L. A. Cupples

Head injury and the risk of AD in the MIRAGE study

Objectives: It has been suggested in some studies that head injury is a risk factor for AD, and that this risk is heightened among carriers of the APOE-ε4 allele. We examined the effects of head injury and APOE genotype on AD risk in a large family study. Subjects: A total of 2,233 probands who met criteria for probable or definite AD and their 14,668 first-degree family members (4,465 parents, 7,694 siblings, and 2,509 spouses) were ascertained at 13 centers in the United States, Canada, and Germany participating in the MIRAGE (Multi-Institutional Research in Alzheimer Genetic Epidemiology) project. Information on head injury was collected by interview of multiple informants and review of medical records. Nondemented relatives and spouses served as control subjects for this study. Methods: Odds of AD for head trauma with or without loss of consciousness were computed by comparing probands with unaffected spouses using conditional logistic regression analysis. To account for the unique biologic relationship between probands and their parents and siblings, odds of AD were computed using a generalized estimating equation (GEE) Poisson regression approach. GEE logistic regression was used to examine the joint effects of APOE genotype and head injury on the odds of AD in probands and a control group comprised of unaffected siblings and spouses. Results: Comparison of probands with their unaffected spouses yielded odds ratios for AD of 9.9 (95% CI, 6.5 to 15.1) for head injury with loss of consciousness and 3.1 (2.3 to 4.0) for head injury without loss of consciousness. The corresponding odds derived from the comparison of probands with their parents and sibs were 4.0 (2.9 to 5.5) for head injury with loss of consciousness and 2.0 (1.5 to 2.7) for head injury without loss of consciousness. Head injury without loss of consciousness did not significantly increase the risk of AD in spouses (OR = 1.3; 95% CI, 0.4 to 4.1). The joint effects of head injury and APOE genotype were evaluated in a subsample of 942 probands and 327 controls (spouses and siblings). Head injury increased the odds of AD to a greater extent among those lacking ε4 (OR = 3.3) than among ε4 heterozygotes (OR = 1.8) or homozygotes (OR = 1.3). Conclusion: Head injury is a risk factor for AD. The magnitude of the risk is proportional to severity and heightened among first-degree relatives of AD patients. The influence of head injury on the risk of AD appears to be greater among persons lacking APOE-ε4 compared with those having one or two ε4 alleles, suggesting that these risk factors may have a common biologic underpinning.

Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: What is in store for the oldest old?

Despite recent advances in the molecular genetics of Alzheimers disease (AD), several fundamental questions concerning risk of illness are unresolved, namely, if Mendelian factors account for the incidence of the disease, and if AD is an inevitable consequence of the aging process. This study was designed to address these issues and other aspects of familial aggregation of the disorder. A consecutive sample of 1,694 patients who met criteria for a diagnosis of probable or definite AD were ascertained in 13 centers participating in the Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) project. Lifetime risk and age at onset of AD among various strata of 12,971 first-degree relatives was estimated using survival analysis procedures. The lifetime risk of AD in first-degree relatives was 39.0% +/- 2.1% by age 96 years. Age-specific risk of AD declined after age 90 and the data set included 61 apparently unaffected persons who survived to age 96 without becoming demented. Female relatives had a higher risk of AD than male relatives at all ages. By age 80, children of conjugal AD couples had a cumulative risk of 54%, 1.5 times greater than the sum of the risks to children having affected mothers or fathers, and nearly 5 times greater than the risk to children having normal parents. Children of affected fathers had a cumulative risk that was 1.4 times the corresponding risk to children of affected mothers. Risk assessment in early-onset and late-onset families, using various strategies for determining the age cut-off, yielded contradictory results. These data suggest the following: (1) the lifetime risk among relatives does not support a simple autosomal dominant inheritance pattern of disease; (2) women are innately more susceptible to AD than men; (3) the proportion of hereditary cases may be higher in men than women; (4) distinction between early- onset and late-onset forms of AD has little meaning in the absence of a biological marker; (5) the risk of AD decreases after age 90; and (6) AD therefore may not be an inevitable concomitant of the aging process, a conclusion that has profound implications for basic and applied AD research. The age- and sex-specific lifetime risks derived from this study are sufficiently robust to be a reliable source of information for counseling relatives of AD patients.

APOE, vascular pathology, and the AD brain

Objective: To use neuropathologic data to examine the association between APOE genotype and cerebrovascular lesions commonly found in Alzheimer disease (AD), as well as neuritic senile plaque (SP) and neurofibrillary tangle (NFT) burden. Methods: The sample comprised brains from 96 men and 3 women who fulfilled NIA-Reagan criteria for intermediate to high likelihood of AD. Region-specific and global measures of gross cerebrovascular disease, arteriolosclerosis, white matter lesions, microinfarcts, amyloid angiopathy, neuritic SP, and NFT burden were compared among those who had at least one APOE-ε4 vs those who did not. Pairwise rank-order correlations between measures were calculated. The association between APOE ε4 status and measures of vascular and AD pathology, adjusting for age at death, sex, brain weight, and Braak stage, were evaluated. Results: APOE-ε4 was not associated with gross cerebrovascular pathology. Compared to those who were negative, brains from ε4 individuals had a greater degree of small vessel arteriolosclerosis (p = 0.04) and perivascular macrophage infiltration (p = 0.06), but not other markers of small vessel disease or white matter myelin loss. Microinfarcts in the deep nuclei were associated with ε4 (p = 0.009), whereas cortical and subcortical microinfarcts were not. There was a trend toward association between APOE genotype and amyloid angiopathy (p = 0.08), and ε4 was associated with neuritic SP burden, but not NFT. Conclusion: APOE-ε4 is associated with small vessel arteriolosclerosis, microinfarcts of the deep nuclei, neuritic senile plaque density, and amyloid angiopathy in patients with autopsy-proven Alzheimer disease (AD). These results suggest a role for ε4 in some of the microvascular changes commonly found in AD and are consistent with a potential amyloidogenic role for ε4.

Transmission and age‐at‐onset patterns in familial Alzheimer's disease Evidence for heterogeneity

We evaluated age at onset and lifetime risk for Alzheimers disease (AD) in 70 kindreds with familial AD (designated FAD) composed of 541 affected and 1,066 unaffected offspring of demented parents who were identified retrospectively. Using a survival analysis method which takes into account affected persons with unknown onset ages and unaffected persons with unknown censoring ages, we found lifetime risk of AD among at-risk offspring by age 87 to be 64%. Analysis of age at onset among kindreds showed evidence for a bimodal distribution: in this sample, families with a mean onset age of less than 58 years were designated as having early-onset, while late-onset families had a mean onset age greater than 58 years. At-risk offspring in early-onset families had an estimated lifetime risk for dementia of 53%, which is significantly less than the risk of 86% that was estimated for offspring in late-onset families. Men and women in early-onset families had equivalent risk of dementia. In late-onset families, the risk to female offspring was somewhat higher than to male offspring but this difference was marginally significant. Lifetime risk of dementia in early-onset FAD kindreds is consistent with an autosomal dominant inheritance model. Our results may suggest that late-onset FAD has at least 2 etiologies; AD in some families may be transmitted as a dominant trait, whereas a proportion of cases in these and other late-onset families may be caused by other genetic or shared environmental factors.

Cerebrovascular hemodynamics, gait, and falls in an elderly population: MOBILIZE Boston Study.

Objective: To determine whether alterations in cerebral blood flow regulation are associated with slow gait speed and falls in community-dwelling elderly individuals. Methods: The study sample consisted of 419 individuals from the MOBILIZE Boston Study (MBS) who had transcranial Doppler ultrasound measures of cerebral blood flow velocity. The MBS is a prospective cohort study of a unique set of risk factors for falls in seniors in the Boston area. We measured beat-to-beat blood flow velocity in the middle cerebral artery in response to 1) changes in end-tidal CO2 (cerebral vasoreactivity) and 2) blood pressure changes during a sit-to-stand protocol (cerebral autoregulation). Gait speed was measured during a 4-meter walk. Falls were tracked by monthly calendars, and demographic and clinical characteristics were assessed at baseline. Results: A multivariate linear regression analysis showed that cerebral vasoreactivity was cross-sectionally related to gait speed (p = 0.039). Individuals in the lowest quintile of vasoreactivity had lower gait speeds as compared to those in the highest quintile (p = 0.047). In a negative binomial regression analysis adjusted for relevant covariates, the relationship between cerebral vasoreactivity and fall rate did not reach significance. However, when comparing individuals in the lowest to highest quintile of cerebral vasoreactivity, those in the lowest quintile had a higher fall rate (p = 0.029). Conclusions: Impaired cerebral blood flow regulation, as measured by cerebral vasoreactivity to CO2, is associated with slow gait speed and may lead to the development of falls in elderly people.

Head circumference, atrophy, and cognition Implications for brain reserve in Alzheimer disease

Background: Clinical and epidemiologic studies suggest that patients with Alzheimer disease (AD) with larger head circumference have better cognitive performance at the same level of brain pathology than subjects with smaller head circumference. Methods: A total of 270 patients with AD participating in the Multi-Institutional Research in Alzheimers Genetic Epidemiology (MIRAGE) study underwent cognitive testing, APOE genotyping, and MRI of the brain in a cross-sectional study. Linear regression analysis was used to examine the association between cerebral atrophy, as a proxy for AD pathology, and level of cognitive function, adjusting for age, duration of AD symptoms, gender, head circumference, APOE genotype, diabetes mellitus, hypertension, major depression, and ethnicity. An interaction term between atrophy and head circumference was introduced to explore if head circumference modified the association between cerebral atrophy and cognition. Results: There was a significant inverse association between atrophy and cognitive function, and a significant interaction between atrophy and head circumference. With greater levels of atrophy, cognition was higher for individuals with greater head circumference. Conclusion: This study suggests that larger head circumference is associated with less cognitive impairment in the face of cerebral atrophy. This finding supports the notion that head circumference (and presumably brain size) offers protection against AD symptoms through enhanced brain reserve.

Interrater agreement for diagnosis of Alzheimer's disease The MIRAGE study

There are standardized criteria to assist in the diagnosis of Alzheimers disease (AD), a disorder that lacks unique clinical, morphologic, or biochemical features. Diagnostic reliability of single groups of investigators using these criteria is moderate to substantial. In this study, seven clinicians at separate sites established a criteria-based diagnosis in 42 consecutive memory disorder patients participating in a national genetic epidemiologic study using a quantitative multiaxis AD rating scale (ADRS) that incorporates NINCDS/ADRDA criteria, reliability of information, and comorbidity. Reliability, measured by a generalized kappa statistic for more than two raters, was substantial (0.63 ± 0.13) when the subjects were grouped as “AD” (probable or possible) versus “not AD,” but somewhat lower (0.52 ± 0.10) when subjects were classified as probable AD, possible AD, or not AD. There was unanimous agreement for two-thirds of the subjects using a dichotomous classification scheme. These findings suggest that the ADRS is a useful diagnostic instrument for multicenter studies.

Comparison of Alzheimer's disease risk factors in white and African American families

The associations between alcohol, smoking, and head injury and the risk of AD in 443 African American and 2,336 white participants in the MIRAGE Study were evaluated. Alcohol had a modest protective effect in whites (odds ratio [OR] = 0.82, 95% CI = 0.68 to 0.99), with a similar trend in African Americans (OR = 0.88, 95% CI = 0.54 to 1.4). Head trauma increased the risk of AD in whites (OR = 2.3, 95% CI = 1.8 to 3.0) and African Americans (OR = 2.9, 95% CI = 1.2 to 7.0). Smoking was not associated with AD risk in whites (OR = 0.88, 95% CI = 0.73 to 1.1) or African Americans (OR = 1.0, 95% CI = 0.69 to 1.5). These risks were similar across subsets stratified by the presence or absence of the APOE ε4 allele.

Quantitative in vivo 31P magnetic resonance spectroscopy of Alzheimer disease.

Summary:The purpose of this study was to determine whether, in Alzheimer disease (AD) patients, abnormalities in energy charge or phospholipid metabolism could be detected during life with quantitative phosphorus magnetic resonance spectroscopy (31P MRS). We performed in vivo 31P MRS in 16 patients with a clinical diagnosis of probable AD with mild to moderate dementia severity (mean Blessed Dementia Score=17.5, range=7-37) and in 8 healthy, nondemented, age-matched, control subjects. MR studies were performed on a commercial 1.5 T MR imager using a volume head coil. We acquired brain spectra by sampling a 6-cm-thick axial slice through the cerebrum (a region that includes ~900 ml of brain tissue); we measured B-nucleoside triphosphate (B-NTP), phosphocreatine (PCr), phosphomonoesters (PME), phosphodiesters (PDE), and inorganic phosphate (P,) concentrations, then calculated ratios of these resonances. The B-NTP, PCr, and P, resonances in AD and control subjects were not significantly different. These data indicate that brain energy stores are not depleted in AD. No significant differences were detected in the absolute measurements of PME and PDE between the AD and control groups. However, among the calculated ratios, an increase in the PME/PDE ratio of ~50%, mostly due to a decrease in the PDE signal, was statistically significant (AD PME/PDE mean=0.35, range 0.13-0.71; normal PME/PDE mean=0.22, range 0.16-0.34). We speculate that the difference in PDE reflects changes in the biophysical state of membrane phospholipids in AD.