Cognitively Unimpaired Research Articles

Synergistic effect of folate and MTHFR C677T on hippocampal subfields and perfusion in Alzheimer's disease

BackgroundLow folate intake and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have been suggested to increase the risk of Alzheimer's disease (AD). However, the synergistic effects and their impact on brain structure and perfusion remain unclear. MethodsThis study explored the effects of dietary and genetic deficiencies in folate metabolism on the volume of the hippocampal subregions, cerebral perfusion, and cognitive decline in 71 cognitively unimpaired (CU) individuals and 102 patients with mild cognitive impairment (MCI) due to AD or AD. All participants underwent magnetic resonance imaging, laboratory examinations, and neuropsychological assessments. The hippocampal subfields were segmented using Freesurfer, and arterial spin labeling was used to measure the cerebral blood flow. ResultsWe found a significant group-by-MTHFR interaction effect on folate. Patients with AD and the 677 T allele showed hypoperfusion in the left precuneus compared to patients without this mutation, which mediated the relationship between low folate level and cognitive decline in patients carrying the 677 T allele. Moreover, a synergistic effect was observed for the combination of decreased folate concentrations and the presence of the MTHFR 677 T allele on the atrophy of specific hippocampal subregions in patients with AD. ConclusionsIn addition to offering insights into the neuronal mechanism underlying gene-dependent folate-induced cognitive impairment in AD, these findings may have clinical significance for the allocation of auxiliary folate supplementation therapy in patients with AD with low folate levels and carrying the MTHFR 677 T allele and may eventually promote the selection of early individualized AD drug therapy.

Relationships between PET and blood plasma biomarkers in corticobasal syndrome.

Corticobasal syndrome (CBS) can result from underlying Alzheimer's disease (AD) pathologies. Little is known about the utility of blood plasma metrics to predict positron emission tomography (PET) biomarker-confirmed AD in CBS. A cohort of eighteen CBS patients (8amyloid beta [Aβ]+; 10Aβ-) and 8 cognitively unimpaired (CU) individuals underwent PET imaging and plasma analysis. Plasma concentrations were compared using a Kruskal-Wallis test. Spearman correlations assessed relationships between plasma concentrations and PET uptake. CBS Aβ+ group showed a reduced Aβ42/40 ratio, with elevated phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentrations, while CBS Aβ- group only showed elevated NfL concentration compared to CU. Both p-tau181 and GFAP were able to differentiate CBS Aβ- from CBS Aβ+ and showed positive associations with Aβ and tau PET uptake. This study supports use of plasma p-tau181 and GFAP to detect AD in CBS. NfL shows potential as a non-specific disease biomarker of CBS regardless of underlying pathology. Plasma phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP) concentrations differentiate corticobasal syndrome (CBS) amyloid beta (Aβ)- from CBS Aβ+. Plasma neurofilament light concentrations are elevated in CBS Aβ- and Aβ+ compared to controls. Plasma p-tau181 and GFAP concentrations were associated with Aβ and tau positron emission tomography (PET) uptake. Aβ42/40 ratio showed a negative correlation with Aβ PET uptake.

Prediction of future cognitive decline among cognitively unimpaired individuals using measures of soluble phosphorylated tau or tau tangle pathology.

Plasma p-tau217 and Tau-PET are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In this head-to-head comparison study including 9 cohorts and 1534 individuals, we found that plasma p-tau217 and medial temporal lobe Tau-PET signal showed similar associations with cognitive decline on a global cognitive composite test (R2 PET=0.32 vs R2 PLASMA=0.32, pdifference=0.812) and with progression to mild cognitive impairment (Hazard ratio[HR]PET=1.56[1.43-1.70] vs HRPLASMA=1.63[1.50-1.77], pdifference=0.627). Combined plasma and PET models were superior to the single biomarker models (R2=0.36, p<0.01). Furthermore, sequential selection using plasma p-tau217 and then Tau-PET reduced the number of participants required for a clinical trial by 94%, compared to a 75% reduction when using plasma p-tau217 alone. We conclude that plasma p-tau217 and Tau-PET showed similar performance for predicting future cognitive decline in CU individuals, and their sequential use (i.e., plasma p-tau217 followed by Tau-PET in a subset with high plasma p-tau217) is useful for screening in clinical trials in preclinical AD.

Awareness of episodic memory and meta-cognitive profiles: associations with cerebrospinal fluid biomarkers at the preclinical stage of the Alzheimer's continuum.

The lack of cognitive awareness, anosognosia, is a clinical deficit in Alzheimer's disease (AD) dementia. However, an increased awareness of cognitive function, hypernosognosia, may serve as a marker in the preclinical stage. Subjective cognitive decline (SCD) might correspond to the initial symptom in the dynamic trajectory of awareness, but SCD might be absent along with low awareness of actual cognitive performance in the preclinical stage. We hypothesized that distinct meta-cognitive profiles, both hypernosognosia and anosognosia, might be identified in preclinical-AD. This research evaluated the association between cerebrospinal fluid (CSF) AD biomarkers and the awareness of episodic memory, further exploring dyadic (participant-partner) SCD reports, in the preclinical Alzheimer's continuum. We analyzed 314 cognitively unimpaired (CU) middle-aged individuals (mean age: 60, SD: 4) from the ALFA+ cohort study. Episodic memory was evaluated with the delayed recall from the Memory Binding Test (MBT). Awareness of episodic memory, meta-memory, was defined as the normalized discrepancy between objective and subjective performance. SCD was defined using self-report, and dyadic SCD profiles incorporated the study partner's report using parallel SCD-Questionnaires. The relationship between CSF Aβ42/40 and CSF p-tau181 with meta-memory was evaluated with multivariable regression models. The role of SCD and the dyadic contingency was explored with the corresponding stratified analysis. CSF Aβ42/40 was non-linearly associated with meta-memory, showing an increased awareness up to Aβ-positivity and a decreased awareness beyond this threshold. In the non-SCD subset, the non-linear association between CSF Aβ42/40 and meta-memory persisted. In the SCD subset, higher Aβ-pathology was linearly associated with increased awareness. Individuals presenting only study partner's SCD, defined as unaware decliners, exhibited higher levels of CSF p-tau181 correlated with lower meta-memory performance. These results suggested that distinct meta-cognitive profiles can be identified in preclinical-AD. While most individuals might experience an increased awareness associated with the entrance in the AD continuum, hypernosognosia, some might be already losing insight and stepping into the anosognosic trajectory. This research reinforced that an early anosognosic profile, although at increased risk of AD-related decline, might be currently overlooked considering actual diagnostic criteria, and therefore its medical attention delayed.

Matrix Remodeling Enzymes as Potential Fluid Biomarkers of Neurodegeneration in Alzheimer's Disease.

This study investigated the diagnostic accuracy of plasma biomarkers-specifically, matrix metalloproteinase (MMP-9), tissue inhibitor of metalloproteinase (TIMP-1), CD147, and the MMP-/TIMP-1 ratio in patients with Alzheimer's disease (AD) dementia. The research cohort comprised patients diagnosed with probable AD dementia and a control group of cognitively unimpaired (CU) individuals. Neuroradiological assessments included brain magnetic resonance imaging (MRI) following dementia protocols, with subsequent volumetric analysis. Additionally, cerebrospinal fluid (CSF) AD biomarkers were classified using the A/T/N system, and apolipoprotein E (APOE) ε4 carrier status was determined. Findings revealed elevated plasma levels of MMP-9 and TIMP-1 in AD dementia patients compared to CU individuals. Receiver operating characteristic (ROC) curve analysis demonstrated significant differences in the areas under the curve (AUC) for MMP-9 (p < 0.001) and TIMP-1 (p < 0.001). Notably, plasma TIMP-1 levels were significantly lower in APOE ε4+ patients than in APOE ε4- patients (p = 0.041). Furthermore, APOE ε4+ patients exhibited reduced hippocampal volume, particularly in total, right, and left hippocampal measurements. TIMP-1 levels exhibited a positive correlation, while the MMP-9/TIMP-1 ratio showed a negative correlation with hippocampal volume parameters. This study sheds light on the potential use of TIMP-1 as a diagnostic marker and its association with hippocampal changes in AD.

Cognitive trajectories preluding the onset of different dementia entities: a descriptive longitudinal study using the NACC database

ObjectiveTo describe the 10-year preclinical cognitive trajectories of older, non-demented individuals towards the onset of the four most prevalent types of dementia, i.e., Alzheimer’s disease(AD), Lewy body(LBD), vascular(VD) and frontotemporal dementia(FTD).MethodsOur analysis focused on data from older (≥ 60years) NACC (National Alzheimer’s Coordinating Center) participants. Four distinct presymptomatic dementia groups (AD-LBD-VD-FTD) and a comparison group of cognitively unimpaired(CU) participants were formed. Comprehensive cognitive assessments involving verbal episodic memory, semantic verbal fluency, confrontation naming, mental processing speed – attention and executive function – cognitive flexibility were conducted at baseline and on an approximately yearly basis. Descriptive analyses (adjusted general linear models) were performed to determine and compare the yearly cognitive scores of each group throughout the follow-up. Exploratory analyses were conducted to estimate the rates of cognitive decline.ResultsThere were 3343 participants who developed AD, 247 LBD, 108 FTD, 155 VD and 3398 composed the CU group. Participants with AD performed worse on episodic memory than those with VD and LBD for about 3 to 4 years prior to dementia onset (the FTD group documented an intermediate course). Presymptomatic verbal fluency and confrontation naming trajectories differentiated quite well between the FTD group and the remaining dementia entities. Participants with incident LBD and VD performed worse than those with AD on executive functions and mental processing speed-attention since about 5 years prior to the onset of dementia, and worse than those with FTD more proximally to the diagnosis of the disorder.ConclusionsHeterogeneous cognitive trajectories characterize the presymptomatic courses of the most prevalent dementia entities.

Neurofilament Light Chain as a Biomarker of Global Cognition in Individuals With Possible Vascular Mild Cognitive Impairment.

Neurofilament Light Chain (NfL) is a biomarker of axonal injury elevated in mild cognitive impairment (MCI) and Alzheimer's disease dementia. Blood NfL also inversely correlates with cognitive performance in those conditions. However, few studies have assessed NfL as a biomarker of global cognition in individuals demonstrating mild cognitive deficits who are at risk for vascular-related cognitive decline. To assess the relationship between blood NfL and global cognition in individuals with possible vascular MCI (vMCI) throughout cardiac rehabilitation (CR). Additionally, NfL levels were compared to age/sex-matched cognitively unimpaired (CU) controls. Participants with coronary artery disease (vMCI or CU) were recruited at entry to a 24-week CR program. Global cognition was measured using the Montreal Cognitive Assessment (MoCA) and plasma NfL level (pg/ml) was quantified using a highly sensitive enzyme-linked immunosorbent assay. Higher plasma NfL was correlated with worse MoCA scores at baseline (β = -.352, P = .029) in 43 individuals with vMCI after adjusting for age, sex, and education. An increase in NfL was associated with worse global cognition (b[SE] = -4.81[2.06], P = .023) over time, however baseline NfL did not predict a decline in global cognition. NfL levels did not differ between the vMCI (n = 39) and CU (n = 39) groups (F(1, 76) = 1.37, P = .245). Plasma NfL correlates with global cognition at baseline in individuals with vMCI, and is associated with decline in global cognition during CR. Our findings increase understanding of NfL and neurobiological mechanisms associated with cognitive decline in vMCI.

The neutrophil to lymphocyte ratio associates with markers of Alzheimer's disease pathology in cognitively unimpaired elderly people.

An elevated neutrophil-lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.

The associations between nutritional status and physical frailty and Alzheimer's disease plasma biomarkers in older cognitively unimpaired adults with positive of amyloid-β PET

Background & AimsIt has been revealed good nutritional status and no physical frailty, which are modifiable lifestyle factors, are linked to less cognitive decline and a lower risk of Alzheimer’s disease (AD). We aimed to investigate the associations between nutritional status and physical frailty and plasma AD biomarkers, especially the Tau-associated biomarkers in older cognitively unimpaired (CU) adults with higher β-amyloid (Aβ) burden. MethodsThe nutritional status and physical frailty were assessed via Mini-Nutritional Assessment Short-Form (MNA-SF) and Fried frailty index. The participants underwent the examination of plasma AD biomarkers and 18F-florbetapir PET scan as well as 18F-MK6240 PET in the validation cohort. Correlation and multiple linear regression analyses were used to investigate the associations between nutritional status and frailty and AD biomarkers. ResultsTwo cohorts were included in our study. A total of 129 participants with Aβ-PET positive were enrolled in the development cohort. Multiple linear regression analysis showed MNA-SF scores, normal nutritional status, Fried frailty index scores, frailty and some domains of frailty including weight loss, maximal grip strength and exhaustion were associated with plasma p-Tau-181. Furthermore, weight loss, Fried frailty index scores and frailty were associated with higher Aβ-PET standard uptake value ratio. We further performed subgroup analyses stratified by age, sex and apolipoprotein E ε4 genotype to investigate the beneficial characteristics of nutrition and frailty in the special subgroups. Validation cohort contained 38 Aβ-PET positive participants. MNA-SF scores, normal nutritional status, Fried frailty index scores and frailty were associated with Tau burden evaluated by 18F-MK6240 PET Braak-like stages. ConclusionsOur data indicates that normal nutritional status and no physical frailty may be associated with expected trend of plasma AD biomarkers, especially less Tau pathology in older CU adults with Aβ deposition. Adjusting to these characteristics of nutrition and physical frailty may help reduce the risk of AD development.

Comparison of plasma and neuroimaging biomarkers to predict cognitive decline in non-demented memory clinic patients.

Plasma biomarkers of Alzheimer's disease (AD) pathology, neurodegeneration, and neuroinflammation are ideally suited for secondary prevention programs in self-sufficient persons at-risk of dementia. Plasma biomarkers have been shown to be highly correlated with traditional imaging biomarkers. However, their comparative predictive value versus traditional AD biomarkers is still unclear in cognitively unimpaired (CU) subjects and with mild cognitive impairment (MCI). Plasma (Aβ42/40, p-tau181, p-tau231, NfL, and GFAP) and neuroimaging (hippocampal volume, centiloid of amyloid-PET, and tau-SUVR of tau-PET) biomarkers were assessed at baseline in 218 non-demented subjects (CU = 140; MCI = 78) from the Geneva Memory Center. Global cognition (MMSE) was evaluated at baseline and at follow-ups up to 5.7 years. We used linear mixed-effects models and Cox proportional-hazards regression to assess the association between biomarkers and cognitive decline. Lastly, sample size calculations using the linear mixed-effects models were performed on subjects positive for amyloid-PET combined with tau-PET and plasma biomarker positivity. Cognitive decline was significantly predicted in MCI by baseline plasma NfL (β=-0.55), GFAP (β=-0.36), hippocampal volume (β = 0.44), centiloid (β=-0.38), and tau-SUVR (β=-0.66) (all p < 0.05). Subgroup analysis with amyloid-positive MCI participants also showed that only NfL and GFAP were the only significant predictors of cognitive decline among plasma biomarkers. Overall, NfL and tau-SUVR showed the highest prognostic values (hazard ratios of 7.3 and 5.9). Lastly, we demonstrated that adding NfL to the inclusion criteria could reduce the sample sizes of future AD clinical trials by up to one-fourth in subjects with amyloid-PET positivity or by half in subjects with amyloid-PET and tau-PET positivity. Plasma NfL and GFAP predict cognitive decline in a similar manner to traditional imaging techniques in amyloid-positive MCI patients. Hence, even though they are non-specific biomarkers of AD, both can be implemented in memory clinic workups as important prognostic biomarkers. Likewise, future clinical trials might employ plasma biomarkers as additional inclusion criteria to stratify patients at higher risk of cognitive decline to reduce sample sizes and enhance effectiveness.

Temporal tau asymmetry spectrum influences divergent behavior and language patterns in Alzheimer‘s disease

Understanding the psychiatric symptoms of Alzheimer s disease (AD) is crucial for advancing precision medicine and therapeutic strategies. The relationship between AD behavioral symptoms and asymmetry in spatial tau PET patterns is not well-known. Braak tau progression implicates the temporal lobes early. However, the clinical and pathological implications of temporal tau laterality remain unexplored.This cross-sectional study investigated the correlation between temporal tau PET asymmetry and behavior assessed using the neuropsychiatric inventory and composite scores for memory, executive function, and language, using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. In the entire cohort, continuous right and left temporal tau contributions to behavior and cognition were evaluated, controlling for age, sex, education, and tau burden on the contralateral side. Additionally, a temporal tau laterality index was calculated to define “asymmetry-extreme” groups (individuals with laterality indices greater than two standard deviations from the mean).695 individuals (age = 73.9 ± 7.6 years, 372 (53.5 %) females) were included, comprising 281 (40%) cognitively unimpaired (CU) amyloid negative, 185 (27%) CU amyloid positive, and 229 (33%) impaired (CI) amyloid positive participants. In the full cohort analysis, right temporal tau was associated with worse behavior (B = 8.14, p-value = 0.007), and left temporal tau was associated with worse language (B = 1.4, p-value < 0.001). Categorization into asymmetry-extreme groups revealed 20 right- and 27 left-asymmetric participants. Within these extreme groups, there was additional heterogeneity along the anterior-posterior dimension.Asymmetrical tau burden is associated with distinct behavioral and cognitive profiles. Wide multi-cultural implementation of social cognition measures is needed to understand right-sided asymmetry in AD.

Specific Association of Worry With Amyloid-β But Not Tau in Cognitively Unimpaired Older Adults

Anxiety disorders and subsyndromal anxiety symptoms are highly prevalent in late life. Recent studies support that anxiety may be a neuropsychiatric symptom during preclinical Alzheimer's disease (AD) and that higher anxiety is associated with more rapid cognitive decline and progression to cognitive impairment. However, the associations of specific anxiety symptoms with AD pathologies and with co-occurring subjective and objective cognitive changes have not yet been established. Baseline data from the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration studies were analyzed. Older adult participants (n = 4,486) underwent assessments of anxiety (State-Trait Anxiety Inventory-6 item version [STAI]), and cerebral amyloid-beta (Aβ; 18F-florbetapir) PET and a subset underwent tau (18F-flortaucipir) PET. Linear regressions estimated associations of Aβ in a cortical composite and tau in the amygdala, entorhinal, and inferior temporal regions with STAI-Total and individual STAI item scores. Models adjusted for age, sex, education, marital status, depression, Apolipoprotein ε4 genotype, and subjective and objective cognition (Cognitive Function Index-participant; Preclinical Alzheimer Cognitive Composite). Greater Aβ deposition was significantly associated with higher STAI-Worry, adjusting for all covariates, but not with other STAI items or STAI-Total scores. In mediation analyses, the association of Aβ with STAI-Worry was partially mediated by subjective cognition with a stronger direct effect. No associations were found for regional tau deposition with STAI-Total or STAI-Worry score. Greater worry was associated with Aβ but not tau deposition, independent of subjective and objective cognition in cognitively unimpaired (CU) older adults. These findings implicate worry as an early, specific behavioral marker and a possible therapeutic target in preclinical AD.

Associations of plasma neurofilament light chain with cognition and neuroimaging measures in community-dwelling early old age men

BackgroundPlasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations.MethodsWe examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61–73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter.ResultsAfter adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals.ConclusionsThese results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature.

Machine Learning-Based Perivascular Space Volumetry in Alzheimer Disease.

Impaired perivascular clearance has been suggested as a contributing factor to the pathogenesis of Alzheimer disease (AD). However, it remains unresolved when the anatomy of the perivascular space (PVS) is altered during AD progression. Therefore, this study investigates the association between PVS volume and AD progression in cognitively unimpaired (CU) individuals, both with and without subjective cognitive decline (SCD), and in those clinically diagnosed with mild cognitive impairment (MCI) or mild AD. A convolutional neural network was trained using manually corrected, filter-based segmentations (n = 1000) to automatically segment the PVS in the centrum semiovale from interpolated, coronal T2-weighted magnetic resonance imaging scans (n = 894). These scans were sourced from the national German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study. Convolutional neural network-based segmentations and those performed by a human rater were compared in terms of segmentation volume, identified PVS clusters, as well as Dice score. The comparison revealed good segmentation quality (Pearson correlation coefficient r = 0.70 with P < 0.0001 for PVS volume, detection rate in cluster analysis = 84.3%, and Dice score = 59.0%). Subsequent multivariate linear regression analysis, adjusted for participants' age, was performed to correlate PVS volume with clinical diagnoses, disease progression, cerebrospinal fluid biomarkers, lifestyle factors, and cognitive function. Cognitive function was assessed using the Mini-Mental State Examination, the Comprehensive Neuropsychological Test Battery, and the Cognitive Subscale of the 13-Item Alzheimer's Disease Assessment Scale. Multivariate analysis, adjusted for age, revealed that participants with AD and MCI, but not those with SCD, had significantly higher PVS volumes compared with CU participants without SCD ( P = 0.001 for each group). Furthermore, CU participants who developed incident MCI within 4.5 years after the baseline assessment showed significantly higher PVS volumes at baseline compared with those who did not progress to MCI ( P = 0.03). Cognitive function was negatively correlated with PVS volume across all participant groups ( P ≤ 0.005 for each). No significant correlation was found between PVS volume and any of the following parameters: cerebrospinal fluid biomarkers, sleep quality, body mass index, nicotine consumption, or alcohol abuse. The very early changes of PVS volume may suggest that alterations in PVS function are involved in the pathophysiology of AD. Overall, the volumetric assessment of centrum semiovale PVS represents a very early imaging biomarker for AD.

Neuropsychiatric symptoms and white matter hyperintensities in older adults without dementia.

We aimed to examine associations between neuropsychiatric symptoms (NPS) and white matter hyperintensities (WMH) status in older adults without dementia under the hypothesis that WMH increased the odds of having NPS. Longitudinal analysis of data acquired from the National Alzheimer's Coordinating Center Uniform Data Set. Data were derived from 46 National Institute on Aging - funded Alzheimer's Disease Research Centers. NACC participants aged ≥50 years with available data on WMH severity with a diagnosis of mild cognitive impairment (MCI) or who were cognitively unimpaired (CU) were studied. Among 4617 CU participants, 376 had moderate and 54 extensive WMH. Among 3170 participants with MCI, 471 had moderate and 88 had extensive WMH. Using Cardiovascular Health Study (CHS) scores, WMH were coded as no to mild (CHS score: 0-4), moderate (score: 5-6) or extensive (score: 7-8). NPS were quantified on the Neuropsychiatric Inventory Questionnaire. Binary logistic regression models estimated the odds of reporting each of 12 NPS by WMH status separately for individuals with MCI or who were CU. Compared to CU individuals with no to mild WMH, the odds of having elation [9.87, (2.63-37.10)], disinhibition [4.42, (1.28-15.32)], agitation [3.51, (1.29-9.54)] or anxiety [2.74, (1.28-5.88)] were higher for the extensive WMH group, whereas the odds of having disinhibition were higher for the moderate WMH group [1.94, (1.05-3.61)]. In the MCI group, he odds of NPS did not vary by WMH status. Extensive WMH were associated with higher odds of NPS in CU older adults but not in those with MCI.

High Contrast PET Imaging of Subcortical and Allocortical Amyloid-β in Early Alzheimer's Disease Using [11C]AZD2184.

Deposits of amyloid-β (Aβ) appear early in Alzheimer's disease (AD). The aim of the present study was to compare the presence of cortical and subcortical Aβ in early AD using positron emission tomography (PET). Eight cognitively unimpaired (CU) subjects, 8 with mild cognitive impairment (MCI) and 8 with mild AD were examined with PET and [11C]AZD2184. A data driven cut-point for Aβ positivity was defined by Gaussian mixture model of isocortex binding potential (BPND) values. Sixteen subjects (3 CU, 5 MCI and 8 AD) were Aβ-positive. BPND was lower in subcortical and allocortical regions compared to isocortex. Fifteen of the 16 Aβ-positive subjects displayed Aβ binding in striatum, 14 in thalamus and 10 in allocortical regions. Aβ deposits appear to be widespread in early AD. It cannot be excluded that deposits appear simultaneously throughout the whole brain which has implications for improved diagnostics and disease monitoring.

Predictive Modeling Using a Composite Index of Sleep and Cognition in the Alzheimer's Continuum: A Decade-Long Historical Cohort Study.

Sleep disturbances frequently affect Alzheimer's disease (AD), with up to 65% patients reporting sleep-related issues that may manifest up to a decade before AD symptoms. To construct a nomogram that synthesizes sleep quality and cognitive performance for predicting cognitive impairment (CI) conversion outcomes. Using scores from three well-established sleep assessment tools, Pittsburg Sleep Quality Index, REM Sleep Behavior Disorder Screening Questionnaire, and Epworth Sleepiness Scale, we created the Sleep Composite Index (SCI), providing a comprehensive snapshot of an individual's sleep status. Initially, a CI conversion prediction model was formed via COX regression, fine-tuned by bidirectional elimination. Subsequently, an optimized prediction model through COX regression, depicted as a nomogram, offering predictions for CI development in 5, 8, and 12 years among cognitively unimpaired (CU) individuals. After excluding CI patients at baseline, our study included 816 participants with complete baseline and follow-up data. The CU group had a mean age of 66.1±6.7 years, with 36.37% males, while the CI group had an average age of 70.3±9.0 years, with 39.20% males. The final model incorporated glial fibrillary acidic protein, Verbal Fluency Test and SCI, and an AUC of 0.8773 (0.792-0.963). In conclusion, the sleep-cognition nomogram we developed could successfully predict the risk of converting to CI in elderly participants and could potentially guide the design of interventions for rehabilitation and/or cognitive enhancement to improve the living quality for healthy older adults, detect at-risk individuals, and even slow down the progression of AD.

Performance of SOBA-AD blood test in discriminating Alzheimer’s disease patients from cognitively unimpaired controls in two independent cohorts

Amyloid-beta (Aβ) toxic oligomers are critical early players in the molecular pathology of Alzheimer’s disease (AD). We have developed a Soluble Oligomer Binding Assay (SOBA-AD) for detection of these Aβ oligomers that contain α-sheet secondary structure that discriminates plasma samples from patients on the AD continuum from non-AD controls. We tested 265 plasma samples from two independent cohorts to investigate the performance of SOBA-AD. Testing was performed at two different sites, with different personnel, reagents, and instrumentation. Across two cohorts, SOBA-AD discriminated AD patients from cognitively unimpaired (CU) subjects with 100% sensitivity, > 95% specificity, and > 98% area under the curve (AUC) (95% CI 0.95–1.00). A SOBA-AD positive readout, reflecting α-sheet toxic oligomer burden, was found in AD patients, and not in controls, providing separation of the two populations, aside from 5 SOBA-AD positive controls. Based on an earlier SOBA-AD study, the Aβ oligomers detected in these CU subjects may represent preclinical cases of AD. The results presented here support the value of SOBA-AD as a promising blood-based tool for the detection and confirmation of AD.

334 Identification of novel plasma protein biomarkers for diagnosis and prediction of Alzheimer’s disease in African Americans

OBJECTIVES/GOALS: To identify novel panel of plasma protein biomarkers to improve prediction and diagnosis of Alzheimer’s disease (AD) for African Americans (AA), who are at greater risk of developing AD compared to non-Hispanic White individuals but are underrepresented in AD research. METHODS/STUDY POPULATION: Pre-existing plasma samples from 460 AA individuals with clinical diagnoses of AD, cognitively unimpaired (CU), mild cognitive impairment (MCI), or dementia with Lewy bodies (DLB) will undergo untargeted proteomics using the SomaScan assay, where modified single stranded DNA aptamers bind to protein targets which are quantified by DNA microarray. Protein expression levels will be compared between diagnostic groups to identify differentially expressed proteins. Additional clinical, genetic, and lifestyle factors will be compared with protein expression when available. Proteins of interest, identified by differential protein expression analysis results, will be included in receiver operating characteristic analyses to identify the optimal set of proteins for diagnostic classification. RESULTS/ANTICIPATED RESULTS: A pilot experiment utilizing plasma from 40 individuals identified multiple differentially expressed proteins (DEPs) between AD and non-AD groups. Eight proteins were nominated from the differential protein analysis into a receiver operating characteristic (ROC) analysis based on pvalue and previous implication in AD genome wide association studies. Proteins involved in microglial activation, neuronal adhesion, cell proliferation, and innate immunity were nominated. The ROC model achieved 100% classification accuracy of AD and CU groups using age, sex, and the eight nominated proteins. It is expected that there will be more significant associations when utilizing the full cohort of 460 AA and that DEPs between AD, CU, MCI, and DLB will be identified. DISCUSSION/SIGNIFICANCE: The nomination of a novel panel of plasma biomarkers developed from an AA cohort will directly serve the AA community by improving access to an early and accurate diagnosis of AD. Access to improved prediction and diagnosis will likely improve disease management, thus improving patient outcomes and decreasing burden on families and caregivers.

Suboptimal self-reported sleep efficiency and duration are associated with faster accumulation of brain amyloid beta in cognitively unimpaired older adults.

This study investigated whether self-reported sleep quality is associated with brain amyloid beta (Aβ) accumulation. Linear mixed effect model analyses were conducted for 189 cognitively unimpaired (CU) older adults (mean±standard deviation 74.0±6.2; 53.2% female), with baseline self-reported sleep data, and positron emission tomography-determined brain Aβ measured over a minimum of three time points (range 33.3-72.7 months). Analyses included random slopes and intercepts, interaction for apolipoprotein E (APOE) ε4 allele status, and time, adjusting for sex and baseline age. Sleep duration<6hours, in APOE ε4 carriers, and sleep efficiency<65%, in the whole sample and APOE ε4 non-carriers, is associated with faster accumulation of brain Aβ. These findings suggest a role for self-reported suboptimal sleep efficiency and duration in the accumulation of Alzheimer's disease (AD) neuropathology in CU individuals. Additionally, poor sleep efficiency represents a potential route via which individuals at lower genetic risk may progress to preclinical AD. In cognitively unimpaired older adults self-report sleep is associated with brain amyloid beta (Aβ) accumulation.Across sleep characteristics, this relationship differs by apolipoprotein E (APOE) genotype.Sleep duration<6hours is associated with faster brain Aβ accumulation in APOE ε4 carriers.Sleep efficiency< 65% is associated with faster brain Aβ accumulation in APOE ε4 non-carriers.Personalized sleep interventions should be studied for potential to slow Aβ accumulation.