Recent technical advances in peripheral blood analysis have enabled precise quantification of Alzheimer´s Disease (AD) biomarkers in the early stages of the AD continuum, in an economical, non-invasive and safe manner. The main objective of this study was to contribute to the clinical-biological characterization of the initial stages of cognitive impairment by measurement of blood and neurostructural AD biomarkers in groups of participants classified according to their cognitive clinical phenotype. Plasma concentrations of p-tau217, p-tau181, total tau, neurofilament light chain and amyloid-β 42/40 ratio biomarkers were measured along with APOE gene variants, hippocampal volume and cortical thickness of the AD signature regions. The cohort of 329 participants included Cognitively Unimpaired (CU), Subjective Cognitive Decline (SCD), single-domain amnestic Mild Cognitive Impairment (sd-aMCI), multidomain aMCI (md-aMCI), and single-domain non-amnestic MCI (sd-naMCI) groups. P-tau217 concentrations were significantly higher in the md-aMCI and sd-aMCI groups than in the CU, SCD and sd-naMCI groups. P-tau181 concentrations were significantly higher in md-aMCI group than in CU, SCD and sd-naMCI groups. Hippocampal volume and AD signature cortical thickness were significantly lower in the md-aMCI group than in the CU, SCD and sd-naMCI groups. No across group differences were found in the distribution of carriers/non-carriers of APOE-ε4. Mediation analysis revealed that hippocampal volume and AD signature cortical thickness mediated the relationship between p-tau217 and p-tau181 levels and cognitive performance. Sd-aMCI and md-aMCI represent two distinct and sequential clinical-biological stages of the AD continuum. Conversely, sd-naMCI does not appear to be associated with AD pathology. Finally, the SCD group does not seem to display a higher risk of progression along the AD continuum than the CU group.

Hippocampal subfields and psychotic symptoms: Functional connectivity insights from pediatric bipolar disorder.

BackgroundIn late‐onset AD, β‐amyloid (Aβ) deposition is associated with limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC), beginning in the amygdala and spreading to the hippocampus and neocortex. The association in Down syndrome (DS) remains unexamined. People with DS are genetically predisposed to early AD, with Aβ accumulation occurring at younger ages. This study investigates the relationship between Aβ deposition and postmortem volumes or neuropathologic changes in DS and late‐onset AD.MethodsDemographic and clinical diagnoses—cognitively stable (CS), mild cognitive impairment (MCI), and dementia—were collected from the Alzheimer Biomarker Consortium – Down Syndrome (ABC‐DS) and Pittsburgh Alzheimer's Disease Research Center (ADRC). Results of Aβ PET scans with 11C‐Pittsburgh compound B and 18F‐florbetapir were expressed in centiloids. Amygdala and hippocampus were manually segmented from postmortem ex vivo 7‐tesla MRI. Histopathology included Thal phase, Braak NFT stage, CERAD score, LATE‐NC stage, hippocampal sclerosis, Lewy body stage, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. T‐tests, linear regressions, and ANCOVA were performed to compare cohorts, examine associations between Aβ and MRI or neuropathology metrics, and compare regression slopes of two cohorts.ResultsThe ABC‐DS cohort showed similar Aβ PET burden but had a lower prevalence of ApoE4 carriers, younger age at clinical diagnosis and autopsy, shorter PET‐autopsy interval, smaller amygdala and hippocampal volumes, more advanced CERAD scores, and no atherosclerosis compared to ADRC cohort (Figure 1). In our existing datasets, the association between age at PET scan and Aβ burden did not reach statistical significance likely due to limited sample size. Antemortem Aβ burden was not associated with postmortem amygdala or hippocampal volumes in either group (Figure 2). Higher Aβ burden was associated with advanced LATE‐NC stage in ABC‐DS but not in ADRC. In ADRC, Aβ burden correlated with postmortem Aβ plaque, neurofibrillary tangles, and neuritic plaques, while no significant associations were found in ABC‐DS for Thal phase, Braak NFT stage, or CERAD score (Figure 3).ConclusionsIn DS, antemortem Aβ PET burden is associated with advanced LATE‐NC stage but not with postmortem amygdala or hippocampal volumes. In ADRC cohort, Aβ burden correlates with postmortem amyloid plaque, neurofibrillary tangle, and neuritic plaque pathology.

BackgroundNeurological manifestations in individuals with Long COVID range from headaches to cognitive impairment and mental health issues. However, it remains unclear whether these individuals exhibit structural changes, functional changes, or both in the brain. In this study, we investigated the impact of Long COVID on mental health symptoms, cortical grey matter volume and thickness, and hippocampal volume in Brazilian individuals.MethodIndividuals were divided into two groups based on Long COVID status: covid (symptoms of Long COVID) and control (No symptoms of Long COVID). Simultaneously, PHQ‐9 and GAD‐7 tests were applied on participants to evaluate severity of depression and generalized anxiety symptoms, respectively. Brain magnetic resonance imaging (MRI) of individuals presenting with Long COVID (n = 58) and of healthy control individuals (n = 21) were used for extracting volume and cortical thickness (CT) of regions of interest using FreeSurfer (v7.4.1). We performed an ANCOVA analysis and a linear regression to assess the difference between groups in PHQ‐9, GAD‐7, mean cortical thickness (CT), mean hippocampal volume, and total cortical grey matter volume. The data were corrected for age, sex, and years of formal education.ResultThe Long Covid group presented significantly lower scores on PHQ‐9 and GAD‐7 than the control group (Beta = 6.20017 and 3.3105; p <0,001 and p <0,006, respectively). However, when comparing Long covid and control groups, we found no significant differences in the mean hippocampal volume (p = 0,831) and in the mean cortical grey matter volume (p = 0.193).ConclusionThese preliminary data indicate significant changes in mental health among individuals with Long Covid; however, these changes do not correspond to observable alterations in brain volume as seen in MRI scans. This suggests that the pathophysiological changes associated with these symptoms are likely functional and metabolic in nature rather than structural and may not be detectable through imaging studies that primarily focus on brain anatomy, such as MRI.

BackgroundMicroglia can take on proinflammatory or anti‐inflammatory phenotypes, but it is unclear how these phenotypes play out along the Alzheimer's disease (AD) continuum. The purpose was to assess regional variances of microglial activation in distinct stages of the disease, and the role of microglial responses on grey matter volume and mean diffusivity in different brain areas and on cognition across the course of AD.Method48 subjects (23 AD patients, 14 mild cognitive impairment [MCI], and 11 healthy controls [HC]) underwent TSPO‐PET, diffusion tensor imaging (DTI) and extensive neuropsychometric assessment. SPM (Statistical parametric mapping) analysis was conducted for single subject analysis. GM volume for each subject was derived from T1 volumetric MRI using the FreeSurfer pipeline, mean diffusivity (DTI), alongside voxel‐based morphometric analysis. Using postmortem brain tissue from 26 AD subjects, we evaluated CD32a and CD163 anti‐bodies, markers of proinflammatory and anti‐inflammatory microglia, respectively.ResultVoxel‐wise analyses identified positive and negative clusters of associations for IRF90 with GM volume and mean diffusivity. The presence of pro‐ and anti‐inflammatory phenotypes was confirmed in human postmortem brain, in the frontal, parietal and entorhinal cortices. In addition, higher TSPO, signal in temporal lobes associated with lower hippocampal volume and mean diffusivity, and higher TSPO, signal across the cortex, correlated with poorer performance on neuropsychometric tests.ConclusionThere may be protective and deleterious microglial phenotypes in an individual, region specific and disease stage dependent. Therapeutic modulation of microglia is warranted to promote anti‐inflammatory functions while suppressing pro‐inflammatory functions.

BackgroundChronic pain affects one in five older adults and is linked to increased risk for Alzheimer's disease (AD) dementia. Few studies have investigated associations between chronic pain and AD biomarkers, especially chronic pain at moderate‐to‐severe levels considered clinically significant.MethodWe included 2487 participants without baseline dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI). At baseline, participants were categorized by absence/presence of moderate‐to‐severe chronic pain, defined as persistent/recurring pain with onset >3 months prior. For sensitivity analyses, we categorized people based on the absence/presence of chronic pain at mild levels. Cognitive outcomes included the Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB), episodic memory, and executive function (minimal n = 1328, mean follow‐up‐years=1.49, SD=2.78). AD biomarkers included cerebrospinal fluid levels of Aβ42, total tau, and phosphorylated tau (minimal n = 1057, mean follow‐up‐years = .53, SD=1.24); and structural MRI (AD structural brain signature, hippocampal volume, entorhinal cortical thickness, and whole brain volume, minimal n = 2136, mean follow‐up‐years=1.11, SD=2.28). Mixed‐effects models assessed differences in baseline levels and change in each outcome between pain groups, and mediation analyses explored Aβ and neurodegeneration pathways. Covariates included baseline age, sex, APOE ε4 status, depressive symptoms, and opioid use (intracranial volume for structural MRI outcomes).ResultModerate‐to‐severe chronic pain relative to mild or none was associated with accelerated decline in global cognition (increase in CDR‐SB: b = .05), memory, executive function (b=‐.04), and whole brain volume (b=‐.02), and faster accumulation of Aβ pathology (CSF Aβ42 decline: b=‐.07, all p's < .05). It was not associated with neurodegeneration in AD brain signature regions, hippocampal volume, or entorhinal cortex (all ps > .05). Accumulation of Aβ pathology (absolute b's range = .03 to .05) and whole brain volume loss (absolute b's range = .001‐.002) mediated associations of moderate‐to‐severe chronic pain with cognitive decline, with Aβ also mediating moderate‐to‐severe chronic pain's association with brain volume loss (b=‐.01, all ps < .05). Mild chronic pain relative to none did not significantly relate to cognitive or biomarker outcomes (all ps > .05).ConclusionModerate‐to‐severe chronic pain contributes to accelerated cognitive decline and general neurodegeneration, primarily via Aβ. These findings highlight the need to consider moderate‐to‐severe chronic pain, rather than just presence/absence of chronic pain in AD risk assessments and interventions.

BackgroundPrior evidence suggests that neocortical tau in those with higher β‐amyloid (Aβ) may be the main driver of Alzheimer's disease (AD)‐related neurodegeneration leading to insidious cognitive decline and ultimately a diagnosis of AD dementia. Resistance to the ‘spread’ of neocortical tau pathology from localized medial temporal (MTL) regions can be defined as individuals having lower neocortical tau than expected given their individual characteristics, such as demographics and Aβ burden. We examined associations between resistance to neocortical tau pathology and various markers of AD pathology, cognitive performance, and brain reserve.MethodWe calculated tau resistance using our published inverse learning method (Figure 1B), which estimates the deviation away from a model trained on an expectation sample (278 Aβ‐PET+ older adults with high neocortical tau‐PET (PVC_SUVRcomposite:inferior temporal/inferior parietal/fusiform/middle temporal) burden based on Gaussian Mixture Modeling;Figure 2A). We ran a series of linear regression models on the remaining 1,374 older adults pooled from the Harvard Aging Brain Study (HABS), ADNI, and A4/LEARN (Demographics in Figure 1A). We examined associations between tau resistance and 1) MTL tau‐PET (PVC_SUVRcomposite; entorhinal/amygdala/parahippocampal), 2) measures of brain reserve (hippocampal volume and entorhinal cortical thickness), 3) neocortical Aβ‐PET burden (Centiloids), 4) an interaction between MTL tau and Aβ‐PET, and 5) cognitive performance (PACC). All models adjusted for age, sex, education, cohort, and APOEε4.ResultsLower MTL tau, lower Aβ, and younger age were significantly associated with higher neocortical tau resistance (βMTL=‐0.22(0.06), p < 0.001, Figure 2B; βAβ=‐0.13(0.03), p <0.001Figure 2C;βAge=‐0.62(0.02), p < 0.001). Higher PACC, greater hippocampal volume and thicker entorhinal cortices were associated with lower resistance (βPACC=‐0.29(0.02), p < 0.001, Figure 2D;βHV=‐0.10(0.03), p < 0.001, βEC_thickness=‐0.14(0.03), p < 0.001). Greater Aβ and MTL tau burden interacted to influence lower resistance (Figure 3). In a sample limited to Aβ+ (N = 537), we found only lower PACC and younger age significantly associated with tau resistance.ConclusionThese findings suggest that baseline levels of MTL tau and age play a role in resisting the advancement of tauopathy into neocortical brain regions, and might be mediated by Aβ in early disease stages. The counter‐intuitive association with cognition and brain reserve measures implies that tau resistance is most likely represented by those with greater cognitive impairment and lower reserve, as neocortical tau burden is much lower in clinically‐normal older adults.

BackgroundVitamin B12 is known to influence cognitive functioning potentially through the influence on the serum levels of homocysteine. There is a dearth of data assessing the association of Vitamin B12 and Homocysteine with MRI brain volumes and cognitive performance in the rural Indian population.MethodWe used baseline cross‐sectional of the non‐demented (Clinical Dementia Rating, CDR score<1) participants aged 45+ years (n = 2784) from the CBR‐SANSCOG (Centre for Brain Research‐Srinivaspura Aging NeuroSenescence and COGnition) study cohort. Cognitive performance was assessed using Hindi Mental State Examination (HMSE) test and the culturally adapted computerized COGNITO (Computerized assessment of adult Information processing) battery. The domain‐specific (attention, memory, language, visuospatial ability) cognitive scores were standardized and a composite score was calculated from the weighted averages of the individual test scores. General linear model was used to assess the association between serum vitamin B12, homocysteine levels and the cognitive performance adjusting for age, sex, education, tobacco, alcohol use, hypertension, diabetes, and depression. Using 3T MRI, Region of Interest (ROI) based‐analysis was done to study the association between vitamin B12, homocysteine, and MRI brain volumes normalized for total intracranial volume (n = 1268), adjusting for age, sex, and education.ResultA total of 36.5%, 34.3%, and 29.3% of the participants had deficient (<200pg/ml), insufficient (200‐300pg/ml), and sufficient vitamin B12 (>300pg/ml) levels, respectively, whereas 56% and 44% had normal (5‐15µmol/l) and high (>15µmol/l) levels of homocysteine, respectively. No association was found between vitamin B12 and the cognitive performance tests or any brain volumes. Increasing homocysteine levels were associated with decreasing scores on HMSE [β=‐0.02,(‐0.03,‐0.01), p = 0.02], visual attention [β=‐0.01,(‐0.02,‐0.00), p = 0.02] and hippocampal volume [β=‐0.01,(‐0.01,‐0.00), p = 0.02]. Homocysteine did not have a mediating effect between vitaminB12 and cognitive performance or any of the brain volumes.ConclusionIncreasing serum homocysteine levels were negatively associated with cognitive performance irrespective of serum vitamin B12 levels in this rural aging Indian population. Therefore, early screening for serum homocysteine could potentially flag individuals at risk for cognitive impairment and thereby, contribute to developing a multimodal composite biomarker for early detection of cognitive impairment.

BackgroundIn neurodegenerative diseases causing dementia, hippocampal atrophy can lead to cognitive decline and emotional dysregulation. Sleep is crucial for memory consolidation and emotional regulation, with the hippocampus being fundamental in forming episodic emotional memories. The Neuropsychiatric Inventory (NPI) evaluates behavioural symptoms like apathy and aberrant behaviors, while the Pittsburgh Sleep Quality Index (PSQI) assesses sleep quality. This study examined correlations between hippocampal volumes with NPI and PSQI scores in patients with neurodegenerative disease.MethodStudy participant data was obtained retrospectively from the Sunnybrook Dementia Study (SDS) and the Ontario Neurodegenerative Disease Research Initiative (ONDRI). A standardized neuroimaging pipeline was used to measure hippocampal atrophy using HippMapp3r, whole brain atrophy was estimated using the brain parenchymal fraction (BPF), and cerebral small vessel disease was derived from white matter hyperintensity volumes (WMH). NPI and PSQI scores were collected during patient visits. Linear regression and correlation analyses examined associations between hippocampal volumes with NPI and PSQI while controlling for age, sex, education, BPF, and WMH.ResultIn the SDS cohort, partial correlations (N = 297) revealed a negative relationship between hippocampal volumes and NPI‐Aberrant scores (ρ=‐0.13, p = 0.029). Regression models (N = 1027) showed hippocampal volumes were negatively associated with NPI‐Apathy scores (β=‐0.085, p = 0.007). In the ONDRI cohort, hippocampal volumes correlated with poorer perceived sleep quality in both the Alzheimer's disease/mild cognitive impairment (ADMCI: N=215, ρ=0.26, p <0.0001) and cerebrovascular disease (CVD: N=331, ρ=0.17, p = 0.002) groups. Smaller hippocampal volumes were correlated with longer sleep duration in the Alzheimer's disease/mild cognitive impairment (ADMCI) group (N=211, ρ=‐0.33, p <0.0001). There was no significant correlation between hippocampal volume and NPI‐apathy scores in ONDRI. Aberrant behaviour was not assessed in ONDRI's NPI‐Q, and PSQI measures were not available in SDS.ConclusionHippocampal atrophy in neurodegenerative diseases may be related to increased apathy, aberrant behaviours, and altered sleep patterns. These findings suggest that diminished hippocampal volumes may impair emotional regulation and introduce compensatory sleep quality mechanisms. Future studies on neurodegenerative diseases with neuroimaging should include full measures of apathy and aberrant behaviour, as well as more objective sleep quality measures (polysomnography or wrist actigraphy) to further explore important relationships with brain atrophy.

BackgroundCognitive decline is a hallmark of aging and neurodegenerative diseases, including Alzheimer's disease, and is considered a cornerstone of early identification efforts. Previous studies have reported that cognitive decline is associated with structural changes in the brain, functional impairment (FAQ), and mood alterations (GDS). However, understanding the combined predictive power of structural changes in the brain, functional impairment (FAQ), and mood alterations (GDS) is critical for identifying their roles as determinants of cognitive decline, thereby improving early detection and targeted interventions.MethodWe analyzed data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify predictors of cognitive decline using the Montreal Cognitive Assessment (MoCA), a tool that evaluates multiple cognitive domains, in participants with a score ≥4 (n = 312). The dependent variable, cognitive change, was quantified as the beta coefficient obtained from the regression analysis of MoCA scores over time (4+ time points). LASSO regression evaluated the baseline relationships between hippocampal volume (HIPPO), functional abilities (FAQ), and depressive symptoms (GDS), with 5‐fold cross‐validation to minimize overfitting. The model was trained on 80% of the data and evaluated on 20% using Mean Squared Error (MSE), Mean Absolute Error (MAE), and R2.ResultIn predicting cognitive trajectories (COGN), the LASSO regression model achieved R2=0.51R^2 = 0.51R2=0.51 on the test set, explaining 51% of the variance in cognitive decline. FAQ accounted for the largest proportion of the explained variance (86.2%), followed by HIPPO (7.7%) and GDS (6.0%). These findings highlight the dominant role of functional abilities (FAQ) in predicting cognitive decline, with depressive symptoms (GDS) and hippocampal volume (HIPPO) contributing minimally.ConclusionThe current findings demonstrate that baseline functional and emotional measures can predict future cognitive decline, with functional difficulties (FAQ) contributing the most, followed by depressive symptoms (GDS), and hippocampal volume (HIPPO). These results suggest that functional and emotional measures vary alongside cognitive decline, with neuroimaging offering complementary insights when combined with behavioral evaluations for early detection.

BackgroundMild behavioural impairment (MBI), characterized by the onset of irreversible neuropsychiatric symptoms is the prodromal stage to cognitive decline seen in older adults. MBI may also show comorbid presentation in individuals with mild cognitive impairment (MCI). The relationship between hippocampal subfield volumes and MBI has yet to be established in the context of MCI. This preliminary study thus aimed to identify the bilateral hippocampal subfield volumes directly associated with MBI and to examine the interactive effects of a diagnosis of MCI on these associations.Method313 cognitively‐normal (CN) (56.0 ± 8.08 years old; 33.5% male) and 293 MCI (63.1 ± 8.66 years old; 42.3% male) individuals were recruited from the Biomarkers and Cognition Study, Singapore (BIOCIS). Participants underwent 3T T1‐weighted MRI scans and data was processed using Freesurfer software ver 7.2. Participants were administered the Mild Behavioural Impairment Checklist (MBI‐C). Impairment in each of the five subdomains (interest, impulse, mood, social and beliefs) was defined as the presence or absence of at least one symptom within each subdomain. Logistic regression modelling was applied to examine the main and interactive effects of diagnosis and subfield volumes. Age, sex, education years and total intracranial volume were controlled for.ResultInterest subdomain impairment was associated with lower right parasubiculum volume, with no significant interactive effects of diagnosis. Mood subdomain impairment was associated with lower left parasubiculum volume. The interactive effect of diagnosis however inversed this relationship. Mood subdomain impairment was also associated with lower left CA3 body volume and this effect remained consistent with the interactive effect of diagnosis. Social subdomain impairment was associated with lower left hippocampal tail volume. The interactive effect of diagnosis however inversed this relationship. Beliefs subdomain impairment was associated with higher right hippocampal fissure volume. The interactive effect of diagnosis inversed this relationship.ConclusionOverall, atrophy in various hippocampal subfields is associated with the specific, individual MBIC subdomains, and these associations may differ across clinical diagnoses.

BackgroundPoor sleep is linked to higher risk of Alzheimer's Disease (AD), yet its relationship with AD‐related biomarkers is not fully understood. This study aimed to examine associations between objective sleep characteristics and three AD‐related magnetic resonance imaging (MRI) biomarkers in a diverse cohort of community‐dwelling older adults.MethodThe Dormir Study recruited participants aged 50 and older enrolled in the ongoing Health and Aging Brain Study‐Health Disparities (HABS‐HD) cohort. Sleep characteristics were objectively measured using 7‐day wrist actigraphy, capturing nighttime sleep duration, total time in bed (TIB), sleep efficiency (SE), wake after sleep onset (WASO) time, average awakening length, and sleep fragmentation index. AD‐related MRI biomarkers included mean hippocampal volume, AD‐signature cortical thickness, and white matter hyperintensity (WMH) volume. We performed multivariable linear regressions adjusting for age, sex, race/ethnicity, education, cognitive status, body mass index, smoking, alcohol consumption, and MRI scanners. We reported results using coefficient per 1‐standard deviation increase in the continuous sleep exposures.ResultWe examined 703 participants (mean age 66.4±8.4 years, 65.6% women), including 164 (23.3%) Black, 223 (31.7%) Hispanic, and 316 (45.0%) Non‐Hispanic White individuals. Seventy‐nine (11%) had nighttime sleep duration<6 hours, 462 (66%) had 6‐8 hours, and 162 (23%) had >8 hours. After multivariable adjustment, nighttime sleep duration>8 hours [β = ‐0.16, 95% confidence interval (CI) ‐0.32, ‐0.002; compared to participants who slept 6‐8 hours], longer TIB (β = ‐0.12, 95%CI ‐0.19, ‐0.05), WASO (β = ‐0.08, 95%CI ‐0.15, ‐0.01), and awakening length (β = ‐0.10, 95%CI ‐0.17, ‐0.03) were associated with smaller hippocampal volume. Similar patterns were observed for nighttime sleep duration>8 hours (β = ‐0.23, 95%CI ‐0.41, ‐0.04), longer TIB (β = ‐0.09, 95% CI ‐0.17, ‐0.02) and awakening length (β = ‐0.12, 95% CI ‐0.20, ‐0.04) with thinner cortex in AD‐signature regions, but not for other sleep characteristics. No associations were found between sleep characteristics with WMH volume.ConclusionNighttime sleep duration>8 hours and poor sleep quality, including longer TIB, WASO, and awakening length, were associated with worse AD‐related MRI patterns among diverse community‐dwelling older adults. Future longitudinal studies are warranted to validate the pathophysiological mechanisms underlying those sleep‐AD associations.

BackgroundAlzheimer's disease (AD) cases often present with TDP‐43 inclusions at autopsy, suggesting comorbid Limbic‐predominant Age‐related TDP‐43 Encephalopathy (LATE). These patients show smaller hippocampal volume and more severe cognitive decline than ‘pure’ AD patients. Distinguishing the contributions of both pathologies to neurodegeneration is crucial for treatment development; but is challenging as both pathologies affect the medial temporal lobe (MTL), share similar clinical symptoms and there is no in‐vivo biomarker for TDP‐43. We aimed to disentangle the relative contribution of tau and TDP‐43 pathologies to the atrophy of MTL substructures in AD patients.MethodsWe conduced antemortem cross‐sectional and longitudinal MRI analyses in participants with neuropathological data obtained at post‐mortem. Participants were selected from the ADNI database (N = 85) and grouped according to Braak stages (Low tau [0‐III] or High Tau [IV‐VI]) and the presence of TDP‐43 in the MTL. Statistical analyses included cross‐sectional correlations, group analyses, and liner‐mixed models predicting volume changes before death. All models were adjusted for MRI‐death‐interval, age, sex and intracranial‐volume.ResultsTDP‐43 was mostly associated with the volume of the hippocampal head (R = ‐0.47; P < 0.01, Figure 1) while NFTs were associated with the thickness of the parahippocampal gryrus (PHG; R = ‐0.41; P < 0.01, Figure 1). Consistently, among individuals with low levels of tau, TDP‐43‐positivity was associated with atrophy in all MTL structures except the parahippocampal cortex (PHC, Figure 2). In contrast, in TDP‐43‐negative individuals, high tau was associated with atrophy in the hippocampal body (β = ‐137mm3, P < 0.05), entorhinal cortex (β = ‐0.49mm, P < 0.01) and PHC (β = ‐0.28mm, P < 0.01, Figure 2). Longitudinal analysis showed that the hippocampal head volume reduction over time was faster in the presence of TDP‐43 in the MTL (β = ‐6.71mm3/year, P < 0.001, Figure 3) while the PHG thickness reduction over time was faster with higher Braak stages (β = ‐0.02mm/year, P < 0.05, Figure 3).ConclusionWe observed an anterior‐posterior effect of TDP‐43 and tau on the MTL with TDP‐43 affecting anterior MTL volumes and tau posterior MTL volumes. Hippocampal head atrophy could help distinguish between AD patients with/without comorbid LATE.

BackgroundRepetitive head impacts (RHI) in athletes, especially those involved in contact sports, have been associated with white matter hyperintensities (WMH), markers of small vessel disease, and neurodegeneration 1, 2, 3, 4. This study investigates the relationships between concussion history, vascular risk factors, and WMH volume, as well as their associations with cognitive outcomes in athletes with RHI.MethodThis cross‐sectional study included 96 male professional contact sports athletes enrolled in the Canadian Concussion Centre's concussion monitoring program and 21 male controls without a history of concussion. WMH volumes were quantified from T2‐weighted FLAIR magnetic resonance imaging using automated segmentation. Vascular risk factors were assessed via questionnaires. Cognitive function was evaluated with standardized neuropsychological tests, and composite scores for memory and executive function were derived using normative data for both athletes and controls. All analyses controlled for age. Linear regression models evaluated associations between concussion history (treated as a continuous variable), WMH volume, cognitive performance, and vascular risk factors.ResultAthletes had significantly greater WMH volume than controls (median 1.3 ml vs. 0.8 ml, p = 0.024), although the difference was insignificant when normalized to total intracranial volume. Age was the strongest predictor of WMH volume (β = 0.3851, p < 0.001) and was associated with reduced hippocampal (right: β = ‐0.012, p < 0.001; left: β = ‐0.011, p = 0.001) and amygdala volumes (right: β = ‐0.003, p = 0.003; left: β = ‐0.004, p = 0.003). Concussion history was associated with declines in executive function (β = ‐0.0244, p = 0.034) and memory (β = ‐0.0539, p = 0.027) but not with WMH volume. Vascular risk factors were not significantly associated with WMH or cognitive outcomes.ConclusionAthletes with RHI demonstrated higher WMH volume than controls, mainly driven by age rather than concussion history or vascular risk factors. Concussion history was associated with cognitive impairments in executive function and memory, emphasizing the importance of cognitive monitoring in aging athletes and the need for longitudinal studies to explore the interplay between RHI, aging, cognition, and neurodegeneration.

Assessing whether grip strength is associated with cognitive decline and brain health could help identify a target to prevent or delay cognitive impairment. Therefore, we tested whether grip strength is associated with brain health as indicated by magnetic resonance imaging and domain specific cognitive decline. We also assessed whether grip strength was a cognitive resilience proxy using moderation tests. This study included cognitive and neuroimaging data from 861 participants in three harmonized cohorts. We fit multivariable linear mixed-effects and linear regression models to test associations between grip strength, neuroimaging markers, and cognition. We also tested moderation by gender and age. Greater grip strength was associated with slower verbal episodic memory decline and greater total gray matter volume. Associations of grip strength with executive function, total hippocampal volume, and white matter hyperintensities were not significant, but in the expected direction. Age moderated associations of grip strength and white matter hyperintensities. Grip strength was a significant proxy for cognitive resilience related to white matter hyperintensity volume and verbal episodic memory decline only. Future research should examine other measures of physical performance that are associated with later-life cognitive and brain health.

Background:Existing literature has shown inconsistencies in the effects of exercise on hippocampal volume. Considering that including individuals without hippocampal atrophy may affect the significance of the results, this study systematically included older adults with preclinical hippocampal atrophy and patients diagnosed with neurodegenerative diseases associated with hippocampal atrophy. Using a meta-analysis approach, it aims to: quantify the effect of exercise intervention on hippocampal volume in high-risk older adults, and identify the moderating factors influencing intervention efficacy.Methods:Databases including Embase, Ebsco, Cochrane Library, PubMed, and Web of Science were systematically searched. Two reviewers used the Cochrane Risk of Bias tool for quality assessment, and statistical analyses were performed using Manager 5.4 software. Sensitivity analyses were conducted via leave-one-out analysis and Stata 16 software to evaluate result robustness. Potential publication bias was assessed using funnel plot asymmetry and Begg test.Results:Database searches identified 2066 studies, and 12 studies (774 participants) met the inclusion criteria after screening. The primary analysis showed no statistically significant effect of exercise intervention on hippocampal volume in older adults (SMD = 0.09, 95% CI: −0.05 to 0.22, P = .20). Subgroup analyses across the time span of exercise intervention, exercise modality, maximum target exercise intensity, health/disease grouping, left/right hippocampus grouping, and maximum duration of single-target exercise also showed no statistically significant effects (all P > .05).Conclusion:Current evidence does not support exercise intervention as an independent therapeutic modality for increasing hippocampal volume in older adults.

Background: Metabolic syndrome (MetS) is linked to brain degeneration and Alzheimer’s disease (AD). Women, especially during menopausal transition, show increased susceptibility to AD-related brain changes. This study investigated the sex-specific neurostructural impact of MetS on brain regions vulnerable to AD. Methods: This cross-sectional study analyzed data from 500 participants (303 women, 197 men) from the Baependi Heart Study cohort, Brazil. High-resolution T1-weighted MRI scans were used for volumetric analysis of AD-related regions of interest (ROIs). Non-parametric quantile regression models compared ROI volumes between MetS and Non-MetS groups, stratified by sex and age (median split), adjusting for age and education. Results: No significant differences in ROI volume were observed between the MetS and Non-MetS groups in men. In women, findings were age-dependent. The younger cohort (≤48 years) with MetS exhibited significantly smaller left hippocampal volume (p = 0.02) and a trend toward smaller left middle temporal gyrus volume (p = 0.05) compared to Non-MetS. The older cohort (>48 years) with MetS showed a significantly larger right amygdala volume (p < 0.001). Furthermore, age-related volume decline in the hippocampus and middle temporal gyrus was significant in Non-MetS women but not in women with MetS, suggesting that MetS may be a confounding factor in age-related neurodegeneration. Conclusions: MetS is associated with sex-specific alterations in AD-vulnerable brain structures. In women, MetS may influence medial temporal lobe atrophy pre-menopause, and is linked to amygdala enlargement post-menopause. These exploratory results generate the hypothesis that MetS may uniquely predispose women to AD-related neurodegeneration, which requires critical longitudinal confirmation.

ImportanceAlzheimer disease biomarkers in cognitively unimpaired older adults are associated with later cognitive and clinical decline, yet substantial heterogeneity in the timing and rate of decline remains insufficiently characterized.ObjectiveTo identify subgroups of cognitive decline among biomarker-defined cognitively unimpaired adults and determine baseline predictors of heterogeneity in preclinical Alzheimer disease progression.Design, Setting, and ParticipantsLongitudinal data were drawn from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Study, which enrolled amyloid-positive participants, and the parallel LEARN Study, which enrolled amyloid-negative individuals meeting all other A4 criteria. Participants completed baseline amyloid PET, plasma P-tau217, structural MRI, and serial cognitive assessments. Latent Class Mixed-Effects Models (LCMMs) were used to identify distinct cognitive trajectory classes. Associations between class membership and demographic, clinical, and biomarker characteristics were evaluated.Main Outcomes and MeasuresThe primary outcome was longitudinal change in the Preclinical Alzheimer’s Cognitive Composite (PACC).ResultsThree cognitive trajectory classes were identified: stable, slow decliners, and fast decliners. Higher plasma P-tau217, smaller hippocampal volume, and elevated tau PET were associated with greater odds of belonging to declining classes. Among amyloid-positive individuals, approximately 70% were classified as stable over the observed follow-up interval.Conclusions and RelevanceLatent class modeling reveals marked heterogeneity in preclinical cognitive trajectories, even among individuals with biomarker evidence of Alzheimer pathology. The high proportion of stable individuals is consistent with the long presymptomatic interval. Identifying subgroups of decline may improve prognostic modeling and guide enrichment strategies for precision secondary prevention trials.

Appetite loss is a non-motor symptom in amyotrophic lateral sclerosis (ALS) linked to poorer prognosis. While the hippocampus regulates "meal memory", a key cognitive modulator of eating behavior, its structural role in ALS-related appetite loss is unknown. To determine if hippocampal subfield integrity influences appetite dysregulation in ALS and to evaluate the strength of neuroanatomical versus demographic factors. Cross-sectional secondary analysis. Thirty-two patients with ALS (mean age: 58.97 ± 8.91 years; 24 males) and 22 non-neurodegenerative controls (NNDc) (mean age: 53.86 ± 9.98 years; 16 males). 3T; 3D T1-weighted magnetization-prepared rapid gradient-echo (MP2RAGE) and 3D T2-weighted turbo spin-echo (T2-SPACE) sequences. Appetite was measured using the Council on Nutrition Appetite Questionnaire (CNAQ). Hippocampal subfield volumes (CA1, CA2/3, CA4/DG, stratum radiatum/lacunosum/moleculare [SRLM], subiculum) and asymmetry indices were segmented from T1w and T2w images using the HIPS automated pipeline. Analysis of Covariance (ANCOVA) (adjusting for age, sex, body mass index (BMI), total intracranial volume (TIV), and subfield volumes/asymmetry) and hierarchical multiple regression analyses were used. Significance was set at p < 0.05. Patients with ALS (adjusted mean: 29.51 ± 0.53) had significantly lower adjusted CNAQ scores compared to controls (adjusted mean: 31.98 ± 0.66; mean difference: -2.47, partial η2 = 0.195). In the ANCOVA model, left SRLM volume was the only significant neuroanatomical covariate (F [1, 30] = 6.45, partial η2 = 0.177). However, hierarchical regression revealed that age was the only consistent independent predictor of CNAQ scores (B = -0.158), explaining the largest variance (ΔR2 = 0.165). Hippocampal volumes and asymmetry did not remain significant predictors after adjusting for age (left SRLM: p = 0.853; SRLM asymmetry: p = 0.868). Appetite loss is a non-motor symptom in ALS. While associated with lower left SRLM volume at the group level, appetite decline is more robustly and independently associated with advancing age. 3. 3.

The aquaporin-4 (AQP4) water channel plays an integral role in clearing brain waste. However, little is known about whether variations in the AQP4 gene contributes to brain health or dementia risk. We aimed to determine whether a functional AQP4 haplotype was associated with cognition, brain volumes, or incident dementia. This study included participants from two prospective cohort studies. Firstly, participants from the Original, Offspring, New Offspring Spouse, and Generation 3 cohorts from the Framingham Heart Study (FHS; enrolled 1948-2005) were included with dementia follow-up until 2022. Original FHS participants were from Framingham, Massachusetts at the time of enrollment. Analyses were replicated for brain MRI outcomes and incident dementia with UK Biobank participants (enrolled 2006-2010) who were followed until 2022. All participants were dementia-free at the time of cognitive assessment, brain MRI, and commencement of dementia follow-up. Linear regression models were conducted to analyze the associations between AQP4 and the cognitive and brain MRI outcomes. Cox proportional hazard regression models were conducted to analyze the association between AQP4 and incident all-cause dementia risk. Data analysis spanned February 2023 to July 2025. The FHS sample comprised 3,847 participants (65% homozygote major, 31% heterozygote, 4% homozygote minor) with cognitive testing (mean age 61±11 years; 54% women); 3,332 had brain MRI. Heterozygotes displayed better verbal episodic memory (β[95% CI], 0.32 [0.09, 0.55], p =0.007, N=1,201) and larger hippocampal volumes (β[95% CI], 0.09 [0.02, 0.16], p =0.012, N=1,052) compared to homozygote majors. Similar findings were observed in the UK Biobank; homozygote minors displayed larger hippocampal volumes (β[95% CI], 0.05 [<0.01, 0.11], p =0.035, N=32,219) and lower amounts of DTI measured free water (β[95% CI], -0.09 [-0.16, - 0.03], p =0.005, N=31,807) compared to homozygote majors. Heterozygotes displayed a statistically significant lower rate of incident all-cause dementia (HR=0.93, 95% CI [0.88, 0.98], p =0.012, N=114,868, incident cases=5,625) compared to homozygote majors. Carrying at least one minor allele at an AQP4 haplotype (homozygote minors or heterozygotes) was linked to better verbal episodic memory, larger hippocampal volumes, lower amounts of free water, and lower dementia risk. Further studies are required to replicate these results amongst diverse samples.