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  • Updated 10.28.2013
  • Released 02.16.2006
  • Expires For CME 10.28.2016

Familial Alzheimer disease

Introduction

This article includes discussion of familial Alzheimer disease, early-onset familial Alzheimer disease, hereditary Alzheimer disease, and late-onset familial Alzheimer disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Alzheimer disease (AD) is the most common cause of late-life dementia; it can begin either in individuals aged 65 years or less (early onset) or after the age of 65 years (late onset). It can also be classified as familial or sporadic. Those instances in which a clear pattern of inheritance within a family is established are termed “familial Alzheimer disease.” Such cases do not seem to be different from those with the sporadic form of this illness. In this article, the author discusses the genetic aspects of familial Alzheimer disease, and in the most recent update, he addresses new evidence of clinical heterogeneity in the disease and new loci of genetic risk factors for Alzheimer disease: TOMM40, the clusterin (CLU) or APOJ gene, and the PICALM gene.

Historical note and terminology

The term “familial Alzheimer disease” means that 2 or more persons in the same family are affected by Alzheimer disease. The first case of familial Alzheimer disease with neuropathological studies was reported in 1932 (126). Since then, more than 500 families have been described with a multigenerational autosomal dominant pattern of Alzheimer disease transmission. In 1979 Cook and colleagues reported 3 new families completing with them 50 described in the medical literature and suggested a link between familial Alzheimer disease and transmissible dementia. Among those families, there was a patient with histologically confirmed Alzheimer disease whose sister had proved spongiform encephalopathy (24). Ten years later, Bird and colleagues suggested genetic heterogeneity by describing the variation of clinical and neuropathological characteristics in 180 demented individuals from 24 kindreds with familial Alzheimer disease, with at least 2 affected generations and neuropathological confirmation in 1 case (13).

Masters and colleagues have purified and characterized the cerebral amyloid protein that forms the plaque core in Alzheimer disease and in aged individuals with Down syndrome. This protein consists of multimeric aggregates of a polypeptide of about 40 residues (4 kDa) but there are no similarities between its amino acid sequence and those of scrapie polypeptides (90). Two years later, amyloid fibrils were purified from the leptomeningeal vessels of a patient who had no clinical signs of dementia, whose family had hereditary cerebral hemorrhage, with amyloidosis restricted to the leptomeninges and cerebral cortex. This protein showed homology to the beta-protein of Alzheimer disease and Down syndrome, which suggested that hereditary cerebral hemorrhage with amyloidosis of Dutch origin was pathogenetically related to Alzheimer disease (144).

As in sporadic forms of Alzheimer disease, there are 2 kinds of familial Alzheimer disease, namely: The early and late-onset varieties. Men and women in early-onset families had equivalent risk of dementia. Lifetime risk of dementia in early-onset familial Alzheimer disease kindreds is consistent with an autosomal dominant inheritance model. Late-onset familial Alzheimer disease has at least 2 etiologies: Alzheimer disease in some families may be transmitted as a dominant trait, whereas in others, it may be caused by other genetic or shared environmental factors (36).

Mendelian inheritance is more commonly related to early-onset familial Alzheimer disease than with the late-onset variety. Martin and colleagues in1991 reported 2 large families with early-onset familial Alzheimer disease in Belgium (89); but worldwide, the largest families with early-onset familial Alzheimer disease in the world have been reported by Lopera and colleagues in Antioquia, Colombia, in several families with E280A mutation in PS1 that exhibit a founder effect (78; 85). So far, 3 genes with a causality relationship to Alzheimer disease have been described (APP, PS1 and PS2), as well as many other loci that behave as risk factors for this disease (see Table 1). Over 500 gene candidates have been associated with Alzheimer disease, but systematic meta-analyses of these candidates suggest that perhaps 20 loci have modest but significant effects on Alzheimer disease risk (11).

Table 1. Genes and Loci with risk for Alzheimer disease

Nomenclature

Gene

Chromosome

Reference

AD1

APP

21

(136)

AD2

ApoE4

19

(26)

AD3

Presenilin1

14

(131)

AD4

Presenilin2

1

(80)

AD5

12p11.23-q13.12

(106)

AD6

10q24

(09)

AD7

10p13

(Zubenko et al 1998)

AD8

20p

(14)

AD9

19p13.2

(148)

AD10

7q36

(113)

MtDNA

mtDNA

(83; 51)

A2M

12

(15)

LRP1

12

(70)

Combination of TF*C2 and HFE C282Y

6

(121)

NOS3

7

(30)

VEGF -2578A/A genotype

6

(32)

UBQLN1

9q22

(10)

Susceptibility locus

8q

(43)

BRI2 gene

13

(41; 40)

Susceptibility locus

3q28

(76)

The neuronal sortilin-related receptor SORL1

11q23.2-q24.2

(122)

Susceptibility locus

7q31.1 and 20q13.33

(75)

Susceptibility locus

TOMM40

(123)

Susceptibility locus

rs5984894 on Xq21.3 in PCDH11X

(20)

Susceptibility loci

CLU (clusterin) or APOJ gene and PICALM gene, CR1

(56; 73; 66)

Susceptibility locus

8q24

(132)

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