MCI based on long-term longitudinal data for middle-aged and older adults.

Design, Setting, And Participants: Data for this cohort study were extracted from the Biomarkers for Older Controls at Risk for Dementia (BIOCARD) cohort, initiated at the National Institutes of Health from January 1, 1995, to December 31, 2005, and continued at Johns Hopkins University from January 1, 2015, to October 31, 2023.

Alzheimer's disease genetic risk and changes in brain atrophy and white matter hyperintensities in cognitively unimpaired adults.

Reduced brain volumes and more prominent white matter hyperintensities on MRI scans are commonly observed among older adults without cognitive impairment. However, it remains unclear whether rates of change in these measures among cognitively normal adults differ as a function of genetic risk for late-onset Alzheimer's disease, including -ɛ4, -ɛ2 and Alzheimer's disease polygenic risk scores (AD-PRS), and whether these relationships are influenced by other variables. This longitudinal study examined the trajectories of regional brain volumes and white matter hyperintensities in relationship to genotypes ( = 1541) and AD-PRS ( = 1093) in a harmonized dataset of middle-aged and older individuals with normal cognition at baseline (mean baseline age = 66 years, SD = 9.

Actigraphy Estimated Sleep Moderates the Relationship between Physical Activity and Cognition in Older Adults.

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.

Tau PET burden in Brodmann areas 35 and 36 is associated with individual differences in cognition in non-demented older adults.

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 F-MK6240 PET, to individual variability in cognition.

Cerebrospinal Fluid Alzheimer's Disease Biomarker Patterns of Change Prior to the Onset of Mild Cognitive Impairment.

Background: Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are altered many years before the onset of clinical symptoms of mild cognitive impairment (MCI). Incorporating clinical symptom onset time into biomarker modeling may enhance our understanding of changes preceding MCI.

Objective: Using a new analytical approach, we examined patterns of biomarker change prior to MCI symptom onset among individuals who progressed from normal cognition to MCI, stratified based on the age of symptom onset.

NPTX2 in Cerebrospinal Fluid Predicts the Progression From Normal Cognition to Mild Cognitive Impairment.

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.

Alzheimer's disease genetic risk and cognitive reserve in relationship to long-term cognitive trajectories among cognitively normal individuals.

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.

Test-retest reliability of 3D velocity-selective arterial spin labeling for detecting normal variations of cerebral blood flow.

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.

Regional White Matter Hyperintensities and Alzheimer's Disease Biomarkers Among Older Adults with Normal Cognition and Mild Cognitive Impairment.

Background: Alzheimer's disease (AD) frequently co-occurs with other brain pathologies. Recent studies suggest there may be a mechanistic link between AD and small vessel cerebrovascular disease (CVD), as opposed to simply the overlap of two disorders.

Objective: We investigated the cross-sectional relationship between white matter hyperintensity (WMH) volumes (markers of CVD) and cerebrospinal fluid (CSF) biomarkers of AD.

Longitudinal CSF Alzheimer's disease biomarker changes from middle age to late adulthood.

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 ( age = 57.

CSF Alzheimer Disease Biomarkers: Time-Varying Relationships With MCI Symptom Onset and Associations With Age, Sex, and .

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, () 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.

Structural and Functional Brain Connectivity Uniquely Contribute to Episodic Memory Performance in Older Adults.

In this study, we examined the independent contributions of structural and functional connectivity markers to individual differences in episodic memory performance in 107 cognitively normal older adults from the BIOCARD study. Structural connectivity, defined by the diffusion tensor imaging (DTI) measure of radial diffusivity (RD), was obtained from two medial temporal lobe white matter tracts: the fornix and hippocampal cingulum, while functional connectivity markers were derived from network-based resting state functional magnetic resonance imaging (rsfMRI) of five large-scale brain networks: the control, default, limbic, dorsal attention, and salience/ventral attention networks. Hierarchical and stepwise linear regression methods were utilized to directly compare the relative contributions of the connectivity modalities to individual variability in a composite delayed episodic memory score, while also accounting for age, sex, cerebrospinal fluid (CSF) biomarkers of amyloid and tau pathology (i.

Longitudinal changes in brain oxygen extraction fraction (OEF) in older adults: Relationship to markers of vascular and Alzheimer's pathology.

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.

Age-Dependent Association Between Cognitive Reserve Proxy and Longitudinal White Matter Microstructure in Older Adults.

Objective: This study examined the association of lifetime experiences, measured by a cognitive reserve (CR) composite score composed of years of education, literacy, and vocabulary measures, to level and rate of change in white matter microstructure, as assessed by diffusion tensor imaging (DTI) measures. We also examined whether the relationship between the proxy CR composite score and white matter microstructure was modified by participant age, -ε4 genetic status, and level of vascular risk.

Methods: A sample of 192 non-demented ( = 166 cognitively normal, = 26 mild cognitive impairment) older adults [mean age = 70.

Dataset of relationship between longitudinal change in cognitive performance and functional connectivity in cognitively normal older individuals.

The data show an association between measured and predicted changes in cognitive performance in older adults who are cognitively normal. Changes in cognitive performance over two years were assessed using the Cognitive Composite Score. The prediction of change in cognitive function was based on changes in pairwise functional connectivity between 80 gray matter regions examined by resting-state functional magnetic resonance imaging.

Actigraphy-estimated physical activity is associated with functional and structural brain connectivity among older adults.

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.

Changes in pairwise functional connectivity associated with changes in cognitive performance in cognitively normal older individuals: A two-year observational study.

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.

Longitudinal Changes in Global Cerebral Blood Flow in Cognitively Normal Older Adults: A Phase-Contrast MRI Study.

Background: Characterization of blood supply changes in older individuals is important in understanding brain aging and diseases. However, prior studies largely focused on cross-sectional design, thus change in cerebral blood flow (CBF) could not be assessed on an individual level.

Purpose: To evaluate longitudinal short-term changes in global CBF in cognitively normal older adults.

Association Between Late-Life Neuropsychiatric Symptoms and Cognitive Decline in Relation to White Matter Hyperintensities and Amyloid Burden.

Background: Neuropsychiatric symptoms (NPS) among cognitively normal older adults are increasingly recognized as risk factors for cognitive decline and impairment. However, the underlying mechanisms remain unclear.

Objective: To examine whether biomarkers of Alzheimer's disease (amyloid burden) and cerebrovascular disease (white matter hyperintensity (WMH) volume) modify the association between NPS and cognitive decline among cognitively unimpaired older adults.