Preclinical Stage Of Alzheimer's Disease Research Articles

Cardiorespiratory fitness mitigates brain atrophy and cognitive decline in preclinical Alzheimer’s disease

AbstractBackgroundCardiorespiratory fitness (CRF) may be a mitigating factor for Alzheimer’s Disease (AD) progression. The purpose of this study was to examine the longitudinal associations of CRF with brain atrophy and cognitive function in a late‐middle‐aged cohort of adults at risk for AD.MethodOne hundred and ten adults (mean age = 64.2 ± 5.7 years, 65% female) from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) completed a baseline graded treadmill exercise test, two brain MRI scans (over 4.67 ± 1.17 years) and neurocognitive assessments (2.18 ± .78 neurocognitive tests over 3.26 ± 1.02 years) as part of their WRAP study involvement. The oxygen uptake efficiency slope (OUES) was calculated for each participant and served as the CRF measure. Total gray matter and hippocampal volumes and the preclinical Alzheimer’s cognitive composite (PACC) score were the primary outcome measures. Linear mixed effects models examined the longitudinal associations adjusted for covariates. The CRF x age (i.e., time) interaction was centered and was the term of interest as it would indicate whether longitudinal decline in volumetrics or cognition differed as a function of CRF.ResultBaseline OUES values were 1.16 ± 0.28. Total gray matter and hippocampal volume declined at a rate of ‐0.73 ± 0.90% and ‐0.16 ± 1.30% per year, and cognitive trajectories decline ‐.047 points (standardized score) per year. The CRF × age interaction was significant for total gray matter volume (β=.26 SE .11; p=.020; Figure 1) and PACC score (β=.07 SE .03; p=.049; Figure 2), but not hippocampal volume (β=.002 SE .002; p=.347). These findings were most pronounced among APOE‐e4 carriers (p<.05).ConclusionCRF may be a modifiable physiological attribute to target during the preclinical stage of AD in effort to delay disease progression.

Cell type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in preclinical Alzheimer's disease.

Conventional polygenic risk score (PRS) summarizes genetic risk throughout the genome and lacks biological specificity. Here, leveraging human brain single nucleus RNA sequencing (sNuc-Seq) data, we introduce a new method to capture cell-type specific Alzheimer's disease (AD) PRS, and implicate different cell types in distinct disease processes in preclinical AD. Cognitively unimpaired (CU) older adults of European descent who participated in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study screening PET were included in this study. Cortical amyloid-β burden (Aβ) was quantified as cortical composite SUVR from the florbetapir PET. Screening cognition was measured with Preclinical Alzheimer Cognitive Composite (PACC). We defined cell type-specific genes as genes expressed higher in a given cell type (FDR<0.05) compared to other cell types in a published human neocortex sNucSeq study, for eight major cell types identified from the same study. Published AD genome-wide association study results were processed with PRS-CS to infer posterior effect size of each genetic variant, and we derived cell type-specific ADPRS by weighted summation and standardization of the genetic risk of AD localized to cell type-specific genes. We excluded the APOE region from ADPRS, and adjusted for APOE ε4, ε2, age, sex, and the first three genotype principal components in all analyses. In CU older adults from the A4 screen data (n=2961; 71.3±4.8 years old), microglia-specific ADPRS had the strongest association with higher Aβ (beta=0.018, p=2.0×10-8 ), while neuron-specific ADPRSs showed weaker associations (Figure 1A). By contrast, excitatory neuron-specific ADPRS had the strongest association with lower PACC (additionally adjusted for years of education; beta=-0.16, p=1.0×10-4 ; Figure 1B), and this association remained significant even after adjusting for Aβ (beta=-0.14, p=6.1×10-4 ). The excitatory neuron-specific ADPRS was negatively associated with years of education (beta=-0.12, p=0.018), suggesting a shared heritability between neuron-specific AD risk and lower cognitive reserve. These results further implicate microglia in fibrillar Aβ accumulation and support the neuronal role in cognitive reserve. Cell type-specific ADPRSs derived using our novel method demonstrate specific relationships with AD pathology and cognition, and may improve power to predict progression during the preclinical stages of AD.

Associations between CSF proteins and medial temporal lobe atrophy across the AD continuum

AbstractBackgroundCortical atrophy is a typical feature of Alzheimer´s disease (AD). The biological processes that associate with or possibly lead to atrophy remain largely unexplored. We hypothesized that disease stage would modulate the associations between cerebrospinal fluid (CSF) proteins and regional cortical thickness in individuals with abnormal CSF beta‐amyloid.MethodCognitively normal (CN), mild cognitive impairment (MCI) and AD individuals were selected from ADNI, based on abnormal CSF beta‐amyloid (&lt;192 ng/l). All examined individuals had cortical thickness measurements and CSF proteomic data available (measured with MRM and RBM). Correlations between 217 CSF proteins and cortical thickness in 34 cortical regions (averaged over the left and right hemispheres) were analyzed with linear models, adjusted for age and sex. Interactions for diagnosis were evaluated for each protein‐cortical thickness association. Protein enrichment analysis was performed with Cytoscape ClueGO.ResultWe included 197 individuals (32 CN; 104 MCI; 61 AD) with a mean age 74.8 (SD 7.1) years, 41.6 % women.Cortical thickness declined according to disease progression in 28 brain regions, most significantly in the entorhinal cortex (ANOVA p‐value &lt;0.0001), the middle temporal gyrus (p&lt;0.0001) and the inferior temporal cortex (p&lt;0.0001). 9 proteins, including phospho‐tau and BACE activity, showed interactions for diagnosis in the entorhinal cortex, 12 in the middle temporal gyrus and 19 inferior temporal cortex. These proteins were associated with beta‐amyloid metabolic process, dendritic cell differentiation, and oligodendrocyte development in ClueGO enrichment analyses. A consistent finding was that higher levels of the majority of these CSF proteins correlated with lower cortical thickness in CN, and that these correlations were attenuated with disease progression.ConclusionAlterations in the levels of CSF proteins are associated with cortical atrophy in the medial temporal regions, and the biological processes underlying cortical atrophy seem to begin already in the preclinical stage of AD. These results suggest that therapies targeted at preventing cortical atrophy would need to be initiated already in the CN stage.

Emotion regulation in mild cognitive impairment and subjective cognitive decline

AbstractBackgroundOur previous research in emotional verbal memory in mild cognitive impairment (MCI) and work from others suggest the hypothesis that emotion dysregulation is a signature of Alzheimer’s disease (AD) risk. Whether subjective cognitive decline (SCD), conceptualized as a possible preclinical stage of AD, is associated with emotion dysregulation is unknown. In the current study, we compared responses on the Cognitive Emotion Regulation Questionnaire (CERQ) and behavioural responses on a threat task amongst SCD, MCI, and cognitively unimpaired (CU) older adults.MethodsThe sample included 146 older adults free of lifetime history of psychiatric illness/neurological conditions: 33 MCI [17F, age 72.3(SD7.6)] defined as subjective memory/other cognitive complaints, impaired neuropsychological (NP) test performance, and functional independence, 71 SCD [49F, age 71.1(SD6.3)] based on subjective memory decline with worry with normal NP performance, and 42 CU [27F, age 70.6(SD6.8)] based on absence of subjective memory decline and normal NP test scores. Participants completed the CERQ which assesses cognitive coping strategies in negative emotional situations. A subset (19 MCI, 43 SCD, 19 CU) completed a computerized task in which they rated a physical feature or threat level of faces with varying degrees of threat. Multivariate ANOVA was used to examine group differences, followed by Sidak‐adjusted post hoc comparisons.ResultsOn the CERQ, groups differed in use of catastrophizing [F(2, 142)=3.51, P=.032], with a trend for use of rumination (P=.07), attributable to greater use of both strategies in MCI compared to CU (P=.04). On the threat task, groups differed in response latencies to judging physical features of threatening faces relative to neutral [F(2, 78)=3.17, P=.048)]. Relative to CU, SCD participants were slower to make physical judgements of threatening faces compared to neutral (P=.026).ConclusionsOlder adults with SCD do not report greater use of maladaptive emotion regulation strategies compared to CU. However, alterations in behavioural responses to threat versus neutral in SCD may represent deficits in regulating attention towards negative emotional information, similar to mood‐congruent cognitive biases observed in depression. These preliminary data highlight the need to increase our understanding of explicit and implicit emotional processing in older adults at risk for AD.

Accumulation of amyloid‐β alters white matter integrity in cognitively unimpaired middle‐aged females

AbstractBackgroundThe APOE‐ε4 allele is the strongest known genetic risk factor for Alzheimer’s disease (AD) and is associated with higher amyloid‐β (Aβ) deposition. White matter (WM) microstructural damages are known to occur early at the preclinical stage of AD. Although stable associations between APOE‐ε4 status and WM alternations have been reported in patients with AD and mild cognitive impairment, few studies have described WM differences in cognitively unimpaired (CU) subjects at risk of AD. We aim to investigate associations of APOE‐ε4 status and Aβ load with WM microstructural changes in mid‐age CU individuals.Method151 CU participants from the Prospective Imaging Study of Ageing (PISA) were included (aged 44‐66, 78% female, 77 APOE‐ε4 carriers (ε4+) and 74 non‐carriers (ε4‐)) and underwent Aβ PET and 3T MRI scans including multi‐shell diffusion‐weighted images. Aβ load was quantified in Centiloid (CL) on PET and Aβ+ was defined as CL ≥ 20. Tract based spatial statistics (TBSS) analysis was performed on fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) to assess WM alternations associated with APOE‐ε4 status and/or Aβ load. All analyses were corrected for age and for multiple comparisons.ResultA significant effect of gender, but not APOE‐ε4 or Aβ status was observed on WM integrity in the full cohort. When considering females only, APOE‐ε4 carriers showed regional increased MD in several right WM tracts. However, these differences were no longer significant when correcting for Aβ status. In contrast, significant WM alternations associated with Aβ+ status were found when correcting for APOE‐ε4 status. In this female‐only subset, widespread WM microstructural damages were observed in Aβ+ε4+ subjects (N=10) compared to Aβ‐ε4+ (N=51) and Aβ‐ε4‐ (N=54) subjects. No significant differences were observed between Aβ‐ε4+ and Aβ‐ε4‐ subjects. Similar differences were also observed in the global diffusion metrics of WM tracts.ConclusionThese findings suggest that WM alternations associated with Aβ accumulation appear in mid‐life CU female subjects. Future studies in larger cohorts enriched for gender, APOE and Aβ status are required to clarify the relative contributions of APOE‐ε4 and Aβ status on WM microstructural damage.

Cognitive testing for early detection of Alzheimer's disease in people with Down syndrome: A systematic review and meta‐analysis

AbstractBackgroundImproved health care for people with Down syndrome (DS) has resulted in an increase in their life expectancy therefore increasing comorbidities associated with age related problems in this population, the most frequent being Alzheimer's disease (AD). The development of brain lesions appears years before AD. Through this progressive neuronal loss, patients can firstly begin to have a perception of cognitive difficulties, i.e., a subjective cognitive decline (SCD). This preclinical phase ends with the onset of mild cognitive impairment (MCI) which is characterized by a set of cognitive symptoms. Knowing that people with DS have already pre‐existing cognitive deficits, screening at the preclinical and clinical stages of AD therefore cannot be done through traditional cognitive tests. The aim of this systematic review is to synthesis cognitive assessment for the diagnosis of AD, MCI or SCD in people with DS.MethodA meta‐analysis is in development. Articles were collected from Pubmed and Psychinfo databases through keywords related to three categories: 1) DS, 2) AD and 3) assessment. The inclusion criteria are studies 1) with participants over 18 years old with DS, 2) which assess cognitive abilities in the context of screening for AD or its early stages, 3) presenting the effect sizes or data allowing their calculation.ResultEighteen articles met the inclusion criteria. Fifty cognitive tests for the diagnosis of AD, MCI or SCD were found. From these tests, fourteen evaluated cognition through an informant questionnaire and thirty‐six directly evaluated the patient’s cognitive abilities.ConclusionTheoretical and practical implications of these results are discussed.

Vascular risk is not associated with PET measures of Alzheimer's disease neuropathology among cognitively normal older adults

Cardiovascular disease (CVD) is associated with a higher risk of developing dementia. Studies have found that vascular risk factors are associated with greater amyloid-β (Aβ) and tau burden, which are hallmark neuropathologies of Alzheimer's disease (AD). Evidence for these associations during the preclinical stages of AD, when Aβ and tau pathologies first become detectable, is mixed. Quantifying the effect of vascular risk among cognitively normal individuals can help focus the efforts to develop therapeutic approaches aimed at modifying the course of preclinical AD.Using Bayesian analysis, we examined the relationship of Aβ and tau pathology with concurrent vascular risk among 87 cognitively normal individuals (median age 77, interquartile range 70–83) in the Baltimore Longitudinal Study of Aging. We quantified vascular risk as the probability of developing CVD within 10 years using published equations from the Framingham Heart Study. Aβ and tau pathologies were measured using positron emission tomography.As expected, Aβ positive participants had greater tau in the entorhinal cortex (EC) and inferior temporal gyrus (ITG) (difference in means = 0.09, p < 0.05 for each region), and 10-year CVD risk was positively correlated with white matter lesion burden (r = 0.24, p = 0.03). However, we did not find any associations between CVD risk and Aβ or tau. The data provided over two- and four-fold evidence towards the lack of a correlation between CVD risk and tau in the EC (Bayes factor BF = 2.4) and ITG (BF = 4.0), respectively. We found over three-fold evidence towards the lack of a difference in mean CVD risk by Aβ group (BF = 3.4). These null findings were replicated using a data-driven vascular risk score in the BLSA based on a principal component analysis of eight indicators of vascular health.Our data provide moderate evidence towards the lack of an association between vascular risk and concurrent AD neuropathology among cognitively normal older adults. This finding suggests that vascular risk and AD neuropathology may constitute independent pathways in the development of cognitive impairment and dementia.

Altered Connectedness of the Brain Chronnectome During the Progression to Alzheimer's Disease.

Graph theory has been extensively used to investigate brain network topology and its changes in disease cohorts. However, many graph theoretic analysis-based brain network studies focused on the shortest paths or, more generally, cost-efficiency. In this work, we use two new concepts, connectedness and 2-connectedness, to measure different global properties compared to the previously widely adopted ones. We apply them to unravel interesting characteristics in the brain, such as redundancy design and further conduct a time-varying brain functional network analysis for characterizing the progression of Alzheimer's disease (AD). Specifically, we define different connectedness and 2-connectedness states and evaluate their dynamics in AD and its preclinical stage, mild cognitive impairment (MCI), compared to the normal controls (NC). Results indicate that, compared to MCI and NC, brain networks of AD tend to be more frequently connected at a sparse level. For MCI, we found that their brains are more likely to be 2-connected in the minimal connected state as well indicating increasing redundancy in brain connectivity. Such a redundant design could ensure maintained connectedness of the MCI's brain network in the case that pathological damages break down any link or silenced any node, making it possible to preserve cognitive abilities. Our study suggests that the redundancy in the brain functional chronnectome could be altered in the preclinical stage of AD. The findings can be successfully replicated in a retest study and with an independent MCI dataset. Characterizing redundancy design in the brain chronnectome using connectedness and 2-connectedness analysis provides a unique viewpoint for understanding disease affected brain networks.

Melatonin and Sleep Disturbances in Alzheimer's Disease.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by sleep, behavioral, memory, and cognitive deteriorations. Sleep disturbance (SD) is a major disease burden in AD, which has a reciprocal relationship with AD pathophysiology. It aggravates memory, behavioral, and cognitive complications in AD. Different studies have found that melatonin hormone levels reduce even in the pre-clinical stages of AD. Melatonin is the primary sleep-regulating hormone and a potent antioxidant with neuroprotective roles. The decrease in melatonin levels can thus promote SD and AD neuropathology. Exogenous melatonin has the potential to alleviate neuropathology and SD in AD by different mechanisms. Various studies have been conducted to assess the efficacy of exogenous melatonin to treat SD in AD. Though most of the studies suggest that melatonin is useful to ameliorate SD in AD, the remaining studies show opposite results. The timing, dosage, and duration of melatonin administration along with disease condition, genetic, environmental, and some other factors can be responsible for the discrepancies between the studies. More extensive trials with longer durations and higher dosage forms and studies including bright light therapy and melatonin agonists (ramelteon, agomelatine, and tasimelteon) should be performed to determine the efficacy of melatonin to treat SD in AD.

Associations between locus coeruleus integrity and nocturnal awakenings in the context of Alzheimer\u2019s disease plasma biomarkers: a 7T MRI study

BackgroundThe brainstem locus coeruleus (LC) constitutes the intersection of the initial pathophysiological processes of Alzheimer’s disease (AD) and sleep-wake dysregulation in the preclinical stages of the disease. However, the interplay between in vivo assessment of LC degeneration and AD-related sleep alterations remains unknown. Here, we sought to investigate whether MRI-assessed LC structural integrity relates to subjective sleep-wake measures in the context of AD plasma biomarkers, in cognitively unimpaired older individuals.MethodsSeventy-two cognitively unimpaired older individuals aged 50–85 years (mean age = 65.2 ± 8.2 years, 37 women, 21 APOE ε4 carriers) underwent high-resolution imaging of the LC at 7 Tesla, and LC structural integrity was quantified using a data-driven approach. Reports on habitual sleep quality and nocturnal awakenings were collected using sleep questionnaires. Plasma levels of total tau, p-tau181, Aβ40, and Aβ42 were measured using single-molecule array technology.ResultsIntensity-based cluster analyses indicated two distinct LC segments, with one covering the middle-to-caudal LC and displaying lower intensity compared to the middle-to-rostral cluster (t70 = −5.12, p < 0.0001). After correction for age, sex, depression, and APOE status, lower MRI signal intensity within the middle-to-caudal LC was associated with a higher number of self-reported nocturnal awakenings (F1,63 = 6.73, pFDR = 0.03). Furthermore, this association was mostly evident in individuals with elevated levels of total tau in the plasma (F1,61 = 4.26, p = 0.04).ConclusionOur findings provide in vivo evidence that worse LC structural integrity is associated with more frequent nocturnal awakenings in the context of neurodegeneration, in cognitively unimpaired older individuals. These results support the critical role of the LC for sleep-wake regulation in the preclinical stages of AD and hold promises for the identification of at-risk populations for preventive interventions.

CSF Synaptic Biomarkers in the Preclinical Stage of Alzheimer Disease and Their Association With MRI and PET: A Cross-sectional Study.

Background and ObjectivesTo determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers.MethodsThis cross-sectional study was performed in the Alzheimer's and Families (ALFA+) cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and growth-associated protein-43 (GAP-43) were measured with immunoassays, and synaptosomal-associated protein-25 (SNAP-25) and synaptotagmin-1 were measured with immunoprecipitation mass spectrometry. AD CSF biomarkers β-amyloid (Aβ)42/40, phosphorylated tau (p-tau), and total tau and the neurodegeneration biomarker neurofilament light chain (NfL) were also measured. Participants underwent structural MRI and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers.ResultsAll CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values), and it is important to note that the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism but lower cortical thickness in AD-related brain regions.DiscussionCSF synaptic biomarkers increase in the early preclinical stages of the Alzheimer continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE ε4, and markers of neurodegeneration.Trial Registration InformationClinicalTrials.gov Identifier NCT02485730.

Neuroticism Is Associated with Tau Pathology in Cognitively Unimpaired Individuals with Autosomal Dominant Alzheimer's Disease.

Greater neuroticism has been associated with higher risk for Alzheimer's disease (AD) dementia. However, the directionality of this association is unclear. We examined whether personality traits differ between cognitively-unimpaired carriers of autosomal-dominant AD (ADAD) and non-carriers, and are associated with in vivo AD pathology. To determine whether personality traits differ between cognitively unimpaired ADAD mutation carriers and non-carriers, and whether the traits are related to age and AD biomarkers. A total of 33 cognitively-unimpaired Presenilin-1 E280A mutation carriers and 41 non-carriers (ages 27-46) completed neuropsychological testing and the NEO Five-Factor Personality Inventory. A subsample (n = 46; 20 carriers) also underwent tau and amyloid PET imaging. Carriers reported higher neuroticism relative to non-carriers, although this difference was not significant after controlling for sex. Neuroticism was positively correlated with entorhinal tau levels only in carriers, but not with amyloid levels. The finding of higher neuroticism in carriers and the association of this trait with tau pathology in preclinical stages of AD highlights the importance of including personality measures in the evaluation of individuals at increased risk for cognitive impairment and dementia. Further research is needed to characterize the mechanisms of these relationships.

Morphological, Structural, and Functional Networks Highlight the Role of the Cortical-Subcortical Circuit in Individuals With Subjective Cognitive Decline.

Subjective cognitive decline (SCD) is considered the earliest stage of the clinical manifestations of the continuous progression of Alzheimer’s Disease (AD). Previous studies have suggested that multimodal brain networks play an important role in the early diagnosis and mechanisms underlying SCD. However, most of the previous studies focused on a single modality, and lacked correlation analysis between different modal biomarkers and brain regions. In order to further explore the specific characteristic of the multimodal brain networks in the stage of SCD, 22 individuals with SCD and 20 matched healthy controls (HCs) were recruited in the present study. We constructed the individual morphological, structural and functional brain networks based on 3D-T1 structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI), respectively. A t-test was used to select the connections with significant difference, and a multi-kernel support vector machine (MK-SVM) was applied to combine the selected multimodal connections to distinguish SCD from HCs. Moreover, we further identified the consensus connections of brain networks as the most discriminative features to explore the pathological mechanisms and potential biomarkers associated with SCD. Our results shown that the combination of three modal connections using MK-SVM achieved the best classification performance, with an accuracy of 92.68%, sensitivity of 95.00%, and specificity of 90.48%. Furthermore, the consensus connections and hub nodes based on the morphological, structural, and functional networks identified in our study exhibited abnormal cortical-subcortical connections in individuals with SCD. In addition, the functional networks presented more discriminative connections and hubs in the cortical-subcortical regions, and were found to perform better in distinguishing SCD from HCs. Therefore, our findings highlight the role of the cortical-subcortical circuit in individuals with SCD from the perspective of a multimodal brain network, providing potential biomarkers for the diagnosis and prediction of the preclinical stage of AD.

Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease

Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear. To examine the prognostic accuracy of baseline fluorine 18 (18F)-flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers. This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ). [18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation. Baseline [18F]flortaucipir/[18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations. Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P < .001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P < .001, bootstrapped for difference) and in the Aβ-positive CU group (R2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P < .001, bootstrapped for difference). These findings were replicated in the [18F]RO948 PET cohort. MRI mediated the association between [18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P = .71). Age (t = -2.28; P = .02), but not sex (t = 0.92; P = .36) or APOE genotype (t = 1.06; P = .29) modified the association between baseline [18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels. The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.

Biomarkers and Tools for Predicting Alzheimer's Disease in the Preclinical Stage.

Alzheimer's disease (AD) is the only leading cause of death for which no disease-modifying therapy is currently available. Over the past decade, a string of disappointing clinical trial results has forced us to shift our focus to the preclinical stage of AD, which represents the most promising therapeutic window. However, the accurate diagnosis of preclinical AD requires the presence of brain β- amyloid deposition determined by cerebrospinal fluid or amyloid-positron emission tomography, significantly limiting routine screening and diagnosis in non-tertiary hospital settings. Thus, an easily accessible marker or tool with high sensitivity and specificity is highly needed. Recently, it has been discovered that individuals in the late stage of preclinical AD may not be truly "asymptomatic" in that they may have already developed subtle or subjective cognitive decline. In addition, advances in bloodderived biomarker studies have also allowed the detection of pathologic changes in preclinical AD. Exosomes, as cell-to-cell communication messengers, can reflect the functional changes of their source cell. Methodological advances have made it possible to extract brain-derived exosomes from peripheral blood, making exosomes an emerging biomarker carrier and liquid biopsy tool for preclinical AD. The eye and its associated structures have rich sensory-motor innervation. In this regard, studies have indicated that they may also provide reliable markers. Here, our report covers the current state of knowledge of neuropsychological and eye tests as screening tools for preclinical AD and assesses the value of blood and brain-derived exosomes as carriers of biomarkers in conjunction with the current diagnostic paradigm.

Bundle-specific associations between white matter microstructure and Aβ and tau pathology in preclinical Alzheimer's disease.

Beta-amyloid (Aβ) and tau proteins, the pathological hallmarks of Alzheimer's disease (AD), are believed to spread through connected regions of the brain. Combining diffusion imaging and positron emission tomography, we investigated associations between white matter microstructure specifically in bundles connecting regions where Aβ or tau accumulates and pathology. We focused on free-water-corrected diffusion measures in the anterior cingulum, posterior cingulum, and uncinate fasciculus in cognitively normal older adults at risk of sporadic AD and presymptomatic mutation carriers of autosomal dominant AD. In Aβ-positive or tau-positive groups, lower tissue fractional anisotropy and higher mean diffusivity related to greater Aβ and tau burden in both cohorts. Associations were found in the posterior cingulum and uncinate fasciculus in preclinical sporadic AD, and in the anterior and posterior cingulum in presymptomatic mutation carriers. These results suggest that microstructural alterations accompany pathological accumulation as early as the preclinical stage of both sporadic and autosomal dominant AD.

Glycolytic Metabolism, Brain Resilience, and Alzheimer's Disease.

Alzheimer’s disease (AD) is the most common form of age-related dementia. Despite decades of research, the etiology and pathogenesis of AD are not well understood. Brain glucose hypometabolism has long been recognized as a prominent anomaly that occurs in the preclinical stage of AD. Recent studies suggest that glycolytic metabolism, the cytoplasmic pathway of the breakdown of glucose, may play a critical role in the development of AD. Glycolysis is essential for a variety of neural activities in the brain, including energy production, synaptic transmission, and redox homeostasis. Decreased glycolytic flux has been shown to correlate with the severity of amyloid and tau pathology in both preclinical and clinical AD patients. Moreover, increased glucose accumulation found in the brains of AD patients supports the hypothesis that glycolytic deficit may be a contributor to the development of this phenotype. Brain hyperglycemia also provides a plausible explanation for the well-documented link between AD and diabetes. Humans possess three primary variants of the apolipoprotein E (ApoE) gene – ApoE∗ϵ2, ApoE∗ϵ3, and ApoE∗ϵ4 – that confer differential susceptibility to AD. Recent findings indicate that neuronal glycolysis is significantly affected by human ApoE isoforms and glycolytic robustness may serve as a major mechanism that renders an ApoE2-bearing brain more resistant against the neurodegenerative risks for AD. In addition to AD, glycolytic dysfunction has been observed in other neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, strengthening the concept of glycolytic dysfunction as a common pathway leading to neurodegeneration. Taken together, these advances highlight a promising translational opportunity that involves targeting glycolysis to bolster brain metabolic resilience and by such to alter the course of brain aging or disease development to prevent or reduce the risks for not only AD but also other neurodegenerative diseases.

SEGMENTATION OF BRAIN STRUCTURES IN ALZHEIMER MR IMAGES USING SPATIAL FUZZY CLUSTERING LEVEL SET

Alzheimer’s Disease (AD) is an irreversible neurodegenerative disorder that affects brain structures. Corpus Callosum (CC) atrophy and Lateral ventricle (LV) enlargement are useful structural biomarkers in distinguishing the preclinical stages of AD. The shape of CC appears to be homogeneous from normal controls to AD images and LV shows shape dissimilarity across subjects. Therefore, effective methods to segment CC and LV are essential to characterize the magnitude of morphometric changes. In this study, an attempt has been made to segment CC and LV from MR brain images using the Spatial Fuzzy Clustering based Level Set (SFC-LS) method. For this, T1-weighted MR images of AD, Mild Cognitive Impairment (MCI), and normal controls are obtained from a public database. Spatial fuzzy clustering forms the initial contour for the level set and regularizes the evolution of curve. The segmented images are validated against ground truth using standard measures. Results indicate that SFC-LS is able to segment CC and LV with automated contour initialization. The final contours obtained are sharp and distinct with a high validation performance of accuracy and specificity greater than 97% for normal controls, MCI, and AD. A dice score of 83% and 84% is achieved in segmenting CC and LV respectively. As structural changes in CC and LV have the potential to predict the early stages of AD, the proposed approach seems to be clinically significant.

Laptop-Administered NIH Toolbox and Cogstate Brief Battery in Community-Dwelling Black Adults: Unexpected Pattern of Cognitive Performance between MCI and Healthy Controls.

Black adults are approximately twice as likely to develop Alzheimer's disease (AD) than non-Hispanic Whites and access diagnostic services later in their illness. This dictates the need to develop assessments that are cost-effective, easily administered, and sensitive to preclinical stages of AD, such as mild cognitive impairment (MCI). Two computerized cognitive batteries, NIH Toolbox-Cognition and Cogstate Brief Battery, have been developed. However, utility of these measures for clinical characterization remains only partially determined. We sought to determine the convergent validity of these computerized measures in relation to consensus diagnosis in a sample of MCI and healthy controls (HC). Participants were community-dwelling Black adults who completed the neuropsychological battery and other Uniform Data Set (UDS) forms from the AD centers program for consensus diagnosis (HC = 61; MCI = 43) and the NIH Toolbox-Cognition and Cogstate batteries. Discriminant function analysis was used to determine which cognitive tests best differentiated the groups. NIH Toolbox crystallized measures, Oral Reading and Picture Vocabulary, were the most sensitive in identifying MCI apart from HC. Secondarily, deficits in memory and executive subtests were also predictive. UDS neuropsychological test analyses showed the expected pattern of memory and executive functioning tests differentiating MCI from HC. Contrary to expectation, NIH Toolbox crystallized abilities appeared preferentially sensitive to diagnostic group differences. This study highlights the importance of further research into the validity and clinical utility of computerized neuropsychological tests within ethnic minority populations.

Pontine Arteriolosclerosis and Locus Coeruleus Oxidative Stress Differentiate Resilience from Mild Cognitive Impairment in a Clinical Pathologic Cohort.

Locus coeruleus (LC) neurodegeneration is associated with cognitive deterioration during the transition from normal cognition to mild cognitive impairment (MCI) and Alzheimer disease (AD). However, the extent to which LC degenerative processes differentiate cognitively normal, "resilient" subjects bearing a high AD pathological burden from those with MCI or AD remains unclear. We approached this problem by quantifying the number of LC neurons and the percentage of LC neurons bearing AT8 tau pathology, TDP-43 pathology, or a marker for DNA/RNA oxidative damage, in well-characterized subjects diagnosed as normal cognition-low AD pathology (NC-LP), NC-high AD pathology (NC-HP), MCI, or mild/moderate AD. In addition, the severity of pontine arteriolosclerosis in each subject was compared across the groups. There was a trend for a step-wise ∼20% loss of LC neuron number between the NC-LP, NC-HP and MCI subjects despite a successive, significant ∼80%-100% increase in tau pathology between these groups. In contrast, increasing pontine arteriolosclerosis severity scores and LC oxidative stress burden significantly separated the NC-LP/HP and MCI/AD groups via comparative, correlation, and regression analysis. Pontine perfusion, as well as LC neuronal metabolic and redox function, may impact noradrenergic LC modulation of cognition during the preclinical and prodromal stages of AD.