Alzheimer's Disease Revealed to Have 5 Molecular Subtypes

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Alzheimer’s Disease Revealed to Have 5 Molecular Subtypes, Significantly Impacting Treatment Response

Alzheimer’s disease (AD) surprisingly exhibits five distinct molecular subtypes, explaining the significant variability in patients’ responses to treatment.

The pathological features of AD include the deposition of β-amyloid proteins and the formation of tau protein fibers in the brain, which are currently the focal points of drug development.

Earlier this month, the monoclonal antibody Luncaneu was approved for sale in China, marking the first domestically marketed anti-β-amyloid drug for treating Alzheimer’s.

However, mounting research suggests that the pathogenic mechanisms of AD are intricate and heterogeneous.

Focusing solely on β-amyloid deposits and tau protein abnormalities may lead to substantial clinical differences in treatment benefits among different patients.

A recent study by Betty M. Tijms and colleagues from the Free University of Amsterdam in the Netherlands conducted proteinomic analysis on the cerebrospinal fluid of 609 participants, revealing five molecular subtypes of AD.

These subtypes are characterized by neurogenesis, innate immune activation, RNA dysregulation, choroid plexus dysfunction, and blood-brain barrier dysfunction, each exhibiting distinct genetic features, clinical outcomes, survival times, and cortical atrophy patterns.

Alzheimer's Disease Revealed to Have 5 Molecular Subtypes, Significantly Impacting Treatment Response

The research underscores the importance of personalized treatment for AD, and the findings were recently published in the journal “Nature Aging.”

Cerebrospinal fluid surrounds the brain and spinal cord, serving as a buffer and protective medium while participating in the transport of nutrients and waste. The proximity of its components to the brain allows changes in cerebrospinal fluid composition to directly reflect the brain’s health.

In 2020, Betty M. Tijms and colleagues identified three molecular subtypes of AD based on cerebrospinal fluid proteinomics. With advancements in proteinomic technology, researchers believe it is time to refine the description of AD subtypes.

For this study, cerebrospinal fluid samples were collected from 609 participants, including 419 diagnosed with different stages of AD through biomarker testing (cognitive normal, mild cognitive impairment, and dementia) and others with normal cognitive abilities not diagnosed with AD.

Overall, 1058 cerebrospinal fluid proteins showed differential expression between non-AD individuals and AD patients.

Researchers further employed non-negative matrix factorization (NMF) to conduct cluster analysis on AD patients, categorizing them into five subtypes based on cerebrospinal fluid proteinomic characteristics.

Subtype 1 is characterized by neurogenesis, with upregulated proteins associated with neuronal plasticity, such as synaptic assembly, axon guidance, neuronal generation, and glial cell generation. The related AD genetic variation is TREM2 R47H.
Subtype 2 is characterized by innate immune activation, displaying elevated levels of specific proteins in microglial cells associated with innate immune activation. The related AD genetic variations include IDUA, CLNK, and SCIMP.
Subtype 3 is characterized by RNA dysregulation, with upregulated proteins involved in cell skeleton composition, axonal transport, proteasome function, protein folding, especially RNA-binding proteins like heterogeneous nuclear ribonucleoproteins (hnRNPs). Related AD genetic variations include BIN1, TREM2 R62H, SPDYE3, SNX1, KAT8.
Subtype 4 is characterized by choroid plexus dysfunction, with upregulated proteins related to choroid plexus development, involving cell adhesion, SMAD pathway, and elevated levels of immune cell-specific proteins such as microglial cells. Related AD genetic variations include ABCA7, PICALM, IL-34, CLNK.
Subtype 5 is characterized by blood-brain barrier dysfunction, with abnormally increased levels of proteins, such as albumin, fibrinogen, plasminogen, and thrombin, not typically found in the brain. This suggests the infiltration of blood-derived proteins into the brain due to blood-brain barrier damage. Proteins associated with blood clotting, B cell-mediated immune response, acute inflammatory response are upregulated. Related AD genetic variations include IL-34, ECHDC3, APP.

Among these, subtypes 1, 2, and 3 exhibit significantly increased levels of tau protein in cerebrospinal fluid, while subtypes 4 and 5 mostly have normal levels.

Compared to the control group, all AD subtypes show higher levels of APOE e4 gene variants and AD polygenic risk scores (PRS). Subtype 5 has the highest proportion of APOE e4 gene variant carriers.

Different subtypes carry varying risks of progression from mild cognitive impairment (MCI) to dementia, with subtypes 2 and 5 having the highest risk, and subtype 4 having the lowest risk.

Survival outcomes differ among subtypes, with subtype 3 having the shortest average survival time of 5.6 years, while subtype 1 has the longest at 8.9 years.

Furthermore, magnetic resonance imaging (MRI) scans reveal varying degrees of cortical atrophy among different subtypes. Compared to subtypes 1, 2, and 5, subtypes 2 and 4 exhibit more severe cortical atrophy.

Finally, researchers validated the AD subtypes identified through cerebrospinal fluid proteinomics using multiple cohort datasets from different countries. The results showed a close resemblance to the proportions observed in the discovery cohort, with 27.9% of AD patients being subtype 1, 35.5% subtype 2, 5.8% subtype 3, 17.1% subtype 4, and 16.6% subtype 5, with consistent characteristics.

These findings imply that identifying AD subtypes based on cerebrospinal fluid may aid in selecting individuals for specific treatments. For instance, subtype 1 patients may benefit from treatments targeting TREM2, subtype 2 may require innate immune suppressors, subtype 3 may need restoration of RNA function, subtype 4 may benefit from inhibiting monocyte infiltration, and subtype 5 may require treatments targeting brain vasculature.

Additionally, the potential side effects of certain treatments may also depend on the subtype. For example, in antibody therapy, although antibodies may more easily penetrate the blood-brain barrier in subtype 5 patients, they may also increase the risk of brain hemorrhage in these individuals.

In conclusion, when it comes to AD, it has been instinctive to consider it as a single disease for treatment. However, this study not only reveals the molecular complexity of AD but also provides a new perspective for personalized medical approaches to AD. As research deepens, there is hope for a better understanding of the intricate mechanisms of AD and the provision of more effective treatment strategies for patients.

Alzheimer’s Disease Revealed to Have 5 Molecular Subtypes, Significantly Impacting Treatment Response

References:

[1]Tijms, B.M., Vromen, E.M., Mjaavatten, O. et al. Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles. Nat Aging (2024). https://doi.org/10.1038/s43587-023-00550-7

[2]Tijms BM, Gobom J, Reus L, Jansen I, Hong S, Dobricic V, Kilpert F, Ten Kate M, Barkhof F, Tsolaki M, Verhey FRJ, Popp J, Martinez-Lage P, Vandenberghe R, Lleó A, Molinuevo JL, Engelborghs S, Bertram L, Lovestone S, Streffer J, Vos S, Bos I; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Blennow K, Scheltens P, Teunissen CE, Zetterberg H, Visser PJ. Pathophysiological subtypes of Alzheimer’s disease based on cerebrospinal fluid proteomics. Brain. 2020 Dec 1;143(12):3776-3792. doi: 10.1093/brain/awaa325

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