Cerebrospinal Fluid Levels of Amyloid Precursor Protein and Amyloid β-Peptide in Alzheimer’s Disease and Major Depression – Inverse Correlation with Dementia Severity

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by progressive dementia that ultimately leads to death. Histopathological hallmarks of AD include brain amyloid deposits and neurofibrillary tangles. Major depression is a frequent diagnosis in every gerontopsychiatric clinic that sees patients with both cognitive and affective disorders. Many depressed patients, in fact, are clinically characterized by cognitive impairments. Thus, an assay that excludes – or confirms – probable AD in cognitively impaired patients is desirable. Such assays may use protein markers that are derived from such histopathologically relevant molecules as the amyloid precursor protein (APP) and its derivatives including the amyloid β-peptides (Aβ). To evaluate the differential diagnostic properties of cerebrospinal fluid (CSF) Aβ and secreted soluble ectodomain (APPs), we quantitated CSF levels of these measures in AD patients and compared them to age-matched control patients with major depression. CSF levels of APPs and Aβ were similar in patients with AD or major depression, and the apolipoprotein E genotype had no influence on CSF levels of Aβ in AD patients. Measurement of Aβ peptide using a novel zinc/copper capture ELISA that detects aggregated Aβ peptides as well demonstrated similar levels in AD and major depression. In AD patients, CSF levels of total Aβ (Aβ1–40 plus Aβ1–42) were inversely correlated with a functional measure of dementia severity (NOSGER), suggesting that CSF levels of Aβ decrease with advancing severity of AD. Thus, CSF levels of Aβ are not useful for the differentiation of AD from major depression. However, CSF levels of Aβ reflect the severity of dementia and may be useful as biological markers of the stage of the disease.

The Cerebrospinal Fluid Levels of Tau, Growth-Associated Protein-43 and Soluble Amyloid Precursor Protein Correlate in Alzheimer’s Disease, Reflecting a Common Pathophysiological Process

“…The increase in CSF-GAP-43 may also reflect degeneration of axons or presynaptic terminals, or it may reflect processes related to regeneration of axons and/or synapses [11,12]. Previous studies using similar ELISAs for sAPP determination as in the present study found normal or decreased CSF-sAPP levels in AD [18,19,33]. The decreased levels have been interpreted as possibly reflecting abnormal metabolism of APP [18].…”

“…The decreased levels have been interpreted as possibly reflecting abnormal metabolism of APP [18]. Tau as well as GAP-43 and APP are found in axons and GAP-43 and APP also in synaptic sites [33][34][35][36][37][38][39][40]. The finding that the CSF levels of tau and GAP-43 correlate in the CSF of normals may reflect this colocalization.…”

“…Upon proteolytic cleavage, soluble forms of APP (sAPP) are secreted to the extracellular fluid and the CSF. Three studies found the CSF levels of total sAPP to be decreased in AD [17][18][19], but the numbers of included AD patients were small. The relation between CSF-sAPP and CSF-Aß 42 has hitherto not been investigated in patient studies.…”

Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid

“…In humans, the presence of A␤ circulating in blood and CSF has been consistently described (17,28,29). Furthermore, A␤ injected into brain and͞or CSF is cleared into blood (30), and A␤ injected into blood is sequestered by microvessels and is present in the CSF and brain parenchyma, where it can bind to existing amyloid deposits (27,31).…”

Antipsychotic medication is associated with selective alterations in ventricular cerebrospinal fluid Aβ 40 and tau in patients with intractable unipolar depression

“…Some limited and equivocal clinical evidence exists regarding such proteins in people with depression. For example, Hock et al (1998) demonstrated similar levels of L-cerebrospinal fluid (CSF) combined total Ab (Ab 1-42 and 1-40) and amyloid precursor protein (APP) in depression and AD, whilst other observers have not identified the reduction in L-CSF Ab 1-42 in depression that is seen in AD (Sjogren et al, 2000;Andreasen et al, 2003;Andersson et al, 2008). Furthermore a recent study reported that elderly women with depression exhibited higher L-CSF levels and L-CSF:serum ratio of Ab 1-42 than controls without depression, but did not identify any alteration in L-CSF total tau (Gudmundsson et al, 2007).…”