Background: Alzheimer's disease (AD) is the most common degenerative neurologic disorder. The onset of symptoms is insidious and follows a long period of progression of an asymptomatic pathology that proceeds in a precise anatomic and temporal sequence. Recent studies with quantitative magnetic resonance imaging techniques have shown the localization of the in vivo pathology of AD and its antecedent, mild cognitive impairment. The objective of the present study was to determine whether a sensitive and reliable marker for the presymptomatic phase of the disorder could be identified by longitudinal analysis of an initially asymptomatic, community-based population.
Methods: One hundred forty-eight healthy, cognitively normal participants in the Cardiovascular Health Study-Cognition Study had detailed clinical examinations and magnetic resonance imaging scans in 1998-1999 and 2002-2003. Modulated voxel-based morphometry was used to compare regional brain volumes in subjects who remained cognitively normal after 5 to 6 years of follow-up (n = 127) with those who developed probable AD during the same period (n = 21).
Results: Among normal subjects destined to develop AD, there was significant atrophy in the basal forebrain area as long as 4.5 years before the development of clinical symptoms. When the left hippocampus was also atrophic, the onset of dementia typically occurred earlier than in cases in which the atrophy was confined to basal forebrain.
Conclusions: Atrophy in the basal forebrain precedes the development of AD in subjects with cognition judged to be normal by neuropsychological testing. The time required to develop dementia appears to be shortened if hippocampal atrophy is also present. These data indicate that atrophy restricted to medial basal forebrain is a biomarker that predicts development of probable AD in asymptomatic elderly subjects.