In 2010, the authors published a hypothetical model of the major biomarkers of Alzheimer’s disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. In the interim, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of the assumptions underlying our original model. Recent evidence has allowed us to modify our original model. Refinements include indexing subjects by time rather than clinical symptom severity; incorporating inter-subject variability in cognitive response to the progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and, recognition that the two major proteinopathies underlying AD biomarker changes, Aβ and tau, may be initiated independently in late onset AD where we hypothesize that an incident Aβopathy can accelerate an antecedent tauopathy.

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.

A secondary prevention trial in older people with amyloid accumulation at high risk for Alzheimer’s disease dementia should provide insights into whether anti-amyloid therapy can delay cognitive decline.

IMPORTANCE Among cognitively normal individuals, elevated brain amyloid (defined by cerebrospinal fluid assays or positron emission tomography regional summaries) can be related to risk for later Alzheimer-related cognitive decline. OBJECTIVE To characterize and quantify the risk for Alzheimer-related cognitive decline among cognitively normal individuals with elevated brain amyloid. DESIGN, SETTING, AND PARTICIPANTS Exploratory analyses were conducted with longitudinal cognitive and biomarker data from 445 cognitively normal individuals in the United States and Canada. Participants were observed from August 23, 2005, to June 7, 2016, for a median of 3.1 years (interquartile range, 2.0–4.2 years; maximum follow-up, 10.3 years) as part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI). EXPOSURES Individuals were classified at baseline as having normal (n = 243) or elevated (n = 202) brain amyloid using positron emission tomography amyloid imaging or a cerebrospinal fluid assay of amyloid β. MAIN OUTCOMES AND MEASURES Outcomes included scores on the Preclinical Alzheimer Cognitive Composite (PACC; a sum of 4 baseline standardized Z scores, which decreases with worse performance), Mini-Mental State Examination (MMSE; 0 [worst] to 30 [best] points), Clinical Dementia Rating Sum of Boxes (CDR–Sum of Boxes; 0 [best] to 18 [worst] points), and Logical Memory Delayed Recall (0 [worst] to 25 [best] story units). RESULTS Among the 445 participants (243 with normal amyloid, 202 with elevated amyloid), mean (SD) age was 74.0 (5.9) years, mean education was 16.4 (2.7) years, and 52% were women. The mean score for PACC at baseline was 0.00 (2.60); for MMSE, 29.0 (1.2); for CDR–Sum of Boxes, 0.04 (0.14); and for Logical Memory Delayed Recall, 13.1 (3.3). Compared with the group with normal amyloid, those with elevated amyloid had worse mean scores at 4 years on the PACC (mean difference, 1.51 points [95% CI, 0.94–2.10]; P < .001), MMSE (mean difference, 0.56 points [95% CI, 0.32–0.80]; P < .001), and CDR–Sum of Boxes (mean difference, 0.23 points [95% CI, 0.08–0.38]; P = .002). For Logical Memory Delayed Recall, between-group score was not statistically significant at 4 years (mean difference, 0.73 story units [95% CI, −0.02 to 1.48]; P = .056). CONCLUSIONS AND RELEVANCE Exploratory analyses of a cognitively normal cohort followed up for a median of 3.1 years suggest that elevation in baseline brain amyloid level, compared with normal brain amyloid level, was associated with higher likelihood of cognitive decline, although the findings are of uncertain clinical significance. Further research is needed to assess the clinical importance of these differences and measure longer-term associations.