Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype

In the paper

“Attempts to quantify the duration of AD should be age-specific, because age imposes the greatest risk for both dementia and mortality, and take into account APOE genotype, sex, and cerebrospinal fluid (CSF) tau levels [4, 6, 10-12].”

What the sources say

• Partly supported

  The Results (Comparison With Prevalence of AD-Type Dementia; page unavailable) compare age- and APOE genotype–specific amyloid prevalence with dementia estimates, supporting the relevance of those factors to estimates of AD timing. The Methods (Statistical Analysis; page unavailable) include sex, but the Discussion reports no association between sex and amyloid positivity. The paper does not recommend accounting for CSF tau levels when estimating AD duration or establish the stated mortality rationale. (LLM, conf=0.84)

  cites [4] Jansen WJ,, Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA, 2015 313(19): p. 1924– 38. 25988462 PMC4486209 sourceExperimental — accuracy not yet measured
• Partly supported

  Section 6 reports age-specific prevalence of AD dementia, and section 15 notes that death rates rise with age during AD’s long preclinical period. Sections 9.3 and 12 discuss CSF tau as a biomarker and APOE ε4 as a risk allele. These passages support considering age, mortality, tau, and genetic risk, but they do not recommend that duration estimates be age-specific or account for APOE genotype, sex, and CSF tau levels as stated. (LLM, conf=0.75)

  cites [6] Jack CR Jr.,, NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement, 2018 14(4): p. 535– 562. 29653606 PMC5958625 sourceExperimental — accuracy not yet measured
• Partly supported

  The Methods and Discussion examine how Alzheimer’s disease risk varies by age, APOE genotype, and sex, supporting consideration of those factors. The paper does not assess disease duration or CSF tau levels, and it does not make the claimed recommendation about duration estimates. (LLM, conf=0.85)

  cites [10] Neu SC,, Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol, 2017 74(10): p. 1178– 1189. 28846757 PMC5759346 sourceExperimental — accuracy not yet measured
• Not checked yetcites [11] Lim YY,, Association of beta-Amyloid and Apolipoprotein E epsilon4 With Memory Decline in Preclinical Alzheimer Disease. JAMA Neurol, 2018 75(4): p. 488– 494. 29356823 PMC5933393
• Partly supported

  The Methods (Statistical analyses; page unavailable) adjust progression analyses for age, gender, and APOE genotype, while the Introduction identifies CSF tau as a marker used to define preclinical AD stages. The Discussion reports that preclinical AD was more common in older participants and APOE-ε4 carriers, but neither age nor APOE genotype predicted the rate of decline in its subgroup analyses. The paper does not recommend age-specific estimates of AD duration or say that duration estimates should account for all four factors. (LLM, conf=0.84)

  cites [12] Vos SJ,, Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. Lancet Neurol, 2013 12(10): p. 957– 65. 24012374 PMC3904678 sourceExperimental — accuracy not yet measured

In the paper

“The estimated preclinical AD stage was shortened by around 3 years and the prodromal AD stage by around 2.5 years (Table 3).”

In the paper

“In prodromal AD, abnormal tau associated with a decreased reversion rate to preclinical AD stage (HR=0.41 [95% CI, 0.23-0.71]) and increased progression rate to the mild AD dementia stage (HR=1.91 [95% CI, 1.48-2.48]).”

In the paper

“Compared to data collected in a research setting, data from clinical settings was associated with a higher progression rate (HR=4.40 [95% CI, 2.80-6.94]) and reversion rate (HR=1.98 [95% CI, 1.15-3.39]) between preclinical and prodromal AD.”

In the paper

“Additionally, in the clinical setting the progression rates from the prodromal AD to the mild AD dementia stage (HR=1.48 [95% CI, 1.34-1.92]) and from the mild AD to the moderate AD dementia stage (HR=1.41 [95% CI,1.16-1.72]) were higher.”

In the paper

“Females had a higher progression rate from mild AD to moderate AD dementia, compared to males (HR=1.24 [95% CI, 1.04-1.47]), while their mortality risk in moderate AD dementia was lower (HR=0.60 [95% CI, 0.46-0.80]).”

In the paper

“The predicted total disease duration, based on the model with age, for an individual with preclinical AD at age 70 was 20 years (95% CI, 17-21), consisting of a preclinical stage of 10 years (95% CI, 8-11), followed by a prodromal stage of 4 years (95% CI, 3-5), mild AD dementia for 3 years (95% CI, 2-3), and moderate AD dementia for 3 years (95% CI, 2-3, Table 2).”

In the paper

“In the clinical setting, for individuals with prodromal AD, the stage duration of prodromal AD was also shorter, and while the dementia stage duration for these individuals was equal between settings, more time was spent in the moderate AD stage (Suppl. table B.7a and b).”

In the paper

“Depending on age, sex, APOE genotype, baseline CSF t-tau and setting, the total disease duration varied between 12 and 25 years, the preclinical stage between 2 and 15, the prodromal stage between 3 to 7, mild AD dementia stage between 2 and 6 and moderate AD dementia stage between 1 and 7 years.”

In the paper

“When compared to a non-carrier, an APOE ε4 carrier aged 70 in the clinical setting had a 1.6 years (95% CI, 0.4-3.3; p=0.0295) shorter estimated preclinical AD stage duration, and 1.1 years (95% CI, 0.3-2.1; p=0.0110) shorter prodromal AD stage duration, but 1.0 year (95% CI, 0.3-1.8; p=0.0050) longer mild dementia stage duration (suppl. table B.4).”

In the paper

“The estimated total duration with starting stage preclinical AD ranged in the clinical setting 19 years (95% CI, 17-20) at age 60 to 11 years (95% CI, 10-12) at age 80 and in the research setting from 26 years (95% CI, 23-28) at age 60 to 15 years (95% CI, 12-17) at age 80.”

In the paper

“APOE ε4 carriers had, compared to non-carriers, an increased rate of progression from the preclinical AD to prodromal AD stage (HR=1.63 [95% CI, 1.11-2.41]) and from the prodromal AD to mild AD dementia stage (HR=1.50 [95% CI, 1.18-1.90]), and a trend for slower decline from the mild to the moderate AD dementia stage (HR 0.77 [95% CI, 0.60-1.00]).”

In the paper

“Unlike previous studies, no effect of tau on mortality and duration of the AD dementia stage were found, which may be explained by dichotomization of CSF t-tau in our analysis [16, 17].”

What the sources say

• Not checked yetcites [16] Rhodius-Meester HFM,, Disease-related determinants are associated with mortality in dementia due to Alzheimer's disease. Alzheimers Res Ther, 2018 10(1): p. 23. 29458426 PMC5819199
• Not checked yetcites [17] Degerman Gunnarsson M,, High tau levels in cerebrospinal fluid predict nursing home placement and rapid progression in Alzheimer's disease. Alzheimers Res Ther, 2016 8(1): p. 22. 27263933 PMC4893835

In the paper

“For example, the residual life expectancy at age 80 was reported to be 8-10 years in the USA and Australia (data from 2010-2012), while in our study this ranged from 4 years for those with moderate AD to 15 years for individuals with preclinical AD.”

What the sources say

• Not checked yetcites [46] www.lifetable.de (2010-2012 USA).

In the paper

“Accumulation of amyloid in the brain is believed to be the first sign of the disease and can precede a clinical diagnosis of dementia by up to 20 years [1, 4, 5].”

What the sources say

• Not checked yetcites [1] Winblad B,, Defeating Alzheimer's disease and other dementias: a priority for European science and society. Lancet Neurol, 2016 15(5): p. 455– 532. 26987701 source
• Not checked yetcites [4] Jansen WJ,, Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA, 2015 313(19): p. 1924– 38. 25988462 PMC4486209 source
• Not checked yetcites [5] Jack CR Jr.,, Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol, 2013 12(2): p. 207– 16. 23332364 PMC3622225 source

In the paper

“Age had the strongest effect on the duration of the preclinical and dementia stages, which could be explained by higher progression and mortality rates.”

In the paper

“The dementia stage duration was longer in women, which was driven by lower mortality in this group.”

In the paper

“Varying the mortality assumptions for unknown mortality dates of those who died, did not change the results.”

In the paper

“The effects of setting on disease progression are consistent with other AD studies [40, 41].”

What the sources say

• Not checked yetcites [40] Qian J,, APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts. PLoS Med, 2017 14(3): p. e1002254. 28323826 PMC5360223
• Not checked yetcites [41] Snitz BE,, Risk of progression from subjective cognitive decline to mild cognitive impairment: The role of study setting. Alzheimers Dement, 2018 14(6): p. 734– 742. 29352855 PMC5994356

In the paper

“While the prodromal stage was shorter in APOE ε4 carriers, the dementia stage was longer which would imply that the total symptomatic disease duration is similar, but differently divided over the stages.”

In the paper

“The patients with prodromal AD and increased CSF t-tau levels tended to convert sooner to AD dementia [19, 20].”

What the sources say

• Not checked yetcites [19] van Rossum IA,, Injury markers predict time to dementia in subjects with MCI and amyloid pathology. Neurology, 2012 79(17): p. 1809– 16. 23019259 PMC3475623 source
• Not checked yetcites [20] Buchhave P,, Cerebrospinal fluid levels of beta-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry, 2012 69(1): p. 98– 106. 22213792 source

In the paper

“Previous studies on the length of the AD dementia stage reported a duration of 3 to 10 years [14, 15].”

What the sources say

• Not checked yetcites [14] Brodaty H, Seeher K, and Gibson L, Dementia time to death: a systematic literature review on survival time and years of life lost in people with dementia. Int Psychogeriatr, 2012 24(7): p. 1034– 45. 22325331 source
• Not checked yetcites [15] Wattmo C, Londos E, and Minthon L, Risk factors that affect life expectancy in Alzheimer's disease: a 15-year follow-up. Dement Geriatr Cogn Disord, 2014 38(5-6): p. 286– 99. 24992891

In the paper

“Younger age, female sex and lower CSF total tau (t-tau) were found to be associated with a longer duration of the AD dementia stage, while the effect of APOE genotype was equivocal [14-17].”

What the sources say

• Not checked yetcites [14] Brodaty H, Seeher K, and Gibson L, Dementia time to death: a systematic literature review on survival time and years of life lost in people with dementia. Int Psychogeriatr, 2012 24(7): p. 1034– 45. 22325331 source
• Not checked yetcites [15] Wattmo C, Londos E, and Minthon L, Risk factors that affect life expectancy in Alzheimer's disease: a 15-year follow-up. Dement Geriatr Cogn Disord, 2014 38(5-6): p. 286– 99. 24992891
• Not checked yetcites [16] Rhodius-Meester HFM,, Disease-related determinants are associated with mortality in dementia due to Alzheimer's disease. Alzheimers Res Ther, 2018 10(1): p. 23. 29458426 PMC5819199
• Not checked yetcites [17] Degerman Gunnarsson M,, High tau levels in cerebrospinal fluid predict nursing home placement and rapid progression in Alzheimer's disease. Alzheimers Res Ther, 2016 8(1): p. 22. 27263933 PMC4893835

In the paper

“For example, exclusion of ε4 carriers during a trial, what happened in the high-dose group of the BAN2401 trial, may affect rate of progression and possibly the power of the study [45].”

What the sources say

• Not checked yetcites [45] https://www.alzforum.org/news/conference-coverage/ban2401-removes-brain-amyloid-possibly-slows-cognitive-decline 20 2 2019].

In the paper

“The median duration of prodromal AD was three years in a pooled memory clinic cohort study, but no age-specific estimates were provided and mortality was not taken into account [18].”

What the sources say

• Not checked yetcites [18] Vos SJ,, Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage. Brain, 2015 138(Pt 5): p. 1327– 38. 25693589 PMC5013930 source

In the paper

“The shorter age-specific duration of the preclinical stage in APOE ε4 carriers is consistent with the observed earlier onset of dementia due to AD in epidemiological studies and the faster cognitive decline of APOE ε4 carriers with preclinical AD in research studies [11, 42-44].”

What the sources say

• Not checked yetcites [11] Lim YY,, Association of beta-Amyloid and Apolipoprotein E epsilon4 With Memory Decline in Preclinical Alzheimer Disease. JAMA Neurol, 2018 75(4): p. 488– 494. 29356823 PMC5933393
• Not checked yetcites [42] Roberts RO,, Prevalence and Outcomes of Amyloid Positivity Among Persons Without Dementia in a Longitudinal, Population-Based Setting. JAMA Neurol, 2018. PMC6142936 29710225 source
• Not checked yetcites [43] van der Lee SJ,, The effect of APOE and other common genetic variants on the onset of Alzheimer's disease and dementia: a community-based cohort study. Lancet Neurol, 2018 17(5): p. 434– 444. 29555425
• Not checked yetcites [44] Mormino EC,, Amyloid and APOE epsilon4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology, 2014 82(20): p. 1760– 7. 24748674 PMC4035706

In the paper

“The duration of the preclinical AD stage has been estimated in combination with the prodromal AD stage, which was 17 years, based on extrapolations of change in positron emission tomography (PET) amyloid load over time [21].”

What the sources say

• Not checked yetcites [21] Villemagne VL,, Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol, 2013 12. 23477989 source

In the paper

“The presence of increased CSF t-tau was associated with a shorter pre-dementia disease duration, which confirms that increased tau is associated with faster disease progression.”

In the paper

“When all variables were combined in one model, most estimates remained unchanged.”

In the paper

“In the additional analysis of the same models in the subset of individuals with all covariates (n=1518, see Suppl. Table B.8), the effects were similar.”

In the paper

“Setting is also important, as progression from MCI to dementia was longer in research settings than in clinical settings [13].”

What the sources say

• Not checked yetcites [13] Farias ST,, Progression of mild cognitive impairment to dementia in clinic- vs community-based cohorts. Arch Neurol, 2009 66(9): p. 1151– 7. 19752306 PMC2863139

In the paper

“Male sex, clinical setting, APOE ε4 genotype and abnormal CSF tau were associated with a shorter duration and these effects depended on disease stage.”

In the paper

“A strength of the study is the large sample of participants with amyloid accumulation.”

In the paper

“Finally, our sample is not representative of the general population, but may be representative of the patients who physicians need to inform, and volunteers that participate in clinical trials.”

In the paper

“Additionally, we used the old criteria for the preclinical AD definition, while the recent research criteria also require tau positivity [8].”

What the sources say

• Not checked yetcites [8] Sperling RA,, Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement, 2011 7. PMC3220946 21514248 source

In the paper

“As such, the sample consisted of over 3000 individuals, still not all the effects were estimable.”

In the paper

“The multi-state model approach is another strength, because it enabled the incorporation of multiple clinical stages, including fluctuations between stage, and the mortality risk in a data driven manner.”

In the paper

“Another limitation was that amyloid status and APOE genotype were unknown for AD-type dementia patients of the ICTUS study, but the sensitivity analysis without the ICTUS, yielded very similar results.”