Cognitive impairments in Parkinson's disease (PD) often emerge alongside motor symptoms, yet most clinical assessments examine these domains separately. This mixed-design study explores the utility of a virtual reality-based Color Trails Test (VR-CTT) as an integrated, immersive tool to assess motor-cognitive interaction in PD. Twenty-three individuals with PD (ON medication) and twenty-three age- and education-matched healthy controls completed both the standard pen-and-paper CTT and the VR-CTT, which preserves the same cognitive demands while introducing an upper-limb motor component through full-arm reaching to virtual targets. As expected, individuals with PD were slower and less accurate across both formats. However, we observed only moderate-to-low correlations between completion times in the two CTTs, thus suggesting that the VR-CTT may capture distinct and ecologically valid aspects of motor-cognitive performance. Indeed, kinematic analysis revealed longer head-hand coordination delays and reduced maximal execution velocities in PD, pointing to subtle, yet specific motor difficulties during cognitive tasks. Beyond confirming feasibility, these results highlight the VR-CTT's potential as a novel tool for identifying motor-cognitive dysfunction and informing targeted rehabilitation strategies. Its immersive nature and multi-competency format position it as a promising intervention platform for cognitive-motor training in PD and related disorders.

OBJECTIVE:Intraindividual cognitive variability (IICV) is a promising measure for early identification of dementia risk. Fewer studies have assessed IICV using high-frequency digital cognitive assessment or in populations with medical conditions. We aimed to characterize associations between IICV for reaction time and accuracy with plasma biomarkers of neurodegeneration (phosphorylated tau 181, phosphorylated tau 217, β-amyloid 42/40 ratio, glial fibrillary acidic protein, and neurofilament light chain) in individuals with Type 1 diabetes. METHOD:We analyzed data from 114 participants from the Glycemic Variability and Fluctuations in Cognitive Status in Adults With Type 1 Diabetes study who provided blood samples (M = 48.9 years, range = 19-84). Cognition was assessed digitally at baseline and three times daily for 15 days via ecological momentary assessment. Hierarchical linear regression models examined associations between biomarkers and IICV, adjusting for demographics, glycemic variability, mean cognition, and nephropathy. Multiple testing correction used Benjamini-Hochberg. RESULTS:IICVs for reaction time at baseline and across repeated assessments were correlated and associated with β-amyloid 42/40, glial fibrillary acidic protein, neurofilament light chain, and phosphorylated tau 217 (small to moderate effect size, p < .05), but associations did not remain significant after adjustment. Exploratory analyses indicated interactions with age and sex. IICV for accuracy was not associated with any biomarker. CONCLUSIONS:Although associations between IICV and plasma biomarkers were not robust after full adjustment, exploratory analyses suggested potential interactions with age and sex. The sample was predominantly non-Hispanic White, limiting the generalizability of our findings. These findings support continued investigation of digital IICV as a dynamic marker of early cognitive vulnerability. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

AIMS:Type 1 diabetes (T1D) is associated with an increased risk of Alzheimer's disease and related dementias (AD/ADRD), although mechanisms remain unclear. This study examined the relationships between blood-based biomarkers of ADRD, diabetes-related factors, and glycemia in adults with T1D. METHODS:This study analyzed 114 adults from the Glycemic Variability and Fluctuations in Cognitive Status in Adults with Type 1 Diabetes (GluCog) Study with available plasma samples. Regression models assessed relationships between biomarkers (Aβ42/Aβ40 ratio, GFAP, NfL, pTau181, pTau217), diabetes characteristics, and continuous glucose monitoring metrics (up to 20 days), adjusting for demographics and kidney disease. False discovery rate (FDR) correction was applied. RESULTS:Lower Aβ42/Aβ40 ratios were associated with older age of T1D diagnosis and higher NfL concentrations with higher mean glucose, lower glucose time in range, more time spent with glucose above 180 and 250 mg/dL, higher HbA1c, neuropathy, and diabetic ketoacidosis. These remained significant after additional adjustment for kidney disease, although residual confounding by renal function cannot be excluded. CONCLUSIONS:Higher NfL was linked with multiple measures of hyperglycemia and other diabetes-related complications, consistent with neuronal injury rather than suggesting an ADRD-specific process. Longitudinal studies are needed to clarify the mechanisms between NfL and glycemia in T1D.

The APOE4 allele significantly increases Alzheimer's disease (AD) risk, often linked to brain lipid imbalance. This study investigated lipid profiles in the brain parenchyma and brain blood vessels (BBV) of APOE3 and APOE4-humanized female mice, assessing the protective effects of an alpha-linolenic acid (ALA)-rich diet on lipid composition and memory in APOE4 mice. Mice received either a Control or an ALA-rich flaxseed oil diet for 6 months. Lipid profiles were analyzed in brain parenchyma, BBV, plasma, and liver, alongside memory performance. In vitro studies explored human brain endothelial cell conversion of ALA to docosahexaenoic acid (DHA). APOE4 mice, compared to APOE3 controls, exhibited significant lipid depletion in brain parenchyma, including reduced cholesterol (32%), phospholipids (10%), and DHA (57%). The ALA-rich diet beneficially restored lipid levels in APOE4 brain parenchyma, increased DHA-containing phospholipids, and improved memory. This diet also elevated n-3 fatty acids and DHA within the BBV, particularly in APOE4 phosphatidylserine, and upregulated lipid-related genes (PLA2, LDLR). In vitro data confirmed that brain endothelial cells synthesize DHA via the ∆6-desaturase pathway, a process suppressed by desaturase inhibitors or external DHA. Collectively, these findings suggest the BBV acts as a crucial hub for lipid homeostasis. An ALA-rich diet effectively mitigates lipid imbalance in APOE4 mice by promoting lipid unsaturation, enhancing DHA synthesis and its incorporation into complex lipids, thereby improving cognitive performance. This research positions dietary ALA as a promising nutritional intervention for APOE4 carriers.

Abstract Background Older adults frequently take both gabapentinoids and dihydropyridine calcium channel blockers (DHP-CCBs), often started years apart as new conditions emerge. A common pattern is the late addition of gabapentin to a regimen that has long included a DHP-CCB. Prior work links concurrent gabapentinoid–DHP-CCB exposure to elevated incident dementia risk, but whether the order in which the two medications are introduced matters has not been examined. We asked whether incident dementia risk differs by the order in which gabapentinoid and DHP-CCB therapy are introduced . Methods Using the Rutgers Clinical Research Data Warehouse (2018–2024) and active-comparator new-user designs with IPTW Cox models, we examined two prescribing scenarios in a hypertensive cohort: gabapentin or pregabalin added after prior DHP-CCB exposure (forward sequence; N=7,141), and a DHP-CCB or ACE inhibitor/ARB added after chronic gabapentinoid therapy (reverse sequence; N=685). Results When gabapentin was added to a regimen that already included a DHP-CCB, incident dementia risk was elevated relative to pregabalin ( IPTW HR 2.44, 95% CI 1.06–5.63, p=0.036 ). When the order was reversed — a DHP-CCB added to chronic gabapentinoid therapy — no elevated risk was observed ( IPTW HR 0.64, 95% CI 0.17– 2.39 ). Pre-specified sensitivity analyses supported the forward-sequence finding. Conclusions In hypertensive older adults, the same two medications were associated with very different dementia signals depending on which was started first: elevated risk when gabapentin was added to chronic DHP-CCB therapy, no elevated signal in the reverse direction. The two prescribing sequences may not be clinically equivalent. If replicated, this pattern would support targeted medication review at the time gabapentin is added to regimens that already include a DHP-CCB.

INTRODUCTION:Adults with Down syndrome (DS) are at risk for Alzheimer's disease (AD), yet identifying the preclinical phase remains challenging. Intraindividual cognitive variability (IICV) may be a sensitive marker of early AD-related changes but remains understudied in DS. METHODS:Adults from the Alzheimer's Biomarker Consortium-DS (ABC-DS) study (N = 460, mean age 43.3 years; 45.7% female) were included. Generalized linear models examined whether baseline IICV predicted incident mild cognitive impairment (MCI)/dementia, cognitive decline, and amyloid and tau positron emission tomography outcomes, adjusting for demographics, intellectual disability, apolipoprotein E ε4, site, assessment interval, and mean cognitive performance, with Bonferroni correction. RESULTS:Greater IICV predicted incident MCI/dementia (odds ratio = 4.63 to 5.13, p < 0.05), greater amyloid burden, early tau accumulation, and higher tau across Braak stages, independent of mean cognition. Exploratory analyses suggested sex-specific interactions with tau outcomes. DISCUSSION:IICV is a sensitive marker of dementia risk and cognitive resilience in DS, with potential utility for secondary prevention and trial enrichment.

INTRODUCTION:Amyloid beta (Aβ) can be detected in vivo years before Alzheimer's disease (AD) symptom onset and, according to recent criteria, is sufficient for a biological diagnosis. This study evaluates emotional responses to Aβ status disclosure in cognitively normal individuals. METHODS:Questionnaires were given before and 6 months after Aβ positron emission tomography results disclosure to assess anxiety and depression related to the possibility of an elevated result, subjective memory complaints, and motivation for risk-reduction behavior. RESULTS:One hundred ninety-nine cognitively normal adults were included. Non-elevated Aβ status disclosure was associated with reductions in all emotional parameters compared to baseline (p < 0.001). Elevated Aβ disclosure was associated with no changes in depression or memory complaints and a modest decrease in anxiety and motivation to change lifestyle (p < 0.048). DISCUSSION:No negative psychological effects were observed after Aβ status disclosure. Decreased motivation for lifestyle changes was seen after disclosure of both elevated and non-elevated amyloid status and should be targeted. HIGHLIGHTS:No negative psychological effects were observed after amyloid beta (Aβ) status disclosure. Motivation for lifestyle changes decreased after Aβ disclosure. Lower education may predict "unfavorable" response to non-elevated Aβ disclosure. Results support personalized communication strategies for Aβ disclosure.

Type 2 diabetes (T2D) is a recognized risk factor for dementia. This study aimed to pinpoint blood DNA methylation biomarkers for cognitive decline in older adults with T2D by comparing those who developed dementia with those who remained cognitively normal during follow-up Illumina Infinium MethylationEPIC microarray was used for the initial 24 couples and Infinium HumanMethylationEPIC microarray version 2.0 for the subsequent 8 couples. Beta and p-values were calculated using Partek genomic suite and SeSAMe for the respective microarray versions. Human CpG annotation manifests for both versions were utilized, and quantile normalization (Partek genomic suite) facilitated comparisons across different arrays. Functional analysis employed Ingenuity IPA. The analysis covered 128 samples (32 converters and 32 matched non-converters) at baseline and a 36-month follow-up. Methylation levels significantly differed between converters and non-converters, with 950 sites altered in converters versus 25 in non-converters (FDR corrected p value ≤0.05) during follow-up. To identify potential biomarkers, methylation changes unique to baseline were examined. Of the 249,490 shared methylation sites, 526 were differentially methylated between converters and non-converters at baseline (p-value ≤0.05, fold change ≥1.5). Notably, 293 sites were altered solely at baseline, while 233 showed differential methylation at both baseline and 36-months follow-up. Among the 169 genes related to the 293 sites altered only at baseline, Ingenuity IPA analysis identified 29 genes linked to neurodegeneration and cognitive impairment (17%) and 38 genes associated with inflammation (22%). Another set of interest included 137 genes related to the 233 sites differentiating converters from non-converters at both time points, with some genes implicated in neurotransmitter secretion and regulation of neuron differentiation. These initial findings indicate significant blood methylation changes early in cognitive decline among older adults with T2D. These alterations, if validated in additional cohorts, could serve as biomarkers for T2D-related cognitive decline.

INTRODUCTION:Impaired cerebrovascular reactivity (CVR) is common in type 2 diabetes (T2D) patients and is a risk factor for dementia. However, most prior functional magnetic resonance imaging (fMRI) studies in T2D disregarded the impact of impaired CVR on brain activation patterns. This study investigated the relationship between CVR and brain activation during an fMRI task in T2D patients. METHODS:Seventy-four T2D patients underwent a working-memory (WM) fMRI task. CVR was measured by the breath-holding index test using transcranial Doppler (TCD). Regression analyses examined associations between CVR and brain activation and between glycated hemoglobin (HbA1c) and activation with/without adjusting for CVR. RESULTS:An association between CVR and brain activation was found in the left middle and inferior frontal gyri. Adjusting for CVR led to a different pattern of HbA1c-related activation. DISCUSSION:The findings highlight methodological implications, emphasizing the importance of accounting for impaired CVR when analyzing and interpreting fMRI data in T2D patients. Highlights:The study found that cerebrovascular reactivity impacts brain activation patterns during a working memory task in type 2 diabetes patients.Accounting for cerebrovascular reactivity altered the brain regions showing activation related to working memory and glycemic control.The findings highlight the importance of considering vascular factors when interpreting fMRI data in populations with vascular dysfunction.

Increasing prevalence of Alzheimer’s Disease (AD) and limited pharmacological intervention benefits to decelerate early neurodegeneration have prompted exploration of non-pharmacological options. Recent studies indicate that combining cognitive-motor training enhances outcomes. In a single-blind, parallel-group, randomized controlled trial of middle-aged adults with a parental history of AD, the experimental group (N = 22) underwent training with newly developed “real-world” intensive, progressive, virtual reality (VR) tasks, while walking on a treadmill. Tasks included challenges to sustained attention, selective attention, working memory, covert rule deduction, and planning, all in daily living contexts. An active control group without treadmill (N = 17) and another group walking on a treadmill while watching scientific documentaries (N = 16) were included. A passive control group received no training (N = 11). Training sessions were 45 minutes, twice a week, for twelve weeks. The primary neurobiological outcome, cerebral blood flow (CBF), in the superior (SFG), middle (MFG) and inferior (IFG) frontal gyri and middle temporal gyrus (MTG), was assessed using MRI arterial spin labeling at 12 weeks (i.e., post training) and at 6 months (3 months follow up). Linear mixed regression models, adjusting for age, sex, education and baseline cognition, assessed group differences. Participants averaged 56.2 (SD = 5.78), were primarily female (70%) and had undergraduate education (mean = 16.4; SD = 3.12). The groups did not differ in any baseline characteristics. The interaction of group X time on CBF of the MFG was significant (p = 0.04), such that the experimental group had an increase in CBF at 3 months which then plateaued, there were no changes in CBF in the active control groups, and the passive control group had a decline in CBF (see Figure ). Similar trends were found for the SFG and IFG (p for interaction 0.07 and 0.08, respectively). No differences were found between the groups in the MTG. The sustained increase in CBF, a major contributor to cognitive functioning, observed in the frontal cortex of the experimental group over three months, implies that our innovative VR intervention may beneficially affect cerebrovascular function, even in midlife. This trend underscores the potential effectiveness of our intervention in preserving healthy cognition among asymptomatic individuals at high AD risk.

AbstractINTRODUCTIONWe developed a tool for objective quantification of apathy.METHODSParticipants (n = 97; 67 with cognitive impairment, 30 cognitively normal; mean age = 74.3 ± 6.2 years, 56.7% females) were exposed to emotional and cognitive stimuli in a virtual reality environment. Gaze metrics (time to first fixation [TTFF] and total fixation duration [TFD]) and autonomic nervous system (ANS) reactivity were measured. Apathy and depression were clinically assessed using the Lille Apathy Rating Scale short version and the Geriatric Depression Scale 15‐item version, respectively. Cutoffs of ≥ –7 and ≥ 5 were used to define apathy and depression, respectively.RESULTSThe sample comprised 14 participants with apathy only, 9 with depression only, 10 with both, 63 with neither, and 1 with missing data. For all emotional stimuli, participants with apathy only showed longer TTFF (P = 0.039, effect sizes [ES] = 0.798), and shorter TFD (P = 0.023, ES = 0.578) compared to those without apathy or depression. ANS reactivity was not associated with apathy.DISCUSSIONApathy is associated with decreased gaze engagement at emotional stimuli.Highlights Apathy measurement via questionnaires is limited by subjectivity biases. Apathy measurement via questionnaires is limited by simplistic scoring. We present a novel method for objective measurement of apathy. Gaze characteristics reflect the emotional and cognitive components of apathy.

OBJECTIVES:Depression is a chronic disorder that significantly affects functional decline in older adults, especially those with type 2 diabetes (T2D). Ethnic groups may experience different depression risks and severities, yet the effect of ethnicity on depression trajectories and specific dimensions in older adults with T2D remains largely unexamined. We examined the longitudinal associations of ethnicity with depression and its specific dimensions over time in older Ashkenazi and non-Ashkenazi Jews with T2D. DESIGN:Generalized estimating equations (GEE) models were employed to analyze the longitudinal associations of ethnicity with numbers of depressive symptoms and specific depression dimension, adjusting for sociodemographics, cognition, T2D characteristics, and cardiovascular risk factors. SETTING:Community-dwelling older adults from the longitudinal Israel Diabetes and Cognitive Decline (IDCD) study. PARTICIPANTS:902 Ashkenazi and non-Ashkenazi Jews, mean age= 72.3 years. MEASUREMENTS:The Geriatric Depression Scale-15 (GDS-15) and its five dimensions: Dysphoric Mood, Withdrawal Apathy-Lack of Vigor, Anxiety, Hopelessness, and Memory Complaint. RESULTS:At baseline, Ashkenazi Jews reported significantly lower GDS-15 scores compared to non-Ashkenazi Jews. They exhibited lower scores in Dysphoric Mood and Hopelessness dimensions. GEE models confirmed these findings, showing Ashkenazi Jews had significantly lower total GDS-15 scores (β = 0.86, 95 % CI 0.75-0.99; p = 0.03), Dysphoric Mood (β = 0.76 (0.52-0.90], p = 0.006), Hopelessness (β = 0.74 [0.58-0.95], p = 0.017) and lower rates of clinical depression (OR= 0.68 [0.52-0.90], p = 0.006). These data offered no evidence of a difference in trends between the Ashkenazi and non-Ashkenazi groups on depression trajectories. CONCLUSIONS:Ethnicity is associated with the longitudinal trajectories of depression and its specific dimensions in older adults with T2D. Further investigation of contributing factors, including social determinants of health, is essential.

We aim to describe the imaging findings in pre-symptomatic and early-symptomatic individuals carrying a recently described novel APP duplication rearrangement causing early-onset AD (EOAD). We studied individuals from one pedigree that carry APP duplication and CH 5 mutation gain that had structural and resting state functional (rs-f) brain MRI. Non-carrier family members were assessed as controls. Volumetric analysis was performed using Freesurfer and normalized to total intracranial volume. Fazekas scores for white matter hyperintensities (WMH) and microbleed count were performed visually by two neuroradiologists. rs-fMRI seed to whole brain analysis was used to create functional connectivity maps of the default mode network (DMN). F18-Flutemetamol amyloid-PET was available for two of the mutation carriers. Amyloid deposition was quantified using SUVR with the pons as reference region and compared to SUVR of young adults and amyloid-positive older adults (Ab+OA). Fourteen mutation carriers (mean age 29.8[19-39], 8 (57%) F, median education 12Y[11-14Y], mean MMSE 28[23-30]), and nine non-carrier family members were included (36.8Y[19-56Y], 5 (55%)F, 12Y[12-19], 29[27-30]). Volumetric analysis revealed an increase in amygdala volume (log) (estimate = 0.01, p = 0.03) and a (non-statistically significant) trend toward decrease in the putamen, globus pallidus, and pons volume with age in mutation carriers (Figure 1A). WMHs and microbleeds were found in some mutation carriers from the age of 28Y (Figure 1B). rs-fMRI showed a trend toward a disconnection between the anterior and the posterior component of the DMN in the APP-dup carriers >30Y (n = 6) compared with non-carrier (n = 8; U = 10, p = 0.08). Moreover, increased connectivity was found between the anterior component of the DMN and the striatum compared to carriers <30Y (n = 8, U = 9, p = 0.06) and to non-carriers (U = 9, p = 0.06) (Figure 2). Cortical amyloid deposition was high but within the range of Ab+OA, and extremely high, above the level of deposition in Ab+OA in the putamen, caudate, and thalamus (Figure 3). We found early basal ganglia abnormalities in presymptomatic and early symptomatic novel APP duplication mutation carriers, including high amyloid deposition, DMN disconnection, increased connectivity between anterior DMN and striatum, and volumetric alterations. These findings point to the basal ganglia as a region of early pathology that requires further research.

Amyloid beta (Aβ) deposition marks an early stage in the progression of Alzheimer's disease (AD), detectable in-vivo years before symptoms emerge and targeted by recently FDA-approved drugs. This has propelled advancements in understanding, measuring, and treating AD, paving the way for disease prevention in those at risk. However, the psychological impact of disclosing Aβ status to cognitively unimpaired individuals remains underexplored. Our study aimed to evaluate the behavioral responses to Aβ status disclosure in this population. Two observational studies and two clinical trials incorporating Aβ-PET were conducted, involving research participants who received information on Aβ-PET scans, results, and interpretation. Questionnaires were administered before the scan and four-to-six months post-disclosure to assess anxiety, depression, subjective memory complaints, and motivation for risk-reduction behaviors. Bivariate analysis and mixed models were employed to analyze responses, with logistic regression used to identify predictors of unfavorable responses to negative scan disclosure. Among 178 participants with amyloid-negative scans (mean age 64, 57% females) and 21 with amyloid-positive scans (mean age 77, 38% females), no significant pre-scan differences were observed. Negative amyloid disclosure correlated with reductions in all domains tested, including memory complaints, depression, anxiety, and motivation to change lifestyle (p≤0.001). Positive amyloid disclosure also resulted in decreases, particularly in anxiety and depression, albeit to a lesser extent and with greater variability (0.007<p<0.07 for pre to post PET change in amyloid positives vs. negatives). Higher education was linked to fewer memory complaints post-negative Aβ PET disclosure (Odds ratio=0.79, CI=0.65-0.97, p=0.02). In conclusion, as AD enters an era of disease-modifying and preventive treatments, understanding how cognitively normal adults respond to AD biomarker status disclosure becomes crucial. Negative amyloid results offer a comforting effect, reflected in reduced subjective memory concerns and lower anxiety, depression, and motivation for lifestyle changes. However, caution is needed to prevent false reassurance. Positive amyloid results also provide comfort, albeit to a lesser extent and with more variability. Lower education levels may predict unfavorable responses to negative amyloid disclosures.

Underlying medical conditions may explain inconsistent reports of the association between sex and dementia risk. The current study aimed to explore the association between sex and the risk of incident dementia, considering a broad range of medical conditions. This prospective national birth cohort study consisted of 53,224 members of a nonprofit health maintenance organization. Participants were born between 1922 and 1946 and entered the cohort on January 1, 2002, aged 55 to 80, without a dementia diagnosis. The cohort was followed up for 18 years to January 1, 2020. Dementia was ascertained based on medical diagnoses. Cox regression models were fitted to quantify the association between sex and the risk of incident dementia with hazard ratios (HR) and their 95

Reduced white-matter integrity, detectable before other brain imaging findings in individuals at risk for Alzheimer's disease and related disorders (ADRD), may underlie both the pathogenesis and consequences of depression. Investigating the relationship between white-matter integrity and depressive symptoms in middle-aged individuals at high risk for ADRD can provide insights into early markers of neurodegeneration. We examined 301 cognitively normal offspring (mean age 54.6±6.9 years; 59.8% female) of ADRD patients from the Israel Registry for Alzheimer's Prevention (IRAP) study. Diffusion tensor imaging (DTI) was used to assess white matter integrity through fractional anisotropy (FA) and mean diffusivity (MD). Depressive symptoms were evaluated using the Center for Epidemiological Studies-Depression (CESD) scale. Linear and logistic regression models, adjusting for age, sex, education, and the time between depression assessment and MRI acquisition, were used to analyze associations between white matter integrity and depressive symptoms. The mean CESD score was 10.9±7.8 representing sub- syndromal depression. Higher FA in the genu and cingulum adjacent to the corpus callosum was associated with lower CESD scores (β=-46.8; SE=16.5; p  = 0.005 and β=-68.2; SE=21.5; p  = 0.002, respectively) and decreased odds of clinical depression (OR [95% CI]=0.89 [0.80-0.99] and OR[95% CI]=0.86 [0.75-0.98], respectively). No significant associations were found between FA in other white matter tracts or MD measures and depressive symptoms. In cognitively normal individuals at increased ADRD risk, disrupted white matter integrity in specific tracts is associated with more depressive symptoms already in midlife. These findings highlight the potential of white matter alterations as early biomarkers of neurodegeneration, creating opportunities for timely intervention and prevention.

Background: New-generation antidiabetic medications may have therapeutic potential for dementia, beyond their glycemic effects. However, information from observational studies exploring the association between new-generation antidiabetic use and dementia risk is limited. Objectives: To examine the association between new-generation antidiabetic medication use and dementia risk. Design: Retrospective cohort study using electronic health records of a large non-profit health maintenance organization. Participants: 84,798 dementia-free individuals aged ≥65y with type 2 diabetes. Measurements: Antidiabetic medication exposure was based on purchased prescriptions and was used as a time-varying variable. Exposure periods were defined as periods in which either dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), or glucagon-like peptide-1 analogs (GLP-1a) or their combinations were used, otherwise unexposed. Dementia classification was based on the International Classification of Diseases, Ninth Revision codes or antidementia medication prescriptions. Cox regression models were fitted to quantify the association between antidiabetic medication use and incident dementia. Models were adjusted for 13 potential sources of confounding using inverse-probability weighting. Results: Among 84,798 individuals with a mean diabetes onset age of 66.4 ± 7.5 years, the median follow-up for dementia risk was 8.7 years (Q1-Q3: 5.4–12.8). Dementia was diagnosed in 11,642 (13.7%) individuals. New-generation medication use was associated with reduced dementia risk (HR = 0.69; 95% CI, 0.66–0.73) and by drug classes (DPP-4i, HR 0.67 [95% CI 0.63–0.71]; SGLT-2i, 0.63 [95% CI 0.56–0.70], GLP-1a, 0.61 [95% CI 0.54–0.69]. Conclusions: The results of this large-scale study suggest that new-generation antidiabetic medication use may be associated with lower dementia risk in older adults with T2D.

Alzheimer's disease (AD) dementia is characterized by significant molecular and phenotypic heterogeneity, which confounds its mechanistic understanding, diagnosis, and effective treatment. In this study, we harness the most comprehensive dataset of paired ante-mortem blood omics, clinical, psychological, and post-mortem brain multi-omics data and neuroimaging to extensively characterize and translate the molecular taxonomy of AD dementia to living individuals. First, utilizing a comprehensive integration of eight complementary molecular layers from brain multi-omics data (N = 1,189), we identified three distinct molecular AD dementia subtypes exhibiting strong associations with cognitive decline, sex, psychological traits, brain morphology, and characterized by specific cellular and molecular drivers involving immune, vascular, and oligodendrocyte precursor cells. Next, in a significant translational effort, we developed predictive models to convert these advanced brain-derived molecular profiles (AD dementia pseudotimes and subtypes) into blood-, MRI- and psychological traits-based markers. The translation results underscore both the promise of these models and the opportunities for further enhancement. Our findings enhance the understanding of AD heterogeneity, underscore the value of multi-scale molecular approaches for elucidating causal mechanisms, and lay the groundwork for the development of novel therapies in living persons that target multi-level brain molecular subtypes of AD dementia.

Hyperbaric oxygen therapy (HBOT) is a treatment in which oxygen-enriched air (up to 100%) is administered to patients in a chamber at a pressure above one atmosphere absolute and is approved for the treatment of T2D ischemic wounds. Type 2 diabetes (T2D) is a risk factor for dementia. Ischemia due to vascular pathology is hypothesized to be an underlying mechanism for this association. Evidence small clinical trials suggests that HBOT improves hypoxic/ischemic brain injuries, consequently inducing brain angiogenesis, leading to cognitive improvement. We have conducted a double blind, placebo controlled, clinical trial on brain and cognitive outcomes in elderly with T2D and mild cognitive impairment (MCI) to compare the effects of HBOT vs. sham. This analysis reports the baseline characteristics of those recruited. A total of 155 participants, comprising 69% males (mean age 71.26) and 31% females (mean age 70.23), met the eligibility criteria to commence hyperbaric oxygen therapy (HBOT) with a Total Clinical Dementia Rating (CDR) of 0.5, Mini-Mental State Examination (MMSE) score greater than 23, and no contraindications for HBOT. The average MMSE score was 28.5 for males and 28.4 for females. Beck’s Depression Inventory (BDI) revealed a mean score of 5.1 for males and 6.1 for females. Notably, 119 participants exhibited impairment in the CDR memory domain (CDR > 0) and other associated domains. Recent studies have indicated that hyperbaric oxygen therapy (HBOT) can stimulate neuroplasticity and enhance cognition in individuals recovering from strokes and traumatic brain injuries. However, the impact of HBOT on cognition in patients with Type 2 Diabetes (T2D) who are at a high risk of dementia remains to be established. The outcomes of this study, if successful, could furnish compelling evidence regarding the potential benefits of HBOT on brain function and cognition within this distinctive patient population.

Type 2 diabetes (T2D) is consistently related to an increased risk of cognitive decline and dementia. However, the molecular underpinnings of this association remain poorly understood. In this study, we applied a novel mass spectrometry-based glycoproteomic methodology to profile serum glycoproteins in older adults with T2D, aiming to identify glycopeptiforms associated with cognitive impairment. Our method allowed comprehensive profiling of N glycosylation in addition to the unique ability to profile glycation events on specific amino acid sites. Serum samples from initially cognitively normal older adults with T2D were collected, with participants classified as cognitive decliners (who developed impairment) and non-decliners (who maintained normal cognition over time). We identified significant differences in the abundance of glycopeptiforms between these groups, noting that certain glycopeptiforms exhibited unique changes over time in decliners. We identified 13 glycopeptiforms that exhibited significant differences between the groups both at baseline and in their rates of change over time. Pathway analysis indicated that glycation events were linked to metabolic pathways while glycosylation to immune-related pathways, aligning with established links between these processes and cognitive decline. This study offers new insights into glycoproteoform alterations in older adults with T2D experiencing cognitive decline. It highlights the potential of specific glycopeptiforms as biomarkers for early cognitive impairment in T2D. Further validation in larger cohorts will enhance our understanding of glycosylation and glycation in T2D and potentially lead to the discovery of novel treatment targets for T2D-related cognitive decline. Raw data and search are available via ProteomeXchange with identifier PXD050780.