Although Alzheimer’s is the most common neurological disease in old age, neither its causes nor its neurophysiological basis are fully understood. This also hinders the development of effective therapies. The new antibody active ingredients Lecanemab and Donanemab slow down the formation of amyloid plaques in the brains of those affected, but can only slow down the progression of dementia, not stop it. One reason for this could be that Alzheimer’s has inconsistent causes, so that therapies only work on some of these subtypes.
There were already initial indications of such subtypes: the breakdown of brain cells begins in different brain regions depending on the activity of the Alzheimer’s risk genes. Four subtypes were also discovered in the accumulation and spread of misfolded tau proteins.
Five subtypes of Alzheimer’s disease
Now there is new, more concrete data on the Alzheimer’s subtypes and their characteristics. It was discovered by a team led by Betty Tijms from the Alzheimer Center Amsterdam when they examined the proteins in the spinal fluid
419 Alzheimer’s patients and
197 healthy controls
analyzed. It reported in the journal “Nature Aging”.
The researchers examined which of the 3,800 proteins in the spinal fluid were increased or decreased in Alzheimer’s patients and what differences there were.
It turned out that 1058 proteins in the spinal fluid are significantly changed in Alzheimer’s patients – and form striking groupings. “The proteome profiles of Alzheimer’s patients form five subtypes,” report Tijms and her colleagues. These subtypes differ in the type and amount of altered proteins as well as other characteristics. Additional genetic analyzes showed that all five subtypes had a specific pattern of risk gene variants in addition to the well-known Alzheimer’s risk gene APOE4-e4.
Symptoms and progression vary
The five identified Alzheimer’s subtypes are also linked to specific symptoms, dementia progression rates and survival times of those affected. “The subtypes differ, for example, in how they progress from mild cognitive impairment to dementia:
Subtypes 2 and 5 have the highest risk.
Subtyp 4 the least”
reports the team. “Brain scans using magnetic resonance imaging also showed that the subtypes also differ in the extent and location of neuronal degradation.”
There are also differences in the rate of neuronal degradation:
patients with Subtyp 3 had the shortest survival time with an average of only around 5.6 years. They also showed a much steeper decline in memory and language tests and the highest levels of misfolded tau proteins, Tijms and her colleagues found. Those affected with Subtyp 1 In contrast, despite relatively high tau protein levels in the CSF, they survived the longest at around 8.9 years after diagnosis.
Five different causes?
But the new data also provides valuable information about the molecular and genetic causes of the five Alzheimer’s subtypes:
As the team determined, Subtyp 1 for example, linked to a high level of neuronal plasticity: in the cerebrospinal fluid of these patients there are a striking number of proteins that indicate the remodeling and increased activity of brain cells. “Such hyperactive neurons secrete more tau and amyloid and were primarily observed in the area of plaques,” report Tijms and her colleagues.
Subtyp 2 On the other hand, it is characterized more by immune-specific messenger substances and proteins. Some gene variants in this subtype are also linked to immune processes. “This suggests that an overactive innate immune system is making the disease worse,” say the researchers.
At Alzheimer-Subtyp 3 They found evidence of RNA dysregulation. A similar disorder has also been observed in frontotemporal dementia.
At the Subtyp 4 The patients show a noticeable accumulation of proteins that come from the so-called choroid plexus. This branched network of veins sits on the walls of the cerebral ventricles, produces cerebrospinal fluid and regulates the transport of substances through the blood-brain barrier. In Alzheimer’s patients with subtype 4, this regulation appears to be disturbed, as Tijms and her team report. The breakdown of brain matter is also relatively pronounced in this type.
In Alzheimer’s disease Subtyps 5 On the other hand, blood-typical proteins in the cerebrospinal fluid indicate that the blood-brain barrier is permeable and can no longer fulfill its protective function.
New starting points for diagnosis and therapy
According to the researchers, these findings open up valuable approaches for better diagnosis and treatment of Alzheimer’s. The differences between the five subtypes could explain why certain therapies only work in some patients. “Given the specific patterns of molecular processes and genetic risk profiles, it is likely that Alzheimer’s subtypes also require specific treatments,” the team writes.
At the same time, the Alzheimer’s subtypes could also explain why, for example, the antibody preparations only cause severe cerebral edema in some patients: those affected with subtype 5 may be particularly susceptible because the blood-brain barrier does not function properly. Knowledge of the subtype could therefore also be important for clinical studies of new active ingredients and therapies.
1.8 million Germans affected
In Germany, 1.8 million people live with dementia, and around 440,000 people become ill every year. And according to projections, this number of dementia sufferers will increase by around another million by 2050. This makes it all the more important to identify risk factors and therefore preventive measures.
How to prevent dementia
We have put together twelve risk factors that everyone can pay attention to in order to prevent Alzheimer’s. These tips are taken from the brochure “Preventing Alzheimer’s – Living Healthily, Aging Healthily”, in which all points are explained in detail. Alzheimer’s is the most common form of dementia.
1. Movement: What’s good for your heart is also good for your brain. This includes getting enough exercise – at least 2.5 hours per week is ideal.
2. Mental Fitness: Learn new things – even as you get older. This keeps your brain busy. Whether it’s a musical instrument, a language or using a computer, try something new.
3. Healthy diet: Follow the classic Mediterranean diet. Eat lots of fruits and vegetables, olive oil and nuts. Choose fish over red meat.
4. Social contacts: Activities are more fun as a couple or in a group and your gray cells are challenged. Arrange to meet up to do sports, play music, play cards or cook together.
5. Reduce excess weight: Be careful not to weigh too many kilos. A healthy diet and regular exercise will help you with this.
6. Enough sleep: Make sure you get good, sufficient sleep so that the brain can break down harmful substances and recover.
7. Don’t smoke: Smoking also damages your brain. Stop smoking, it’s never too late.
8. Avoid Head Injuries: Take care of your head in everyday life and during sport and, for example, wear a helmet when riding a bike.
9. Check high blood pressure: Have your blood pressure checked regularly. High blood pressure should definitely be treated.
10. Check Diabetes: Keep an eye on your blood sugar levels. If it is permanently too high, you should take action in consultation with your doctor.
11. Treat Depression: Take good care of yourself. If you feel listless or depressed for a long period of time, it makes sense to see your doctor to clarify the cause. Depression should not go untreated.
12. Pay attention to hearing loss: Take it seriously if you notice that your hearing is getting worse. With a hearing aid you can easily correct declining hearing ability.
Von Nadja Podbregar