Blood protein structure changes may enable earlier detection of Alzheimer’s

Your competent? doctor figured out what to do about proteostasis years ago, right.

• proteostasis (4 posts to March 2023)

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Blood protein structure changes may enable earlier detection of Alzheimer’s

A recent study in Nature Aging combined mass spectrometry-based structural proteomics with machine learning to establish a minimally invasive, reliable, and potentially scalable research strategy for early detection and classification of Alzheimer’s disease (AD) and related cognitive conditions.

Protein homeostasis disruption and structural biomarkers in Alzheimer’s disease

Proteostasis, or protein homeostasis, refers to the cellular processes that maintain proper protein folding, stability, and degradation. These mechanisms are crucial because a substantial proportion of newly synthesized proteins can misfold, disrupting normal cell function if not managed by cellular quality control systems.

In AD, the machinery responsible for proteostasis becomes less effective, allowing misfolded proteins and damaged cellular components to build up over time. This impaired clearance supports the early accumulation of amyloid-β aggregates, abnormal protein clumps that can form in the brain years before the first signs of Alzheimer’s symptoms appear. A comprehensive understanding of protein conformational changes and interactions, beyond the traditional focus on amyloid plaques and tau tangles, could uncover disease mechanisms and plasma-based structural biomarkers.

Apolipoprotein E (APOE) is a polymorphic plasma protein with three major isoforms (ε2, ε3, ε4) differing by one or two amino acids, leading to altered binding properties. The ε4 allele is strongly associated with increased AD risk, while ε2 confers protection. Despite extensive characterization of APOE genotype expression profiles and network effects, the impact of APOE variants on the structure of ApoE-interacting proteins remains underexplored.

Neuropsychiatric symptoms (NPSs) are prevalent in AD, with sex differences noted in progression and symptomatology. Women tend to experience more rapid cognitive decline and higher rates of delusion, while men exhibit increased apathy and agitation. Despite growing efforts to define molecular correlates of NPSs, the relationship between sex and NPSs remains unclear due to clinical heterogeneity in AD.

Assessing protein structure alterations in Alzheimer’s disease

Blood samples were collected from participants at the University of California, San Diego (UCSD) and the University of Southern California Alzheimer’s Disease Research Centers. Alzheimer’s pathology in the UCSD cohort was supported by cerebrospinal fluid (CSF) measurements of amyloid-β and tau, while clinical status across cohorts was evaluated using established diagnostic criteria. Participants were assessed biannually for cognitive function and categorized using standard criteria, including the Clinical Dementia Rating (CDR) and neuropsychological testing.

Peptide samples were analyzed by Liquid Chromatography–Tandem Mass Spectrometry (LC–MS/MS) coupled to a timsTOF Pro mass spectrometer. A machine learning framework was used to classify mass spectrometry data, with a deep neural network selected after benchmarking against 17 additional machine learning algorithms.

Identification of structural blood biomarkers for early AD detection

A total of 520 blood samples were obtained from two large cohorts. By combining blood assessment findings with detailed clinical and biomarker data, including cognitive tests and cerebrospinal fluid (CSF) measures, where available, researchers classified Alzheimer’s disease (AD) status and progression.