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MANUSCRIPT ID

• Title

• Reference

• Abstract

• Keywords

• Input Author

MANUSCRIPT DETAILS

• Introduction/Aims

• Methods

• Results

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MANUSCRIPT ID

• Title

Longitudinal Modeling of Age-Related Memory Decline and the APOE epsilon4 Effect

• Reference

Caselli RJ, Dueck AC, Osborne D, Sabbagh MN, Connor DJ, Ahern GL, Baxter LC, Rapcsak SZ, Shi J, Woodruff BK, Locke DE, Snyder CH, Alexander GE, Rademakers R, Reiman EM. N Engl J Med. 2009 Jul 16;361(3):255-63.

• Abstract

Background: The APOEepsilon4 allele is associated with the risk of late-onset Alzheimer's disease. The age at which memory decline diverges among persons who are homozygous for the APOEepsilon4 allele, those who are heterozygous for the allele, and noncarriers is unknown.

Methods: Using local advertisements, we recruited cognitively normal subjects between the ages of 21 and 97 years, who were grouped according to their APOEepsilon4 status. We then followed the subjects with longitudinal neuropsychological testing. Anyone in whom mild cognitive impairment or dementia developed during follow-up was excluded. We compared the rates of decline in predetermined cognitive measures between carriers and noncarriers of the APOEepsilon4 allele, using a mixed model for longitudinal change with age.

Results: We analyzed 815 subjects: 317 APOEepsilon4 carriers (79 who were homozygous for the APOEepsilon4 allele and 238 who were heterozygous) and 498 noncarriers. Carriers, as compared with noncarriers, were generally younger (mean age, 58.0 vs. 61.4 years; P<0.001) and were followed for a longer period (5.3 vs. 4.7 years, P=0.01), with an equivalent duration of formal education (15.4 years) and proportion of women (69%). Longitudinal decline in memory in carriers began before the age of 60 years and showed greater acceleration than in noncarriers (P=0.03), with a possible allele–dose effect (P=0.008). We observed similar although weaker effects on measures of visuospatial awareness and general mental status.

Conclusions: Age-related memory decline in APOEepsilon4 carriers diverges from that of noncarriers before the age of 60 years, despite ongoing normal clinical status.

• Keywords

memory decline, APOE4, memory disorders, longitudinal neuropsychological testing

• Input Author

Kelley O'Donnell

MANUSCRIPT DETAILS

• Introduction/Aims

Alzheimer's disease is a neurodegenerative disease characterized cognitively by a progressive memory loss, and pathologically by the buildup of abnormal protein plaques in the brain. Both familial and sporadic forms of the disease exist; the sporadic form typically has a later onset.

The epsilon4 allele of apolipoprotein E (APOE4) is the most prevalent genetic risk factor for sporadic Alzheimer's disease identified to date.

At what point does one transition from normal aging, with its associated age-related memory decline, to AD? Population-based studies have attempted to address this question, but demographic differences among test subjects can alter the results of neuropsychological tests, so any conclusions drawn must be qualified. Further, most longitudinal studies are conducted with elderly subjects, precluding the evaluation of the age at which memory decline in APOE4 carriers diverges from normal age-related memory loss.

In order to strengthen the results, this is a longitudinal study that uses a "mixed-model" approach, in which both fixed effects (e.g. genotype) and random effects are taken into consideration. Further, the subjects vary in age, from 21-97 years at the start of the study.

This study investigates whether the APOE4 allele affects the onset and time-course of age-related memory decline BEFORE the appearance of overt clinical symptoms of AD in either group.

• Methods

• Results

• Summary

• Discussion

INFORMATICS: GenBank

GenBank is an open-access database of annotated sequences of DNA, mRNA, and the corresponding proteins. One can add [1] to the database, submitting sequences, further annotations, and corrections. Alternatively (and likely more usefully), one can search GenBank. Searches are conducted via Entrez Nucleotide [2].