Self- and study partner-reported cognitive decline in older adults without dementia: The role of α-synuclein and amyloid biomarkers in the Alzheimer's Disease Neuroimaging Initiative.

INTRODUCTION: Subjective cognitive decline (SCD) may be an early marker of Alzheimer's disease (AD) pathology. Until recently, it was impossible to measure biomarkers specific for α-synuclein pathology; therefore, its association with subjective reports of cognitive decline is unknown. METHODS: Alzheimer's Disease Neuroimaging Initiative participants without dementia (n = 918) were classified as positive or negative for amyloid beta (Aß+ or Aß-) and α-synuclein (α-syn+ or α-syn-) biomarkers. Self- and study partner-reported cognitive decline was measured with the Everyday Cognition (ECog) questionnaire. RESULTS: Per self-report, Aß+/α-syn+ had the greatest cognitive decline. Aß-/α-syn+ did not differ from Aß-/α-syn- across ECog scores. Study partner-reported results had a similar pattern, but Aß+/α-syn- and Aß+/α-syn+ did not differ across ECog scores. Mild cognitive impairment classification moderated the study partner-reported memory score. DISCUSSION: While α-syn+ alone did not increase subjective reports of cognitive decline, Aß+/α-syn+ had the most self- and study partner-rated cognitive decline. Therefore, the presence of multiple pathologies was associated with greater SCD. HIGHLIGHTS: Cerebrospinal fluid α-synuclein (α-syn) seed amplification assay was used to determine α-syn positivity. Amyloid beta (Aß)-/α-syn-, Aß-/α-syn+, Aß+/α-syn-, and Aß+/α-syn+ biomarker groups were created. Aß+/α-syn+ had greater subjective cognitive decline (SCD) than the other biomarker groups. Aß-/α-syn+ did not differ from Aß-/α-syn- across self- or study-partner reported SCD scores. Study partner-reported subjective memory results were largely driven by participants with mild cognitive impairment.

PTSD moderates the association between subjective cognitive decline and Alzheimer's disease biomarkers in older veterans.

OBJECTIVES: Post-traumatic stress disorder (PTSD) and subjective cognitive decline (SCD) are independent risk factors for Alzheimer's disease (AD) and dementia, but the association of their interaction on AD biomarkers have yet to be characterized. This study aimed to examine the impact of PTSD on the association between SCD and tau and amyloid positron emission tomography (PET) as well as global cognition in older Veterans. METHOD: This study included 87 Vietnam-Era Veterans without dementia (42 with PTSD; 45 without PTSD) from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative. All participants had both tau and amyloid PET imaging as well as cognitive testing. SCD was measured using the Everyday Cognition questionnaire. RESULTS: While SCD was associated with tau PET, amyloid PET, and global cognition, PTSD moderated these associations for tau and amyloid PET levels. Specifically, Veterans without PTSD had a stronger positive relationship between SCD and AD biomarkers when compared to those with PTSD. CONCLUSION: Higher SCD was associated with greater tau and amyloid burden and worse cognitive performance across the sample, though the tau and amyloid associations were stronger for Veterans without PTSD. Results highlight the potential benefit of comprehensive clinical assessments including consideration of mental health among older Veterans with SCD to understand the underlying cause of the cognitive concerns. Additionally, more work is needed to understand alternative mechanisms driving SCD in older Veterans with PTSD.

Associations of Post-Traumatic Stress Disorder and Objective Subtle Cognitive Difficulties in Cognitively Unimpaired Older Veterans.

INTRODUCTION: Psychiatric conditions such as post-traumatic stress disorder (PTSD) and depression have a two-fold increased dementia risk in Veterans. Prior work has shown that psychiatric factors can both impact cognitive functioning and be early symptoms associated with Alzheimer's disease (AD). Objectively defined subtle cognitive difficulties (Obj-SCD) has been associated with cognitive decline and AD biomarkers. However, Obj-SCD has not yet been investigated in the context of psychiatric disorders. METHODS: A total of 179 cognitively unimpaired Veterans (50-92 years old) underwent a comprehensive neuropsychological evaluation at VA San Diego and a retrospective medical record review. Chi-squared tests compared rates of psychiatric diagnoses in Veterans with and without Obj-SCD. RESULTS: About 21% of the sample was classified as Obj-SCD. Relative to cognitively unimpaired Veterans, Veterans classified as Obj-SCD had higher rates of PTSD, but not higher rates of other psychiatric conditions (e.g., depression). The PTSD findings appear to be driven by measures of cognitive efficiency. CONCLUSION: Elevated rates of PTSD, but not other psychiatric conditions, were observed among Veterans with Obj-SCD. The prevalence and type of subtle cognitive difficulties associated with PTSD in older Veterans demonstrates a need, and informs potential targets, for intervention. Further work is needed to determine mechanisms of subtle cognitive difficulties in older Veterans with PTSD.

Cognition and Amyloid-ß in Older Veterans: Characterization and Longitudinal Outcomes of Data-Derived Phenotypes.

Background: Within older Veterans, multiple factors may contribute to cognitive difficulties. Beyond Alzheimer's disease (AD), psychiatric (e.g., PTSD) and health comorbidities (e.g., TBI) may also impact cognition. Objective: This study aimed to derive subgroups based on objective cognition, subjective cognitive decline (SCD), and amyloid burden, and then compare subgroups on clinical characteristics, biomarkers, and longitudinal change in functioning and global cognition. Methods: Cluster analysis of neuropsychological measures, SCD, and amyloid PET was conducted on 228 predominately male Vietnam-Era Veterans from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative. Cluster-derived subgroups were compared on baseline characteristics as well as 1-year changes in everyday functioning and global cognition. Results: The cluster analysis identified 3 groups. Group 1 (n = 128) had average-to-above average cognition with low amyloid burden. Group 2 (n = 72) had the lowest memory and language, highest SCD, and average amyloid burden; they also had the most severe PTSD, pain, and worst sleep quality. Group 3 (n = 28) had the lowest attention/executive functioning, slightly low memory and language, elevated amyloid and the worst AD biomarkers, and the fastest rate of everyday functioning and cognitive decline. CONCLUSIONS: Psychiatric and health factors likely contributed to Group 2's low memory and language performance. Group 3 was most consistent with biological AD, yet attention/executive function was the lowest score. The complexity of older Veterans' co-morbid conditions may interact with AD pathology to show attention/executive dysfunction (rather than memory) as a prominent early symptom. These results could have important implications for the implementation of AD-modifying drugs in older Veterans.

Representation of women in neuropsychology research prior to the COVID-19 pandemic.

OBJECTIVE: Prior work has demonstrated that women have been historically underrepresented across various research fields, including neuropsychology. Given these disparities, the goal of this study was to systematically evaluate the inclusion of women as participants in neuropsychology research. The current study builds upon previous research by examining articles from eight peer-reviewed neuropsychology journals published in 2019. METHOD: Empirical articles examining human samples were included in the current review if they were available in English. Eligible articles were examined to glean whether the main topic of the article was related to a gender issue, how gender was categorized, the gender distribution of the sample, whether gender was considered in analyses, whether gender was addressed in the discussion, and what age categories the study examined. RESULTS: There was a relatively even distribution of men (51.76%) and women (48.24%) in neuropsychological research studies reviewed. There were twice as many studies that included only men compared to only women (16 vs. 8 studies), and nearly twice as many studies consisted of ≥ 75% men (16.6%) compared to ≥75% of women (8.5%). Gender-focused research was limited (3%). Furthermore, gender was frequently disregarded in analyses (58%) and often not addressed in the discussion (75%). CONCLUSIONS: The current study highlights the limitations within neuropsychology related to the representation of women in research. Although it is encouraging that neuropsychological research is generally inclusive of women participants, future research should aim to more comprehensively investigate how gender may influence cognitive risk and resilience factors across different clinical presentations. Recommendations to begin addressing this challenge and to move toward more gender-equitable research are provided.

Pulse pressure and APOE ε4 dose interact to affect cerebral blood flow in older adults without dementia.

This study assessed whether the effect of vascular risk on cerebral blood flow (CBF) varies by gene dose of apolipoprotein (APOE) ε4 alleles. 144 older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative underwent arterial spin labeling and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure (BP) assessment. Vascular risk was assessed using pulse pressure (systolic BP - diastolic BP). CBF was examined in six AD-vulnerable regions: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regressions tested the interaction between APOE ε4 dose and pulse pressure on CBF in each region, adjusting for age, sex, cognitive classification, antihypertensive medication use, FDG-PET, reference CBF region, and AD biomarker positivity. There was a significant interaction between pulse pressure and APOE ɛ4 dose on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex, such that higher pulse pressure was associated with lower CBF only among ε4 homozygous participants. These findings demonstrate that the association between pulse pressure and regional CBF differs by APOE ε4 dose, suggesting that targeting modifiable vascular risk factors may be particularly important for those genetically at risk for AD.

Greater subjective cognitive decline severity is associated with worse memory performance and lower entorhinal cerebral blood flow in healthy older adults.

OBJECTIVE: Subjective cognitive decline (SCD) is a potential early risk marker for Alzheimer's disease (AD), but its utility may vary across individuals. We investigated the relationship of SCD severity with memory function and cerebral blood flow (CBF) in areas of the middle temporal lobe (MTL) in a cognitively normal and overall healthy sample of older adults. Exploratory analyses examined if the association of SCD severity with memory and MTL CBF was different in those with lower and higher cardiovascular disease (CVD) risk status. METHODS: Fifty-two community-dwelling older adults underwent magnetic resonance imaging, neuropsychological testing, and were administered the Everyday Cognition Scale (ECog) to measure SCD. Regression models investigated whether ECog scores were associated with memory performance and MTL CBF, followed by similar exploratory regressions stratified by CVD risk status (i.e., lower vs higher stroke risk). RESULTS: Higher ECog scores were associated with lower objective memory performance and lower entorhinal cortex CBF after adjusting for demographics and mood. In exploratory stratified analyses, these associations remained significant in the higher stroke risk group only. CONCLUSIONS: Our preliminary findings suggest that SCD severity is associated with cognition and brain markers of preclinical AD in otherwise healthy older adults with overall low CVD burden and that this relationship may be stronger for individuals with higher stroke risk, although larger studies with more diverse samples are needed to confirm these findings. Our results shed light on individual characteristics that may increase the utility of SCD as an early risk marker of cognitive decline.

Parental, caregiving, and family leave during clinical neuropsychology postdoctoral training: Recommendations and guidelines from the Women in Neuropsychology (WIN) committee and Education Advisory Committee (EAC) of the Society for Clinical Neuropsychology (SCN; APA division 40).

Objective: Parental and other caregiving leave is important to postdoctoral fellows, yet there is no field-wide recommendation for leave policies among clinical neuropsychology postdoctoral training programs, which is of particular relevance given the two-year requirement for eligibility for board certification. The aims of this manuscript are to (a) discuss general guidelines and recommendations for leave policies, both informed by prior empirical evidence as well as relevant existing policy guidelines from various academic and healthcare organizations, and (b) use vignettes to provide possible solutions for potential leave scenarios. Method: A critical review of literature on family leave from public policy and political science, industrial-organizational psychology, academic medicine, and psychology was conducted and findings were synthesized. Results and Conclusions: Fellowship training programs are encouraged to adopt a competency-based model that permits flexibility in leave during training without necessarily requiring an extended end date. Programs should adopt clear policies and make this information readily available to trainees and think flexibly about training options that best meet the training needs and goals of each individual. We also encourage neuropsychologists at all levels to engage in advocacy for broader systemic supports of trainees seeking equitable family leave.

Type 2 Diabetes Moderates the Association Between Amyloid and 1-Year Change in Everyday Functioning in Older Veterans.

BACKGROUND: Type 2 diabetes mellitus (T2DM) affects ∼25% of Veterans, a prevalence rate double that of the general population. T2DM is associated with greater dementia risk and has been shown to exacerbate the impact of Alzheimer's disease (AD) risk factors on declines in daily functioning; however, there are few studies that investigate these patterns in older Veterans. OBJECTIVE: This study sought to determine whether T2DM moderates the association between amyloid-ß (Aß) positron emission tomography (PET) and 1-year change in everyday functioning in older Veterans. METHODS: One-hundred-ninety-eight predominately male Vietnam-Era Veterans without dementia from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DoD-ADNI) with (n = 74) and without (n = 124) T2DM completed Aß PET imaging and everyday functioning measures, including the Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Everyday Cognition (ECog). Linear mixed effects models tested the moderating role of T2DM on the association between Aß PET and 1-year change in everyday functioning. RESULTS: The 3-way T2DM×Aß PET×time interaction was significant for CDR-SB (p < 0.001) as well as the Memory (p = 0.007) and Language (p = 0.011) subscales from the ECog. Greater amyloid burden was associated with greater increases in functional difficulties, but only in Veterans with T2DM. CONCLUSIONS: Higher Aß was only associated with declines in everyday functioning over 1 year in Veterans with T2DM. Given that people with T2DM are more likely to have co-occurring cerebrovascular disease, the combination of multiple neuropathologies may result in faster declines. Future studies should examine how diabetes duration, severity, and medications impact these associations.

Regional White Matter Hyperintensities Relate to Specific Cognitive Abilities in Older Adults Without Dementia.

INTRODUCTION: White matter hyperintensities (WMHs) are magnetic resonance imaging markers of small vessel cerebrovascular disease that are associated with cognitive decline and clinical Alzheimer disease. Previous studies have often focused on global or total WMH; less is known about associations of regional WMHs and cognitive abilities among older adults without dementia. METHODS: A total of 610 older adults with normal cognition (n=302) or mild cognitive impairment (n=308) from the Alzheimer's Disease Neuroimaging Initiative underwent neuropsychological testing and magnetic resonance imaging. Linear regression models examined associations between regional WMH volumes and cognition, adjusting for age, sex, education, apolipoprotein E ε4 allele frequency, and pulse pressure. RESULTS: Among all participants, greater regional WMH volume in all lobes was associated with poorer performance on memory and speed/executive functioning. Among participants with normal cognition, greater temporal and occipital WMH volumes were associated with poorer memory, whereas no regional WMH volumes were associated with speed/executive function. DISCUSSION: Results show that greater regional WMH volume relates to poorer cognitive functioning-even among those with normal cognition. Together with results from previous studies, our findings raise the possibility that WMH may be a useful therapeutic target and/or important effect modifier in treatment or prevention dementia trials.

Research Letter: TBI Severity Moderates the Association Between Subjective and Objective Attention in Older Veterans.

OBJECTIVE: This study examined the moderating effect of traumatic brain injury (TBI) history on subjective and objective cognition across multiple cognitive domains. SETTING, PARTICIPANTS, AND DESIGN: Participants included 242 Vietnam-era veterans with a history of no TBI (n = 86), mild TBI (n = 74), or moderate-to-severe TBI (n = 82) from the observational Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DoD-ADNI) study. MAIN MEASURES: Objective cognition was the outcome and was measured using neuropsychological measures in the domains of memory, attention/executive functioning, and language. Subjective cognition was measured using the memory, divided attention, and language subscales from the Everyday Cognition (ECog) measure. TBI severity status was the moderating variable. RESULTS: Veterans with a history of moderate-to-severe TBI had a stronger negative association between subjective and objective attention relative to participants without a TBI (P = .002). Although this association did not differ between mild TBI and no TBI history groups (P = .100), the association between subjective and objective attention for the mild TBI group was intermediate to the no TBI and moderate-to-severe TBI history groups. TBI status did not moderate associations between subjective and objective memory or language. CONCLUSION: Results highlight the importance of assessing subjective and objective cognition in older veterans and the relevance of attention in the context of TBI history. More work is needed to better understand the intersection of TBI and aging and how these factors may be used to guide individualized assessment and treatment approaches for older veterans.

White Matter Hyperintensity Volume and Amyloid-PET Synergistically Impact Memory Independent of Tau-PET in Older Adults Without Dementia.

BACKGROUND: Alzheimer's disease (AD) and cerebrovascular disease are common, co-existing pathologies in older adults. Whether the effects of cerebrovascular disease and AD biomarkers on cognition are additive or synergistic remains unclear. OBJECTIVE: To examine whether white matter hyperintensity (WMH) volume moderates the independent association between each AD biomarker and cognition. METHODS: In 586 older adults without dementia, linear regressions tested the interaction between amyloid-ß (Aß) positron emission tomography (PET) and WMH volume on cognition, independent of tau-PET. We also tested the interaction between tau-PET and WMH volume on cognition, independent of Aß-PET. RESULTS: Adjusting for tau-PET, the quadratic effect of WMH interacted with Aß-PET to impact memory. There was no interaction between either the linear or quadratic effect of WMH and Aß-PET on executive function. There was no interaction between WMH volume and tau-PET on either cognitive measure. CONCLUSION: Results suggest that cerebrovascular lesions act synergistically with Aß to affect memory, independent of tau, highlighting the importance of incorporating vascular pathology into biomarker assessment of AD.

Brain Derived Neurotrophic Factor Interacts with White Matter Hyperintensities to Influence Processing Speed and Hippocampal Volume in Older Adults.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in regulating synaptic activity and plasticity. OBJECTIVE: Given that type-2 diabetes (T2DM) increases the risk of cognitive decline, and studies have suggested lower BDNF levels may be a risk factor of diabetic neurovascular complications, we sought to investigate total white matter hyperintensities (WMH) as a moderator of the effect of BDNF on hippocampal volume and cognition. METHODS: Older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative (N = 454 including 49 with T2DM and 405 without diabetes) underwent neuropsychological evaluation, magnetic resonance imaging to quantify hippocampal and WMH volumes, and blood draw to assess BDNF. RESULTS: Adjusting for age, sex, and APOE ɛ4 carrier status, there was a significant interaction between total WMH and BDNF on bilateral hippocampal volume in the non-T2DM group (t = 2.63, p = 0.009). Examination of main effect models with a dichotomous high/low BNDF group revealed a significant main effect for low BDNF (t = -4.98, p < 0.001), such that as WMH increased, bilateral hippocampal volume decreased. There was also a significant interaction between total WMH and BDNF on processing speed in the non-T2DM group (t = 2.91, p = 0.004). There was a significant main effect for low BDNF (t = -3.55, p < 0.001) such that as WMH increased, processing speed decreased. The interactions were not significant in the T2DM group. CONCLUSION: These results further elucidate the protective role that BDNF plays on cognition, as well as the cognitive effects of WMH.

Cognitive reserve moderates the association between cerebral blood flow and language performance in older adults with mild cognitive impairment.

Higher cognitive reserve (CR) may offer protection from cognitive changes associated with reduced cerebral blood flow (CBF). We investigated CR as a moderator of the effect of CBF on cognition in older adults with mild cognitive impairment (MCI; N = 46) and those who are cognitively unimpaired (CU; N = 101). Participants underwent arterial spin labeling MRI, which was used to quantify CBF in 4 a priori regions. Estimated verbal intelligence quotient (VIQ) served as a proxy for CR. Multiple linear regressions examined whether VIQ moderated associations between CBF and cognition and whether this differed by cognitive status. Outcomes included memory and language performance. There were 3-way interactions (CBF*VIQ*cognitive status) on category fluency when examining hippocampal, superior frontal, and inferior frontal CBF. Follow-up analyses revealed that, within the MCI but not CU group, there were CBF*VIQ interactions on fluency in all a priori regions examined, where there were stronger, positive associations between CBF and fluency at higher VIQ. Conclusion: In MCI, higher CR plays a role in strengthening CBF-fluency associations.

Greater accelerometer-measured physical activity is associated with better cognition and cerebrovascular health in older adults.

OBJECTIVES: Physical activity (PA) may help maintain brain structure and function in aging. Since the intensity of PA needed to effect cognition and cerebrovascular health remains unknown, we examined associations between PA and cognition, regional white matter hyperintensities (WMH), and regional cerebral blood flow (CBF) in older adults. METHOD: Forty-three older adults without cognitive impairment underwent magnetic resonance imaging (MRI) and comprehensive neuropsychological assessment. Waist-worn accelerometers objectively measured PA for approximately one week. RESULTS: Higher time spent in moderate to vigorous PA (MVPA) was uniquely associated with better memory and executive functioning after adjusting for all light PA. Higher MVPA was also uniquely associated with lower frontal WMH volume although the finding was no longer significant after additionally adjusting for age and accelerometer wear time. MVPA was not associated with CBF. Higher time spent in all light PA was uniquely associated with higher CBF but not with cognitive performance or WMH volume. CONCLUSIONS: Engaging in PA may be beneficial for cerebrovascular health, and MVPA in particular may help preserve memory and executive function in otherwise cognitively healthy older adults. There may be differential effects of engaging in lighter PA and MVPA on MRI markers of cerebrovascular health although this needs to be confirmed in future studies with larger samples. Future randomized controlled trials that increase PA are needed to elucidate cause-effect associations between PA and cerebrovascular health.

Pulse pressure trajectories predict brain microstructure in community-dwelling older adults: Associations with executive function and modification by APOE.

INTRODUCTION: Effects of chronic arterial stiffness on brain aging remain unclear. We, therefore, examined whether long-term trajectories of pulse pressure (PP) predicted brain microstructure, microstructure mediated PP-executive function associations, and APOE genotype modified PP-microstructure associations. METHODS: We examined associations of PP trajectories with brain microstructure measured using restriction spectrum imaging in 146 community-dwelling older adults, whether microstructure mediated PP trajectory-executive function associations, and whether PP-restriction spectrum imaging correlations were modified by APOE-ε4 status. RESULTS: Participants with trajectories of high PP had lower restricted isotropic diffusion (RI) compared to those with low PP trajectories and PP-executive function associations were mediated by subcortical and white matter RI. High PP more strongly correlated with lower RI and higher hindered diffusion among APOE-ε4 carriers than non-carriers. DISCUSSION: Prolonged elevated PP predicts microstructural abnormalities which may contribute to impaired executive function. APOE-ε4 carriers may be most vulnerable to the adverse effects of PP on brain microstructure.

Cognitive dispersion is elevated in amyloid-positive older adults and associated with regional hypoperfusion.

OBJECTIVE: Cognitive dispersion across neuropsychological measures within a single testing session is a promising marker predictive of cognitive decline and development of Alzheimer's disease (AD). However, little is known regarding brain changes underlying cognitive dispersion, and the association of cognitive dispersion with in vivo AD biomarkers and regional cerebral blood flow (CBF) has received limited study. We therefore examined associations among cognitive dispersion, amyloid-beta (Aß) positivity, and regional CBF among older adults free of dementia. METHOD: One hundred and forty-eight Alzheimer's Disease Neuroimaging Initiative (ADNI) participants underwent neuropsychological testing and neuroimaging. Pulsed arterial spin labeling (ASL) magnetic resonance imaging (MRI) was acquired to quantify CBF. Florbetapir positron emission tomography (PET) imaging determined Aß positivity. RESULTS: Adjusting for age, gender, education, and mean cognitive performance, older adults who were Aß+ showed higher cognitive dispersion relative to those who were Aß-. Across the entire sample, higher cognitive dispersion was associated with reduced CBF in inferior parietal and temporal regions. Secondary analyses stratified by Aß status demonstrated that higher cognitive dispersion was associated with reduced CBF among Aß+ individuals but not among those who were Aß-. CONCLUSIONS: Cognitive dispersion may be sensitive to early Aß accumulation and cerebrovascular changes adjusting for demographics and mean neuropsychological performance. Associations between cognitive dispersion and CBF were observed among Aß+ individuals, suggesting that cognitive dispersion may be a marker of brain changes among individuals on the AD continuum. Future studies should examine whether cognitive dispersion predicts brain changes in diverse samples and among those with greater vascular risk burden.

Sex moderates the association between age and myelin water fraction in the cingulum and fornix among older adults without dementia.

Background: Decreasing white matter integrity in limbic pathways including the fornix and cingulum have been reported in Alzheimer's disease (AD), although underlying mechanisms and potential sex differences remain understudied. We therefore sought to explore sex as a moderator of the effect of age on myelin water fraction (MWF), a measure of myelin content, in older adults without dementia (N = 52). Methods: Participants underwent neuropsychological evaluation and 3 T MRI at two research sites. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) quantified MWF in 3 a priori regions including the fornix, hippocampal cingulum (CgH), and cingulate cingulum (CgC). The California Verbal Learning Test-Second Edition assessed learning and delayed recall. Multiple linear regressions assessed for (1) interactions between age and sex on regional MWF and (2) associations of regional MWF and memory. Results: (1) There was a significant age by sex interaction on MWF of the fornix (p = 0.002) and CgC (p = 0.005), but not the CgH (p = 0.192); as age increased, MWF decreased in women but not men. (2) Fornix MWF was associated with both learning and recall (ps < 0.01), but MWF of the two cingulum regions were not (p > 0.05). Results were unchanged when adjusting for hippocampal volume. Conclusion: The current work adds to the literature by illuminating sex differences in age-related myelin decline using a measure sensitive to myelin and may help facilitate detection of AD risk for women.

Comprehensive characterization of elevated tau PET signal in the absence of amyloid-beta.

Recently proposed biomarker-only diagnostic frameworks propose that amyloid-beta is necessary for placement on the Alzheimer's disease continuum, whereas tau in the absence of amyloid-beta is considered to be a non-Alzheimer's disease pathologic change. Similarly, the pathologic designation of tau in the absence of amyloid-beta is characterized as primary age-related tauopathy and separable from Alzheimer's disease. Our study sought to identify an early-to-moderate tau stage with minimal amyloid-beta using PET imaging and characterize these individuals in terms of clinical, cognitive and biological features. Seven hundred and three participants from the Alzheimer's Disease Neuroimaging Initiative were classified into one of the four groups (A-/T-, A-/T+, A+/T- and A+/T+) based on PET positivity or negativity for cortical amyloid-beta (A-/A+) and early-to-moderate stage (i.e. meta-temporal) tau (T-/T+). These groups were then compared on demographic and clinical features, vascular risk, multi-domain neuropsychological performance, multi-domain subjective cognitive complaints, apolipoprotein E epsilon-4 carrier status and cortical thickness across Alzheimer's disease-vulnerable regions. The proportion of participants classified in each group was as follows: 47.23% A-/T-, 13.51% A-/T+, 12.23% A+/T- and 27.03% A+/T+. Results indicated that the A-/T+ and A+/T+ groups did not statistically differ on age, sex, depression levels, vascular risk and cortical thickness across temporal and parietal regions. Additionally, both A-/T+ and A+/T+ groups showed significant associations between memory performance and cortical thickness of temporal regions. Despite the different pathologic terminology used for A-/T+ and A+/T+, these groups did not statistically differ on a number of clinical, cognitive and biomarker features. Although it remains unclear whether A-/T+ reflects a pathologic construct separable from Alzheimer's disease, our results provide evidence that this group typically characterized as 'non-Alzheimer's pathologic change' or 'primary age-related tauopathy' should be given increased attention, given some similarities in cognitive and biomarker characteristics to groups traditionally considered to be on the Alzheimer's continuum.

Cognitive Heterogeneity and Risk of Progression in Data-Driven Subtle Cognitive Decline Phenotypes.

BACKGROUND: There is increasing recognition of cognitive and pathological heterogeneity in early-stage Alzheimer's disease and other dementias. Data-driven approaches have demonstrated cognitive heterogeneity in those with mild cognitive impairment (MCI), but few studies have examined this heterogeneity and its association with progression to MCI/dementia in cognitively unimpaired (CU) older adults. OBJECTIVE: We identified cluster-derived subgroups of CU participants based on comprehensive neuropsychological data and compared baseline characteristics and rates of progression to MCI/dementia or a Dementia Rating Scale (DRS) of ≤129 across subgroups. METHODS: Hierarchical cluster analysis was conducted on individual baseline neuropsychological test scores from 365 CU participants in the UCSD Shiley-Marcos Alzheimer's Disease Research Center longitudinal cohort. Cox regressions examined the risk of progression to consensus diagnosis of MCI or dementia, or to DRS score ≤129, by cluster group. RESULTS: Cluster analysis identified 5 groups: All-Average (n = 139), Low-Visuospatial (n = 46), Low-Executive (n = 51), Low-Memory/Language (n = 83), and Low-All Domains (n = 46). Subgroups had unique demographic and clinical characteristics. Rates of progression to MCI/dementia or to DRS ≤129 were faster for all subgroups (Low-All Domains progressed the fastest > Low Memory/Language≥Low-Visuospatial and Low-Executive) relative to the All-Average subgroup. CONCLUSION: Faster progression in the Low-Visuospatial, Low-Executive, and Low-Memory/Language groups compared to the All-Average group suggests that there are multiple pathways and/or unique subtle cognitive decline profiles that ultimately lead to a diagnosis of MCI/dementia. Use of comprehensive neuropsychological test batteries that assess several domains may be a key first step toward an individualized approach to early detection and fewer missed opportunities for early intervention.