BackgroundThe apolipoprotein E epsilon 4 (APOE-4) is associated with a genetic vulnerability to Alzheimer's disease (AD) and with AD-related abnormalities in cortical rhythms. However, it is unclear whether APOE-4 is linked to a specific pattern of intrinsic functional disintegration of the brain after the development of the disease or during its different stages. This study aimed at identifying spatial patterns and effects of APOE genotype on resting-state oscillations and functional connectivity in patients with AD, using a physiological connectivity index called “lagged phase synchronization”.Methodology/Principal FindingsResting EEG was recorded during awake, eyes-closed state in 125 patients with AD and 60 elderly controls. Source current density and functional connectivity were determined using eLORETA. Patients with AD exhibited reduced parieto-occipital alpha oscillations compared with controls, and those carrying the APOE-4 allele had reduced alpha activity in the left inferior parietal and temporo-occipital cortex relative to noncarriers. There was a decreased alpha2 connectivity pattern in AD, involving the left temporal and bilateral parietal cortex. Several brain regions exhibited increased lagged phase synchronization in low frequencies, specifically in the theta band, across and within hemispheres, where temporal lobe connections were particularly compromised. Areas with abnormal theta connectivity correlated with cognitive scores. In patients with early AD, we found an APOE-4-related decrease in interhemispheric alpha connectivity in frontal and parieto-temporal regions.Conclusions/SignificanceIn addition to regional cortical dysfunction, as indicated by abnormal alpha oscillations, there are patterns of functional network disruption affecting theta and alpha bands in AD that associate with the level of cognitive disturbance or with the APOE genotype. These functional patterns of nonlinear connectivity may potentially represent neurophysiological or phenotypic markers of AD, and aid in early detection of the disorder.

About 80% of functional genes in the human genome are expressed in the brain and over 1,200 different genes have been associated with the pathogenesis of CNS disorders and dementia. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variations in specific candidate genes and the positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. 10-20% of Western populations are defective in genes of the CYP superfamily; and the pharmacogenomic response of psychotropic drugs also depends on genetic variants associated with dementia. Prospective studies with anti-dementia drugs or with multifactorial strategies have revealed that the therapeutic response to conventional drugs in Alzheimer’s disease is genotype-specific. The disease-modifying effects (cognitive performance, biomarker modification) of therapeutic intervention are APOE-dependent, with APOE-4 carriers acting as the worst responders (APOE-3/3 > APOE-3/4 > APOE-4/4). APOE-CYP2D6 interactions also influence the therapeutic outcome in patients with dementia.

Treatment with neurotrophic agents might enhance and/or prolong the effects of cholinesterase inhibitors (ChEIs) in Alzheimer's disease (AD). We compared the safety and efficacy of the neurotrophic compound Cerebrolysin (10 ml; n=64), donepezil (10 mg; n=66) and a combination of both treatments (n=67) in mild-to-moderate (mini-mental state examination-MMSE score 12-25) probable AD patients enrolled in a randomized, double-blind trial. Primary endpoints were global outcome (Clinician's Interview-Based Impression of Change plus caregiver input; CIBIC+) and cognition (change from baseline in AD Assessment Scale-cognitive subscale+; ADAS-cog+) at week 28. Changes in functioning (AD Cooperative Study-Activities of Daily Living scale, ADCS-ADL) and behaviour (Neuropsychiatric Inventory, NPI) were secondary endpoints. Treatment effects in cognitive, functional and behavioral domains showed no significant group differences; whereas improvements in global outcome favored Cerebrolysin and the combination therapy. Cognitive performance improved in all treatment groups (mean±SD for Cerebrolysin: -1.7±7.5; donepezil: -1.2±6.1; combination: -2.3±6.0) with best scores in the combined therapy group at all study visits. Cerebrolysin was as effective as donepezil, and the combination of neurotrophic (Cerebrolysin) and cholinergic (donepezil) treatment was safe in mild-to-moderate AD. The convenience of exploring long-term synergistic effects of this combined therapy is suggested.

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