OBJECTIVE: To define the clinical and neuropsychological features of dementia due to hippocampal sclerosis (HS) and to compare it to Alzheimer's disease (AD). BACKGROUND: Several autopsy studies have identified HS as an etiology of dementia in the elderly. More recently, dementia due to HS was found to be frequently misdiagnosed as AD. In this study, we attempt to differentiate HS dementia from AD using data collected from subjects enrolled at the Johns Hopkins Alzheimer's Disease Research Center. DESIGN/METHODS: Eight cases of HS and 84 cases of definite AD were included in the study. All 84 AD cases were diagnosed using CERAD criteria and were free of additional pathology. HS was defined by a combination of neuronal loss and gliosis in the hippocampus in the absence of senile plaques, neurofibrillary tangles, or other potential causes of dementia. All subjects were followed longitudinally until death. Data was collected at 6-month intervals. Mean scores on several clinical and cognitive measures from both groups were compared at study entry using the Wilcoxon Rank Sum (nonparametric) test. A group of 23 AD subjects, matched with the HS group on MMSE at study entry, were used for analysis of rate of decline. A weighted regression procedure was used for the latter analysis. RESULTS: The HS group did not differ significantly from the AD group in age at onset, duration of illness prior to study entry, age at death, or education level. At study entry, the HS group had significantly(p<0.05) better test scores on several measures including the Mini-Mental State Exam (MMSE), verbal fluency task, Boston Naming Test, and the orientation subscale of the Psychogeriatric Dependency Rating Scale (PGDRS). There were no significant differences on the physical and behavior subscales of the PGDRS, nor on the Hamilton Depression Scale. Analysis of rate of decline showed significantly slower cognitive decline over 5 years in the HS group, notably on the MMSE (-0.90 points/yr in HS vs. -2.80 points/yr in AD, p<0.01). Surprisingly, the HS group slightly improved on the Boston Naming Test during follow-up (0.26 points/yr in HS vs. -3.2 points/yr in AD, p<0.01). CONCLUSIONS: Dementia due to hippocampal sclerosis appears to be clinically different from Alzheimer's disease. Particularly, patients with HS appear to have slower cognitive decline than AD patients. Larger studies are needed to further characterize HS dementia.

The brains of individuals with Alzheimer's disease (AD) are characterized by extracellular deposition of beta-amyloid protein (Abeta), intracellular neurofibrillary tangles, and loss of neurons. To study molecular markers associated with dying cells in the AD brain, in situ DNA labeling techniques were used to visualize cells with DNA fragmentation. We observed that intracellular accumulation of apolipoprotein E (apoE) is correlated with the detection of intracellular Abeta-like immunoreactivity within the same cytoplasmic granules, suggesting that uptake of lipids may have stabilized the hydrophobic Abeta protein within the cell. These apoE-containing neurons also exhibit high expression of a cell surface receptor, gp330, which is known to bind apoE. Cells containing significant nuclear DNA fragmentation express the highest level of cell surface gp330. Extracellular deposition of Abeta is detected only upon neuronal cell death, initially as halos of Abeta immunoreactivity around individual dying neurons, and subsequently as Abeta plaques containing numerous neuronal cell ghosts. Based on our in situ analysis of nuclear DNA fragmentation, we conclude that neuronal cell death likely occurs before the extracellular deposition of Abeta in AD brains.

Data from an ongoing study of differences in the total number of neurons in the five major subdivisions of the hippocampal regions of the brains of patients with Alzheimer's disease (AD) and normal age-matched controls confirm an earlier finding from our laboratories of a pronounced loss of CA1 neurons associated with AD. In view of an earlier finding that the CA1 region does not suffer normal age-related neuronal loss, these data support the earlier conclusion that the neuropathologic mechanisms involved in the AD-related losses in CA1 are not related to normal aging and that the study of the cellular and molecular events involved in the AD-related loss of CA1 cells can aid in the identification of the unique pathologic processes associated with AD.

Introduction

There is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C.

Methods

Ten single nucleotide polymorphisms within the CETP locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger.

Results

Based on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the CETP locus, we found that HDL-C was not associated with risk of AD (P > .7).

Discussion

Our study does not support the role of HDL-C on risk of AD through HDL-C altered by CETP. This study does not rule out other mechanisms by which HDL-C affects risk of AD.