As usual and truly amazing reply @DrFraser
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The dementia that often strikes in midlife — and the signs people miss
Initial symptoms of frontotemporal dementia (FTD) are easy to miss, since they can look more like a psychiatric condition than a neurodegenerative one.
September 4, 2026 at 6:00 a.m. EDT
If you’ve heard of frontotemporal dementia (FTD), it may be because of Bruce Willis or Wendy Williams — two celebrities whose diagnoses in recent years have shed light on this infrequently discussed neurodegenerative disease. Though FTD is relatively rare, accounting for about 5 percent to 10 percent of all dementia cases and affecting an estimated 50,000 to 60,000 people in the United States, it’s the most common form of early-onset dementia.
In fact, 60 percent of people who get diagnosed with it are ages 45 to 64, decades younger than the average person diagnosed with Alzheimer’s disease (which causes most cases of dementia). And yet, experts believe this is a significant undercount because it’s “rare enough that most medical providers, even specialists, don’t have experience with it, and so they don’t know what it looks like,” said Brad Dickerson, neurologist at the Mass General Brigham Neuroscience Institute and director of the Frontotemporal Disorders Unit at Massachusetts General Hospital.
The initial symptoms of FTD also diverge sharply from those of the more common Alzheimer’s disease because of the parts of the brain it attacks. FTD often starts “in the front of the brain, which is very important for behavior, regulation of social interactions, addiction, drive, organizing and planning,” said Bruce Miller, a professor of neurology and director of the Edward and Pearl Fein Memory and Aging Center at the University of California at San Francisco.
So, FTD generally manifests first with behavior or mood changes — rather than the memory loss and thinking problems of Alzheimer’s (which typically first affects the areas of the brain responsible for these tasks, including the hippocampus). It’s the reason FTD is often misread as a psychiatric issue, Miller said. On average, it takes about three to four years for people to get a diagnosis of FTD, according to the Association for Frontotemporal Degeneration.
Below, experts explain why FTD tends to hit earlier in life than other dementias, the often-overlooked signs to know and what care for people with the condition looks like.
FTD most often begins in the frontal lobe and its earliest symptoms typically include behavior or personality changes — called behavioral-variant FTD. The most common ones are easily mistaken as signs of psychiatric conditions such as depression or bipolar disorder, or dismissed as the effects of stress, burnout or even a midlife crisis. They include:
- Apathy. “People lose interest in doing things, they move less and they are less interested in the stories of loved ones,” Miller said.
- Addictive behaviors. They might turn to compulsive drinking, drugs, sex or several of the above, Miller pointed out.
- Loss of empathy. People with FTD tend to become alienated from their partners, children, friends and co-workers — and a big reason for that is losing the ability to feel what others are feeling, Miller said.
- Difficulty with planning, organizing and managing money. FTD often hinders executive function, which refers to high-level cognitive skills including problem-solving, abstract thinking, regulating sensory input and decision-making. One way this could manifest: Dickerson said he’s seen many patients who have fallen victim to scams that might have seemed obviously problematic to someone without FTD.
- Disinhibition. FTD can cause people to lose their filter or start acting in ways that are socially inappropriate, Dickerson said. He gave the example of someone urinating in a public bathroom without closing the door behind them.
Read the full story: The dementia that often strikes in midlife — and the signs people miss
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Fibronectin mediates APOE4-driven blood–brain barrier dysfunction in Alzheimer’s disease
Conclusion from study:
“Despite the robust findings in this study, we note some limitations. To further enhance the applicability of these findings to human AD, validation can be conducted in additional human brains and in reductionist models of the human vascular niche. Furthermore, the known overlap of other comorbidities, such as diabetes and hypertension, could contribute to the observed relationships among fibronectin, VEGFA, HB-EGF, IGF-1 and AD pathology. Although we identified inflammation as one driver of fibronectin deposition, the specific inflammatory signals and their roles at different stages of the disease require further investigation. While this study establishes fibronectin as a mechanistic mediator of BBB dysfunction, the consequences of this pathway for cognition and higher-order brain function were not directly assessed and remain an important area for future investigation.”
GPT summary:
"The researchers identify an ECM component as a causal mediator of pathology and then partially reverse the pathology by manipulating it, which is much closer to the kind of ECM work we’ve been waiting for. Nature
The protein is fibronectin (FN1), an extracellular matrix glycoprotein. The researchers connect APOE4 to abnormal fibronectin accumulation around the brain vasculature:
APOE4 / amyloid / inflammation → astrocytes produce excess fibronectin → abnormal perivascular ECM deposition → disrupted integrin/FAK signalling → impaired VEGF, HB-EGF and IGF-1 signalling → blood-brain barrier dysfunction. Nature
That chain is supported unusually thoroughly. They combine human postmortem brain tissue, CSF and plasma data, single-cell transcriptomics, human iPSC-derived astrocytes, 3D human vascular models, zebrafish and aged mouse models. In 21 to 22-month-old APOE4 knock-in mice, brain fibronectin was almost double that of APOE3 animals. Nature
The intervention experiments are what push this over the line for me. Reducing fibronectin restored BBB integrity, and independently restoring the growth-factor signalling suppressed by excess fibronectin also rescued BBB function in experimental models. So the ECM alteration is not merely correlated with the disease state. Nature
There is also a fascinating human-genetics clue behind the whole project. Previous work identified a rare loss-of-function FN1 variant associated with a 71% reduction in Alzheimer’s risk among APOE4 carriers. The new study provides a plausible mechanistic explanation for why reducing fibronectin activity might be protective. Nature
Why I think it’s especially worth your time
This gets at something broader than Alzheimer’s.
Fibronectin is normally useful. It is an important part of wound healing and ECM remodeling. The problem appears to be excessive or misplaced deposition of an otherwise useful matrix protein, which then alters how neighboring cells behave.
That is exactly the sort of feedback relationship that makes ECM aging interesting. Aging cells remodel the matrix, but the remodeled matrix can subsequently alter signalling, vascular function, inflammation and cellular behavior. The ECM therefore stops looking like passive scaffolding and starts looking like another information-bearing component of the aged tissue environment.
The authors explicitly connect pathological fibronectin accumulation with broader vascular basement-membrane remodeling, impaired metabolic-waste clearance and neuroinflammation. They also note that the protective FN1 variant has been associated with reduced Lewy body disease risk, raising the possibility that this mechanism extends beyond Alzheimer’s. Nature
There are important limitations. They have not demonstrated that lowering fibronectin prevents dementia in humans, cognition was not directly tested in the experimental intervention, and several authors have patents related to FN1-targeted therapies and are founders/shareholders of KVM Therapeutics. Those conflicts are disclosed in the paper."
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The preliminary analysis, published in Nature Metabolism, finds initial evidence that a popular supplement, taken by more than 40 million Americans, is associated with faster progression to dementia in people with early memory problems.
Glucosamine is a natural sugar-related molecule widely sold over the counter as a supplement in the US.
It is especially popular among older adults, who use it to support joint health and manage arthritis symptoms or joint discomfort.
But it may have an insidious downside for a certain subset of older adults.
Using electronic health record data, researchers at the University of Florida (UF) have now found that glucosamine use was associated with a 25 percent higher likelihood that mild cognitive impairment would progress to dementia.
“People take the supplement based on anecdotal reports that it improves joint health, especially in the knees,” writes biochemist Ramon Sun from UF for The Conversation.
Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse model of tauopathy
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Also, it’s almost worthless for its intended use. IMO benefits obtained are mostly placebo.
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There’s already been a thread opened about this some time ago with a discussion. Maybe they can be merged.
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