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 CSF Aβ and 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 demonstrated as well 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 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.Levels of the major protein component of NFTs, the microtubule protein Tau, were shown to be increased in CSF of AD patients as compared to age-matched controls. The presence of the apolipoprotein E-e4 allele (APOE4) is a risk factor for sporadic and familial late-onset AD. ApoE may interact with the binding of Tau to microtubules and Tau phosphorylation in an isotorm-specific manner. We investigated whether direct evidence of an isoform- specific interaction of apoE and Tau can be demonstrated in CSF of live AD patients. We measured the apoE genotype and CSF levels of Tau in 19 patients with probAβ1e AD and 12 age-matched control subjects. We found that CSF levels of Tau increase with increasing APOE4 allele frequency (Spearman rank correlation, z = 2.71, p = 0.007). This finding may be in agreement with reports of a lesser binding of apoE4 to Tau, compared to apoE2 and apoE3, resulting in higher levels of unbound Tau in CSF.