the presence of an apolipoprotein e4 allele ( apoe4 ) increases the risk of , and reduces the age at onset of , alzheimer 's disease ( ad ) in a dose - dependent manner . additionally , apoe4 carriers have been reported to have higher rates of cognitive decline than noncarriers before the diagnosis of mild cognitive impairment . apolipoprotein e ( apoe ) plays a significant role in cholesterol delivery to neurons and ad pathogenesis associated with amyloid beta ( a ) . the plasma level of apoe has been shown to depend upon the apoe genotype . in elderly individuals without dementia , the interactive effect of apoe and other plasma lipids on cognitive function has also been reported to vary , depending upon the apoe genotype . 
  a complex synergism of apoe4 and cerebrovascular pathology in cognitive function of the elderly has been reported . the detrimental effect of apoe4 may be exacerbated by synergistic preventable risk factors such as plasma apoe / lipids . with stratification by apoe allele status , we examined the effect of plasma apoe / lipids on longitudinal change in the cognitive function of community - dwelling elderly using the data from a 3-year follow - up study . participants were recruited in the present study from the  tone project  in tone town , ibaraki , japan . a total of 1395 volunteers participated in the first baseline study between december 2001 and april 2002 . three years later , 622 of them who had no history of stroke during follow - up were able to be evaluated again between december 2004 and april 2005 , and we used the results from those subjects tested twice . at the initial examination , all of the eligible subjects provided written informed consent for their participation in the study . all participants underwent the same cognitive assessment at the baseline and 3-year examinations using a set of four tests to measure the following cognitive domains : attention , memory , language , and reasoning . we evaluated attention by using the japanese version of a set - dependent activity , memory ability using the category cued recall test , and language ability with a category fluency test . abstract reasoning ability was evaluated with the similarities subtest of the wechsler adult intelligence scale - revised ( wais - r ) . a composite cognitive score was computed from the four scores using the first component of the scores of principal component analysis . plasma levels of lowdensity lipoprotein ( ldl ) , high - density lipoprotein ( hdl ) , triglycerides ( tg ) , and total cholesterol ( tc ) were measured using standard enzymatic methods on routine automated chemistry systems . subjects were divided into two apoe groups by e4 status with e4-(n=509 ) ( genotypes 2/3 [ n=52 ] , 3/3 [ n=457 ] ) and e4 + ( n=113 ) ( genotypes [ 2/4 n=6 ] , 3/4 [ n=99 ] and 4/4 [ n=8 ] ) to test for the influence of genotype on the association between lipids and cognitive function . the subjects in each category were divided into three strata according to the plasma concentrations of lipids . to examine the influence of plasma lipids on cognitive function , composite cognitive scores of the three strata of plasma concentrations were compared in e4- and e4 + groups separately by ancova , with age , sex , years of education , geriatric depression scale score , cigarette smoking , and medical history of diseases as covariates . the demographic data for the e4- and e4 + groups in the analysis of the effect of lipids/ apoe on cognitive function are shown in table i. there were no group differences in demographic characteristics , except for the cognitive score . our finding of a higher cognitive score at 2002 and 2005 in the e4- group is consistent with previous studies . figure 1 and 2 show the median plasma concentrations of lipids for the three strata according to the tertiles of plasma levels of lipids / apoe , and the mean cognitive scores of the e4- and e4 + groups at 2002 and 2005 according to the three strata of plasma concentrations of lipids / apoe . ancova analysis evaluating the influence of lipids level on cognitive function showed a significant influence of the hdl level on composite cognitive scores at both 2002 and 2005 in the e4- group ( f2,498=9.3 , p<0.001 for 2002 , f2,498=9.3 , p<0.001 for 2005 ) . the effect size of the influence of the plasma hdl level on cognitive score was more than 0.01(=0.04 for 2002 , =0.04 for 2005 ) . no such significant association was observed in the e4 + group ( figure 2 ) . a significant main effect of the apoe level was found by ancova on composite cognitive scores at 2002 and 2005 in both of the e4- and e4 + group ( f2,498=11.3 , p<0.001 for 2002 , f2,498=7.3 , p=0.001 for 2005 in the e4- , and f2,102=7.0 , p=0.001 for 2002 , f2,102=4.0 , p=0.02 for 2005 in the e4 + ) . the effect size of the association of the plasma apoe level on these cognitive scores was more than 0.01(=0.04 for 2002 , =0.03 for 2005 in the e4-,and =0.12 for 2002 , =0.07 for 2005 in the e4 + ) . each of the analyses using the data from the baseline and 3-year follow - up examinations revealed that cognitive scores were associated with the plasma apoe level in both e4- and e4 + , and the hdl level in e4- . apoe plays a significant role in response to neuronal injury by reducing inflammation , endothelial dysfunction , and lipid oxidation . an antioxidant role of apoe in promoting the regression of atherosclerosis has also been reported . if this is the case , a lower plasma apoe level may lead to cognitive decline and the exacerbation of cerebral degenerative changes . on the other hand , apoe is thought to bind a and promote its clearance and degradation , such that a lower apoe level may reduce the efficiency of a clearance , and contribute to ad pathogenesis . the expression of apoe is transcriptionally regulated by the ligand - activated nuclear receptors , peroxisome proliferator - activated receptor gamma ( ppar ) and liver x receptors ( lxrs ) , which form obligate heterodimers with retinoid x receptors ( rxrs ) . recently , cramer et al tested whether the rxr agonist bexarotene , which activates both the ppar - rxr and lxr - rxr receptors , would rapidly alter the amount of a , and diminish behavioral abnormalities , in mice genetically engineered to express a mutant form of the app gene . they observed rapid clearance of soluble a from the brain , reduction in neuritic plaque burden , and reversal of behavioral deficits . the effects of bexarotene were not observed when the drug was administered to mice lacking the apoe gene . these observations support our finding of the significant protective effect of apoe on cognitive decline in later life , and that the strategies increasing apoe expression might prevent cognitive decline in old age . higher plasma levels of hdl were associated with better cognitive function in the e4- group . low - level hdl is thought to be a risk factor for atherosclerotic diseases , and it has been reported that hdl might prevent aggregation and polymerization of amyloid in the human brain . recent studies have presented evidence for the involvement of internalized triglyceride - rich lipoprotein ( trl)derived apoe in the regulation of hdl metabolism . the greater portion of trl - derived apoe remains in peripheral recycling endosomes . this pool of apoe is then mobilized by hdl to be recycled back to the plasma membrane , followed by apoe resecretion and the subsequent formation of apoe - containing hdl . we found no significant association between hdl and cognitive function in the e4 + group . a recent study has shown that hdl - induced recycling of trl - derived apoe4 is relatively inefficient . thus , in the e4 + group , the inefficiency might reduce the recycling of apoe and decrease the protective effect of hdl on cognitive decline . our findings showed positive effect of plasma apoe and hdl on better cognitive function of elderly . they suggest a possible interaction between apoe and hdl may be linked to a protective effect on cognitive decline and that the interaction is affected by apoe4 allele in later life . it is known that neuropathological cascades leading to cognitive impairment and ad start to develop before the manifestation of cognitive impairment . therefore , ensuring higher plasma apoe and hdl from an earlier stage of life may be useful for the maintenance of cognitive function in later life , and especially for apoe4 carriers .
a central tenet of brain aging is that  what is good for the heart is good for the brain . 
 we examined the combined effect of plasma lipids and apoe genotype on cognitive function in elderly individuals . 
 plasma concentrations of high - density lipoprotein ( hdl ) , low - density lipoprotein , triglyceride , total cholesterol , and apolipoprotein e ( apoe ) were evaluated in 622 community - dwelling individuals aged 65 years and older . 
 we investigated the associations between plasma lipids and cognitive function in apoe4 carrier ( e4 + ) and apoe4 noncarrier ( e4- ) groups using 3-year longitudinal data . at baseline and 
 3 years later , cognitive scores were correlated with plasma apoe levels in both e4- and e4 + , and hdl level in e4- . 
 our findings suggest that an interaction between apoe and hdl is facilitated by apoe4 , and is possibly linked with an enhancement of neuroplasticity and with resultant protective effects on cognitive function in later life . 
 preservation of higher plasma apoe and hdl from early life is proposed as a possible strategy for maintaining cognitive function in later life , especially for apoe4-positive individuals .