An MRI Metric Identifies Early, Multifactorial White Matter Damage in Alzheimer’s Disease

Alzheimer’s disease has traditionally been studied as a condition that primarily affects the brain’s gray matter, where neuronal cell bodies are located and some of the disease’s most characteristic lesions accumulate. However, growing evidence indicates that white matter is also impacted during the early stages of the neurodegenerative process.

A study led by the Neuroimaging of Aging and Neurodegenerative Diseases research group at the Sant Pau Research Institute (IR Sant Pau) analyzed these abnormalities using a diffusion magnetic resonance imaging metric known as PSMD—short for peak width of skeletonized mean diffusivity—which can detect microscopic changes in white matter tracts that may not be visible on conventional MRI scans.

The findings, published in the journal Alzheimer’s & Dementia, show that PSMD identifies early white matter abnormalities in both sporadic Alzheimer’s disease and Alzheimer’s disease associated with Down syndrome. In the latter population, these changes are observed at around age 38, approximately 15 years before Alzheimer’s dementia typically becomes clinically apparent.

“This study supports the idea that Alzheimer’s disease does not affect only gray matter. White matter is also altered early in the disease and can provide relevant information about its progression,” explains Dr. Alexandre Bejanin, head of the Neuroimaging of Aging and Neurodegenerative Diseases research group at IR Sant Pau and corresponding author of the study.

The study included 496 participants from two Sant Pau cohorts: the Down-Alzheimer Barcelona Neuroimaging Initiative (DABNI) and the Sant Pau Initiative on Neurodegeneration (SPIN). Overall, the researchers analyzed 150 cognitively healthy individuals, 118 patients with sporadic Alzheimer’s disease, and 228 adults with Down syndrome.

Down Syndrome as a Model of Alzheimer’s Disease

People with Down syndrome represent a particularly relevant population for studying Alzheimer’s disease. Trisomy 21 involves an additional copy of the APP gene, which is associated with the production of beta-amyloid, one of the key proteins involved in the disease. For this reason, people with Down syndrome experience very early accumulation of amyloid pathology and have a very high lifetime risk of developing Alzheimer’s disease.

This more predictable progression makes Down syndrome a unique model for studying the early stages of Alzheimer’s disease and gaining a more profound understanding of which changes occur in the brain before symptoms emerge. This population also frequently develops cerebral amyloid angiopathy, a vascular condition caused by amyloid deposits in the brain’s blood vessels that may also contribute to white matter damage.

“Down syndrome offers us a unique opportunity to study the earliest stages of Alzheimer’s disease because its biological progression is more predictable. This allows us to analyze changes that are much more difficult to detect in the general population before symptoms emerge,” Dr. Bejanin notes.

Until now, PSMD had been studied in several diseases associated with white matter damage and cerebral small vessel disease, including cerebral amyloid angiopathy, but it had not been extensively applied to people with Down syndrome. “This metric had not been studied in Down syndrome. We therefore wanted to compare it with sporadic Alzheimer’s disease to determine whether our observations in this population followed a similar pattern and could help us understand shared disease mechanisms,” says Dr. Alejandra Morcillo-Nieto, first author of the study and a researcher with the Neuroimaging of Aging and Neurodegenerative Diseases research group at IR Sant Pau.

A Tool for Detecting Microscopic Changes

PSMD is obtained from diffusion imaging, a type of magnetic resonance imaging that analyzes the movement of water molecules in brain tissue. In healthy white matter, this movement is influenced by the organization of axons and myelin. When axonal damage, myelin loss, or microvascular abnormalities occur, diffusion becomes more heterogeneous.

“PSMD focuses on white matter tracts and provides an overall value for each individual. This makes it relatively easy to calculate and potentially useful as a complementary tool in research, clinical practice, and clinical trials,” Dr. Morcillo-Nieto explains. Unlike other diffusion metrics more commonly used in group analyses, PSMD provides an overall measurement for each individual, which may facilitate its interpretation and its potential incorporation as a complementary marker in clinical studies.

One of the main advantages of this measurement is its ability to detect microstructural abnormalities before the damage becomes visible using conventional MRI techniques. In the study, particularly among people with Down syndrome, PSMD identified abnormalities in cases where white matter hyperintensities were not yet present. These are MRI-visible lesions typically associated with vascular damage and loss of brain tissue integrity.

“Diffusion imaging is inherently more sensitive to subtle changes than other conventional sequences. The value of PSMD is that it provides an overall measurement and can detect abnormalities that are not yet visible as clearly defined lesions on structural MRI,” the researcher adds.

Changes Detectable Before Symptoms Emerge

The study indicates that PSMD increases with age across all the groups studied, but the increase is particularly pronounced among people with Down syndrome. In this population, differences compared with the control group began to emerge at around age 38, approximately 15 years before Alzheimer’s dementia typically becomes clinically apparent.

“This is a relevant finding, but it must be interpreted with caution. The study does not yet follow the same individuals over time. Instead, it compares participants of different ages within a population in which the natural history of Alzheimer’s disease is very well characterized. The next step will be to confirm these findings through longitudinal studies,” Morcillo-Nieto says.

PSMD was also higher among individuals who already had symptoms of Alzheimer’s disease, both in the general population and among people with Down syndrome. However, once symptoms had appeared, the metric could not clearly distinguish between the prodromal and dementia stages.

Higher PSMD values were also associated with poorer overall cognitive performance, both among people with sporadic Alzheimer’s disease and those with Down syndrome. In the latter group, the researchers used neuropsychological tests adapted to the characteristics of this population, allowing them to link white matter abnormalities to cognitive functioning in both clinical contexts.

“We observed a substantial increase when individuals progressed from an asymptomatic to a symptomatic stage. After that point, although PSMD may continue to increase, it does not appear to be as precise a tool for classifying disease severity. It may therefore be more useful as an early biomarker than as a staging marker,” Morcillo-Nieto summarizes.

Damage With a Multifactorial Origin

The study also analyzed the relationship between PSMD and several cerebrospinal fluid biomarkers. The marker showing the most consistent association was neurofilament light chain (NfL), a protein released when axonal damage occurs. This relationship supports the idea that PSMD captures relevant structural abnormalities in white matter tracts, which are primarily composed of myelinated axons.

PSMD was also associated with established Alzheimer’s disease biomarkers, including beta-amyloid and tau, as well as markers of glial activation and inflammation. In the case of tau, the researchers observed an apparently unexpected result in sporadic Alzheimer’s disease: the association with pTau181 did not increase in parallel with PSMD but was instead inverse. According to the authors, one possible explanation is that this biomarker may reach a plateau and decline during more advanced stages, when neuronal loss reduces the amount of tissue capable of releasing it into the cerebrospinal fluid.

PSMD was also associated with cerebral microbleeds and white matter hyperintensities, two radiological markers linked to vascular damage and cerebral small vessel disease. Taken together, these findings suggest that white matter damage in Alzheimer’s disease does not depend on a single mechanism but instead results from a combination of neurodegenerative, vascular, and inflammatory processes.

“White matter damage is multifactorial. Alzheimer’s pathology, cerebral amyloid angiopathy, axonal damage, and other vascular processes all interact. We still do not know which comes first—whether white matter abnormalities subsequently promote Alzheimer’s pathology or whether Alzheimer’s pathology induces this damage. There is probably an interaction between the two,” Dr. Morcillo-Nieto says.

A Complementary Tool in the Context of New Treatments

The researchers believe that this information may be particularly relevant in the current context, as new treatments for Alzheimer’s disease emerge and the need grows for tools that can better characterize each patient’s brain health. In this setting, identifying the presence of amyloid or tau pathology is not enough. It is also important to determine the extent to which other components of the brain are affected, including white matter, axonal integrity, and vascular health.

PSMD is not intended as a stand-alone diagnostic test but as a complementary biomarker that could help monitor the progression of brain damage. Because it is obtained from diffusion imaging, a sequence already included in many MRI protocols, this metric could be incorporated into clinical studies and trials to provide additional information about white matter integrity and how it may change during follow-up.

“In the context of new treatments, it will become increasingly significant to have tools that help us monitor not only the established hallmarks of Alzheimer’s disease but also the overall condition of brain tissue. PSMD can provide complementary information about white matter and help us better understand how damage progresses in each patient,” Bejanin says.

The authors also believe that this measurement could help investigate the relationship between Alzheimer’s disease, vascular damage, and potential complications associated with certain treatments, at a time when magnetic resonance imaging is playing an increasingly important role in patient monitoring. Although longitudinal studies are still needed to validate its predictive value, PSMD’s ability to detect microstructural abnormalities before lesions become visible on conventional MRI makes it a promising tool for monitoring high-risk populations.

A More Comprehensive View of Alzheimer’s Disease

The study supports the idea that Alzheimer’s disease does not affect only gray matter and cannot be explained solely by the accumulation of amyloid and tau. White matter involvement, axonal damage, cerebral amyloid angiopathy, and cerebral small vessel disease form part of a more complex process that must be studied in an integrated manner.

“These findings require us to think about Alzheimer’s disease more comprehensively. To better understand its progression, we need to incorporate tools that allow us to study not only the established disease pathology but also vascular, axonal, and white matter damage,” Dr. Bejanin concludes. The study opens the door to future longitudinal research to determine whether changes in PSMD predict clinical progression, the emergence of MRI-visible lesions, or the development of dementia, particularly in high-risk populations such as people with Down syndrome.

Reference Article:

Morcillo-Nieto AO, Franquesa-Mullerat M, Zsadanyi SE, Arriola-Infante JE, Vaqué-Alcázar L, Rozalem-Aranha M, Parra JA, Zhao Z, Arranz J, Rodríguez-Baz Í, Maure-Blesa L, Videla L, Barroeta I, Del Hoyo Soriano L, Benejam B, Fernández S, Sanjuan Hernandez A, Pertierra L, Giménez S, Santos-Santos M, Dols-Icardo O, Illán-Gala I, Alcolea D, Belbin O, Lleó A, Carmona-Iragui M, Fortea J, Bejanin A. Peak width of skeletonized mean diffusivity reveals early and multifactorial white matter injury across sporadic and Down syndrome-associated Alzheimer’s disease. Alzheimers Dement 2026;22:e71507. https://doi.org/10.1002/alz.71507.