The research, published in the Journal of Neurology, focused on a measurable feature of the brain’s outer mantle known as cortical thickness. The cerebral cortex, the wrinkled sheet of gray matter responsible for memory, language, and reasoning, gradually thins as neurons and their connections are lost in neurodegenerative disease. Previous large-scale studies, including work from the Longitudinal Early-Onset Alzheimer’s Disease Study consortium, had established that patients with dementia from early-onset Alzheimer’s show a characteristic pattern of thinning concentrated in the posterior parietal and lateral temporal regions of the brain, including the precuneus, the inferior and superior parietal lobules, and the supramarginal gyrus, while relatively sparing the medial temporal areas typically affected first in older-onset disease. What remained unknown was when this signature emerges along the clinical trajectory, particularly in people who do not carry rare genetic mutations but instead develop the disease sporadically.

To address this, the researchers studied 292 patients under the age of 65 who had been referred to the Karolinska memory clinic with cognitive concerns between April 2018 and May 2024. Every participant underwent a 3 Tesla structural MRI scan and a lumbar puncture to obtain cerebrospinal fluid, which was analyzed for two key Alzheimer’s biomarkers: the Aβ42/40 ratio, which signals the accumulation of amyloid-beta plaques in the brain, and phosphorylated tau 181, a protein released when tau pathology begins to damage neurons. Using these markers, the team stratified patients into three biologically defined groups: a reference group of 107 individuals negative for both markers, 76 patients with amyloid positivity alone, and 109 patients positive for both amyloid and p-tau181. Clinically, the cohort spanned the full spectrum of the disease, from subjective cognitive decline, in which patients report symptoms but perform normally on testing, through mild cognitive impairment, to frank dementia.

The first step was to define the early-onset Alzheimer’s cortical signature itself. Comparing patients with biomarker-confirmed Alzheimer’s dementia against the biomarker-negative reference group, using a vertex-wise analysis across the entire cortex, the researchers identified a robust and spatially coherent pattern of thinning. The most severely affected areas lay in the bilateral posterior parietal and lateral association cortices, particularly the precuneus, the inferior and superior parietal lobules, and the supramarginal gyrus. Additional atrophic clusters extended into the banks of the superior temporal sulcus, the superior frontal gyrus, the middle temporal gyrus, and the fusiform gyrus, with a notable predominance in the left hemisphere. This left-sided emphasis echoes earlier reports in younger populations and reinforces the idea that early-onset Alzheimer’s is not merely early-arriving late-onset disease, but a distinct neurodegenerative phenotype with its own spatial and possibly molecular underpinnings.

With the signature established, the team then traced it backward through the earlier clinical stages, and this is where the findings become striking. Among patients with mild cognitive impairment and Alzheimer’s biomarkers, cortical thinning was already present across most signature regions, accompanied by significant hippocampal atrophy. But when the researchers separated the amyloid-positive patients according to their tau status, a clear gradient emerged. Patients with amyloid positivity alone showed focal thinning confined to a handful of regions, including the signature composite, the banks of the superior temporal sulcus, the middle temporal gyrus, and the supramarginal gyrus, while their hippocampal volumes remained statistically intact. Patients with combined amyloid and p-tau181 positivity, by contrast, displayed far more extensive thinning that encompassed the precuneus, fusiform gyrus, inferior parietal lobule, superior parietal lobule, and superior frontal gyrus, together with marked hippocampal volume loss that was significantly greater than in the amyloid-only group.

Even more remarkable were the results at the earliest stage, subjective cognitive decline, when patients are aware something is wrong but still score normally on cognitive tests. Among these individuals, those with amyloid positivity alone showed no detectable structural brain changes whatsoever compared with the reference group. But those with both amyloid and p-tau181 positivity exhibited subtle yet statistically significant thinning in the early-onset signature regions, the precuneus, and the banks of the superior temporal sulcus. In other words, the structural footprint of Alzheimer’s disease is already present in the brains of some younger patients who appear, by every conventional clinical measure, to be functioning normally. This finding parallels evidence from studies of autosomal dominant Alzheimer’s, in which mutation carriers show cortical thinning years before expected symptom onset, but it extends that principle to the predominantly sporadic form of the disease seen in real-world memory clinics.

The study also connected these structural changes to actual cognitive performance, and here a threshold effect became apparent. In the dementia group, thinner cortex within the signature regions correlated with lower scores on global screening measures, the Mini-Mental State Examination and the Montreal Cognitive Assessment. At the mild cognitive impairment stage, the correlations became more specific: thinner inferior parietal cortex and precuneus were associated with poorer episodic memory on verbal learning tests, while thinning in the fusiform gyrus and the banks of the superior temporal sulcus tracked impaired visuospatial memory on complex figure recall tasks. Crucially, no such brain-behavior relationships were observed in the subjective cognitive decline group, suggesting that structural and cognitive changes become coupled only once neurodegeneration crosses a critical threshold, even though the structural changes themselves are already underway.

Why should amyloid positivity alone be so structurally silent? The authors offer two complementary interpretations. The first is temporal: amyloid accumulation precedes tau-related neurodegeneration, and patients with isolated amyloid positivity may simply be at an earlier point on the continuum, destined to convert to tau positivity later, a pattern supported by longitudinal biomarker studies. Consistent with this, amyloid-only patients were proportionally more represented in the earlier clinical stages of the cohort. The second interpretation is more provocative: amyloid-positive, tau-negative and amyloid-positive, tau-positive individuals may represent biologically distinct subtypes of Alzheimer’s disease, with the tau-negative group following a more indolent course and the tau-positive group facing a substantially higher risk of near-term progression. A further speculative possibility raised by the authors is that early amyloid-related processes may transiently increase cortical thickness, potentially masking subtle atrophy in the amyloid-only group, a phenomenon previously reported in presymptomatic carriers of PSEN1 mutations. Notably, the two biomarker groups did not differ in their frequency of the APOE ε4 allele, the major genetic risk factor for sporadic Alzheimer’s, indicating that the structural differences were not simply explained by genetic loading.

The translational implications are considerable. As disease-modifying therapies targeting amyloid move into clinical practice, identifying which patients have biologically active neurodegeneration, rather than amyloid deposition alone, becomes essential for timing intervention and selecting trial participants. The findings suggest that regional cortical thickness measured on a standard structural MRI could serve as a staging marker in biologically defined early-onset Alzheimer’s, complementing fluid biomarkers. Perhaps most importantly, the identification of focal cortical thinning in amyloid- and tau-positive patients who still have only subjective complaints defines a clinically silent but biologically progressive phase of the disease, a window in which closer surveillance and enrollment in secondary prevention trials could alter the trajectory before irreversible damage accumulates.

The authors are careful to note the limitations of their work. The cross-sectional design cannot establish individual disease trajectories, comprehensive neuropsychological testing was available for only a subset of participants, and the cohort lacked systematic genetic testing for monogenic Alzheimer’s genes such as PSEN1, PSEN2, and APP. The cortical signature was also derived and tested within the same clinical cohort, meaning that external replication in independent samples will be required before the pattern can be considered diagnostically applicable. Nevertheless, as one of the largest biomarker-stratified studies of early-onset Alzheimer’s conducted in a real-world memory clinic setting, the study provides a rigorous template for how imaging and fluid biomarkers can be combined to stage the disease in younger patients. It demonstrates that the atrophy signature of early-onset Alzheimer’s dementia is not a late-breaking phenomenon but a process that unfolds along a biomarker-defined gradient, becoming visible to the MRI scanner precisely when amyloid pathology is joined by the tau response that signals the brain’s descent into active neurodegeneration.

Subject of Research: Cortical thickness changes across clinical stages and amyloid/tau biomarker profiles in early-onset Alzheimer's disease

Article Title: Cortical thickness signature of early-onset Alzheimer’s disease across clinical stages and A/T1 biomarker profiles

Article References: Cortical thickness signature of early-onset Alzheimer’s disease across clinical stages and A/T1 biomarker profiles. (n.d.). https://doi.org/10.1007/s00415-026-14187-0

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14187-0

Keywords: early-onset Alzheimer's disease, cortical thickness, p-tau181, amyloid biomarkers, cerebrospinal fluid, MRI, mild cognitive impairment, subjective cognitive decline, hippocampal atrophy, precuneus, biomarker staging, memory clinic