The eye has been considered a ‘window to the brain’ and to several neurodegenerative brain disorders including Alzheimer's disease (AD) that display alterations in the eye, especially the retina. Plasma levels of AD biomarkers, including Aβ42/Aβ40 ratio, pTau 181, glial fibrillary acidic protein (GFAP), total Tau (tTau), and Neurofilament lightchain (NfL) are significantly altered in AD patients. We sought to evaluate the association of retinal perfusion measured using optical coherence tomography angiography (OCTA) with plasma biomarkers of AD. Participants (31; 5 mild cognitive decline/AD, 6 subjective cognitive decline and 20 cognitively normal) underwent ophthalmological evaluation including OCTA and a blood sample. Single molecule array (Simoa) assays were used to measure plasma concentrations of Aβ42, and Aβ40, pTau181, GFAP, Ttau, and NfL. Partial Pearson correlations, covaried for age and sex, were used to compare retinal vessel and perfusion density with plasma level of the Aβ42/Aβ40 ratio, pTau181, GFAP, tTau and NfL. Plasma Aβ42/Aβ40 showed a significant positive association with retinal vessel density (r=0.398 p  = 0.036) and perfusion density ( r  = 0.384 p  = 0.044). pTau 181 showed a significant negative association with retinal perfusion density (r=-0.499 p  = 0.041). GFAP showed a significant positive association with foveal avascular zone area in the superficial capillary plexus (r=0.554 p  = 0.021). The majority of the sample was cognitively normal or mildly impaired, suggesting that retinal perfusion may be a useful tool for early diagnosis of AD-related pathophysiology. Future longitudinal studies in larger samples and evaluating the utility of combining retinal and plasma biomarkers for predicting future progression to AD are needed.

The growing availability of large-scale biomarker datasets has allowed data-driven methods to characterize Alzheimer's disease biological heterogeneity. However, most prior studies have focused on cohorts of late-onset amnestic cases, leaving early-onset Alzheimer's disease underexplored. We aimed to characterize tau-PET-based subtypes through a robust data-driven approach in the Longitudinal Early-Onset Alzheimer's Disease Study. Baseline [18F]Flortaucipir PET scans from 365 amyloid-PET-positive participants with sporadic early-onset Alzheimer's disease were quantified in the left and right medial temporal, lateral temporal, occipital, parietal, and frontal cortices. Tau PET values were z-scored against 85 amyloid-PET-negative cognitively normal age-matched participants and fitted into Subtype and Stage Inference (SuStaIn)-an unsupervised clustering algorithm that simultaneously models subtypes and progression from cross-sectional data. The derived subtypes were subsequently characterized by baseline and longitudinal clinical, cognitive, MRI, tau and amyloid PET features. We identified three tau-PET-based subtypes: on average, Subtype 1/Typical (n = 144, 40%) showed a predominant bilateral temporoparietal pattern typical of Alzheimer's disease. Subtype 2/Left temporal (n = 111, 31%) showed predominant left temporal binding. Subtype 3/Posterior (n = 104, 29%) showed early and permeating occipitoparietal involvement. Subtypes did not differ in demographics or global amyloid burden, but were relatively more enriched for specific clinical presentations: S1/Typical for amnestic presentations, S2/Left Temporal for primary progressive aphasia, and S3/Posterior for posterior cortical atrophy. Baseline tau PET subtypes aligned with cortical atrophy patterns and domain-specific cognitive impairment. When follow-up tau PET scans were fitted to SuStaIn trained on baseline data, 85.6% (n = 172/201) of participants retained the same subtype classification, indicating subtype temporal stability, and progressed within subtypes by 0.56 ± 0.70 SuStaIn stage/year. Longitudinal voxel-wise linear mixed-effects modelling revealed tau accumulation patterns for each subtype in regions relatively spared at baseline: occipital lobe accumulation predominated in S1/Typical, bilateral frontal and right temporal in S2/Left Temporal, and bilateral frontotemporal lobes in S3/Posterior. All subtypes showed longitudinal increases in Clinical Dementia Rating-Sum of Boxes, but with slower worsening in S3/Posterior compared with the other subtypes. Our findings reveal robust subtypes in sporadic early-onset Alzheimer's disease characterized by distinct spatiotemporal tau patterns that parallel differences in clinical presentations and trajectories of neurodegeneration. These subtypes extend beyond traditional clinical syndromes and support a more nuanced framework for individualized prognosis and care. Incorporating tau PET subtyping into clinical trial design could enable more targeted therapeutic approaches for this younger population.

Early-onset Alzheimer's disease (EOAD) and Late-onset AD (LOAD) differ in clinical presentations and rates of progression. We aimed to compare baseline and longitudinal tau PET burden, and their relationship with clinical variables in amyloid-PET positive, cognitively impaired participants from the Longitudinal Early-Onset Alzheimer's Disease Study (EOAD; n=390) and Alzheimer's Disease Neuroimaging Initiative (LOAD; n=211). Patients with EOAD showed higher baseline tau PET retention, broader neuroanatomical involvement and faster accumulation rates over time compared to LOAD, after adjusting for amyloid load and clinical stage. Tau PET showed stronger correlations with baseline amyloid burden and clinical measures of global cognition and function in EOAD than LOAD. We conclude that earlier age of onset in AD is linked to a more aggressive tauopathy, which in turn is a primary driver of clinical decline. These findings suggest that optimal therapeutic targets and strategies may differ between EOAD and LOAD.

Hearing loss is linked to dementia, yet its relationship with Alzheimer's disease (AD) biomarkers remains unclear. This study examines associations between performance on auditory and speech perception measures with neuroimaging measures of neurodegeneration (N; cortical volume), amyloid (A), and tau (T) to aid early AD detection. 121 participants from the Indiana Alzheimer's Disease Research Center underwent auditory testing and neuroimaging. Auditory assessments included CUNY sentences, Speech-in-Noise (QuickSiN), and Letter Number Sequencing (LNS). Neuroimaging measures included MRI-based cortical volume extracted with Freesurfer v6 (N), cortical Centiloid value from amyloid PET (A), and bilateral mean meta-temporal tau standardized uptake value ratio from tau PET (T). A one-way ANCOVA was used to compare differences in auditory tests between diagnostic groups, while partial Pearson correlations were used to assess associations of auditory tests with A/T/N biomarkers, covaried for age, sex, and total intracranial volume ( N only). The sample (age=71.90±6.6; 63.9% female) included 49 cognitively normal older adults, 40 with subjective cognitive decline, 23 with mild cognitive impairment (MCI) due to AD, 7 with MCI due to other conditions, and 2 with AD. Significant diagnostic differences were observed in SNR loss on QuickSiN ( p  = .006) and CUNY subtests, including AV words ( p  <.001), AV sentences ( p  = .037), and A words ( p  = .002). Cortical amyloid correlated with SNR loss (r=.231, p  = .045) and CUNY subscores, including auditory (Au) words (r=-.272, p  = .018) and word gain (r=-.250, p  = .031). LNS raw scores correlated with cortical volume (r=-.311, p  = .008). Associations were found between cortical volume and CUNY audiovisual (AV) words (r=.254, p  = .023), A words (r=.395, p  < .001), and sentence gain (r=-.261, p  = .020), but not with SNR loss. Meta-temporal tau SUVR was associated with CUNY A words (r=-.294, p  = .021), A sent (r=-.276, p  = .031), word gain (r=.303, p  = .016), and LNS raw scores (r=-.276, p  = .036), but not with SNR measures. Findings suggest that auditory and speech perception tests are associated with neuroimaging biomarkers of AD, supporting the potential utility of hearing assessments as early screening tools for AD-related pathology. Further research with larger sample sizes is warranted to strengthen these findings and explore their clinical implications.

The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet has been associated with cognitive benefits and reduced risk of Alzheimer's disease. Adherence is typically assessed using comprehensive but time-consuming food frequency questionnaires (FFQs). We examined concurrent validity between a brief MIND diet screener and a more extensive FFQ. 94 participants (51 cognitively normal (CN), 31 subjective cognitive decline (SCD), 12 mild cognitive impairment (MCI)) from the Indiana Alzheimer's Disease Research Center (IADRC) who participated in the Alzheimer's Gut Microbiome Project (AGMP) completed both the self-reported 15-item MIND screener and computerized Vioscreen FFQ. For both measures, we used the same cutoff criteria to assign values of 0, 0.5, or 1 corresponding to low, medium, and high intake for the ‘healthy’ food groups and reverse correspondence for the ‘unhealthy’ food groups, which were then summed to generate a total MIND diet score (0-15) with higher scores indicating greater adherence. Agreement between the two methods was assessed using Pearson correlation, intraclass correlation coefficient (ICC) for absolute agreement and consistency, and a tertile-based cross-classification. ANOVA was used to test differences in MIND scores between diagnostic groups, adjusting for age, sex, and education. The mean MIND diet score from the FFQ was 7.49 (range: 2.5-11), and from the screener was 10.05 (range: 5-13.5), with a mean 2.56-point difference showing consistently higher scores on the screener (Figure 1). The screener demonstrated moderate correlation with the FFQ score ( r  = 0.63, p  <0.001, R2=0.40). Absolute agreement was low (ICC=0.34), while consistency was moderate (ICC=0.64) (Figure 2). In cross-classification, 19.15% of individuals were classified into disparate tertiles. A significant difference was observed between CN and MCI groups using both methods, but only the screener-derived score remained marginally significant after adjustments ( p  = 0.05) (Figure 3). The MIND screener shows moderate correlation and consistency with the FFQ, with participants systematically reporting higher scores on the screener, indicating overestimation of their MIND diet score. While the screener does not capture detailed or food item specific dietary variations assessed by the FFQ, it is a valid tool for rapid estimation of MIND diet score and may be useful in research and clinical practice.

BACKGROUND:Agitation is a clinically significant symptom contributing to behavioral and psychological symptoms of dementia (BPSD) but is poorly understood across the different syndromes related to Frontotemporal Lobar Degeneration (FTLD). This study investigates sex differences in agitation across FTLD-related syndromes and its relationship to various neuropsychiatric symptoms (NPS). METHOD:We analyzed data from 1,654 participants (916 males, 738 females; average ages 65.8 and 65.9, respectively) from the National Alzheimer's Coordinating Center (NACC) and ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study with a FTLD-related syndrome: behavioral variant FTD (bvFTD), Primary Progressive Aphasia (non-fluent variant (nfvPPA), semantic variant (svPPA)), Corticobasal syndrome (CBS) and Progressive Supranuclear Palsy (PSP). Participants' symptoms were assessed using the Neuropsychiatric Inventory (NPI). Prevalence ratios and odds ratios were computed to assess the likelihood of NPS comorbidities when agitation was present in males and females. Principal Component Analysis (PCA) was performed to identify NPS associated with agitation and how they varied by sex. RESULT:Males were more likely to experience anxiety (bvFTD: p <0.001, CBS: p <0.01, PSP: p <0.0001), apathy (nfvPPA: p <0.01, PSP: p <0.01), depression (bvFTD: p <0.0001, PSP<0.01), disinhibition (nfvPPA: p <0.0001), PSP: p <0.001), and motor symptoms (bvFTD: p <0.01, CBS: p <0.01) when agitation was present. In contrast, females had a higher likelihood of experiencing disinhibition in svPPA (p <0.001). These findings suggest that agitation is associated with a wider range of NPS in males than in females. Agitation and NPS are especially prominent in males with PSP. CONCLUSION:This study reveals significant sex differences in NPS in FTLD-related syndromes when agitation is present. Males and especially PSP, are more likely to experience a broader range of NPS in association with agitation. These findings underscore the need for further investigation into the underlying mechanisms driving these sex differences, particularly focusing on the neurobiological impact of agitation, the recognition of symptoms in the presence of greater behavioral disturbances, and potential variations from informant reports. Understanding these factors will provide valuable insights into the role of agitation in the presentation of NPS across FTLD-related syndromes. Ultimately, addressing these gaps will enhance our ability to effectively treat and manage agitation in both male and female patients with FTLD-related syndromes.

The Mediterranean diet has been associated with decreased brain atrophy (Staubo et al. 2016, Alz&Dem ), but the MIND (Mediterranean-Dietary Approaches to Stop Hypertension (DASH) Intervention for Neurodegenerative Delay) diet, designed for dementia prevention (Morris et al. 2015, Alz&Dem ), remains underexplored for its impact on brain atrophy. We investigated the MIND diet’s association with cortical thickness (CT) in the Indiana Alzheimer’s Disease Research Center (IADRC) sample. 134 participants (49 CN, 45 SCD, 30 MCI, 10 AD/other) completed a self-report MIND diet questionnaire at the IADRC, which was coded into high, medium, or low intake groups for each food (5 ‘unhealthy’ food groups were reverse scored) and completed an MRI scan on a 3T scanner. The cortical surface was parcellated using FreeSurfer v6. We selected two regions of interest (ROIs) reflecting AD-associated neurodegeneration: temporal and global CT. We examined the association of MIND diet scores (0-15) and food groups with CT using regression models adjusted for age, sex, race, education, and diagnosis. Higher MIND diet scores were associated with greater mean temporal CT (r = 0.269, p = 0.002) and greater mean global CT (r = 0.230, p = 0.008). In multivariable-adjusted models, the association persisted for temporal but not global CT. Among the 15 food components, greater olive oil (r = 0.034, p<0.001), fish (r = 0.181, p = 0.040), beans (r = 0.237, p = 0.008), and nuts (r = 0.214, p = 0.014), and reduced fast food intake (r = 0.188, p = 0.035) were significantly associated with temporal CT. These associations, except for nuts, remained significant in multivariable-adjusted models, with an additional relationship found for chicken (r = 0.189, p = 0.038). Among the 15 food components, greater olive oil (r = 0.243, p = 0.008), and beans (0.180, p = 0.044), and reduced fast food (r = 0.212, p = 0.017) were significantly associated with global CT. Only reduced fast food retained significance in the multivariable-adjusted models. Greater adherence to the MIND diet was associated with greater CT in both global and temporal regions. Specific components, including increased olive oil, beans, nuts, fish, and reduced fast food, showed significant associations with CT, suggesting elements within the diet driving this association. These findings highlight the potential neuroprotective effects of the MIND diet, emphasizing the importance of dietary patterns in preserving brain health during aging.

Staging disease severity in dementia research requires input from an informant. The Clinical Dementia Rating Sum of Boxes (CDR) is the most used instrument for staging in Alzheimer's Disease (AD); but has been expanded to stage patients with frontotemporal lobar degeneration (FTLD) with the CDR PLUS NACC-FTLD. An informant effect on the CDR has been reported in AD. The aim of this study is to evaluate whether informant characteristics influence the CDR PLUS NACC-FTLD in a large cohort of participants with frontotemporal dementia (FTD). We included participants with a FTLD-related syndrome from the ALLFTD study. We included participants with a CDR PLUS NACC-FTLD higher than 0, information on the Montreal Cognitive Assessment (MoCA) scores, and the Neuropsychiatric Inventory Questionnaire (NPI-Q). We performed a conditional growth model using multilevel linear regression analysis. We performed an exploratory stratified analysis by patient sex. We included 1411 participants, totalling 2063 visits. The patient's age at the initial visit was 64.7±9.4 years and 44.0% were females. Females were 69.2% of the informants, and the relationship was 79.1% spouse or partner, 10.6% children, 4.1% were siblings and 6.2% other. The CDR PLUS NACC-FTLD scores were affected by informant characteristics. The CDR PLUS NACC-FTLD scores were 0.41 (CI 95%:0.08 to 0.75) higher with female informants. The frequency of visits was associated with a CDR PLUS NACC-FTLD score 0.86 higher (CI 95%:0.17 to 0.56) when visiting at least once a week, 1.46 higher (CI 95%:0.46 to 2.47) when visiting daily, and 0.83 higher (CI 95%:0.06 to 1.60) when living with the patient compared with visiting less than once a week. As expected, CDR-FLTD scores increased with lower MoCA and higher NPI-Q scores. In the stratified analysis by sex, we found that female informant was associated with higher CDR PLUS NACC-FTLD scores only when patients were male. We found that the CDR PLUS NACC-FTLD is influenced by informant sex and frequency of visits in patients with FTLD-related syndromes. These results are similar to those observed in AD patients and underscore the need to recognize that informant characteristics may impact dementia severity scales.

A common neuropsychological test for assessing episodic memory is the Rey Auditory Verbal Learning Test (RAVLT), a sequence of 8 word-list learning and recall tasks (five learning trials, immediate recall of an intrusion list, short-delay and long-delay recall). There is extensive research correlating patterns of RAVLT performance with clinical dementia syndromes, but little work relating these patterns to biomarkers in early-onset dementia. Here, we analyze the relationship between patterns of tau deposition and RAVLT performance in early-onset populations. We transcribed RAVLT recordings from 249 subjects in the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS). We calculated three composite scores from scores on the individual RAVLT tasks: learning ratio, raw learning score, and recency ratio. We then performed principle components analysis (PCA) on tau measurements in 108 regions of interest, identifying five components accounting for 90.9% of the variance. We entered RAVLT composite scores as dependent variables in a series of linear regression models. The PCA components, along with diagnostic syndrome and nuisance variables (age, sex, education), were entered as independent variables. Principal component 1 loaded positively in all ROIs in both hemispheres, with weaker loadings in the motor strip, occipital region, and subcortical nuclei. Principal component 5 loaded positively on left > right temporal lobes and white matter. These two were significant predictors of both learning ratio and raw learning score, showing that an increase in tau affects the performance of these RAVLT metrics. Loadings for principal component 4 were more complex, but in general were positive in the right > left hemisphere, including parietal lobes and superior temporal gyri, with negative loadings elsewhere in the temporal lobes. This component was a significant predictor of recency ratio. In all cases, regression coefficients were negative, indicating that tau within ROIs with positive loadings was negatively correlated with the memory score in question. RAVLT measures are sensitive to the effects of tau deposition in early-onset Alzheimer’s disease. Further work is needed to evaluate these scores as predictors of specific forms of pathology in early-onset dementia.

We evaluated the sensitivity of a novel score, derived from automatically transcribed verbal fluency (VF) tasks, in distinguishing individuals who later develop cognitive impairment from those who do not. We used longitudinal Six-Item Screener (SIS) evaluations to identify case and control subjects from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) dataset. Cases of Incident Cognitive Impairment (ICI) were defined as individuals with at least one normal SIS score (> 4) followed by an unbroken series of abnormal scores (<= 4). Controls were defined as those who never failed the SIS. Because we wished to assess the potential prognostic value of a novel VF score, we examined VF word lists along with the number of days before conversion (for ICI) and days to censoring (for controls). Subjects who had a stroke were excluded. We automatically transcribed animal and letter VF tasks and applied a coarse automatic correction to the transcriptions by selecting only valid words contained in a corpus of manually transcribed VF tasks. For each transcription, we obtained a word list embedding using a sentence transformers library for Python. We fit a mixed-effects Cox proportional hazards model with ICI and number of days to convert (or censor) as the outcome, using a centroid-based impairment score derived from the embeddings, raw score, and demographic covariates as independent variables. For animal fluency, we had 2,076 case observations and 36,299 control observations. For letter fluency, we had 1,399 case observations and 24,736 control observations. For both animal and letter fluency analyses, our novel vector-based scores were significant predictors (animal: β=5.45, p <0.05; letter: β=5.50, p <0.01) for future ICI after controlling for demographics and VF raw score. Both VF raw scores were significant as well (animal: β=-0.03, p <0.001; letter: β=-0.03, p <0.05). Sentence transformers offer a straightforward and unbiased method for converting a VF word list into a vector representation containing prognostically relevant information beyond that afforded by raw scores. Future work will assess the predictive value of this additional information.

The eye often reflects changes seen in the brain in neurodegenerative diseases. This study sought to examine the relationship of retinal vasculature measured using optical coherence tomography angiography (OCTA) with temporal lobe neurodegeneration, and cerebral amyloid and tau deposition, in older adults along the Alzheimer’s disease (AD) continuum. Participants included 13 cognitively normal subjects, 5 with subjective cognitive decline (SCD), 7 with cognitive impairment (mild cognitive impairment [MCI] and AD) from the Indiana Memory and Aging Study at the Indiana ADRC. Participants were excluded from the study if they had significant eye disease determined to interfere with OCTA, non-AD dementia, or exclusion for MRI or PET. OCTA scans were obtained from each eye to measure retinal vessel density and perfusion density. MRI scans were processed using Freesurfer v6 to measure medial (MTL) and lateral temporal lobe (LTL) volumes. LTL SUVR values were extracted from [18F]flortaucipir PET scans. Finally, the association between retinal perfusion and vessel density with hippocampal volume, MTL tau, and lateral parietal amyloid was assessed using a partial Pearson correlation, covaried for age, sex, and diagnosis. p<0.05 was considered significant. Retinal vessel and perfusion density were decreased in patients with AD. The right and left hippocampal volume were significantly correlated with retinal vessel density and perfusion density in the right eye and left hippocampal volume was correlated with vessel density in the left eye, but it did not reach significance. The retinal vessel density and perfusion density in the right eye correlated significantly with lateral parietal lobe amyloid and medial temporal lobe tau. Finally, the total gray matter volume correlated significantly with the retinal vessel density and perfusion density in the right eye and inversely with the foveal avascular zone in the right eye. Retinal perfusion and vessel density correlates with hippocampal atrophy, and general atrophy of the gray matter. It is also significantly correlated with the deposition of amyloid and tau in the brain. Imaging the retinal vasculature may represent a useful biomarker to screen patients at risk for AD prior to more invasive and prolonged testing.

Agitation is a clinically significant symptom contributing to behavioral and psychological symptoms of dementia (BPSD) but is poorly understood across the different syndromes related to Frontotemporal Lobar Degeneration (FTLD). This study investigates sex differences in agitation across FTLD-related syndromes and its relationship to various neuropsychiatric symptoms (NPS). We analyzed data from 1,654 participants (916 males, 738 females; average ages 65.8 and 65.9, respectively) from the National Alzheimer's Coordinating Center (NACC) and ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study with a FTLD-related syndrome: behavioral variant FTD (bvFTD), Primary Progressive Aphasia (non-fluent variant (nfvPPA), semantic variant (svPPA)), Corticobasal syndrome (CBS) and Progressive Supranuclear Palsy (PSP). Participants’ symptoms were assessed using the Neuropsychiatric Inventory (NPI). Prevalence ratios and odds ratios were computed to assess the likelihood of NPS comorbidities when agitation was present in males and females. Principal Component Analysis (PCA) was performed to identify NPS associated with agitation and how they varied by sex. Males were more likely to experience anxiety (bvFTD: p  <0.001, CBS: p  <0.01, PSP: p  <0.0001), apathy (nfvPPA: p  <0.01, PSP: p  <0.01), depression (bvFTD: p  <0.0001, PSP<0.01), disinhibition (nfvPPA: p  <0.0001), PSP: p  <0.001), and motor symptoms (bvFTD: p  <0.01, CBS: p  <0.01) when agitation was present. In contrast, females had a higher likelihood of experiencing disinhibition in svPPA ( p  <0.001). These findings suggest that agitation is associated with a wider range of NPS in males than in females. Agitation and NPS are especially prominent in males with PSP. This study reveals significant sex differences in NPS in FTLD-related syndromes when agitation is present. Males and especially PSP, are more likely to experience a broader range of NPS in association with agitation. These findings underscore the need for further investigation into the underlying mechanisms driving these sex differences, particularly focusing on the neurobiological impact of agitation, the recognition of symptoms in the presence of greater behavioral disturbances, and potential variations from informant reports. Understanding these factors will provide valuable insights into the role of agitation in the presentation of NPS across FTLD-related syndromes. Ultimately, addressing these gaps will enhance our ability to effectively treat and manage agitation in both male and female patients with FTLD-related syndromes.

INTRODUCTION:We investigated associations of plasma proteins with blood-based amyloid/tau/neurodegeneration/inflammation (A/T/N/I) biomarkers for Alzheimer's disease (AD). METHODS:Plasma proteomics and clinical data from the Indiana AD Research Center (N = 498) were used. Association analysis of plasma proteins with blood A/T/N/I biomarkers as well as diagnosis was performed, followed by replication in an independent cohort (N = 323), network analysis, pathway enrichment, and machine learning classification to identify proteins and pathways related to AD risk. RESULTS:We identified 35 proteins associated with AD, 20 of which were replicated in the independent cohort. We identified 150, 448, and 219 proteins associated with T/N/I biomarkers, respectively, revealing biomarker-specific pathways. Network analysis identified two modules associated with T/N/I biomarkers, preserved in cerebrospinal fluid (CSF), and their enriched pathways. The classification model of proteins effectively differentiated AD (area under the curve [AUC] = 0.930). CONCLUSION:Our findings suggest dysregulated plasma proteins and pathways in AD, enhancing our understanding of molecular mechanisms and diagnostic strategies for AD. HIGHLIGHTS:Plasma proteins were identified as being associated with Alzheimer's disease (AD) and plasma biomarkers. The identified proteins were replicated in both plasma and cerebrospinal fluid (CSF) proteomics. The identified proteins were associated with AD biomarker-specific pathways. The identified proteins improved the performance of the AD classification. Protein network analysis identified network modules and their enriched pathways.

INTRODUCTION:The Cognitive Change Index (CCI) is a brief questionnaire that assesses self and informant perceptions regarding cognitive function. We examined the ability of the CCI to distinguish between cognitively unimpaired (CU) older adults and those with mild cognitive impairment (MCI) or Alzheimer's disease (AD) dementia. METHODS:485 individuals from the Indiana Alzheimer's Disease Research Center (IADRC) and their study partners completed 20-item self and informant versions of the CCI. Receiver operator characteristic (ROC) curves were analyzed to assess differentiation between CU and those with impairment. RESULTS:High area under the ROC curve (AUC) values were obtained when using the self and informant CCI forms to distinguish CU individuals from those with impairment, with AUC values of 0.803 (95% confidence interval [CI] = 0.761-0.844) and 0.914 (95% CI = 0.886-0.942) for the self and informant forms, respectively. DISCUSSION:The CCI can serve as a useful screening instrument in the context of a multimodal assessment strategy for MCI and dementia. HIGHLIGHTS:Novel research that uses the Cognitive Change Index (CCI) for dementia screening. Our findings suggest that CCI can distinguish those with dementia compared to those without. These findings can be correlated to other screening instruments. Results could see the CCI play a role in early Alzheimer's disease (AD) screening and diagnosis.

INTRODUCTION:Higher adherence to the Mediterranean-DASH (Dietary Approaches to Stop Hypertension) Intervention for Neurodegenerative Delay (MIND) diet has been associated with reduced Alzheimer's disease (AD) risk. This study assessed the validity of a brief 15-item MIND diet screener compared to a comprehensive food frequency questionnaire (FFQ). METHODS:The validity of an adapted MIND diet screener relative to the VioScreen FFQ was evaluated in 92 older adults from the Indiana Alzheimer's Disease Research Center (IADRC). Correlation coefficients and tertile-based classification statistics were used, and FFQ nutrient profiles were examined across screener-based MIND diet tertiles. RESULTS:MIND diet scores from the screener showed strong positive correlation (r = 0.71, ρ = 0.70, p < 0.001) and comparable ranking ability (63% correctly classified, 1% grossly misclassified, kw = 0.67) compared to those from the FFQ, as well as significant associations with nutrient profiles. CONCLUSION:The MIND diet screener is an acceptable, time-efficient tool for estimating MIND diet scores in older adults. HIGHLIGHTS:The MIND diet screener effectively differentiated participants by diet quality. Agreement between instrument scores was consistent across diagnostic groups. Reliability of the screener over approximately 1 year was comparable to the FFQ. The MIND diet screener is an acceptable tool for use in time-constrained settings. Future studies should confirm validity using objective biomarkers.

Abstract Objective To contrast longitudinal patterns of functional decline between groups of cognitively impaired individuals with or without biomarker support for Alzheimer’s disease (ad). Method We requested data from the National Alzheimer’s Coordinating Center on individuals who underwent serial evaluation with the Functional Activities Questionnaire (FAQ) and those for whom cerebrospinal fluid biomarkers for ad were available. By cross-referencing the two datasets, we identified 570 subjects, 71 of whom were biomarker positive and 499 biomarker negative. Item-level FAQ item-level scores were then entered as predictor variables into lagged mixed-effects regression models with a single FAQ item as the dependent variable in each model (one model for each of the ten FAQ items). Coefficients for statistically significant predictors of follow-up FAQ items were plotted as arcs on a directed graph, with one vertex for each of the ten FAQ items. We repeated this process for biomarker positive and negative individuals and created a map depicting effect size differences, i.e., biomarker positive minus biomarker-negative regression coefficients (Δ = β + − β-) for statistically significant arcs (α = 0.05). Results Twelve out of 21 arcs that were significant in the biomarker-positive individuals were significant only for this group. The largest effect size difference was STOVE → STOVE (Δ = 0.233). Twenty of 29 arcs that were significant in the biomarker-negative individuals were significant only for this group. The largest effect size difference was GAMES → GAMES (Δ = −0.168). Conclusion ad biomarker status modulated the patterns of longitudinal functional change in this sample.

BACKGROUND:Predictors have not been determined of serum brain-derived neurotrophic factor (BDNF) levels among patients with heart failure (HF). OBJECTIVE:The primary purpose was to evaluate history of atrial fibrillation, age, gender, and left ventricular ejection fraction as predictors of serum BDNF levels at baseline, 10 weeks, and 4 and 8 months after baseline among patients with HF. METHODS:This study was a retrospective cohort analyses of 241 patients with HF. Data were retrieved from the patients' health records (coded history of atrial fibrillation, left ventricular ejection fraction), self-report (age, gender), and serum BDNF. Linear multiple regression analyses were conducted. RESULTS:One hundred three patients (42.7%) had a history of atrial fibrillation. History of atrial fibrillation was a significant predictor of serum BDNF levels at baseline (β = -0.16, P = .016), 4 months (β = -0.21, P = .005), and 8 months (β = -0.19, P = .015). Older age was a significant predictor at 10 weeks (β = -0.17, P = .017) and 4 months (β = -0.15, P = .046). CONCLUSIONS:Prospective studies are needed to validate these results. Clinicians need to assess patients with HF for atrial fibrillation and include treatment of it in management plans.

Amyloid-β (Aβ) and tau proteins accumulate within distinct neuronal systems in Alzheimer’s disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aβ and tau pathologies than others, gene expression may play a role. We study the association between brain-wide gene expression profiles and regional vulnerability to Aβ (gene-to-Aβ associations) and tau (gene-to-tau associations) pathologies by leveraging two large independent AD cohorts. We identify AD susceptibility genes and gene modules in a gene co-expression network with expression profiles specifically related to regional vulnerability to Aβ and tau pathologies in AD. In addition, we identify distinct biochemical pathways associated with the gene-to-Aβ and the gene-to-tau associations. These findings may explain the discordance between regional Aβ and tau pathologies. Finally, we propose an analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations.

BackgroundCognitive dysfunction predicts mortality in heart failure (HF). Computerized cognitive training (CCT) has shown preliminary efficacy in improving cognitive function. However, the relationship between CCT and mortality is unclear. Aims were to evaluate (1) long-term efficacy of CCT in reducing 24-month mortality and (2) age, HF severity, global cognition, memory, working memory, depressive symptoms, and health-related quality of life as predictors of 24-month mortality among patients with HF.MethodsIn this prospective longitudinal study, 142 patients enrolled in a 3-arm randomized controlled trial were followed for 24 months. Logistic regression was used to achieve the aims.ResultsAcross 24 months, 16 patients died (CCT, 8.3%; control groups, 12.8%). Computerized cognitive training did not predict 24-month mortality (odds ratio [OR], 0.65). Older age (OR, 1.08), worse global cognition (OR, 0.73), memory (OR, 0.81), and depressive symptoms (OR, 1.10) at baseline predicted 24-month mortality.ConclusionsEfficacious interventions are needed to improve global cognition, memory, and depressive symptoms and reduce mortality in HF.

The Rey Auditory Verbal Learning Test (RAVLT) is a neuropsychological test used for assessing episodic memory impairment. The sequence of the RAVLT consists of five learning trials, an intrusion list recall, a subsequent recall (short delay), and a delayed recall (approximately thirty minutes after the short delay recall). The RAVLT has been studied extensively in various presentations of dementia, but there is limited research for early-onset Alzheimer’s disease (EOAD). We analyze the influence of amyloid and diagnostic syndrome on traditional and novel RAVLT scores in EOAD. We transcribed RAVLT recordings from 303 subjects in the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS). Subjects were group by amyloid status (control/EOnonAD vs EOAD) and syndrome: posterior cortical atrophy (PCA), primary progressive aphasia (PPA), amnestic, and non-amnestic presentations. The traditional method of scoring the RAVLT is to count the total number of correct words recalled for each task (i.e., raw score). Two other count-based scores were calculated by examining serial position effects (SPEs). SPEs describe the tendencies to remember words in the beginning (primacy) or end (recency) of the list. A relational SPE score, known as J-curve, is examined here and is defined as primacy minus recency. Three timing-based scores were analyzed: duration, stopping time, and speed. The seven scores were entered separately into linear mixed effects models as dependent variables. Amyloid status, syndrome, and nuisance variables (age, sex, education) were entered as independent variables. Compared with amyloid-negative subjects, amyloid-positive subjects showed negative effects on raw score, primacy and recency. The presence of amyloid increased stopping time by 5%. Duration and speed were not found to be associated with amyloid. Significant differences among clinical syndromes were observed with recency, duration, and stopping time. RAVLT measures are sensitive to the effects of amyloid and syndrome in early-onset dementia. Stopping time is a novel score that may complement existing measures for describing amyloid-positive individuals. Further work is needed to quantify the predictive value of these scores.