Work

Mechanisms linking proteins and structural brain integrity to biological markers of Alzheimer’s Disease

Year: 2023

Type: article

Abstract: Background Medial temporal lobe (MTL) networks, including posterior‐medial (PM) and anterior‐temporal (AT) subnetworks, are early affected by Alzheimer’s disease (AD) pathologies (tau, neurodegeneration) and are critical for memory, which declines in AD. The biological pathways linking AD pathology, changes in MTL‐AT‐PM structural connectivity (SC), and cognitive decline, are unknown. Plasma protein levels reflect those in the cerebrospinal fluid, providing a low‐invasive potential means of understanding molecular brain changes that occur in AD. These measures may help explain how AD pathology, MTL‐AT‐PM SC, and cognitive decline are linked at the molecular level. We used predefined aging‐related plasma proteins from a meta‐analysis to explore links between MTL‐AT‐PM SC, AD pathologies, and cognitive decline. Method MTL‐AT‐PM SC scores and plasma protein levels from 100 participants (Stanford ADRC: mean age = 73.7y, 82 healthy control, 16 mild cognitive impairment, and 2 AD) were entered into an Coupled tensor and matrix factorization algorithm, generating clusters based on shared SC‐protein variance. Linear regression analyses were conducted to evaluate cluster relationships with domains of AD (memory, plasma tau, and neurodegeneration by plasma NfL and cortical thickness index). Result Two (out of 12 total) SC‐protein clusters significantly related to both tau and neurodegeneration. Both had similar highly contributing proteins (TNFRSF1B.3152.57.1, TNFRSF1B.8368.102.3, GRN.4992.49.1, TNC.4155.3.2, RPS3A.5484.63.3, CD163.5028.59.1, EFNA4.2614.28.2) and SC regions (bilateral: hippocampus, and left: parahippocampal cortex, precuneus, thalamus, and isthmus cingulate). Hippocampal laterality (bilateral vs. opposite directions for left vs. right) and the direction of their relationship to tau/neurodegeneration differentiated these clusters. A 3rd cluster was uniquely associated with composite memory (SC: bilateral: lateral occipital and parahippocampus, left: inferior temporal and hippocampus; proteins: EGFR.2677.1.1, SFRP1.3221.54.1, FAS.9459.7.3, ERBB3.2617.56.35, CFD.13678.169.3, LRP1.8601.167.3, and LPO.4801.13.3). Conclusion Protein‐SC clusters showed both overlapping and unique associations to AD‐associated memory, tau, and neurodegeneration. Two clusters centered on the hippocampus and proteins related to inflammation showed relationships to both tau and neurodegeneration, suggesting they may be important for linking these two aspects of AD pathology. A memory‐related cluster was dominated by neurogenesis related proteins, and occipital/parahippocampal cortex. These findings suggest molecular pathways may differentially affect the left vs. right hippocampus, and AD‐associated pathologies vs. cognition.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz.077279

Authors: Adam Turnbull, Yejin Kim, Kai Zhang, Tianrui Mao, Xiaoqian Jiang, Victor Henderson, Zihuai He, Feng Vankee Vankee Lin, Feng Vankee Vankee Lin

Institutions: University of Rochester, The University of Texas Health Science Center at Houston, Stanford University, Stanford Medicine

Language: English

Topic: Dementia and Cognitive Impairment Research

Subfield: Psychiatry and Mental health

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: bronze

OpenAlex ID: W4390194112

FWCI:

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