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J. Neurochem. (2012) 120 (Suppl. 1), 186–193. Abstract Recent advances in the understanding of Alzheimer’s disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β (Aβ) peptide represents an important molecular target for intervention in Alzheimer’s disease. Several types of Aβ peptide immunotherapy for Alzheimer’s disease are under investigation, direct immunization with synthetic intact Aβ42, active immunization involving the administration of synthetic fragments of Aβ peptide conjugated to a carrier protein and passive administration with monoclonal antibodies directed against Aβ peptide. Pre‐clinical studies showed that immunization against Aβ peptide can provide protection and reversal of the pathology of Alzheimer’s disease in animal models. Indeed, several adverse events have been described like meningoencephalitis with AN1792, vasogenic edema and microhemorrhages with bapineuzumab. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer’s disease, this clearance did not show significant cognitive effect for the moment. Currently, several Aβ peptide immunotherapy approaches are under investigation but also against tau pathology.

It has been shown that, during several years preceding the diagnosis of Alzheimer's disease there is a gradual cognitive decline with a continuum between the pre-dementia stage (still known as the prodromal stage but now included within the general concept of mild cognitive impairment [MCI]) and the other stages of the disease. In MCI, the use of cholinesterase inhibitors (ChEIs) is not associated with any delay in the onset of Alzheimer's disease or dementia. During the dementia stages, the three ChEIs (donepezil, galantamine and rivastigmine) are efficacious for mild to moderate Alzheimer's disease; therefore, monotherapy with a ChEI can be envisaged as initial treatment. Confirmation of the efficacy of ChEIs in the mild dementia stage is essentially based on the results from a single, randomized study carried out specifically among patients at this stage of severity. Memantine can represent an alternative to ChEIs in the moderate stage of Alzheimer's disease. At the severe stage of the disease, memantine and donepezil are currently indicated. Indeed, memantine has been approved by numerous drug regulatory agencies for use in severe stages of the disease, whereas donepezil has only been approved by the US FDA. There is currently insufficient evidence for recommending combination therapy in Alzheimer's disease.

Introduction Multinutrient approaches may produce more robust effects on brain health through interactive qualities. We hypothesized that a blood‐based nutritional risk index (NRI) including three biomarkers of diet quality can explain cognitive trajectories in the multidomain Alzheimer prevention trial (MAPT) over 3‐years. Methods The NRI included erythrocyte n‐3 polyunsaturated fatty acids (n‐3 PUFA 22:6n‐3 and 20:5n‐3), serum 25‐hydroxyvitamin D, and plasma homocysteine. The NRI scores reflect the number of nutritional risk factors (0–3). The primary outcome in MAPT was a cognitive composite Z score within each participant that was fit with linear mixed‐effects models. Results Eighty percent had at lease one nutritional risk factor for cognitive decline (NRI ≥1: 573 of 712). Participants presenting without nutritional risk factors (NRI=0) exhibited cognitive enhancement (β = 0.03 standard units [SU]/y), whereas each NRI point increase corresponded to an incremental acceleration in rates of cognitive decline (NRI‐1: β = −0.04 SU/y, P = .03; NRI‐2: β = −0.08 SU/y, P < .0001; and NRI‐3: β = −0.11 SU/y, P = .0008). Discussion Identifying and addressing these well‐established nutritional risk factors may reduce age‐related cognitive decline in older adults; an observation that warrants further study.

Physical activity (PA) demonstrated benefits on brain health but its relationship with blood biomarkers of neurodegeneration remains poorly investigated. We explored the cross-sectional associations of physical activity with blood concentrations of neurofilament light chain (NFL) and beta amyloid (Aβ)42/40. We further examined whether the interaction between PA and these biomarkers was longitudinally related with cognition. Four-hundred and sixty-five non-demented older adults engaged in an interventional study and who had concomitant assessment of PA levels and blood measurements of NFL (pg/ml) and Aβ42/40 were analysed. A composite Z score combining 4 cognitive tests was used for cognitive assessment up to a 4-year follow-up. Multiple linear regressions demonstrated that people achieving 500-999 and 2000 + MET-min/week of PA had lower (ln)NFL concentrations than their inactive peers. Logistic regressions revealed that achieving at least 90 MET-min/week of PA was associated with lower probability of having high NFL concentrations (i.e ≥ 91.961 pg/ml (3 rd quartile)). PA was not associated with (Aβ)42/40. Mixed-model linear regressions demonstrated that the reverse relationship between PA and cognitive decline tended to be more pronounced as Aβ42/40 increased, while it was dampened with increasing levels of (ln)NFL concentrations. This study demonstrates that PA is associated with blood NFL but not with Aβ42/40. Further, it suggests that PA may attenuate the negative association between amyloid load and cognition, while having high NFL levels mitigates the favourable relationship between PA and cognition. More investigations on older adults not involved any interventional study are required for further validation of the present findings.