Early Markers of Alzheimer Disease

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The Baltimore Longitudinal Study of Aging (BLSA) was established in 1958 and is one the oldest prospective studies of aging in the USA and the world. The mission of the BLSA is to learn what happens to people as they get old and how to sort out changes due to aging and from those due to disease or other causes. In 1986, an autopsy program combined with comprehensive neurologic and cognitive evaluations was established in collaboration with the Johns Hopkins University Alzheimer's Disease Research Center (ADRC). Since then, 211 subjects have undergone autopsy. All brains were examined in the Division of Neuropathology of the Johns Hopkins University. After weighing and external examination, the right hemibrain is cut in 1-cm coronal slabs and a standard set of tissue blocks is removed for overnight fixation in 4% paraformaldehyde or snap freezing. The remaining coronal slabs are frozen on prechilled aluminum plates and then maintained at -80C. The left hemibrain is fixed in 10% buffered formaldehyde for at least 2 weeks and then cut coronally. For diagnostic purposes, tissue blocks are dissected from middle frontal gyrus, superior and middle temporal gyri, inferior parietal cortex, occipital cortex, cingulate gyrus, hippocampus, entorhinal cortex, amygdala, thalamus, basal ganglia, midbrain, pons, medulla, and cerebellum. We obtainin large tissue blocks containing the entire temporal lobe including hippocampus and entorhinal cortex, and a set from the brainstem and lower diencephalon containing the entire substantia nigra and locus coeruleus. The severity of neuritic plaques is assigned a semiquantitative and age-adjusted score (0, A, B, or C) according to CERAD, and the distribution of neurofibrillary tangles is assigned a stage score (0VI) according to Braak. A substantial part of our efforts has been devoted to the understanding of the morphological substrate and underlying mechanisms by which some individuals remain cognitively intact in spite of considerable AD pathology. Initially, we defined this condition as preclinical AD, but subsequently we used the term asymptomatic AD (ASYMAD), mostly because we do not know a priori whether with longer survival, these subjects would have remained clinically normal or would have eventually progressed to MCI. In the BLSA autopsy series, ASYMAD subjects represent approximately 50% of individuals with preserved cognition beyond 75 years of age. We believe that these participants are extremely important because they may represent a group of individuals resistant to the toxic effects of AD pathology. An important caveat to the interpretation of our findings is that participants in the BLSA cohort are highly educated (mean 17.4 2.3 years), a factor that may contribute to the resistance to the clinical manifestations of the disease or to brain reserve." In advanced age, it is common to find both AD lesions and cerebrovascular disease. In this context, it becomes important to define the contribution of each pathologic change to the development of dementia and to ask whether AD and cerebrovascular disease are independent, additive, or synergistic. The wealth of the longitudinal clinical information, the large number of autopsies, and the large number of subjects made the BLSA cohort unique for elucidating the contribution of cerebrovascular pathology to dementia. To this end, we examined the effects of brain infarcts and AD pathology on the risk for dementia in 179 subjects from the BLSA Autopsy Program. All subjects had longitudinal clinical and cognitive evaluations, and underwent a postmortem examination of the brain. Of the 179 subjects, 89 (50%) were demented and 79 (44%) had cerebral infarcts. Our observations indicate that brain infarcts were common in our cohort, and both symptomatic and asymptomatic infarcts conferred a significant increase in the odds of dementia. Risk factors for stroke in the absence of an infarct did not increase the odds of dementia, which was quantitatively related to the number but not the size of hemispheric infarcts; deep subcortical infarcts conferred no increased risk for dementia either. The contribution of microscopic infarcts to dementia was significant and equivalent to that of macroscopic infarcts (i.e., size did not matter). In subjects with intermediate AD pathology scores, a single macroscopic hemispheric infarct was sufficient to cause dementia. A logistic regression model of the effect of infarcts and AD pathology on dementia indicated that AD pathology alone accounts for 50% of the dementia seen in this cohort, and that hemispheric infarcts alone or in conjunction with AD pathology account for 35%. Based on these observations, we concluded that cerebrovascular disease is a significant and potentially preventable cause of dementia in the BLSA and that the burden and location of infarcts are significantly associated with cognitive decline. We also found that AD and cerebrovascular disease are independent pathologies and that their effects are additive, but not synergistic An important conclusion from our series of neuropathologic studies is that many individuals can reach advanced age without clinical or neurological impairment while leading independent and fulfilling lives. This group of individuals who represent successful aging is not homogeneous. Whereas some individuals remain practically free of neuropathology, others bear abundant AD lesions (i.e., neuritic plaques score CERAD C and NFT Braak stage VI). This latter group, which we have called ASYMAD, shows marked hypertrophy of cerebral neurons, a change that may account for the functional compensation reflected in the different clinical outcome compared to MCI and AD subjects. But this possible compensatory hypertrophy is not limited to the cerebral cortex. We also observe neuronal hypertrophy in the substantia nigra, where the age-associated loss of neurons is accompanied by hypertrophy of a magnitude such that the total volume of substantia nigra remains similar to that of young controls. We believe that the hypertrophy of neurons, both in the cerebral cortex and the substantia nigra, is not limited to cell bodies and probably includes axonal terminals and dendritic spines that allow compensation for loss or injury of nerve cells. Overall, our studies suggest that in some individuals, successful cognitive aging results from compensatory mechanisms that occur at the neuronal level; whereas a failure of compensation (i.e., synaptic plasticity) may culminate in disease. Understanding and harnessing the underlying mechanism of neuronal hypertrophy in the cerebral cortex of ASYMAD and the SN of normal aging is an important endeavor bound to open new therapeutic approaches for age-associated neurodegenerative disease.