A follow-up study of the family with the Swedish APP 670/671 Alzheimer's disease mutation

Objective: To study the progression of Alzheimer's disease (AD) at a very e arly stage and to evaluate clinical markers of presymptomatic AD. Setting: Longitudinal study at a university hospital. Subjects: A Swedish family har boring a double mutation at codons 670/671 of the APP gene on chromosome 21 was followed longitudinally for 3 years. Both mutation carriers and noncar riers participated. Outcome Measurements: Results from clinical investigati ons, electroencephalography, neuropsychological and neuroradiological exami nations including magnetic resonance imaging, single-photon emission comput ed tomography and positron emission tomography were assessed and compared o n two or more occasions. Main Outcome: During follow-up, 1 initially asympt omatic mutation carrier who was near the expected age of onset for this fam ily, developed cognitive symptoms, and at the end of the follow-up fulfille d the diagnostic criteria for AD. One mutation carrier with cognitive sympt oms at the first examination showed clinical deterioration and was diagnose d with AD. One demented mutation carrier died and was shown to have typical AD neuropathology at autopsy. The two remaining asymptomatic mutation carr iers, as well as all the noncarriers were asymptomatic. These mutation carr iers who were near the expected age of onset of AD but without clinical sig ns of the disease, did not show changes in either electrophysiological para meters or volumes of the temporal robes. However, in these 2 individuals th e blood flow in the temporal lobe showed intermediate values between the sy mptomatic mutation carriers and healthy noncarriers. Two neuropsychological tests showed a deterioration that paralleled clinical symptoms in 1 of the mutation carriers who was close to the expected age of onset and who at th e end of the followup had clinical signs of AD. In the same subject, brain glucose metabolism was pathologically reduced in the temporal lobes before other clinical symptoms were obvious. Conclusion: In this familiar form of AD a reduced temporal lobe glucose metabolism was indicative of AD before t he expected clinical onset. Reduced glucose metabolism even preceded the de velopment of subjective or objective cognitive dysfunction and might theref ore serve as a clinical marker for AD before the onset of clinical symptoms . Reduced cerebral blood flow in the temporal lobes and cognitive deteriora tion paralleled the clinical decline in the early stage of the disease. Cop yright (C) 1999 S. Karger AG, Basel.