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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.

Objective: To investigate in vivo the relationship of regional brain b-amyloid (Ab) to gait speed in a group of elderly individuals at high risk for dementia. Methods: Cross-sectional associations between brain Ab as measured with [18 F]florbetapir PET and gait speed were examined in 128 elderly participants. Subjects ranged from healthy to mildly cognitively impaired enrolled in the control arm of the multidomain intervention in the Multidomain Alzheimer Preventive Trial (MAPT). Nearly all participants presented spontaneous memory complaints. Regional [18 F]florbetapir (AV45) standardized uptake volume ratios were obtained via semiautomated quantitative analysis using the cerebellum as reference region. Gait speed was measured by timing participants while they walked 4 meters. Associations were explored with linear regression, correcting for age, sex, education, body mass index (BMI), and APOE genotype. Results:We found a significant association between Ab in the posterior and anterior putamen, occipital cortex, precuneus, and anterior cingulate and slow gait speed (all corrected p , 0.05). A multivariate model emphasized the locations of the posterior putamen and the precuneus. Ab burden explained up to 9% of the variance in gait speed, and significantly improved regression models already containing demographic variables, BMI, and APOE status.Conclusions: The present PET study confirms, in vivo, previous postmortem evidence showing an association between Alzheimer disease (AD) pathology and gait speed, and provides additional evidence on potential regional effects of brain Ab on motor function. More research is needed to elucidate the neural mechanisms underlying these regional associations, which may involve motor and sensorimotor circuits hitherto largely neglected in the pathophysiology of AD. According to recent research, postmortem indices of Alzheimer disease (AD) pathology in older adults are associated with decline in gait speed prior to death, suggesting that AD pathology may account for a substantial proportion of not only cognitive but also motor decline.1 These findings are in line with prior reports of declining gait speed in patients with mild cognitive impairment (MCI) 2 and in healthy adults converting to MCI years later. 3 The mechanisms by which AD pathology may lead to motor dysfunction remain unknown.The striatum plays a pivotal role in neurodegenerative disorders characterized by motor symptoms. Although this brain region is not conventionally associated with AD, striatal b-amyloid (Ab) plaques have been observed in patients with AD 4 and in people without dementia. 5The striatum is also one of the earliest brain sites showing Ab deposition in presymptomaticFrom Gérontopôle, Institute of Ageing

High-level improvement of diagnostic certainty and management is provided by selective and hierarchical implementation of florbetaben PET into current standard practices for the most complex dementia cases.

Empirical evidence suggests that a fair proportion of dementia cases are preventable, that some preventive actions can be taken immediately, and others may soon be implemented. Primary prevention may target cognitively normal persons with modifiable risk factors through lifestyle and multiple domain interventions (including general cardiovascular health). While the effect on individuals may be modest, it might have a large societal impact by decreasing overall dementia incidence by up to 35%.

Objective: The Multidomain Alzheimer Preventive Trial (MAPT study) was designed to assess the efficacy of isolated supplementation with omega-3 fatty acid, an isolated multidomain intervention (consisting of nutritional counseling, physical exercise, cognitive stimulation) or a combination of the two interventions on the change of cognitive functions in frail subjects aged 70 years and older for a period of 3 years. Ancillary neuroimaging studies were additionally implemented to evaluate the impact of interventions on cerebral metabolism (FDG PET scans) and atrophy rate (MRIs), as well as brain amyloïd deposit (AV45 PET scans). Design, patients: 1680 subjects (mean age: 75.3 years; female: 64.8 %), enrolled by 13 memory clinics, were randomized into one of the following four groups: omega-3 supplementation alone, multidomain intervention alone, omega-3 plus multidomain intervention, or placebo. Participants underwent cognitive, functional and biological assessments at M6, M12, M24 and M36 visits. The primary endpoint is a change of memory function at 3 years, as assessed by the Free and Cued Selective Reminding test. All participants will be followed for 2 additional years after the 3-years intervention (MAPT PLUS extension study). Interventions: 1/ Omega-3 supplementation: two soft capsules daily as a single dose, containing a total of 400 mg docosahexaenoic acid (DHA), i.e., 800 mg docosahexaenoic acid per day, for 3 years. 2/ Multidomain intervention: collective training sessions conducted in small groups (6–8 participants) in twelve 120-minute sessions over the first 2 months (two sessions a week for the first month, and one session a week the second month) then a 60-minute session per month in the following three areas: nutrition, physical activity, and cognition until the end of the 3 years. In addition to the collective sessions, individualized preventive outpatient visits exploring possible risk factors for cognitive decline are performed at baseline, M12 and M24. Baseline population: For cognition, the mean MMSE at baseline was 28.1 (± 1.6). About 58% and 42% of participants had a CDR score equal to 0 and 0.5, respectively. Regarding mobility status, 200 (11.9%) had a 4-m gait speed lower or equal to 0.8 m/s. According to the Fried criteria, 673 (42.1%) participants were considered pre frail, and 51 (3.2%) frail. The red blood cell DHA content was 26.1 ± 8.1 µg/g. Five hundred and three participants underwent baseline MRI. AV45 PET scans were performed in 271 individuals and preliminary results showed that 38.0% had a cortical SUVR > 1.17, which gave an indication of significant brain amyloïd deposit. Discussion: The MAPT trial is presently the first largest and longest multidomain preventive trial relevant to cognitive decline in older adults with subjective memory complaints. The multidomain intervention designed for the MAPT trial is likely to be easily implemented within the general population.

The presence of apathy in MCI patients is associated with AD-specific pattern of brain metabolic defect. These results could suggest that apathy belongs to the spectrum of prodromal AD symptoms.

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