ad is a progressive and invariably fatal neurodegenerative disease 
 and the leading cause of senile dementia .  

metabolic imbalance in diseased 
 neurons may contribute to neuropsychiatric symptoms that include 
 delusions and hallucinations , anxiety , mood disorder , and sleep 
 disturbance that are common in ad . 

recently we proposed a hypothesis that explains 
 why elevated plasma homocysteine is a risk factor for ad 
 [ 4 , 5 ] . 

implicit in that hypothesis is development of neuronal 
 heme deficiency , and evidence of heme deficiency in ad brains has 
 been reported . 
 here , we extend this theme by considering 
 the possible impact of porphyria on ad .
the porphyrias are 
 metabolic disorders characterized by enzyme deficiencies in the 
 heme biosynthesis pathway .
we propose that an understanding of 
 porphyria may provide novel insights into ad pathogenesis .
molecular and biochemical aspects of the porphyrias and their 
 diagnosis and treatment are the subject of several excellent 
 reviews [ 713 ] .
eight enzymes are required for 
 de novo heme biosynthesis . with the exception of 
 5-aminolevulinic acid synthase [ alas , ec 2.3.1.37 ]
, the initial 
 and rate - limiting enzyme of the heme biosynthesis pathway , 
 deficiency in one of the other seven enzymes is associated with a 
 specific form of inherited porphyria .
four of the 
 hepatic porphyrias , so - called because liver is the major site of 
 expression of the enzymatic defect in heme biosynthesis , are 
 designated  acute  porphyrias because clinical expression of the 
 disease is associated with an acute neurologic syndrome ( the acute 
 attack or porphyric crisis ) [ 8 , 
 11 ] .
these are the extremely 
 rare doss porphyria ( deficiency of ala dehydratase , ec 4.2.1.24 ) , 
 acute intermittent porphyria ( deficiency of porphobilinogen 
 deaminase , ec 4.3.1.8 ) , hereditary coproporphyria ( deficiency of 
 coproporphyrinogen oxidase , ec 1.3.3.3 ) , and variegate porphyria 
 ( deficiency of protoporphyrinogen oxidase , ec 1.3.3.4 ) .
acute 
 intermittent porphyria is generally the most common form of acute 
 hepatic porphyria encountered .
significantly , enzyme deficiencies 
 are present in other organs , including the brain , and the enzyme 
 deficiency is life - long .
acute neurologic syndrome associated with clinical attacks of 
 acute hepatic porphyria can include both neuropsychiatric symptoms 
 and neurodegenerative change [ 8 , 
 11 , 12 ] . 

neuropsychiatric symptoms that include anxiety , insomnia , confusion , 
 hallucinations , agitation , and paranoia ( so - called porphyric 
 encephalopathy-8 ) underscore cns involvement .
autonomic neuropathy 
 may underlie severe abdominal pain and cardiovascular symptoms . in 
 severe cases ,
a peripheral neuropathy resembling guillain - barre 
 syndrome can develop [ 8 , 
 11 ] .
clinical attacks of acute 
 porphyria can be induced in latent individuals by a variety of 
 environmental factors including many common medications , 
 nutritional factors , restricted carbohydrate and calorie intake , 
 smoking , and hormones such as progesterone ; lists of safe and 
 unsafe drugs are available [ 9 , 
 11 , 12 ] . 
 a common mechanism of inducing agents is believed to be greatly increased hepatic heme 
 demand .
thus , biosynthesis of cytochrome p450 enzymes that utilize 
 heme as a prosthetic group can be induced as much as 4050-fold 
 in liver by drugs such as barbiturates . 

increased heme demand results in the induction of alas and increased synthesis of 
 the heme precursor , 5-aminolevulinic acid [ ala ] . in individuals 
 who have inherited a partial deficiency in one of the enzymes of 
 the heme biosynthesis pathway , that enzyme and not alas
then , ala and other heme 
 precursors can accumulate . moreover , heme biosynthesis is 
 insufficient to meet demand and heme deficiency is unresolved . 

acute attacks are treated with infusions of glucose and hemin 
 [ 9 , 12 ] . 

this 
 suppresses hepatic alas induction and the overproduction of ala 
 and other heme precursors .
fasting , which can induce the acute 
 attack , appears to activate transcriptional coactivator 
 pgc-1 ( via a camp / creb pathway ) and pgc-1 greatly increases hepatic alas expression by activating transcription 
 factors nrf-1 and foxo1 [ 14 , 
 15 ] .
in addition , alas may 
 respond directly to camp [ 14 , 
 15 ] .
abdominal pain and psychotic symptoms 
 resolve quickly upon timely treatment of the acute attack but 
 peripheral neuropathy can require months to resolve and recovery 
 is often incomplete .
one suggests functional heme deficiency develops during the acute 
 attack , in liver and possibly in neural tissues , and impairs 
 critical cell processes dependent on hemoproteins such as energy 
 production by the mitochondrial electron transport chain .
studies 
 utilizing mice deficient in porphobilinogen deaminase , an 
 experimental model of acute intermittent porphyria , underscore the 
 importance of functional heme deficiency in nervous tissue in the 
 development of motor neuropathy [ 1618 ] . 

the second hypothesis suggests that heme precursors and their metabolites 
 accumulate to toxic levels during the acute attack .
ala , in 
 particular , is implicated because it is produced excessively in 
 all the acute hepatic porphyrias and may have neurotoxic 
 properties [ 8 , 
 11 ] .
excessive ala production occurs in lead 
 poisoning due to lead - mediated inhibition of ala dehydratase , and 
 also in hereditary infantile tyrosinemia ( type i ) in which the 
 enzyme defect leads to endogenous production of the ala 
 dehydratase inhibitor , succinylacetone . in both 
 diseases , neuropsychiatric symptoms that resemble
while recent clinical studies 
 underscore the potential importance of excessive hepatic 
 production of heme precursors as the primary cause of the 
 neurologic complications in the acute porphyric attack 
 [ 20 , 21 ] , 
 induced elevation of plasma ala in a human 
 volunteer , by itself , did not produce symptoms of porphyria 
 .
we hypothesize that heme deficiency is important in ad 
 pathogenesis and that ad may differ significantly in individuals 
 possessing the genetic trait for an acute hepatic porphyria 
 because there is the potential to develop more severe heme 
 deficiency .
ad - related factors may create an imbalance in neuronal heme supply 
 and demand . in ad , heme supply may be reduced .
aging is the 
 greatest risk factor for development of ad , and at least in rat 
 brain , heme biosynthesis declines in normal aging . 

pyridoxine deficiency in 
 the aged could contribute to age - related decrease in heme 
 biosynthesis because pyridoxal phosphate is a cofactor for alas 
 .
glycoxidation reactions 
 are prominent in ad brain , 
 and glycoxidation reactions might inactivate enzymes 
 required for heme biosynthesis . 

moreover , heme biosynthesis requires mitochondrial integrity and mitochondrial 
 damage is prominent in ad . 
 in ad , heme demand may be increased .
mitochondrial damage would necessitate increased 
 mitochondrial turnover and de novo synthesis of 
 heme - containing proteins such as cytochromes . moreover
, 
 mitochondrial damage may itself be caused by heme deficiency 
 [ 29 , 30 ] 
 thus creating a vicious cycle further impairing heme 
 biosynthesis .
heme degradation may be favored over heme 
 biosynthesis in ad neurons because of chronically elevated ho-1 
 [ 32 , 33 ] . 

thus , amyloid- [ a ] binds heme , which may 
 contribute to development of a functional heme deficiency 
 and affect a toxicity by inhibiting a aggregation [ 34 , 
 35 ] .
we speculate that the reduced 
 capacity to synthesize heme in individuals with porphyria could exacerbate such an 
 imbalance in heme supply and demand .
in addition , the two proposed mechanisms of nervous system 
 dysfunction in the acute porphyric attack , functional heme 
 deficiency and toxic accumulation of ala , have cellular effects 
 that could be important in ad pathogenesis . inhibition of heme 
 biosynthesis produced senescence - associated changes in gene 
 expression in cultured mouse cortical neurons  
 and was proapoptotic in ngf - induced pc12 cells 
 . increased 
 oxidative stress , which is one of the earliest observed events in 
 ad pathogenesis , 
 and heme deficiency may help explain 
 several pathophysiological features of ad including mitochondrial 
 abnormalities and impaired energy metabolism , cell cycling and 
 cell signaling abnormalities , neuritic pathology , and abnormal 
 expression of iron regulatory protein 2 ( irp2 ) . 

ala is a source of oxygen free radicals in the presence of heavy metals 
 such as iron . 

the product of iron - catalyzed oxidation of 
 ala , 4 , 5-dioxovaleric acid , is an effective alkylating agent of 
 guanine moieties in dna in vitro 
 [ 40 , 41 ] , 
 and ala - induced mitochondrial and nuclear dna damage has been shown in 
 several cell lines including pc12 cells . 

it released 
 iron from ferritin in vitro [ 43 , 
 44 ] and caused 
 oxidative damage to the ferritin molecule . 

as in the toxic mechanism proposed for homocysteine in ad pathogenesis 
 [ 4 , 5 ] , 
 ala may make available a catalytic metal that can 
 promote oxidative stress .
clinically overt acute hepatic porphyria ( predominantly acute 
 intermittent porphyria ) is relatively rare with a prevalence of 
 perhaps 5 per 100,000 .
however , the prevalence of the 
 genetic trait for acute porphyria is far greater because perhaps 
 90% of affected individuals are clinically latent 
 [ 7 , 12 ] . in 
 a finnish population
the estimated prevalence of porphobilinogen 
 deaminase deficiency , the biochemical defect in acute intermittent 
 porphyria , was 1 per 500 . 

using gene analysis to 
 supplement enzymatic analysis , the estimated prevalence of 
 porphobilinogen deaminase deficiency in a french population was 1 
 per 1675 .
consistent with the possibility that 
 deficiency in heme biosynthesis could increase susceptibility for 
 ad is the intriguing observation that the chromosomal location of 
 genes encoding enzymes in the heme biosynthesis pathway correlate 
 with genetic loci linked to sporadic , late - onset alzheimer 's 
 disease ( maximum lod score  1 ) 
 ( table 1 ) .
however , the significance of this 
 observation is unclear . in cases such as deficiency in 
 porphobilinogen deaminase , heme deficiency alone
may be 
 insufficient to cause ad but could contribute to disease 
 progression when superimposed on other disease processes . however , 
 effects may be indirect and not related to heme levels . for 
 example , the proximity of the ala dehydratase gene to an 
 ad - related locus is noted in table 1 .
ala 
 dehydratase - porphyria is an extremely rare form of acute hepatic 
 porphyria .
moreover , ala dehydratase activity is far in excess of 
 the activities of other enzymes in the heme biosynthetic pathway 
 and for that reason > 95% loss of activity is needed before 
 clinical symptoms of porphyria develop . 
 however , ala dehydratase is also a high km enzyme . under 
 ad - associated conditions , toxic levels of ala
may possibly 
 accumulate and contribute to ad pathogenesis . while 
 interesting , any relationship between heme deficiency and ad is 
 speculative .
if the genetic trait for one of the acute hepatic 
 porphyrias is a risk factor for ad , why has this relationship gone 
 unnoticed ?
the answer simply may be that the majority of 
 individuals with the biochemical defects of acute porphyria are 
 clinically latent , and that many genetic and environmental factors 
 likely contribute to the development of sporadic , late - onset ad .
ad may differ significantly in individuals who have the genetic 
 trait for acute hepatic porphyria because there is the potential 
 to develop more severe neuronal heme deficiency and possibly 
 accumulate ala and other heme precursors .
epidemiological data 
 confirming a link between ad and porphyria would be an important 
 test of the hypothesis .
ad progression ( from disease - free state , 
 to mild cognitive impairment , to ad ) in individuals with a genetic 
 trait for acute hepatic porphyria could be compared with ad 
 progression in an unaffected cohort .
testing for the presence of a 
 genetic trait for acute porphyria in individuals diagnosed with 
 mild cognitive impairment or early ad might identify a unique 
 subset of ad patients .
management decisions may need to be 
 adjusted in such individuals to avoid potential sensitivity to 
 common medications and novel therapeutic agents which , if 
 porphyrinogenic , could exacerbate porphyria and possibly ad 
 symptoms . approaches such as these could yield significant new 
 information on ad pathogenesis and treatment .
ad and porphyria . oxidative stress and free radical 
 damage occur early in ad . 

a consequence of oxidative stress predicted by the ferric cycle 
 hypothesis is heme deficiency [ 4 , 
 5 ] .
moreover , ad - related 
 factors such as accumulation of amyloid- may limit heme 
 bioavailability . 

we hypothesize that reduced capacity for 
 cells to synthesize heme , in individuals with the genetic trait 
 for acute hepatic porphyria , contributes to development of heme 
 deficiency ( and possibly oxidative stress ) .
ad - related 
 pathological change and neuropsychiatric and behavioral symptoms 
 associated with ad may be more severe in these individuals .
chromosomal locations of genes encoding enzymes of the 
 heme biosynthesis pathway and genes linked to development of 
 late - onset alzheimer 's disease .   from meissner et al .  
 mechanisms that cause alzheimer 's disease ( ad ) , an invariably 
 fatal neurodegenerative disease , are unknown . 
 important recent 
 data indicate that neuronal heme deficiency may 
 contribute to ad pathogenesis . 
 if true , factors that contribute to 
 the intracellular heme deficiency could potentially alter the 
 course of ad . 
 the porphyrias are metabolic disorders characterized 
 by enzyme deficiencies in the heme biosynthetic pathway . 
 we 
 hypothesize that ad may differ significantly in individuals 
 possessing the genetic trait for an acute hepatic porphyria .   
 we 
 elaborate on this hypothesis and briefly review the 
 characteristics of the acute hepatic porphyrias that may be 
 relevant to ad . 
 we note the proximity of genes encoding enzymes of 
 the heme biosynthesis pathway to genetic loci linked to sporadic , 
 late - onset ad . 
 in addition , we suggest that identification of 
 individuals carrying the genetic trait for acute porphyria may 
 provide a unique resource for investigating ad pathogenesis and 
 inform treatment and management decisions . 
INTRODUCTION
GENERAL CONSIDERATIONS
DOES PORPHYRIA OFFER INSIGHT ON AD?
DOES PORPHYRIA INCREASE THE RISK OF AD?
CONCLUSIONS
Figures and Tables