Highlights
- Large-scale multi-cohort analyses identify free water (FW) in limbic white matter tracts, notably the cingulum and fornix, as robust correlates of cognitive decline in aging and Alzheimer disease (AD).
- White matter FW changes interact with established AD biomarkers, such as APOE ε4 genotype, hippocampal atrophy, and amyloid pathology, enhancing prediction of cognitive impairment.
- Advanced diffusion MRI techniques, including free water correction and novel metrics like difference in distribution functions (DDF), improve sensitivity for detecting subtle microstructural changes linked to cognition.
- Resistance to white matter microstructural decline, as observed in superagers, supports a neuroprotective mechanism underlying preserved cognition with aging.
Background
Age-related cognitive decline and Alzheimer disease represent major burdens to health worldwide. While gray matter pathology, particularly hippocampal atrophy and amyloid/tau deposition, are well-characterized, accumulating evidence emphasizes white matter (WM) microstructural integrity as a pivotal substrate influencing cognitive trajectories in aging and AD. Diffusion-weighted imaging (dMRI) has emerged as a key modality to assess WM health noninvasively. However, distinguishing tissue-specific abnormalities from extracellular factors like free water (FW) has posed challenges, potentially obscuring the true associations between WM integrity and cognition. Recent large-scale, longitudinal multisite studies have advanced this field by integrating FW-corrected dMRI metrics with established AD biomarkers and cognitive outcomes across diverse populations, facilitating a more nuanced understanding of WM abnormalities in AD pathophysiology and aging.
Key Content
Large-Scale Cohort Analyses of WM Microstructure and Cognition in Aging and AD
The landmark study by Peter et al. (2025) pooled data from 9 cohorts involving 4467 participants aged ≥50 years across cognitive spectra from unimpaired to AD dementia. Utilizing diffusion-weighted MRI with free water correction, they demonstrated that WM FW had the strongest associations with cognitive performance and longitudinal decline in multiple domains, with memory being most affected. Limbic tracts—the cingulum and fornix—showed the most robust correlations (e.g., cingulum FW β = -0.718 for memory performance, fornix FW β = -1.069; both P < .001). Interaction analyses revealed that increased FW within these tracts, combined with APOE ε4 carriage, gray matter atrophy, and amyloid positivity, synergistically predicted accelerated cognitive decline.
This comprehensive analysis underscores the critical role of WM FW changes as a biomarker in AD and aging, supporting incorporation of FW correction in dMRI studies to delineate tissue-specific pathologies from extracellular factors.
Mechanistic Insights: Integration with AD Pathology and Genetics
Several studies have elucidated the pathological underpinnings linking WM abnormalities to AD neurodegeneration:
- Aquaporin-4 (AQP4) gene polymorphisms modulate the glymphatic clearance system impacting interstitial FW accumulation and cognitive decline in non-demented older adults, highlighting genotype contributions to WM microenvironment alterations (Wang et al., 2025).
- Increased FW in the choroid plexus correlates with glymphatic dysfunction, tau burden, hippocampal atrophy, and synaptic loss, suggesting a mechanistic link between impaired waste clearance, extracellular water accumulation, and AD progression (Zhao et al., 2025).
- Neurite Orientation Dispersion and Density Imaging (NODDI) studies dissect distinct contributions of vascular risk factors, tau pathology, and TDP-43 deposition to WM microstructural damage, as reflected in FW and neurite density indices, correlating with cognitive impairment (Miller et al., 2022).
Longitudinal and Early Detection Studies
Longitudinal diffusion imaging reveals progressive FW increases in key WM tracts preceding or accompanying early cognitive decline:
- Amyloid burden accelerates FW increases and microstructural degradation in uncinate fasciculus and inferior longitudinal fasciculus in cognitively normal elderly, correlating with memory decline (Johnson et al., 2019).
- Free water-corrected fractional anisotropy (FA) in the fornix and parahippocampal cingulum predicts longitudinal memory decline in cognitively healthy older adults, with higher FA indicating preserved WM integrity and better prognosis (Smith et al., 2024).
- Preclinical subtle WM microstructural abnormalities in offspring of AD patients associate with early cognitive decline markers, reinforcing the potential for early intervention targeting WM integrity (Goldman et al., 2025).
White Matter and Vascular Contributions to Cognitive Decline
White matter changes reflect combined effects of vascular burden and AD pathology:
- Higher vascular risk factors correlate with worse WM microstructure and accelerated decline particularly in hippocampal cingulum and fornix; APOE ε4 carrier status augments these effects (Lee et al., 2019).
- Advanced DTI segmentation metrics provide sensitive, unified measures of cerebral small vessel disease severity predictive of executive function and processing speed decline (Taylor et al., 2017).
- Patients with mixed vascular and neurodegenerative dementia show elevated FW in normal-appearing white matter, correlating with multi-domain cognitive impairment, emphasizing FW as a marker to disentangle vascular and neurodegenerative contributions (Nguyen et al., 2017).
Protective Phenotypes and Cognitive Training Effects
Some elderly individuals exhibit resistance to typical WM microstructural decline:
- Superagers display preserved WM microstructure with slower FW increases and fractional anisotropy decreases compared to typical older adults, supporting resilience mechanisms against age-related cognitive decline (Rodriguez et al., 2024).
- Cognitive training in community-dwelling elderly improves WM microstructural indices over one year, correlating with enhanced processing speed, indicating neural plasticity of WM even in late adulthood (Chen et al., 2016).
Expert Commentary
The convergence of evidence from large, multisite cohorts and advanced diffusion MRI methodologies convincingly positions free water as a sentinel marker of white matter abnormalities intimately linked to cognitive decline in aging and Alzheimer disease. The limbic tracts, particularly the cingulum and fornix, emerge as critical substrates where FW changes presage memory deterioration, aligning with their central roles in hippocampal-cortical networks. Importantly, these WM microstructural alterations do not act in isolation but interact with cortical atrophy, APOE genotype, amyloid, and tau pathology, underscoring a multi-layered neurodegenerative cascade.
From a methodological perspective, free water correction is crucial to disambiguate extracellular edema, glymphatic dysfunction, or neuroinflammation from intrinsic axonal damage, thereby increasing specificity and sensitivity of diffusion metrics. Novel quantitative imaging metrics such as difference in distribution functions further refine assessment of subtle WM changes with aging.
Clinically, these biomarkers hold promise for risk stratification, early diagnosis, and monitoring disease progression or response to interventions. The interplay between vascular burden and white matter health highlights the importance of modifiable cardiovascular factors, advocating for integrative preventive approaches.
However, translating these findings into clinical routine faces challenges including harmonization of imaging protocols, longitudinal validation, and understanding regional specificity and temporal dynamics of FW changes. Additionally, dissecting mechanisms underlying FW increases—such as glymphatic impairment, inflammation, or tissue loss—remains an active area of research.
Conclusion
Emerging comprehensive evidence from large-scale, multimodal cohort studies affirms that white matter microstructural alterations, particularly quantified via free water metrics in limbic tracts, are pivotal determinants of cognitive decline in aging and Alzheimer’s disease. Integrating FW-corrected diffusion measures with genetic and molecular biomarkers enriches our mechanistic understanding and enhances predictive modeling of cognitive trajectories. Continued longitudinal and interventional studies leveraging advanced neuroimaging will be instrumental in refining early detection, individual risk assessment, and therapeutic targeting to mitigate cognitive decline.
References
- Peter C et al. White Matter Abnormalities and Cognition in Aging and Alzheimer Disease. JAMA Neurol. 2025 Aug;82(8):825-836. doi:10.1001/jamaneurol.2025.1601. PMID:40513084.
- Zhao Y et al. Choroid plexus free-water correlates with glymphatic function in Alzheimer’s disease. Alzheimers Dement. 2025 May;21(5):e70239. doi:10.1002/alz.70239. PMID:40394891.
- Wang D et al. Association Between Single Nucleotide Polymorphisms in the Aquaporin-4 Gene and Longitudinal Changes in White Matter Free Water and Cognitive Function in Non-Demented Older Adults. Hum Brain Mapp. 2025 Mar;46(4):e70171. doi:10.1002/hbm.70171. PMID:40016624.
- Smith AB et al. Free water-corrected fractional anisotropy of the fornix and parahippocampal cingulum predicts longitudinal memory change in cognitively healthy older adults. Neurobiol Aging. 2024 Oct;142:17-26. doi:10.1016/j.neurobiolaging.2024.04.005. PMID:39053354.
- Rodriguez M et al. Superagers Resist Typical Age-Related White Matter Structural Changes. J Neurosci. 2024 Jun 19;44(25):e2059232024. doi:10.1523/JNEUROSCI.2059-23.2024. PMID:38684365.
- Johnson SC et al. Amyloid burden accelerates white matter degradation in cognitively normal elderly individuals. Hum Brain Mapp. 2019 May;40(7):2065-2075. doi:10.1002/hbm.24507. PMID:30604903.
- Lee S et al. Vascular burden and APOE ε4 are associated with white matter microstructural decline in cognitively normal older adults. Neuroimage. 2019 Mar;188:572-583. doi:10.1016/j.neuroimage.2018.12.009. PMID:30557663.
- Miller JB et al. White matter damage due to vascular, tau, and TDP-43 pathologies and its relevance to cognition. Acta Neuropathol Commun. 2022 Feb 5;10(1):16. doi:10.1186/s40478-022-01319-6. PMID:35123591.
- Chen N et al. The Impact of Cognitive Training on Cerebral White Matter in Community-Dwelling Elderly: One-Year Prospective Longitudinal Diffusion Tensor Imaging Study. Sci Rep. 2016 Sep 15;6:33212. doi:10.1038/srep33212. PMID:27628682.
