3. Dementia Phenotype and Biomarkers
The phenotypic features of the disease represent the biomarkers to be modified with an effective therapeutic intervention. Important differences have been found in the AD population as compared with healthy subjects in different biological parameters, including blood pressure, glucose, cholesterol and triglyceride levels, transaminase activity, hematological parameters, metabolic factors, thyroid function, brain hemodynamic parameters, and brain mapping activity [6,7,8,11,12,13,14,15,16]. Blood pressure values, glucose levels and cholesterol levels are higher in AD than in healthy elderly subjects. Approximately 20% of AD patients are hypertensive, 25% are diabetics, 50% are hypercholesterolemic, and 23% are hypertriglyceridemic. Over 25% of the patients exhibit high GGT activity, 5–10% show anemic conditions, 30–50% show an abnormal cerebrovascular function characterized by poor brain perfusion, and over 60% have an abnormal electroencephalographic pattern, especially in frontal, temporal, and parietal regions, as revealed by quantitative EEG (qEEG) or computerized mapping [6,7,8]. Significant differences are currently seen between females and males, indicating the effect of gender on the phenotypic expression of the disease. In fact, the prevalence of dementia is 10–15% higher in females than in males from 65 to 85 years of age. All these parameters are highly relevant when treating AD patients because some of them reflect a concomitant pathology which also needs therapeutic consideration. They can also represent general biomarkers together with regional brain atrophy and perfusion and cognitive function, which may serve as therapeutic outcome measures. Other biomarkers of potential interest include cerebrospinal fluid (CSF) and peripheral levels of Aβ42, protein tau, histamine, interleukins, and some other candidate markers [7,108,109]. In proteomic studies, several candidate CSF protein biomarkers have been assessed in neuropathologically confirmed AD, non-demented (ND) elderly controls and non-AD dementias (NADD). Markers selected included apolipoprotein A-1 (ApoA1), hemopexin (HPX), transthyretin (TTR), pigment epithelium-derived factor (PEDF), Aβ1-40, Aβ1-42, total tau, phosphorylated tau, α-1 acid glycoprotein (A1GP), haptoglobin, zinc α-2 glycoprotein (Z2GP) and apolipoprotein E (ApoE). The concentrations of Aβ1-42, ApoA1, A1GP, ApoE, HPX and Z2GP differed significantly among AD, ND and NADD subjects. The CSF concentrations of these three markers distinguished AD from ND subjects with 84% sensitivity and 72% specificity, with 78% of subjects correctly classified. By comparison, using Aβ1-42 alone gave 79% sensitivity and 61% specificity, with 68% of subjects correctly classified. For the diagnostic discrimination of AD from NADD, only the concentration of Aβ1-42 was significantly related to diagnosis, with a sensitivity of 58% and a specificity of 86% [110].