Cognitive Trajectories and Alzheimer Disease Biomarkers: From Successful Cognitive Aging to Clinical Impairment.

OBJECTIVE: Cross-sectional definitions of successful cognitive aging have been widely utilized, but longitudinal measurements can identify people who do not decline. We performed this study to contrast maintenance with declining trajectories, including clinical conversion. METHODS: We included baseline cognitively unimpaired Alzheimer's Disease Neuroimaging Initiative participants with 3 or more cognitive testing sessions (n = 539, follow-up 6.1 ± 3.5 years) and calculated slopes of an episodic memory composite (MEM) to classify them into two groups: maintainers (slope ≥ 0) and decliners (slope < 0). Within decliners, we examined a subgroup of individuals who became clinically impaired during follow-up. These groups were compared on baseline characteristics and cognitive performance, as well as both cross-sectional and longitudinal Alzheimer disease (AD) biomarker measures (beta-amyloid [Aß], tau, and hippocampal volume). RESULTS: Forty-one percent (n = 221) of the cohort were MEM maintainers, and 33% (n = 105) of decliners converted to clinical impairment during follow-up. Compared to those with superior baseline scores, maintainers had lower education and were more likely to be male. Maintainers and decliners did not differ on baseline MEM scores, but maintainers did have higher non-MEM cognitive scores. Maintainers had lower baseline global Aß, lower tau pathology, and larger hippocampal volumes than decliners, even after removing converters. There were no differences in rates of change of any AD biomarkers between any cognitive trajectory groups except for a higher rate of hippocampal atrophy in clinical converters compared to maintainers. INTERPRETATION: Using longitudinal data to define cognitive trajectory groups reduces education and sex bias and reveals the prognostic importance of early onset of accumulation of AD pathology. ANN NEUROL 2024.

Behaviorally meaningful functional networks mediate the effect of Alzheimer's pathology on cognition.

Tau pathology is associated with cognitive impairment in both aging and Alzheimer's disease, but the functional and structural bases of this relationship remain unclear. We hypothesized that the integrity of behaviorally meaningful functional networks would help explain the relationship between tau and cognitive performance. Using resting state fMRI, we identified unique networks related to episodic memory and executive function cognitive domains. The episodic memory network was particularly related to tau pathology measured with positron emission tomography in the entorhinal and temporal cortices. Further, episodic memory network strength mediated the relationship between tau pathology and cognitive performance above and beyond neurodegeneration. We replicated the association between these networks and tau pathology in a separate cohort of older adults, including both cognitively unimpaired and mildly impaired individuals. Together, these results suggest that behaviorally meaningful functional brain networks represent a functional mechanism linking tau pathology and cognition.

Tau accumulation and atrophy predict amyloid independent cognitive decline in aging.

INTRODUCTION: Amyloid beta (Aß) and tau pathology are cross-sectionally associated with atrophy and cognitive decline in aging and Alzheimer's disease (AD). METHODS: We investigated relationships between concurrent longitudinal measures of Aß (Pittsburgh compound B [PiB] positron emission tomography [PET]), tau (flortaucipir [FTP] PET), atrophy (structural magnetic resonance imaging), episodic memory (EM), and non-memory (NM) in 78 cognitively healthy older adults (OA). RESULTS: Entorhinal FTP change was correlated with EM decline regardless of Aß, but meta-temporal FTP and global PiB change were only associated with EM and NM decline in Aß+ OA. Voxel-wise analyses revealed significant associations between temporal lobe FTP change and EM decline in all groups. PiB and FTP change were not associated with structural change, suggesting a functional or microstructural mechanism linking these measures to cognitive decline. DISCUSSION: Our results show that longitudinal Aß is linked to cognitive decline only in the presence of elevated Aß, but longitudinal temporal lobe tau is associated with memory decline regardless of Aß status. HIGHLIGHTS: Entorhinal tau change was associated with memory decline in older adults (OA), regardless of amyloid beta (Aß). Greater meta-region of interest (ROI) tau change correlated with memory decline in Aß+ OA. Voxel-wise temporal tau change correlated with memory decline, regardless of Aß. Meta-ROI tau and global amyloid change correlated with non-memory change in Aß+ OA. Tau and amyloid accumulation were not associated with structural change in OA.

Individuals with Alzheimer's disease and low tau burden: Characteristics and implications.

INTRODUCTION: Abnormal amyloid-beta (Aß) and tau deposition define Alzheimer's Disease (AD), but non-elevated tau is relatively frequent in patients on the AD pathway. METHODS: We examined characteristics and regional patterns of 397 Aß+ unimpaired and impaired individuals with low tau (A+T-) in relation to their higher tau counterparts (A+T+). RESULTS: Seventy-one percent of Aß+ unimpaired and 42% of impaired Aß+ individuals were categorized as A+T- based on global tau. In impaired individuals only, A+T- status was associated with older age, male sex, and greater cardiovascular risk. α-synuclein was linked to poorer cognition, particularly when tau was low. Tau burden was most frequently elevated in a common set of temporal regions regardless of T+/T- status. DISCUSSION: Low tau is relatively common in patients on the AD pathway and is linked to comorbidities that contribute to impairment. These findings have implications for the selection of individuals for Aß- and tau-modifying therapies.

Successful cognitive aging is associated with thicker anterior cingulate cortex and lower tau deposition compared to typical aging.

INTRODUCTION: There is no consensus on either the definition of successful cognitive aging (SA) or the underlying neural mechanisms. METHODS: We examined the agreement between new and existing definitions using: (1) a novel measure, the cognitive age gap (SA-CAG, cognitive-predicted age minus chronological age), (2) composite scores for episodic memory (SA-EM), (3) non-memory cognition (SA-NM), and (4) the California Verbal Learning Test (SA-CVLT). RESULTS: Fair to moderate strength of agreement was found between the four definitions. Most SA groups showed greater cortical thickness compared to typical aging (TA), especially in the anterior cingulate and midcingulate cortices and medial temporal lobes. Greater hippocampal volume was found in all SA groups except SA-NM. Lower entorhinal 18 F-Flortaucipir (FTP) uptake was found in all SA groups. DISCUSSION: These findings suggest that a feature of SA, regardless of its exact definition, is resistance to tau pathology and preserved cortical integrity, especially in the anterior cingulate and midcingulate cortices. HIGHLIGHTS: Different approaches have been used to define successful cognitive aging (SA). Regardless of definition, different SA groups have similar brain features. SA individuals have greater anterior cingulate thickness and hippocampal volume. Lower entorhinal tau deposition, but not amyloid beta is related to SA. A combination of cortical integrity and resistance to tau may be features of SA.

Regional Tau Deposition Reflects Different Pathways of Subsequent Neurodegeneration and Memory Decline in Cognitively Normal Older Adults.

OBJECTIVE: Tau pathology is recognized as a primary contributor to neurodegeneration and clinical symptoms in Alzheimer's disease (AD). This study aims to localize the early tau pathology in cognitively normal older people that is predictive of subsequent neurodegeneration and memory decline, and delineate factors underlying tau-related memory decline in individuals with and without ß-amyloid (Aß). METHODS: A total of 138 cognitively normal older individuals from the Berkeley Aging Cohort Study underwent 11 C-Pittsburgh Compound-B (PiB) positron emission tomography (PET) to determine Aß positivity and 18 F-Flortaucipir (FTP) PET to measure tau deposition, with prospective cognitive assessments and structural magnetic resonance imaging. Voxel-wise FTP analyses examined associations between baseline tau deposition and longitudinal memory decline, longitudinal hippocampal atrophy, and longitudinal cortical thinning in AD signature regions. We also examined whether hippocampal atrophy and cortical thinning mediate tau effects on future memory decline. RESULTS: We found Aß-dependent tau associations with memory decline in the entorhinal and temporoparietal regions, Aß-independent tau associations with hippocampal atrophy within the medial temporal lobe (MTL), and that widespread tau was associated with mean cortical thinning in AD signature regions. Tau-related memory decline was mediated by hippocampal atrophy in Aß- individuals and by mean cortical thinning in Aß+ individuals. INTERPRETATION: Our results suggest that tau may affect memory through different mechanisms in normal aging and AD. Early tau deposition independent of Aß predicts subsequent hippocampal atrophy that may lead to memory deficits in normal older individuals, whereas elevated cortical tau deposition is associated with cortical thinning that may lead to more severe memory decline in AD. ANN NEUROL 2024;95:249-259.

Socioemotional and Behavioral Problems of Grandchildren Raised by Grandparents: The Role of Grandparent-Grandchild Relational Closeness and Conflict.

This study examined the associations of grandparent-grandchild relational closeness and conflict with grandchildren's socioemotional and behavioral problems, including emotional symptoms, conduct problems, hyperactivity, peer problems, and abnormal prosocial behaviors. We analyzed primary cross-sectional survey data collected from custodial grandparents in the United States using logistic regression models. The results indicated that grandparent-grandchild relational closeness was significantly associated with lower odds of custodial grandchildren having emotional symptoms, conduct problems, peer problems, and abnormal prosocial behaviors, whereas grandparent-grandchild relational conflict was significantly associated with higher odds of emotional symptoms, conduct problems, hyperactivity, peer problems, and abnormal prosocial behaviors. Implications for increasing grandparent-grandchild relational closeness and decreasing relational conflicts among grandparent-headed families are discussed, which might improve grandchildren's socioemotional and behavioral well-being.

Global brain activity and its coupling with cerebrospinal fluid flow is related to tau pathology.

Amyloid-ß (Aß) and tau deposition constitute Alzheimer's disease (AD) neuropathology. Cortical tau deposits first in the entorhinal cortex and hippocampus and then propagates to neocortex in an Aß-dependent manner. Tau also tends to accumulate earlier in higher-order association cortex than in lower-order primary sensory-motor cortex. While previous research has examined the production and spread of tau, little attention has been paid to its clearance. Low-frequency (<0.1 Hz) global brain activity during the resting state is coupled with cerebrospinal fluid (CSF) flow and potentially reflects glymphatic clearance. Here we report that tau deposition in subjects with evaluated Aß, accompanied by cortical thinning and cognitive decline, is strongly associated with decreased coupling between CSF flow and global brain activity. Substantial modulation of global brain activity is also manifested as propagating waves of brain activation between higher- and lower-order regions, resembling tau spreading. Together, the findings suggest an important role of resting-state global brain activity in AD tau pathology.

Effect of Alzheimer's Pathology on Task-Related Brain Network Reconfiguration in Aging.

Large-scale brain networks undergo widespread changes with older age and in neurodegenerative diseases such as Alzheimer's disease (AD). Research in young adults (YA) suggest that the underlying functional architecture of brain networks remains relatively consistent between rest and task states. However, it remains unclear whether the same is true in aging and to what extent any changes may be related to accumulation of AD pathology such as ß-amyloid (Aß) and tau. Here, we examined age-related differences in functional connectivity (FC) between rest and an object-scene mnemonic discrimination task using fMRI in young and older adults (OA; both females and males). We used an a priori episodic memory network (EMN) parcellation scheme associated with object and scene processing, that included anterior-temporal regions and posterior-medial regions. We also used positron emission topography to measure Aß and tau in older adults. The correlation between rest and task FC (i.e., FC similarity) was reduced in older compared with younger adults. Older adults with lower FC similarity in EMN had higher levels of tau in the same EMN regions and performed worse during object, but not scene, trials during the fMRI task. These findings link AD pathology, particularly tau, to a less stable functional architecture in memory networks. They also suggest that smaller changes in FC organization between rest and task states may facilitate better performance in older age. Interpretations are limited by methodological factors related to different acquisition directions and durations between rest and task scans.SIGNIFICANCE STATEMENT The brain's large-scale network organization is relatively consistent between rest and task states in young adults (YA). We found that memory networks in older adults (OA) were less correlated between rest and (memory) task states compared with young adults. Older adults with less correlated brain networks also had higher levels of Alzheimer's disease (AD) pathology in the same regions, suggesting that a less stable network architecture may reflect the early evolution of AD. Older adults with less correlated brain networks also performed worse during the memory task suggesting that more similar network organization between rest and task states may facilitate better performance in older age.

Protective effects of sleep duration and physical activity on cognitive performance are influenced by ß-amyloid and brain volume but not tau burden among cognitively unimpaired older adults.

BACKGROUND AND OBJECTIVES: Sleep and physical activity have gained traction as modifiable risk factors for Alzheimer's disease. Sleep duration is linked to amyloid-ß clearance while physical activity is associated with brain volume maintenance. We investigate how sleep duration and physical activity are associated with cognition by testing if the associations between sleep duration or physical activity to cognition are explained by amyloid-ß burden and brain volume, respectively. Additionally, we explore the mediating role of tau deposition in sleep duration-cognition and physical activity-cognition relationships. METHODS: This cross-sectional study obtained data from participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, a randomized clinical trial. In trial screening, cognitively unimpaired participants (age 65-85 years) underwent amyloid PET and brain MRI; APOE genotype and lifestyle questionnaire data were obtained. Cognitive performance was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Self-reported nightly sleep duration and weekly physical activity were the primary predictors. Regional Aß and tau pathologies and volumes were the proposed variables influencing relationships between sleep duration or physical activity and cognition. RESULTS: Aß data were obtained from 4322 participants (1208 with MRI, 59% female, 29% amyloid positive). Sleep duration was associated with a Aß composite score (ß = -0.005, CI: (-0.01, -0.001)) and Aß burden in the anterior cingulate (ACC) (ß = -0.012, CI: (-0.017, -0.006)) and medial orbitofrontal cortices (MOC) (ß = -0.009, CI: (-0.014, -0.005)). Composite (ß = -1.54, 95% CI:(-1.93, -1.15)), ACC (ß = -1.22, CI:(-1.54, -0.90)) and MOC (ß = -1.44, CI:(-1.86, -1.02)) Aß deposition was associated with PACC. Sleep duration-PACC association was explained by Aß burden in path analyses. Physical activity was associated with hippocampal (ß = 10.57, CI: (1.06, 20.08)), parahippocampal (ß = 9.3, CI: (1.69, 16.91)), entorhinal (ß = 14.68, CI: (1.75, 27.61), and fusiform gyral (ß = 38.38, CI: (5.57, 71.18)) volumes, which were positively associated with PACC (p < 0.02 for hippocampus, entorhinal cortex and fusiform gyrus). Physical activity-cognition relationship was explained by regional volumes. PET tau imaging was available for 443 participants. No direct sleep duration-tau burden, physical activity by tau burden, or mediation by regional tau was observed in sleep duration-cognition or physical activity-cognition relationships. DISCUSSION: Sleep duration and physical activity are associated with cognition through independent paths of brain Aß and brain volume, respectively. These findings implicate neural and pathological mechanisms for the relationships between sleep duration and physical activity on cognition. Dementia risk reduction approaches that emphasize the adequate sleep duration and a physically active lifestyle may benefit those with risk for Alzheimer's disease.

New perspectives on the basal forebrain cholinergic system in Alzheimer's disease.

The basal forebrain cholinergic system (BFCS) has long been implicated in age-related cognitive changes and the pathophysiology of Alzheimer's disease (AD). Limitations of cholinergic interventions helped to inspire a shift away from BFCS in AD research. A resurgence in interest in the BFCS following methodological and analytical advances has resulted in a call for the BFCS to be examined in novel frameworks. We outline the basic structure and function of the BFCS, its role in supporting cognitive and affective function, and its vulnerability to aging and AD. We consider the BFCS in the context of the amyloid hypothesis and evolving concepts in AD research: resilience and resistance to pathology, selective neuronal vulnerability, trans-synaptic pathology spread and sleep health. We highlight 1) the potential role of the BFCS in cognitive resilience, 2) recent work refining understanding about the selective vulnerability of BFCS to AD, 3) BFCS connectivity that suggests it is related to tau spreading and neurodegeneration and 4) the gap between BFCS involvement in AD and sleep-wake cycles.

An empirical measure of resilience explains individual differences in the effect of tau pathology on memory change in aging.

Accurately measuring resilience to preclinical Alzheimer's disease (AD) pathology is essential to understanding an important source of variability in cognitive aging. In a cohort of cognitively normal older adults (n = 123, age 76.75 ± 6.15 yr), we built a multifactorial measure of resilience which moderated the effect of AD pathology on longitudinal cognitive change. Linear residuals-based measures of resilience, along with other proxy measures (education and vocabulary), were entered into a hierarchical partial least-squares path model defining a putative consolidated resilience latent factor (model goodness of fit = 0.77). In a set of validation analyses using linear mixed models predicting longitudinal cognitive change, there was a significant three-way interaction among consolidated resilience, tau and time on episodic memory change (P = 0.001) such that higher resilience blunted the effect of tau pathology on episodic memory decline. Interactions between consolidated resilience and amyloid pathology on non-memory cognition decline suggested that resilience moderates pathology-specific effects on different cognitive domains.

Optimizing quantification of MK6240 tau PET in unimpaired older adults.

Accurate measurement of Alzheimer's disease (AD) pathology in older adults without significant clinical impairment is critical to assessing intervention strategies aimed at slowing AD-related cognitive decline. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (POINTER) is a 2-year randomized controlled trial to evaluate the effect of multicomponent risk reduction strategies in older adults (60-79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting tau-PET ([18F]MK6240), beta-amyloid (Aß)-PET ([18F]florbetaben [FBB]) and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at-risk sample. Here 481 participants (70.0±5.0; 66% F) with baseline MK6240, FBB and structural MRI scans were included. PET scans were coregistered to the structural MRI which was used to create FreeSurfer-defined reference regions and target regions of interest (ROIs). We also created off-target signal (OTS) ROIs to examine the magnitude and distribution of MK6240 OTS across the brain as well as relationships between OTS and age, sex, and race. OTS was unimodally distributed, highly correlated across OTS ROIs and related to younger age and sex but not race. Aiming to identify an optimal processing approach for MK6240 that would reduce the influence of OTS, we compared our previously validated MRI-guided standard PET processing and 6 alternative approaches. The alternate approaches included combinations of reference region erosion and meningeal OTS masking before spatial smoothing as well as partial volume correction. To compare processing approaches we examined relationships between target ROIs (entorhinal cortex (ERC), hippocampus or a temporal meta-ROI (MetaROI)) SUVR and age, sex, race, Aß and a general cognitive status measure, the Modified Telephone Interview for Cognitive Status (TICSm). Overall, the processing approaches performed similarly, and none showed a meaningful improvement over standard processing. Across processing approaches we observed previously reported relationships with MK6240 target ROIs including positive associations with age, an Aß+> Aß- effect and negative associations with cognition. In sum, we demonstrated that different methods for minimizing effects of OTS, which is highly correlated across the brain within subject, produced no substantive change in our performance metrics. This is likely because OTS contaminates both reference and target regions and this contamination largely cancels out in SUVR data. Caution should be used when efforts to reduce OTS focus on target or reference regions in isolation as this may exacerbate OTS contamination in SUVR data.

Quantification of amyloid beta and tau PET without a structural MRI.

INTRODUCTION: Relying on magnetic resonance imaging (MRI) for quantification of positron emission tomography (PET) images may limit generalizability of the results. We evaluated several MRI-free approaches for amyloid beta (Aß) and tau PET quantification relative to MRI-dependent quantification cross-sectionally and longitudinally. METHODS: We compared baseline MRI-free and MRI-dependent measurements of Aß PET ([18F]florbetapir [FBP], N = 1290, [18F]florbetaben [FBB], N = 290) and tau PET ([18F]flortaucipir [FTP], N = 768) images with respect to continuous and dichotomous agreement, effect sizes of Aß+ impaired versus Aß- unimpaired groups, and longitudinal standardized uptake value ratio (SUVR) slopes in a subset of individuals. RESULTS: The best-performing MRI-free approaches had high continuous and dichotomous agreement with MRI-dependent SUVRs for Aß PET and temporal flortaucipir (R2 ≥0.95; ± agreement ≥92%) and for Alzheimer's disease-related effect sizes; agreement was slightly lower for entorhinal flortaucipir and longitudinal slopes. DISCUSSION: There is no consistent loss of baseline or longitudinal AD-related signal with MRI-free Aß and tau PET image quantification.

Locus coeruleus catecholamines link neuroticism and vulnerability to tau pathology in aging.

Higher neuroticism is a risk factor for Alzheimer's disease (AD), and is implicated in disordered stress responses. The locus coeruleus (LC)-catecholamine system is activated during perceived threat and is a centerpiece of developing models of the pathophysiology of AD, as it is the first brain region to develop abnormal tau. We examined relationships among the "Big 5" personality traits, LC catecholamine synthesis capacity measured with [18F]Fluoro-m-tyrosine PET, and tau burden measured with [18F]Flortaucipir PET in cognitively normal older adults (n = 47). ß-amyloid (Aß) status was determined using [11C]Pittsburgh compound B PET (n = 14 Aß positive). Lower LC catecholamine synthesis capacity was associated with higher neuroticism, more depressive symptoms as measured by the Geriatric Depression Scale, and higher amygdala tau-PET binding. Exploratory analyses with other personality traits revealed that low trait conscientiousness was also related to both lower LC catecholamine synthesis capacity, and more depressive symptoms. A significant indirect path linked both high neuroticism and low conscientiousness to greater amygdala tau burden via their mutual association with low LC catecholamine synthesis capacity. Together, these findings reveal LC catecholamine synthesis capacity to be a promising marker of affective health and pathology burden in aging, and identifies candidate neurobiological mechanisms for the effect of personality on increased vulnerability to dementia.

Mental/behavioural health and educational outcomes of grandchildren raised by custodial grandparents: A mixed methods systematic review.

Grandparents caring for grandchildren has increased globally in the past two decades, but we have a limited understanding of its effects on custodial grandchildren's mental/behavioural health and educational outcomes. This mixed methods systematic review aims to synthesise mental/behavioural health and educational outcomes of custodial grandchildren within custodial grandparent-headed families and with comparison to other types of household structure and further examine factors associated with these outcomes. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted. We searched ERIC, Family Studies Abstracts, PsycINFO, PubMed, Scopus, Social Work Abstract and SocINDEX in March 2021 and screened 14,515 articles, which resulted in the inclusion of 42 studies, including 33 quantitative, seven qualitative and two mixed methods studies. The quality of included studies was assessed. This review covered 10 countries, yet most studies revealed that grandchildren raised by grandparents had adverse mental/behavioural health and educational outcomes compared to their peers raised by biological parents. This review further identified multi-level factors contributing to custodial grandchildren's adverse outcomes. Methodological limitations and implications for future practice and research were discussed.

Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease.

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, ß (females) = 0.08, P (females) = 5.76 × 10-09, ß (males) = -0.01, P(males) = 0.70, ß (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer's disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer's disease may be personalized based on their biological sex and genetic context.

Rates of ß-amyloid deposition indicate widespread simultaneous accumulation throughout the brain.

Amyloid plaque aggregation is a pathologic hallmark of Alzheimer's disease (AD) that occurs early in the disease. However, little is known about its progression throughout the brain. Using Pittsburgh Compound B (PIB)-PET imaging, we investigated the progression of regional amyloid accumulation in cognitively normal older adults. We found that all examined regions reached their peak accumulation rates 24-28 years after an estimated initiation corresponding to the mean baseline PIB-PET signal in amyloid-negative older adults. We also investigated the effect of increased genetic risk conferred by the apolipoprotein-E ɛ4 allele on rates of amyloid accumulation, as well as the relationship between regional amyloid accumulation and regional tau pathology, another hallmark of AD, measured with Flortaucipir-PET. Carriers of the ɛ4 allele had faster amyloid accumulation in all brain regions. Furthermore, in all regions excluding the temporal lobe, faster amyloid accumulation was associated with greater tau burden. These results indicate that amyloid accumulates near-simultaneously throughout the brain and is associated with higher AD pathology, and that genetic risk of AD is associated with faster amyloid accumulation.

Associations among locus coeruleus catecholamines, tau pathology, and memory in aging.

The locus coeruleus (LC) is the brain's major source of the neuromodulator norepinephrine, and is also profoundly vulnerable to the development of Alzheimer's disease (AD)-related tau pathology. Norepinephrine plays a role in neuroprotective functions that may reduce AD progression, and also underlies optimal memory performance. Successful maintenance of LC neurochemical function represents a candidate mechanism of protection against the propagation of AD-related pathology and may facilitate the preservation of memory performance despite pathology. Using [18F]Fluoro-m-tyrosine ([18F]FMT) PET imaging to measure catecholamine synthesis capacity in LC regions of interest, we examined relationships among LC neurochemical function, AD-related pathology, and memory performance in cognitively normal older adults (n = 49). Participants underwent [11C]Pittsburgh compound B and [18F]Flortaucipir PET to quantify ß-amyloid (n = 49) and tau burden (n = 42) respectively. In individuals with substantial ß-amyloid, higher LC [18F]FMT net tracer influx (Kivis) was associated with lower temporal tau. Longitudinal tau-PET analyses in a subset of our sample (n = 30) support these findings to reveal reduced temporal tau accumulation in the context of higher LC [18F]FMT Kivis. Higher LC catecholamine synthesis capacity was positively correlated with self-reported cognitive engagement and physical activity across the lifespan, established predictors of successful aging measured with the Lifetime Experiences Questionnaire. LC catecholamine synthesis capacity moderated tau's negative effect on memory, such that higher LC catecholamine synthesis capacity was associated with better-than-expected memory performance given an individual's tau burden. These PET findings provide insight into the neurochemical mechanisms of AD vulnerability and cognitive resilience in the living human brain.

Distinct Factors Drive the Spatiotemporal Progression of Tau Pathology in Older Adults.

Mechanisms underlying the initial accumulation of tau pathology across the human brain are largely unknown. We examined whether baseline factors including age, amyloid-ß (Aß), and neural activity predicted longitudinal tau accumulation in temporal lobe regions that reflect distinct stages of tau pathogenesis. Seventy cognitively normal human older adults (77 ± 6 years, 59% female) received two or more 18F-flortaucipir (FTP) and 11C-Pittsburgh Compound B (PiB) PET scans (mean follow-up, 2.5 ± 1.1 years) to quantify tau and (Aß). Linear mixed-effects models were used to calculate the slopes of FTP change in entorhinal cortex (EC), parahippocampal cortex (PHC), and inferior temporal gyrus (IT), and slopes of global PiB change. Thirty-seven participants underwent functional MRI to measure baseline activation. Older age predicted EC tau accumulation, and baseline EC tau levels predicted subsequent tau accumulation in EC and PHC. In IT, however, baseline EC tau interacted with Aß to predict IT tau accumulation. Higher baseline local activation predicted tau accumulation within EC and PHC, and higher baseline hippocampal activation predicted EC tau accumulation. Our findings indicate that factors predicting tau accumulation vary as tau progresses through the temporal lobe. Older age is associated with initial tau accumulation in EC, while baseline EC tau and neural activity drive tau accumulation within medial temporal lobe. Aß subsequently facilitates tau spread from medial to lateral temporal lobe. Our findings elucidate potential drivers of tau accumulation and spread in aging, which are critical for understanding Alzheimer's disease pathogenesis.SIGNIFICANCE STATEMENT To further understand the mechanisms leading to tau pathogenesis and spread, we tested whether baseline factors such as age, amyloid-ß pathology, and activation predicted longitudinal tau accumulation in cognitively normal older adults. We found that distinct mechanisms contribute to tau accumulation as tau progresses across the temporal lobe, with initial tau accumulation in entorhinal cortex driven by age and subsequent spread driven by neural activity and amyloid-ß. We demonstrate that higher baseline activation predicts increased longitudinal tau accumulation, providing novel evidence that activation-dependent tau production may occur in the human brain. Our findings support major hypotheses generated from preclinical research, and have important translational implications, suggesting that the reduction of hyperactivation may help prevent the development of tau pathology.