TDP-43 Type C: A Type of Neurodegeneration That Begins with Language Ability, Not Memory

We are used to thinking of dementia as something that begins with memory loss. The "where did I put the keys?", the "what's the girl's name?". But there is a type of dementia that begins differently. Semantic dementia impairs the ability to understand words. A 65-year-old suddenly doesn't know what an "umbrella" is. He knows it's something you use, but the word itself is empty. The cause: TDP-43 Type C neurodegeneration. A new study published in Neurology Genetics reveals the unique genetics of this disease.

What is TDP-43?

TDP-43 (TAR DNA-binding protein 43) is a normal protein found in every cell in the body. Its role: to bind between DNA and RNA and help process genetic instructions. The problem: in several neurological diseases, TDP-43 begins to misfold and cause damage. It accumulates in aggregates that harm neurons. TDP-43 is the defining pathology of ALS (Amyotrophic Lateral Sclerosis, in about 97% of cases), about half of FTLD (Frontotemporal Lobar Degeneration) cases, and LATE (Limbic-predominant Age-related TDP-43 Encephalopathy), and it also appears as a secondary pathology in other diseases.

TDP-43 was classified into four types, A through D, based on the structure of the aggregates:

• Type A: Linked to FTD (Frontotemporal Dementia) and ALS
• Type B: Most cases of ALS, some FTD
• Type C: Semantic dementia only, a unique variant
• Type D: A rare genetic disease (IBMPFD)

The Peculiar Type: Type C

For decades, type C was a mystery. While types A and B are found throughout brain regions, type C consistently begins in the anterior temporal lobe. This explains why its symptoms are so unique:

• If left-sided damage: Loss of the ability to understand words. The symptom is semantic variant primary progressive aphasia (svPPA). A person hears "umbrella" but doesn't understand what it is. He knows it's an object, but the category is empty.
• If right-sided damage: Loss of the ability to recognize faces or objects. A person sees his wife and cannot say who she is, even though he knows she is a woman. Or sees a dog and knows it's an animal but not that it's a "dog."

Episodic memory is preserved. Calculation is preserved. But meaning disappears.

The Puzzle: Why Specifically the Anterior Temporal Lobe?

For a long time, there was no consensus on the genetic cause of type C. While types A and B are clearly linked to genes like C9orf72, GRN, and MAPT, type C appeared "random" - without families with clear inheritance.

This led researchers to think that this type has no genetic cause, but is caused solely by environmental factors. But the new study changes the picture.

The Discovery: ANXA11 is the Link

An academic research group led by Northwestern University performed whole genome sequencing on 37 confirmed or probable TDP-43 type C patients with pathological documentation, compared to 290 control subjects. They found that a gene called ANXA11 (Annexin A11) appears in rare variants in some patients, in a way not found in types A or B. Concurrently, genetic associations were also identified with FIG4 and UBQLN2, genes previously linked to ALS.

ANXA11 is an interesting protein: cryo-electron microscopy studies showed that TDP-43 and ANXA11 bind to each other and form common aggregates in almost all type C cases - a feature not present in types A or B. Under normal conditions, ANXA11 and TDP-43 work together in transporting RNA to different areas of the cell. This pathological binding is characteristic of type C regardless of the presence of a mutation, but rare variants in ANXA11 are found only in some patients and may increase the predisposition to this process.

This is an elegant explanation: ANXA11 is not the sole cause of type C, but it is a specific component that characterizes this type and is not present in other types.

What Does This Mean for Patients?

The discovery affects three groups of people:

1. Existing patients with semantic dementia: Can now undergo genetic testing. If an ANXA11 mutation is found, the diagnosis is confirmed. If not, there may be another, still uncharacterized type.
2. Family members: If a patient has an ANXA11 mutation, family members can be tested. If they are carriers, they can be monitored and start early treatment if effective.
3. Drug development: Now that there is a target (ANXA11 protein), pharmaceutical companies can develop drugs that stabilize it. Currently, there is no drug for FTD at all.

How Does This Relate to Normal Aging?

An interesting question: TDP-43 accumulates in every elderly person, even without disease. Pathological TDP-43 accumulation in limbic structures (hippocampus and amygdala) is found in about 40% of elderly people over 80, even in those without dementia. This condition is called LATE (Limbic-predominant Age-related TDP-43 Encephalopathy), and as its name suggests, it is concentrated in limbic regions rather than the entire temporal lobes.

If you want to know if your brain is at risk:

• CSF (cerebrospinal fluid) testing can diagnose pathological TDP-43
• Advanced MRI can detect atrophy in the anterior temporal lobe
• Tailored language tests (assessing semantic comprehension) can detect early

The Mechanism: Why the Anterior Temporal Lobe?

Researchers are now examining the most interesting question: why specifically this region? Possible answers (hypotheses not yet proven):

• Neurons there are more sensitive: They may express more ANXA11 and TDP-43
• Impaired blood supply: The anterior temporal lobe, as a watershed area receiving less blood flow, may be more vulnerable to damage (hypothesis)
• Unique role: This area stores the brain's "dictionary of meanings." Perhaps this requires high protein production that poses greater risk

How is it Diagnosed?

If you or a relative experience signs of semantic dementia:

1. Neurological examination: Including specific language tests (Boston Naming Test, Pyramids and Palm Trees)
2. MRI: Look for atrophy in the anterior temporal lobe
3. PET: See reduced metabolic activity
4. Genetic testing: ANXA11, GRN, MAPT
5. In rare cases: CSF testing

What Can Be Done?

There is currently no cure for FTD or semantic dementia. But there are ways to slow it down:

• Speech therapy: Working with a speech-language pathologist, a person can slow the decline in language ability
• Mental activity: Maintaining the brain region through reading, conversations, puzzles
• Vascular health: Low blood pressure, managed diabetes, physical activity - prolong the initial stage
• Avoiding medications that worsen it: Benzodiazepines, anticholinergics
• Mediterranean diet: With emphasis on omega-3, polyphenols, quality proteins

The Broader Message

Brain aging is not a uniform process. Each brain region can fail differently. The discovery of ANXA11 shows that each type of neurodegeneration requires a unique approach. The precision medicine of 2030 and beyond will be able to test your specific gene, predict where the first damage will be, and give you tailored interventions years before symptoms begin. Until then, maintaining the brain through lifestyle remains the strongest shield.