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Alzheimer's Disease Risk Factors: exercise, metabolics, lifestyle, genetics
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"regular physical activity could be an important component of a preventive strategy against Alzheimer's disease and many other conditions.....study showed that raised systolic blood pressure and high serum cholesterol concentrations in midlife increased the risk of Alzheimer's disease in later life.....observed relation between midlife vascular risk factors and Alzheimer's disease later in life may have implications for the prevention of dementia as both hypertension and hypercholesterolaemia can be treated.....insulin resistance with hyperinsulinemia and subsequent impairment of glucose metabolism especially in affective disorder patients may promote neurodegeneration and facilitate the onset of AD. According to our hypothesis.....Metabolic syndrome (Met.S) is a group of heart disease risk factors that includes abdominal obesity, elevated blood pressure, high triglycerides, elevated blood sugar and low HDL cholesterol. Those who have Met.S are at higher risk for developing diabetes, hypertension, and stroke, all of which
increase the risk of developing dementia, including Alzheimer's disease.......It is now recognized that subjects with cardiovascular risk factors and a history of stroke have an increased risk of both vascular dementia and Alzheimer's disease.2,3,4 Plasma total homocysteine has recently emerged as a major vascular risk factor. Elevated total homocysteine levels have been associated with an increased risk of atherosclerotic sequelae, including death from cardiovascular causes,5,6 coronary heart disease,6,7 carotid atherosclerosis,8 and clinical stroke.9,10 These observations led to the hypothesis that elevated plasma homocysteine may....An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer's disease.......Elevated plasma homocysteine levels are associated with carotid atherosclerosis and an increased risk of stroke.8,10 Atherosclerosis and stroke, in turn, increase the risk of clinical Alzheimer's disease.2,4 Hyperhomocysteinemia has been related to cerebral microangiopathy,44 endothelial dysfunction,45 impaired nitric oxide activity,46 and increased oxidative stress47 - all factors associated with the aging of the brain........Vitamin therapy with folic acid, alone or in combination with vitamins B6 and B12, and dietary supplementation with enriched cereal-grain products and breakfast cereals containing folate can reduce plasma homocysteine levels.54,55,56 The U.S. government now mandates folic acid fortification of the food supply.55 Current plasma homocysteine levels in the Framingham Study population are significantly lower than those that were estimated at the 16th and 20th biennial examinations.56 However, only 20 cases of dementia were diagnosed between 1997 and the time the levels were remeasured, and therefore it is not possible to assess the effect of recent increases in folic acid fortification on the risk of dementia in this cohort. Furthermore, since there have been no prospective trials of the effect of vitamin supplementation on the incidence of dementia, our findings cannot be used as a basis for setting health policy or treatment recommendations....The relation between elevated plasma homocysteine levels and dementia must be evaluated in other cohort studies..."
Lifestyle Factors Contribute to Lowering and Raising Risk of Alzheimer's Disease
Wed Jul 30, 2008
- Unmarried Status in Mid-Life and Heart Disease Factors May Increase
Alzheimer's Risk -
- Repeatedly Thinking About Problems May Reduce Alzheimer's Risk -
CHICAGO, July 30 /PRNewswire-USNewswire/ -- A new study suggests that those
who are unmarried or not living with a partner in midlife could have an
increased risk of developing Alzheimer's disease, according to research
reported today at the 2008 Alzheimer's Association International Conference on
Alzheimer's Disease (ICAD 2008), in Chicago.
Additional research on Alzheimer risk factors presented at ICAD 2008 indicates
that people who ruminate, or repeatedly think about their problems, may be
less likely to develop the disease, while people with metabolic syndrome (a
combination of cardiovascular health related symptoms) are at higher risk.
Finally, a large meta-analysis of nine European risk factor surveys confirmed
a well recognized group of Alzheimer risk factors, including memory complaint,
severe head trauma, diabetes, stroke and low education.
"We may not be able to do anything about aging, genetics or family history,
but research shows us that there are lifestyle decisions we all can make to
keep our brains healthier as we age, and that also may lower our risk of
developing Alzheimer's disease," said William Thies, PhD, vice president for
Medical & Scientific Relations at the Alzheimer's Association.
Unmarried Life: Paving the Way for Dementia?
Research suggests that maintaining regular social interaction can contribute
to maintaining brain health as we age and possibly decrease one's risk of
developing Alzheimer's. When people are married they are able to have close
interaction on a regular basis. This may reduce the occurrence of dementia.
Krister Hakansson, BA, of Karolinska Institutet, KI Alzheimer Research Center,
Stockholm, Sweden and Vaxjo University, School of Social Sciences, Vaxjo,
Sweden, conducted a first-of-its-kind evaluation of whether midlife marital
status is related to late-life cognitive function. The study examined 1,449
individuals from the Finnish Cardiovascular Risk Factors, Aging, and Dementia
(CAIDE) study in midlife and then again in 1998, an average of 21 years later.
At re-examination, 139 persons were diagnosed with some form of cognitive
impairment: 82 with mild cognitive impairment (MCI) and 48 with Alzheimer's.
Persons in the study who were living with a partner in midlife were
significantly less likely to show cognitive impairment compared to all other
categories (single, separated, divorced or widowed). Those in the study who
were married or lived with a significant other in midlife had a 50% lower risk
of having dementia in late-life compared to those who lived alone, even after
adjustments for education, BMI, cholesterol, blood pressure, occupation,
physical activity, smoking habits, depression, ApoE status, age at follow-up
and gender.
The researcher observed that there were differences between groups of people
who had been living alone for different reasons. The all-life singles had a
doubled risk, whereas the ones who stayed divorced from midlife onwards had a
tripled risk. The most dramatic risk increase was found for those widowed
before midlife and who stayed widowed. Compared to those married at midlife
and still so at late-life, they had more than a six-fold risk of developing
Alzheimer's.
"Living in a couple relationship is normally one of the most intense forms of
social and intellectual stimulation. If social and cognitive challenges can
protect against dementia, so should living in a couple relation," said
Hakansson. "This study points to the beneficial effects of a married life,
consistent with the general hypothesis of social stimulation as a protective
factor against dementia."
Tendency for Rumination in Midlife May Decrease Risk for Dementia Decades
Later
According to Ramit Ravona-Springer, MD, of Sheba Medical Center, Tel Hashomer,
Ramat Gan, Israel and colleagues, "rumination" refers to the disposition for
repetitive thinking over one's problems.
Tendency for rumination when confronting difficulties in family and work
settings was assessed in about 9,000 participants in the IIHD study, a
longitudinal investigation of the incidence and risk factors for
cardiovascular disease among Jewish male civil servants in Israel. Tendency
for rumination was assessed as 1=always forget, 2=tend to forget, 3=tend to
ruminate, 4=usually ruminate.
Dementia was assessed three decades later in 1,890 participants among 2,604
survivors of the original cohort. Mean age of the participants was 82 at the
time of final assessment. 308 were diagnosed as demented, 175 as having mild
cognitive impairment, and 1,407 had no cognitive impairment.
The prevalence rates of dementia (adjusted for age, area of birth, and
socioeconomic status) were 21% for those who always forget difficulties in
familial settings, 18% for those who tend to forget, 14% for those who tend to
ruminate over difficulties, and 14% for those who usually ruminate. When
rumination in response to difficulties at work was assessed, prevalence rates
of dementia were 24% for those who always forget difficulties, 19% for those
who tend to forget, 15% for those who tend to ruminate over difficulties, and
15% for those who usually ruminate.
A total score for rumination in both family and work settings was calculated,
and subjects were divided into four groups according to this score. Relative
to the group with the lowest total rumination score, dementia prevalence was
30 to 40 percent less in groups with higher scores.
"Your personality traits, specifically your psychological and cognitive style
when confronting distress, may be associated with your risk for dementia,"
said Ravona-Springer. "However, exactly how this works still needs to be
determined."
Metabolic Syndrome May Lead to Cognitive Decline
Metabolic syndrome (Met.S) is a group of heart disease risk factors that
includes abdominal obesity, elevated blood pressure, high triglycerides,
elevated blood sugar and low HDL cholesterol. Those who have Met.S are at
higher risk for developing diabetes, hypertension, and stroke, all of which
increase the risk of developing dementia, including Alzheimer's disease.
Matheus Roriz-Cruz, MD, PhD, Federal University of Rio Grande do Sul State,
Brazil and colleagues studied the effects of Met.S on the development of
cognitive impairment in people who have not had a stroke. Researchers
evaluated 422 healthy elderly men and women over age 60 in Brazil and used a
battery of scales to assess cognition, depression, planning and activities of
daily living. Met.S was present in 39.3% of participants.
Data from the study revealed that all neurofunctional scores were
significantly lower for those with Met.S, and the difference increased with
age. Older people with Met.S had an almost 35% higher level of cognitive
compromise when compared to those without Met.S.
"Met.S was independently associated with lower cognitive, planning, neuromotor
and functional scores, and with more depressive symptoms," said Roriz-Cruz.
"The results from this study reinforce the importance of maintaining good
physical health in order to reduce one's risk of experiencing cognitive
decline, and possibly developing Alzheimer's disease."
Risk Factors for Progression to Dementia in General Population
In the general population, many risk factors and predictors for dementia have
been identified. However, a combination of risk factors may give a more
accurate prediction for dementia than each individual risk factor.
Sylvaine Artero, of INSERM, Montpellier, France; Pieter Jelle Visser, of the
University of Maastricht, The Netherlands; and colleagues analyzed a pooled
database constructed from nine European surveys of dementia risk factors,
including a total of 16,261 participants over age 55 without dementia.
Potential risk factors were evaluated at baseline and incident dementia was
assessed over a follow up period of up to 15 years. Risk factors included
cardiovascular disorders, endocrine disorders, depression, head trauma,
intoxicants (including alcohol, smoking and drugs), physical and intellectual
activities, performance in activities of daily living, Apolipoprotein E
genotype, cognitive complaint, and cognitive test performance.
In total, 1,530 subjects (9%) progressed towards dementia. In order, the most
predictive variables were: impairment in executive function (planning), memory
problems (as measured on tests), subjective complaints about memory/cognitive
failure, Apolipoprotein E (ApoE) genotype, use of psychotropic medication,
severe head trauma, diabetes, stroke, and problems with language. In addition,
problems with activities of daily living, smoking, no drinking, no use of
hypertensive drugs, low education, and female gender all independently
predicted dementia at follow-up.
"Cases of dementia in the general population can be best identified by a
combination of socio-demographic, clinical and cognitive factors," said
Artero. "Developing a better understanding of the factors that increase risk
for Alzheimer's will help us to create more effective methods to prevent
people from developing the disease."
About ICAD 2008
The 2008 Alzheimer's Association International Conference on Alzheimer's
Disease (ICAD 2008) is the largest gathering of international leaders in
Alzheimer research and care ever convened. At ICAD 2008, more than 5,000
researchers from 60 countries will share groundbreaking information and
resources on the cause, diagnosis, treatment and prevention of Alzheimer's and
related disorders. As a part of the Association's research program, ICAD
serves as a catalyst for generating new knowledge about dementia and fostering
a vital, collegial research community. ICAD 2008 will be held in Chicago at
McCormick Place, Lake Side Center from July 26-31.
About the Alzheimer's Association
The Alzheimer's Association is the leading voluntary health organization in
Alzheimer's research, care and support. Our mission is to eliminate
Alzheimer's disease through the advancement of research, provide and enhance
care and support for all affected, and reduce the risk of dementia through the
promotion of brain health. Our vision is a world without Alzheimer's. For more
information, visit www.alz.org.
-- Krister Hakansson - "Unmarried life: Paving the way for dementia?"
(Funders: Gun and Bertil Stohne Foundation)
-- Ramit Ravona-Springer - "Tendency for rumination as a psychological
cognitive style in midlife is associated with decreased risk for dementia
three decades later." (Funders: Israel Science Foundation, Israel Academy of
Sciences and Humanities)
-- Matheus Roriz-Cruz - "Metabolic syndrome, successful and pathological
neuroaging in a stroke-free elderly population." (Funders: Ministries of
Education, Brazil and Japan)
-- Sylvaine Artero, Pieter Jelle Visser - "Risk factors for progression to
dementia in general population: the Descripa study (European pooled data
base)." (Funder: European Commission, 5th framework programme
(QLK-6-CT-2002-02455))
Second Genetic Risk Factor For Late-onset Alzheimer's Disease Found
ScienceDaily (June 26, 2008) - Researchers have discovered the second, strong genetic risk factor for developing late-onset Alzheimer's disease, according to a new report in the June 27th issue of the journal Cell, a Cell Press publication.
The newly discovered gene, which previously had no known function, is predominantly active in a region of the brain that is hit early in the disease, where it acts as a channel for calcium, they show. Called calcium homeostasis modulator 1 (CALHM1), their evidence shows that different variants of the gene also influence the levels of amyloid-β peptides. Those peptides make up the plaques that form in the brains of those with Alzheimer's.
" We are very excited about the idea that CALHM1 could be an important target for anti-amyloid therapy in Alzheimer's disease," said Philippe Marambaud of The Feinstein Institute for Medical Research and Albert Einstein College of Medicine. CALHM1's presence at the cell surface should ease the process of drug design, he explained. And because its activity is restricted to the brain, drugs aimed at CALHM1 are less likely to have peripheral side effects.
The possibility for side effects is a "big question mark" for other drugs now under clinical study, Marambaud said. Those drugs primarily target enzymes responsible for producing amyloid-β peptides, he noted, but those enzymes are also found in other parts of the body.
The new findings come just as another group has reported the identification of an imbalance of calcium in early-onset Alzheimer's disease, linked to a calcium release ion channel. Those results appear in the June 26th issue of Neuron, also a Cell Press publication.
Alzheimer's disease is a progressive neurodegenerative disorder characterized by a massive loss of neurons in several brain regions and by the presence of amyloid-β plaques. While the rarer, early-onset form of the disease has been tied to a few dominant mutations, the vast majority of late-onset cases are thought to result from complex interactions among different genetic variants and environmental factors.
Previously, the only susceptibility gene unambiguously demonstrated worldwide is a particular variant of the gene known as APOE, found on chromosome 19. Other evidence suggested a second gene could be found on chromosome 10. However, despite intensive research efforts to characterize the genetic factor or factors located, no gene within the chromosome 10 region had been conclusively linked to late-onset Alzheimer's risk, Marambaud said.
Marambaud's team suspected that susceptibility to late-onset Alzheimer's disease might stem from genes active primarily in affected brain regions, such as the hippocampus. Following that logic in the new study, the researchers screened for genes expressed predominantly in the hippocampus that also fell within the Alzheimer's-linked chromosomal region.
That exercise led them to CALHM1, a gene of unknown function. Indeed, they found, a variant of CALHM1 is found more frequently in people with Alzheimer's disease than in those without. They estimate that a single copy of that variant, which results in a proline-to-leucine amino acid substitution (designated as p86L because it occurs at codon 86), increases one's chance of getting late-onset Alzheimer's disease by 1.44-fold. The risk for those with two copies of the p86L variant would be higher still, Marambaud said.
" We quickly found that this variant was associated with the disease," Marambaud said. "The problem was it was a variant in a gene with no known function. We had no idea what it was."
Further study showed that CALHM1 is a calcium channel. They also found evidence that the CALHM1 variant more often found in those with Alzheimer's disease increases amyloid-β levels by interfering with the passage of calcium into cells.
Several groups had proposed before that calcium dysregulation could be causative for Alzheimer's disease, but the notion had not been proven, Marambaud said.
" The present work provides strong support for the calcium hypothesis of Alzheimer's disease and is also an important step toward understanding the potential pathological cross talk between calcium signaling disturbances and pathways of amyloid-β accumulation," the researchers concluded. "Moreover, the identification of CALHM1 as a key modulator of calcium homeostasis will allow us to further dissect the precise mechanism by which cytosolic calcium modulates amyloid precursor protein metabolism."
Researchers include Ute Dreses-Werringloer, Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY; Jean-Charles Lambert, INSERM, U744, Institut Pasteur de Lille, UniversiteL de Lille, Lille, France; Valerie Vingtdeux, Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY; Haitian Zhao, Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY; Horia Vais, University of Pennsylvania School of Medicine, Philadelphia, PA; Adam Siebert, University of Pennsylvania School of Medicine, Philadelphia, PA; Ankit Jain, University of Pennsylvania School of Medicine, Philadelphia, PA; Jeremy Koppel, Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY; Anne Rovelet-Lecrux, INSERM, U614, FaculteL de medecine, Rouen, France; Didier Hannequin, INSERM, U614, FaculteL de medecine, Rouen, France; Florence Pasquier, University Hospital, Lille, France; Daniela Galimberti, University of Milan, Milan, Italy; Elio Scarpini, University of Milan, Milan, Italy; David Mann, Greater Manchester Neurosciences Centre, University of Manchester, Salford, UK; Corinne Lendon, Queensland Institute of Medical Research, Brisbane, Australia; Dominique Campion, INSERM, U614, FaculteL de medecine, Rouen, France; Philippe Amouyel, INSERM, U744, Institut Pasteur de Lille, UniversiteL de Lille, Lille, France; Peter Davies, Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY, Albert Einstein College of Medicine, Bronx, NY; J. Kevin Foskett, University of Pennsylvania School of Medicine, Philadelphia, PA; Fabien Campagne, Department of Physiology and Biophysics, and HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY; and Philippe Marambaud, Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY, Albert Einstein College of Medicine, Bronx, NY.
Journal reference:
1. Dreses-Werringloer et al. A Polymorphism in CALHM1 Influences Ca2+ Homeostasis, A_ Levels, and Alzheimer's Disease Risk. Cell, 133, 1149-1161, June 27, 2008 DOI: 10.1016/j.cell.2008.05.048
BMJ 2001;322:1447-1451 ( 16 June )
Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study
Miia Kivipelto, research fellow a, Eeva-Liisa Helkala, neuropsychologist b, Mikko P Laakso, research fellow, Academy of Finland c, Tuomo Hnninen, neuropsychologist d, Merja Hallikainen, research fellow a, Kari Alhainen, department head physician e, Hilkka Soininen, professor d, Jaakko Tuomilehto, professor f, Aulikki Nissinen, professor b.
a Department of Neuroscience and Neurology, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland, b Department of Public Health and General Practice, University of Kuopio, c Department of Clinical Radiology, Kuopio University Hospital, PO Box 1777, 70211, Kuopio, Finland, d Department of Neurology, Kuopio University Hospital, e North Karelia Central Hospital, 80210 Joensuu, Finland, f National Public Health Institute, 00300 Helsinki, Finland
Abstract
Objective: To examine the relation of midlife raised blood pressure and serum cholesterol concentrations to Alzheimer's disease in later life.
Design: Prospective, population based study.
Setting: Populations of Kuopio and Joensuu, eastern Finland.
Participants: Participants were derived from random, population based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average of 21 years' follow up, a total of 1449 (73%) participants aged 65-79 took part in the re-examination in 1998.
Main outcome measures: Midlife blood pressure and cholesterol concentrations and development of Alzheimer's disease in later life.
Results: People with raised systolic blood pressure (>= 160 mm Hg) or high serum cholesterol concentration (>= 6.5 mmol/l) in midlife had a significantly higher risk of Alzheimer's disease in later life, even after adjustment for age, body mass index, education, vascular events, smoking status, and alcohol consumption, than those with normal systolic blood pressure (odds ratio 2.3, 95% confidence interval 1.0 to 5.5) or serum cholesterol (odds ratio 2.1, 1.0 to 4.4). Participants with both of these risk factors in midlife had a significantly higher risk of developing Alzheimer's disease than those with either of the risk factors alone (odds ratio 3.5, 1.6 to 7.9). Diastolic blood pressure in midlife had no significant effect on the risk of Alzheimer's disease.
Conclusion: Raised systolic blood pressure and high serum cholesterol concentration, and in particular the combination of these risks, in midlife increase the risk of Alzheimer's disease in later life.
Introduction
Risk factors for vascular disease may also be risk factors for Alzheimer's disease. Some cross sectional studies have investigated the relation of blood pressure and cholesterol concentration to cognitive function in late life, but with conflicting results. Furthermore, one limitation of cross sectional studies is that they cannot readily determine causality. This shortcoming can to some extent be overcome with longitudinal, population based studies. Two such studies have found that raised blood pressure precedes the development of Alzheimer's disease---one conducted in a Swedish population aged 70 years and followed for 9-15 years and the other in Japanese-American men with a mean age of 53 followed for 25 years. 1 2 In addition, Finnish men aged 70-89 with Alzheimer's disease were found to have had raised serum cholesterol concentrations 15-25 years before the onset of the disease.3
It is important to identify early risk factors for Alzheimer's disease because the neurodegenerative processes of Alzheimer's disease may begin in midlife.4 Identification of these risk factors may shed some light on the pathophysiology of Alzheimer's disease and also provide new potential avenues for its prevention and treatment. The preliminary findings showing an association between vascular risk factors and Alzheimer's disease need to be replicated in independent populations, and no population based study has yet evaluated the association of both midlife blood pressure and cholesterol concentrations with Alzheimer's disease in later life in both sexes. We investigated the putative impact of raised blood pressure and cholesterol concentrations in midlife on the subsequent development of Alzheimer's disease in a population based sample.
Discussion
This study showed that raised systolic blood pressure and high serum cholesterol concentrations in midlife increased the risk of Alzheimer's disease in later life. The combination of these risk factors in midlife, even when participants with borderline high systolic blood pressure were included, increased the risk to a greater extent than either of the risk factors on its own. Diastolic blood pressure in midlife was not associated with Alzheimer's disease in later life.
The role of blood pressure
Two previous longitudinal, population based studies have shown an association between raised blood pressure and subsequent Alzheimer's disease. 1 2 These studies, however, suggested that the risk was related to raised diastolic blood pressure rather than raised systolic pressure. Differences in the study settings and populations could account for the discrepancy. For instance, treatment patterns may have contributed to our finding. Participants with Alzheimer' s disease were more likely to have received antihypertensive drug treatment in midlife but, despite the treatment, still had higher systolic blood pressure in midlife than their counterparts without dementia. This is in line with findings that a considerable proportion of treated hypertensive patients do not achieve the target blood pressure and the fact that diastolic blood pressure has traditionally been the main indication for antihypertensive treatment. 2 9 10
Our study, including both treated and untreated participants, may underestimate the risk related to diastolic blood pressure. Notably, in Japanese-American men the raised diastolic blood pressure in midlife predicted Alzheimer's disease only in participants never treated with antihypertensive drugs.2 From this perspective, our data should not be interpreted as discounting the potential risk of Alzheimer's disease related to raised diastolic blood pressure but rather as emphasising the importance of raised systolic blood pressure, even in people with normal diastolic blood pressure. Our findings are partly corroborated by the only drug trial to date showing that blood pressure control may prevent dementia, which was carried out in patients with isolated systolic hypertension.11
High serum total cholesterol concentration in midlife also predicted Alzheimer's disease in later life. This finding is consistent with the findings in elderly Finnish men.3 Our study extends these findings to younger age groups and both sexes, making these data more representative.
The role of cholesterol
In this study, clinical indicators of atherosclerosis were more common in patients with Alzheimer's disease than in participants without dementia. A population based, cross sectional study has previously indicated an increased risk of Alzheimer's disease in patients with atherosclerosis.12 Hypertension and hypercholesterolaemia may increase the risk of dementia by inducing atherosclerosis and impairing blood flow, but they may also directly induce the neurodegeneration of Alzheimer's disease.13 Controlling for vascular events did not change the association between midlife high systolic blood pressure and cholesterol concentration and subsequent Alzheimer's disease, suggesting that hypertension and hypercholesterolaemia themselves pose a risk for Alzheimer's disease. Furthermore, the combination of hypertension and hypercholesterolaemia in midlife was a particularly strong predictor of Alzheimer's disease; these factors may accelerate the development of Alzheimer's disease partly through different pathophysiological mechanisms.
Apolipoprotein E genotype may influence the observed associations, but more than 85% of the variation in serum cholesterol concentrations is thought to be independent of the apolipoprotein E genotype.14 Accordingly, the findings in elderly Finnish men suggested that high serum cholesterol concentration was an independent risk factor for Alzheimer's disease regardless of the apolipoprotein E genotype.3 However, more research is needed to determine if apolipoprotein E genotype modulates the effects of risk factors for Alzheimer's disease.
Study methodology
The design of our study as a population based, longitudinal study with a large cohort of participants and substantial response rate increases the credibility of these findings. No autopsy data were available to confirm the clinical diagnosis, although the accuracy of the clinical diagnosis of Alzheimer's disease at Kuopio University Hospital, verified by neuropathology, has been reported to be 96%.15
We investigated the possibility of selection bias due to non-participation. The prevalences of both raised systolic blood pressure and hypercholesterolaemia in midlife were higher among non-participants. People with cognitive decline are less likely to participate in clinical studies.16 Hence, if non-participants were at an increased risk of cognitive impairment and dementia, our results would represent an underestimate of the true effect of the risk factors rather than the opposite. Only participants scoring =<24 in the mini-mental state examination in the screening phase underwent the exhaustive examinations needed for the diagnosis of dementia. Some dementia cases may have been lost because of this cut-off score, and this may also have resulted in underestimation of the prevalence of dementia.
Conclusion
As the proportion of elderly people in the population increases, Alzheimer's disease will become an enormous public health problem. Interventions that could delay the onset of the disease, even modestly, would therefore have a major impact on public health.17 The observed relation between midlife vascular risk factors and Alzheimer's disease later in life may have implications for the prevention of dementia as both hypertension and hypercholesterolaemia can be treated.
Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer's Disease
NEJM Feb 202
Sudha Seshadri, M.D., Alexa Beiser, Ph.D., Jacob Selhub, Ph.D., Paul F. Jacques, Sc.D., Irwin H. Rosenberg, M.D., Ralph B. D'Agostino, Ph.D., Peter W.F. Wilson, M.D., and Philip A. Wolf, M.D.
ABSTRACT
Background In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies.
Methods A total of 1092 subjects without dementia (667 women and 425 men; mean age, 76 years) from the Framingham Study constituted our study sample. We examined the relation of the plasma total homocysteine level measured at base line and that measured eight years earlier to the risk of newly diagnosed dementia on follow-up. We used multivariable proportional-hazards regression to adjust for age, sex, apolipoprotein E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6.
Results Over a median follow-up period of eight years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer's disease. The multivariable-adjusted relative risk of dementia was 1.4 (95 percent confidence interval, 1.1 to 1.9) for each increase of 1 SD in the log-transformed homocysteine value either at base line or eight years earlier. The relative risk of Alzheimer's disease was 1.8 (95 percent confidence interval, 1.3 to 2.5) per increase of 1 SD at base line and 1.6 (95 percent confidence interval, 1.2 to 2.1) per increase of 1 SD eight years before base line. With a plasma homocysteine level greater than 14 μmol per liter, the risk of Alzheimer's disease nearly doubled.
Conclusions An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer's disease.
Alzheimer's disease accounts for more than 70 percent of all cases of dementia, so it is important to identify modifiable risk factors for the disease.1 During the past decade, there has been growing interest in vascular factors that may underlie Alzheimer's disease. It is now recognized that subjects with cardiovascular risk factors and a history of stroke have an increased risk of both vascular dementia and Alzheimer's disease.2,3,4 Plasma total homocysteine has recently emerged as a major vascular risk factor. Elevated total homocysteine levels have been associated with an increased risk of atherosclerotic sequelae, including death from cardiovascular causes,5,6 coronary heart disease,6,7 carotid atherosclerosis,8 and clinical stroke.9,10 These observations led to the hypothesis that elevated plasma homocysteine may be a risk factor for dementia and Alzheimer's disease. If this hypothesis is valid, it points to a modifiable risk factor, since plasma homocysteine levels can be lowered by supplementation with folic acid.11
Previous studies have reported an inverse association between plasma total homocysteine levels and simultaneously assessed cognitive function.12,13,14,15,16 Two case-control studies have found higher plasma homocysteine levels in persons with Alzheimer's disease.17,18 However, in a prospective study plasma homocysteine levels were not related to cognitive decline during follow-up in a community-based sample.19 Elevated plasma homocysteine levels in subjects with cognitive impairment or dementia might be the result of poor nutrition and vitamin deficiencies.20 A prospective study should be able to show whether elevated plasma homocysteine in cognitively intact adults is associated with an increased risk of dementia and Alzheimer's disease on follow-up. We therefore examined plasma total homocysteine in relation to newly diagnosed dementia and Alzheimer's disease in the elderly, population-based cohort of Framingham Study participants.
Discussion
The results of our prospective, observational study indicate that there is a strong, graded association between plasma total homocysteine levels and the risk of dementia and Alzheimer's disease. An increment in the plasma homocysteine level of 5 μmol per liter increased the risk of Alzheimer's disease by 40 percent. A plasma homocysteine level in the highest age-specific quartile doubled the risk of dementia or Alzheimer's disease. A similar result was found when the single criterion of hyperhomocysteinemia (base-line plasma homocysteine, >14 μmol per liter) was used. The magnitude of this effect is similar to the magnitude of the increases in the risks of death from cardiovascular causes and stroke associated with a similar increment in the plasma homocysteine level, which have been previously described in the Framingham cohort.6,10
The observed association appeared to be independent of age, sex, APOE genotype, plasma vitamin levels, and other putative risk factors for dementia and Alzheimer's disease. The prospective nature of this study and the strong association between newly diagnosed dementia and Alzheimer's disease and plasma homocysteine levels measured eight years before base line suggest that the elevation in the homocysteine level preceded the onset of dementia. Finally, subjects with a sustained elevation of plasma homocysteine had the greatest risk of dementia.
Two case-control studies have specifically addressed the relation between homocysteine levels and the risk of Alzheimer's disease.17,18 Both studies found a significant elevation of the serum homocysteine level in patients with Alzheimer's disease as compared with age-matched controls. A report from the Rotterdam Study did not show an association between the base-line homocysteine level and a decline in the score on the Mini-Mental State Examination, perhaps because the follow-up period was only 2.7 years.19 In our study population, an elevated homocysteine level at base line was related to a decline in the scores on the Mini-Mental State Examination, but only after a follow-up period of at least four years (data not shown).
Elevated plasma homocysteine levels are associated with carotid atherosclerosis and an increased risk of stroke.8,10 Atherosclerosis and stroke, in turn, increase the risk of clinical Alzheimer's disease.2,4 Hyperhomocysteinemia has been related to cerebral microangiopathy,44 endothelial dysfunction,45 impaired nitric oxide activity,46 and increased oxidative stress47 - all factors associated with the aging of the brain.48,49 Increased concentrations of homocysteic acid, an N-methyl-D-aspartate receptor agonist and a metabolite of homocysteine, may result in excitotoxic damage to neurons.50 Homocysteine promotes copper-mediated and {beta}-amyloid-peptide-mediated toxic effects in neuronal cell cultures51 and induces apoptosis in hippocampal neurons in rats.52
The strengths of our investigation include its prospective design, the large community-based sample, the long follow-up period, and the availability of prestudy plasma homocysteine levels and base-line values for plasma B vitamins and other covariates. A limitation of this study is the lack of racial diversity in the overwhelmingly white Framingham cohort. It is possible that our use of samples obtained from nonfasting subjects resulted in estimates of plasma homocysteine levels that were up to 20 percent higher than they would have been in fasting subjects,53 but any increase in the variability in plasma homocysteine values caused by this approach is likely to be random and is unlikely to have altered the results.
Vitamin therapy with folic acid, alone or in combination with vitamins B6 and B12, and dietary supplementation with enriched cereal-grain products and breakfast cereals containing folate can reduce plasma homocysteine levels.54,55,56 The U.S. government now mandates folic acid fortification of the food supply.55 Current plasma homocysteine levels in the Framingham Study population are significantly lower than those that were estimated at the 16th and 20th biennial examinations.56 However, only 20 cases of dementia were diagnosed between 1997 and the time the levels were remeasured, and therefore it is not possible to assess the effect of recent increases in folic acid fortification on the risk of dementia in this cohort. Furthermore, since there have been no prospective trials of the effect of vitamin supplementation on the incidence of dementia, our findings cannot be used as a basis for setting health policy or treatment recommendations.
The relation between elevated plasma homocysteine levels and dementia must be evaluated in other cohort studies. If such studies confirm our findings, proof of a causal association between plasma homocysteine and the development of dementia and Alzheimer's disease will require further elucidation of the pathophysiologic mechanisms and direct evidence from controlled clinical trials in humans that interventions that reduce plasma homocysteine levels can reduce the risk of clinical dementia and Alzheimer's disease.
Supported by the Framingham Heart Study's National Heart, Lung, and Blood Institute contract (N01-HC-38038) and by grants (NIA-5R01-AG08122-11 and NIA-5R01-AG16495-02) from the National Institute on Aging and a grant (NINDS-5R01-NS17950-19) from the National Institute of Neurological Disorders and Stroke.
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