Harvard scientists propose new indicator of Alzheimer's disease that can predict the time and severity of onset

▎WuXi AppTec Content Team Editor In the field of Alzheimer's disease research, the amyloid cascade hypothesis is one of the most popular hypotheses
.

According to this theory, excess or failure to clear amyloid beta (Aβ) fragments leads to the deposition of soluble Aβ oligomers and insoluble amyloid in the brain, forming amyloid plaques
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The Aβ aggregates in the brains of Alzheimer's disease patients are mostly long fragments with a relatively large number of amino acids, namely Aβ42 and Aβ40
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Therefore, detecting the ratio of Aβ42/Aβ40 in plasma or cerebrospinal fluid has become a biomarker and entered clinical practice
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Image source: 123RF However, a new study recently published in Alzheimer's and Dementia, a professional journal in the field of Alzheimer's disease research, found that the ratio of short fragments of Aβ37 to long fragments of Aβ42 may be related to the ratio of Aβ42/Aβ40.
Better prediction of Alzheimer's disease as a biomarker
.

In this study, Dr.
Lei Liu and colleagues at Harvard's Brigham and Women's Hospital found that lower Aβ37/Aβ42 ratios in cerebrospinal fluid were associated with earlier onset of symptoms in familial Alzheimer's disease associated with more severe cognitive impairment in sporadic Alzheimer's disease
.

In this study, the scientists measured Aβ peptides of all six lengths produced by presenilin-1 mutant cells using an immunoassay they developed
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Aβ polypeptide fragments are formed by multiple cleavage of amyloid precursor (APP) by γ-secretase
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γ-secretase cleaves three or four amino acids at a time, and when certain mutations occur in the catalytic subunit of the γ-secretase complex (such as presenilin) ​​or its substrates, the processing function of the γ-secretase complex is disrupted, resulting in more Long, aggregation-prone Aβ42 or Aβ43 are overproduced, and short fragments such as Aβ37 are relatively scarce
.

The researchers found that the ratio of short peptides to long peptides could not only distinguish presenilin mutant cells from normal cells, but in more than 100 mutant cells, the ratio of Aβ37/42 was more sensitive to detect presenilin than Aβ42/40.
Aβ37/42 ratio can be used to assess the age of onset of familial Alzheimer's disease
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This ratio of short to long peptides has also demonstrated utility in assessing sporadic Alzheimer's disease
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The researchers compared the brain tissue and cerebrospinal fluid of Alzheimer's disease patients with those of cognitively normal subjects and found that the ratio of Aβ37/42 could better distinguish cognitively normal people from cognitively impaired people than Aβ42/40
.

The research paper concludes that measuring this new ratio of Aβ37/42, combined with other hallmark pathological features of Alzheimer's disease (such as hyperphosphorylated tau protein), is expected to provide a high degree of discrimination for Alzheimer's disease.
fluid detection biomarkers
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Reference: [1] Lei Liu et al.
, (2022) Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease.
Alzheimers Dement.
Doi: 10.
1002/alz.
12646