When Alzheimer's hides a second dementia, certain psychiatric symptoms give it away

For decades, a definitive diagnosis of frontotemporal lobar degeneration has required something no patient or family wants to wait for: an autopsy. FTLD - a neurodegenerative disorder marked by personality changes, disinhibition, and apathy - frequently co-occurs with Alzheimer's disease, yet clinicians have had no reliable way to identify the combination in a living patient. That may be changing.

A new study published in Neurology analyzed data from 919 patients across 29 NIH-funded Alzheimer's Disease Research Centers, all of whom had received autopsy-confirmed diagnoses of intermediate to high Alzheimer's disease and/or FTLD neuropathology. The researchers, led by postdoctoral fellow Daliah Ross at Brown University's Warren Alpert Medical School, found that patients carrying both pathologies displayed a distinct psychiatric fingerprint that set them apart from those with either condition alone.

A psychiatric fingerprint for dual pathology

Compared to patients with FTLD only, those with both Alzheimer's and FTLD were significantly more likely to have experienced anxiety, delusions, and irritability before death. And compared to the Alzheimer's-only group, the dual-pathology patients showed higher rates of personality change and disinhibition - hallmarks of FTLD that would not typically be expected in someone diagnosed solely with Alzheimer's.

The pattern is not subtle. These are symptoms that caregivers notice and clinicians can assess. "We saw that there were different neuropsychiatric symptoms if people had both pathologies, which could inform diagnosis and treatment plans," Ross said.

The practical implications are significant. Patients with both disorders may face a more complicated disease trajectory, faster decline, or unexpected responses to emerging Alzheimer's therapies. Knowing what lies ahead lets families prepare - emotionally, financially, and logistically.

Why most dementia does not travel alone

Ross's interest in dual pathology grew from a striking observation in the scientific literature: most people with neurodegenerative disorders do not have Alzheimer's in isolation. Co-occurring conditions are the norm, not the exception. Yet research has overwhelmingly focused on single diagnoses.

"We tend to study cognitive disorders in isolation, but people don't usually have just Alzheimer's by itself," Ross said. The disconnect between how researchers study dementia and how dementia actually presents in patients has left a significant gap in clinical understanding.

FTLD is particularly tricky as a co-occurring condition. Its signature symptoms - personality shifts, socially inappropriate behavior, loss of empathy - overlap poorly with what clinicians expect from Alzheimer's patients. When a person with a known Alzheimer's diagnosis begins exhibiting disinhibition or dramatic personality changes, the tendency has been to attribute it to disease progression rather than to consider a second underlying pathology.

What this means for Alzheimer's treatments

The timing of this research is not incidental. New disease-modifying treatments for Alzheimer's - including anti-amyloid antibodies like lecanemab and donanemab - have generated considerable excitement. But virtually all clinical trial data on these drugs comes from patients selected for Alzheimer's pathology alone. How they perform in someone whose brain also harbors FTLD is largely unknown.

Dr. Edward Huey, associate director of Brown's Center for Alzheimer's Disease Research and director of the Memory and Aging Program at Butler Hospital, underscored the gap. "While there are treatments for Alzheimer's disease, there aren't currently any known disease-modifying treatments for FTLD, and we desperately need them," he said. In the meantime, simply knowing that a patient has FTLD alongside Alzheimer's could help families and care teams set more realistic expectations.

The limits of an autopsy-era dataset

The study's strength is also its constraint. Because FTLD confirmation required autopsy, the 919 patients in this analysis had all died. Their neuropsychiatric symptoms were assessed retrospectively, using records gathered during life. That means the researchers could identify associations between dual pathology and symptom patterns, but they could not test whether prospective screening using these symptoms would accurately flag FTLD in living patients.

The sample also skews toward patients seen at specialized academic research centers, which may not reflect the broader dementia population. And while the neuropsychiatric differences between groups were statistically significant, individual variation is wide. Not every patient with both pathologies will display the same cluster of symptoms.

Still, the findings offer something clinicians have not previously had: a data-driven rationale for suspecting FTLD co-pathology based on observable psychiatric features. That is a starting point for developing screening protocols that could eventually be validated in prospective studies.

What comes next

Ross sees this work as one piece of a much larger puzzle. "The literature on looking at mixed dementia and multiple co-pathologies is really important," she said. The next steps involve understanding whether the neuropsychiatric patterns identified here hold up in larger, more diverse populations - and whether they can be used to guide treatment decisions in real time.

For now, the practical takeaway is straightforward. When a patient with Alzheimer's develops anxiety, delusions, irritability, or marked personality changes, clinicians should consider the possibility that a second neurodegenerative process is at work. It will not change the course of the disease. But it might change how families understand what is happening - and that matters.