Alzheimer’s Disease: Identification of Five Distinct Subtypes

New insights into forms of dementia based on CSF proteomics, disease progression and molecular basis

A new study from the Netherlands provides insights into the heterogeneity of Alzheimer’s disease. Alzheimer’s dementia, known as the most common neurological disease in old age, shows a remarkable heterogeneity that has not yet been fully understood. This knowledge gap has proven to be an obstacle in the development of effective therapies. Current treatments, including novel antibody therapies such as lecanemab and donanemab, aim to slow the formation of amyloid plaques in the brain. However, these measures are not sufficient to slow or even stop the progression of dementia in the long term. One reason for the limited effectiveness could be the diversity of Alzheimer’s subtypes, which have not yet been sufficiently differentiated.

Detailed proteome analysis reveals five subtypes

A research team led by Betty Tijms at the “Alzheimer Center Amsterdam” has now made a significant breakthrough by identifying five distinct Alzheimer’s subtypes. This discovery is based on a detailed analysis of the proteins in the cerebrospinal fluid of 419 Alzheimer’s patients and 197 healthy controls. Using mass spectrometry and AI-assisted methods, the researchers were able to identify significant differences in the proteome profiles of the Alzheimer’s patients, indicating five clearly distinguishable subtypes.

Subtypes with different clinical and molecular characteristics

Each of the identified subtypes has unique characteristics, both in terms of the composition and concentration of altered proteins and in their genetic risk profiles. These distinctions are not only significant at the molecular level, but also correlate with clinical features such as the rate of progression of dementia, specific symptoms and survival times of those affected. For example, subtypes 2 and 5 show a higher risk of a faster transition from mild cognitive impairment to full-blown dementia, while subtype 4 makes this transition more slowly.

Subtype-specific molecular and genetic findings

Interestingly, the study also revealed subtype-specific patterns in terms of molecular and genetic causes. Subtype 1, for example, is associated with high neuronal plasticity, while subtype 2 is characterized by immune-specific markers. Subtype 3 showed abnormalities in RNA regulation, similar to findings in frontotemporal dementia. Subtype 4 is characterized by impaired choroid plexus function, and in subtype 5, an impaired blood-brain barrier indicates reduced protective function. Patients with subtype 5 are therefore particularly susceptible to the dreaded cerebral edema caused by the antibodies lecanemab and donanemab.

Potential impact on diagnosis and therapy

These findings could have far-reaching implications for the diagnosis and treatment of Alzheimer’s disease. Understanding the specific differences between subtypes could explain why certain therapies are only effective in some patients. The identification of subtypes could thus lead to personalized treatment approaches and improve the effectiveness of clinical trials and new therapies.

Non-invasive brain stimulation (NIBS) as an option for Alzheimer’s treatment

Non-invasive brain stimulation (NIBS) methods such as repetitive transcranial magnetic stimulation (rTMS) or Transcranial Pulse Stimulation (TPS), which uses low-energy shock waves, have also shown promise in improving cognition and neuropsychiatric symptoms in Alzheimer’s patients. The findings from their research could be relevant for the specific Alzheimer’s subtypes by offering targeted and personalized therapeutic approaches for improving cognitive functions, which can also be performed on an outpatient basis and are far less organizationally complex than infusion therapies. Due to their safety and low side effects, they are also well tolerated by patients and eliminate the need for close MRI checks.


Nature Aging, 2024; doi: 10.1038/s43587-023-00550-7