Familial Alzheimer disease

Francisco Lopera MD (Dr. Lopera, Director of the Neuroscience Program at Universidad de Antioquia, Medellin, Colombia, has received research grants from Genetech for a clinical trial.)
Martin R Farlow MD, editor. (

Dr. Farlow of Indiana University received research grant support from AbbVie, Biogen, Boehringer Ingelheim, Eisai, Eli Lilly, Genentech, Roche, Novartis, Suven Life Sciences Ltd, and vTv Therapeutics; fees from Cerecin/Accera, Allergan, Avanir, AZ Therapies, Eli Lilly, Kyowa Kirin Pharma, Longeveron, Medavante, Merck, Neurotrope Biosciences, Proclara, Takeda, and vTv Therapeutics for consultancy, or advisory board/DSMB membership; licensing fees from Elan; and consulting fees from Cortexyme, Green Valley, Regenera, Samumed, Zhejiang Hisun Pharmaceuticals, Cognition Therapeutics, Danone, Eisai, and Otsuka.

Originally released February 16, 2006; last updated October 28, 2013; expires October 28, 2016
Notice: This article has expired and is therefore not available for CME credit.

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.


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 (Schottky 1932). 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 (Cook et al 1979). 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 (Bird et al 1989b).

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 (Masters et al 1985). 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 (van Duinen et al 1987).

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 (Farrer et al 1990).

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 (Martin et al 1991); 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 (Lendon et al 1997; Lopera et al 1997). 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 (Bertram and Tanzi 2008).

Table 1. Genes and Loci with risk for Alzheimer disease








(Tanzi et al 1987)




(Corder et al 1993)




(Sherrington et al 1995)




(Levy-Lahad et al 1996)




(Pericak-Vance et al 1997)




(Bertram et al 2000)




(Zubenko et al 1998)




(Blacker et al 1997)




(Wijsman et al 2004)




(Rademakers et al 2005)




(Lin et al 1992; Grazina et al 2006)




(Blacker et al 1998)




(Kounnas et al 1995)


Combination of TF*C2 and HFE C282Y


(Robson et al 2004)




(Dahiyat et al 1999)


VEGF -2578A/A genotype


(Del Bo et al 2005)




(Bertram et al 2005)


Susceptibility locus


(Giedraitis et al 2006)


BRI2 gene


(Ghiso et al 2001; 2006)


Susceptibility locus


(Lee et al 2006)


The neuronal sortilin-related receptor SORL1


(Rogaeva et al 2007)


Susceptibility locus

7q31.1 and 20q13.33

(Lee et al 2008)


Susceptibility locus


(Roses et al 2010)


Susceptibility locus

rs5984894 on Xq21.3 in PCDH11X

(Carrasquillo et al 2009)


Susceptibility loci

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

(Harold et al 2009; Lambert et al 2009; Jun et al 2010)


Susceptibility locus


(Sillen et al 2011)

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