MRI-derived brain aging trajectories across the Alzheimer's continuum: links to cognition, pathology and lifestyle risk factors

Sex Differences in the Alzheimer's Brain Age Gap: APOE ε4 Plays a Major Role

Sex differences in BAG across the AD continuum were largely explained by APOE {epsilon}4-related acceleration rather than by an independent effect of sex alone, which suggests that females may be more vulnerable to APOE {epsilon}4-associated structural brain aging over time.

Stage-dependent effects of cognitive reserve on memory and brain structural integrity across the spectrum from healthy aging to Alzheimer’s disease

Introduction Cognitive reserve (CR) has been proposed as a key factor explaining inter-individual variability in cognitive performance despite comparable neuropathology. However, its role across the Alzheimer’s disease (AD) continuum remains unclear. This study investigates stage-dependent effects of CR on the relationship between memory performance and brain structural network integrity across healthy subjects (HS), individuals with subjective cognitive decline (SCD), and patients with amnestic mild cognitive impairment (a-MCI), and AD dementia. Materials and methods A total of 209 participants underwent a comprehensive neuropsychological assessment and 3T MRI. Source-based morphometry identified three grey matter structural covariance networks, involving orbitofrontal-temporal-insular regions (OTIN), precuneus-posterior cingulate cortex (PreCiN), and cingulate-hippocampal regions (CHiN). A composite memory score was derived using factor analysis. Regression and moderation models examined the predictive and moderating effects of CR (operationalized as years of education) and network integrity on cognitive performance within each group. Results OTIN and PreCiN showed progressive structural vulnerability along the AD continuum, whereas CHiN showed no significant between-group differences. Across the sample, OTIN and PreCiN integrity significantly predicted cognitive performance. In HS, CR was positively associated with memory performance independently of structural network integrity, suggesting an additive protective role of cognitive reserve in healthy aging. In the SCD group, CR was not directly associated with memory, and only limited effects emerged, indicating early alterations in reserve-related processes. In a-MCI patients, the significant interaction between CR and OTIN integrity suggested patterns consistent with compensatory mechanisms, with higher reserve supporting memory despite structural decline. In AD patients, CR and its interaction with structural networks no longer predicted cognitive outcomes, suggesting a possible exhaustion of reserve capacity. Conclusion These findings support a stage-dependent model of CR, characterized by an additive protective role in healthy aging, patterns consistent with compensatory recruitment in early cognitive decline, and a possible loss of reserve effectiveness beyond a critical neuropathological threshold. Distinct network vulnerabilities and stage-specific CR effects highlight potential windows for reserve-enhancing interventions across the AD continuum.

Comparison of Brain Age With Standard MRI Assessment for Dementia Risk Stratification in Subjective and Mild Cognitive Impairment

Background and Objectives Early dementia risk-stratification is crucial for timely intervention. Brain-predicted age difference (brain-PAD) derived from structural MRI reflects the gap between computer-estimated age and chronological age and has been linked to clinical progression to dementia. We evaluate whether brain-PAD has prognostic value for progression to dementia in subjective cognitive decline (SCD) and mild cognitive impairment (MCI) and whether brain-PAD provides added value beyond visual rating scales. Methods This retrospective cohort study included patients with SCD and MCI with up to 10-year follow-up assessments from the Amsterdam Dementia Cohort and SCIENCe project. Brain-PAD was computed from baseline MRI using 2 pretrained methods. Cox proportional hazards models assessed the association between brain-PAD and risk of progression to dementia, controlling for age, sex, Mini Mental State Examination, and visual rating scales. We tested interactions between brain-PAD and baseline diagnosis to assess stage-specific value and evaluated the added value beyond amyloid status in a biomarker-available subset. Results The study included 799 patients (SCD 412, MCI 387; 39.4% female, 63.3 ± 8.0 years). During a median follow-up of 3.2 years, 235 (29.4%) progressed to dementia. Higher brain-PAD was associated with an increased risk of progression to dementia (hazard ratio [HR] 1.04, 95% CI 1.02–1.06) and improved model fit beyond visual ratings (χ2 = 12.24, p = 0.003). Following a significant interaction between brain-PAD and baseline diagnosis (p = 0.013), stratified analyses demonstrated brain-PAD was a stronger predictor in SCD (HR 1.09, 95% CI 1.03–1.15) than in MCI (HR 1.01, 95% CI 0.99–1.04). In SCD, brain-PAD improved model fit beyond visual rating scales (χ2 = 10.17, p = 0.003) and modestly increased discrimination (C-index +0.02). A data-driven brain-PAD cutoff of −2.6 years corresponded to a high negative predictive value (0.91–0.99) over 2–10 years. Although brain-PAD improved model fit beyond amyloid status (χ2 = 6.44, p = 0.018), it did not improve discrimination. In MCI, brain-PAD provided no additional value (χ2 = 0.88, p = 0.351). Discussion MRI-derived brain-PAD predicts progression to dementia in memory clinic patients with SCD or MCI. In particular, brain-PAD provided additional predictive value to visual rating scales in patients with SCD.

Blood Biomarkers of Alzheimer's Disease and Patterns of Structural Brain Changes in the Community.

In cognitively unimpaired older adults, elevated blood p-tau217 was linked to faster shrinkage in AD-specific brain regions, whereas NfL and GFAP were associated with more widespread atrophy, with NfL also associated with accelerated WMH accumulation.

Hearing in noise and cognitive status in older adults: Biomarker associations and bidirectional survival analyses.

BackgroundHearing impairment (HI) has been identified as a potentially modifiable risk factor for dementia, yet its relationship with Alzheimer's disease (AD) neuropathology and the temporal directionality remain unclear, particularly in late life.ObjectiveTo examine cross-sectional and longitudinal associations between HI, clinical cognitive status, and AD biomarkers in community-dwelling older adults.MethodsWe included 474 DRIVES Project participants (mean age 73.5 ± 5.2 years). Hearing was assessed using the NIH Toolbox Words-in-Noise (WIN) test. Clinical cognitive status was assessed using Clinical Dementia Rating (CDR). AD biomarkers included cerebrospinal fluid (CSF) Aβ42/Aβ40, t-tau/Aβ42, and p-tau/Aβ42 ratios and amyloid PET imaging. Multivariable linear, logistic, Cox proportional hazards, and Fine-Gray competing-risk models were used.ResultsHI was more prevalent among participants with mild cognitive impairment (MCI; defined as CDR = 0.5) than cognitively normal individuals (50% versus 24%, p < 0.001), and MCI status was independently associated with worse baseline WIN thresholds (β = 1.55 dB SNR; 95% CI 0.72-2.37). HI was not cross-sectionally associated with CSF amyloid or tau ratios or amyloid PET positivity. Longitudinally, baseline MCI was associated with a higher risk of incident HI (Cox HR = 2.63, 95% CI 1.48-4.67; Fine-Gray sHR = 2.79, 95% CI 1.06-7.40), whereas baseline HI was not associated with subsequent CDR progression.ConclusionsIn older adults, HI was associated with MCI but not core AD biomarkers or future CDR progression, suggesting that late-life HI may reflect cognitive vulnerability or broader brain aging rather than independently driving AD pathology.

The value of brain age as a transdiagnostic biomarker of neurodegeneration