Kathleen A. Welsh

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part V. A normative study of the neuropsychological battery

The neuropsychological tests developed for the Consortium to Establish a Registry for Alzheimers Disease (CERAD) are currently used to measure cognitive impairments of Alzheimers disease (AD) in clinical investigations of this disorder. This report presents the normative information for the CERAD battery, obtained in a large sample (n = 413) of control subjects (ages 50 to 89) who were enrolled in 23 university medical centers in the United States participating in the CERAD study from 1987 to 1992. We compared separately the performance of subjects with high (≥12) and low (<12) years of formal education. For many of the individual cognitive measures in the highly educated group, we observed significant age and gender effects. Only the praxis measure showed a significant age effect in the low-education group. Delayed recall, when adjusted for amount of material acquired (savings), was relatively unaffected by age, gender, and level of education. Our findings suggest that the savings scores, in particular, may be useful in distinguishing between AD and normal aging.

Inverse association of anti‐inflammatory treatments and Alzheimer's disease Initial results of a co‐twin control study

We conducted a co-twin control study among 50 elderly twin pairs with onsets of Alzheimers disease (AD) separated by 3 or more years. Twenty-three male pairs (46%) were screened from the (U.S.) National Academy of Sciences-National Research Council Registry (NAS-NRC Registry) of World War II veteran twins; others (mostly women) had responded to advertisements or were referred from AD clinics. Twenty-six pairs (52%) were monozygous. The onset of AD was inversely associated with prior use of corticosteroids or ACTH (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.06 to 0.95; p = 0.04). Similar but weaker trends were present among pairs discordant for history of arthritis or for prior daily use of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin. The association was strongest when we combined use of steroids/ACTH or NSAIDs post hoc into a single variable of anti-inflammatory drugs (AIs) (OR, 0.24; CI, 0.07 to 0.74; p = 0.01). The inverse relation was strong in female (volunteer) twin pairs but was not present in the younger men from the NAS-NRC Registry. AIs had typically been taken for arthritis or related conditions, but a similar result was apparent after controlling statistically for the arthritis variable (OR, 0.08; CI, 0.01 to 0.69; p = 0.02). AIs have been proposed as a means of retarding the progression of AD symptoms, and these data suggest that AIs may also prevent or delay the initial onset of AD symptoms. Because of limitations in the case-control method, our results require corroboration with hypothesis-driven research designed to control bias and confounding.

Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs.

Factors that modify onset of Alzheimers disease (AD) may be revealed by comparing environmental exposures in affected and unaffected members of discordant twin pairs or sibships. Among siblings at high risk of AD, sustained use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with delayed onset and reduced risk of AD. After adjustment for use of NSAIDs, there was minimal effect on onset with reported history of any of three common illnesses (arthritis, diabetes, or acid-peptic disease). However, independent of exposure to NSAIDs, onset was unexpectedly delayed in those reporting extended use of histamine H2 blocking drugs. Randomized clinical trials will be needed to affirm the utility of these drugs for prevention, but the present findings may have implications for pathogenesis: because NSAIDs block the calcium-dependent postsynaptic cascade that induces excitotoxic cell death in NMDA-reactive neurons, and because histamine potentiates such events, excitotoxicity may deserve additional investigation in AD.

Intelligence and education as predictors of cognitive state in late life A 50-year follow-up

We evaluated the relation of education and intelligence in early adult life to cognitive function in a group of elderly male twins.The Army General Classification Test (AGCT) was administered to US armed forces inductees in the early 1940s. Fifty years later, as part of a study of dementia in twins, we tested the cognitive status of 930 of these men using the modified Telephone Interview for Cognitive Status (TICS-m). TICS-m scores obtained in later life were correlated with AGCT scores (r equals 0.457) and with years of education (r equals 0.408). Thus, in univariate analyses, the AGCT score accounted for 20.6% and education accounted for 16.7% of variance in cognitive status. However, these two effects were not fully independent. A multivariable model using AGCT score, education, and the interaction of the two variables as predictors of the TICS-m score explained 24.8% of the variance, a slightly but significantly greater proportion than was explained by either factor alone. In a separate analysis based on 604 pairs of twins who took the AGCT, heritability of intelligence (estimated by AGCT score) was 0.503. Although this study does not address the issue of education and premorbid IQ as risk factors for dementia, the findings suggest that basic cognitive abilities in late life are related to cognitive performance measures from early adult life (ie, education and IQ).

Characteristics of Nonresponders in A Community Survey of the Elderly

OBJECTIVE: To identify predictors of nonresponse in a community survey of cognitive status in the elderly.

Neuropsychological test performance in African-American* and white patients with Alzheimer's disease

Little information exists on the performance of black versus white patients with Alzheimers disease on neuropsychological tests for dementia.In this study, we compared performance on the CERAD (Consortium to Establish a Registry for Alzheimers Disease) neuropsychological battery between white (n equals 830) and black (n equals 158) patients with Alzheimers disease enrolled in the CERAD study at 23 university medical centers in the United States. The black patients were older, had fewer years of formal education, and were more impaired in their activities of daily living than were the white patients. After controlling for these characteristics and for duration of the disease and severity of dementia, there were differences in the performance of black and white patients on several of the cognitive measures. Black patients scored lower than whites on tests of visual naming and constructional praxis and on the Mini-Mental State Examination. There were no statistical differences in performance on tests of fluency and word list memory. These findings suggest that cultural or experiential differences may modify performance on specific neuropsychological tests. These factors, in addition to age and educational background, should be considered when interpreting performance on neuropsychological tests in elderly black patients with dementia. NEUROLOGY 1995;45: 2207-2211

Caregiver ratings of personality change in Alzheimer's disease patients : a replication

Caregivers of 26 patients with Alzheimers disease (AD) rated current and premorbid personality patterns with the NEO Personality Inventory. Results replicated previous findings on the degree of change reported in a previous group of patients with mixed memory disorder diagnoses. After a diagnosis of AD, the patients were rated as significantly more neurotic, less extraverted, less open, and less conscientious. There were no rated differences of changes in the personality domain of Agreeableness. These results strengthen the usefulness of caregiver ratings of personality change of patients with memory problems who cannot be useful informants on their own behalf.

Issues affecting minority participation in research studies of Alzheimer disease.

Despite the need for minority subjects in research studies of Alzheimer disease (AD), the successful involvement of minority patients in such studies has been difficult. This report discusses the many societal, economic, logistical, and attitudinal barriers that have inhibited the participation of minority patients and their families in medical research programs of AD. Special consideration is given to the unique cultural issues that arise when conducting studies involving African-American elderly subjects. Methods are considered for overcoming the barriers to participation gleaned from the national study CERAD (Consortium to Establish a Registry of Alzheimer Disease) and other investigations of AD. Recommendations are made for future research programs targeted on the specific health care needs and concerns of the minority segments of our population.

Risk of Alzheimer disease with the ε4 allele for apolipoprotein E in a population-based study of men aged 62-73 years

The ±4 allele at APOE, the polymorphic locus for apolipoprotein E, increases the risk of Alzheimer disease (AD), especially among those with the homozygous ±4/±4 genotype. In family studies, ±4 homozygotes typically develop AD at 55–75 years, an age range when AD is otherwise relatively infrequent. Population-based studies of the AD risk associated with allele ±4 (and especially with genotype ±4/±4) are limited in number, and most such studies have included few AD cases between the ages of 55 and 75 years. In a large population-based twin registry, the screening of 12,709 men who were 62–73 years old yielded 38 prevalent cases of AD whose onset age ranged from 54 to 73. Genotype at APOE was determined for 37 of these cases and, independently, for a similarly aged probability sample of 344 men from the same registry. The ±4 allele frequencies among the AD cases and the population samples were 0.39 and 0.15, respectively. The odds ratios (ORs) for AD were 17.7 for genotype ±4/±4 versus ±3/±3 and 13.8 for ±4/±4 versus all remaining genotypes. By contrast, the ORs with heterozygous ±4/±3 were only 2.76 versus ±3/±3 and 2.01 versus all genotypes other than ±4/±3 (p for homozygote vs. heterozygote ORs = 0.002). The estimated etiologic fraction for AD with homozygous ±4 among men in their mid-50s to mid 70s is therefore 0.20; for the much more common heterozygous genotype ±4/±3, the fraction is 0.18. In combination with other studies that have adjusted statistically for age, these results suggest that the effect of the ±4 allele dose is neither linear nor homogeneous for age. Homozygous ±4/±4 appears to confer an extreme risk of AD at the age when onset with this genotype is most likely. These results are consistent with the view that individual genotypes modify risk by predisposing to substantially different distributions of AD onsets.

Use of twin cohorts for research in Alzheimer's disease*

The causes of Alzheimers disease (AD) remain a mystery despite the recent identification of several putative environmental risk factors and the discovery of several linked genetic loci and point mutations associated with the disease. Particularly uncertain is the generalizability of the genetic findings to the common forms of disease encountered in clinical practice or population research. Twin studies of AD can illuminate causal mechanisms, both genetic and environmental. This consensus document explores the rationale for such twin studies, as well as a number of methodologic problems that render them difficult to implement or interpret. We review existing twin studies of AD and note several ambitious new studies. Finally, we delineate several practical strategies for the near future of twin research in AD.