Apolipoprotein E Genotype and Its Pathological Correlation in Chinese Alzheimer's Disease With Late Onset LAN CHEN, MB, LARRY BAUM, PHD, HO-KEUNG NG, MD, FRCPATH, FRCPA, LISA Y,S, CHAN, PHD, AND CHI-PUI PANG, PHD In this study, we attempted to find a relationship between apoliprotein E (ApoE) genotypes and Alzheimer's disease (AD) pathology in different areas of the brain in Chinese. We also studied the borderline group of possible AD (Poss). There were 34 definite or probable AD (Ad), 18 Poss, and 123 brains from age-matched normal subjects (N). ApoE genotype was determined by nested polymerase chain reaction on genomic DNA extracted from archival paraffin- embedded materials. Hippocampus (including eutorhinal cortex), amygdala, superior temporal lobe, middle frontal gyrus, and inferior parietal lobule of the brains of Ad and Poss were examined with 13 amyloid (A13) immunostaining, and the same regions plus medial occipital lobe were examined with tau immunostaining. The percent- age of plaque area stained for A13 in each brain region was obtained by an image analyzer, and the average number of neurofibrillary tangles stained for tau was counted with an eyepiece graticule. ApoE ¢4 frequency was increased in both Ad (22.1%, X 2, df= 1, P = .00005), and Poss (33.3%, P = .000005) compared with N (5.3%). A13 load was A diagnosis of definite Alzheimer's disease (AD) requires confirmation by histology and autopsy even though the clinical diagnosis for AD generally exceeds 80% accuracy) Although histological criteria remain imperfect, neuropathologists involved in the Consor- tium to Establish a Registry for Alzheimer's Disease (CERAD) established simple and practical neuropatho- logical criteria for AD in 1991 z and updated them in 19933 and 1997. 4 Criteria for levels of AD diagnosis from definite, probable, to possible AD are provided, and they depend on the presence or absence of a history of dementia and the severity of neuritic plaques in relation to age. In a general hospital where not all elderly patients are assessed carefully as to their mental status and subtle mental deterioration may be overlooked, autopsy brains that demonstrate significant Alzheimer- type pathology may be categorized as possible AD (Poss). Currently, there have been few studies on these possible AD cases. Although the apolipoprotein E (ApoE) e4 allele is known to be a strong risk factor for AD, how its presence affects the development of AD is still uncertain. ApoE From the Department of Anatomical and Cellular Pathology, Department of Ophthalmology and Visual Sciences, Department of Chemical Pathology, Chinese University of Hong Kong, Shatin, Hong Kong. Accepted for publication May 12, 1999. Address correspondence and reprint requests to Ho-keung Ng, MD, FRCPath, FRCPA, Department of Anatomical & Cellular Pathol- ogy, Prince of Wales Hospital, Shatin, Hong Kong. Copyright © 1999 by W.B. Saunders Company 0046-8177/99/3010-0009510.00/0 significantly increased in the neocortex in Ad examined with at least 1 copy of ~4 compare d with subjects without ~4 (Mann-Whitney, P = .014). The same trend, though not statistically significant, oc- curred in Poss (P = .15). Tan expression was associated with ApoE ~4 in neither Ad nor Poss. Poss is genetically and histologically similar to Ad, although the overall A[~ load is significantly increased in the latter. These findings support the recent Consensus Report's findings that all Alzheimer-type pathology may be significant. HUM PATUOL30:1172- 1177. Copyright © 1999 byW.B. Saunders Company Key words: Alzheimer's disease, 13-amyloid plaque, neurofibriliary tangle, apolipoprotein E, possible AD. Abbreviations: AD, Alzheimer's disease; CERAD, the Consortium to Establish a Registry for Alzheimer's Disease; ApoE, apolipoprotein E; A13, 13 amyloid; NFI', neurofibrillary tangle; Ad, definite or probable Alzheimer's disease; Poss, possible Alzheimer's disease; N, normal controls; PAP, peroxidase anti-peroxidase; PCR, polymerase chain reaction; OR, odds ratio; CI, 95% confidence intervals. has a high avidity to [3 amyloid (A~), and it is found in neuritic plaques and some neurons. It is hypoth- esized that ApoE4 might be involved in AD patho- genesis by its effects on amyloid aggregation in neuritic plaques or formation of paired helical filaments in the neurofibrillary tangle (NFT). 5 A[3 plaque de- posits and NFTs have been observed to be increased in brains of AD patients with ~4 compared with patients without e4. 6,7 However, the association of ApoE e4 with AD pathology is still controversial according to other authors 8-12and deserves further study. Studies suggest that there might be a difference in AD between Chinese and Western populations. AD accounts for approximately 4% of the population older than age 70 years in Hong Kong is and 3% older than 65 years in Shanghai. 14 These figures are at the lower margin of the prevalence reported in Americans ]~ (10 % over the age of 65) and Europeans TM (3% to 11% over the age of 60). Alzheimer-type change in brains from nondemented elderly has also been found to be less than that in Caucasians. 17,1s However, there have been no studies correlating different ApoE genotypes with postmortem AD changes in Chinese. In this study, we attempted to perform ApoE genotyping and examine its relationship to A[3 plaque deposits and NFT formation in different areas of au- topsy brains in Chinese late onset AD. We also tried to delineate the ApoE genetics and the pathological char- acteristics of Poss, which to our knowledge has not previously been performed in Chinese. 1172