Objective. —To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations. Data Sources. —Forty research teams contributed data onAPOEgenotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources. Main Outcome Measures. —Odds ratios (ORs) and 95% confidence intervals (Cls) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed forAPOEgenotypes ∈2/∈2,∈2/∈3,∈2/∈4,∈3/∈4 and ∈4/∈4 relative to the ∈3/∈3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures. Results. —Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes ∈2/∈4 (OR=2.6, 95% Cl=1.6-4.0), ∈3/∈4 (OR=3.2, 95% Cl=2.8-3.8), and ∈4/∈4 (OR=14.9, 95% CI=10.8-20.6); whereas, the ORs were decreased for people with genotypes ∈2/∈2 (OR=0.6, 95% Cl=0.2-2.0) and ∈2/∈3 (OR=0.6, 95% Cl=0.5-0.8). TheAPOE∈4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P Conclusions. —TheAPOE∈4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association betweenAPOE∈4 and AD in African Americans requires clarification, and the attenuated effect ofAPOE∈4 in Hispanics should be investigated further.

https://jamanetwork.com/journals/jama/articlepdf/418446/jama_278_16_041.pdf

Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis

BACKGROUND: The serum concentration of interleukin 6 (IL-6), a cytokine that plays a central role in inflammation, increases with age. Because inflammation is a component of many age-associated chronic diseases, which often cause disability, high circulating levels of IL-6 may contribute to functional decline in old age. We tested the hypothesis that high levels of IL-6 predict future disability in older persons who are not disabled.



METHODS: Participants at the sixth annual follow-up of the Iowa site of the Established Populations for Epidemiologic Studies of the Elderly aged 71 years or older were considered eligible for this study if they had no disability in regard to mobility or in selected activities of daily living (ADL), and they were re-interviewed 4 years later. Incident cases of mobility-disability and of ADL-disability were identified based on responses at the follow-up interview. Measures of IL-6 were obtained from specimens collected at baseline from the 283 participants who developed any disability and from 350 participants selected randomly (46.9%) from those who continued to be non-disabled.



FINDINGS: Participants in the highest IL-6 tertile were 1.76 (95% CI, 1.17-2.64) times more likely to develop at least mobility-disability and 1.62 (95% CI, 1.02-2.60) times more likely to develop mobility plus ADL-disability compared with to the lowest IL-6 tertile. The strength of this association was almost unchanged after adjusting for multiple confounders. The increased risk of mobility-disability over the full spectrum of IL-6 concentration was nonlinear, with the risk rising rapidly beyond plasma levels of 2.5 pg/mL.



INTERPRETATION: Higher circulating levels of IL-6 predict disability onset in older persons. This may be attributable to a direct effect of IL-6 on muscle atrophy and/or to the pathophysiologic role played by IL-6 in specific diseases. J Am Geriatr Soc 47:639–646, 1999.

Serum IL-6 level and the development of disability in older persons.

Objective To study differences between subjects with Alzheimer disease (AD) and cognitively intact control subjects, with respect to brain histologic markers of AD, and the relationship of those markers in the AD group to severity of dementia, age at death, sex, and apolipoprotein E genotype. Setting Washington University Alzheimer's Disease Research Center, St Louis, Mo. Design and Subjects Consecutive neuropathologic series of 224 prospectively studied volunteer research subjects, 186 with dementia of the Alzheimer type (DAT) or "incipient" DAT and confirmed to have AD by postmortem examination and 13 cognitively intact subjects, confirmed to lack postmortem findings of AD. Main Outcome Measures Brain densities (number per square millimeter) of senile plaques and neurofibrillary tangles, extent of cerebral amyloid angiopathy, cortical Lewy bodies, and apolipoprotein E genotype. Results Neocortical neurofibrillary tangle densities were substantially correlated with dementia severity, and to a greater degree than was true for senile plaque densities. When infarcts, hemorrhages, and Parkinson disease changes coexisted with AD, neurofibrillary tangle and senile plaque densities were lower. Plaque-predominant AD was found in a greater proportion of subjects with milder than more severe dementia. Entorhinal cortical Lewy bodies were no more frequent in plaque-predominant AD than in the remaining AD cases. Increasing age at death was negatively correlated with dementia severity and densities of senile plaques and neurofibrillary tangles. The apolipoprotein E ϵ4 allele frequency was greater in AD than in control subjects but decreased with increasing age. After controlling for dementia severity, senile plaque densities were only weakly related to ϵ4 allele frequency, and only in hippocampus. However, the degree of cerebral amyloid angiopathy was clearly related to ϵ4 allele frequency. Among subjects diagnosed during life as having DAT or incipient DAT, only 7% were found to have a neuropathologic disorder other than AD causing their dementia. Conclusions (1) The order of the strength of relationships between densities of histologic markers and dementia severity in AD is neurofibrillary tangles greater than cored senile plaques greater than total senile plaques. (2) Advanced age at death is associated with somewhat less severe dementia and fewer senile plaques and neurofibrillary tangles. (3) Plaque-predominant AD may represent a developmental stage in AD. (4) Despite a substantial effect of apolipoprotein E ϵ4 as a risk factor for AD, on decreasing the age at AD onset, and increasing the amount of cerebral amyloid angiopathy, its effect on senile plaque densities is variable and complex, being confounded with age, dementia severity, and methodologic differences. (5) Stringent clinical diagnostic criteria for DAT, even in the very mild stage, and senile plaque–based neuropathologic criteria for AD are highly accurate.

Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype.

Background The e4 allele of apolipoprotein E has been associated with an increased risk of late-onset Alzheimer's disease. In a cohort of elderly subjects we prospectively investigated the relation between the apolipoprotein E genotype, dementia, and the accumulation of β-amyloid protein in the cerebral cortex. Methods Autopsy involving neuropathological analysis and DNA analysis of frozen blood samples was performed in 92 of 271 persons who were at least 85 years of age, who had been living in Vantaa, Finland, on April 1, 1991, and who had died between that time and the end of 1993. All subjects had been tested for dementia. Apolipoprotein E genotyping was done with a solid-phase minisequencing technique. The percentage of the cortex occupied by methenamine silver–stained plaques was used as an estimate of the extent of β-amyloid protein deposition. Results The frequency of the e4 allele was significantly higher in the subjects with Alzheimer's disease than in the subjects without dementia (30 percent vs...

https://www.nejm.org/doi/pdf/10.1056/NEJM199511093331902

Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein.

The role of genetics in determining life-span is complex and paradoxical. Although the heritability of life-span is relatively minor, some genetic variants significantly modify senescence of mammals and invertebrates, with both positive and negative impacts on age-related disorders and life-spans. In certain examples, the gene variants alter metabolic pathways, which could thereby mediate interactions with nutritional and other environmental factors that influence life-span. Given the relatively minor effect and variable penetrance of genetic risk factors that appear to affect survival and health at advanced ages, life-style and other environmental influences may profoundly modify outcomes of aging.

https://science.sciencemag.org/content/sci/278/5337/407.full.pdf

Genetics of aging

No association between Alzheimer's disease (AD) and apolipoprotein E type epsilon 4 (ApoE epsilon 4) phenotype was found among centenarians in Finland (N = 179). The data are based on ascertainment of all centenarians in Finland in 1991. All examinations were conducted during 1991. The diagnoses of dementia and AD were based on clinical grounds, conforming to DSM-III-R and NINCDS-ADRDA criteria. The percentage of ApoE epsilon 4 alleles among the centenarians was 8.7% (31 of 358 alleles). This is significantly lower than percentages found in younger Finnish populations. Thirty (16.8%) of the 179 centenarians were epsilon 4 allele carriers. One hundred fifty-one (84.4%) of the centenarians were women. Twenty-eight (18.5%) of the women had at least one epsilon 4 allele, as did two (7.1%) of the men. The prevalence of clinically diagnosed AD was 26.8%; 44% of the subjects were cognitively normal, 23% had signs of cognitive decline or at most mild dementia (with no differential diagnosis), and 6% had a dementia clinically diagnosed as being due to some cause other than AD. For AD cases versus cognitively normal subjects, the odds ratio associated with being a carrier of the epsilon 4 allele was 1.34 (p = 0.64; 95% CI = [0.5, 3.3]). Among women, the odds ratio was 0.99 (p = 1.0; 95% CI = [0.4, 2.6]). There were fewer, but not significantly so, epsilon 4 carriers among subjects with cognitive decline or at most mild dementia (12.2%) than there were among the cognitively normal subjects (16.5%). The AD patients had no evidence of difficulty standing on a flat stationary surface unless the surface suddenly moved.(ABSTRACT TRUNCATED AT 250 WORDS)

J. Louhija

Papers

Lack of association of apolipoprotein E allele ϵ4 with late‐onset Alzheimer's disease among Finnish centenarians