To clarify the alterations of tau, amyloid beta protein (A beta) 1-40 and A beta1-42(43) in the cerebrospinal fluid (CSF) that accompany normal aging and the progression of Alzheimer's disease (AD), CSF samples of 93 AD patients, 32 longitudinal subjects among these 93 AD patients, 33 patients with non-AD dementia, 56 with other neurological diseases, and 54 normal control subjects from three independent institutes were analyzed by sensitive enzyme-linked immunosorbent assays. Although the tau levels increased with aging, a significant elevation of tau and a correlation between the tau levels and the clinical progression were observed in the AD patients. A significant decrease of the A beta1-42(43) levels and a significant increase of the ratio of A beta1-40 to A beta1-42(43) were observed in the AD patients. The longitudinal AD study showed continuous low A beta1-42(43) levels and an increase of the ratio of A beta1-40 to A beta1-42(43) before the onset of AD. These findings suggest that CSF tau may increase with the clinical progression of dementia and that the alteration of the CSF level of A beta1-42(43) and the ratio of A beta1-40 to A beta1-42(43) may start at early stages in AD. The assays of CSF tau, A beta1-40, and A beta1-42(43) provided efficient diagnostic sensitivity (71%) and specificity (83%) by using the production of tau levels and the ratio of A beta1-40 to A beta1-42(43), and an improvement in sensitivity (to 91%) was obtained in the longitudinal evaluation.

Apolipoprotein E σ4 allele (ApoE σ4) is associated with Alzheimer’s disease (AD) in familial and sporadic cases, but the associations of ApoE σ4 allele and vascular dementia (VD) and/or ischemic cerebrovascular disease (ICVD) are still controversial. To clarify the associations of ApoE polymorphism with AD, VD and ICVD in Japanese, we examined ApoE polymorphism in samples of 255 patients with AD, 87 patients with VD, and 123 patients with ICVD, as compared with 117 age-matched healthy control subjects (CTL). The frequency of the ApoE σ4 allele was significantly higher in the VD group (0.21), the ICVD group (0.15) as well as in the AD group (0.26) than in the CTL subjects (0.08). These findings suggest that the genotype of ApoE σ4 is associated with not only AD but also VD and ICVD, and that ApoE σ4 plays an important role in the development of dementia and ICVD.

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We carried out two separate epidemiological studies on long-term changes, 10 years apart, on the prevalence rate of dementia in the elderly by the same method for the same area in Japan. We also performed a genetic study of patients with dementia of the Alzheimer type (DAT) based on the epidemiological studies. The number of patients with dementia was much larger in 1990 than in 1980. Especially, the number of mildly demented patients was significantly larger in 1990 than in 1980. The 35 patients with DAT did not show any mutations of amyloid-β protein precursor, presenilin 1 and presenilin 2 genes. The frequency of apolipoprotein E (apo E) σ4 allele in DAT was significantly higher than that in control subjects (p < 0.005). This study suggests that the frequency of DAT may increase by aging of the population in the future and we confirm the close association between apoE σ4 allele and DAT in a community-based study in Japan.

We investigated the genetic association between intronic polymorphism in Presenilin-1 (PS-1) gene and patients with various types of dementia such as Alzheimer's disease (AD), vascular dementia (VD) and alcohol associated dementia (ALD), in Japanese population. Homozygosity for allele 1 of the PS-1 polymorphism was significantly increased in late-onset sporadic AD, but not in early-onset sporadic AD, familial AD, VD and ALD. When late-onset sporadic AD patients were divided on the basis of apolipoprotein E (APOE) genotype, homozygosity for the allele 1 of the PS-1 polymorphism was significantly increased in patients with late-onset sporadic AD without APOE epsilon 4 allele, but not in those with APOE epsilon 4 allele. Intronic mutation in PS-1 gene may be specific and one of the genetic risk factor for late-onset sporadic AD.

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