ABSTRACT
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. It is well
established that the number of affected individuals will grow dramatically with increasing life
expectancy. In the absence of a definitive biomarker, early diagnosis and disease progression are
assessed with clinical and neuropsychometric measures. While these are certainly essential, the link
between cognitive performance and pathological disease stage is often less direct than desirable.
Improved noninvasive surrogate measures for early diagnosis and assessment of disease progression
are therefore desirable for clinical management in individual cases. In addition, because disease-
modifying therapies are being developed and evaluated, surrogate markers of disease progression
are also required for measuring treatment effects in therapeutic trials. The ideal surrogate marker
should be able to detect a fundamental feature of Alzheimer’s neuropathology, be diagnostically
sensitive and specific as verified through neuropathologically confirmed cases, and have high test
re-test reproducibility. Few biomarkers are likely to perform ideally in all three categories. The most
promising candidates in neuroimaging are amyloid labeling agents used in positron emission
tomography (PET) imaging (1-3). It is our belief that indirect measures of AD with quantitative
magnetic resonance (MR) techniques can also be valid biomarkers as well, particularly of disease
progression. This is the subject matter addressed in this review. Various quantitative MR techniques
that measure the anatomic, biochemical, microstructural, functional, and blood-flow changes in AD
have been and continue to be evaluated. Validating the utility of MR measurements as surrogate
markers for AD ideally follows hierarchical testing in the following sequential manner:
