Normals (N = 42) and patients with mild memory difficulty (N = 123) were given a neuropsychological test battery, and then followed annually for 3 years to determine which individuals developed sufficient functional change that they met clinical criteria for AD. Twenty-three of the 123 participants with mild memory difficulty converted to a diagnosis of probable Alzheimer's disease (AD) within 3 years of follow-up. Four of the 20 neuropsychological measures obtained at baseline, were useful in discriminating the groups on the basis of their status 3 years after the tests were given. The 4 discriminating tests pertained to assessments of memory and executive function. When the controls were compared to the individuals with memory impairments who ultimately developed AD (the converters), the accuracy of discrimination was 89%, based on the neuropsychological measures at baseline. The discrimination of the controls from the individuals with mild memory problems who did not progress to the point where they met clinical criteria for probable AD over the 3 years of follow-up (the Questionables) was 74% and the discrimination of the questionables from the converters was 80%. The specific tests that contributed to these discriminations, in conjunction with recent neuropathological and neuroimaging data from preclinical cases, have implications for which brain regions may be affected during the prodromal phase of AD. (JINS, 2001, 7, 631–639.)

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These findings are consistent with neuropathologic data showing substantial involvement of the entorhinal cortex in the preclinical phase of AD and suggest that, as the disease spreads, atrophic change develops within the hippocampus, which is measurable on MRI.

We evaluated brain tissue compartments in 72 healthy volunteers between the ages of 18 and 81 years with quantitative MRI. The intracranial fraction of white matter was significantly lower in the age categories above 59 years. The CSF fraction increased significantly with age, consistent with previous reports. The intracranial percentage of gray matter decreased somewhat with age, but there was no significant difference between the youngest subjects and the subjects above 59. A covariance adjustment for the volume of hyperintensities did not alter the foregoing results. The intracranial percentage of white matter volume was strongly correlated with the percentage volume of CSF. The finding of a highly significant decrease with age in white matter, in the absence of a substantial decrease in gray matter, is consistent with recent neuropathologic reports in humans and nonhuman primates.

Amyloid beta protein (A beta) accumulates in the brains of aging humans, amyloid precursor protein (APP) transgenic mouse lines, and rhesus monkeys. We tested the hypothesis that aging was associated with increased activity of the beta-site amyloid precursor protein cleaving enzyme (beta-secretase, BACE) in brain. We evaluated BACE activity, BACE protein, and formic acid-extractable A beta levels in cohorts of young (4 months old) and old (14 to 18 months old) nontransgenic mice (n = 16) and Tg2576 APP transgenic mice (n = 17), young (4.4 to 12.7 years old) and old (20.9 to 30.4 years old) rhesus monkeys (n = 17), and a wide age range (18 to 92 years old) of nondemented human brains (n = 25). Aging was associated with increased brain A beta levels in each cohort. Furthermore BACE activity increased significantly with age in mouse, monkey, and human brains, independent of brain region. BACE protein levels, however, were unchanged with age. BACE activity correlated with formic acid-extractable A beta levels in transgenic mouse, nontransgenic mouse, and human cortex, but not in monkey brain. These data suggest that an age-related increase of BACE activity contributes to the increased production and accumulation of brain A beta, and potentially predisposes to Alzheimer's disease in humans.

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Damage to the hippocampus has been implicated in the permanent loss of memory in patients with medial temporal lobe resections. In two previous studies, it was established that bilateral ablations of the hippocampus in the monkey impaired performance on an associative learning task and on an object discrimination retention task. The two objectives of the present study were to assess the long term effects of hippocampal resections in the monkey and to extend the analysis of the effects of these resections to recognition memory.Therefore, the performance of monkeys with either hippocampal ablations or fornix transections, sustained 5 years earlier, was compared (1) on a concurrent discrimination task-a previously unencountered associative learning task-and (2) on a nonmatching-to-sample recognition task with either delays interposed between the presentation of the sample object and the recognition trial or with lists of either l-, 3-, 5-, or lo-object samples. Significant impairment on both tasks was found after hippocampal, but not after fornix, damage. Though monkeys in the hippocampal group were impaired on both delays and lists, the impairment was more severe on the lists, with abnormal sensitivity to pro-and retroactive interference as a possible source of difficulty. Thus, in parallel with clinical findings, ablations of the hippocampus in the nonhuman primate produce an enduring disruption of memory.When a severe and permanent loss of memory was found in patients after resections of medial temporal lobe structures which included the hippocampal formation, hippocampal gyrus, amygdala, and uncus (