To determine the size of the impairment across different cognitive domains in preclinical Alzheimer's disease (AD), a meta-analysis based on 47 studies involving 9,097 controls and 1,207 preclinical AD cases was conducted. There were marked preclinical deficits in global cognitive ability, episodic memory, perceptual speed, and executive functioning; somewhat smaller deficits in verbal ability, visuospatial skill, and attention; and no preclinical impairment in primary memory. Younger age (Ͻ 75 years) and shorter follow-up intervals (Ͻ 3 years) were associated with larger effect sizes for both global cognitive ability and episodic memory. For global cognitive ability, studies that used population-based sampling yielded larger effect sizes; for episodic memory, larger differences were seen in studies that preidentified groups in terms of baseline cognitive impairment. Within episodic memory, delayed testing and recall-based assessment resulted in the largest effect sizes. The authors conclude that deficits in multiple cognitive domains are characteristic of AD several years before clinical diagnosis. The generalized nature of the deficit is consistent with recent observations that multiple brain structures and functions are affected long before the AD diagnosis.

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

The literature on cognitive markers in preclinical AD is reviewed. The findings demonstrate that impairment in multiple cognitive domains is typically observed several years before clinical diagnosis. Measures of executive functioning, episodic memory and perceptual speed appear to be most effective at identifying at-risk individuals. The fact that these cognitive domains are most implicated in normal cognitive aging suggests that the cognitive deficit observed preclinically is not qualitatively different from that observed in normal aging. The degree of cognitive impairment prior to the diagnosis of Alzheimer's disease (AD) appears to generalize relatively well across major study characteristics, including sample ascertainment procedures, age and cognitive status of participants, as well as time to diagnosis of dementia. In episodic memory, there is evidence that the size of the preclinical deficit increases with increasing cognitive demands. The global cognitive impairment observed is highly consistent with observations that multiple brain structures and functions are affected long before the diagnosis of AD. However, there is substantial overlap in the distribution of cognitive scores between those who will and those who will not be diagnosed with AD, hence limiting the clinical utility of cognitive markers for early identification of cases. Future research should consider combining cognitive indicators with other types of markers (i.e. social, somatic, genetic, brain-based) in order to increase prediction accuracy.

Associations between genotypes and cognitive outcomes may provide clues as to which mechanisms cause individual differences in old-age cognitive performance. We investigated the effects of five polymorphisms on cognitive functioning in a population-based sample of 2,694 persons without dementia (60-102 years). A structural equation model (SEM) was fit to the cognitive data, yielding five specific latent factors (perceptual speed, episodic memory, semantic memory, category fluency, and letter fluency), as well as a global cognitive factor. These factors showed the expected associations with chronological age. Genotyping was performed for five single-nucleotide polymorphisms that have been associated with cognitive performance: APOE (rs429358), COMT (rs4680), BDNF (rs6265), KIBRA (rs17070145), and CLSTN2 (rs6439886). After controlling for age, gender, and education, as well as correcting for multiple comparisons, we observed negative effects of being an APOE ε4 carrier on episodic memory and perceptual speed. Furthermore, being a CLSTN2 TT carrier was associated with poorer semantic memory. For the global factor, the same pattern of results was observed. In addition, being a BDNF any A carrier was associated with better cognitive performance. Also, older age was associated with stronger genetic effects of APOE on global cognition. However, this interaction effect was partly driven by the presence of preclinical dementia cases in our sample. Similarly, excluding future dementia cases attenuated the effects of APOE on episodic memory and global cognition, suggesting that part of the effects of APOE on old-age cognitive performance may be driven by dementia-related processes.

Between-person differences in white matter microstructure may partly generalize across the brain and partly play out differently for distinct tracts. We used diffusion-tensor imaging and structural equation modeling to investigate this issue in a sample of 260 adults aged 60-87 years. Mean fractional anisotropy and mean diffusivity of seven white matter tracts in each hemisphere were quantified. Results showed good fit of a model positing that individual differences in white matter microstructure are structured according to tracts. A general factor, although accounting for variance in the measures, did not adequately represent the individual differences. This indicates the presence of a substantial amount of tract-specific individual differences in white matter microstructure. In addition, individual differences are to a varying degree shared between tracts, indicating that general factors also affect white matter microstructure. Age-related differences in white matter microstructure were present for all tracts. Correlations among tract factors did not generally increase as a function of age, suggesting that aging is not a process with homogenous effects on white matter microstructure across the brain. These findings highlight the need for future research to examine whether relations between white matter microstructure and diverse outcomes are specific or general.

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Background:Olfactory dysfunction (OD) in old age is associated with poor health outcomes. Interrelationships among different correlates of OD can offer insights into the underlying mechanisms, but to date remain understudied.Methods:Odor identification performance and self-reported olfactory functioning were studied in 2,234 people aged 60–90 years, who were free of neurodegenerative disease and enrolled in the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) study, Stockholm, Sweden. OD was defined as the inability to identify more than 10 out of 16 odors (free or cued identification) in a standardized odor identification task. OD prevalence was estimated, and associations with demographic, genetic, vascular, clinical, and behavioral factors, as well as their interactions were examined using multiple logistic regression analyses.Results:Overall prevalence of OD was 24.8% (CI: 23.1; 26.6). Self-reports were characterized by low sensitivity (35%), but high specificity (87%). Advancing age (OR = 15.50, CI = 9.40; 26.10 between the first and last age group), and history of coronary heart disease (OR = 1.35, 95% CI = 1.04; 1.75) were the principal factors associated with an increased probability of OD, whereas female gender (OR = 0.53, 95% CI = 0.43; 0.66) and more years of education (OR = 0.97, CI 0.94; 0.99) were linked to a lower probability. Exploratory interaction analyses indicated that prevalence of OD was particularly elevated among Apolipropotein E (APOE) ε4 allele carriers who were also obese, and that being physically active counteracted the negative impact of cerebrovascular disease on OD.Conclusion:Demographic and genetic factors, but also prior and current health insults, are linked to OD in old age. Modulatory effects of behavioral factors highlight their value as possible prevention targets.

Loss of olfactory function is common in old age, but evidence regarding qualitative olfactory dysfunction in the general older population is scarce. The current study investigates the prevalence and correlates of phantom smell experiences (phantosmia) in a population-based study (Swedish National Study on Aging and Care in Kungsholmen [SNAC-K]) of Swedish adults (n = 2569) aged between 60 and 90 years. Phantosmia was assessed through a standardized interview and defined as reporting having experienced an odor percept in the absence of any stimuli in the surrounding environment that could emit the odor. The relationships between phantosmia and demographic, genetic, health-related, and behavioral variables were analyzed with hierarchical logistic regression analyses. The overall prevalence of phantom smells was 4.9%, and was associated with female gender, carrying the met allele of the BDNF gene, higher vascular risk burden, and reporting distorted smell sensations (parosmia). Olfactory dysfunction was, however, not related to phantosmia. The most frequently reported phantom smell was smoky/burnt. A novel finding was that some individuals reported phantom smells with an autobiographical connotation. The results from this study indicate that the prevalence of phantosmia in the general older population is not negligible and that some factors that are beneficial for preserved olfactory function, such as female gender and the BDNF met allele, are also associated with the occurrence of phantom smells.