The two genetic polymorphisms, rs7412 and rs429358, that collectively form the ε2, ε3, and ε4 alleles of apolipoprotein E (APOE)are among the most widely studied sequence variants in the genome. The predominant model for testing APOE involves the haplotype combinations of ε2, ε3, and ε4 and has been basis of associations with dementia, atherosclerosis, and serum lipid levels. Here, we demonstrate the functional independence of these two component sites, with rs7412 contributing to the majority of variance in serum LDL (p = 10−20), whereas rs429358 alone influences variance in CSF Aβ42(p = 10 −17). This latter relationship is also reflected in the association of APOE with dementia, where rs429358 strongly influences disease (p = 10−67), but rs7412 does not. Models based upon ε2, ε3, and ε4 explained less variance for both dementia risk and CSF Aβ42 than did rs429358 alone. When adjusted for CSF Aβ42, the association of rs429358 with dementia is greatly reduced but remains significant indicating that APOE polymorphism influences disease by additional mechanisms distinct from Aβ42 metabolism. We reach four principal conclusion from this study; 1) rs429358 alone is responsible for the association of APOE with dementia 2) The association of APOE with dementia is substantially mediated by its effect on CNS Aβ42 levels 3) The association of APOE with dementia is not mediated by its impact on peripheral lipid metabolism 4) The dichotomy of effects of rs429358 and rs7412 represents one of the best examples of genetic pleiotropy for complex traits known and illustrates the importance of allelic heterogeneity in APOE.
LDL; Alzheimer Disease; amyloid; association; CSF
We examined job control, job demands, social support at work, and job strain (ratio of demands to control) in relation to risk of any dementia, Alzheimer’s disease (AD), and vascular dementia (VaD).
A cohort study.
The population-based Study of Dementia in Swedish Twins.
A total of 257 dementia cases (167 AD, 46 VaD) and 9,849 non-demented individuals.
Dementia diagnoses were based on telephone screening for cognitive impairment followed by in-person clinical work-up. An established job exposure matrix was matched to main occupation categories to measure work characteristics.
In generalized estimating equations (adjusted for the inclusion of complete twin pairs), lower job control was associated with greater risk of any dementia (odds ratio [OR]=1.17, 95% confidence interval [95%CI] 1.04-1.31) and VaD specifically (OR=1.39, 95% CI 1.07-1.81). Lower social support at work was associated with increased risk of dementia (OR=1.15, 95% CI 1.03-1.28), AD (OR=1.14, 95% CI 1.00-1.31), and VaD (OR=1.28, 95% CI=1.02-1.60). Greater job strain was associated with increased risk of VaD only (OR=1.28, 95% CI 1.02-1.60), especially in combination with low social support (OR=1.35, 95% CI 1.11-1.64). Age, gender, education, and cardiovascular disease were controlled. Results were not explained by work complexity or manual work. No differences in work-related stress scores were observed in the 54 twin pairs discordant for dementia, although only two pairs included a twin with VaD.
Work-related stress including low job control and low social support at work may increase the risk of dementia, particularly VaD. Modification to work environment that includes attention to social context and provision of meaningful roles for the workers may contribute to the efforts to promote cognitive health.
Work-related stress; job strain; dementia; vascular dementia
Research has found that patients treated for cancer generally have an increased risk for cognitive problems. However, many studies have focused on cognitive performance of cancer patients under the age of 65 who received chemotherapy treatment. Less studied is the extent to which cancer diagnosis may be associated with cognitive impairment as a late effect for older adults.
In this retrospective, co-twin design study, twin pairs 65 years of age and older discordant for cancer were identified from the Swedish Twin Registry. A pair was included if both twins participated in cognitive screening, and the twin with the cancer history was screened at least 3 years after cancer diagnosis and treatment.
Female, but not male, survivors of cancer were significantly (odds ratio = 2.42, 95% confidence interval = 1.23–4.74) more likely to exhibit cognitive impairment 3 or more years after cancer diagnosis and treatment as their co-twin without a history of cancer. In particular, risk was higher among survivors of gynecologic cancers (odds ratio = 10.00, 95% confidence interval = 1.28–78.11) and those who had treatments directly or potentially affecting ovarian functioning (odds ratio = 13.00, 95% confidence interval = 1.70–99.36) compared with their respective co-twins.
These findings suggest that localized treatments and other cancer-related factors should be explored as determinants that underlie the association between cancer diagnosis and long-term cognitive impairment.
Cancer treatment; Long-term effects; Cognitive impairment; Twin analysis
Several occupations and occupational exposures have been investigated for associations with Parkinson’s disease. Common findings are increased risk associated with pesticide exposure and no association between Parkinson’s disease and welding.
We explored the association between a broad range of possible occupational risk factors and Parkinson’s disease as well as Parkinson’s disease plus other forms of parkinsonism (referred to as Parkinsonian disorders), using prospectively collected data in the population-based Swedish Twin Registry. A cohort of 14,169 Swedish men was followed for up to 43 years. We identified 234 Parkinsonian disorders cases including 204 Parkinson’s disease cases with complete data. We assessed exposure to 14 chemical and biological compounds through a job exposure matrix. Hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, smoking, and education were used to estimate the relative risk of disease associated with exposure.
Exposure to inorganic dust was associated with increased risk of Parkinson’s disease and Parkinsonian disorders, HR 1.6 (95% CI 1.1–2.4) and 1.5 (1.0–2.2) respectively. There was no association between Parkinson’s disease or Parkinsonian disorders and occupational exposure to pesticides, welding smoke, metal dust, wood dust, animal handling, stone and concrete dust, chrome and nickel dust, quartz dust, organic dust, oil, asbestos, organic solvents and irritating gas.
Inorganic dust should be explored further as a potential risk factor for Parkinson’s disease. Occupational exposure to pesticides and twelve other compounds explored in this study may not be associated with risk of Parkinson’s disease in Swedish men.
Parkinson disease; Occupational exposure; Prospective studies
We performed a survey of sequence variation in a series of 20 genes involved in inflammation-related pathways for association with dementia risk in twin and unrelated case-control samples consisting in total of 1462 Swedish dementia cases and 1929 controls. For a total of 218 tested genetic markers, strong evidence was obtained implicating a region near AGER and NOTCH4 on chromosome 6p with replication across both samples and maximum combined significance at marker rs1800625 (OR = 1.37, 95% CI 1.19–1.56, p = 1.36 × 10−6). Imputation of the associated genomic interval provided an improved signal at rs8365, near the 3'UTR of AGER (p = 7.34 × 10−7). The associated region extends 120kb encompassing 11 candidate genes. While AGER encodes a key receptor for β-amyloid protein, an analysis of network context based upon genes now confirmed to contribute to dementia risk (APP, PSEN1, PSEN2, CR1, CLU, PICALM, and APOE) suggested strong functional coupling to NOTCH4, with no significant coupling to the remaining candidates. The implicated region occurs in the broad HLA locus on chromosome 6p, but associated markers were not in strong LD with known variants that regulate HLA gene function, suggesting that this may represent a signal distinct from immune-system pathways.
Dementia; NOTCH4; gene; association; inflammation
The purpose of this study was to review the relationship between education and dementia.
A systematic literature review was conducted of all published studies examining the relationship between education and dementia listed in the PubMed and PsycINFO databases from January 1985 to July 2010. The inclusion criteria were a measure of education and a dementia diagnosis by a standardized diagnostic procedure. Alzheimer’s disease and Total Dementia were the outcomes.
A total of 88 study populations from 71 articles met inclusion criteria. Overall, 51 (58%) reported significant effects of lower education on risk for dementia whereas 37 (42%) reported no significant relationship. A relationship between education and risk for dementia was more consistent in developed compared to developing regions. Age, gender, race/ethnicity, and geographical region moderated the relationship.
Lower education was associated with a greater risk for dementia in many but not all studies. The level of education associated with risk for dementia varied by study population and more years of education did not uniformly attenuate the risk for dementia. It appeared that a more consistent relationship with dementia occurred when years of education reflected cognitive capacity, suggesting that the effect of education on risk for dementia may be best evaluated within the context of a lifespan developmental model.
Alzheimer’s disease; dementia; education; risk factors
Children of persons with Alzheimer disease (AD), as a group, face an increased risk of developing AD. Many of them, throughout their adult lives, seek input on how to reduce their chances of one day suffering their parent’s fate. We examine the state of knowledge with respect to risk and protective factors for AD and recommend a research agenda with special emphasis on AD offspring.
Alzheimer disease offspring; risk factors
Inflammatory mechanisms have been implicated in Alzheimer’s disease (AD) and dementia. We therefore sought to study DNA sequence variation and serum levels of the potent inflammatory mediators Interleukin-6 (IL6) and C-reactive protein (CRP) in relation to AD and dementia.
Tagging single nucleotide polymorphisms (tagSNPs) were chosen to capture most variation in and around CRP and IL6 in 3937 elderly Swedish men and women (1,265 AD cases). A subset of the population (N=723) with serum measurements of CRP and IL6 was included in A) a nested case-control study of incident dementia cases, and B) a case-control study of prevalent dementia cases. None of the SNPs or haplotypes was significantly associated with AD or dementia after correcting for multiple testing nor were elevated baseline levels of hsCRP or IL6 (measured on average 4.3 years before dementia onset) significantly associated with risk of future AD or dementia. However, prevalent AD cases had higher levels of IL6 (measured on average 5.5 years after dementia onset) than age- and sex-matched controls, OR 2.24 (95% CI 1.27–3.95), p-value 0.006.
In summary, this data suggests that AD patients have an altered immune profile with higher circulating levels of IL6 than age-and sex-matched controls. However, neither variation in the CRP and IL6 genes nor circulating levels of their respective protein products were associated with an increased risk of developing late-life dementias.
Alzheimer disease; dementia; inflammation; interleukin-6; C-reactive protein; biological markers; candidate gene analysis; matched case-control studies; nested case-control studies
We examined the association between extremely low-frequency magnetic fields (EMF) and the risk of dementia and Alzheimer’s disease using all 9,508 individuals from the Study of Dementia in Swedish Twins (HARMONY) with valid occupational and diagnostic data.
Dementia diagnoses were based on telephone screening followed by in-person clinical workup. Main lifetime occupation was coded according to an established EMF exposure matrix. Covariates were age, gender, education, vascular risk factors, and complexity of work. Based on previous research, data were also analyzed separately for cases with disease onset by age 75 years versus later, men versus women, and those with manual versus nonmanual main occupation. We used generalized estimating equations with the entire sample (to adjust for the inclusion of complete twin pairs) and conditional logistic regression with complete twin pairs only.
Level of EMF exposure was not significantly associated with dementia or Alzheimer’s disease. However, in stratified analyses, medium and high levels of EMF exposure were associated with increased dementia risk compared with low level in cases with onset by age 75 years (odds ratio: 1.94, 95% confidence interval: 1.07–3.65 for medium, odds ratio: 2.01, 95% confidence interval: 1.10–3.65 for high) and in participants with manual occupations (odds ratio: 1.81, 95% confidence interval: 1.06–3.09 for medium, odds ratio: 1.75, 95% confidence interval: 1.00–3.05 for high). Results with 42 twin pairs discordant for dementia did not reach statistical significance.
Occupational EMF exposure appears relevant primarily to dementia with an earlier onset and among former manual workers.
Dementia; Magnetic fields; Occupation; Alzheimer’s disease
This study examined whether there were neuroanatomical differences evident on CT scans of individuals with dementia who differed on depression history. Neuroanatomical variables consisted of visual ratings of frontal lobe deep white matter, subcortical white matter, and subcortical gray matter hypodensities in the CT scans of 182 individuals from the Study of Dementia in Swedish Twins who were diagnosed with dementia and had information on depression history. Compared to individuals with Alzheimer's disease and no depression, individuals with Alzheimer's disease and late-onset depression (first depressive episode at age 60 or over) had a greater number of striatal hypodensities (gray matter hypodensities in the caudate nucleus and lentiform nucleus). There were no significant differences in frontal lobe deep white matter or subcortical white matter. These findings suggest that late-onset depression may be a process that is distinct from the neurodegenerative changes caused by Alzheimer's disease.
Unresolved issues in dementia research include 1) the association between non-stroke cardiovascular disease (CVD) and Alzheimer's disease (AD) and 2) whether the association between CVD and dementia is mediated by familial factors (i.e. genes and early life environment). We therefore conducted a study with both a longitudinal and a co-twin control design in 2,214 Swedish twins with clinical dementia evaluation and APOE4 genotyping. The analyses were then replicated in a register-based cohort of 18,405 individuals. Results show that CVD increases the risk of AD in carriers (but not non-carriers) of the APOE4 allele (Hazard Ratio [HR] 2.39, 95% confidence interval 1.15-4.96). CVD was also associated with an almost two-fold increased risk of developing late-life dementia (HR 1.83, 1.23-2.72). Within twin pairs, the dementia-affected twin was more likely to have had CVD than the non-demented twin partner (Odds Ratio 1.86, 1.11-3.13). In conclusion, this study shows that 1) non-stroke CVD increases the risk of late-life dementia but that it is only a risk factor for AD in carriers of the APOE4 allele and 2) the association between CVD and dementia is not explained by genetic or early life environmental factors in common to both disorders.
Alzheimer's disease; cardiovascular disease; risk factor; APOE; longitudinal; co-twin control
We conducted dense linkage disequilibrium (LD) mapping of a series of 25 genes putatively involved in lipid metabolism in 1567 dementia cases [including 1270 with Alzheimer disease (AD)] and 2203 Swedish controls. Across a total of 448 tested genetic markers, the strongest evidence of association was as anticipated for APOE (rs429358 at P ∼ 10−72) followed by a previously reported association of ABCA1 (rs2230805 at P ∼ 10−8). In the present study, we report two additional markers near the SREBF1 locus on chromosome 17p that were also significant after multiple testing correction (best P = 3.1 × 10−6 for marker rs3183702). There was no convincing evidence of association for remaining genes, including candidates highlighted from recent genome-wide association studies of plasma lipids (CELSR2/PSRC1/SORT1, MLXIPL, PCSK9, GALNT2 and GCKR). The associated markers near SREBF1 reside in a large LD block, extending more than 400 kb across seven candidate genes. Secondary analyses of gene expression levels of candidates spanning the LD region together with an investigation of gene network context highlighted two possible susceptibility genes including ATPAF2 and TOM1L2. Several markers in strong LD (r2 > 0.7) with rs3183702 were found to be significantly associated with AD risk in recent genome-wide association studies with similar effect sizes, providing independent support of the current findings.
Diet may be associated with risk of dementia and Alzheimer's disease (AD). We examined the association between fruit and vegetable consumption in midlife and risk for all types of dementia and AD.
Participants were 3,779 members of the Swedish Twin Registry who completed a diet questionnaire approximately 30 years prior to cognitive screening and full clinical evaluation for dementia as part of the HARMONY study. Among the participants, 355 twins were diagnosed with dementia. Among these, 81 twin pairs were discordant for dementia (50 discordant for AD). Data were analyzed with logistic regression for the entire sample using generalized estimating equations to adjust for relatedness of twins, and with conditional logistic regression for the co-twin control design.
In fully-adjusted models, a medium or great proportion of fruits and vegetables in the diet, compared to no or small, was associated with a decreased risk of dementia and AD. This effect was observed among women and those with angina. Similar, but non-significant, odds ratios were found in the co-twin control analyses.
Our findings suggest that higher fruit and vegetable consumption may reduce the risk of dementia, especially among women and those with angina pectoris in midlife.
dementia; Alzheimer's disease; diet; fruits and vegetables
The gene encoding the cholesteryl ester transfer protein (CETP) plays an integral role in lipid metabolism. We evaluated common genetic variation spanning CETP for association with cognitive decline as well as incident and prevalent dementia and Alzheimer disease risk. Data from four population-based twin studies and a case-control sample were included, encompassing an analysis sample of 1513 dementia cases and 2137 controls with available CETP genotypes and covariates. Memory and perceptual speed performance was assessed over 16 years in up to 1540 participants. Only sporadic associations were observed across 26 markers and were largely consistent with statistical noise. Polymorphism in CETP is unlikely to contribute to cognitive change or dementia risk.
Alzheimer disease; dementia; cognitive decline; CETP association; cholesteryl ester transfer protein
The purpose of this study was to examine whether openness to experience is related to longitudinal change in cognitive performance across advancing age. Participants were 857 individuals from the Swedish Adoption/Twin Study of Aging (SATSA). Factors for 5 cognitive domains were created including: verbal ability, spatial ability, memory, processing speed, and a global score, “g”. Latent growth curve models were used to assess level and longitudinal trajectories of cognitive performance. It was hypothesized that individuals who endorsed higher levels of openness would have higher cognitive test scores and lesser rates of cognitive decline. As predicted, higher openness to experience was associated with significantly higher performance across all cognitive tests for both males and females even after adjusting for education, cardiovascular disease and activities of daily living. Openness, however, was not predictive of differences in the trajectories of cognitive performance over age.
aging; cognitive engagement; cognitive decline; openness to experience; personality
To assess the importance of lipids and lipoproteins on longitudinal cognitive performance and cognitive health in late life and to consider moderating factors such as age and sex which may clarify conflicting prior evidence.
A 16-year prospective cohort study of health and cognitive aging.
819 adults from the Swedish Adoption Twin Study of Aging (SATSA), 50 years and older at the first cognitive testing, including 21 twin pairs discordant for dementia.
Up to five occasions of cognitive measurements encompassing verbal, spatial, memory and perceptual speed domains across a 16-year span. Baseline serum lipids and lipoproteins including HDL, apoA1, apoB, total serum cholesterol, and triglycerides.
The effect of lipids on cognitive change was most evident prior to age 65. In women higher HDL and lower apoB and triglycerides predicted better maintenance of cognitive abilities over age, particularly verbal ability and perceptual speed. Lipid values were less predictive of cognitive trajectories in men and, where observed, were in the contrary direction: i.e., higher total cholesterol and apoB values predicted better perceptual speed performance though faster rates of decline. In twin pairs discordant for dementia, higher total cholesterol and apoB levels were observed in the twin who subsequently developed dementia.
Elevated lipids may constitute a more important risk factor for cognitive health before age 65 than after. Findings for women are consistent with clinical recommendations, while for men the findings correspond with earlier age-associated shifts in lipid profiles and the importance of lipid homeostasis to cognitive health.
Lipids; lipoproteins; cognitive change; gender differences
The gene encoding the neuronal sortilin-related receptor SORL1 has been claimed to be associated with Alzheimer Disease by independent groups and across various human populations. We evaluated six genetic markers in SORL1 in a sample of 1558 Swedish dementia cases (including 1270 Alzheimer disease cases) and 2179 controls. For both single marker and haplotype-based analyses we found no strong support for SORL1 as a dementia- or AD-risk modifying gene in our sample in isolation, nor did we observe association with AD/dementia-related traits, including CSF β-amyloid1–42, tau levels, or age-at-onset. However, meta-analyses of markers in this study together with previously published studies on SORL1 encompassing in excess of 13,000 individuals does suggest significant association with AD (best OR 1.097; 95% CI 1.038–1.158, p = 0.001). All six markers were significant in meta-analyses and it is notable that they occur in two distinct LD blocks. These data are consistent with either allelic heterogeneity or the existence of as yet untested functional variants and these will be important considerations in further attempts to evaluate the importance of sequence variation in SORL1 with AD risk.
SORL1; Alzheimer; meta-analysis; association; Swedish
This study examines if overweight in midlife increases dementia risk later in life.
In 1963 Body Mass Index was assessed in 1152 participants of The Swedish Twin Registry, then at the age of 45 to 65 years. These participants were later screened for dementia in a prospective study with up to 40 years follow-up. A total of 312 participants were diagnosed with dementia.
Logistic regression analyses, adjusted for demographic factors, smoking and alcohol habits, indicated that men and women categorized as overweight in their midlife had an elevated risk of dementia (OR = 1.59; 95% CI: 1.21 to 2.07, p = .002), Alzheimer’s disease (OR = 1.71; 95% CI: 1.24 to 2.35, p = .003), and vascular dementia (OR = 1.55; 95% CI: 0.98 to 2.47, p = .059). Further adjustments for diabetes and vascular diseases did not substantially affect the associations, except for vascular dementia (OR = 1.36; 95% CI: 0.82 to 2.56, p = .116), reflecting the significance of diabetes and vascular diseases in the aetiology of vascular dementia. There was no significant interaction between overweight and APOE ε4 status, indicating that having both risk factors does not have a multiplicative effect concerning dementia risk.
This study gives further support to the notion that overweight in midlife increases later risk of dementia. The risk is increased for both Alzheimer’s disease and vascular dementia, and follows the same pattern for men and women.
Although an increasing body of evidence links being overweight in midlife with an increased risk for dementia in late life, no studies have examined the association between being overweight in midlife and cognitive ability in late life. Our aim was to examine the association between being overweight in midlife as measured by body mass index (BMI) and cognitive ability assessed over time.
Participants in the Swedish Adoption/Twin Study Aging were derived from a population-based sample. The participants completed baseline surveys in 1963 or 1973 (mean age 41.6 years, range 25–63 years). The surveys included questions about height, weight, diseases, and lifestyle factors. Beginning in 1986, the same individuals were assessed on neuropsychological tests every 3 years (except in 1995) until 2002. During the study period, 781 individuals who were 50 years and older (60% women) had at least one complete neuropsychological assessment. A composite score of general cognitive ability was derived from the cognitive test battery for each measurement occasion.
Latent growth curve models adjusted for twinness showed that persons with higher midlife BMI scores had significantly lower general cognitive ability and significantly steeper longitudinal decline than their thinner counterparts. The association did not change substantially when persons who developed dementia during the study period were excluded from the analysis.
Higher midlife BMI scores precede lower general cognitive ability and steeper cognitive decline in both men and women. The association does not seem to be mediated by an increased risk for dementia.
Body mass index; Cognition; Dementia; Epidemiology
Thirty same-sex twin pairs were identified in which both members were assessed at baseline and one twin subsequently developed dementia, at least 3 years subsequent to the baseline measurement, while the partner remained cognitively intact for at least three additional years. Eighteen of the 30 cases were diagnosed with Alzheimer’s disease. Baseline assessments, conducted when twins’ average age was 70.6 (SD = 6.8), included a mailed questionnaire and in-person testing. Which twin would develop dementia was predicted by less favorable lipid values (higher apoB, ratio of apoB to apoA1, and total cholesterol), poorer grip strength, and—to a lesser extent—higher emotionality on the EAS Temperament Scale. Given the long preclinical period that characterizes Alzheimer’s disease, these findings may suggest late life risk factors for dementia, or may reflect changes that are part of preclinical disease.
Twins; Dementia; Alzheimer’s disease; Cholesterol; Grip strength; Emotionality
In this report we describe problems associated with the administration of binary choice response questionnaires, with particular attention to depression measures given to older adults. A convenience sample of 77 respondents aged 70+ completed two different versions of the 8-item Center for Epidemiologic Studies-Depression (CES-D) scale. Versions were identical except for having either two- or four- response option formats. Within-person responses were compared to determine equivalence across formats. We found that a binary-response option format over- or under-estimated depressive symptomatology. Thus, a four-response option for the CES-D may be a more precise estimate of currently experienced symptoms.
response format; survey methods; depression; older adults
We examined the association between complexity of the main lifetime occupation and changes in cognitive ability in later life. Data on complexity of work with data, people, and things and on four cognitive factors (verbal, spatial, memory, and speed) were available from 462 individuals in the longitudinal Swedish Adoption/Twin Study of Aging. Mean age at the first measurement wave was 64.3 (s.d. = 7.2) and 65% of the sample had at least 3 waves of data. Occupational complexity with people and data were both correlated with cognitive performance. Individuals with more complex work demonstrated higher mean performance on the verbal, spatial, and speed factors. Latent growth curve analyses indicated that, after correcting for education, only complexity with people was associated with differences in cognitive performance and rate of cognitive change. Continued engagement as a result of occupational complexity with people helped to facilitate verbal function before retirement, while a previous high level of complexity of work with people was associated with faster decline after retirement on the spatial factor.
Occupational complexity; cognitive change; retirement
We and others have conducted targeted genetic association analyses of ABCA1 in relation to Alzheimer disease risk with a resultant mixture of both support and refutation, but all previous studies have been based upon only a few markers. Here, a detailed survey of genetic variation in the ABCA1 region has been performed in a total of 1567 Swedish dementia cases (including 1275 with Alzheimer disease) and 2203 controls, providing evidence of association with maximum significance at marker rs2230805 (OR = 1.39; 95% CI 1.23–1.57, P = 7.7 × 10−8). Haplotype-based tests confirmed association of this genomic region after excluding rs2230805, and imputation did not reveal additional markers with greater support. Significantly associating markers reside in two distinct linkage disequilibrium blocks with maxima near the promoter and in the terminal exon of a truncated ABCA1 splice-form. The putative risk allele of rs2230805 was also found to be associated with reduced cerebrospinal fluid levels of β-amyloid. The strongest evidence of association was obtained when all forms of dementia were considered together, but effect sizes were similar when only confirmed Alzheimer disease cases were assessed. Results further implicate ABCA1 in dementia, reinforcing the putative involvement of lipid transport in neurodegenerative disease.
ABCA1; Alzheimer; dementia; SNP; amyloid
We sought to identify two sets of familial/genetic risk factors for major depression (MD): 1) high familial loading for MD, which we predicted would be most prominent in cases of MD with an early age at onset (AAO), and 2) high familial loading for vascular disease (VD), which should be strongest in MD cases with a late AAO.
We examined 4785 twin pairs from the Swedish Twin Registry, assessed at a mean age of 54.0 (SD = 7.4), where both members of the pair were evaluated by interview and at least one member reported a lifetime history of modified DSM-IV MD. Risk for VD was assessed from hospital discharge information and death certificates.
Using Cox proportional hazard models and controlling for zygosity, age, and sex, early AAO in depressed twins predicted risk for MD in their cotwins, whereas late AAO predicted cotwin risk for VD. Using piecewise regression, the hazard ratio (HR) relating AAO per decade to risk for MD in cotwin was much stronger for AAO from 13–23 years (HR = .62) than for AAO 24 – 65 years (HR = 0.94). The HR relating AAO of MD in twin and risk for VD in cotwin was twice as strong for AAO from 47– 65 years (HR = 1.17) as for AAO 13– 46 years (1.08).
From a familial/genetic perspective, MD is etiologically heterogeneous. Early and late onset MD are indexed, respectively, by the risk for MD and VD in relatives.
Age at onset; depression; genetics; heterogeneity; twin study; vascular disease
Depression is less prevalent among older adults than among younger adults but can have serious consequences. Over half of cases represent a first onset in later life. Although suicide rates in the elderly are declining, they are still higher than in younger adults and more closely associated with depression. Depressed older adults are less likely to endorse affective symptoms and more likely to display cognitive changes, somatic symptoms, and loss of interest than are younger adults. Risk factors leading to the development of late life depression likely comprise complex interactions among genetic vulnerabilities, cognitive diathesis, age-associated neurobiological changes, and stressful events. Insomnia is an often overlooked risk factor for late life depression. We suggest that a common pathway to depression in older adults, regardless of which predisposing risks are most prominent, may be curtailment of daily activities. Accompanying self-critical thinking may exacerbate and maintain a depressed state. Offsetting the increasing prevalence of certain risk factors in late life are age-related increases in psychological resilience. Other protective factors include higher education and socioeconomic status, engagement in valued activities, and religious or spiritual involvement. Treatments including behavioral therapy, cognitive behavioral therapy, cognitive bibliotherapy, problem-solving therapy, brief psychodynamic therapy, and life review/reminiscence therapy are effective but too infrequently used with older adults. Preventive interventions including education for individuals with chronic illness, behavioral activation, cognitive restructuring, problem-solving skills training, group support, and life review have also received support.
Epidemiology; Etiology; Treatment; Prevention; Elderly