Articles
Neuropathological Diagnosis of Alzheimer’s Disease: A Perspective from Longitudinal Clinicopathological Studies

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Abstract

Alzheimer’s disease (AD) is the most common cause of primary progressive dementia. It is defined by its pathological features, because the clinical syndrome of dementia lacks specificity. Although the brain in AD has many structural alterations, the two cardinal pathological features and sine qua non of AD are senile plaques and neurofibrillary degeneration. The latter takes the form of neurofibrillary tangles composed of paired helical filaments, as well as degenerating neurites within the neuropil (“neuropil threads”) and within a diagnostically significant subset of SP, referred to as “neuritic plaques.” All SP contain amyloid, but not all have pair helical filament-type neurites. The presence of even a small number of plaques with paired helical filament-type neurites in the neocortex is associated with cognitive impairment, and this lesion may be the most specific histopathological feature of AD. Although these observations suggest that the major difference between SP in aging and AD relate to differences in neuritic degeneration, more recent studies have also indicated that amyloid deposits are biochemically heterogenous and that amyloid deposits in aging may be different from those in AD. As more specific markers become available for recognizing AD-specific structural lesions, refined neuropathological diagnostic criteria will evolve. In the meantime, a practical neuropathological approach to the diagnosis of AD requires both widespread neocortical SP and an advanced stage of neurofibrillary degeneration. Using these criteria, it is very unlikely that AD will be diagnosed in an individual who was not demented in life. The rationale for adopting this conservative approach is that our knowledge is incomplete with respect to fundamental differences between the lesions in aging and AD.

Section snippets

Neurofibrillary Tangles and Other Cytoskeletal Pathology

The cardinal pathological feature of AD, which has been known since Alzheimer’s original descriptions, is neurofibrillary degeneration, and more specifically neurofibrillary tangles (NFTs). Biochemical, molecular biological, and modern neuropathological methods have increased our understanding of the nature of the paired helical filaments (PHFs) that are the major ultrastructural component of NFTs. Biochemical analyses of brains with many NFTs have demonstrated that the major protein component

Clinicopathological Studies of Aging and Dementia

Few postmortem analyses of prospective, longitudinal clinical studies of elderly people have been reported; however, the number of studies dealing with differences between aging and AD are now considerable. Certain consistencies that emerge from these data will be discussed with reference to our own clinicopathological studies.

Histopathological Diagnosis of AD

With these historical perspectives and general comments as a preface, the following is a brief consideration of how we approach a histopathological diagnosis of AD.

Acknowledgements

This study was supported by National Institute on Aging Grants AG06803 and NIA03949.

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