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.

Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00015548 [ClinicalTrials.gov].).

Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.

Background Epidemiologic evidence suggests that non-steroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer’s dementia (AD), but randomized trials show no benefit from NSAIDs in symptomatic AD. ADAPT randomized 2,528 elderly persons to naproxen or celecoxib vs. placebo for two years (s.d. 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups. Methods We continued the double-masked ADAPT protocol for two additional years to investigate incidence of AD (primary outcome). We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Aβ1–42. Results Including 40 new events observed during follow-up of 2,071 randomized individuals (92% of participants at treatment cessation), there were now 72 AD cases. Overall NSAID-related harm was no longer evident, but secondary analyses showed that increased risk remained notable in the first 2.5 years of observations, especially in 54 persons enrolled with Cognitive Impairment – No Dementia (CIND). These same analyses showed later reduction in AD incidence among asymptomatic enrollees given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration. Conclusions These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, thus: NSAIDs have an adverse effect in later stages of AD pathogenesis, while asymptomatic individuals treated with conventional NSAIDs like naproxen experience reduced AD incidence, but only after 2 – 3 years. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies.

A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.