6-months Of Low-and Moderate-intensity Supervised Exercise Is Associated With Improved Cognition In Healthy Older Adults

Medicine & Science in Sports & Exercise · 2025-09-16

PURPOSE: Memory decline is an early indicator of cognitive impairment in aging adults, and research suggests regular exercise participation may help preserve memory function. This randomized clinical trial (NCT03727360) aimed to determine the effects of a 6-month supervised exercise intervention on cognitive function, particularly memory, in cognitively healthy and physically inactive older adults aged 60-89 years. METHOD: One hundred and six cognitively intact older adults were randomized into an experimental group (n = 55) and a control group (n = 51). Both groups participated in a progressive online group exercise regimen, beginning with 30-minute sessions twice a week and gradually increasing the frequency, duration, and intensity over 7 weeks to reach 60-minute sessions 4 times a week. The experimental group exercised at a higher intensity (80% of maximal heart rate). Cognitive function was assessed at baseline (BL) and after the 6-month (6 M) intervention using the Rey Auditory Verbal Learning Test (RAVLT) for memory and the Delis-Kaplan Executive Function System (D-KEFS) for executive function. Physical fitness was evaluated at each time point using 6-minute walk and graded exercise tests. Linear mixed effects models with TIME (BL vs. 6 M) and CONDITION (Experimental vs. Control) as fixed factors were employed to detect changes in memory and fitness from baseline to follow-up. RESULTS: There were no significant changes in the 6-minute walk or VO2max tests, but cognitive performance improved significantly across both groups. Notably, participants demonstrated substantial gains in the RAVLT (sum of trials 1-5) (df = 104, t = 2.09, p = 0.039) and D-KEFS free sorting task (df = 93.375, t = 3.462, p < 0.001). CONCLUSION: These findings suggest that a 6-month supervised exercise program can significantly enhance memory and executive function in healthy older adults, even in the absence of measurable improvements in fitness. Regular, structured exercise may be valuable to support cognitive health and potentially delay age-related cognitive decline. Supported by: NIH-NIA R01AG057552

<i>APOE, ABCA7</i> , and <i>RASGEF1C</i> are associated with earlier onset of amyloid deposition from more than 4000 harmonized positron emission tomography images

Alzheimer s & Dementia · 2025-12-01

INTRODUCTION: New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes. METHODS: Harmonized amyloid PET data from 4216 participants were used in genome-wide survival, tissue-specific gene expression, and genetic covariance analyses of EAOA. RESULTS: Variants in apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7, associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7, which was associated with increased amyloid pathology at autopsy. Multiple immune-related diseases shared genetic covariance with EAOA. DISCUSSION: APOE, ABCA7, and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue-specific expression analyses, offering insights into intervenable targets at early stages of AD. HIGHLIGHTS: Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue-specific expression analyses.

Lifetime risk and projected burden of dementia

Nature Medicine · 2025-01-13 · 100 citations

Predicting future cognitive impairment in preclinical Alzheimer’s disease using amyloid PET and MRI: a multisite machine learning study

medRxiv · 2025-10-17

Abstract Predicting the likelihood of developing Alzheimer’s disease (AD) dementia in at-risk individuals is important for the design of and optimal recruitment for clinical trials of disease-modifying therapies. Machine learning (ML) has been shown to excel in this task; however, there remains a lack of models developed specifically for the preclinical AD population, who display early signs of abnormal brain amyloidosis but remain cognitively unimpaired. Here, we trained and evaluated ML classifiers to predict whether individuals with preclinical AD will progress to mild cognitive impairment or dementia within multiple fixed time windows, ranging from one to five years. Models were trained on regional imaging features extracted from amyloid positron emission tomography and magnetic resonance imaging pooled across seven independent sites and from two amyloid radiotracers ([ 18 F]-florbetapir and [ 11 C]-Pittsburgh-compound-B). Out-of-sample generalizability was evaluated via a leave-one-site-out and leave-one-tracer-out cross-validation. Classifiers achieved an out-of-sample receiver operating characteristic area-under-the-curve of 0.66 or greater when applied to all except one hold-out sites and 0.72 or greater when applied to each hold-out radiotracer. Additionally, when applying our models in a retroactive cohort enrichment analysis on A4 clinical trial data, we observed increased statistical power of detecting differences in amyloid accumulation between placebo and treatment arms after enrichment by ML stratifications. As emerging investigations of new disease-modifying therapies for AD increasingly focus on asymptomatic, preclinical populations, our findings underscore the potential applicability of ML-based patient stratification for recruiting more homogeneous cohorts and improving statistical power for detecting treatment effects for future clinical trials. Highlights Machine learning can predict future cognitive impairment in preclinical Alzheimer’s Models achieved high out-of-sample ROC-AUC on external sites and PET tracers Models were able to distinguish cognitively stable from decliners in the A4 cohort ML cohort enrichment enhanced secondary treatment effect detection in the A4 cohort

Tau <scp>PET</scp> Burden Is Associated With Hippocampal Microstructure and Episodic Memory in Amyloid Positive Older Adults

Hippocampus · 2025-09-29 · 1 citations

Growing evidence suggests that hippocampal gray matter microstructure, assessed through diffusion-weighted imaging (DWI), is a sensitive marker of neurodegeneration in Alzheimer's disease (AD). While hippocampal atrophy is a characteristic feature of AD, microstructural changes likely precede macrostructural changes such as volumetric loss, offering important insights into the early phases of the disease. This study assessed the relationships between hippocampal microstructure (assessed with mean diffusivity [MD] from DWI) and Braak-staged tau burden (measured by positron emission tomography [PET]) with performance on an episodic memory composite score, among individuals with and without amyloid burden, assessed by PET imaging. The study included 192 participants without dementia (14 with mild cognitive impairment [MCI]) from the BIOCARD cohort (mean age = 68), of which 52 (27%) were amyloid positive. In multiple linear regression analyses, increased hippocampal MD was associated with worse memory and greater tau PET burden in Braak stages II-IV, but only in individuals who were amyloid positive (e.g., significant amyloid × hippocampal MD interactions). Building on prior findings linking early Braak-staged tau to memory, we further assessed whether tau PET burden statistically mediated the relationship between elevated hippocampal MD and poorer memory performance. Tau PET burden in Braak stages II-IV was found to statistically mediate the relationship between elevated hippocampal MD and poorer memory performance, independent of hippocampal volume, but only in amyloid-positive participants. These associations were only significant when MCI participants were included in the analysis. These findings suggest hippocampal microstructure may be sensitive to AD-related pathological burden and associated neurodegeneration, particularly in the early symptomatic phase, and is associated with tau PET and cognitive decline, even after accounting for hippocampal volume.

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer’s disease

Genome biology · 2025-07-17 · 12 citations

BACKGROUND: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. RESULTS: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). CONCLUSIONS: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.

MULti‐TImepoint VElocity‐selective Reconciled with Spatially‐sElective (MULTIVERSE) ASL: Improving robustness to both shortened and prolonged arterial transit time

Magnetic Resonance in Medicine · 2025-05-19

PURPOSE: To improve the quantification of existing multi-timepoint arterial spin labeling (ASL) methods in estimating cerebral blood flow (CBF) and arterial transit time (ATT) for a wider range of ATTs. METHODS: MULti-TImepoint VElocity-selective Reconciled with Spatially-sElective (MULTIVERSE) ASL utilizes multi-delay pseudo-continuous (PC) ASL and velocity-selective (VS) ASL with spatially defined bolus, and joint fitting to estimate CBF and ATT. Numerical simulations were performed to evaluate the accuracy and precision of single-delay and multi-delay PCASL and VSASL, as well as the proposed MULTIVERSE ASL, in quantifying CBF and ATT across an extended range of ATTs. The CBF and ATT estimates between multi-delay PCASL, VSASL, and MULTIVERSE ASL were compared across healthy volunteers. RESULTS: Numerical simulations showed that the utility of MULTIVERSE ASL improved the accuracy and precision over an extended ATT range of up to 4000 ms. In vivo scans from healthy subjects demonstrated that MULTIVERSE ASL led to reduced uncertainty in CBF and ATT quantification compared to multi-post-labeling delay PCASL while maintaining comparable repeatability. CONCLUSION: This novel and straightforward approach improves the accuracy and precision of the fitted CBF and ATT over an extended range of ATT, which is not possible with existing ASL methods. Brain scans from healthy subjects demonstrated the feasibility and reliability of the technique, highlighting the clinical potential of ASL-based perfusion mapping in various altered physiological and pathological conditions.

Proper Name Recall as an Early Indicator of Preclinical Alzheimer Disease Pathology

Alzheimer Disease & Associated Disorders · 2025-10-01 · 1 citations

BACKGROUND: Early detection of Alzheimer disease (AD) is crucial; however, standard neuropsychological tests often lack sensitivity. Process scores, such as proper name (PN) recall from Logical Memory, may improve the detection of AD-related biomarker positivity. We examined whether baseline PN recall predicted future cerebrospinal fluid (CSF) amyloid (Aβ42/Aβ40) and tau (pTau 181 ) status, and whether biomarker status predicted PN recall trajectories. METHODS: We analyzed 271 cognitively unimpaired BIOCARD participants (mean age=57.3, 60.3% female, mean follow-up=15.5) using logistic regression and mixed-effects models to examine the associations between PN recall and CSF biomarkers. RESULTS: Higher baseline PN recall predicted lower amyloid positivity [odds ratio (OR)=0.72, P =0.015]. Amyloid and tau positivity have been linked to a faster decline in PN. Biomarker-positive participants in the biomarker-negative group lacked practice effects. CONCLUSIONS: PN recall predicts future AD biomarker positivity and may enhance early detection of AD-related cognitive decline.

The role of venous hemodynamics in cerebral small vessel disease

Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition · 2025-09-16

Motivation: Post-mortem studies suggested that vascular cognitive impairment and dementia (VCID) are more strongly related to small vein abnormalities than to arteriolosclerosis. However, few studies have investigated the relationship between venous dysfunction and VCID in vivo. Goal(s): To study the role of venous hemodynamics in cerebral small vessel disease (CSVD). Approach: VICTR MRI was applied to patients with CSVD-related VCID to measure venous transit time (VTT) and venous cerebral blood volume (vCBV). Associations with imaging and clinical features were studied. Results: Patients with longer VTT and larger vCBV were associated with more extensive white matter hyperintensities and greater vascular risks, particularly hypertension and diabetes. Impact: Venous hemodynamics such as transit time and blood volume are associated with white matter hyperintensity and vascular risks. These measures may be useful as imaging markers to characterize venous abnormalities in cerebral small vessel disease.

Independent Associations Of Sleep And Physical Activity With Cognition Are Mediated By Hippocampal Microstructure In Middle-aged And Older Adults

Medicine & Science in Sports & Exercise · 2025-09-16

PURPOSE: Better sleep and higher physical activity levels are both associated with improved cognitive performance in older adults at heightened risk of cognitive impairment; however, the neural mechanisms that support these relationships remain poorly understood. Medial temporal lobe (MTL) microstructural integrity, measurable through diffusion imaging, may serve as an earlier and more sensitive indicator of neurodegenerative processes than MTL volume or visible atrophy. METHODS: This study investigated cross-sectional associations of actigraphic estimates of physical activity and sleep with cognition and diffusion imaging-based measures of MTL microstructural integrity in dementia free adults. Participants were 132 older adults from the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD) cohort study (119 cognitively unimpaired and 13 with mild cognitive impairment; mean age = 70.8 years). Multiple linear regression analyses assessed the relationships between total volume of physical activity (TVPA), total sleep time (TST), and sleep efficiency (SE) with cognitive performance and MTL microstructural integrity, adjusting for age, sex, education, diagnostic status, vascular risk, APOE-e4 status, MTL volume, and Alzheimer’s pathology. RESULTS: Results showed that greater TVPA and SE were both independently associated with higher hippocampal microstructural integrity (indicated by lower mean diffusivity; β = -.256, p = .002 and β = -.247, p = .002, respectively) and enhanced visuospatial processing (β = .212, p = .015 and β = .233, p = .007, respectively), independent of hippocampal volume and amyloid-beta (Aβ) burden measured by Positron Emission Tomography. Moreover, hippocampal microstructure mediated the relationships between physical activity and sleep with visuospatial abilities (indirect effect 95% CI [.007, .131] for physical activity and [.006, .121] for sleep), independent of MTL volume and Aβ burden. CONCLUSIONS: These findings suggest that physical activity and sleep are independently associated with cognitive performance, and that hippocampal microstructural integrity may be an underlying mechanism supporting these associations independent of structural atrophy and Alzheimer's pathology burden. Supported by: This work was supported by the National Institutes of Health [grant numbers U19-AG033655, P30-AG005146].