Mild cognitive impairment – signs and susceptibility

Understanding the pre-symptomatic changes underlying Alzheimer’s disease and other dementias is of hugely importance significance when seeking to delay onset of or slow cognitive decline. Furthermore, ancestry may influence susceptibility. Considerable progress in this field is being made and was reported during AAIC 2021.

Amyloid raised in cognitively unimpaired individuals

Data presented by two speakers, Jonathan M Schott, University College, London, UK, and Dorene M Rentz, Harvard Medical School, Boston, MN, USA, pin-pointed the fact that raised levels of amyloid β (Aβ) and tau in cognitively-normal individuals are already present, the effect of which may not be benign. All too often subtle cognitive changes are taking place, the effects of which the individual already suspects.

All too often subtle cognitive changes are taking place, the effects of which the individual already suspects

The MRC National Survey of Health and Development British 1946 birth cohort is the longest studied birth cohort in the world. Insight 46, a two time-point study, evaluated cognitively-normal individuals included in the 1946 cohort at baseline (n=502) and after 2 years (n=406). Compared to Aβ negative individuals, Aβ positive individuals did worse across a score of cognitive tests (PACC) and had atrophy rates that correlated with cognitive decline, indicating that even subtle cognitive changes are far from benign.1

Even subtle cognitive changes are far from benign


Subtle shifts may distinguish Aβ status

Two new tests of early cognitive decline designed to assess very subtle changes – a visual blinding, circle tracing test and ‘what was where’ assessment - supported this finding.2 Accelerating forgetfulness was also demonstrated with Aβ positive individuals becoming significantly more forgetful 7 days after completing a memory test compared to Aβ negative individuals. That individuals were aware of these shortcomings was noted following administration of a MyCog subjective questionnaire.3

Outcomes from the Anti-Amyloid in Asymptomatic Alzheimer’s disease (4A) study, too, show that Aβ accumulation is significantly linked to cognitive dysfunction in cognitively unimpaired individuals.4 Further sub-analyses support elevated Aβ being associated with the subjective cognitive changes and daily functioning.5,6 

All these studies suggest ways and means of identifying early cognitive and functional changes in at-risk individuals - changes important for recruitment to AD prevention trials. Are there any other risk factors that might be targeted?

Studies suggest ways and means of identifying early cognitive and functional changes in at-risk individuals


APOE and ancestry

APOE status is one of the best established risk – or rather susceptibility - factor for Alzheimer’s disease. Jessica B Langbaum, Banner Alzheimer’s Institute, Phoenix, AZ, USA, explained how homozygosity and heterozygosity for APOE ε4 are associated with progressively increased risk of cognitive decline and earlier onset of Alzheimer’s disease, respectively, compared to the absence of ε4.

Imaging studies, be they FDG PET measurements or assessments of Aβ deposition, support brain imaging changes in APOE ε4 homozygotes occurring ahead of any clinical impairment. Furthermore, cognitive decline in these patients occurs earlier.7-11 However, as pointed out, it is important to remember that all these studies have been conducted in individuals of predominantly European ancestry. Might ethnic ancestry influence these findings?

The strongest association so far reported between APOE ε4 and cognitive decline is noted in Cubans – with predominantly European ancestry

Protective effects of APOE alleles in non-European ethnicities

It appears it does. A study of APOE allelic frequency among diverse Latino populations (total n>10,000 individuals) showed that ε3/ε4 and ε3/ε3 allelic frequency was highest among Cubans and Dominicans who have European and African ancestry, respectively, and lowest in Mexicans with a predominantly Amerindian ancestry.12 The strongest association so far reported between APOE ε4 and cognitive decline is noted in Cubans. It’s thought that European ancestry may be responsible for this effect; Amerind ancestry may offer some level of protection.13

This inconsistent association between APOE ε4 and cognitive decline in Latinos, possibly due to genetic ancestry means that care has to be taken when making generalizations in those of non-European ancestry. Indeed, ethnicity also appears to influencing risk in non-Hispanic Black people; the lower the percentage of African ancestry, the higher the levels of amyloid that accumulate.14 Thus, as with Latinos, ancestry matters when assessing AD susceptibility.

Ancestry matters when assessing AD susceptibility


AAIC : Alzheimer's Association International Conference 
UK: United Kingdom
MN: Minnesota
US: United States
Aβ: amyloid β
MRC: medical research council
PACC: Preclinical Alzheimer Cognitive Composite 
AD: Alzheimer's disease
AZ: Arizona
APOE ε4: apolipoprotein E 4 gene 
FDG PET: Positron Emission Tomografy with a specific (FDG)

BE-NOTPR-0134, approval date 07/2022

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

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  2. Lu K et al. Visuomotor integration deficits are common to familial and sporadic preclinical Alzheimer’s disease. Brain Communications 2021;doi:10.1093/braincomms/fcab003
  3. Pavisic IM et al. Subjective cognition complaints at age 70; associations with amyloid and mental health.  J neurol Neurosurg Psychiatry 2021;0:1-7
  4. Insel PS et al. The A4 study: β-amyloid and cognition in 4432 cognitively unimpaired adults. Annals of Clinical and Translational Neurology 2020;7:776-785
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  11. Ghisays V et al. Brain imaging measurements of fibrillary amyloid-β burden, paired helical filament tau burden, and atrophy in cognitively unimpaired persons with one, two, and no copies of the APOE ε4 allele. Alzheimer’s and Dementia 2020;16:598-609.
  12. González HM et al. Apoliporotein E genotypes among diverse middle-aged and older Latinos: study of Latinos – investigation of neurocognitive aging results (HCHC/SOL). Scientific Reports 2018;8:17578. 
  13. Granot-Hershkovitz E et al. APOE alleles’ association with cognitive function differs across Hispanic/Latino froups and genetic ancestry in the study of Latinos-investigation of neurocognitive aging (HCHS/SOL). Alzheimer’s and Dementia 2021;17:466-474.
  14. Deters KD, et al. Neurology, 2021;96(11):e1491-e1500. doi: 10.1212/WNL.0000000000011599. 
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