the scientific reasoning for the distinction between ad and vd was based on evidence collected during the 1970s and 1980s , leading investigators to conclude that a vascular pathology was not the main underlying pathology for most demented individuals . first , many demented individuals had diffuse amyloid deposits or plaques and neurofibrillary tangles as the predominant postmortem pathology , with no or minimal vascular pathology or infarcts . second , in some of these demented individuals with predominantly plaques and tangles , the counts of the cholinergic cells in the nucleus basalis of meynert were diminished , as was the activity of the neurotransmitter acetylcholine in the cortex . taken together , these findings convinced researchers that ad was a unique and discrete disease entity with well - defined histology ( presence of plaques and tangles ) and neurochemistry ( cholinergic deficiency ) , thus leading a sustainable hypothesis regarding its pathophysiology . on the other hand , as vd was conceptualized as a  matter of strokes large and small ,  the hachinski ischemic score was developed in order to differentiate it from ad . the scale is based on presence of risk factors for vd , such as hypertension , history of strokes , and evidence of associated atherosclerosis , and on the clinical characteristics of strokes ( abrupt , onset , stepwise deterioration , fluctuating course , focal neurological signs , and symptoms ) . additional support for a vascular origin of dementia according to the hachinski ischemic score were the presence of nocturnal confusion , relative preservation of personality , depression , somatic complaints , and emotional incontinence . the items making up the scale reflect the conceptualization of vascular risk factors as exclusively associated with brain infarcts , which , in turn , are responsible for the clinical manifestations of mid ( and later vd ) . the pragmatic reasoning for the distinction between ad and vd was the assumption in the late 1970s and early 1980s that specific treatments for ad exist , this assumption was based on the apparent finding that increasing cholinergic activity by pharmacological manipulations could improve symptoms in demented individuals . in order to increase the likelihood of demonstrating an effect for drugs enhancing cholinergic activities , it was believed to be essential to identify patients affected by a cholinergic deficit , ic , ad patients , and distinguish them from vd patients , who were not expected to benefit from cholinergic enhancement . however , since the late 1990s , this distinction has been challenged by clinical , neuropathological , epidemiological , and even therapeutic studies . the following paragraphs will elaborate on this challenge , attempt to explain the role of cardiovascular risk factors in the ad syndrome , and propose possible interactions between ad and vd . the traditional characterization of ad ( an insidious and gradual progression with no focal neurological signs ) and vd ( an abrupt onset with stepwise progression and focal neurological signs ) was not . significant numbers of patients were described who had predominantly brain infarcts , but an ad - like course , and vice versa . also , the availability of advanced imaging methods lead to the recognition of diverse neuroanatomical vascular brain lesions ( thromboembolic stroke , small lacunar infarcts , and white matter lesions ) , whose implication and etiology are still debatable but are probably the result of hypoperfusion to brain tissue . it was also recognized that , many of the infarcts identified by imaging techniques or at postmortem examination are silent infarcts , which do not necessarily contribute to clinical expression in terms of focal signs or symptoms or cognitive impairment . furthermore , for some vd subtypes , namely subcortical microvascular disease , mild cognitive impairment . neuropathologically , the seminal  nun study ,  which followed 102 elderly nuns to postmortem , demonstrated that , among those who met neuropathological criteria for ad , those with brain infarcts had higher prevalence of clinically expressed dementia than those without infarcts . similarly , the complex interaction between ad and vascular pathology was demonstrated in a 3-year follow - up study of stroke patients who were not demented before the stroke . one third of the patients who developed poststroke dementia were diagnosed as suffering from ad . finally , a substantial proportion of brains who meet neuropathological criteria , for ad show lesions such as cerebral amyloid angiopathy , microvascular degeneration , periventricular white matter lesions , and other vascular pathology , further complicating the neuropathological distinction between the two disease entities . epidemiologically , it has been demonstrated that individuals affected by vascular risk factors during midlife are more likely to manifest , dementia associated with adlike brain pathology in old age . hence , it appears that most of the risk factors for cardiovascular disease , such as diabetes , hypertension , abnormal plasma cholesterol , high intake of saturated fat , thromboembolic episodes , high fibrinogen concentrations , high serum homocysteine , atrial fibrillation , smoking , alcoholism , atherosclerosis , and apolipoprotein e4 ( apoe4 ) allele , are also risk factors for ad and not exclusively for vd . therapeutically , it was recently shown that drugs enhancing cholinergic activity arc as effective in patients suffering from vd as they are in ad patients , hence eliminating the pragmatic justification for the distinction . the simple solution to the challenge brought to the distinction between ad and vd is to invoke the mixed dementia  notion , by which dementia is caused by the concomitant , presence of both ad - like pathology ( plaques and tangles ) and infarcts , which contribute to the manifestation of dementia in a cumulative fashion . this explanation has much face validity , since both ad pathology and vd pathology are age - dependent manifestations , hence the idea that they converge to manifest dementia is a plausible one . a corollary explanation is that the incidence of cardiovascular risk factors , such as diabetes and hypertension and additional constituents of the metabolic syndrome ( hyperlipidemia , central obesity ) , progressively increase after the fifth and sixth decades of life , and contribute to a pathway during the seventh and eighth decades of life leading to vd , which , together with ad - like pathology , reaches the threshold for clinical manifestation of dementia . however , the high prevalence of demented individuals whose neuropathological examination reveals both ad and vd pathology does not necessarily prove a synergetic relationship between the two types of lesions to produce dementia . it is conceivable that either the neurodegenerative or the vascular lesions do not contribute to the clinical manifestation until a certain load of pathology is reached . thus , in some patients with cooccurrence of both types of lesions , one type of lesion could be regarded as an  innocent , bystander .  indeed , the correlations between clinically diagnosed mixed dementia and neuropathological examination remain poor . a more interesting hypothesis of heuristic value would indicate that , the risk conferred by the presence of cardiovascular risk factors , such as diabetes , hypertension , or hyperlipidemia , toward ad disease is independent of the risk conferred by the same risk factors toward vd . the following paragraphs will review this possibility , provide suggestions for mechanisms by which cardiovascular risk factors contribute directly to ad pathology , and discuss possible ways for interaction and overlap between ad and vd . finally , treatment and prevention implications based on the overlap between the two pathologies will be briefly discussed . the idea that abnormal lipoprotein metabolism in general , and cholesterol in particular , affects the risk for ad derives from long - term follow - up of cohorts from middle age into senescence . some , but not all , long - term follow - up studies have demonstrated a positive relationship between plasma hypercholesterolemia in midlife and rates of ad in old age . furthermore , high plasma levels of high - density lipoprotein ( hdl ) cholesterol in midlife were found to be associated with a greater load of plaques and tangles in some , but not all , studies . the simple assumption would be that , in the same way as a high blood level of cholesterol damages the vascular endothelium in the periphery , it also damages the brain vasculature , hence increasing the risk for vd . however , it is also possible that abnormal cholesterol metabolism has a direct effect on the brain not mediated by its effect on the cerebral vasculature . this is supported by data showing that brain cholesterol metabolism and transfer is at least partly independent of systemic cholesterol metabolism . the main source of brain cholesterol is de novo synthesis in the brain itself , rather than transport from plasma , which possesses a distinct set of lipoproteins . furthermore , it is assumed that the major role of the apolipoproteins implicated in ad in the brain is redistribution of cholesterol between different brain compartments rather than transfer to and from the plasma . there exist a number of hypotheses explaining the direct effect of cholesterol on the brain and on brain pathological processes . the degree of activity of the different amyloid precursor proteins ( apps ) cleaving enzymes varies according to the surrounding lipid moiety : environments richer in cholesterol promote - and -secretase , which produce insoluble amyloid plaques . furthermore , -amyloid also acts as a seed for the amyloid plaque in a lipidrich membrane . on the other hand , conditions poorer in cholesterol hence brain cholesterol metabolism has an independent , effect on amyloid plaque formation , not mediated by vascular pathology , thus potentially directly contributing to ad pathology . interestingly , recent , studies have shown a decrease in ad prevalence among patients treated with cholesterollowering drugs from the statin group . statins are compounds that inhibit hmg coa ( 3-hydroxy-3-methyl - glutaryl coenzyme a ) reductase , a enzyme central to the process of de novo cholesterol synthesis . studies have shown that statins lower the risk of developing dementia independently of their effect , on plasma lipid levels or exposure to other lipid - lowering drugs . these results suggest that statins have properties additional to their systemic lipid - lowering effect , some of which are probably associated with central nervous system ( cns ) protection . taken together , these lines of evidence suggest that , apart from its atherogenic effect , cholesterol is involved in several metabolic pathways in the brain , some of which may be relevant to the pathological process associated with plaque and tangle formation . the relationship between ad and apolipoprotein e ( apoe ) also indicates a direct role for abnormal lipoprotein metabolism on ad pathology that , is not mediated by vascular lesions . apoe ' is a protein involved in lipid transport and has three isoforms : apoe2 , apoe3 , and apoe4 . the protein 's polymorphism affects hepatic binding , uptake , and catabolism of chylomicrons , chylomicron remnants , very - low - density lipoprotein cholesterol , and subspecies of hdl cholesterol . in the brain apoe complex has a central role in neuronal repair and maintenance processes , in which apoe4 is less efficient than apoe2 and apoe3 . these differences in the efficacy of neuronal repair will not be expressed clinically in a young healthyperson with an intact brain . however , when a brain disease such as ad develops , the presence of the apoe4 isoform reduces repair efficacy , enhancing tissue and function loss . in agreement , with the theories presented above , some , but not all , population - based studies have shown the association between apoe4 allele and ad to be independent of the lipoprotein 's effect , on systemic dyslipidemia and atherogenesis . however , other data support the vascular mechanism in apoe pathology , showing that apoe4 is a risk factor for dementia with stroke - either vd or ad with stroke . neuropathological studies of ad brains demonstrated that apoe4 frequency is higher in ad brains with some kind of cerebrovascular pathology . the frequency of the apoe4 alleles was six times higher in ad brains with moderate - to - severe cerebral amyloid angiopathy , when compared with mild amyloid angiopathy , and the severity was correlated with apoe4 load ( one versus two alleles ) . diabetes , like hypercholesterolemia , is a complex systemic metabolic disorder , traditionally regarded as a risk factor for stroke and consequently for vd . diabetic patients who suffer strokes are at greater risk for subsequent dementia than nondiabetic individuals who suffer strokes . the association between ad and diabetes is supported by some , but not all , epidemiological studies . in middle - aged men followed until old age , for example , there is an association between diabetes and neuropathological finding of both ad and vd dementia . several mechanisms have been invoked to account for the direct relationship between diabetes and ad . hyperglycemia causes high levels of advanced glycation end - products ( ages ) , which have been found in high concentrations in neuritic plaques and neurofibrillary tangles . agfs have been shown to cause cross - linkage of extracellular proteins and promote aggregation of pamyloid . alternatively , insulin at high levels ( characteristic of some phases of type 2 diabetes ) could be a competitive substrate for insulin - degrading enzyme ( ide ) . this enzyme has been found to be involved in the degradation of other substrates as well as insulin , amyloid being one of them . it is thus conceivable that high insulin levels cause competitive inhibition of amyloid degradation , thus leading to less effective dissolution of seeds for amyloid plaques . also , elevated levels of blood insulin have been suggested to impair cognitive performance , leading to the hypothesis that serum insulin may alter cognitive function by affecting brain regions rich in insulin receptors , such as the hypothalamus , olfactory bulb , and hippocampus . hypertension , like diabetes , has been directly implicated in ad by epidemiological studies in which midlife hypertension was associated with greater number of neurofibrillary tangles and neuritic plaques in the hippocampus and neocortex , and a more pronounced brain atrophy compared with midlife normotensive individuals . furthermore , the association between midlife hypertension and ad remained unchanged after controlling for vascular lesions , such as large infarcts or lacunar infarcts . although hypertension exerts its deleterious effect through damage to blood vessels of all calibers and in all end organs by producing ischemia and infarcts , it is also plausible that , hypertension causes more subtle damage to very small blood vessels , which results in abnormal endothelial permeability and extravasation of plasma constituents . these , in turn , could interact with amyloid or amyloid precursor to promote plaque formation . a corollary possibility is that hypertension - induced vascular lesions , which lead to tissue ischemia , disrupt endothelial integrity . this enables interaction between plasma constituents or an effect , on amyloid , thus promoting plaque formation . white matter lesions are an additional phenomenon linking cardiovascular risk factors and ad pathology . cardiovascular risk factors , such as hypertension , diabetes , and ischemic heart , disease , have been found to be associated with white matter lesions by leading to a dysfunction of the blood - brain barrier , which , in turn , either through plasma component extravasation or brain cell reaction , promotes white matter changes . white matter lesions have been suggested to be a common finding in ad and vd , and have the same neuropathological appearance in the two disorders . it has been hypothesized that subcortical white matter lesions interact with ad pathology to produce dementia . irrespective of the mechanism involved , midlife and latelife hypertension has been demonstrated to be positively associated with dementia in old age in several , but not all , population - based studies . hyperhomocysteinemia ( higher than 14 micromolar ) , which reflects folic acid deficiency , has been associated with increased incidence of coronary artery disease , stroke , and cancer , as well as impaired cognition and dementia in some studies . however , in one study , total levels of homocysteine were associated with silent brain infarcts and white matter lesions independently of each other and of other cardiovascular risk factors . the contribution of hyperhomocysteinemia to dementia could be thus mediated by periventricular white matter lesions , which , in their severe form , were found to be independently associated with cognitive decline at a three times faster rate than average . alternatively , studies supporting the direct effect of homocysteine on ad pathology have demonstrated that homocysteine causes neurotoxicity in cultured neurons by activating n - methyl - d - aspartate ( nmda ) receptors or causing dna damage and thus triggering apoptosis . experiments in cell cultures and mouse models of ad suggest that folic acid deficiency and homocysteine impair dna repair in neurons , which exposes them to oxidative damage induced by amyloid . finally , in addition to the independent , role of promoting ad pathology , all the risk factors presented above share the ability to promote atherosclerosis . this raises the question of whether atherosclerosis itself is the final common pathway through which they are involved in the pathogenesis of ad . supporting this possibility is a population - based study of newly diagnosed demented patients , in which the frequency of ad and vd was correlated with the severity of atherosclerosis . the odds ratio for ad in those with severe atherosclerosis compared with those without was 3.0 . an alternative explanation for these results could be that dementia causes an aggravation of atherosclerosis by alteration in lifestyle and diet . the traditional characterization of ad ( an insidious and gradual progression with no focal neurological signs ) and vd ( an abrupt onset with stepwise progression and focal neurological signs ) was not . significant numbers of patients were described who had predominantly brain infarcts , but an ad - like course , and vice versa . also , the availability of advanced imaging methods lead to the recognition of diverse neuroanatomical vascular brain lesions ( thromboembolic stroke , small lacunar infarcts , and white matter lesions ) , whose implication and etiology are still debatable but are probably the result of hypoperfusion to brain tissue . it was also recognized that , many of the infarcts identified by imaging techniques or at postmortem examination are silent infarcts , which do not necessarily contribute to clinical expression in terms of focal signs or symptoms or cognitive impairment . furthermore , for some vd subtypes , namely subcortical microvascular disease , mild cognitive impairment . neuropathologically , the seminal  nun study ,  which followed 102 elderly nuns to postmortem , demonstrated that , among those who met neuropathological criteria for ad , those with brain infarcts had higher prevalence of clinically expressed dementia than those without infarcts . similarly , the complex interaction between ad and vascular pathology was demonstrated in a 3-year follow - up study of stroke patients who were not demented before the stroke . one third of the patients who developed poststroke dementia were diagnosed as suffering from ad . finally , a substantial proportion of brains who meet neuropathological criteria , for ad show lesions such as cerebral amyloid angiopathy , microvascular degeneration , periventricular white matter lesions , and other vascular pathology , further complicating the neuropathological distinction between the two disease entities . epidemiologically , it has been demonstrated that individuals affected by vascular risk factors during midlife are more likely to manifest , dementia associated with adlike brain pathology in old age . hence , it appears that most of the risk factors for cardiovascular disease , such as diabetes , hypertension , abnormal plasma cholesterol , high intake of saturated fat , thromboembolic episodes , high fibrinogen concentrations , high serum homocysteine , atrial fibrillation , smoking , alcoholism , atherosclerosis , and apolipoprotein e4 ( apoe4 ) allele , are also risk factors for ad and not exclusively for vd . therapeutically , it was recently shown that drugs enhancing cholinergic activity arc as effective in patients suffering from vd as they are in ad patients , hence eliminating the pragmatic justification for the distinction . the simple solution to the challenge brought to the distinction between ad and vd is to invoke the mixed dementia  notion , by which dementia is caused by the concomitant , presence of both ad - like pathology ( plaques and tangles ) and infarcts , which contribute to the manifestation of dementia in a cumulative fashion . this explanation has much face validity , since both ad pathology and vd pathology are age - dependent manifestations , hence the idea that they converge to manifest dementia is a plausible one . a corollary explanation is that the incidence of cardiovascular risk factors , such as diabetes and hypertension and additional constituents of the metabolic syndrome ( hyperlipidemia , central obesity ) , progressively increase after the fifth and sixth decades of life , and contribute to a pathway during the seventh and eighth decades of life leading to vd , which , together with ad - like pathology , reaches the threshold for clinical manifestation of dementia . however , the high prevalence of demented individuals whose neuropathological examination reveals both ad and vd pathology does not necessarily prove a synergetic relationship between the two types of lesions to produce dementia . it is conceivable that either the neurodegenerative or the vascular lesions do not contribute to the clinical manifestation until a certain load of pathology is reached . thus , in some patients with cooccurrence of both types of lesions , one type of lesion could be regarded as an  innocent , bystander .  indeed , the correlations between clinically diagnosed mixed dementia and neuropathological examination remain poor . a more interesting hypothesis of heuristic value would indicate that , the risk conferred by the presence of cardiovascular risk factors , such as diabetes , hypertension , or hyperlipidemia , toward ad disease is independent of the risk conferred by the same risk factors toward vd . the following paragraphs will review this possibility , provide suggestions for mechanisms by which cardiovascular risk factors contribute directly to ad pathology , and discuss possible ways for interaction and overlap between ad and vd . finally , treatment and prevention implications based on the overlap between the two pathologies will be briefly discussed . the idea that abnormal lipoprotein metabolism in general , and cholesterol in particular , affects the risk for ad derives from long - term follow - up of cohorts from middle age into senescence . some , but not all , long - term follow - up studies have demonstrated a positive relationship between plasma hypercholesterolemia in midlife and rates of ad in old age . furthermore , high plasma levels of high - density lipoprotein ( hdl ) cholesterol in midlife were found to be associated with a greater load of plaques and tangles in some , but not all , studies . the simple assumption would be that , in the same way as a high blood level of cholesterol damages the vascular endothelium in the periphery , it also damages the brain vasculature , hence increasing the risk for vd . however , it is also possible that abnormal cholesterol metabolism has a direct effect on the brain not mediated by its effect on the cerebral vasculature . this is supported by data showing that brain cholesterol metabolism and transfer is at least partly independent of systemic cholesterol metabolism . the main source of brain cholesterol is de novo synthesis in the brain itself , rather than transport from plasma , which possesses a distinct set of lipoproteins . furthermore , it is assumed that the major role of the apolipoproteins implicated in ad in the brain is redistribution of cholesterol between different brain compartments rather than transfer to and from the plasma . there exist a number of hypotheses explaining the direct effect of cholesterol on the brain and on brain pathological processes . the degree of activity of the different amyloid precursor proteins ( apps ) cleaving enzymes varies according to the surrounding lipid moiety : environments richer in cholesterol promote - and -secretase , which produce insoluble amyloid plaques . furthermore , -amyloid also acts as a seed for the amyloid plaque in a lipidrich membrane . on the other hand , conditions poorer in cholesterol promote -secretase activity , which docs not create plaques . hence brain cholesterol metabolism has an independent , effect on amyloid plaque formation , not mediated by vascular pathology , thus potentially directly contributing to ad pathology . interestingly , recent , studies have shown a decrease in ad prevalence among patients treated with cholesterollowering drugs from the statin group . statins are compounds that inhibit hmg coa ( 3-hydroxy-3-methyl - glutaryl coenzyme a ) reductase , a enzyme central to the process of de novo cholesterol synthesis . studies have shown that statins lower the risk of developing dementia independently of their effect , on plasma lipid levels or exposure to other lipid - lowering drugs . these results suggest that statins have properties additional to their systemic lipid - lowering effect , some of which are probably associated with central nervous system ( cns ) protection . taken together , these lines of evidence suggest that , apart from its atherogenic effect , cholesterol is involved in several metabolic pathways in the brain , some of which may be relevant to the pathological process associated with plaque and tangle formation . the relationship between ad and apolipoprotein e ( apoe ) also indicates a direct role for abnormal lipoprotein metabolism on ad pathology that , is not mediated by vascular lesions . apoe ' is a protein involved in lipid transport and has three isoforms : apoe2 , apoe3 , and apoe4 . the protein 's polymorphism affects hepatic binding , uptake , and catabolism of chylomicrons , chylomicron remnants , very - low - density lipoprotein cholesterol , and subspecies of hdl cholesterol . in the brain apoe complex has a central role in neuronal repair and maintenance processes , in which apoe4 is less efficient than apoe2 and apoe3 . these differences in the efficacy of neuronal repair will not be expressed clinically in a young healthyperson with an intact brain . however , when a brain disease such as ad develops , the presence of the apoe4 isoform reduces repair efficacy , enhancing tissue and function loss . in agreement , with the theories presented above , some , but not all , population - based studies have shown the association between apoe4 allele and ad to be independent of the lipoprotein 's effect , on systemic dyslipidemia and atherogenesis . however , other data support the vascular mechanism in apoe pathology , showing that apoe4 is a risk factor for dementia with stroke - either vd or ad with stroke . neuropathological studies of ad brains demonstrated that apoe4 frequency is higher in ad brains with some kind of cerebrovascular pathology . the frequency of the apoe4 alleles was six times higher in ad brains with moderate - to - severe cerebral amyloid angiopathy , when compared with mild amyloid angiopathy , and the severity was correlated with apoe4 load ( one versus two alleles ) . diabetes , like hypercholesterolemia , is a complex systemic metabolic disorder , traditionally regarded as a risk factor for stroke and consequently for vd . diabetic patients who suffer strokes are at greater risk for subsequent dementia than nondiabetic individuals who suffer strokes . the association between ad and diabetes is supported by some , but not all , epidemiological studies . in middle - aged men followed until old age , for example , there is an association between diabetes and neuropathological finding of both ad and vd dementia . several mechanisms have been invoked to account for the direct relationship between diabetes and ad . hyperglycemia causes high levels of advanced glycation end - products ( ages ) , which have been found in high concentrations in neuritic plaques and neurofibrillary tangles . agfs have been shown to cause cross - linkage of extracellular proteins and promote aggregation of pamyloid . alternatively , insulin at high levels ( characteristic of some phases of type 2 diabetes ) could be a competitive substrate for insulin - degrading enzyme ( ide ) . this enzyme has been found to be involved in the degradation of other substrates as well as insulin , amyloid being one of them . it is thus conceivable that high insulin levels cause competitive inhibition of amyloid degradation , thus leading to less effective dissolution of seeds for amyloid plaques . also , elevated levels of blood insulin have been suggested to impair cognitive performance , leading to the hypothesis that serum insulin may alter cognitive function by affecting brain regions rich in insulin receptors , such as the hypothalamus , olfactory bulb , and hippocampus . hypertension , like diabetes , has been directly implicated in ad by epidemiological studies in which midlife hypertension was associated with greater number of neurofibrillary tangles and neuritic plaques in the hippocampus and neocortex , and a more pronounced brain atrophy compared with midlife normotensive individuals . furthermore , the association between midlife hypertension and ad remained unchanged after controlling for vascular lesions , such as large infarcts or lacunar infarcts . although hypertension exerts its deleterious effect through damage to blood vessels of all calibers and in all end organs by producing ischemia and infarcts , it is also plausible that , hypertension causes more subtle damage to very small blood vessels , which results in abnormal endothelial permeability and extravasation of plasma constituents . these , in turn , could interact with amyloid or amyloid precursor to promote plaque formation . a corollary possibility is that hypertension - induced vascular lesions , which lead to tissue ischemia , disrupt endothelial integrity . this enables interaction between plasma constituents or an effect , on amyloid , thus promoting plaque formation . cardiovascular risk factors , such as hypertension , diabetes , and ischemic heart , disease , have been found to be associated with white matter lesions by leading to a dysfunction of the blood - brain barrier , which , in turn , either through plasma component extravasation or brain cell reaction , promotes white matter changes . white matter lesions have been suggested to be a common finding in ad and vd , and have the same neuropathological appearance in the two disorders . it has been hypothesized that subcortical white matter lesions interact with ad pathology to produce dementia . irrespective of the mechanism involved , midlife and latelife hypertension has been demonstrated to be positively associated with dementia in old age in several , but not all , population - based studies . hyperhomocysteinemia ( higher than 14 micromolar ) , which reflects folic acid deficiency , has been associated with increased incidence of coronary artery disease , stroke , and cancer , as well as impaired cognition and dementia in some studies . however , in one study , total levels of homocysteine were associated with silent brain infarcts and white matter lesions independently of each other and of other cardiovascular risk factors . the contribution of hyperhomocysteinemia to dementia could be thus mediated by periventricular white matter lesions , which , in their severe form , were found to be independently associated with cognitive decline at a three times faster rate than average . alternatively , studies supporting the direct effect of homocysteine on ad pathology have demonstrated that homocysteine causes neurotoxicity in cultured neurons by activating n - methyl - d - aspartate ( nmda ) receptors or causing dna damage and thus triggering apoptosis . experiments in cell cultures and mouse models of ad suggest that folic acid deficiency and homocysteine impair dna repair in neurons , which exposes them to oxidative damage induced by amyloid . finally , in addition to the independent , role of promoting ad pathology , all the risk factors presented above share the ability to promote atherosclerosis . this raises the question of whether atherosclerosis itself is the final common pathway through which they are involved in the pathogenesis of ad . supporting this possibility is a population - based study of newly diagnosed demented patients , in which the frequency of ad and vd was correlated with the severity of atherosclerosis . the odds ratio for ad in those with severe atherosclerosis compared with those without was 3.0 . an alternative explanation for these results could be that dementia causes an aggravation of atherosclerosis by alteration in lifestyle and diet . the data presented above lend themselves to several interpretations . it is possible that , pure  neurohistological vascular or  pure  plaques and/or tangles dementias constitute the extreme and rare end of a continuous process . in fact , a significant proportion of dementia cases present vascular lesions upon neurohistological examination - the location , extent , and clinical implications of which depend on the damaged vessel , and the insidious formation of plaques and tangles . the cooccurrence of two pathological processes acting in parallel damages brain tissue , which , in turn , leads to a threshold of brain dysfunction viewed as clinical symptoms . it is thus conceivable that cerebrovascular damage is caused in individuals affected in midlife by vascular risk factors , which later joins progressive and age - dependent formation of amyloid plaques , thus damaging brain tissue and being expressed as dementia . conceptually , this would not be different , from other aging processes leading to organ failure via several , concomitant processes , such as cardiac failure due to coronary ischemia and valvulopathy , or leading to functional failure , such as visual failure due to concomitant cataract and retinopathy . alternatively , rather than comorbidity of vd and adtype dementia , part of the ad pathological pathway could involve a vascular component , in which impairment of blood - brain barrier leads to disruption of selective permeability ( by altering endothelial functioning ) , which , in turn , stimulates plaque and tangle formation . an additional option for the conceptualization of the role of risk factors discussed above , and of other risk factors in ad , is that ad is a complex , multifactorial disease . at various points of the pathway towards amyloid plaque and neurofibrillary tangle formation , different contributing factors could pose their effect : the lipid milieu of the neuronal membrane could contribute to enhancement of app - cleaving enzymes ( - and -secretase ) leading to insoluble products ; hypcrinsulinemia could compete with amyloid for ide and thus enable less dissolution of amyloid , competitive inhibition of amyloiddegrading enzyme , and promotion of cross - linkage of extracellular proteins by age ; and the presence of the apoe4 allele could be less effective in neuronal repair when disease processes exist . thus , every risk factor discussed above could contribute to a different phase of plaque formation or consolidation . although this theory provides an opportunity for an integrative conceptualization regarding the role of the various risk factors involved in the ad pathway , we are aware of the fact that it is still speculative in nature and demands further evidence . because some of the cardiovascular risk factors are modifiable , investigating the mechanisms by which they contribute to ad pathology and the manifestation of dementia has implications in prevention . this is particularly interesting , since in other multifactorial diseases , such as stroke , coronary heart , disease , and colon cancer , modifiable environmental factors such as diet , physical activity , and smoking may account for over half of the variability leading to the disease . not surprising therefore are studies demonstrating that physical and total activity in midlife , diet , and mild - to - moderate alcohol consumption are protective against ad . however , these data should be seen with caution since there are not enough prospective studies to set clear guidelines regarding the medical and nonmedical strategies for dementia prevention or delay .
advances in epidemiological , clinical , imaging , and neuropathological studies have undermined the clear distinction between vascular and alzheimer - type dementia , which has characterized the last two decades of research in dementia . 
 a significant degree of overlap between the two entities was demonstrated in terms of clinical expression , risk factors , and postmortem brain autopsy . in this article , we propose mechanisms by which cardiovascular risk factors might affect the manifestation of alzheimer 's disease , suggest possible explanations for the overlap with vascular dementia , and discuss the implications this might have on future differential diagnosis and treatment strategies .