- Email: [email protected]
Mid-life plasma folate and vitamin B12 levels and cognitive function in older women
S28
Abstracts: Identification of Risk Factors / 1 (Suppl 1) (2005)
HMG-CoA reductase polymorphism during the two year follow up. Conclusions: This is the first investigation showing a genetic association of HMG-CoA Red gene with the risk and clinical progression of AD. Therefore, this SNP can be considered a genetic modifier of AD. These observations reinforce the notion that molecules with regulatory effect upon cholesterol metabolism may play a relevant role in the pathogenesis and progression of the disease. P-063
THE IMPACT OF APOE ALLELES ON AGERELATED MYELIN BREAKDOWN
George Bartzokis, Po H. Lu, Daniel H. Geschwind, Nancy Edwards, Jim Mintz, Jeffrey L. Cummings; UCLA, Los Angeles, CA, USA Background: By shifting the age at onset of Alzheimer’s disease (AD), Apolipoprotein E (ApoE) genotype is the most influential AD risk factor after age itself. ApoE4 alleles decrease while ApoE2 alleles increase age at onset. Human and non-human primate data suggest that in middle age, the structural integrity of myelin sheaths begins breaking down with an accelerating age-related trajectory most evident in the brain’s later-myelinating association regions. This results in a progressive “disconnection” of widely distributed neural networks that may underlie the age risk factor for AD. Objective: Assess whether ApoE genotype shifts the age at onset of AD by altering the trajectory of age-related myelin breakdown. Methods: Healthy individuals (N⫽104) between 55 and 75 years of age were ApoE genotyped. The late-myelinating frontal lobe white matter (Fwm) as well as early- and later-myelinating regions of the corpus callosum, the splenium (Swm) and genu (Gwm) respectively, were assessed using MRI and transverse relaxation rates (R2) were calculated. R2 is an indirect measure of white matter structural integrity; it declines with age-related myelin breakdown and is significantly lower in AD. As hypothesized, presence of the protective ApoE2 allele was associated with significantly higher R2 values in Fwm and Gwm, but not in Swm. Furthermore, ApoE status impacted the trajectory of age-related myelin breakdown in late-myelinating regions (Fwm and Gwm) but not in the Swm. In the Fwm and Gwm ApoE4⫹ individuals had a steeper slope of decline in R2 with age than ApoE2⫹ individuals, while Apoe3⫹ individuals had an intermediate slope. Conclusions: These data suggest that the severity and rate of myelin breakdown in healthy older individuals is associated with ApoE status. The findings are consistent with the hypothesis that later-myelinating regions are more susceptible to the myelin breakdown process and that this process may determine the age at onset of AD. Combining ApoE status with non-invasive measures of myelin breakdown may be useful in designing treatment studies directed at primary prevention of AD. P-064
SEARCHING FOR PRO-INFLAMMATORY GENE CLUSTERS TO ASSESS THE ALZHEIMER’S DISEASE (AD) RISK PROFILE FOR THE PREVENTION AND EARLY THERAPY OF THE DISEASE
Federico Licastro1,2, Elisa Porcellini1, Martina Chiappelli1, Luca Morandi1; 1University of Bologna, Bologna, Italy; 2Department of Experimental Pathology, University of Bologna, Italy Background: Epidemiological studies showed that anti-inflammatory drugs decreased the incidence and prevalence of AD. Inflammatory responses are associated with neuropathology hallmarks of AD brain and mechanisms regulating inflammation and immune responses have been suggested to be involved in the pathogenesis of age-associated cognitive decline and AD. Investigations focused on SNPs in immunoregulatory genes showed that selected immune genes were associated with an increased risk of the disease and/or a differential rate of cognitive decline. Objective(s): The combination of different SNPs of diverse immune genes may have an addictive effect on cognitive decline in the elderly and AD risk. In particular, pooling several SNPs of these genes gives rise to a
pro-inflammatory genetic cluster associated with abnormal or poorly regulated inflammatory responses. The identification of these pro-inflammatory gene clusters can be applied to healthy subjects to determine their intrinsic risk of pro-inflammatory predisposition with relevance for brain degeneration. Methods: Several hundreds of patients with clinical diagnosis of AD and non demented controls have been genotyped for SNPs in IL-1, IL-6, IL-10, ACT, APOE and Hydroxy-Methyl-Glutaryl- Coenzime A reductase (HMG-CoA red.). The association of each SNP with AD risk has been determined. A score for each allele or genotype has been assigned and an algoritm to assess individual intrinsic risk has been developed. A longitudinal study (a four year follow-up) of a 1000 elderly living in the Northern Italy has been concluded. Each participants has been genotyped for the above SNPs and the predictive power for age associated cognitive impairment and senile dementia of gene clusters for pro-inflammatory predisposition (PIP) has been tested. Conclusions: Using the gene clusters associated with (PIP) and associated with AD is possible to predict the individual intrinsic risk of developing age associated cognitive impairment in healthy subjects. These groups of subjects will be offered to enter a follow up with annual clinical examination, cognitive testing and functional neuro-imaging. An anti-inflammatory therapy will be suggested, when cognitive testing and/or functional neuro-imaging would detect abnormalities. If this approach is correct, by using this technology a substantial decrement of prevalence and incidence of dementia in near future might be achieved
P-065
MID-LIFE PLASMA FOLATE AND VITAMIN B12 LEVELS AND COGNITIVE FUNCTION IN OLDER WOMEN
Jae Hee Kang, Francine Grodstein; Harvard Medical School, Boston, MA, USA Background: Plasma folate and vitamin B12 are involved in homocysteine metabolism, and both are commonly deficient in older populations. In previous studies, homocysteine has been implicated Alzheimer disease, yet population based studies on these B vitamins and cognitive function in non-demented subjects have been limited and inconsistent. Objective(s):We examined the relationship between plasma folate and B12 levels and cognitive function among 619 older participants of the Nurses Health Study (NHS). Methods: The NHS is an ongoing, prospective cohort of female nurses; in 1989-1990, blood samples were collected from one-third of participants. From 1995-2001, subjects aged 70 years or above, and free of stroke completed a telephone cognitive interview consisting of tests measuring general cognitive ability, episodic memory, category fluency and attention. Participation was high, at 93%. In total, 619 women also had plasma folate and b12 levels measured, as controls in other cohort research projects. We performed multivariable analyses of plasma levels of these B vitamins in relation to cognitive performance, adjusting for numerous potential confounders. Results: We found little relation between plasma folate and cognitive function; for example, after adjustment, women in the highest quartile of plasma folate (⬎⫽13 ng/mL) scored 0.09 units higher (95% CI⫽-0.08, 0.25; p-linear trend⫽0.40) on a global composite score combining all cognitive tests, compared to the women in the lowest quartile. On the other hand, women in the highest quartile of plasma vitamin B12 levels (⬎⫽541 pg/mL) scored significantly higher by 0.18 units (95% CI⫽0.02,0.34; p linear trend⫽0.05). In our cohort, each year of age was associated with a deficit of 0.05 units, thus having highest B12 levels was cognitively equivalent to being about 4 years younger in age. Women who were in the highest quartile for both plasma folate and vitamin B12 performed significantly higher by 0.22 units (95% CI⫽0.01, 0.42) compared to women in the lowest quartiles for both nutrients. Conclusions: Higher levels of vitamin B12, especially in combination with high folate levels, may be associated with better cognitive performance many years later among older women.
Abstracts: Identification of Risk Factors / 1 (Suppl 1) (2005)
HMG-CoA reductase polymorphism during the two year follow up. Conclusions: This is the first investigation showing a genetic association of HMG-CoA Red gene with the risk and clinical progression of AD. Therefore, this SNP can be considered a genetic modifier of AD. These observations reinforce the notion that molecules with regulatory effect upon cholesterol metabolism may play a relevant role in the pathogenesis and progression of the disease. P-063
THE IMPACT OF APOE ALLELES ON AGERELATED MYELIN BREAKDOWN
George Bartzokis, Po H. Lu, Daniel H. Geschwind, Nancy Edwards, Jim Mintz, Jeffrey L. Cummings; UCLA, Los Angeles, CA, USA Background: By shifting the age at onset of Alzheimer’s disease (AD), Apolipoprotein E (ApoE) genotype is the most influential AD risk factor after age itself. ApoE4 alleles decrease while ApoE2 alleles increase age at onset. Human and non-human primate data suggest that in middle age, the structural integrity of myelin sheaths begins breaking down with an accelerating age-related trajectory most evident in the brain’s later-myelinating association regions. This results in a progressive “disconnection” of widely distributed neural networks that may underlie the age risk factor for AD. Objective: Assess whether ApoE genotype shifts the age at onset of AD by altering the trajectory of age-related myelin breakdown. Methods: Healthy individuals (N⫽104) between 55 and 75 years of age were ApoE genotyped. The late-myelinating frontal lobe white matter (Fwm) as well as early- and later-myelinating regions of the corpus callosum, the splenium (Swm) and genu (Gwm) respectively, were assessed using MRI and transverse relaxation rates (R2) were calculated. R2 is an indirect measure of white matter structural integrity; it declines with age-related myelin breakdown and is significantly lower in AD. As hypothesized, presence of the protective ApoE2 allele was associated with significantly higher R2 values in Fwm and Gwm, but not in Swm. Furthermore, ApoE status impacted the trajectory of age-related myelin breakdown in late-myelinating regions (Fwm and Gwm) but not in the Swm. In the Fwm and Gwm ApoE4⫹ individuals had a steeper slope of decline in R2 with age than ApoE2⫹ individuals, while Apoe3⫹ individuals had an intermediate slope. Conclusions: These data suggest that the severity and rate of myelin breakdown in healthy older individuals is associated with ApoE status. The findings are consistent with the hypothesis that later-myelinating regions are more susceptible to the myelin breakdown process and that this process may determine the age at onset of AD. Combining ApoE status with non-invasive measures of myelin breakdown may be useful in designing treatment studies directed at primary prevention of AD. P-064
SEARCHING FOR PRO-INFLAMMATORY GENE CLUSTERS TO ASSESS THE ALZHEIMER’S DISEASE (AD) RISK PROFILE FOR THE PREVENTION AND EARLY THERAPY OF THE DISEASE
Federico Licastro1,2, Elisa Porcellini1, Martina Chiappelli1, Luca Morandi1; 1University of Bologna, Bologna, Italy; 2Department of Experimental Pathology, University of Bologna, Italy Background: Epidemiological studies showed that anti-inflammatory drugs decreased the incidence and prevalence of AD. Inflammatory responses are associated with neuropathology hallmarks of AD brain and mechanisms regulating inflammation and immune responses have been suggested to be involved in the pathogenesis of age-associated cognitive decline and AD. Investigations focused on SNPs in immunoregulatory genes showed that selected immune genes were associated with an increased risk of the disease and/or a differential rate of cognitive decline. Objective(s): The combination of different SNPs of diverse immune genes may have an addictive effect on cognitive decline in the elderly and AD risk. In particular, pooling several SNPs of these genes gives rise to a
pro-inflammatory genetic cluster associated with abnormal or poorly regulated inflammatory responses. The identification of these pro-inflammatory gene clusters can be applied to healthy subjects to determine their intrinsic risk of pro-inflammatory predisposition with relevance for brain degeneration. Methods: Several hundreds of patients with clinical diagnosis of AD and non demented controls have been genotyped for SNPs in IL-1, IL-6, IL-10, ACT, APOE and Hydroxy-Methyl-Glutaryl- Coenzime A reductase (HMG-CoA red.). The association of each SNP with AD risk has been determined. A score for each allele or genotype has been assigned and an algoritm to assess individual intrinsic risk has been developed. A longitudinal study (a four year follow-up) of a 1000 elderly living in the Northern Italy has been concluded. Each participants has been genotyped for the above SNPs and the predictive power for age associated cognitive impairment and senile dementia of gene clusters for pro-inflammatory predisposition (PIP) has been tested. Conclusions: Using the gene clusters associated with (PIP) and associated with AD is possible to predict the individual intrinsic risk of developing age associated cognitive impairment in healthy subjects. These groups of subjects will be offered to enter a follow up with annual clinical examination, cognitive testing and functional neuro-imaging. An anti-inflammatory therapy will be suggested, when cognitive testing and/or functional neuro-imaging would detect abnormalities. If this approach is correct, by using this technology a substantial decrement of prevalence and incidence of dementia in near future might be achieved
P-065
MID-LIFE PLASMA FOLATE AND VITAMIN B12 LEVELS AND COGNITIVE FUNCTION IN OLDER WOMEN
Jae Hee Kang, Francine Grodstein; Harvard Medical School, Boston, MA, USA Background: Plasma folate and vitamin B12 are involved in homocysteine metabolism, and both are commonly deficient in older populations. In previous studies, homocysteine has been implicated Alzheimer disease, yet population based studies on these B vitamins and cognitive function in non-demented subjects have been limited and inconsistent. Objective(s):We examined the relationship between plasma folate and B12 levels and cognitive function among 619 older participants of the Nurses Health Study (NHS). Methods: The NHS is an ongoing, prospective cohort of female nurses; in 1989-1990, blood samples were collected from one-third of participants. From 1995-2001, subjects aged 70 years or above, and free of stroke completed a telephone cognitive interview consisting of tests measuring general cognitive ability, episodic memory, category fluency and attention. Participation was high, at 93%. In total, 619 women also had plasma folate and b12 levels measured, as controls in other cohort research projects. We performed multivariable analyses of plasma levels of these B vitamins in relation to cognitive performance, adjusting for numerous potential confounders. Results: We found little relation between plasma folate and cognitive function; for example, after adjustment, women in the highest quartile of plasma folate (⬎⫽13 ng/mL) scored 0.09 units higher (95% CI⫽-0.08, 0.25; p-linear trend⫽0.40) on a global composite score combining all cognitive tests, compared to the women in the lowest quartile. On the other hand, women in the highest quartile of plasma vitamin B12 levels (⬎⫽541 pg/mL) scored significantly higher by 0.18 units (95% CI⫽0.02,0.34; p linear trend⫽0.05). In our cohort, each year of age was associated with a deficit of 0.05 units, thus having highest B12 levels was cognitively equivalent to being about 4 years younger in age. Women who were in the highest quartile for both plasma folate and vitamin B12 performed significantly higher by 0.22 units (95% CI⫽0.01, 0.42) compared to women in the lowest quartiles for both nutrients. Conclusions: Higher levels of vitamin B12, especially in combination with high folate levels, may be associated with better cognitive performance many years later among older women.