Defective mitophagy is consistently found in postmortem brain and iPSC-derived neurons from Alzheimer disease (AD) patients. However, there is a lack of extensive examination of mitophagy status in serum or cerebrospinal fluid (CSF), and the clinical potential of mitophagy biomarkers has not been tested. We quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1, BNIP3L and TFEB) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n = 100), dementia due to AD (AD-dementia, n = 100), and cognitively unimpaired individuals (CU, n = 46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Specifically, levels of PINK1 positively correlated with phosphorylated (p)-MAPT/tau (181), total (t)-MAPT/tau, NEFL (neurofilament light chain), and NRGN (neurogranin) levels in CSF and negatively with memory, executive function, and language domain. Serum TFEB levels negatively correlated with NEFL and positively with executive function and language. This study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology.Abbreviation: Aβ: amyloid beta; AD: Alzheimer disease; AVs: autophagic vacuoles; BNIP3L: BCL2 interacting protein 3 like; CU: cognitively unimpaired; CSF: cerebrospinal fluid; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCI: mild cognitive impairment; NRGN: neurogranin; NEFL: neurofilament light chain; p-MAPT/tau: phosphorylated microtubule associated protein tau; PINK1: PTEN induced kinase 1; t-MAPT/tau: total microtubule associated protein tau; TFEB: transcription factor EB; TMT: Trail Making Test.

• Keywords
• Autophagy, BNIP3L, PINK1, TFEB, mild cognitive impairment, mitophagy,
• MeSH
• Alzheimer Disease * cerebrospinal fluid   blood   diagnosis   MeSH
• Biomarkers * cerebrospinal fluid   blood   metabolism   MeSH
• Cognitive Dysfunction cerebrospinal fluid   blood   diagnosis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Membrane Proteins cerebrospinal fluid   metabolism   blood   MeSH
• Mitophagy * MeSH
• Brain metabolism   pathology   MeSH
• Tumor Suppressor Proteins MeSH
• Protein Kinases metabolism   MeSH
• tau Proteins cerebrospinal fluid   metabolism   MeSH
• Proto-Oncogene Proteins cerebrospinal fluid   blood   metabolism   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers * MeSH
• BNIP3L protein, human MeSH Browser
• Membrane Proteins MeSH
• Tumor Suppressor Proteins MeSH
• Protein Kinases MeSH
• tau Proteins MeSH
• Proto-Oncogene Proteins MeSH
• PTEN-induced putative kinase MeSH Browser
• TFEB protein, human MeSH Browser
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors MeSH