Clinical and pathological correlates of apolipoprotein E ε4 in Alzheimer's disease

Abstract

Inheritance of the apolipoprotein E (apoE) epsilon 4 allele is associated with a high likelihood of developing Alzheimer's disease (AD). The pathophysiologic basis of this genetic influence is unknown. We reasoned that understanding the influence of apoE epsilon 4 on the clinical course and neuropathological features of AD may provide tests of potential mechanisms. We carried out a prospective longitudinal study to compare the age of onset, duration, and rate of progression of 359 AD patients to apoE genotype. Thirty-one of the individuals who died during the study were available for quantitative neuropathological evaluation. Statistically unbiased stereological counts of neurofibrillary tangles (NFTs) and A beta deposits were assessed in a high-order association cortex, the superior temporal sulcus. Analysis of clinical parameters compared with apoE genotype showed that the epsilon 4 allele is associated with an earlier age of onset but no change in rate of progression of dementia. Quantitative neuropathological assessment revealed that NFTs were strongly associated with clinical measures of dementia duration and severity but not with apoE genotype. A beta deposition, by contrast, was not related to clinical features but was elevated in association with apoE epsilon 4. These results indicate that apoE epsilon 4 is associated with selective clinical and neuropathological features of AD and support hypotheses that focus on an influence of apoE epsilon 4 on amyloid deposition.

Neuropsychological deficits associated with Alzheimer's disease in the very-old: Discrepancies in raw vs. standardized scores

“…Consistent with previous studies (Basun et al, 1995;Bondi et al, 1999;Corder et al, 1995;Normann et al, 1995;Dal Forno et al, 1996;DeKosky et al, 1995;Gomez-Isla et al, 1996;Growdon et al, 1996;Kurz et al, 1996;Small et al, 1998;Smith et al, 1998), there was little overall effect of APOE genotype on the cognitive performance of the NC participants or AD patients in the Very-Old or Young-Old cohorts (e.g., no main effect of APOE genotype in the multivariate analysis and in all but one of the ANOVAs). However, there were interactions between age and the presence of the APOE ε4 allele on the severity of impairment exhibited by patients with AD on some measures of memory, visuomotor sequencing, and perseverative responding, but these interaction effects were not consistent across measures.…”

Apolipoprotein E ε4 is associated with disease-specific effects on brain atrophy in Alzheimer's disease and frontotemporal dementia

“…Although this was not a longitudinal study, apoE 4 dose has also been correlated with the rate of hippocampal atrophy (25). When considering the effect of apoE4 on AD pathology, 4 carriers have more senile plaques than noncarriers (14).…”

Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice

“…Amyloid deposition was quantified using Ah immunostaining (monoclonal anti-Ah 4G8 and hrp-anti-mouse) and the anaLYSIS image system (Gomez-Isla et al, 1996;Irizarry et al, 1997). Video images were captured of each region of interest on 30 Am sections, and a threshold of optical density was obtained that discriminated staining from background.…”