Disorders with Complex Genetics

Signs & Symptoms: Memory loss for recent events Progresses into dementia  almost total memory loss Inability to converse, loss of language ability Affective/personality disturbance (fatuous, hostile) Death from opportunistic infections, etc. Confirmation of Diagnosis: Neuronal (amyloid,  amyloid, A  amyloid, A  ) plaques Neurofibrillary tangles Brain Atrophy

Neuronal (A  42) Plaques in Alzheimer ’ s Disease From

Neurofibrillary Tangles in Alzheimer ’ s Disease From

Plaques and neurofibrillary tangles From Department of Pathology, Virginia Commonwealth University

Following are from the NIA, Alzheimer ’ s Disease Education and Referral Center, Alzheimer ’ s Disease: Unraveling the Mystery ( pubs/unraveling/01.htm ff.)

Amyloid precursor protein (APP) is membrane protein that sits in the membrane and extends outward. It is though to be important for neuronal growth, survival, and repair.

Enzymes cut the APP into fragments, the most important of which for AD is called  -amyloid (beta-amyloid) or A .

Beta-amyloid is “ sticky ” so the fragments cling together along with other material outside of the cell, forming the plaques seen in the AD brain.

Microtubules are like railroad tracks that transport nutrition and other molecules. Tau-proteins act as “ ties ” that stabilize the structure of the microtubules. In AD, tau proteins become tangled, unstabilizing the structure of the microtubule.

WRONG! Brain Atrophy in AD

Classification: (1) FAD v SAD: Familial AD versus Sporadic AD No complete consensus Usually FAD = at least 1 first degree relative affected Sometimes 2 second degree relatives (2) Early v Late Onset: Early onset (EOAD) = usually before 65 Early onset correlated with FAD LOAD = late onset AD

Breakthrough: (1) Down’s Syndrome Have AD brain pathology in later life (2) Pedigrees with dominant-like transmission: Studied these first Concentrated on chromosome 21

Alzheimer ’ s Disease, Type 1: Several mutations in AAP gene on chromosome 21 Most common = Val717Iso Produce abnormal beta amyloid fragment 15%-20% of early onset, familial AD Autosomal dominant

Alzheimer ’ s Disease, Type 3: Mutations (> 130) in the presenilin1 gene on chromosome 14 Most mutations lead to amino acid substitution Overproduction of the beta amyloid fragment 30% - 70% of early onset, familial AD Autosomal dominant

Alzheimer ’ s Disease, Type 4: Mutations in the presenilin2 gene on chromosome 1 2 alleles: Asn141Iso and Met239Val Overproduction of the beta amyloid fragment < 5% of early onset, familial AD (only a few families world wide) Autosomal dominant

Alzheimer ’ s Disease, Type 2: Epsilon 4 (  4, AKA E4) allele of the Apolipoprotein E (ApoE) gene on chromosome 19 confers risk Epsilon 2 (  2, AKA E2) allele of the Apolipoprotein E gene on chromosome 19 confers protection Mechanism unclear; ApoE is a very low density lipoprotein that transports cholesterol Most cases are late onset, familial Susceptibility Locus

Prevalence of APOE genotypes in Alzheimer ’ s disease (AD) and controls. Genotype:ControlsAD E2/E21.3%0% E2/E312.5%3.4% E2/E44.9%4.3% E3/E359.9%38.2% E3/E420.7%41.2% E4/E40.7%12.9% Jarvik G, Larson EB, Goddard K, Schellenberg GD, Wijsman EM (1996) Influence of apolipoprotein E genotype on the transmission of Alzheimer disease in a community-based sample. Am J Hum Genet 58: genotype

AD: The Great Unknown: What is causing the majority of AD cases? 1.Unknown Mendelian forms (probably not) 2.Unknown major loci (probably not) 3.Phencopies 4.Multifactorial-threshold

Current theory: Multifactorial, involving several pathways. Protein accumulation:  placques & tangles Inflammation: Unregulated activation of glia Lipid distribution: Lipid membrane site of APP cleavage.

From Sleegers et al. (2010) Trends in Genetics, 26, 84-94, p. 87

Nature Genetics 41, (2009)

Cases with no known etiology: (theoretical extremes) Mendelian/ Phenocopy Multifactorial/ Threshold CDCV Common disease/ common variant Disease (Genetic) Heterogeneity

Heterogeneity Mendelian/Phenocopy Many rare alleles with high penetrance (“Mendelian” forms of the disorder). Almost no person will get two or more of these AD alleles. Non familial cases due to phenocopies.

Multifactorial Threshold Model Many common alleles with “low” penetrance. Most people will have several risk alleles. Risk alleles are additive (multiplicative). Many additive environmental factors. Genes and environment  liability. Once liability reaches a certain value (i.e., the threshold) a disease process begins.

HGSS: Carey: Figure 6.1

Mice gratia Human APP gene Human ApoE gene Human Presenilin gene Animal Models

Figure 1. Development of the Transgenic Mouse Model of Alzheimer's Disease. The transgene consists of the human APP gene containing a mutation causing a rare form of early-onset familial Alzheimer's disease (Val717Phe). The transgene, whose expression is driven by the platelet-derived growth factor (PDGF) promoter, is microinjected into mouse eggs and implanted in a pseudopregnant female mouse. After the progeny are screened for the presence of the transgene, they are bred and their offspring are analyzed for pathologic features characteristic of Alzheimer's disease. The brains of the transgenic PDAPP (PDGF promoter expressing amyloid precursor protein) mice have abundant -amyloid deposits (made up of the A peptide), dystrophic neurites, activated glia, and overall decreases in synaptic density. From NEJM Volume 332:

From McGowan, Erikson & Hutton (2006), Trend in Genetics, 22: