S1-01-06

Symposia S1-02: Disease Mechanisms (APP and A␤) S1-01-04

ESTROGENS / ENDOGENEOUS & EXOGENEOUS

S1-01-06

Kristine Yaffe, UCSF, San Francisco, CA, USA. Contact e-mail: [email protected] Cognitive impairment affects at least 10% of elders aged 65 years and older, increasing in prevalence to 50% of elders 85 years of age and older. In hopes of identifying agents that may prevent cognitive impairment, there has been tremendous interest in the role of both exogenous and endogenous hormones and risk of Alzheimer’s disease (AD) and pre-clinical cognitive decline, especially in women. Indeed, estogen receptors (ER) (both ER ␣ and ER ␤) are located throughout the brain, especially in regions involved in learning and memory such as the hippocampus and amygdala. However, studies in women involving estrogens have been conflicting with the predonderance of observational studies suggesting benefit and the randomized trials suggesting no benefit and possible harm. We will review the current evidence of the effect of exogenous estrogen and the risk of developing dementia. In addition, we will discuss results from studies of selective estrogen receptor modulators (SERMs) and highlight areas of future research with these and other novel estrogenic compounds. We will also review the literature on endogenous estrogens and cognitive function and risk of AD and suggest future directions for research. S1-01-05

TESTERONE LEVELS, GENETIC POLYMORPHISMS AND ALZHEIMER’S DISEASE

Eva Hogervorst, Formerly OPTIMA, Current Loughborough University, Formerly Oxford, Current Loughborough, United Kingdom. Contact e-mail: [email protected] Background: We were the first to show that low testosterone (T) levels were associated Alzheimer disease (AD) but it remains unclear whether this is a co-morbid effect due to cachexia, subclinical hyperthyroidism or other co-morbidity. The biological plausibility for potential protective effects of T on brain functions is substantial. In addition, higher levels of gonadotropins found in older cases with AD suggest that low levels of T are not due to brain degeneration and that the hypothalamicpituitary-gonadal (HPG) axis is still intact. In fact, there may be a role for elevated gonadotropin levels in promoting AD pathology. Results: Data from the Oxford Project to Investigate Memory and Ageing showed that men genetically at risk for AD were also already found to have lower levels of T. However, despite having lower levels of T, women do not show accelerated cognitive decline with age when compared to men. In addition, castration has not necessarily shown a decline in cognitive functions, but improvement of memory functions. Age may be an important factor when assessing optimal levels of T and several studies suggest that bioavailable T may be a better marker than total T levels when investigating associations of androgen activity with cognitive function. Small-scale T intervention trials in elderly men with and without dementia suggest that some cognitive deficits may be reversed, at least in part, by short term T supplementation. Conclusions: Age, optimal bioavailable T levels and prior hypogonadism may play an important role in therapy success and these factors should be investigated in more detail in future large scale randomized controlled studies. Professor Hogervorst has been Chair of Biological Psychology at the Department of Human Sciences, Loughborough University,UK, since 2005. She is also a Visiting Senior Research Fellow at Cambridge University where she investigates hormone levels in the MRC Cognitive Function and Ageing Study. Prior to this she worked at the University of Oxford, Department of Pharmacology with Professor David Smith to investigate modifiable risk factors in Alzheimer’s disease. Her validated differential dementia diagnostic computerized system and complementary cognitive test battery are used in studies in the USA, Europe and Indonesia.

S3

INTEGRATIVE VIEW OF METABOLIC SYNDROME FEATURES—FROM CARDIOVASCULAR DISEASE TO DEMENTIA

Miia Kivipelto, Stockholm Gerontology Research Center, Stockholm, Sweden. Contact e-mail: [email protected] Background: During the past decade, evidence has accumulated suggesting that cardiovascular conditions and conditions associated with cognitive impairment have common risk factors. Objective(s): This is a brief review of current epidemiological evidence and new findings from the Finnish population-based CAIDE study linking features of the metabolic syndrome to dementia/AD. Results: Diabetes mellitus, features of impaired glucose tolerance, high blood pressure (BP), serum cholesterol and body mass index (BMI) at midlife have been associated with subsequent dementia/AD in several epidemiological studies. In the CAIDE study (mean follow-up 21 years), midlife obesity (BMIⱖ30kg/m2), hypercholesterolemia (ⱖ6.5mmol/l) and hypertension (ⱖ160mmHg) were all significant risk factors for dementia/AD, with ORs of around 2 for each factor, and they increased the risk additively (OR 6.2 for the combination). Risk scores including features of the metabolic syndrome have been developed to predict cardiovascular events. From our data, we derived a Dementia Risk Score based on age, education, hypertension, hypercholesterolemia and obesity (AUC 0.77; CI 0.71-0.83), which may be helpful in identifying individuals who can benefit from therapeutic interventions. Apart from drug treatments, as indicated by the CAIDE study, physical activity and diet may also be important in preventing dementia, especially in APOE ⑀4 carriers. Conclusions: Features of the metabolic syndrome may be linked not only to cardiovascular conditions, but to dementia/AD as well. However, while it is obvious that these risk factors tend to cluster, the metabolic syndrome is not precisely defined, and its pathogenesis needs to be further clarified. When it comes to dementia, it seems that identifying all the risk factors is more important than attaching the label "metabolic syndrome" to a patient. The "syndrome" concept is nevertheless important in this context, as identification of one of its features should immediately prompt a search for others and also the initiation of adequate treatment, as intervention strategies for cardiovascular conditions are likely to be beneficial for the brain as well. SUNDAY, JULY 16, 2006 SYMPOSIA S1-02 DISEASE MECHANISMS (APP AND A␤) S1-02-01

GAMMA-SECRETASE: RELATIONSHIP BETWEEN GAMMA-CLEAVAGE AND EPSILONCLEAVAGE

Maho Morishima-Kawashima, Yasuo Ihara, University of Tokyo, Tokyo, Japan. Contact e-mail: [email protected]

␥-Secretase cleaves the transmembrane domain of ␤ amyloid precursor protein (APP) at least at two sites. ␥-Cleavage in the middle of the transmembrane domain releases A␤40 and A␤42, and ⑀-cleavage at the cytoplasmic/membrane boundary generates predominantly APP intracellular domain (AICD) 50-99. We have been long concerned about the relationship between the two cleavages. Whereas the cells expressing wildtype APP and presenilin 1/2 predominantly produced AICD50-99, those expressing familial AD mutant APP or presenilin 1/2 preferentially produced AICD49-99. In addition, the expression of A␤49, a major product that would have been generated by ⑀-cleavage, resulted in predominant release of A␤40, while that of A␤48, a putative counterpart of AICD49-99, preferentially produced A␤42. These strongly suggest that ⑀-cleavage and ␥-cleavage are interrelated, and further led us to hypothesize that ⑀-cleavage comes first. Along this line of scenario, we have developed a new gel system and identified longer A␤s, including A␤45, A␤46, and A␤48, within the cells. The treatment of the cells with DAPT built up A␤43 and A␤46 in a dose-dependent manner, concomitantly with a decrease in