TY - JOUR
T1 - Cerebrospinal fluid proteomic signatures in cognitively normal individuals identify distinct clusters linked to neurodegeneration
AU - Seo, Dahun
AU - Do, Anh N.
AU - Heo, Gyujin
AU - Kwon, Jiseon
AU - Song, Soomin
AU - Apio, Catherine
AU - Lee, Cheolmin Matthew
AU - Timsina, Jigyasha
AU - Gong, Katherine
AU - Chen, Yike
AU - Liu, Menghan
AU - Kohlfeld, Pat
AU - Budde, John
AU - Boada, Merce
AU - Orellana, Adelina
AU - Fernandez, Maria Victoria
AU - Ruiz, Agustin
AU - Morris, John C.
AU - Schindler, Suzanne E.
AU - Ibanez, Laura
AU - Park, Taesung
AU - Cruchaga, Carlos
AU - Sung, Yun Ju
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.
PY - 2025/10
Y1 - 2025/10
N2 - Age and APOE ε4 are major risk factors for Alzheimer’s disease (AD), while sex differences exist in disease prevalence and progression. Cerebrospinal fluid (CSF) proteomics can provide additional insights into brain aging and AD. To examine proteomic changes due to age, sex and apolipoprotein E (APOE) ε4 along with amyloid status before clinical AD occurs, we profiled 6,175 proteins in the CSF from 994 cognitively normal individuals aged 43–91 years. We identified and replicated 2,172 age-associated, 711 sex-associated, 193 APOE ε4-associated and 1,807 amyloid-associated proteins, with extensive overlap suggesting their interplay. These CSF-specific signatures were distinct from those in plasma. Network analysis revealed two proteomic modules—M2 (age-associated, sex-associated and amyloid-associated) and M6 (age-associated and sex-associated)—which were linked to neuropsychiatric and aging-related diseases. Together, our study provides proteomic changes during the early phase of AD, which may help identify new therapeutic targets of AD.
AB - Age and APOE ε4 are major risk factors for Alzheimer’s disease (AD), while sex differences exist in disease prevalence and progression. Cerebrospinal fluid (CSF) proteomics can provide additional insights into brain aging and AD. To examine proteomic changes due to age, sex and apolipoprotein E (APOE) ε4 along with amyloid status before clinical AD occurs, we profiled 6,175 proteins in the CSF from 994 cognitively normal individuals aged 43–91 years. We identified and replicated 2,172 age-associated, 711 sex-associated, 193 APOE ε4-associated and 1,807 amyloid-associated proteins, with extensive overlap suggesting their interplay. These CSF-specific signatures were distinct from those in plasma. Network analysis revealed two proteomic modules—M2 (age-associated, sex-associated and amyloid-associated) and M6 (age-associated and sex-associated)—which were linked to neuropsychiatric and aging-related diseases. Together, our study provides proteomic changes during the early phase of AD, which may help identify new therapeutic targets of AD.
UR - https://www.scopus.com/pages/publications/105019064665
U2 - 10.1038/s43587-025-00971-6
DO - 10.1038/s43587-025-00971-6
M3 - Article
C2 - 41087722
AN - SCOPUS:105019064665
SN - 2662-8465
VL - 5
SP - 2125
EP - 2141
JO - Nature Aging
JF - Nature Aging
IS - 10
ER -