PET imaging detected amyloid-beta (AB) deposition 15 years prior to expected onset of symptoms among persons with genetic mutations, predisposing them to autosomal-dominant Alzheimer’s disease, according to a study published July 12 in the New England Journal of Medicine. The researchers also reported concentrations of AB in cerebrospinal fluid (CSF) 25 years before symptom onset and increased tau protein in CSF 15 years prior to symptoms.

Autosomal dominant Alzheimer’s disease, which accounts for approximately 1 percent of Alzheimer’s cases, shares pathophysiological features with late-onset Alzheimer’s disease. Randall J. Bateman, MD, of the Washington University School of Medicine in St. Louis, Mo., and colleagues noted the hypothesized slow progression of Alzheimer’s disease before symptom onset. Researchers require well-validated biomarkers of disease processes “to improve the design of clinical trials, develop more effective therapeutics, and offer the opportunity for prevention trials,” the researchers wrote.

Thus, Bateman et al analyzed comprehensive clinical, cognitive, imaging and biochemical assessments from 128 participants enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. 

The imaging assessment included volumetric MRI and FDG and Pittsburgh compound (PIT) B PET scans, which were co-registered with MRI data. The clinical assessment used the Clinical Dementia Rating scale, and neuropsychological testing included the Mini-Mental State Examination and Story A from the Wechsler Memory Scale-Revised. Researchers analyzed CSF for AB, total tau and tau phosphorylated at threonine 181.

Age of expected symptom onset was calculated as the age of the participant at the time of the assessment minus the age of the parent at symptom onset.  

Approximately 50 percent of the asymptomatic participants were mutation carriers. The researchers noted significant differences in clinical impairment and neuropsychometric assessments between mutation carriers and noncarriers five years before expected symptom onset.

MRI data revealed increased atrophy of bilateral hippocampi in mutation carriers 15 years before symptom onset. Mutation carriers had significant amyloid deposition in the precuneus 15 years before expected symptom onset.

The CSF of mutation carriers showed increased levels of tau 15 years before symptom onset, while concentration of AB₄₂ reached low levels 10 years before expected symptom onset.

“With the use of estimates of years from expected symptom onset , the order and magnitude of changes indicate that genetic mutations cause increased AB₄₂, which is followed by brain amyloidosis, tauopathy, brain atrophy, and decreased glucose metabolism,” wrote Bateman et al. Clinical impairment and dementia follows these changes. “These findings suggest that the diagnosis of clinical dementia is made late in the course of the biologic cascade of autosomal dominant Alzheimer’s disease.”

The researchers noted that sporadic Alzheimer’s disease also likely follows a pathophysiological cascade, which may be common between autosomal dominant and sporadic disease.

However, Bateman and colleagues noted some differences between the two forms of the disease: trends for increased AB₄₂ have not been reported for sporadic Alzheimer’s disease, though they were predicted among autosomal dominant participants. Autosomal dominant Alzheimer’s disease typically presents with early and pronounced PIB-PET signaling in the neostriatum, but sporadic disease does not. Finally, the prevalence of confounders is lower in the younger participants at risk for autosomal dominant disease.

“The definition of the timing and magnitude of pathophysiological changes associated with Alzheimer’s disease has implications for the development and implementation of diagnostic and predictive tests and the disease of preventive trials,” wrote Bateman and colleagues.

The researchers suggested that if these patterns are similar in both late-onset and autosomal dominant Alzheimer’s disease, persons with positive scans for amyloid deposition will eventually develop Alzheimer’s disease. Finally, “treatment and prevention trials can incorporate these pathophysiological changes to gauge the likelihood of future clinical success.”