Alzheimer's disease (AD) is the most common cause of irreversible, chronic dementia. Although AD may be familial in only one third of all cases, the main justification for studying autosomal dominant cases lies in the accuracy of diagnosis which may be inferred through post-mortem examination of other affected family members. Neuropathological examination in our cases of dominantly inherited AD reveals changes in Sommer's sector of the hippocmpus in half of the examined cases. There is marked variability among 4 cases within one large kindred. No definite evidence for AD was found in the brain of an asymptomatic at-risk family member. Previous genetic studies have not clarified the role of inheritance. Skin fibroblast and peripheral blood lymphoblast cultures are being established from members of large kindreds with familial AD. These cultures serve as a renewable source of DNA and cell lines which can be used for genetic linkage, viability, and biochemical studies. A study of 22 twin pairs revealed concordance of only 7 of 17 monozygotic and also 2 of 5 dizygotic pairs suggesting that factors other than heredity are involved in AD. The development of recombinant DNA technology is being applied to genetic linkage analysis in our large kindreds with dominant AD. Approximately 70% of chromosome 21 can confidently be excluded. The Gm locus on chromosome 14 has also been excluded through the use of the D14S1 probe. Linkage analyses of other single candidate genes are in progress. Preliminary studies show that DNA repair in lymphoblasts from inherited AD patients is significantly less than in control lines. A longitudinal investigation of clinical, biochemical, metabolic, and neuropharmacological changes in affected and at-risk members of these families is being conducted. Global and regional glucose metabolic rate (CGMR), measured by PET scanning, were reduced in two patients with dominantly inherited AD. Supramarginal gyri and temporal lobes were involved out of proportion to other brain regions. Further studies are necessary to determine whether changes in CGMR preceed clinical expression of the disease.
