Maria M. Corrada

Risk of Alzheimer's disease and duration of NSAID use

Article abstract-In a longitudinal study of 1,686 participants in the Baltimore Longitudinal Study of Aging, we examined whether the risk of Alzheimers disease (AD) was reduced among reported users of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). In addition, we examined use of acetaminophen, a pain-relief medication with little or no anti-inflammatory activity, to assess the specificity of the association between AD risk and self-reported medications. Information on use of medications was collected during each biennial examination between 1980 and 1995. The relative risk (RR) for AD decreased with increasing duration of NSAID use. Among those with 2 or more years of reported NSAID use, the RR was 0.40 (95% confidence interval [CI]: 0.19-0.84) compared with 0.65 (95% CI: 0.33-1.29) for those with less than 2 years of NSAID use. The overall RR for AD among aspirin users was 0.74 (95% CI: 0.46-1.18), and no trend of decreasing risk of AD was observed with increasing duration of aspirin use. No association was found between AD risk and use of acetaminophen (RR = 1.35; 95% CI: 0.79-2.30), and there was no trend of decreasing risk with increasing duration of use. These findings are consistent with evidence from cross-sectional studies indicating protection against AD risk among NSAID users and with evidence suggesting that one stage of the pathophysiology leading to AD is characterized by an inflammatory process. NEUROLOGY 1997;48: 626-632

A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease : The Baltimore Longitudinal Study of Aging

Previous reports have suggested that estrogen replacement therapy (ERT) in women may exert a protective effect on their risk of developing Alzheimers disease (AD). We investigated this relationship in the Baltimore Longitudinal Study of Aging (BLSA), a prospective multidisciplinary study of normal aging conducted by the National Institute on Aging. The sample consisted of 472 post- or perimenopausal women followed for up to 16 years in the BLSA. We documented ERT prospectively at each BLSA visit, and we categorized women who had used oral or transdermal estrogens at anytime as ERT users. We used Cox proportional hazards models with time-dependent covariates to estimate the relative risk of developing AD after ERT as compared with women who had not used estrogen replacement. Approximately 45% of the women in the cohort had used ERT, and we diagnosed 34 incident cases of AD (NINCD/ADRDA criteria) during follow-up, including nine estrogen users. After adjusting for education, the relative risk for AD in ERT users as compared with nonusers was 0.46 (95% CI, 0.209–0.997), indicating a reduced risk of AD for women who had reported the use of estrogen. Our data did not show an effect for duration of ERT usage. Our finding offers additional support for a protective influence of estrogen in AD. Randomized clinical trials are necessary to confirm this association, which could have significant public health impact.

Dementia Incidence Continues to Increase with Age in the Oldest Old The 90+ Study

The oldest old are the fastest growing segment of the US population, and accurate estimates of dementia incidence in this group are crucial for healthcare planning. Although dementia incidence doubles every 5 years from ages 65 to 90 years, it is unknown if this exponential increase continues past age 90 years. Here, we estimate age‐ and sex‐specific incidence rates of all‐cause dementia in people aged 90 years and older, including estimates for centenarians.

Visual memory predicts Alzheimer's disease more than a decade before diagnosis

Background: Recent studies have suggested that AD may reflect a chronic process that begins many years before the clinical expression of dementia. The current study examines premorbid Benton Visual Retention Test (BVRT) and Wechsler Adult Intelligence Scale–vocabulary (WAIS-voc) test scores in order to determine whether long-term deficits in these tests can predict the development of AD decades later in the Baltimore Longitudinal Study of Aging (BLSA). Method: Participants are volunteers from the BLSA, a multidisciplinary study of normal aging conducted by the National Institute on Aging. A total of 1,425 BLSA participants who were older than 60 years were included in the analyses. Cox proportional hazards models were used to estimate the relative risk of developing AD associated with BVRT and WAIS-voc scores at different time periods up to 20 years before the diagnosis of AD. Results: The relative risks for 6 or more BVRT errors vs less than 6 errors at 1 to 3, 3 to 5, 5 to 10, and 10 to 15 years before the diagnosis of AD were 5.69, 2.11, 1.76, and 1.83 (p < 0.05). The relative risk for 15 or more years before diagnosis was not significant (p > 0.10). WAIS-voc scores were not significantly associated with the risk of AD in any time period. Conclusions: A greater number of errors on the BVRT is associated with an increased risk of AD up to 15 years later. Poor visual memory performance may represent an early expression of AD years before diagnosis. This result suggests the need to continue to revise views on the natural history of AD and the possibility of an increased window of opportunity for preventive treatment before definitive diagnosis.

Prevalence of dementia after age 90 Results from The 90+ Study

Background: Although the prevalence of dementia increases with age from ages 65 to 85, whether this increase continues after age 90 is unclear. Most studies reporting on dementia prevalence do not have sufficient participants to estimate prevalence for specific ages and sexes above age 90. Here, we estimate age- and sex-specific prevalence of all-cause dementia in the oldest-old, those aged 90 and older. Methods: Participants are 911 elderly from The 90+ Study, a population-based study of aging and dementia in people aged 90 and above. Dementia was diagnosed using in-person examinations as well as telephone and informant questionnaires. Results: The overall prevalence of all-cause dementia was higher in women (45%, 95% CI = 41.5–49.0) than men (28%, 95% CI = 21.7–34.2). Among women, prevalence increased with age after age 90, essentially doubling every 5 years. A lower prevalence of dementia was significantly associated with higher education in women but not in men. Conclusions: In a very large sample of participants aged 90 and older, prevalence of all-cause dementia doubled every 5 years for women but not men.

Reliability of the Blessed Telephone Information-Memory-Concentration Test

In-person cognitive evaluations can be costly and labor intensive in geographically widespread populations. Reliable telephone instruments that screen for cognitive status would greatly facilitate epidemiologic and other longitudinal studies. We evaluated the reliability of the Blessed Information-Memory-Concentration (IMC) test when administered by telephone. Eighty-four subjects with a wide range of cognitive abilities were administered the Blessed IMC twice over a 3-week interval. Forty-nine of the subjects were administered the test both by telephone and in-person, and 35 of the subjects were tested twice by telephone. Spearmans rank correlation was used to compare scores of the different administrations (.96; P < .001) and to examine test-retest reliability (.96; P < .001). The Blessed Telephone IMC (TIMC) test exhibits excellent reliability both when compared to in-person administration as-well as in test-retest results. The Blessed TIMC appears to be a practical instrument for population and longitudinal studies when in-person assessment is not feasible.

Reduced risk of Alzheimer’s disease with high folate intake: The Baltimore Longitudinal Study of Aging

Study findings have suggested an association between Alzheimers disease (AD) risk and several vitamins and have speculated about their use as preventive agents. Here, we examine whether total intake (intake from diet plus supplements) of antioxidant vitamins (E, C, carotenoids) and B vitamins (folate, B6, and B12) is associated with a reduced risk of AD.

APOE ε2 is associated with intact cognition but increased Alzheimer pathology in the oldest old

Background: Many studies have examined the role of APOE genotype in the development of dementia, specifically Alzheimer disease (AD). The APOE ε4 allele (APOE4) is a risk factor for both clinical and neuropathologic AD whereas the APOE ε2 allele (APOE2) seems to be protective. This would predict, even with advanced age, that APOE2 carriers would be less likely to have dementia and less likely to meet pathologic criteria for AD. Methods: The first 85 genotyped participants from The 90+ Study to come to autopsy were included. All-cause dementia (using DSM-IV criteria) and AD (using National Institute of Neurological and Communicative Disorders and Stroke–Alzheimers Disease and Related Disorders Association criteria) diagnoses were made by consensus conference using all available information including neuropsychological testing, neurologic examination, and medical records. Neuropathologic examination included Braak and Braak staging for plaques and tangles and diagnosis of neuropathologic AD using National Institute on Aging–Reagan criteria. Results: Across all genotypes, 58.5% of subjects were diagnosed with clinical dementia (81% of dementia was AD) and 50.0% met neuropathologic criteria for AD. Compared to those with an APOE ε3/ε3 genotype (APOE3/3), APOE4 carriers were more likely to be diagnosed with dementia (odds ratio [OR] = 12.2, 95% confidence interval [CI] = 1.5–102.0), whereas APOE2 carriers were not (OR = 0.3, 95% CI = 0.1–1.3). Surprisingly, both APOE4 (OR = 4.6, 95% CI = 1.3–16.5) and APOE2 (OR = 7.8, 95% CI = 1.5–40.2) carriers were more likely to meet neuropathologic criteria for AD than those with APOE3/3 genotype. Conclusions: In the oldest old, the presence of the APOE ε2 allele (APOE2) was associated with a somewhat reduced risk of dementia, but paradoxically was associated with increased Alzheimer disease (AD) neuropathology. Therefore, oldest old APOE2 carriers may have some mechanism that contributes to the maintenance of cognition independently of the formation of AD pathology.

No advantage of Aβ 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies

Introduction: Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs known as selective Aβ42-lowering agents (SALAs) is responsible for this apparent reduction in AD risk. Methods: We pooled individual-level data from six prospective studies to obtain a sufficient sample to examine AD risk in users of SALA vs non-SALA NSAIDs. Results: Of 13,499 initially dementia-free participants (70,863 person-years), 820 developed incident AD. Users of NSAIDs (29.6%) showed reduced risk of AD (adjusted hazard ratio [aHR] 0.77, 95% CI 0.65–0.91). The point estimates were similar for SALAs (aHR 0.87, CI 0.72–1.04) and non-SALAs (aHR 0.75, CI 0.56–1.01). Because 573 NSAID users (14.5%) reported taking both a SALA and non-SALA, we examined their use alone and in combination. Resulting aHRs were 0.82 (CI 0.67–0.99) for SALA only, 0.60 (CI 0.40–0.90) for non-SALA only, and 0.87 (CI 0.57–1.33) for both NSAIDs (Wald test for differences, p = 0.32). The 40.7% of participants who used aspirin also showed reduced risk of AD, even when they used no other NSAIDs (aHR 0.78, CI 0.66–0.92). By contrast, there was no association with use of acetaminophen (aHR 0.93, CI 0.76–1.13). Conclusions: In this pooled dataset, nonsteroidal anti-inflammatory drug (NSAID) use reduced the risk of Alzheimer dementia (AD). However, there was no apparent advantage in AD risk reduction for the subset of NSAIDs shown to selectively lower Aβ42, suggesting that all conventional NSAIDs including aspirin have a similar protective effect in humans.

Calcium channel blockers and risk of AD: the Baltimore Longitudinal Study of Aging.

OBJECTIVE To investigate the association between use of calcium channel blockers (CCB), dihydropyridine (DHP) or nondihydropyridine (nonDHP) type CCB and risk of developing Alzheimers Disease (AD) or mortality. There is evidence suggesting that calcium plays a key role in changes in the brain leading to AD. Previous reports suggest a possible role for CCB in the treatment of AD. However, there are some indications that CCB increase mortality in patients with cardiac disease. METHODS Subjects were 1092 participants in the Baltimore Longitudinal Study of Aging (BLSA) older than 60 years of age. Data on CCB use was collected prospectively for up to 19 years. Cox proportional hazards regression was used to estimate relative risks (RR) and confidence intervals (CI) of AD and mortality associated with use of CCB or use of only DHP or nonDHP-CCB. Analyses were adjusted for gender, education, smoking, blood pressure and history of heart problems. RESULTS Use of DHP-CCB was not associated with a significantly reduced risk of AD compared to non-users, although the estimate of the RR was low with DHP-CCB (RR = 0.30, 95% CI = 0.07-1.25, P = 0.10). Use of nonDHP-CCB was not associated with reduced risk of AD and the estimate of the RR risk was close to one (RR = 0.82, 95% CI = 0.37-1.83, P = 0.63). In addition, there was no increase in mortality among users of DHP-CCB (RR = 0.64, 95% CI = 0.32-1.29, P = 0.21) or nonDHP-CCB (RR = 1.10, 95% CI = 0.65-1.87, P = 0.72). CONCLUSION Users of DHP-CCB and nonDHP-CCB in this study did not have a significantly reduced risk of AD.