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Genetic influence during the early phases of Alzheimer's disease on longitudinal cognitive impairment

Kumar, Atul LU orcid ; Shoai, Maryam ; Palmqvist, Sebastian LU orcid ; Stomrud, Erik LU orcid ; Hardy, John ; Mattsson-Carlgren, Niklas LU orcid and Hansson, Oskar LU orcid (2021) In Alzheimer's & dementia : the journal of the Alzheimer's Association 17.
Abstract

BACKGROUND: The rate of cognitive decline in the early stages of Alzheimer's disease (AD) is variable, which may be partly due to genetic factors. We therefore investigated genetic predictors of longitudinal cognitive decline in AD. METHOD: In the Swedish BioFINDER study, we used polygenic scores (PGS) (of AD, intelligence and educational attainment), and genetic variants (in a genome-wide association study [GWAS]) to predict longitudinal change in cognition (measured by MMSE) over a mean of 4.2 years. We included 555 b-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 206 Aβ-positive CU (preclinical AD), 110 Aβ-negative mild cognitive impairment (MCI) patients, and 146 Aβ-positive MCI patients (prodromal AD). Mixed-effect... (More)

BACKGROUND: The rate of cognitive decline in the early stages of Alzheimer's disease (AD) is variable, which may be partly due to genetic factors. We therefore investigated genetic predictors of longitudinal cognitive decline in AD. METHOD: In the Swedish BioFINDER study, we used polygenic scores (PGS) (of AD, intelligence and educational attainment), and genetic variants (in a genome-wide association study [GWAS]) to predict longitudinal change in cognition (measured by MMSE) over a mean of 4.2 years. We included 555 b-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 206 Aβ-positive CU (preclinical AD), 110 Aβ-negative mild cognitive impairment (MCI) patients, and 146 Aβ-positive MCI patients (prodromal AD). Mixed-effect models were fitted with longitudinal MMSE data as dependent variable. Random slopes and intercepts were extracted and were rank-based inverse normal transformed (INT) to be used as dependent variables in linear regression models. RESULT: AD polygenic risk score (PRS) and intelligence PGS (but not education PGS) were associated with rate of cognitive decline (Figure 1). The AD PRS was only associated with decline in Ab-positive individuals, but the intelligence PGS was protective irrespective of Ab-status (Figure 2). The model containing only the APOE burden (ε4 and ε2 counts) was associated with cognitive decline with a nominal level of significance, whereas this was not found for the early-stage AD cohort (Figure 1 and 2). Our GWAS identified 8 genes (out of which 3 genes independent of Aβ-status) associated with rate of cognitive decline at a p-value ≤ 5e-05 (Table 1). CONCLUSION: An a priori defined genetic risk score for AD was only associated with rate of cognitive decline in early stage AD (Aβ+ CU and Aβ+ MCI) and not in an unselected population, while a polygenic score for intelligence was protective irrespective of Aβ status. Together with novel genetic associations for rate of cognitive decline in AD, this may provide new insights into the pathophysiology of AD and new therapeutic development targets.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Alzheimer's & dementia : the journal of the Alzheimer's Association
volume
17
article number
e053474
publisher
Wiley
external identifiers
  • pmid:35109116
  • scopus:85124060520
ISSN
1552-5279
DOI
10.1002/alz.053474
language
English
LU publication?
yes
id
1a437b2f-6b0c-40f9-9756-2c7bcd7d4f1a
date added to LUP
2022-04-05 14:45:16
date last changed
2023-12-20 03:02:32
@article{1a437b2f-6b0c-40f9-9756-2c7bcd7d4f1a,
  abstract     = {{<p>BACKGROUND: The rate of cognitive decline in the early stages of Alzheimer's disease (AD) is variable, which may be partly due to genetic factors. We therefore investigated genetic predictors of longitudinal cognitive decline in AD. METHOD: In the Swedish BioFINDER study, we used polygenic scores (PGS) (of AD, intelligence and educational attainment), and genetic variants (in a genome-wide association study [GWAS]) to predict longitudinal change in cognition (measured by MMSE) over a mean of 4.2 years. We included 555 b-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 206 Aβ-positive CU (preclinical AD), 110 Aβ-negative mild cognitive impairment (MCI) patients, and 146 Aβ-positive MCI patients (prodromal AD). Mixed-effect models were fitted with longitudinal MMSE data as dependent variable. Random slopes and intercepts were extracted and were rank-based inverse normal transformed (INT) to be used as dependent variables in linear regression models. RESULT: AD polygenic risk score (PRS) and intelligence PGS (but not education PGS) were associated with rate of cognitive decline (Figure 1). The AD PRS was only associated with decline in Ab-positive individuals, but the intelligence PGS was protective irrespective of Ab-status (Figure 2). The model containing only the APOE burden (ε4 and ε2 counts) was associated with cognitive decline with a nominal level of significance, whereas this was not found for the early-stage AD cohort (Figure 1 and 2). Our GWAS identified 8 genes (out of which 3 genes independent of Aβ-status) associated with rate of cognitive decline at a p-value ≤ 5e-05 (Table 1). CONCLUSION: An a priori defined genetic risk score for AD was only associated with rate of cognitive decline in early stage AD (Aβ+ CU and Aβ+ MCI) and not in an unselected population, while a polygenic score for intelligence was protective irrespective of Aβ status. Together with novel genetic associations for rate of cognitive decline in AD, this may provide new insights into the pathophysiology of AD and new therapeutic development targets.</p>}},
  author       = {{Kumar, Atul and Shoai, Maryam and Palmqvist, Sebastian and Stomrud, Erik and Hardy, John and Mattsson-Carlgren, Niklas and Hansson, Oskar}},
  issn         = {{1552-5279}},
  language     = {{eng}},
  publisher    = {{Wiley}},
  series       = {{Alzheimer's & dementia : the journal of the Alzheimer's Association}},
  title        = {{Genetic influence during the early phases of Alzheimer's disease on longitudinal cognitive impairment}},
  url          = {{http://dx.doi.org/10.1002/alz.053474}},
  doi          = {{10.1002/alz.053474}},
  volume       = {{17}},
  year         = {{2021}},
}