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Familial Alzheimer disease

Familial Alzheimer's disease (FAD) is an uncommon form of Alzheimer's disease that comes on earlier in life (usually between 30 and 60 years of age) and is inherited in an autosomal dominant fashion. While it only accounts for 5% or less of total Alzheimer's disease, it has presented a useful model in studying various aspects of the disorder. more...

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Familial Alzheimer disease

Clinical features

Alzheimer disease (AD) is the most common form of dementia. It usually occurs in old age, and starts gradually with early signs being forgetfulness, particularly in remembering recent events and the names of people and things. There may be some other cognitive difficulties early on, but nothing overly alarming.

As the disease progresses, the patient may start to exhibit greater problems. They may forget how to do simple things such as brushing their hair, and later in the disease may become anxious or aggressive, ultimately needing full-time care.

Familial Alzheimer disease is an uncommon form of Alzheimer's that comes on earlier in life (usually between 30 and 60 years) and is inherited in an autosomal dominant fashion. There are a number of types of familial (or early-onset) AD, which are identified by their genetics and other characteristics such as the age of onset. As a whole, this form of the disease only accounts for roughly 10% to 15% of all cases of AD.

Histologically, familial AD is practically indistinguishable from other forms of the disease. Deposits of amyloid can be seen in sections brain tissue (visible as an apple-green yellow birefringence under polarised light). This amyloid protein forms plaques and neurofibrillary tangles that progress through the memory centres of the brain. Very rarely the plaque may be unique, or uncharacteristic of AD; this can happen when there is a mutation in one of the genes that creates a functional, but malformed, protein instead of the ineffective gene products that usually result from mutations.

Genetic causes and mutations

There are multiple genetic causes of Alzheimer disease. Two of these are the presenilin polymorphisms on chromosomes 1 and 14, Others include several amyloid precursor protein polymorphisms and one of the four common alleles of apolipoprotein E. Several other gene polymorphisms have also been identified to increase susceptibility to Alzheimer's.

PSEN1 - Presenilin 1

The presenilin 1 gene (PSEN1) was linked to the long arm of chromosome 14 (14q24.3) using a pedigree of 34 people suffering from early-onset Alzheimer disease by Campion (1995). The actual gene was identified by Sherrington (1995) to be PSEN1, and multiple mutations were identified. Mutations in this gene cause familial Alzheimer's type 3. This protein has been identified as part of the enzymatic complex that cleaves amyloid beta peptide from APP (see below).

The gene contains 14 exons, and the coding portion is estimated at 60 kb, as reported by Rogaev (1997) and Del-Favero (1999). The protein the gene codes for (PS1) is an integral membrane protein. As stated by Ikeuchi (2002) it cleaves the protein Notch1 so is thought by Koizumi (2001) to have a role in somitogenesis in the embryo. It also has an action on an amyloid precursor protein, which gives its probable role in the pathogenesis of FAD. Homologs of PS1 have been found in plants, invertebrates and other vertebrates.


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Familial Alzheimer's disease and vitamin B12 deficiency
From Age and Ageing, 7/1/94 by A. McCaddon


A kindred with autosomal dominant familial Alzheimer's disease in which a mutation results in a valine to glycine substitution at amyloid precursor protein codon 717 has recently been described. Individuals in this pedigree were studied retrospectively and prospectively, to evaluate the relationship, if any, between Alzheimer's disease and vitamin [B.sub.12] deficiency. The presence of Alzheimer's disease was found to be associated with lower serum vitamin [B.sub.12] values compared with unaffected family members. There were no significant differences between macrocytosis, the presence of anaemia, serum folate or red cell folate between affected and unaffected family members. The implications of this finding are discussed with regard to previous descriptions of an association, and in relation to the clinical features of this particular kindred.


Recent reports suggest that an association may exist between Alzheimer's disease (AD) and vitamin [B.sub.12] deficiency(1)(2)(3)(4)(5)(6)(7). [B.sub.12] levels have been found to be lower in patients with AD than in patients with multi-infarct dementia and this deficiency appears to be independent of nutritional intake(4). One possible criticism of this relationship, however, is that AD is essentially a histopathological diagnosis, and patients with Alzheimertype dementia and low [B.sub.12] may represent a previously undetected sub-group of patients with AD.

Familial Alzheimer's disease (FAD) is a better model to study this association further, since affected patients conform to the NINCDS/ADRDA criteria for definite AD(8). Three distinct point mutations have now been found in the amyloid precursor protein gene at codon 717 that co-segregate with affected individuals in chromosome 21 linked families(9)(10)(11). One such kindred has been well documented with regard to the clinical features of the disease(12). The diagnosis has also been confirmed histopathologically in one individual(13). The index case in this family was noted to have a profound [B.sub.12] deficiency at initial presentation, which prompted us to review the records of affected family members for evidence of [B.sub.12] deficiency. In addition, it was possible to obtain blood samples from other affected and unaffected members after obtaining informed consent. These were assayed for routine haematological indices, serum [B.sub.12], serum folate, and red cell folate. The aims were to assess the degree of correlation, if any, between the presence of AD and levels of serum [B.sub.12] in order to explore further the validity of an association between the two diseases.

Material and Methods

A genealogical history was constructed from available medical records with the assistance of the patients' family. Records of affected siblings were obtained, where possible, and reviewed for documented evidence of cognitive impairment, relevant investigations including assay of [B.sub.12] and folate, and evidence of a formal diagnosis of Alzheimer's disease.

Blood samples were taken from affected and unaffected individuals after obtaining informed consent. In the case of affected subjects consent was also obtained from the next of kin. All samples were taken within a 2-month period in 1991 under the auspices of the Alzheimer Disease Research Group, London, who kindly agreed to provide serum for this study. Cognitive impairment was assessed using the Mini-Mental State Examination(14), and some members of the family were offered a more detailed clinical and neuro-psychological examination by the Research Group, St Mary's Hospital London, the results of which are presented elsewhere(12). Samples were analysed by Coulter counter for routine haematological indices. Serum [B.sub.12], serum folate, and red cell folate were assayed by radio-immunoassay.

Results were divided into two main groups, confirmed Alzheimer's Disease (group 1) and unaffected family members (group 2). The second group included both unaffected family members (generation III) and 'at risk' members (generation IV). The 'at risk' members are not depicted for ethical reasons. In view of the inevitably small sample sizes, results were analysed using Student's t test.


The genealogical chart is shown in the Figure. Haemoglobin (Hb), haematocrit (Hct), mean corpuscular volume (MCV), serum [B.sub.12] ([B.sub.12]), serum folate (fol), and red cell folate (RCF) for the two groups are presented in Tables I and II. The Tables are incomplete owing to difficulty in obtaining medical records, lack of measuring or recording of [B.sub.12] values in the records of affected members, or reluctance to donate blood samples.


Table I. Group 1: confirmed AD

(*)Reported as normal but no value stated in notes.

Table II. Group 2: unaffected and 'at risk' patients

(*)'At risk' (generation IV) patients.

It can be seen that four out of six of the subjects with confirmed AD in whom it was measured have low [B.sub.12] values, compared with only one of the unaffected at risk relatives. The mean [B.sub.12] for group 1 is 196, and is only 137.5 when the outlying value of 430 is excluded. The mean [B.sub.12] for group 2 is 306.9. Results for mean [B.sub.12] values for these two groups were analysed by Student's t test, both with and without the outlying value of 430 in group 1. A statistically significant difference was found when the outlying value was excluded (p < 0.001). Significance fell to (p < 0.08) when this value was included.

No [B.sub.12]-deficient subject was anaemic, and only one had evidence of a macrocytosis (Index case, III.14). No significant differences were found between Hb, Hct, and MCV values for the two groups. Mean serum folate was not significantly diferent between the groups. RCF is a more reliable guide to folate status, but was impossible to compare between the groups as RCF had not been evaluated in older patients.


These data require cautious interpretation for several reasons. Statistical significance of the results may not be valid in view of the unavoidably small sample sizes. Retrospective appraisal of medical records is often unreliable for obvious reasons. Furthermore, older microbiological assays for [B.sub.12] do not completely correspond to modern radio-immunoassay techniques. Given these constraints however, there does appear to be an association between AD and low [B.sub.12] values. This correlates with earlier reports of low serum [B.sub.12] in AD (1)(2)(3)(4)(5)(6), and more recently, low cerebrospinal fluid [B.sub.12] in AD (6)(7).

The previous accounts are open to criticism. As no confirmatory tissue diagnosis of AD was made, they may simply represent a hitherto unrecognized prevalence of [B.sub.12] deficiency encephalopathy, rather than constituting a subset of AD patients with [B.sub.12] deficiency. In this study of FAD, however, affected subjects fulfil the NINCDS/ADRDA criteria of definite AD by virtue of histopathological confirmation in an affected relative(8). Furthermore, this family has an undoubtedly pathogenic mutation in the amyloid precursor protein gene resulting in a valine to glycine substitution at APP 717 which co-segregates with the disease. A genuine association therefore exists in this pedigree between AD pathology and [B.sub.12] deficiency.

The exact nature of this association remains unclear, but a number of possibilities have been proposed(3):

1. [B.sub.12] deficiency occurs secondary to impaired dietary intake in AD. However, [B.sub.12] deficiency has been shown to occur independently of nutritional intake (4).

2. Development of dementia may be secondary to impaired intake of other essential nutrients associated with [B.sub.12] malabsorption.

3. Patients may have a tendency to develop both AD and [B.sub.12] deficiency, although the nature of such an association is, at present, unclear.

The underlying cause of the deficit in this particular kindred requires further investigation, but the presence of a pathogenic mutation at codon 717 of APP suggests a novel and intriguing possibility. It has been suggested that proteolysis on either side of the beta-amyloid region of APP is enhanced by these mutations(11). One possible consequence of aberrant proteolytic processing of APP could be the release of alpha-1-antichymotrypsin (ACT), a powerful inhibitor of trypsin and chymotrypsin(15). ACT has been found to be elevated in sera of patients with AD(16). Pancreatic proteolytic enzymes, in particular trypsin, are necessary for optimal [B.sub.12] absorption(17), and it has been suggested that pancreatic dysfunction could be responsible for some cases of impaired protein-bound [B.sub.12] absorption(18). Interestingly, patients with impaired protein-bound [B.sub.12] absorption are frequently reported as being demented or confused(18)(19)(20). There has also been one report of demonstrable impaired protein-bound [B.sub.12] absorption in three patients with a diagnosis of AD(21). Whether elevated ACT secondary to aberrant APP processing is the cause of the [B.sub.12] deficiency in this particular family remains to be seen. Only the index patient (III.14) has had a Schilling test to date. This was found to be normal. A modified Schilling test(22), to detect protein-bound [B.sub.12] absorption, had not been performed.

It is also conceivable that any subsequent [B.sub.12] deficiency per se could subsequently contribute to some of the features of AD. Models have been proposed extrapolating the wealth of data regarding the haematological effects of [B.sub.12] deficiency to the nervous system which may account for a possible underlying mechanism (23)(24). Essentially it has been proposed that [B.sub.12] deficiency results in impaired methylation reactions in the central nervous system owing to a reduced supply of S-adenosyl methionine (SAM). SAM provides methyl groups for the conversion of phosphatidylethanolamine to phosphatidylcholine (PC). PC can act as a source of choline for the synthesis of acetylcholine. [B.sub.12] deficiency could therefore theoretically result in the characteristic cholinergic deficit of AD. Recently a pronounced deficit of SAM in CSF of AD patients has been demonstrated, as predicted by such a hypothesis(25).

It has also been proposed that [B.sub.12] deficiency could account for a monoaminergic deficit via impaired biosynthesis of biopterin(23). It is therefore interesting in this regard that depression is a common feature in this particular pedigree(12). Furthermore, myoclonic jerks and seizures were also commonly observed in this kindred(12), and severe myoclonic epilepsy is a feature of many cases of biopterin deficiency(26).

Several other important points are raised by these results. During the study it was noted that longitudinal evaluation of [B.sub.12] status in AD patients is important, as two of the affected patients with [B.sub.12] deficiency had documented evidence of normal [B.sub.12] levels in the early stages of the disease process (III.15, III.16)(12). This does not preclude the possibility of a contributory role for [B.sub.12] in AD however, as [B.sub.12] deficiency may take many months to develop, and newer models suggest that metabolic abnormalities may precede a decline in serum [B.sub.12] levels(27). Homocysteine (and transcobalamin II saturation) would be more reliable indicators of early [B.sub.12] deficient states(27)(28).

There have been no previous specific reports of [B.sub.12] deficiency in FAD, but some epidemiological studies have suggested an association with auto-immune disorders, including pernicious anaemia(29).

Finally, this study highlights the importance of recognizing that [B.sub.12] deficiency may not always present with a macrocytosis or anaemia(30). Indeed, disorientation and confusion are a common manifestation of such subtle deficiencies(31).


We would like to thank all members of the family for their assistance and co-operation during this study, and Dr P. C. Taylor, Mary McKeon, Jane Baker, and Linda Roberts for additional help in the preparation of this article. We would also like to thank Angus Kennedy, Penelope Roques, Martin Rossor and all other members of the Alzheimer Disease Research Group for their advice and support.


(1.)Regland B, Gottfries CG, Oreland L. Low [B.sub.12] levels related to high activity of platelet MAO in patients with dementia disorders. Acta Psychiatr Scand 1988;78:451-7.

(2.)Cole MG, Prchal JF. Low serum vitamin [B.sub.12] in Alzheimer-type dementia. Age Ageing 1984;13:101-5.

(3.)Karnaze DS, Carmel R. Low serum cobalamin levels in primary degenerative dementia. Arch Intern Med 1987; 147:429-31.

(4.)Renval MJ, Spindler AA, Ramsdell JW, Paskvan M. Nutritional status of free-living Alzheimer's patients. Am J Med Sci 1989;298:20-7.

(5.)Van Tiggelen CJM. Alzheimer's disease/alcohol dementia: association with zinc deficiency and cerebral vitamin [B.sub.12] deficiency. J Orthomol Psychiatry 1983;13:97-104.

(6.)Nijst T, Wevers R, Schoonderwaldt H, Hommes O, de Haan A. Vitamin [B.sub.12] and folate concentrations in serum and CSF of neurological patients with special reference to multiple sclerosis and dementia. J Neurol Neurosurg Psychiatry 1990;53:951-4.

(7.)Ikeda T, Furukawa Y, Mashimoto S, Takahashi K, Yamada M. Vitamin [B.sub.12] levels in serum and cerebrospinal fluid of people with Alzheimer's disease. Acta Psychiatr Scand 1990;82:327-9.

(8.)McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS/ADRDA workgroup under the auspices of Department of Health and Human Services task force on Alzheimer's disease. Neurology 1984;34:939-44.

(9.)Goate A, Chartier-Harlin M-C, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 1991;349:704-6.

(10.)Murrell J, Farlow M, Ghetti B, Benson MD. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 1991;254:97-9.

(11.)Chartier-Harlin M-C, Crawford F, Houlden H, et al. Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 1991;353:844-6.

(12.)Kennedy AM, Newman S, McCaddon A, et al. Familial Alzheimer's disease: a pedigree with a mis-sense mutation in the amyloid precursor protein gene (amyloid precursor protein 717 valine[right arrow]glycine). Brain 1993;116:309-24.

(13.)Mann D, Jones D, Snowden J, Neary D, Hardy J. Pathological changes in the brain of a patient with familial Alzheimer's disease having a missense mutation at codon 717 in the amyloid precursor protein gene. Neurosci Lett 1993;137:225-8.

(14.)Folstein M, Folstein S, McHugh PR. Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-98.

(15.)Van Nostrand WE, Wagner SL, Suzuki M. Protease nexin II, a potent antichymotrypsin, shows identity to amyloid beta-protein precursor. Nature 1989;341:546-9.

(16.)Matsubara E, Amari M, Shoji M, et al. Serum concentration of alpha-1-antichymotrypsin is elevated in patients with senile dementia of the Alzheimer type. Alzheimer's disease and related disorders, Alan R. Liss, Inc. 1989; 707-14.

(17.)Toskes PP, Deren JJ, Conrad ME. Trypsin-like nature of the pancreatic factor that corrects vitamin [B.sub.12] malabsorption associated with pancreatic dysfunction. J Clin Invest 1973;62:1660-64.

(18.)Carmel R, Sinow RM, Siegel ME, Samloff IM. Food cobalamin malabsorption occurs frequently in patients with unexplained low serum cobalamin levels. Arch Intern Med 1988;148:1715-19.

(19.)Jones BP, Broomhead AF, Kwan YL. Incidence and clinical significance of protein bound vitamin [B.sub.12] malabsorption. Eur J Haematol 1987;38:131-6.

(20.)King CE, Leibach J, Toskes P. Clinically significant vitamin [B.sub.12] deficiency secondary to malabsorption of protein-bound vitamin [B.sub.12]. Dig Dis Sci 1979;24:397-402.

(21.)Burns A, Gillett DS, Jacoby R, Mibashan RS. Vitamin [B.sub.12] absorption in psychogeriatric patients. Int J Geriatr Psychiatry 1986;1:141-3.

(22.)Dawson DW, Sawers AH, Sharma RK. Malabsorption of protein-bound vitamin [B.sub.12]. Br Med J 1984;288:675-8.

(23.)McCaddon A, Kelly CL. Alzheimer's disease: a 'cobalaminergic' hypothesis. Med Hypotheses 1992;37:161-5.

(24.)Regland B, Gottfries CG. Slowed synthesis of DNA and methionine is a pathogenetic mechanism common to dementia in Down's syndrome, AIDS and Alzheimer's disease? Med Hypotheses 1992;38:011-019.

(25.)Bottiglieri T, Godfrey P, Flynn T, Carney M, Toone B, Reynolds E. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry 1990;53:1096-8.

(26.)Niederwieser A, Curtius H-C. Tetrahydrobiopterin biosynthetic pathway and deficiency. Enzyme 1987;38: 302-11.

(27.)Herbert V, Herzlich B. A proposed model of sequential stages in the development of vitamin [B.sub.12] deficiency [Abstract]. Blood 1985;66(suppll):45a.

(28.)Stabler S, Marcell P, Podell E, Allen R, Savage D, Lindenbaum J. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatograpy-mass spectrometry. J Clin Invest 1988;81:466-74.

(29.)Heston LL, White J. Pedigrees of 30 families with Alzheimer's disease. Behav Genet 1978;8:315-31.

(30.)Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anaemia or macrocytosis. N Engl J Med 1988; 318:1720-8.

(31.)Carmel R. Pernicious anaemia: the expected findings of very low serum cobalamin levels, anaemia, and macrocytosis are often lacking. Arch Intern Med 1988;148: 1712-14.

Authors' addresses

A. McCaddon

Gardden Road Surgery, Rhosllanerchrugog, Wrexham LL14 2EN, Clwyd, North Wales

C. L. Kelly

Rotherham General Hospital, Moorgate Road, Rotherham S60 2UD, S. Yorkshire

Received in revised form 7 February 1994

COPYRIGHT 1994 Oxford University Press
COPYRIGHT 2004 Gale Group

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