2026 ECNP Congress

PS02-2138

Expanding the horizon of Alzheimer's risk: the independent impact of WMH volume and location

Hyun Ju Yang — M.D. Kim, W.M. Bahk, Y.E. Jung · Jeju National University Hospital, Neuropsychiatry, Jeju si, Korea- Rep

2026 ECNP Congress

Objectives

The clinical significance of white matter hyperintensities (WMH) in the pathogenesis of Alzheimer’s disease (AD) has gained increasing attention, moving beyond the traditional view of WMH as mere incidental findings of aging[1]. Recent neuroimaging hypotheses suggest that the impact of these lesions on cognitive outcomes may be topographically determined, depending on their anatomical proximity to the ventricular surface[2]. While total WMH volume is a known risk factor, the differential contributions of specific white matter regions remain insufficiently characterized. This study aimed to rigorously investigate the independent effects of WMH volume and its precise neuroanatomical location—classified by distance from the ventricular surface—on AD risk and specific cognitive domains. We specifically sought to determine whether these effects persist when accounting for the confounding influence of hippocampal atrophy.

Methods

A comprehensive cross-sectional analysis was conducted involving a total of 283 participants, comprising 112 cognitively normal (CN) individuals and 171 patients diagnosed with Alzheimer’s disease. All participants underwent a standardized clinical evaluation, which included high-resolution volumetric magnetic resonance imaging (MRI). To ensure a robust assessment of cognitive function, the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD-K) neuropsychological battery was administered[3]. WMH volume was quantified and segmented into three distinct spatial categories based on their distance from the ventricular lining: juxtaventricular WMH (JVWMH; defined as <3 mm from the ventricle), periventricular WMH (PVWMH; between 3 and 13 mm), and deep WMH (DWMH; >13 mm). Statistical models were adjusted for age, sex, and educational attainment to isolate the independent role of WMH topography.

Results

The quantitative analysis revealed that the mean total WMH volume was markedly and significantly higher in the AD group (20.7±18.21 ml) compared to the cognitively normal group (6.8±8.1ml,p < 0.001), suggesting a substantial burden of small vessel disease in the clinical population. Logistic regression analysis demonstrated that a tenfold increase in total WMH volume was associated with a 5.967-fold increased risk of AD (95% CI 1.550–22.986). When examining specific regions, PVWMH exhibited a strong risk association (OR 4.021, 95% CI 1.592–10.156), and DWMH also showed a significant, albeit lower, risk correlation (OR 2.873, 95% CI 1.227–6.731). Most notably, the neuropsychological impact was region-specific; increased volumes of total WMH, JVWMH, and PVWMH were significantly correlated with poorer performance in verbal fluency and memory consolidation tasks. In contrast, DWMH volume showed no significant association with these cognitive domains, suggesting that lesions closer to the ventricles may more severely disrupt the cholinergic fibers and long-association tracts essential for executive and mnemonic processes.

Conclusions

In conclusion, this study provides compelling evidence that both the volume and the neuroanatomical location of WMH serve as independent and critical contributors to Alzheimer’s disease risk and cognitive impairment. These findings highlight that PVWMH and JVWMH are particularly detrimental to executive and memory functions. Crucially, these associations remained significant even after adjusting for hippocampal atrophy, reinforcing the premise that white matter pathology represents a distinct and potent pathway in the manifestation of AD symptoms, separate from traditional neurodegenerative markers.

References

  1. . van den Berg E, Geerlings MI, Biessels GJ, Nederkoorn PJ Kloppenborg RP. White Matter Hyperintensities and Cognition in Mild Cognitive Impairment and Alzheimer’s Disease: A Domain-Specific Meta-Analysis. J Alzheimers Dis 2018; 63: 515-527.
  2. . Kim KW, MacFall JR Payne ME. Classification of white matter lesions on magnetic resonance imaging in elderly persons. Biol Psychiatry 2008; 64: 273-280.
  3. . Lee JH, Lee KU, Lee DY, Kim KW, Jhoo JH, Kim JH, et al. Development of the Korean Version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet (CERAD-K): Clinical and Neuropsychological Assessment Batteries. The Journals of Gerontology: Series B 2002; 57: P47-P53.