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.

These findings highlight the need for population-based norms for the MoCA and use of caution when applying established cut scores, particularly given the high failure rate on certain items. Demographic factors must be considered when interpreting this measure.

Results provide support for the validity of a Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score that can be used along with the normative data to provide an index of overall level of cognitive functioning from the CERAD neuropsychological battery.

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Potentially harmful caregiver behavior is more likely in spouse caregiving situations and when care recipients have greater needs for care and caregivers are more cognitively impaired, have more physical symptoms, and are at risk for clinical depression. This risk profile is similar to that for negative caregiver outcomes.