Alzheimer’s gene variant may influence toxic protein spread in ALS
Discovery could explain why pathology differs among patients
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- The APOE4 gene variant influences the spread of toxic TDP-43 protein clumps in ALS.
- APOE4 carriers are more likely to have widespread TDP-43 clumps, affecting cognition and behavior.
- Assessing APOE4 status may help predict ALS prognosis and guide targeted therapies.
The APOE4 gene variant, an established genetic risk factor for Alzheimer’s disease, may also influence how toxic TDP-43 protein clumps spread in people with amyotrophic lateral sclerosis (ALS), a study suggested.
Researchers found that people with ALS who carried the variant were significantly more likely to show TDP-43 clumps extending beyond movement-related areas of the brain into regions involved in thinking and behavior. The effect seems to occur independently of the protein changes typically linked to Alzheimer’s disease, they said.
“Our findings suggest that [APOE4] may influence ALS [disease] through mechanisms distinct from those involved in Alzheimer’s disease,” Tomohiko Ishihara, MD, study lead at Niigata University in Japan, said in a university news story. “This provides a new perspective on why ALS pathology spreads differently among patients.”
The findings were reported in the study, “APOE ε4 influences the widespread TDP-43 pathological subtype in sporadic amyotrophic lateral sclerosis,” published in Acta Neuropathologica.
ALS is caused by the progressive loss of motor neurons, the nerve cells that control voluntary movements such as walking, speaking, swallowing, and breathing.
Variation among patients
A hallmark feature of ALS is the buildup of abnormal TDP-43 protein clumps inside nerve cells and supportive brain cells called glia. Scientists believe these toxic clumps interfere with normal cell function and contribute to nerve cell death.
However, the extent of this buildup varies considerably from patient to patient and cannot be explained solely by the length of time someone has been living with ALS. In some people, the clumps remain mostly confined to areas involved in movement; these patients are classified as having type 1 TDP-43 disease. In patients with type 2, clumps spread more widely into parts of the brain associated with memory, thinking, and behavior.
Because the APOE4 gene variant is known to promote the abnormal spread of amyloid-beta and tau proteins in Alzheimer’s disease, researchers wanted to investigate whether it might also affect the spread of TDP-43 clumps in ALS.
To find out, the team analyzed brain tissue and genetic data from 145 people with autopsy-confirmed ALS. About one-quarter of patients with available clinical data had dementia.
Based on the distribution of TDP-43 clumps in the brain, about half of the participants (55.2%) were classified as having type 1, and the rest as type 2. Compared with type 1 patients, those with type 2 were older at disease onset and at death, had shorter survival times, and were more likely to have dementia.
Genetic analyses showed that the most common APOE variant in the study population was APOE3, with about 20% of patients carrying APOE4. Most patients did not carry rare mutations in known ALS-related genes.
When the team compared gene and brain tissue data, they found that 65.5% of APOE4 carriers had the more widespread type 2 TDP-43 disease, compared with 39.7% of noncarriers. Statistical analyses showed carriers were nearly three times more likely to have type 2 disease.
Still, there were no significant differences between APOE4 carriers and noncarriers in age at onset, survival time, dementia prevalence, or the proportion of patients whose first symptoms affected speech and swallowing.
Further analyses suggested the relationship between the APOE4 variant and TDP-43 spread was independent of amyloid-beta and tau. In other words, the variant’s effect on TDP-43 changes did not seem to rely on the same protein pathways involved in Alzheimer’s disease.
“[APOE4] status is associated with the widespread TDP-43 pathological subtype evident in sporadic ALS,” the researchers wrote. Assessing APOE4 carrier status may help to better predict prognosis in people with ALS and “facilitate the development of targeted therapeutic strategies tailored to specific molecular subtypes of ALS,” they said.
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