Relative Risk For Alzheimer's Disease Research Articles

Lipid levels and the risk of dementia: A dose-response meta-analysis of prospective cohort studies.

ObjectivesWe performed a dose–response meta‐analysis to estimate the association between lipid profiles with the risk of dementia and the potential differences according to the subtype of dementia based on prospective studies.MethodsWe searched PubMed, Embase and Web of Science for relevant articles and performed a meta‐analysis. We applied fixed or random‐effects models to calculate pooled relative risk (RR) with their 95% confidence intervals (CI). The dose–response relationship was assessed by restricted cubic spline.ResultsTwenty‐five prospective studies comprising 362,443 participants and 20,121 cases were included in the final analysis. We found that increased risk of all‐cause dementia could be predicted by elevated total cholesterol (TC) (RR = 1.13, 95% CI 1.04–1.22). When looking at dementia subtypes, we also observed high TC and triglycerides (TG) may increase the future risk of Alzheimer's disease (AD), with a pooled RR of 1.13 (95% CI: 1.06–1.21) and 1.10 (95% CI: 1.04–1.15) respectively. Moreover, a dose–response analysis revealed a linear association between TC or TG and the risk of AD, with a pooled RR of 1.09 (95% CI: 1.02–1.16) and 1.12 (95% CI: 1.05–1.21) for per 3‐mmol/L increment in TC and TG, respectively.ConclusionsCurrent evidence suggest that every 3‐mmol/L increase in blood TC or TG is linearly associated with a 9% or 12% increase in RR of AD, supporting the notion that high TC and TG levels appear to play a causal role in the development of AD.

Alzheimer’s Risk Goes Beyond Parents, Grandparents

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessAlzheimer’s Risk Goes Beyond Parents, GrandparentsTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:3 May 2019https://doi.org/10.1176/appi.pn.2019.4b23AbstractEven when there is no Alzheimer’s in a person’s first- or second-degree relatives, the risk of Alzheimer’s increases if there are at least two third-degree relatives with the disease in a person’s family tree.Having third-degree relatives—great-grandparents or first cousins—with Alzheimer’s disease may raise a person’s risk of developing the disease, a study published in Neurology has found.Estimating individualized risk for Alzheimer’s disease based on family history can prompt preventive measures, such as more aggressive treatment of vascular disease, says Lisa A. Cannon-Albright, Ph.D.Lisa A. Cannon-Albright, Ph.D., a professor and division chief of the Division of Genetic Epidemiology at the University of Utah School of Medicine, and colleagues studied records from the Utah Population Database, which includes genealogy data of Utah pioneers going back to the 1800s, and compared them with the cause of death listed on Utah death certificates from 1904 to 2014. Of the 149,303 people who died after 1978, Alzheimer’s was listed as a primary or contributing cause of death for 4,436.The researchers found that even when there is no Alzheimer’s in a person’s first-degree relatives (parents, full siblings, or children) or second-degree relatives (grandparents, grandchildren, aunts, uncles, nieces, nephews, or half-siblings), the risk of Alzheimer’s increases if there are at least two third-degree relatives (great-grandparents, great-grandchildren, great-aunts, great-uncles, or cousins) with the disease in a person’s family tree. Risk increases by 17%, 43%, or 44% if an individual has two, three, or four third-degree relatives with Alzheimer’s, respectively.“It was a little surprising that even if your closest affected relatives are cousins, you are still at increased risk,” Cannon-Albright told Psychiatric News. “Most clinicians consider only your closer relatives when they ask about family history.”Cannon-Albright noted the practical implications of the results. “It’s fair to say that everyone spends some time considering their risk as they age. At the very least, having a risk prediction that is somewhat individualized to your own situation can lead to mental preparation for what might come,” she said.“In the best case, it can also lead to some preventive measures. It’s possible that more aggressive treatment of contributors to vascular disease makes sense for people at increased risk for Alzheimer’s,” Cannon-Albright added. “We hope [our research] will encourage clinicians to take an adequate family history and that it will allow clinicians to provide patients with the best advice concerning their risk.”This study was supported by the National Institute on Aging, National Cancer Institute, Huntsman Cancer Institute, Huntsman Cancer Foundation, University of Utah, and the George E. Wahlen Department of Veterans Affairs Medical Center. ■“Relative Risk for Alzheimer Disease Based on Complete Family History” can be accessed here. ISSUES NewArchived

Relative risk for Alzheimer disease based on complete family history.

ObjectiveThe inherited component for Alzheimer disease (AD) risk has focused on close relatives; consideration of the full family history may improve accuracy and utility of risk estimates.MethodsA population resource including a genealogy of Utah pioneers from the 1800s linked to Utah death certificates was used to estimate relative risk for AD based on specific family history constellations, including from first- to third-degree relatives.ResultsAny affected first-degree relatives (FDR) significantly increased risk of AD (≥1 FDRs: relative risk [RR] 1.73, 95% confidence interval [CI] [1.59–1.87]; ≥2 FDRs: RR 3.98 [3.26–4.82]; ≥3 FDRs: RR 2.48 [1.07–4.89]; ≥4 FDRs: RR 14.77 [5.42–32.15]). Affected second-degree relatives (SDR) increased risk even in the presence of affected FDRs (FDR = 1 with SDR = 2: RR 21.29 [5.80–54.52]). AD only in third-degree relatives (TDR) also increased risk (FDR = 0, SDR = 0, TDR ≥3: RR 1.43 [1.21–1.68]). Mixed evidence was observed for differences in risk based on maternal compared to paternal inheritance; higher risks for men than women with equivalent family history, and higher risk for individuals with at least one affected FDR regardless of the relative's age at death, were observed.ConclusionsThis population-based estimation of RRs for AD based on family history ascertained from extended genealogy data indicates that inherited genetic factors have a broad influence, extending beyond immediate relatives. Providers should consider the full constellation of family history when counseling patients and families about their risk of AD.

Thiamine Metabolites and Dementia?

The determinants of amyloid deposition in the brain, increased intracerebral phosphorylated tau, hippocampal atrophy, and loss of synapses in areas of brain (the pathogenic determinants of most dementia) remain undetermined except for Mendelian genetic disorders and higher risk of both amyloid deposition and dementia among individuals who carry the apolipoprotein e4 (APOE e4) genotype, especially homozygous e4 (Kuller et al., 2015, Vardarajan et al., 2014, Leduc et al., 2010). The incidence of dementia doubles every 5 years after the age of 65 and probably 2/3 or more of incident dementia cases occur over the age of 80 (Prince et al., 2013). The increasing longevity of the population is a major determinant of the ‘epidemic of dementia’ in many countries. There is little evidence that Alzheimer's disease (AD) pathology or incidence of dementia varies substantially among countries or within countries. Better-educated individuals and those with higher IQ have lower age-specific incidence of dementia attributed to ‘brain reserve.’ An excess or restriction of an exposure in the environment, lifestyle, such as consumption of a nutrient like thiamine, could be a determinant of increased or decreased risk of an age-associated disease like dementia, specifically AD. The brain requirement of a specific nutrient, e.g. thiamine, could increase with aging, either due to loss of a cellular receptor or changes in intracellular metabolism, greater degradation of the metabolite or increase in interfering agents, e.g. drugs. A vitamin deficiency in the past, e.g. pellagra, was a ‘cause of dementia’ that was successfully treated by diet change well before the specific vitamin was identified (nicotinic acid) (Terris, 1964). There is no evidence at present that deficiency of thiamine or any other B vitamin decreases risk of dementia. However, it could be necessary to consume a specific metabolite of the vitamin to have a beneficial effect in the brain. An alternative hypothesis is that lower thiamine metabolites in patients with AD identified in the paper by Xiaoli Pan and colleagues in EBioMedicine (Pan et al., 2015) is due to changes in patients' diet after diagnosis of dementia or secondary to comorbidity after diagnosis of dementia, e.g. reverse causality. The next steps would be to compare blood levels of thiamine metabolites in longitudinal studies with available stored blood samples prior to diagnosis of dementia. If the relative risk of AD or dementia is increased in relation to thiamine metabolites independent of age and education, then small feeding experiments in humans could evaluate whether thiamine metabolites have any effect on cognition in cognitively normal, mild cognitive impairment (MCI), and dementia patients and finally test the hypothesis by feeding metabolites in larger clinical trials of both risk of dementia among those who are cognitively normal and effects on changes in cognition in MCI and possibly dementia patients. The search for a nutrient that could prevent or delay onset or even reverse pathology of AD or other pathologies associated with dementia should have high priority given the worldwide magnitude of dementia, growing incidence and prevalence, and lack of effective therapies for prevention and treatment. It is very possible that a deficiency of a nutrient could be a cause of dementia among older individuals, possibly the nutrient is important only in susceptible individuals based on unique genotype, older ages, or comorbidities.

Diabetes mellitus and risk of dementia: A meta-analysis of prospective observational studies.

The aim of the present study was to investigate the association between diabetes and the risk of all type dementia (ATD), Alzheimer's disease (AD) and vascular dementia (VaD). Prospective observational studies describing the incidence of ATD, AD and VaD in patients with diabetes mellitus were extracted from PubMed, EMBASE and other databases up to January 2012. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random-effects model. Subgroup analyses and sensitivity analysis were also carried out. A total of 28 studies contributed to the analysis. Pooled RR of developing ATD (n=20) was 1.73 (1.65-1.82, I (2)=71.2%), AD (n=20) was 1.56 (1.41-1.73, I (2)=9.8%) and VaD (n=13) was 2.27 (1.94-2.66, I (2)=0%) in patients with diabetes mellitus. Higher and medium quality studies did not show any significant difference for pooled RR for ATD, AD or VaD. Sensitivity analyses showed robustness of pooled RR among ATD, AD and VaD, showing no single study had a major impact on pooled RR. The results showed a 73% increased risk of ATD, 56% increase of AD and 127% increase of VaD in diabetes patients.

New therapeutic strategy for Alzheimer's disease using antidiabetes agents.

New therapeutic strategy for Alzheimer's disease using antidiabetes agents.

Vascular cognitive impairment – definition and terms

Vascular cognitive impairment (VCI) incorporates the complex interactions between vascular etiologies, risk factors and cellular changes within the brain and cognition. It includes the patients with vascular disease sufficient to cause a dementia syndrome . It may includes cases with cognitive impairment related to hypertension, silent infarcts, strategic infarcts, diabetes or atherosclerosis. The spectrum of brain changes comprise both ischemic factors and cellular processes such as demyelination, axonal damage, diastasis and atrophy. The studies suggest the association between vascular factors predisposing to cerebrovascular diseases and Alzheimer disease (AD). The hypertension, atrial fibrillation, carotid thickening and diabetes can increase the relative risk for Alzheimer disease. Studies of computed tomography (CT) and magnetic resonance imaging (MRI) showed that bilateral as opposed to unilateral ischemic lesions are critical. They showed the importance of deep infarcts in the frontal and limbic areas. Other studies indicated that the cortical lesions in the parietal and temporal areas are more important. Focal clinical signs, neuroimaging and neuropsychological findings may be reliably used to predict the neuropathologic diagnosis of vascular dementia (VaD) (1).

The effects of APOE on brain activity do not simply reflect the risk of Alzheimer's disease

Possession of the APOE-ε4 allele is the best established genetic risk factor for sporadic Alzheimer's disease (AD), while the ε2 allele may confer protection against the disease. Previous functional magnetic resonance imaging (fMRI) studies have shown an effect of APOE genotype on brain function, typically by comparing only ε4 carriers with noncarriers. Here we included a wide range of genotype groups to determine how closely the effects of APOE on brain function are related to differences in relative risk for AD. We used functional magnetic resonance imaging (fMRI) to compare the pattern of activation during an episodic encoding task and during a counting Stroop task in 76 adults, aged 32 to 55, with different APOE genotypes (23 ε2/ε3, 20 ε3/ε3, 26 ε3/ε4, and 7 ε4/ε4). Strikingly, participants with an increased risk (ε4 carriers) and with a decreased risk (ε2 carriers) for AD both showed increased activation, relative to ε3 homozygotes, during both tasks. The increased activation was due to decreased deactivation or paradoxical activation of nontask-related regions of the brain, which suggests an intrinsic effect of APOE on the differentiation of functional cortical networks. These results question the often assumed link between APOE, the blood oxygenation level dependent (BOLD) response, and AD risk.

Genetic Association between the Apolipoprotein E (APOE) Gene and Different Forms of Alzheimer's Disease

Allele e4of the apolipoprotein E (APOE) gene is associated with higher risk for family or sporadic Alzheimer's disease (AD) in many, though not all, ethnic groups. The APOEallele and genotype frequency distributions were evaluated in 207 AD patients without vascular disorders, 62 AD patients with vascular disorders (combined AD), and 206 control individuals (ethnic Russians from the Russian population). The frequency of allele e4in patients with early-onset and late-onset AD was three times higher than in controls (P< 0.000001). The increase in the frequency of e4in mixed dementia cases over controls was somewhat less but still significant (P= 0.0019). Relative risk of AD in carriers of allele e4was five times higher than in carriers of alleles e2and e3(P< 0.000001). Allele e2showed evidence of a protective effect in the early-onset AD group (P= 0.015). These results suggest that APOEallele e4is a universal factor of early-onset, late-onset, and combined AD in ethnic Russians from Russia.

Clinical Studies of Oestrogen Therapy for Dementia

The positive effects of oestrogen on the maintenance of brain function and the prevention of Alzheimer's disease (AD) have recently been reported. Oestrogen is considered to 1) improve depression, 2) increase brain blood flow, 3) stimulate neuronal function, 4) increase the number of developed gliacytes, and 5) suppress amyloid deposition and protect from the oxidative stress induced by amyloid deposition. The use of hormone replacement therapy (HRT) for the prevention and treatment of AD has received considerable attention. Treatment with conjugated equine oestrogens 0.625mg daily produces improvement during the third week, and this is maintained for as long as therapy is continued. Medroxyprogesterone acetate seems to have an unfavourable effect on AD, causing a depressive status. Therefore systemic oestrogen treatment with vaginally administered progesterone for endometrial protection may be a suitable combination for non hysterectomised women with AD. Recent epidemiological studies have suggested that oestrogen use is associated with a reduction in the relative risk of AD with greater protection with increasing dose and duration of use.

A Prospective Study of Estrogen Replacement Therapy and the Risk of Developing Alzheimer's Disease

Previous reports have suggested that estrogen replacement therapy (ERT) in women may exert a protective effect on their risk of developing Alzheimer's 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 (NINCDS/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.

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 Alzheimer's 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 (NINCDS/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.

Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer's disease?

Based on reports that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk for Alzheimer's disease (AD), we studied the cross-sectional relation between NSAID use and the risk for AD in a population-based study of disease and disability in older people. After controlling for age, education, gender, and use of benzodiazepines, we found a relative risk (RR) for AD of 0.38 (0.15 to 0.95) when comparing NSAID users (n = 365) to NSAID non-users (n = 5,893). To address confounding by indication or contraindication, we compared NSAID users with a subset of NSAID non-users who were using topical medication for ear, eye, or dermatologic conditions (n = 365). In this comparison, the adjusted RR for AD was 0.54 (0.16 to 1.78). These findings are compatible with a possible protective effect of NSAIDs on the risk for AD.