Defining Overlooked Structures Reveals New Associations between the Cortex and Cognition in Aging and Alzheimer's Disease.

Recent work suggests that indentations of the cerebral cortex, or sulci, may be uniquely vulnerable to atrophy in aging and Alzheimer's disease (AD) and that the posteromedial cortex (PMC) is particularly vulnerable to atrophy and pathology accumulation. However, these studies did not consider small, shallow, and variable tertiary sulci that are located in association cortices and are often associated with human-specific aspects of cognition. Here, we manually defined 4,362 PMC sulci in 432 hemispheres in 216 human participants (50.5% female) and found that these smaller putative tertiary sulci showed more age- and AD-related thinning than larger, more consistent sulci, with the strongest effects for two newly uncovered sulci. A model-based approach relating sulcal morphology to cognition identified that a subset of these sulci was most associated with memory and executive function scores in older adults. These findings lend support to the retrogenesis hypothesis linking brain development and aging and provide new neuroanatomical targets for future studies of aging and AD.

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.

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.

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.

Poorer aging trajectories are associated with elevated serotonin synthesis capacity.

The dorsal raphe nucleus (DRN) is one of the earliest targets of Alzheimer's disease-related tau pathology and is a major source of brain serotonin. We used [18F]Fluoro-m-tyrosine ([18F]FMT) PET imaging to measure serotonin synthesis capacity in the DRN in 111 healthy adults (18-85 years-old). Similar to reports in catecholamine systems, we found elevated serotonin synthesis capacity in older adults relative to young. To establish the structural and functional context within which serotonin synthesis capacity is elevated in aging, we examined relationships among DRN [18F]FMT net tracer influx (Ki) and longitudinal changes in cortical thickness using magnetic resonance imaging, longitudinal changes in self-reported depression symptoms, and AD-related tau and ß-amyloid (Aß) pathology using cross-sectional [18F]Flortaucipir and [11C]Pittsburgh compound-B PET respectively. Together, our findings point to elevated DRN [18F]FMT Ki as a marker of poorer aging trajectories. Older adults with highest serotonin synthesis capacity showed greatest temporal lobe cortical atrophy. Cortical atrophy was associated with increasing depression symptoms over time, and these effects appeared to be strongest in individuals with highest serotonin synthesis capacity. We did not find direct relationships between serotonin synthesis capacity and AD-related pathology. Exploratory analyses revealed nuanced effects of sex within the older adult group. Older adult females showed the highest DRN synthesis capacity and exhibited the strongest relationships between entorhinal cortex tau pathology and increasing depression symptoms. Together these findings reveal PET measurement of the serotonin system to be a promising marker of aging trajectories relevant to both AD and affective changes in older age.

Striatal dopamine synthesis and cognitive flexibility differ between hormonal contraceptive users and nonusers.

In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine (DA) neurotransmission. Yet less is known about hormonal regulation of the DA system in the human brain. Using positron emission tomography (PET), we address this gap by comparing hormonal contraceptive users and nonusers across multiple aspects of DA function: DA synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and DA release using methylphenidate-paired [11C]raclopride. Participants consisted of 36 healthy women (n = 15 hormonal contraceptive users; n = 21 naturally cycling/non users of hormonal contraception), and men (n = 20) as a comparison group. A behavioral index of cognitive flexibility was assessed prior to PET imaging. Hormonal contraceptive users exhibited greater DA synthesis capacity than NC participants, particularly in dorsal caudate, and greater cognitive flexibility. Furthermore, across individuals, the magnitude of striatal DA synthesis capacity was associated with cognitive flexibility. No group differences were observed in D2/3 receptor binding or DA release. Analyses by sex alone may obscure underlying differences in DA synthesis tied to women's hormone status. Hormonal contraception (in the form of pill, shot, implant, ring, or intrauterine device) is used by ~400 million women worldwide, yet few studies have examined whether chronic hormonal manipulations impact basic properties of the DA system. Findings from this study begin to address this critical gap in women's health.

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.

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.

Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup.

The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 and single work groups in 2012 and 2018 to create recommendations for the diagnosis and characterization of Alzheimer's disease (AD). The present document updates the 2018 research framework in response to several recent developments. Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine (e.g., oncology), and is becoming a unifying concept common to all neurodegenerative diseases, not just AD. The present document is consistent with this principle. Our intent is to present objective criteria for diagnosis and staging AD, incorporating recent advances in biomarkers, to serve as a bridge between research and clinical care. These criteria are not intended to provide step-by-step clinical practice guidelines for clinical workflow or specific treatment protocols, but rather serve as general principles to inform diagnosis and staging of AD that reflect current science. HIGHLIGHTS: We define Alzheimer's disease (AD) to be a biological process that begins with the appearance of AD neuropathologic change (ADNPC) while people are asymptomatic. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms. Early-changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid biomarkers, and accurate plasma biomarkers [especially phosphorylated tau 217]) map onto either the amyloid beta or AD tauopathy pathway; however, these reflect the presence of ADNPC more generally (i.e., both neuritic plaques and tangles). An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making throughout the disease continuum. Later-changing Core 2 biomarkers (biofluid and tau PET) can provide prognostic information, and when abnormal, will increase confidence that AD is contributing to symptoms. An integrated biological and clinical staging scheme is described that accommodates the fact that common copathologies, cognitive reserve, and resistance may modify relationships between clinical and biological AD stages.

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve Alzheimer's disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, and biofluid samples. We used conventional search methods to identify 1459 publications from 2021 to 2022 using ADNI data/samples and reviewed 291 impactful studies. This review details how ADNI studies improved disease progression understanding and clinical trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, and modeling improved clinical trials and plasma biomarkers like phosphorylated tau showed promise for clinical use. Biomarkers of amyloid beta, tau, neurodegeneration, inflammation, and others were prognostic with individualized prediction algorithms available online. Studies supported the amyloid cascade, emphasized the importance of neuroinflammation, and detailed widespread heterogeneity in disease, linked to genetic and vascular risk, co-pathologies, sex, and resilience. Biological subtypes were consistently observed. Generalizability of ADNI results is limited by lack of cohort diversity, an issue ADNI-4 aims to address by enrolling a diverse cohort.

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.

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.

NREM sleep as a novel protective cognitive reserve factor in the face of Alzheimer's disease pathology.

BACKGROUND: Alzheimer's disease (AD) pathology impairs cognitive function. Yet some individuals with high amounts of AD pathology suffer marked memory impairment, while others with the same degree of pathology burden show little impairment. Why is this? One proposed explanation is cognitive reserve i.e., factors that confer resilience against, or compensation for the effects of AD pathology. Deep NREM slow wave sleep (SWS) is recognized to enhance functions of learning and memory in healthy older adults. However, that the quality of NREM SWS (NREM slow wave activity, SWA) represents a novel cognitive reserve factor in older adults with AD pathology, thereby providing compensation against memory dysfunction otherwise caused by high AD pathology burden, remains unknown. METHODS: Here, we tested this hypothesis in cognitively normal older adults (N = 62) by combining 11C-PiB (Pittsburgh compound B) positron emission tomography (PET) scanning for the quantification of ß-amyloid (Aß) with sleep electroencephalography (EEG) recordings to quantify NREM SWA and a hippocampal-dependent face-name learning task. RESULTS: We demonstrated that NREM SWA significantly moderates the effect of Aß status on memory function. Specifically, NREM SWA selectively supported superior memory function in individuals suffering high Aß burden, i.e., those most in need of cognitive reserve (B = 2.694, p = 0.019). In contrast, those without significant Aß pathological burden, and thus without the same  need for cognitive reserve, did not similarly benefit from the presence of NREM SWA (B = -0.115, p = 0.876). This interaction between NREM SWA and Aß status predicting memory function was significant after correcting for age, sex, Body Mass Index, gray matter atrophy, and previously identified cognitive reserve factors, such as education and physical activity (p = 0.042). CONCLUSIONS: These findings indicate that NREM SWA is a novel cognitive reserve factor providing resilience against the memory impairment otherwise caused by high AD pathology burden. Furthermore, this cognitive reserve function of NREM SWA remained significant when accounting both for covariates, and factors previously linked to resilience, suggesting that sleep might be an independent cognitive reserve resource. Beyond such mechanistic insights are potential therapeutic implications. Unlike many other cognitive reserve factors (e.g., years of education, prior job complexity), sleep is a modifiable factor. As such, it represents an intervention possibility that may aid the preservation of cognitive function in the face of AD pathology, both present moment and longitudinally.

Imaging the evolution and pathophysiology of Alzheimer disease.

Technologies for imaging the pathophysiology of Alzheimer disease (AD) now permit studies of the relationships between the two major proteins deposited in this disease - amyloid-ß (Aß) and tau - and their effects on measures of neurodegeneration and cognition in humans. Deposition of Aß in the medial parietal cortex appears to be the first stage in the development of AD, although tau aggregates in the medial temporal lobe (MTL) precede Aß deposition in cognitively healthy older people. Whether aggregation of tau in the MTL is the first stage in AD or a fairly benign phenomenon that may be transformed and spread in the presence of Aß is a major unresolved question. Despite a strong link between Aß and tau, the relationship between Aß and neurodegeneration is weak; rather, it is tau that is associated with brain atrophy and hypometabolism, which, in turn, are related to cognition. Although there is support for an interaction between Aß and tau resulting in neurodegeneration that leads to dementia, the unknown nature of this interaction, the strikingly different patterns of brain Aß and tau deposition and the appearance of neurodegeneration in the absence of Aß and tau are challenges to this model that ultimately must be explained.

Cortical hypometabolism reflects local atrophy and tau pathology in symptomatic Alzheimer's disease.

Posterior cortical hypometabolism measured with 18F-fluorodeoxyglucose (FDG)-PET is a well-known marker of Alzheimer's disease-related neurodegeneration, but its associations with underlying neuropathological processes are unclear. We assessed cross-sectionally the relative contributions of three potential mechanisms causing hypometabolism in the retrosplenial and inferior parietal cortices: local molecular (amyloid and tau) pathology and atrophy, distant factors including contributions from the degenerating medial temporal lobe or molecular pathology in functionally connected regions, and the presence of the apolipoprotein E (APOE) ε4 allele. Two hundred and thirty-two amyloid-positive cognitively impaired patients from two cohorts [University of California, San Francisco (UCSF), and Alzheimer's Disease Neuroimaging Initiative (ADNI)] underwent MRI and PET with FDG, amyloid-PET using 11C-Pittsburgh Compound-B, 18F-florbetapir or 18F-florbetaben, and 18F-flortaucipir tau-PET in 1 year. Standard uptake value ratios (SUVRs) were calculated using tracer-specific reference regions. Regression analyses were run within cohorts to identify variables associated with retrosplenial or inferior parietal FDG standard uptake value ratios. On average, ADNI patients were older and were less impaired than the UCSF patients. Regional patterns of hypometabolism were similar between cohorts, although there were cohort differences in regional grey matter atrophy. Local cortical thickness and tau-PET (but not amyloid-PET) were independently associated with both retrosplenial and inferior parietal FDG SUVRs (ΔR2 = 0.09 to 0.21) across cohorts in models that also included age and disease severity (local model). Including medial temporal lobe volume improved the retrosplenial FDG model in the ADNI cohort (ΔR2 = 0.04, P = 0.008) but not for the UCSF (ΔR2 < 0.01, P = 0.52), and did not improve the inferior parietal models (ΔR2 < 0.01, P > 0.37). Interaction analyses revealed that medial temporal volume was more strongly associated with retrosplenial FDG SUVRs at earlier disease stages (P = 0.06 in UCSF, P = 0.046 in ADNI). Exploratory analyses across the cortex confirmed overall associations between hypometabolism and local tau pathology and thickness and revealed associations between medial temporal degeneration and hypometabolism in retrosplenial, orbitofrontal and anterior cingulate cortices. Finally, our data did not support hypotheses of a detrimental effect of pathology in connected regions or of an effect of the APOE ε4 allele in impaired participants. Overall, in two independent groups of patients at symptomatic stages of Alzheimer's disease, cortical hypometabolism mainly reflected structural neurodegeneration and tau, but not amyloid, pathology.

Autosomal dominant and sporadic late onset Alzheimer's disease share a common in vivo pathophysiology.

The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-ß42, amyloid-ß40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-ß42, amyloid-ß40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.

Elevated Dopamine Synthesis as a Mechanism of Cognitive Resilience in Aging.

Aging is associated with declines in multiple components of the dopamine system including loss of dopamine-producing neurons, atrophy of the dopamine system's cortical targets, and reductions in the density of dopamine receptors. Countering these patterns, dopamine synthesis appears to be stable or elevated in older age. We tested the hypothesis that elevation in dopamine synthesis in aging reflects a compensatory response to neuronal loss rather than a nonspecific monotonic shift in older age. We measured individual differences in striatal dopamine synthesis capacity in cognitively normal older adults using [18F]Fluoro-l-m-tyrosine positron emission tomography cross-sectionally and tested relationships with longitudinal reductions in cortical thickness and working memory decline beginning up to 13 years earlier. Consistent with a compensation account, older adults with the highest dopamine synthesis capacity were those with greatest atrophy in posterior parietal cortex. Elevated dopamine synthesis capacity was not associated with successful maintenance of working memory performance overall, but had a moderating effect such that higher levels of dopamine synthesis capacity reduced the impact of atrophy on cognitive decline. Together, these findings support a model by which upregulation of dopamine synthesis represents a mechanism of cognitive resilience in aging.

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.