**6. Conclusions and Future Perspectives**

As summarized in Figure 3, recent evidence supports a central role of ABCA7 in AD. Increase of ABCA7 expression in the first step of the disease would help to maintain the cerebral lipid homeostasis and the balance between the amyloid synthesis and clearance. This latter process is controlled by microglial cell degradation and elimination across the blood–brain barrier. Aging, genetic polymorphisms and probably external factors such as diet or physical activity, influence ABCA7 expression, thereby promoting or slowing down amyloid deposition and then AD onset and evolution (Figure 3).

**Figure 3.** Potential roles of ABCA7 in brain cholesterol homeostasis and Aβ clearance and synthesis. (**Left**), in healthy brains, ABCA7 is normally expressed by neurons, glial cells and blood–brain barrier endothelial cells where it mediates Aβ clearance (1 and 3) as well cellular and toxic lipid (TL) efflux (2). Because Aβ peptide production is also linked with cellular lipid levels, it is likely that ABCA7 can also regulate Aβ synthesis. (**Right**) Single nucleotide polymorphisms (SNPs), aging and diet can affect ABCA7 function and expression, thus downregulating Aβ peptide clearance, decreasing toxic lipid recycling and then promoting Aβ burden. Aβ peptides: amyloid-β peptides; ABCA7: ATP-binding cassette subfamily A member 7; AJs: Adherent junctions of the BBB; BBB: blood–brain barrier; SNP: single nucleotide polymorphism; TJs: tight junctions of the BBB; TL: toxic lipids.

> To exploit ABCA7 for therapeutic purposes, more attention needs to be given to its role in phagocytosis processes, in particular at the level of microglial cells that remove amyloid and play a central role in inflammatory processes. Then, it might be essential to better characterize ABCA7 regulatory sequences and signaling pathways in order to develop new molecules or approaches able to promote its cerebral expression, in healthy and AD patients. It might be also suggested that development of new tracers for measuring

ABCA7 activity at the brain level should be useful to detect AD or other neurodegenerative diseases at early stages.

At last, gender differences reported in several studies might also be taken into account to understand if ABCA7 has a different role in females rather in males, as highlighted by the role of ABCA7 in ovarian cancer [93]. This hypothesis is also strongly supported by the fact that AD deficiencies in mouse models affect more females than males [95,96] and that cognitive decline has been observed in females bearing ABCA7 SNPs when compared with males [70].

**Author Contributions:** S.D., J.P. and F.G. reviewed the literature, drafted and edited the manuscript and all figures. All authors have read and agreed to the published version of the manuscript.

**Funding:** S.D. has received fellowships from the Region Hauts-de-France and the University of Artois. F.G. has been supported by internal grants from University of Artois (BQR-ABCA7), from foundation France Alzheimer et Maladies apparentées (AAP 2013, #22) and under the ERANET JPcofuND 2-NET-PETABC collaborative project by grants from the French national agency (ANR, grant number ANR-20-JPW2-0002-04). The work of J.P. was supported by the following grants: Deutsche Forschungsgemeinschaft/Germany (DFG 263024513); Ministerium für Wirtschaft und Wissenschaft Sachsen-Anhalt/Germany (ZS/2016/05/78617); Latvian Council of Science/Latvia (lzp-2018/1-0275); Nasjonalforeningen (16154 to Luisa Möhle), HelseSØ/Norway (2019054, 2019055); Barnekreftforeningen (19008); EEA grant/Norges grants (TACR TARIMAD TO100078); Norges ˇ forskningsrådet/Norway (260786 PROP-AD, 295910 NAPI, 327571 PETABC). PROP-AD and PETABC are EU Joint Programme-Neurodegenerative Disease Research (JPND) projects. PROP-AD is supported through the following funding organizations under the aegis of JPND—www.jpnd.eu (accessed on 31 December 2020) (AKA #301228—Finland, BMBF #01ED1605—Germany, CSO-MOH #30000-12631—Israel, NFR #260786—Norway, SRC #2015-06795—Sweden). PETABC is supported through the following funding organisations under the aegis of JPND—www.jpnd.eu (NFR #32757— Norway, FFG #882717—Austria, BMBF #XXXXX—Germany, MSMT #8F21002—Czech Republic, VIAA #ES RTD/2020/26—Latvia, ANR #20-JPW2-0002-04—France, SRC #2020-02905—Sweden). The projects receive funding from the European Union's Horizon 2020 research and innovation programme under grant agreement #643417 (JPco-fuND).

**Acknowledgments:** Authors would like to acknowledge Julien Saint-Pol for designing the final version of the figure n◦3.

**Conflicts of Interest:** The authors declare no conflict of interest.
