Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease in the Era of Disease-Modifying Treatments

Abstract

Correct in vivo diagnosis of Alzheimer’s disease (AD) helps to avoid administration of disease-modifying treatments in non-AD patients, and allows the possible use of such treatments in clinically atypical AD patients. Cerebrospinal fluid (CSF) biomarkers offer a tool for AD diagnosis. A reduction in CSF β-amyloid (marker of amyloid plaque burden), although compatible with Alzheimer’s pathological change, may also be observed in other dementing disorders, including vascular cognitive disorders due to subcortical small-vessel disease, dementia with Lewy bodies and normal-pressure hydrocephalus. Thus, for the diagnosis of AD, an abnormal result of CSF β-amyloid may not be sufficient, and an increase in phospho-tau (marker of tangle pathology) is also required in order to confirm AD diagnosis in patients with a typical amnestic presentation and reveal underlying AD in patients with atypical or mixed and diagnostically confusing clinical presentations.

Proteome-wide association studies using summary proteomic data identified 23 risk genes of Alzheimer’s disease

“…Blood plasma contains proteins that affect brain functions from the periphery, as well as proteins exported from the brain 42 . Especially, recent studies have shown that amyloid beta and phosphorylated tau presenting in CSF and plasma could be used as biomarkers for detecting AD dementia in early stages [13][14][15][16] . Therefore, our PWAS results leveraging proteomics data of plasma and CSF tissues in addition to brain are expected to reveal important risk genes of AD mediated through protein abundances in biofluids, providing valuable insights into future biomarker discovery of AD dementia.…”

“…In this work, we utilized our recently developed OTTERS 11 tool to expand the PWAS analyses of AD dementia, by leveraging pQTL summary data of not only brain (parietal lobe cortex, n=380) but also other important tissues such as cerebrospinal fluid (CSF, n=835) and plasma (n=529) tissues 12 . Recent studies have shown that amyloid beta (A𝛽)1-42/A𝛽1-40 and phosphorylated tau/A𝛽1-42 ratios in CSF 13,14 and plasma 15,16 could be used as biomarkers for early diagnosis of AD. Thus, conducting PWAS with the recent GWAS summary data of AD dementia (n=~762K) 2 in all three tissues (brain, CSF, and plasma) is expected to identify more risk genes of AD whose genetic effects are potentially mediated through the genetically regulated protein abundances.…”

Critical Factors in Sample Collection and Preparation for Clinical Metabolomics of Underexplored Biological Specimens

“…Thus, the CSF is a key biological specimen for analyzing brain metabolism and understanding CNS diseases, providing insights into disease mechanisms [ 95 ]. Due to the increasing number of patients diagnosed with neurodegenerative and mental disorders such as multiple sclerosis [ 96 ], Parkinson’s disease [ 97 , 98 ], Alzheimer’s disease [ 99 ], epilepsy [ 100 ], and other slowly progressive diseases, the interest in the study of the CSF has expanded [ 93 , 101 , 102 , 103 ].…”

Plasma Phospho-Tau-181 as a Diagnostic Aid in Alzheimer’s Disease

“…More recently, they have been considered as core features for the definition of AD as an in vivo biological process [ 4 ], regardless of the presence or absence of symptoms and their type or severity (mild cognitive impairment or dementia). They have proven to be useful as diagnostic tools for the diagnostic work-up of dementia [ 5 , 6 , 7 , 8 ] and some movement disorders [ 9 , 10 ] during life. Additional candidate CSF biomarkers, including α-synuclein [ 11 , 12 ] and the transactive response DNA binding protein-43 (TDP-43) [ 13 ], are being thoroughly investigated, but work still has to be done before they become established biomarkers.…”