Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment

Abstract

One of the major neuropathological findings in the brains of individuals with Alzheimer's disease (AD) is a loss of synaptic contacts in both the neocortex and hippocampus. Here we report, for the first time, an estimate of the total number of synapses in the outer molecular layer (OML) of the human dentate gyrus, in individuals with early Alzheimer's disease (eAD), mild cognitive impairment (MCI), or no cognitive impairment (NCI). An unbiased stereologic sampling scheme coupled with transmission electron microscopy to directly visualize synaptic contacts, was used to estimate the total number of synapses in short postmortem autopsy tissue. Individuals with eAD had significantly fewer synapses than the other two diagnostic groups. Seventy-five percent of the individuals with MCI had synaptic values that were lower than the NCI group mean. The number of synapses showed a significant correlation with the subject's Mini-Mental State score and with cognitive tests involving delayed recall. Synaptic loss showed no relationship to Braak stage or to apoE genotype. The volume of the OML was significantly reduced in eAD compared to the other two diagnositic groups that were not different from each other. These data suggest that a loss of afferents from the entorhinal cortex underlie the synapse loss seen in eAD. This study supports the concept that synapse loss is an early event in the disease process and suggests that MCI may be a transition stage between eAD and NCI with synaptic loss a structural correlate involved in cognitive decline.

Introduction

Alzheimer's disease (AD) is a progressive dementing disorder afflicting an estimated 4.5 million Americans [46]. Clinically the disease results in impairment of memory, cognition and behavior. Histopathologically, AD is characterized by the presence of increased numbers of neurofibrillary tangles (NFT) and amyloid containing senile plaques (SP) in the neocortex and hippocampus [6]. However, numerous neuropathologic studies have documented the presence of both NFT and SP in the cortex and hippocampus of non-demented elderly individuals, with densities approaching those found in demented individuals [1], [16], [19], [36], [50], [56], [57], [72], [73], [84], [97]. While these findings suggest that a certain level of this neuropathology may be a feature of normal brain aging, some of the elderly individuals have been labeled as “preclinical” AD, suggesting that they would eventually progress to AD had they lived long enough [40], [71], [72], [83].

There is also a subset of elderly individuals who manifest cognitive deficits that are atypical of those observed in normal aging but are not clinically demented [12], [77]. These individuals are thought to be in the transitional zone between dementia and normal aging and have been termed mild cognitive impaired (MCI) [81]. At present, the structural changes underlying cognitive decline in MCI is unclear. NFT pathology in medial temporal lobe and nucleus basalis has been suggested as an early event involved in MCI [40], [69]. White matter changes as detected by diffusion tensor imaging have been shown to occur in MCI, prior to the development of early AD (eAD) in areas typically affected in AD, including the cingulate cortex, frontal cortex, entorhinal cortex and hippocampus [28], [68]. Non-demented individuals with MCI and individuals with early to mid AD manifest significant loss of neurons in lamina II of the entorhinal cortex compared to cases with no cognitive impairment (NCI) [38], [59]. These neurons provide a direct glutaminergic projection to the hippocampal dentate gyrus. This cellular dysconnection coupled with MRI showing that the entorhinal cortex volume is reduced early in the onset of AD [14], [23], [24], [108], [115] suggests that the dentate gyrus may be one of the earliest sites to show synapse change in MCI and, contribute to cognitive decline in this syndrome.

It is now well documented that one of the major neuropathological findings in the brains of individuals with AD is a loss of synaptic contacts in both the neocortex and hippocampus [4], [9], [17], [22], [39], [44], [51], [60], [64], [65], [78], [79], [91], [92], [93], [94], [96], [103], [104], [118]. Synaptic loss demonstrates a strong association with cognitive ability and may provide the best correlate of dementia [7], [22], [61], [89], [104], [105], [106]. It is unclear whether or not individuals with MCI manifest synaptic loss compared to non-demented individuals clinically classified as NCI. The present study used an unbiased stereologic counting scheme to estimate the total number of synapses in the outer molecular layer (OML) of the hippocampal dentate gyrus and to test whether or not individuals with MCI and eAD manifest synaptic loss compared to NCI individuals. The present study also investigated associations between the estimates of synaptic numbers in the OML with performance on cognitive tests sensitive to hippocampal function.