To study longitudinal changes that culminate in symptomatic disease, 128 participants with a family history of dominantly inherited Alzheimer disease underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests.
Autosomal dominant Alzheimer’s disease has a predictable age of onset which allowed researchers to estimate the number of years to expected symptom onset. Specifically, the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease was used to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset).
The authors found that concentrations of beta-amyloid 42 in the CSF started to decline 25 years before expected symptom onset. Positron-emission tomography data showed that Aβ deposition could start as early as 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were also detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset. Patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.
The authors concluded that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Whether these results apply to sporadic Alzheimer’s disease requires further investigation.
Bateman RJ, Xiong C, Benzinger TL et al: Clinical and Biomarker Changes in Dominantly Inherited Alzheimer ’s Disease. New Engl. J. Med. [Epub ahead of print, July 11, 2012]. (10.1056/NEJMoa1202753)