The current findings provide support for mild but robust cognitive dysfunction in first-degree relatives of late-onset Alzheimer's disease affected individuals

Cognitive Functioning of Unaffected First-degree Relatives of Individuals With Late-onset Alzheimer's Disease: A Systematic Literature Review and Meta-analysis. Ari Alex Ramos, Noelia Galiano-Castillo & Liana Machado. Neuropsychology Review, Sep 3 2022. https://rd.springer.com/article/10.1007/s11065-022-09555-2

Abstract: First-degree relatives of individuals with late-onset Alzheimer's disease (LOAD) are at increased risk for developing dementia, yet the associations between family history of LOAD and cognitive dysfunction remain unclear. In this quantitative review, we provide the first meta-analysis on the cognitive profile of unaffected first-degree blood relatives of LOAD-affected individuals compared to controls without a family history of LOAD. A systematic literature search was conducted in PsycINFO, PubMed /MEDLINE, and Scopus. We fitted a three-level structural equation modeling meta-analysis to control for non-independent effect sizes. Heterogeneity and risk of publication bias were also investigated. Thirty-four studies enabled us to estimate 218 effect sizes across several cognitive domains. Overall, first-degree relatives (n = 4,086, mean age = 57.40, SD = 4.71) showed significantly inferior cognitive performance (Hedges’ g = -0.16; 95% CI, -0.25 to -0.08; p < .001) compared to controls (n = 2,388, mean age = 58.43, SD = 5.69). Specifically, controls outperformed first-degree relatives in language, visuospatial and verbal long-term memory, executive functions, verbal short-term memory, and verbal IQ. Among the first-degree relatives, APOE ɛ4 carriership was associated with more significant dysfunction in cognition (g = -0.24; 95% CI, -0.38 to -0.11; p < .001) compared to non-carriers (g = -0.14; 95% CI, -0.28 to -0.01; p = .04). Cognitive test type was significantly associated with between-group differences, accounting for 65% (R23 = .6499) of the effect size heterogeneity in the fitted regression model. No evidence of publication bias was found. The current findings provide support for mild but robust cognitive dysfunction in first-degree relatives of LOAD-affected individuals that appears to be moderated by cognitive domain, cognitive test type, and APOE ɛ4.

Discussion

To our knowledge, this is the first meta-analysis to quantify the impact of family history of LOAD on cognition, summarizing 218 effect sizes from 34 empirical studies. The results provide compelling evidence that first-degree relatives show a mild but robust amount of overall cognitive dysfunction compared to controls without LOAD-affected relatives. Cognitive deficits in first-degree relatives were evident in executive functions, language, verbal IQ, verbal and visuospatial LTM, and verbal STM or IM. These outcomes indicate that, compared to controls without a family history of LOAD, first-degree relatives have higher chances of obtaining lower scores on neuropsychological measures across multiple cognitive domains. One plausible explanation for these findings relates to altered biomarkers in probands of LOAD-affected individuals. For instance, previous studies have indicated that unaffected offspring of individuals with LOAD show morphological and metabolic brain changes that resemble the preclinical manifestations of LOAD-related pathology (Dubois et al., 2016), including increased global brain atrophy rates (Debette et al., 2009), reduced medial temporal lobe activation (Donix et al., 2010; Johnson et al., 2006), higher levels of beta-amyloid deposition (Clark et al., 2016; Duarte-Abritta et al., 2018), and decreased gray matter volume (Berti et al., 2011; Honea et al., 2010). On the other hand, the lack of significant group differences in premorbid intelligence and visuospatial STM or IM, and especially the near null effects in performance IQ and visual perception, suggest that having a family history of LOAD does not seem to be associated with significant decline in these domains. Alternatively, first-degree relatives may exhibit distinct patterns of cognitive dysfunction related to phenotypic differences in LOAD (Carrasquillo et al., 2014; Ferreira et al., 2020; Snowden et al., 2007; Vogel et al., 2021). For example, recent research indicated that the limbic-predominant phenotype is strongly associated with the amnestic presentation of the disease (e.g., LTM dysfunction), whereas the posterior phenotype is characterized by visuospatial or perceptual abnormalities (Vogel et al., 2021).

Notably, subgroup analyses revealed that the APOE ɛ4 genotype moderates performance differences between first-degree relatives and controls without a family history of LOAD, which makes sense given that the APOE ɛ4 genotype is the most replicated risk factor for LOAD in genetics studies (Cacabelos, 2003; Yang et al., 2021). Specifically, relative groups documented as ɛ4 carriers exhibited more significant dysfunction in cognition (g = -0.24) compared to relative groups documented as non-ɛ4 carriers (g = -0.14). This finding is consistent with preliminary research (Debette et al., 2009; Tsai et al., 2021) demonstrating that first-degree relatives with both risk factors (APOE ɛ4 genotype and a family history of LOAD) are more likely to present with deficits in cognition (e.g., executive dysfunction and verbal and visuospatial LTM difficulties). Evidence also suggests that first-degree relatives with both risk factors exhibit greater beta-amyloid deposition (Yi et al., 2018), higher brain atrophy rates (Debette et al., 2009), and reduced gray matter volume (Ten Kate et al., 2016) compared to those with only one risk factor. Nevertheless, the current systematic synthesis revealed that few studies on the topic document separate scores for ɛ4 carriers verses non-carriers. Hence, the lack of control for APOE ɛ4 status might help account for the contradictory findings from empirical studies on cognition of first-degree relatives of LOAD-affected individuals previously noted in the introduction, and if factored in to analyses of cognitive domains, could potentially paint a different picture with regard to the domains that did not reach statistical significance. Moving forward from the current outcomes, a major challenge for future research on the topic is to determine the combined effects and parse out the unique contributions of APOE ɛ4 carriership and a family history of LOAD in profiling cognitive dysfunction in first-degree relatives. Importantly, the APOE ε4 effect on cognition reported here is based on a specific sample (first-degree relatives of LOAD-affected individuals) and hence our results do not apply to the general population of APOE ε4 carriers.

Although relative group mean age was not a significant moderator and the null hypothesis on the equality of effect sizes in the subgroup analysis on age category was not rejected, the dysfunction effect size for samples intermixing middle-aged (40–65 years) and older (> 65 years) first-degree relatives (g = -0.23, 95% CI [-0.37, -0.09], p = 0.002) was statistically significant and nearly twice the size of the dysfunction effect for samples including only middle-aged individuals (g = -0.12, 95% CI [-0.26, 0.02], p = 0.081). This suggests that the inclusion of a large percentage of middle-aged individuals in the studies analyzed here may have led to an overall smaller dysfunction effect size (g = -0.16, 95% CI [-0.25, -0.08], p < 0.001) than might be expected in older cohorts, thus calling into question the generalizability of the current findings. This conjecture seems in line with findings from a previous study noted in the introduction (Zeng et al., 2013), in which, compared to controls, family members of LOAD-affected individuals showed substantial differences on neuropsychological measures only quite late in life (70 or more years).

The effects of a family history of LOAD on cognition remain poorly understood. Cognitive dysfunction in first-degree relatives of AD-affected individuals has gained attention only in the last two decades. Figure 2 shows that out of 34 empirical works, only three studies (Green & Levey, 1999; La Rue et al., 1995, 1996) were published before the current century, and all of the studies were published within the past 30 years. As previously noted, LOAD-related neuropathological changes precede the clinical diagnosis of LOAD by many years, hence, an increasing number of studies has attempted to longitudinally follow cognitive changes and brain abnormalities in earlier first-degree relatives. In this meta-analytic review, some included studies were drawn from ongoing prospective studies, thus, follow-up research on these cohorts as they grow older is expected. This will allow investigation of cognitive dysfunction in older cohorts of first-degree relatives with a family history of LOAD.

Implications

Findings from the current quantitative review may have important clinical and theoretical implications. LOAD is an age-dependent dementing disease with cognitive symptoms that appear after a lengthy period of evolving neuropathophysiological abnormalities, and thus the effect sizes for between-group differences in several cognitive domains reported here may assist in establishing sensitive cognitive markers for first-degree relatives. This assertion builds on previous empirical research indicating that impairments in cognitive abilities such as premorbid intelligence, memory, and language are deemed potential markers for future development of LOAD (Blacker et al., 2007; Chen et al., 2000; Rapp & Reischies, 2005; Yeo et al., 2011). Equally important, executive dysfunction can be detected in middle-aged offspring many years before the affected parent develops dementia (Debette et al., 2009; Eyigoz et al., 2020). Hence, developing cognitive-based interventions for first-degree relatives, especially APOE ɛ4 carriers, is a pressing need. In relation to this, recent randomized controlled trials have shown that cognitive training benefits individuals at the early stages of LOAD (Cavallo et al., 2016; Kang et al., 2019; Lee et al., 2013). To our knowledge, however, no study has addressed the potential benefit of such a therapeutic strategy in buffering against cognitive decline in unaffected first-degree relatives of LOAD-affected individuals.