Frontotemporal dementia: Protein changes may trigger it in middle age

Medical News Today

21-05-2025

Key protein changes could trigger frontotemporal dementia in middle age, a recent study has found. Image credit: Westend61/Getty Images. A new study from UC San Francisco may offer the first clear biological markers for frontotemporal dementia, a condition that often affects people in midlife and is difficult to diagnose.
By analysing spinal fluid from patients with inherited frontotemporal dementia , researchers uncovered protein changes linked to RNA regulation and brain connectivity; early indicators that could lead to earlier, more accurate diagnosis.
These findings could open the door to precision treatments and expanded access to clinical trials for those living with the disease.
Dementia typically affects older adults, so when it appears in middle age it can be difficult to identify.
Frontotemporal disorders are caused by damage to the frontal and temporal regions of the brain, leading to dementia. The effects vary by type but may include changes in behaviour, language, and overall wellbeing.
Now, researchers at UC San Francisco have uncovered new insights into how frontotemporal dementia develops.
The study, published in Nature Aging , involved the analysis of over 4,000 proteins in spinal fluid samples from 116 individuals with inherited frontotemporal dementia .
Researchers compared these samples to those from 39 of their healthy relatives.
Since all participants with frontotemporal dementia had genetic forms of the disease, the team was able to study confirmed cases in living individuals.
This would not be not possible with non-inherited frontotemporal dementia, as this can only be definitively diagnosed postmortem.
The changes in protein composition suggest that those with frontotemporal dementia experience disruptions in RNA regulation , which is essential for proper gene expression in the brain, as well as issues with brain connectivity.
The team believes these proteins could serve as the first specific biomarkers for frontotemporal dementia that become detectable as the disease begins to manifest in middle age.
By identifying frontotemporal dementia at an earlier stage, potentially through the proteins highlighted in their findings, patients could be referred to appropriate resources, enrolled in relevant clinical trials, and eventually benefit from more targeted, precision-based treatments.
First author Rowan Saloner, PhD, scientist-practitioner and Assistant Professor at the UCSF Memory and Aging Center, explained the key findings to Medical News Today .
'We analyzed cerebrospinal fluid samples from individuals with inherited forms of frontotemporal dementia, a group of progressive dementias that primarily affect individuals in midlife (40s, 50s, and 60s),' Saloner explained.
'Studying inherited forms of [frontotemporal dementia] allows us to know the underlying brain pathology in living patients with high confidence, making it a powerful model for detecting biological changes, even before symptoms begin. By measuring concentrations of thousands of proteins in cerebrospinal fluid, we identified biological changes related to RNA processing, synaptic health, and immune responses that were associated with greater severity of disease.'
– Rowan Saloner, PhD
'Importantly, we replicated many of our findings in people with sporadic (noninherited) forms of [frontotemporal dementia], showing that the biological changes we uncovered could be relevant to a large percentage of [frontotemporal dementia] patients,' he added.
James Giordano, PhD, MPhil, professor emeritus in the Departments of Neurology and Biochemistry at Georgetown University Medical Center, Washington, told MNT that 'this is an important study utilizing proteomic analytic techniques to assess putative biomarkers for frontotemporal lobe dementia (FTLD).'
'In the main, this study, utilizing a relatively large cohort of patient samples, revealed viable proteomic biomarkers for both genetic deletion mechanisms — which prevent the expression of beneficial substrates of neural and glial factors that can remove certain forms of cellular end-product debris — and addition processes, which contribute proteins such as tau, which are contributory to mechanisms of neurodegeneration in FTLD, and other neurologic diseases.
– James Giordano, PhD
'One constraint of this study was the use of a particular proteomic scanning tool,' Giordano added. This is because it 'may introduce some 'selection preference' or bias in protemic biomarker, identification.'
However, 'it is nonetheless important in that it establishes the opportunity to utilize other proteomic scanning tools, as well as prompting development of new biomarker assessments that may be even more useful in this type of assessment and potentially predictive analyses,' he explained.
'The benefit of studies such as this is that early identification of proteomic biomarkers can lead to new trajectories of drug development that can divert pathogenic mechanisms of aberrant, protein production and aggregation, which thereby might prevent or mitigate progression of FTLD, and other neurodegenerative conditions.'
– James Giordano, PhD
Saloner explained that 'unlike Alzheimer's disease, which now has biomarkers and emerging treatments, frontotemporal dementia still has no approved therapies.'
'In sporadic (nongenetic) [frontotemporal dementia] cases, we also lack reliable ways to determine a given patient's brain pathology during life.'
'Our study moves the field closer to molecular tests that could detect disease earlier, monitor its progression, and guide personalized treatments based on underlying biology. Our findings could also inform clinical trials targeting the specific disease processes that drive [frontotemporal dementia].'
– Rowan Saloner, PhD
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