Alzheimer Disease 4

A number sign (#) is used with this entry because Alzheimer disease-4 (AD4) is caused by heterozygous mutation in the presenilin-2 gene (PSEN2; 600759) on chromosome 1q42.

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

Bird et al. (1988) described 5 German kindreds with an autosomal dominant early-onset form of Alzheimer disease. All families were descendants of a group of immigrants, known as the Volga Germans, who came to the United States between 1870 and 1920. Their ancestors had moved from Germany to the southern Volga region of Russia in the 1760s. All 5 were descendants of persons who originally lived in 2 small adjacent Volga German villages and shared several surnames known to have been present in the census records of those villages. There are more than 300,000 American descendants of the Volga Germans (see HISTORY).

Further studies of this group by Levy-Lahad et al. (1995) found that the mean ages at onset for the families ranged from 50.2 to 64.8 years. Other than the relatively early age at onset, AD in the Volga group was clinically and pathologically indistinguishable from typical AD. Bird et al. (1996) reported that the mean age at onset in the Volga Germans is 54.9 years, mean age at death is 65.9 years, and mean disease duration is 11.3 years. These findings contrasted with families with chromosome 14-linked AD (AD3; 607822), in which the mean age at onset is 44.8 years, mean age at death is 52.6 years, and mean disease duration is 7.6 years. Bird et al. (1996) concluded that chromosome 1-linked AD (AD4) is characterized by a later age of onset that overlaps with the more common sporadic form of the disease.

Finckh et al. (2000) reported a family in which 3 sibs with a mutation in the PSEN2 gene (600759.0006) were affected with early-onset AD and 2 sibs with the mutation were not affected. The affected sibs had onset at ages 44, 50, and 58. The disorder was characterized by anxiety, irritability, memory deficits, and impairment of language and attention. Two patients developed seizures and myoclonic jerks. Autopsy of 1 patient showed diffuse cortical atrophy, senile plaques, and neurofibrillary tangles. Finckh et al. (2000) noted that there may be variable age at onset, reduced penetrance, or other genetic disease modifiers.

Ezquerra et al. (2003) reported a family in which 3 members were affected with AD. Age of onset ranged from 45 to 64 years, and there appeared to be reduced penetrance.

Piscopo et al. (2008) reported a Sardinian family in which 4 sibs had dementia associated with a mutation in the PSEN2 gene (600759.0009). At age 60 years, the proband had an insidious onset of personality changes, with irritability, apathy, and visual hallucinations, followed by difficulties in attention and motivation, depression, and less willingness to participate in social activities. At age 74 years, the patient developed difficulties in memory, language, reasoning, behavior, and visuospatial functions, recurrent episodes of visual hallucinations, and delirium. Neurologic examination showed aboulia, anomic dysphasia, hypomimia, unstable gait, and mild parkinsonism with postural instability, bradykinesia, resting tremor, and rigidity. The findings were consistent with a clinical diagnosis of probable dementia with Lewy bodies (DLB; 127750). Two additional affected sibs also had parkinsonism; 1 had visual hallucinations. These sibs had classic features of Alzheimer disease.

Neuropathologic Features

Nochlin et al. (1998) reported the neuropathologic features of 6 members of the Volga German family with Alzheimer disease due to mutation in the PSEN2 gene. The most significant feature in this family was the presence of severe or moderately severe amyloid angiopathy in 5 family members with clinical dementia. The index case had late-onset dementia at age 73 years, died of an acute intracerebral hemorrhage, and pathologically showed severe amyloid angiopathy but only rare neuritic senile plaques and neurofibrillary tangles. That she was apolipoprotein E2/3 heterozygous suggested that the E2 allele may have exerted a selective protective effect resulting in late onset and relatively mild Alzheimer disease despite severe amyloid angiopathy.

Leverenz et al. (2006) found that 9 (64%) of 14 AD patients from the Volga German kindred with the PSEN2 N141I mutation (600759.0001) had Lewy body pathology in the amygdala. Lewy body pathology was much less frequent outside of the amygdala but was detected in some patients. AD patients with PSEN2 mutations had less frequent Lewy body pathology compared to AD patients with PSEN1 (104311) mutations. There was no clinical correlation between age at onset or disease severity with Lewy body pathology in either group.

In a patient with AD4 and features of Lewy body dementia, Piscopo et al. (2008) observed beta-amyloid plaques and neurofibrillary tangles, but also found diffuse deposition of Lewy bodies throughout the brain. The findings added complexity to the phenotypes associated with PSEN2 mutations.

In several families with AD, including the Volga families reported by Bird et al. (1988), Schellenberg et al. (1988) excluded linkage to chromosome 21.

In the Volga German group with Alzheimer disease, in which linkage of AD to chromosome 21 (AD1; 104760) and to chromosome 14 (AD3) had been excluded, Levy-Lahad et al. (1995) demonstrated linkage to microsatellite marker D1S479, which placed the mutation for AD in this group to 1q31-q42.

In affected members of 7 families of the Volga German group with Alzheimer disease, Levy-Lahad et al. (1995) identified heterozygosity for a mutation in the PSEN2 gene (N141I; 600759.0001). Two affected patients from the families with AD lacked the mutation. Age at onset and APOE4 (see 107741) status suggested that these patients had a phenocopy (or genocopy) of the AD4 present in most of their relatives. Levy-Lahad et al. (1995) found that all the affected Volga German individuals except one who did not have the N141I mutation shared a haplotype between D1S238 and D1S235. Furthermore, the age of onset in this person, 67 years, was greater than 2 standard deviations above the family mean.

In all 4 affected members of an extended pedigree of Italian origin with early-onset, pathologically confirmed FAD (onset at 50 years), Rogaev et al. (1995) identified a heterozygous mutation in the PSEN2 gene (600759.0002).

In affected members of a family with Alzheimer disease, Ezquerra et al. (2003) identified a mutation in the PSEN2 gene (600759.0004). The mutation was also found in a cognitively healthy sib older than the proband, suggesting either reduced penetrance or a later onset in this individual.

Yu et al. (2010) demonstrated that a family from Fulda (Hesse), Germany with AD4 caused by the N141I mutation in the PSEN2 gene (600759.0001) shared the same haplotype as affected Volga German families reported earlier. This finding indicated that the N141I mutation must have occurred prior to the emigration of the Volga Germans from the Hesse region of Germany to Russia in the 1760s during the reign of Catherine the Great. In addition, the original patient with AD reported by Alzheimer (1907) also lived in the same Hesse region as the modern family, which raised the possibility that the original patient may have had the N141I mutation. However, Muller et al. (2011) sequenced exon 5 of the PSEN2 gene in DNA extracted from a tissue section prepared from the brain of the original patient with AD ('Auguste D'), and found that she did not carry the N141I mutation, thus disproving the hypothesis of Yu et al. (2010).