Alzheimer Disease 3

A number sign (#) is used with this entry because early-onset familial Alzheimer disease-3 (AD3) is caused by heterozygous mutation in the presenilin-1 gene (PSEN1; 104311) on chromosome 14q24.

For a phenotypic description and a discussion of genetic heterogeneity of Alzheimer disease, see 104300.

Campion et al. (1995) studied a large pedigree that included 34 subjects with early-onset progressive dementia with mean age at onset at 46 plus or minus 3.5 years and mean age at death at 52.6. Myoclonus and extrapyramidal signs were common; seizures were present in all affected subjects. There were neuropathologic changes typical of Alzheimer disease in the 2 brains examined.

Lopera et al. (1997) described a large pedigree with early-onset Alzheimer disease from a community based in Antioquia, Colombia. Affected patients had a mean age at onset of 46.8 years (range, 34 to 62 years) with an average interval of 8 years until death. Headache was noted in affected individuals significantly more frequently than in those not affected. The most frequent presentations were memory loss followed by behavioral and personality changes and progressive loss of language ability. In the final stages, gait disturbances, seizures, and myoclonus were frequent.

Hull et al. (1998) described a German family with early-onset Alzheimer disease with a mutation in the PSEN1 gene. From the age of 43 years, the proband had complained of deficits in short-term memory. Relatives had noticed his symptoms even earlier and dated the onset of deficits to age 38 years when he showed increasing interruptions during speech followed by social withdrawal. There was a strong family history of dementia. Through 3 generations the onset of dementia in this family was between 42 and 45 years.

Rippon et al. (2003) reported an African American family with autosomal dominant rapidly progressive dementia and psychosis occurring early in the fifth decade. Two brothers presented with personality changes, labile mood, language difficulties, psychosis, primitive reflexes consistent with frontotemporal dementia (600274), but also were found to have memory impairment and neuropathologic findings diagnostic of AD. Both brothers had a mutation in the PSEN1 gene (104311.0006). Their father reportedly had died in his sixth decade with a similar illness. The authors commented on the atypical clinical presentation.

Godbolt et al. (2004) reported 2 sibs with early-onset Alzheimer disease confirmed by genetic analysis (104311.0030). Both patients presented at around age 50 with difficulty in word finding and impaired frontal executive function, but with relative preservation of memory. The sister exhibited dysfluent speech with phonemic paraphasias, dysgraphia, and dyspraxia. She later developed mutism, generalized rigidity, myoclonus of the upper limbs, dystonic posturing of the right hand, and shuffling gait. The brother exhibited impaired repetition of sentences and polysyllabic words, nominal dysphasia, dysgraphia, and dyscalculia. MRI of both patients showed multiple foci of white matter signal changes.

Ataka et al. (2004) reported a Japanese patient with onset of memory impairment and difficulty driving a car at age 26. Neuropsychologic testing showed that he had visual constructional apraxia, visuospatial agnosia, and optic ataxia, consistent with the 'visual variant' of AD in which there is a visuospatial cognitive deficit. The patient was heterozygous for a PSEN1 mutation (104311.0031).

Halliday et al. (2005) reported 2 sibs with early-onset FAD and mutation (M146L; 104311.0001) in the PSEN1 gene. Family history suggested that their father was also affected. Neuropathologic examination of both patients showed numerous cortical plaques and neurofibrillary tangles, consistent with AD. In addition, both cases showed ballooned neurons and numerous tau (MAPT; 157140)-immunoreactive Pick bodies in upper frontotemporal cortical layers and in the hippocampal dentate gyrus. Halliday et al. (2005) suggested that the M146L mutation may specifically predispose to both AD and Pick pathology by affecting multiple intracellular pathways involving tau phosphorylation.

Leverenz et al. (2006) found that 24 (96%) of 25 patients with AD3 had Lewy body pathology in the amygdala. Most patients also had Lewy body pathology in other brain regions, including the cingulate gyrus and neocortex, although there was variability. AD patients with PSEN1 mutations had more frequent Lewy body pathology compared to AD patients with PSEN2 (600759) mutations. There was no clinical correlation between age at onset or disease severity onset and Lewy body pathology in either group, although those with longer disease duration tended to have more Lewy body pathology.

Piccini et al. (2007) reported a patient who presented at age 28 years with delusions and lower limb jerks accompanied by intentional myoclonus and cerebellar ataxia. He had rapid progression with global impairment of all cognitive functions and became bedridden, anarthric, and incontinent by age 33. He died of bronchopneumonia at age 35. Postmortem examination showed severe beta-amyloid deposition in the cerebral and cerebellar cortices, amyloid angiopathy, and severe loss of Purkinje cells and fibers in the cerebellum. Neurofibrillary tangles were also present. Genetic analysis revealed a heterozygous mutation in the PSEN1 gene (S170F; 104311.0036).

FAD with spastic paraparesis and unusual plaques

In a family with onset of AD in the early forties reported by the Alzheimer's Disease Collaborative Group (1995), O'Riordan et al. (2002) described an atypical disease pattern in 3 additional members from the third generation. One had cognitive impairment, spastic paraparesis, and white matter abnormalities on MRI. One of his sibs developed dementia and myoclonus and had white matter abnormalities on MRI. Another sib had ophthalmoplegia, spastic-ataxic quadriparesis, and cotton-wool plaques with amyloid angiopathy on brain biopsy (MRI was not performed). The authors suggested that the MRI findings may reflect an ischemic leukoencephalopathy due to amyloid angiopathy affecting meningocortical vessels.

Crook et al. (1998) reported a Finnish pedigree with 17 affected individuals of both sexes in 3 generations suffering from a novel variant of Alzheimer disease characterized by progressive dementia that was in most cases preceded by spastic paraparesis. Neuropathologic investigations showed numerous distinct, large, round, and eosinophilic plaques, as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton-wool balls and were immunoreactive for A-beta, but lacked a congophilic dense core or marked plaque-related neuritic pathology.

Matsubara-Tsutsui et al. (2002) reported a Japanese family in which 6 individuals in 2 generations were affected with presenile dementia preceded by spastic gait. Detailed information was available in 1 patient who had disease onset at age 35 with spasticity, motor apraxia, and cognitive decline. Neuropathologic examination was not done.

Rogaeva et al. (2003) reported the neuropathologic findings of a patient with FAD and spastic paraplegia with onset at 52 years of age. The brain had severe cortical atrophy with neuronal loss, as well as atrophy of the caudate, hippocampus, amygdala, and entorhinal cortex. The substantia nigra was pale, depopulated, and had rare tangles and Lewy bodies. Neurofibrillary tangles and amyloid plaques with a cotton-wool appearance were identified. Consistent with spastic paraplegia, the spinal cord was smaller than usual and flattened in its anteroposterior dimension, and there was degeneration of the corticospinal tracts.

Moretti et al. (2004) reported 2 sibs with early-onset dementia and spastic paraparesis. Their father, paternal grandfather, and paternal great-grandfather reportedly died in their thirties of a dementing illness associated with severe progressive gait impairment. The proband developed memory problems at age 28 years. At age 31, he had mild bilateral limb apraxia, dystonia, mild dementia, and hypometabolism of the temporoparietal association cortex on PET scan. By age 34, he was profoundly demented, with dysarthria, dysphagia, and spasticity of the arms and legs. Postmortem examination showed moderate brain atrophy with amyloid plaques and neurofibrillary tangles consistent with AD throughout the neocortex, limbic regions, and striatum, as well as large eosinophilic cotton-wool plaques. His sister had a similar disease course. Moretti et al. (2004) identified a heterozygous 6-bp insertion in the PSEN1 gene (104311.0029) in both sibs.

Marrosu et al. (2006) reported a family in which 4 members had memory loss and personality changes ranging in onset from 32 to 45 years of age followed by a rapidly progressive disease course resulting in dementia, spastic tetraparesis, and anarthria in the most severely affected patients. Brain imaging showed multiple white matter lesions reminiscent of those seen in multiple sclerosis (see 126200). Genetic analysis confirmed a heterozygous mutation in the PSEN1 gene.

St. George-Hyslop et al. (1992), Van Broeckhoven et al. (1992), and Mullan et al. (1992) presented evidence of linkage of early-onset FAD to chromosome 14q.

In 2 Belgian families with early-onset autosomal dominant AD, Van Broeckhoven et al. (1987) excluded linkage to the APP locus on chromosome 21q. One pedigree contained 36 patients in 6 generations, and the second had 22 patients spanning 5 generations. By linkage analysis of the 2 Belgian families studied by Van Broeckhoven et al. (1987), Van Broeckhoven et al. (1992) found linkage to chromosome 14q. They narrowed the candidate region to an 8.9-cM area between D14S42 and D14S53, flanking D14S43 on both sides.

Mullan et al. (1992) placed the gene proximal to that for alpha-1-antichymotrypsin (AACT; 107280), thus excluding AACT, which is a component of plaque cores and a protease inhibitor, as a possible candidate gene for AD.

In 9 non-Volga German kindreds with autosomal dominant AD, Schellenberg et al. (1992) found linkage to chromosome 14: a total lod score of 9.15 at theta = 0.01 was obtained with the marker D14S43 at 14q24.3. A single early-onset family yielded a lod score of 4.89 (theta = 0.0). When no assumptions were made about age-dependent penetrance, significant results were still obtained (maximum lod = 5.94 at theta = 0.0) despite the loss of power. Results for several Volga German families were either negative or nonsignificant for markers in this region of chromosome 14.

Schellenberg et al. (1993) explored the role of chromosome 14 in late-onset FAD. They studied 49 families with a mean age of onset of 60 years or more. No evidence of linkage was obtained, and strong evidence against linkage to chromosome 3 markers was found. Evidence of linkage to D14S52 was found for a subgroup of families of intermediate age of onset, namely, older than 60 but less than 70 years of age. They concluded that the chromosome 14 locus was not responsible for Alzheimer disease in most late-onset FAD kindreds.

In 2 large early-onset FAD pedigrees, Nechiporuk et al. (1993) found tight linkage to D14S43 and D14S53. In a large pedigree with early-onset FAD, Campion et al. (1995) observed a lod score of 5.48 at a recombination fraction of theta = 0.0 with the genetic marker D14S43, confirming the location of the responsible gene on chromosome 14q24.3.

Sherrington et al. (1995) identified 5 different missense mutations in the PSEN1 gene that cosegregated with early-onset familial Alzheimer disease type 3 (104311.0001-104311.0005).

Lopera et al. (1997) stated that affected members of a large Colombian kindred with early-onset AD had a glu280-to-ala mutation in the PSEN1 gene (E280A; 104311.0009). By genotype analysis of 109 carriers of the E280A PSEN1 mutation, including 52 individuals with AD, Pastor et al. (2003) found that those with at least 1 APOE4 (see 107741) allele were more likely to develop AD at an earlier age than those without an APOE4 allele, indicating an epistatic effect.

In affected members of 24 of 31 families with early-onset AD, Raux et al. (2005) identified mutations in the PSEN1 gene. The mean age of disease onset was 41.7 years. Combined with earlier studies, the authors estimated that 66% of families with early-onset AD are attributable to mutations in the PSEN1 gene.

Bruni et al. (2010) identified an AD3 family from Naples, Italy, with the PSEN1 M146L mutation (104311.0001). The 40-year-old proband showed memory loss with attention and planning deficits. Six other family members spanning 4 generations had developed dementia.

FAD with Spastic Paraparesis and Unusual Plaques

In a family with FAD with onset in the early forties, O'Riordan et al. (2002) identified a mutation in the PSEN1 gene (E280G; 104311.0010). Three additional members with the same mutation also had spastic paraparesis and unusual plaques. In a patient with FAD, spastic paraplegia, and cotton-wool plaques, Rogaeva et al. (2003) identified the E280G mutation. The authors noted that the E280G mutation had been found in patients with classic FAD, suggesting that genetic modifiers may exist.

In a Finnish family with FAD with spastic paraparesis and unusual plaques, Crook et al. (1998) identified a mutation in the PSEN1 gene that caused deletion of exon 9 (104311.0012). They stated that it was the only known structural mutation in the PSEN1 gene; previously identified mutations had been missense mutations.

In a Japanese patient with early-onset FAD, spasticity, and apraxia, Matsubara-Tsutsui et al. (2002) identified a mutation in the PSEN1 gene (104311.0022).

Clinical Variability

Dolzhanskaya et al. (2014) reported 3 brothers with early-onset Alzheimer disease with spastic paraparesis and unusually rapid progression. The boys' father and paternal grandmother were reportedly similarly affected. The brothers had onset of progressive dementia and ataxia between ages 29 and 32 years; 2 died at age 32 and the other died at age 36. The proband presented with memory deficits and ataxia, and later developed dysarthria and spastic paraparesis. Electron microscopy of a skin biopsy showed lipofuscin-containing phagocytic cells and distinct curvilinear lysosomal inclusion bodies, suggestive of neuronal ceroid lipofuscinosis. Neuropathologic examination showed changes consistent with Alzheimer disease, including neuritic and amyloid-containing plaques and neurofibrillary tangles. Additional findings included Hirano bodies and granulovacuolar degeneration in the hippocampus. The proband was originally ascertained from a cohort of patients clinically thought to have autosomal dominant adult-onset neuronal ceroid lipofuscinosis (CLN4B; 162350) who were negative for mutations in the DNAJC5 gene (611203). Whole-exome sequencing of the proband identified a heterozygous mutation in the PSEN1 gene (L381F; 104311.0039) that segregated with the disorder in the family.

Yescas et al. (2006) identified a heterozygous mutation in the PSEN1 gene (A431E; 104311.0033) in affected members of 9 Mexican families with early-onset Alzheimer disease, All families were from the state of Jalisco in western Mexico, and haplotype analysis indicated a founder effect. The A431E mutation was found in 19 (32%) of 60 apparently unaffected family members, suggesting either a presymptomatic state or reduced penetrance. Murrell et al. (2006) found the A431E mutation in 20 individuals with AD3 from 15 families identified in Guadalajara, southern California, and Chicago. Age at disease onset ranged from 33 to 44 years, and spasticity was a common clinical feature. Fourteen families were of Mexican mestizo descent, and of these families, 9 traced the illness to ancestors from the state of Jalisco in Mexico. The remaining proband had a more remote Mexican ancestry. The findings further supported a founder effect for the A431E mutation.

Bruni et al. (2010) retrospectively identified 7 articles reporting AD3 families with the PSEN1 M146L mutation (104311.0001), including those reported by Sorbi et al. (1995) and Halliday et al. (2005). They also reviewed the Calabrian families reported by Sherrington et al. (1995). The reconstituted Calabrian families, a family from Naples, and the Australian family comprised 148 affected individuals, and a genealogic link from the 17th century was established with all the patients with the M146L mutation. The ancestral mutation originated from southern Italy. Phenotypic cluster analysis applied to 50 patients at onset and during the first 2 years identified 4 subgroups: 2 with a cognitive onset (58%), including memory loss or disorientation, and 2 with a behavioral onset (42%), including apathy, depression, and executive dysfunction. Neuropathologic examination of 2 patients showed substantial beta-amyloid and phosphorylated tau immunoreactivity throughout the cortex, deep brain regions, and brainstem, consistent with AD.

Early-onset Alzheimer disease with spastic paraparesis was first reported by Barrett (1913).

Ettinger et al. (1994) proposed that familial Alzheimer disease is associated with chromosomal instability and breakage at nonrandom sites. Using a novel gene cotransfer technique involving X-linked markers, they found decreased cotransfer of markers in FAD fibroblasts compared to controls, suggesting increased chromosomal breakage. The authors hypothesized a role for the trifunctional protein C(1)-THF synthase (172460), which maps to 14q24, in the generation of chromosomal instability in FAD.