The APOE ε4 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 APOE ε4 allele, those who are heterozygous for the allele, and noncarriers is unknown. Using local advertisements, we recruited cognitively normal subjects between the ages of 21 and 97 years, who were grouped according to their APOE ε4 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 APOE ε4 allele, using a mixed model for longitudinal change with age. We analyzed 815 subjects: 317 APOE ε4 carriers (79 who were homozygous for the APOE ε4 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. Age-related memory decline in APOE ε4 carriers diverges from that of noncarriers before the age of 60 years, despite ongoing normal clinical status.

Background: A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders. Results: The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed. Conclusions: Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.

Objective: To determine whether memory loss is detectable before the symptomatic presentation of mild cognitive impairment (MCI) in those at greater genetic risk for Alzheimer disease (AD) based upon presence or absence of the e4 allele of APOE. Methods: Participants were age 50 years or older who responded to newspaper advertisements. A total of 212 cognitively normal individuals of known APOE genotype were initially enrolled in a match paradigm that included e4 homozygotes, e3/4 heterozygotes, and e4 noncarriers in a 1:1:2 ratio (53 sets). Of the original 212 individually matched participants, 180 completed at least two epochs of testing including 45 APOE e4/4 homozygotes, 42 APOE e3/4 heterozygotes, and 93 APOE e4 noncarriers, mean age 60 (±6.2) years. Of these, four developed MCI or AD during the follow-up period and were excluded from analysis. Longitudinal neuropsychological study included two verbal (Auditory Verbal Learning Test [AVLT], Selective Reminding Test [SRT]) and two visual (Complex Figure Test [CFT], Visual Retention Test) memory tests. Results: Multiple measures on both verbal memory tests showed poorer performance over a mean interval of 33 months in e4 carriers than noncarriers: AVLT total learning, long term delayed recall; SRT free and cued recall. Among those age 50 to 59 years, AVLT long term delayed recall, SRT free and cued recall, and CFT recall declined more in APOE e4 carriers. No differences were found in the domains of language, spatial skills, or executive function. Conclusions: Memory declined in APOE e4 carriers before the symptomatic presentation of MCI in a cohort whose mean age was 60 years over a median period of 33 months. The decline began prior to age 60.

Apolipoprotein E (APOE) ε4 reduces the median age at Alzheimer disease (AD) onset by gene dose from 84 years in APOE ε4 noncarriers to 68 years in APOE ε4 homozygotes.^1-6 Breitner et al,⁴ for example, found a disproportionately high number of APOE ε4 homozygotes in a population with AD onset between the ages of 55 and 75 years. Since 1994 we have been enrolling and following up a cohort of healthy APOE ε4 homozygotes aged 50 to 69 years at entry, demographically matched to APOE ε3/4 heterozygotes and APOE ε4 noncarriers. As a group, these APOE ε4 carriers have reduced cerebral metabolism in the same brain regions as patients with probable AD, which correlates with the APOE ε4 gene dose⁷ and is progressive.⁸ Memory declines more rapidly with age in APOE ε4 carriers than in APOE ε4 noncarriers,⁹ and the APOE ε4 homozygotes' cognitive performances correlate with stressors, including fatigue¹⁰ and anxiety.¹¹ These changes could represent presymptomatic disease in some, despite their youth. We postulated, therefore, that cognitively healthy APOE ε4 homozygotes must be at greater risk for neuropsychological decline than APOE ε4 heterozygotes and noncarriers preceding clinical conversion to mild cognitive impairment (MCI) and AD as they age into their 60s.

Studies of asymptomatic carriers of genes that are known to predispose to Alzheimer's disease (AD) have facilitated the characterization of preclinical AD. The most prevalent genetic risk factor is the ε4 allele of apolipoprotein E (APOE). Neuropatho