Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665 .).

We investigated factors associated with falls in a community-based prospective study of 761 subjects 70 years and older. The group experienced 507 falls during the year of monitoring. On entry to the study a number of variables had been assessed in each subject. Variables associated with an increased risk of falling differed in men and women. In men, decreased levels of physical activity, stroke, arthritis of the knees, impairment of gait, and increased body sway were associated with an increased risk of falls. In women, the total number of drugs, psychotropic drugs and drugs liable to cause postural hypotension, standing systolic blood pressure of less than 110 mmHg, and evidence of muscle weakness were also associated with an increased risk of falling. Most falls in elderly people are associated with multiple risk factors, many of which are potentially remediable. The possible implications of this in diagnosis and prevention are discussed.

A sample of 761 subjects 70 years and over was drawn from general-practice records of a rural township. Each subject was assessed and followed for 1 year to determine the incidence of and factors related to falls. The fall rate (number of falls per 100 person-years) increased from 47 for those aged 70-74 years to 121 for those 80 years and over. There was no sex difference in fall rate but men were more likely than women to fall outside and at greater levels of activity. Twenty per cent of falls were associated with trips and slips but we found no evidence that inspection of homes and installation of safety features would have decreased the fall rate. Ten per cent of falls resulted in significant injury. Men who fell had an increased subsequent risk of death compared with those who did not fall (relative risk 3.2, 95% CI 1.7-6.0). Subsequent mortality was increased among women who fell but not to significant levels (relative risk 1.6, 95% CI 0.9-2.7).

Ventricular enlargement may be an objective and sensitive measure of neuropathological change associated with mild cognitive impairment (MCI) and Alzheimer's disease (AD), suitable to assess disease progression for multi-centre studies. This study compared (i) ventricular enlargement after six months in subjects with MCI, AD and normal elderly controls (NEC) in a multi-centre study, (ii) volumetric and cognitive changes between Apolipoprotein E genotypes, (iii) ventricular enlargement in subjects who progressed from MCI to AD, and (iv) sample sizes for multi-centre MCI and AD studies based on measures of ventricular enlargement. Three dimensional T(1)-weighted MRI and cognitive measures were acquired from 504 subjects (NEC n = 152, MCI n = 247 and AD n = 105) participating in the multi-centre Alzheimer's Disease Neuroimaging Initiative. Cerebral ventricular volume was quantified at baseline and after six months using semi-automated software. For the primary analysis of ventricle and neurocognitive measures, between group differences were evaluated using an analysis of covariance, and repeated measures t-tests were used for within group comparisons. For secondary analyses, all groups were dichotomized for Apolipoprotein E genotype based on the presence of an epsilon 4 polymorphism. In addition, the MCI group was dichotomized into those individuals who progressed to a clinical diagnosis of AD, and those subjects that remained stable with MCI after six months. Group differences on neurocognitive and ventricle measures were evaluated by independent t-tests. General sample size calculations were computed for all groups derived from ventricle measurements and neurocognitive scores. The AD group had greater ventricular enlargement compared to both subjects with MCI (P = 0.0004) and NEC (P < 0.0001), and subjects with MCI had a greater rate of ventricular enlargement compared to NEC (P = 0.0001). MCI subjects that progressed to clinical AD after six months had greater ventricular enlargement than stable MCI subjects (P = 0.0270). Ventricular enlargement was different between Apolipoprotein E genotypes within the AD group (P = 0.010). The number of subjects required to demonstrate a 20% change in ventricular enlargement was substantially lower than that required to demonstrate a 20% change in cognitive scores. Ventricular enlargement represents a feasible short-term marker of disease progression in subjects with MCI and subjects with AD for multi-centre studies.