Patients with autosomal dominant Alzheimer’s disease undergo a series of pathophysiologic changes to the brain more than 20 years prior to the clinical onset of dementia, according to a study published in the July 11 online New England Journal of Medicine. These changes occur in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism, and they ultimately lead to cognitive impairment.
The earliest change—a decline in concentrations of amyloid-b42 in the CSF—occurred 25 years before the expected onset of dementia symptoms. “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,” said Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at the Washington University School of Medicine in St. Louis, and colleagues.
Findings From the DIAN Study
The researchers analyzed data from 128 participants, all of whom were enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. Each individual had a parent with a known mutation for the disease, and participants were evaluated in a cross-sectional fashion, with estimates of stage of disease made by the Estimated Years to Symptom onset (the age of the participant minus the age of the parent at first symptom onset).
At baseline, the participants underwent clinical and cognitive assessment, brain imaging, and CSF and blood tests. Clinical assessments of cognitive change were conducted with the Clinical Dementia Rating scale and with a comprehensive battery of neuropsychologic tests, including the Mini-Mental State Examination (MMSE). MRI scans, as well as PET imaging with fluorodeoxyglucose and Pittsburgh compound B, were used to determine region of interest metabolic activity and amyloid deposition, respectively.
The investigators calculated the estimated years from expected symptom onset by using the patient’s age at baseline and the parent’s age at the onset of Alzheimer’s disease. To determine the relative order and degree of pathophysiologic changes, the study authors conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset.
A Cascade of Brain Changes
Results showed that a decline in concentrations of amyloid-b42 in the CSF occurred 25 years before expected symptom onset, and this marked the beginning of the pathophysiologic cascade in the brains of mutation carriers.
Fifteen years prior to symptom onset, carriers of a mutation in one of three genes (APP, PSEN1, and PSEN2) showed amyloid-b deposition in the precuneus, while noncarriers had no detectable amyloid deposits.
Protein tau levels in the CSF and brain atrophy also increased 15 years before expected symptom onset in mutation carriers. These changes were followed by cerebral hypometabolism and impaired episodic memory, which were observed 10 years before expected symptom onset.
Additional cognitive changes were evident five years before expected symptom onset, when MMSE and the Clinical Dementia Rating scale scores indicated global cognitive impairment in mutation carriers. Patients met diagnostic criteria for dementia at an average of three years after expected symptom onset, according to the researchers.
Dr. Bateman and his colleagues explained the timing of the pathophysiologic cascade. “With the use of estimate of years from expected symptom onset, the order and magnitude of changes indicate that genetic mutations cause increased amyloid-b42, which is followed by brain amyloidosis, tauopathy, brain atrophy, and decreased glucose metabolism. After these biologic changes, cognitive impairment can be detected, which culminates in clinical impairment and eventually dementia.”
Implications of a Timeline
The study authors noted that their research concerns autosomal dominant Alzheimer’s disease and therefore may not extend to patients with nongenetic, sporadic Alzheimer’s disease. Nonetheless, they believe the results support the hypothesis of a common pathophysiology between the autosomal dominant form and the sporadic form of the disease, including the possibility that amyloid deposition may be detectable in asymptomatic persons.
“If autosomal dominant Alzheimer’s disease is similar to late-onset Alzheimer’s disease, this finding suggests that Alzheimer’s dementia will eventually develop in persons with positive scans for amyloid deposition,” Dr. Bateman said, adding that targeting amyloid-b earlier in the disease progression may lead to better clinical outcomes.
The study results also have implications for the design of tests and clinical trials. “Treatment and prevention trials can incorporate these pathophysiologic changes to gauge the likelihood of future clinical success. Secondary prevention trials that are designed to prevent or delay cognitive and clinical impairment may ultimately test the amyloid hypothesis,” the researchers concluded.
Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012 Jul 11; [Epub ahead of print].